[Federal Register Volume 72, Number 121 (Monday, June 25, 2007)]
[Rules and Regulations]
[Pages 34752-34958]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-3039]
[[Page 34751]]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 111
Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements; Final Rule
Petition To Request an Exemption From 100 Percent Identity Testing of
Dietary Ingredients; Interim Final Rule
Federal Register / Vol. 72, No. 121 / Monday, June 25, 2007 / Rules
and Regulations
[[Page 34752]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 111
[Docket No. 1996N-0417] (formerly Docket No. 96N-0417)
RIN 0910-AB88
Current Good Manufacturing Practice in Manufacturing, Packaging,
Labeling, or Holding Operations for Dietary Supplements
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
regarding current good manufacturing practice (CGMP) for dietary
supplements. The final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, or holding
dietary supplements to ensure the quality of the dietary supplement.
The final rule is one of many actions related to dietary supplements
that we are taking to promote and protect the public health.
DATES: This rule is effective August 24, 2007.
Compliance Dates: The compliance date is June 25, 2008; except that
for businesses employing fewer than 500, but 20 or more full-time
equivalent employees, the compliance date is June 25, 2009; and except
that for businesses that employ fewer than 20 full-time equivalent
employees, the compliance date is June 25, 2010.
FOR FURTHER INFORMATION CONTACT: Vasilios H. Frankos, Center for Food
Safety and Applied Nutrition (HFS-810), Food and Drug Administration,
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1696.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background and Related Information
II. How is the Final Rule Organized?
III. What Does the Final Rule Do?
A. Overview of CGMP
B. Highlights of the Final Rule
IV. What General Comments Did We Receive?
A. What Comments Did We Receive on the Structure and Organization
of the Rule?
B. What Comments Did We Receive on the Need for Dietary Supplement
CGMP Requirements?
C. What Comments Did We Receive on Written Procedures?
1. Overview
2. Written Procedures That Are Required by This Final Rule
3. Written Procedures That Are Not Required by This Final Rule
D. Other Comments on Written Procedures
E. What Other General Comments Did We Receive?
V. What Legal Authority Comments Did We Receive?
A. Modeled After CGMP for Food
B. Records Authority
C. Public Health Service Act Authority
1. The Communicable Disease Risk Posed by Dietary Supplements
2. Activities For Which We Are Asserting Legal Authority Under the
PHS Act
D. The Interstate Commerce Nexus for the Final Rule
1. The PHS Act
2. The Act
3. Commerce Clause
E. Fifth Amendment
F. Miscellaneous
VI. What Comments Did We Receive on the General Provisions? (Subpart A)
A. Organization of Final Subpart A
B. Who Is Subject to This Part? (Final Sec. 111.1)
C. What Definitions Apply to This Part? (Final Sec. 111.3)
1. Actual Yield
2. Batch
3. Batch Number, Lot Number, or Control Number
4. Component
5. Contact Surface
6. Ingredient
7. In-Process Material
8. Lot
9. Microorganisms
10. Must
11. Pest
12. Physical Plant
13. Product Complaint
14. Quality
15. Quality Control
16. Quality Control Personnel
17. Representative Sample
18. Reprocessing
19. Reserve Sample
20. Sanitize
21. Theoretical Yield
22. Water Activity
23. We
24. You
25. What Other Terms Did the Comments Want Defined?
26. What Definitions Did the Comments Want Us to Delete?
D. Do Other Statutory Provisions and Regulations Apply? (Final
Sec. 111.5)
E. What Sections Did We Remove From the Rule, and Why?
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed
Sec. 111.2)
2. ``Exclusions'' (Proposed Sec. 111.6)
VII. Comments on Personnel (Final Subpart B)
A. Organization of Final Subpart B
B. Highlights of Changes to the Proposed Requirements for Personnel
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart B
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.8)
E. What Requirements Apply for Preventing Microbial Contamination
From Sick or Infected Personnel and for Hygienic Practices? (Final
Sec. 111.10)
1. Final Sec. 111.10(a)
2. Final Sec. 111.10(b)
F. What Personnel Qualification Requirements Apply? (Final Sec.
111.12)
G. What Supervisor Requirements Apply? (Final Sec. 111.13)
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.14)
VIII. Comments on Physical Plant and Grounds (Final Subpart C)
A. Organization of Final Subpart C
B. Highlights of Changes to the Proposed Requirements for Physical
Plant and Grounds
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Subpart C
D. What Sanitation Requirements Apply to Your Physical Plant and
Grounds? (Final Sec. 111.15)
1. Final Sec. 111.15(a)
2. Final Sec. 111.15(b)(1)
3. Final Sec. 111.15(c)
4. Final Sec. 111.15(d)
5. Final Sec. 111.15(e)
6. Final Sec. 111.15(f)
7. Final Sec. 111.15(g)
8. Final Sec. 111.15(h)
9. Final Sec. 111.15(i)
10. Final Sec. 111.15(j)
11. Final Sec. 111.15(k)
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.16)
F. What Design and Construction Requirements Apply to Your Physical
Plant? (Final Sec. 111.20)
1. Final Sec. 111.20(a) and (b)
2. Final Sec. 111.20(c)
3. Final Sec. 111.20(d)
4. Final Sec. 111.20(e)
5. Final Sec. 111.20(f)
6. Final Sec. 111.20(g)
7. Final Sec. 111.20(h)
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G. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.23)
IX. Comments on Requirements Related to Equipment and Utensils (Subpart
D)
A. Organization of Final Subpart D
B. Highlights of Changes to the Proposed Requirements for Equipment
and Utensils
1. Revisions
2. Revisions Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Subpart D
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.25)
E. What Requirements Apply to the Equipment and Utensils That You
Use? (Final Sec. 111.27)
1. Final 111.27(a)
2. Final Sec. 111.27(b)
3. Final Sec. 111.27(c)
4. Final Sec. 111.27(d)
F. Reorganization of Certain Paragraphs in Proposed Sec. 111.25
G. What Requirements Apply to Automated, Mechanical, or Electronic
Equipment? (Final Sec. 111.30)
1. Comments on the Organization and Framework of Proposed Sec.
111.30
2. Comments Specific to Proposed Sec. 111.30
3. Reorganization of Certain Paragraphs in Proposed Sec. 111.30
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.35)
1. Final Sec. 111.35(a)
2. Final Sec. 111.35(b)(1) and (b)(2)
3. Final Sec. 111.35(b)(3)
4. Final Sec. 111.35(b)(4)
5. Final Sec. 111.35(b)(5)
6. Final Sec. 111.35(b)(6)
X. Comments on Requirement to Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed Sec. 111.35 Into Final Subpart E
B. General Comments on Proposed Sec. 111.35
C. Final Subpart E and Highlights of Changes to the Proposed
Regulations
D. What Are the Requirements to Implement a Production and Process
Control System? (Final Sec. 111.55)
E. What Are the Design Requirements for the Production and Process
Control System? (Final Sec. 111.60)
F. What Are the Requirements for Quality Control Operations? (Final
Sec. 111.65)
G. What Specifications Must You Establish? (Final Sec. 111.70)
1. Final Sec. 111.70(a)
2. Final Sec. 111.70(b)
3. Final Sec. 111.70(c)
4. Final Sec. 111.70(d)
5. Final Sec. 111.70(e)
6. Final Sec. 111.70(f)
7. Final Sec. 111.70(g)
H. What is Your Responsibility for Determining Whether Established
Specifications Are Met? (Final Sec. 111.73)
I. What Must You Do to Determine Whether Specifications Are Met?
(Final Sec. 111.75)
1. Final Sec. 111.75(a)
2. Final Sec. 111.75(b)
3. Final Sec. 111.75(c) and (d)
4. Final Sec. 111.75(e)
5. Final Sec. 111.75(f)
6. Final Sec. 111.75(g)
7. Final Sec. 111.75(h)
8. Final Sec. 111.75(i)
J. What Must You Do if Established Specifications Are Not Met?
(Final Sec. 111.77)
1. Final Sec. 111.77
2. Final Sec. 111.77(a)
3. Final Sec. 111.77(b)
4. Final Sec. 111.77(c)
K. Comments on Shelf Life
L. What Representative Samples Must You Collect? (Final Sec.
111.80)
1. Final Sec. 111.80(a)
2. Final Sec. 111.80(b)
3. Final Sec. 111.80(c)
4. Final Sec. 111.80(d)
5. Final Sec. 111.80(e)
M. What Are the Requirements for Reserve Samples? (Final Sec.
111.83)
1. Final Sec. 111.83(a)
2. Final Sec. 111.83(b)(1)
3. Final Sec. 111.83(b)(2)
4. Final Sec. 111.83(b)(3)
5. Final Sec. 111.83(b)(4)
N. Who Conducts a Material Review and Makes a Disposition Decision?
(Final Sec. 111.87)
O. What Requirements Apply to Treatments, In-Process Adjustments,
and Reprocessing When There is a Deviation or Unanticipated Occurrence
or When a Specification Established in Accordance With Sec. 111.70 Is
Not Met? (Final Sec. 111.90)
1. Final Sec. 111.90
2. Final Sec. 111.90(a)
3. Final Sec. 111.90(b)
4. Final Sec. 111.90(c)
P. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.95)
1. Final Sec. 111.95(a)
2. Final Sec. 111.95(b)
XI. Comments on Requirements for Quality Control (Final Subpart F)
A. Organization of Final Subpart F
B. Highlights of Changes to the Proposed Requirements for Quality
Control Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.37 (Final Subpart F)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.103)
E. What Must Quality Control Personnel Do? (Final Sec. 111.105)
1. Final Sec. 111.105(a)
2. Final Sec. 111.105(b), (c), (d), and (e)
3. Final Sec. 111.105(f)
4. Final Sec. 111.105(g)
5. Final Sec. 111.105(h)
6. Final Sec. 111.105(i)
F. What Quality Control Operations Are Required for Laboratory
Operations Associated With the Production and Process Control System?
(Final Sec. 111.110)
1. Final Sec. 111.110(a)
2. Final Sec. 111.110(b)
3. Final Sec. 111.110(c)
G. What Quality Control Operations Are Required for a Material
Review and Disposition Decision? (Final Sec. 111.113)
1. Final Sec. 111.113(a)
2. Final Sec. 111.113(b)
3. Final Sec. 111.113(c)
H. What Quality Control Operations Are Required for Equipment,
Instruments, and Controls? (Final Sec. 111.117)
1. Final Sec. 111.117(a) through (c)
2. Final Sec. 111.117(d)
I. What Quality Control Operations Are Required for Components,
Packaging, and Labels Before Use in the Manufacture of a Dietary
Supplement? (Final Sec. 111.120)
1. Final Sec. 111.120(a)
2. Final Sec. 111.120(b)
3. Final Sec. 111.120(c)
4. Final Sec. 111.120(d)
5. Final Sec. 111.120(e)
J. What Quality Control Operations Are Required for the Master
Manufacturing Record, the Batch Production Record, and Manufacturing
Operations? (Final Sec. 111.123)
1. Final Sec. 111.123(a)(1)
2. Final Sec. 111.123(a)(2)
3. Final Sec. 111.123(a)(3)
4. Final Sec. 111.123(a)(4)
5. Final Sec. 111.123(a)(5)
6. Final Sec. 111.123(a)(6)
7. Final Sec. 111.123(a)(7)
8. Final Sec. 111.123(a)(8)
9. Final Sec. 111.123(b)
K. What Quality Control Operations Are Required for Packaging and
Labeling Operations? (Final Sec. 111.127)
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1. Final Sec. 111.127(a) and (b)
2. Final Sec. 111.127(c)
3. Final Sec. 111.127(d)
4. Final Sec. 111.127(e)
5. Final Sec. 111.127(f) and (g)
6. Final Sec. 111.127(h)
L. What Quality Control Operations Are Required for Returned
Dietary Supplements? (Final Sec. 111.130)
1. Final Sec. 111.130(a)
2. Final Sec. 111.130(a)(1) and (a)(2)
3. Final Sec. 111.130(b)
4. Final Sec. 111.130(c)
5. Final Sec. 111.130(d)
M. What Quality Control Operations Are Required for Product
Complaints? (Final Sec. 111.135)
N. What Records Must You Make and Keep? (Final Sec. 111.140)
1. Final Sec. 111.140(a)
2. Final Sec. 111.140(b)(1)
3. Final Sec. 111.140(b)(2)
4. Final Sec. 111.140(b)(3)
XII. Comments on the Production and Process Control System:
Requirements for Components, Packaging, and Labels, and for Product
That You Receive for Packaging or Labeling as a Dietary Supplement
(Final Subpart G)
A. Organization of Final Subpart G
B. Highlights of Changes to the Proposed Requirements for
Components, Packaging, and Labels, and Product That You Receive for
Packaging or Labeling as a Dietary Supplement
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.40 (Final Subpart G)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.153)
E. What Requirements Apply to Components of Dietary Supplements?
(Final Sec. 111.155)
1. Proposed Sec. 111.35(d)
2. Final Sec. 111.155(a)
3. Final Sec. 111.155(b)
4. Final Sec. 111.155(c)
5. Final Sec. 111.155(d)
6. Final Sec. 111.155(e)
F. What Requirements Apply to Packaging and Labels Received? (Final
Sec. 111.160)
1. Final Sec. 111.160(a)
2. Final Sec. 111.160(b)
3. Final Sec. 111.160(c)
4. Final Sec. 111.160(d)
5. Final Sec. 111.160(e)
G. What Requirements Apply to a Product Received for Packaging or
Labeling as a Dietary Supplement (and for distribution rather than for
return to the supplier)? (Final Sec. 111.165)
1. Final Sec. 111.165(a)
2. Final Sec. 111.165(b)
3. Final Sec. 111.165(c)
4. Final Sec. 111.165(d)
5. Final Sec. 111.165(e)
H. What Requirements Apply to Rejected Components, Packaging, and
Labels, and to Rejected Products That Are Received for Packaging or
Labeling as a Dietary Supplement? (Final Sec. 111.170)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.180)
1. Final Sec. 111.180(a)
2. Final Sec. 111.180(b)(1)
3. Final Sec. 111.180(b)(2)
4. Final Sec. 111.180(b)(3)
XIII. Comments on the Production and Process Control System:
Requirements for the Master Manufacturing Record (Final Subpart H)
A. Organization of Final Subpart H
B. Highlights of Changes to the Proposed Requirements for the
Master Manufacturing Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.45 (Final Subpart H)
1. Comments on Written Procedures
2. Comments That Support Proposed Sec. 111.45
D. What Is the Requirement to Establish a Master Manufacturing
Record? (Final Sec. 111.205)
1. Final Sec. 111.205(a)
2. Final Sec. 111.205(b)(1)
3. Final Sec. 111.205(b)(2)
4. Final Sec. 111.205(c)
E. What Must the Master Manufacturing Record Include? (Final Sec.
111.210)
1. Final Sec. 111.210(a)
2. Final Sec. 111.210(b)
3. Final Sec. 111.210(c)
4. Final Sec. 111.210(d)
5. Final Sec. 111.210(e)
6. Final Sec. 111.210(f)
7. Final Sec. 111.210(g)
8. Final Sec. 111.210(h)(1)
9. Final Sec. 111.210(h)(2)
10. Final Sec. 111.210(h)(3)
11. Final Sec. 111.210(h)(4)
12. Final Sec. 111.210(h)(5)
F. Quality Control Responsibility (Proposed Sec. 111.45(c))
XIV. Comments on the Production and Process Control System:
Requirements for the Batch Production Record (Final Subpart I)
A. Organization of Final Subpart I
B. Highlights of Changes to the Proposed Requirements for the Batch
Production Record
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Is the Requirement to Establish a Batch Production Record?
(Final Sec. 111.255)
D. What Must the Batch Record Include? (Final Sec. 111.260)
1. Final Sec. 111.260(a)
2. Final Sec. 111.260(b)
3. Final Sec. 111.260(c)
4. Final Sec. 111.260(d)
5. Final Sec. 111.260(e) and (f)
6. Final Sec. 111.260(g)
7. Final Sec. 111.260(h)
8. Final Sec. 111.260(i)
9. Final Sec. 111.260(j)
10. Final Sec. 111.260(k)
11. Final Sec. 111.260(l)
12. Final Sec. 111.260(m)
13. Final Sec. 111.260(n)
E. Review of Batch Production Record Deviations (Proposed Sec.
111.50(d)(1), (e)(2), (e)(3), and (e)(4))
XV. Comments on Production and Process Control System: Requirements for
Laboratory Operations (Final Subpart J)
A. Organization of Final Subpart J
B. Highlights of the Changes to the Proposed Requirements for
Laboratory Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.303)
D. What Are the Requirements for the Laboratory Facilities That You
Use? (Final Sec. 111.310)
E. What Are the Requirements for Laboratory Control Processes?
(Final Sec. 111.315)
1. Final Sec. 111.315(a)
2. Final Sec. 111.315(b)
3. Final Sec. 111.315(c)
4. Final Sec. 111.315(d)
5. Final Sec. 111.315(e)
F. What Requirements Apply to Laboratory Methods for Testing and
Examination? (Final Sec. 111.320)
1. Final Sec. 111.320(a)
2. Final Sec. 111.320(b)
G. Appropriate Test Method Validation (Proposed Sec.
111.60(b)(1)(v))
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.325)
1. Final Sec. 111.325(a)
2. Final Sec. 111.325(b)(1)
3. Final Sec. 111.325(b)(2)
XVI. Comments on the Production and Process Control System:
Requirements for Manufacturing Operations (Final Subpart K)
A. Organization of Final Subpart K
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B. Highlights of Changes to the Proposed Requirements for
Manufacturing Operations
1. Revisions
2. Changes Made After Considering Comments
3. Revisions Associated With the Reorganization
C. General Comments on Manufacturing Operations
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.353)
E. What Are the Design Requirements for Manufacturing Operations?
(Final Sec. 111.355)
F. What Are the Requirements for Sanitation? (Final Sec. 111.360)
G. What Precautions Must You Take to Prevent Contamination? (Final
Sec. 111.365)
1. Final Sec. 111.365(a)
2. Final Sec. 111.365(b)
3. Final Sec. 111.365(c)
4. Final Sec. 111.365(d)
5. Final Sec. 111.365(e)
6. Final Sec. 111.365(f)
7. Final Sec. 111.365(g)
8. Final Sec. 111.365(h)
9. Final Sec. 111.365(i)
10. Final Sec. 111.365(j)
11. Final Sec. 111.365(k)
H. What Requirements Apply to Rejected Dietary Supplements? (Final
Sec. 111.370)
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.375)
XVII. Comments on the Production and Process Control System:
Requirements for Packaging and Labeling Operations (Final Subpart L)
A. Organization of Final Subpart L
B. Highlights of Changes to the Proposed Requirements for Packaging
and Labeling Operations
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Requirements for Packaging and
Labeling Operations
D. General Comments on Requirements for What Must Be on the Product
Label Rather Than for Labeling Operations
E. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.403)
F. What Requirements Apply to Packaging and Labels? (Final Sec.
111.410)
1. Final Sec. 111.410(a)
2. Final Sec. 111.410(b)
3. Final Sec. 111.410(c)
4. Final Sec. 111.410(d)
G. What Requirements Apply to Filling, Assembling, Packaging,
Labeling, and Related Operations? (Final Sec. 111.415)
H. What Requirements Apply to Repackaging and Relabeling? (Final
Sec. 111.420)
1. Final Sec. 111.420(a)
2. Final Sec. 111.420(b) and (c)
I. What Requirements Apply to a Packaged and Labeled Dietary
Supplement That Is Rejected for Distribution? (Final Sec. 111.425)
J. Under this Subpart, What Records Must You Make and Keep? (Final
Sec. 111.430)
1. Final Sec. 111.430(a)
2. Final Sec. 111.430(b)
XVIII. Comments on Holding and Distributing (Final Subpart M)
A. Organization of Final Subpart M
B. Highlights of Changes to the Proposed Requirements for Holding
and Distributing
1. Revisions
2. Changes Associated With the Reorganization
3. Changes After Considering Comments
C. General Comments on Proposed Sec. Sec. 111.80, 111.82, 111.83,
and 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.453)
E. What Requirements Apply to Holding Components, Dietary
Supplements, Packaging, and Labels? (Final Sec. 111.455)
1. Final Sec. 111.455(a)
2. Final Sec. 111.455(b)
3. Final Sec. 111.455(c)
F. What Requirements Apply to Holding In-Process Material? (Final
Sec. 111.460)
1. Final Sec. 111.460(a)
2. Final Sec. 111.460(b)
G. Proposed Requirement for Holding Reserve Samples of Components
(Proposed Sec. 111.83(a))
H. What Requirements Apply to Holding Reserve Samples of Dietary
Supplements? (Final Sec. 111.465)
1. Final Sec. 111.465(a)
2. Final Sec. 111.465(b)
I. What Requirements Apply to Distributing Dietary Supplements?
(Final Sec. 111.470)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.475)
XIX. Comments on Returned Dietary Supplements (Final Subpart N)
A. Organization of Final Subpart N
B. Highlights of Changes to the Proposed Requirements for Returned
Dietary Supplements
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.85
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.503)
E. What Requirements Apply When a Returned Dietary Supplement is
Received? (Final Sec. 111.510)
F. When Must a Returned Dietary Supplement be Destroyed, or
Otherwise Suitably Disposed Of? (Final Sec. 111.515)
G. When May a Returned Dietary Supplement Be Salvaged? (Final Sec.
111.520)
H. What Requirements Apply to a Returned Dietary Supplement That
Quality Control Personnel Approve for Reprocessing? (Final Sec.
111.525)
I. When Must an Investigation Be Conducted of Your Manufacturing
Processes and Other Batches? (Final Sec. 111.530)
J. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.535)
1. Final Sec. 111.535(a)
2. Final Sec. 111.535(b)(1)
3. Final Sec. 111.535(b)(2)
4. Final Sec. 111.535(b)(3)
5. Final Sec. 111.535(b)(4)
XX. Comments on Product Complaints (Final Subpart O)
A. Organization of Final Subpart O
B. Highlights of Changes to the Proposed Requirements for Product
Complaints
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed Sec. 111.95 (Final Subpart O)
D. What Are the Requirements Under This Subpart for Written
Procedures? (Final Sec. 111.553)
E. What Requirements Apply to the Review and Investigation of a
Product Complaint? (Final Sec. 111.560)
1. Final Sec. 111.560(a)(1)
2. Final Sec. 111.560(a)(2), (b), and (c)
F. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.570)
1. Final Sec. 111.570(a)
2. Final Sec. 111.570(b)(1)
3. Final Sec. 111.570(b)(2)
4. Final Sec. 111.570(b)(2)(i)
5. Final Sec. 111.570(b)(2)(ii)
XXI. Comments on Records and Recordkeeping (Final Subpart P)
A. Organization of Final Subpart P
B. Highlights of Changes to the Proposed Requirements for Records
and Recordkeeping
1. Revisions
2. Changes After Considering Comments
C. General Comments on Proposed
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Sec. 111.125
D. What Requirements Apply to the Records That You Make and Keep?
(Final Sec. 111.605)
1. Final Sec. 111.605(a)
2. Final Sec. 111.605(b)
3. Final Sec. 111.605(c)
E. What Records Must Be Made Available to FDA? (Final Sec.
111.610)
1. Final Sec. 111.610(a)
2. Final Sec. 111.610(b)
XXII. Other Comments and Miscellaneous
A. Comments on Guidance Documents To Be Used With the Final Rule
B. Comments on Consideration for Other CGMP Programs
C. Comments on Public Involvement
D. Comments on Implementation and Enforcement
E. Removal of References to Part 112
XXIII. Paperwork Reduction Act of 1995
XXIV. Analysis of Impacts
A. Introduction
1. Summary of the Economic Analysis
2. Summary of Comments on the Economic Analysis
B. Final Regulatory Impact Analysis
1. The Need for the Final Current Good Manufacturing Practice Rule
2. Regulatory Options
3. Coverage of the Final Rule
4. Baseline Practices
5. Baseline Risk
6. Benefits
7. Costs
8. Summary of Benefits and Costs
9. Benefits and Costs of Regulatory Options
10. Cost Effectiveness Analysis
11. Uncertainties in the Analysis
C. Final Regulatory Flexibility Analysis
1. Introduction
2. Economic Effects on Small Entities
3. Regulatory Options
4. Description of Recordkeeping and Reporting
5. Summary
D. Unfunded Mandates
XXV. Analysis of Environmental Impact
XXVI. Federalism
XXVII. References
I. Background and Related Information
On October 25, 1994, the Dietary Supplement Health and Education
Act (DSHEA) (Public Law 103-417) was signed into law. DSHEA, among
other things, amended the Federal Food, Drug, and Cosmetic Act (the
act) by adding section 402(g) of the act (21 U.S.C. 342(g)). Section
402(g)(2) of the act provides, in part, that the Secretary of Health
and Human Services (the Secretary) may, by regulation, prescribe good
manufacturing practices for dietary supplements. Section 402(g) of the
act also stipulates that such regulations shall be modeled after CGMP
regulations for food and may not impose standards for which there are
no current and generally available analytical methodology. The final
rule establishes, in part 111 (21 CFR part 111), the minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary supplements to ensure the quality of the dietary
supplement. The final rule is one of many actions related to dietary
supplements that we are taking to promote and protect the public
health.
In response to DSHEA, we issued an Advance Notice of Proposed
Rulemaking (the 1997 ANPRM) in the Federal Register of February 6, 1997
(62 FR 5700). The 1997 ANPRM contained a CGMP outline submitted to us
on November 20, 1995, by representatives of the dietary supplement
industry. The 1997 ANPRM also asked nine questions that addressed
issues that the industry outline did not. For example, we asked if
there is a need to develop specific defect action levels (DALs) for
dietary ingredients. We also asked whether a CGMP rule should require
manufacturers to establish procedures to document, on a continuing or
daily basis, that they followed pre-established procedures for making
dietary supplements.
We received more than 100 comments in response to the 1997 ANPRM.
We evaluated these comments before we drafted and ultimately issued a
proposed rule on CGMPs for dietary ingredients and dietary supplements
(which we discuss later in this section of this document).
Additionally, during 1999, we conducted a number of outreach
activities related to dietary supplements. We held several public
meetings to develop our overall strategy for achieving effective
regulation of dietary supplements, which could include establishing
CGMP regulations. We also held public meetings focused specifically on
CGMPs and the economic impact that any CGMP rule for dietary
ingredients and dietary supplements might have on small businesses.
Further, we toured several dietary supplement manufacturing facilities
to better understand the manufacturing processes and practices that
potentially would be subject to CGMP requirements for dietary
ingredients and dietary supplements (Refs. 1 through 6). These
activities contributed to our knowledge about the industry.
In the Federal Register of March 13, 2003 (68 FR 12157), we
published a proposed rule to establish CGMP requirements for dietary
ingredients and dietary supplements (the 2003 CGMP Proposal). The
preamble to the 2003 CGMP Proposal addressed the comments we had
received regarding the nine questions in the 1997 ANPRM, discussed our
legal authority to issue a CGMP rule, and described the basis for each
proposed requirement.
The 2003 CGMP Proposal specifically requested comment on a variety
of areas, including the need for written procedures and recordkeeping
requirements. Although the proposed rule's comment period was scheduled
to end on June 11, 2003, in the Federal Register of May 19, 2003 (68 FR
27008), we extended the comment period to August 11, 2003.
After we published the proposed rule, we conducted and/or
participated in outreach activities related to dietary supplements and
dietary ingredients. We held public stakeholder meetings on April 29,
2003, in College Park, MD, and on May 6, 2003, in Oakland, CA. We also
held a public meeting, via satellite downlink, on May 9, 2003, with
viewing sites at our district and regional offices throughout the
country. These public meetings gave an overview of the proposed rule,
and clarified specific points in the proposed rule. Since the public
stakeholder meetings held as part of our outreach efforts, we also have
participated in several meetings with industry and other interested
parties which are reflected in the public docket.
We received approximately 400 comments in response to the proposal.
The comments came from trade associations, government organizations and
officials, manufacturers of dietary supplements and dietary
ingredients, health care practitioners, consumer groups, and
individuals. In general, the comments supported the idea of CGMPs,
although many comments disagreed with specific aspects of the proposal.
Published elsewhere in this issue of the Federal Register we are
also issuing an interim final rule that sets forth a procedure for
requesting an exception to a CGMP requirement in this final rule. The
interim final rule allows for submission to, and review by, FDA of an
alternative to the required 100-percent identity testing of components
that are dietary ingredients (as discussed in section X of this
document (subpart E)), provided certain conditions are met. The interim
final rule also includes a requirement for retention of records related
to the FDA grant of an exception request.
[[Page 34757]]
II. How is the Final Rule Organized?
The 2003 CGMP Proposal was divided into eight subparts, with each
subpart devoted to a particular topic. For example, proposed subpart A
was titled ``General Provisions'' and contained sections describing the
rule's scope, purpose, definitions, applicability of other statutory
and regulatory provisions, and exclusions. As another example, proposed
subpart B was titled ``Personnel'' and described microbial
contamination and hygiene requirements, personnel qualification
requirements, and supervisor requirements.
In response to comments seeking a simpler, more ``user-friendly''
final rule or seeking clarification of the rule's applicability to
certain persons, items, or activities, and to reduce redundant
provisions or combine similar provisions, we have reorganized the final
rule into 16 subparts, with new subparts focusing on specific aspects
of the manufacturing process or addressing specific issues. For
example, the proposed rule placed all production and process control
requirements for manufacturing, packaging, labeling, and laboratory
operations in a single subpart (proposed subpart E). The final rule
creates separate subparts for the specific operations to make it easier
to find the relevant production and process control requirements for a
particular activity.
Table 1 of this document summarizes how we reorganized the rule. We
are providing this information to help readers understand the
structural changes we made between the proposed and final rules.
Table 1.--Reorganization and Revisions: 2003 CGMP Proposal and Final
Rule
------------------------------------------------------------------------
Final Final
Proposed Subpart Proposed Sections in Subpart and Sections in
and Title the Subpart Title the Subpart
------------------------------------------------------------------------
A--General 111.1 A--General 111.1
Provisions 111.2 Provisions 111.3
111.3 111.5
111.5
111.6
------------------------------------------------------------------------
B--Personnel 111.10 B--Personnel 111.8 (new)
111.12 111.10
111.13 111.12
111.13
111.14 (new)
------------------------------------------------------------------------
C--Physical Plant 111.15 C--Physical 111.15
111.20 Plant and 111.16 (new)
Grounds 111.20
111.23
(formerly
proposed
Sec.
111.15(d)(3)
and (e)(2))
------------------------------------------------------------------------
D--Equipment and 111.25 D--Equipment 111.25
Utensils 111.30 and (formerly
Utensils proposed
Sec.
111.25(c)(1)
and (e)(1))
111.27
(formerly
proposed
Sec.
111.25 (a),
(b), (d)\1\,
and (e))
111.30
111.35
(formerly
proposed
Sec. Sec.
111.25
(c)(1),
(c)(2), (d),
(f),
111.30(b)(2)
, (b)(5),
and (c),
111.50(c)(4)
)
------------------------------------------------------------------------
[[Page 34758]]
E--Production and 111.35 E--Requireme 111.55
Process Controls 111.37 nt to (formerly
111.40 Establish a proposed
111.45 Production Sec.
111.50 and Process 111.35(a))
111.60 Control 111.60
111.65 System (formerly
111.70 proposed
111.74 Sec.
111.35(b))
111.65
(formerly
proposed
Sec.
111.35(c))
111.70
(formerly
proposed
Sec.
111.35(e),
(f), (g),
and (k))
111.73
(formerly
proposed
Sec.
111.35(f),
(g), and (h)
111.75
(formerly
proposed
Sec.
111.35(e)
through (i),
(k), and
(l)), Sec.
111.37(b)(11
(iv), and
Sec.
111.40(a)(2)
111.77 (new)
111.80
(formerly
proposed
Sec.
111.37(b)(11
))
111.83
(formerly
proposed
Sec. Sec.
111.37(b)(12
),
111.50(h),
and
111.83(b)(2)
)
111.87
(formerly
proposed
Sec. Sec.
111.35(i)
and (n),
111.37(b)(5)
and (b)(14),
111.40(a)(3)
,
111.50(d)(1)
, and
111.85(a)
and (c))
111.90
(formerly
proposed
Sec. Sec.
111.35(i)(4)
,
111.50(d)(1)
, (f), and
(g), and
111.65(d))
111.95
(formerly
proposed
Sec.
111.35(o))
------------------------------------------------------------------------
[[Page 34759]]
....................... F--Productio 111.103 (new)
n and 111.105
Process (formerly
Control proposed
System: Sec.
Requirement 111.37(a),
s for (b)(1),
Quality (b)(11), and
Control (b)(12))
111.110
(formerly
proposed
Sec.
111.37(b)(9)
and (b)(13))
111.113
(formerly
proposed
Sec. Sec.
111.35(i)(2)
, (i)(3),
(i)(4)(i),
(i)(4)(ii),
(j), and
(n),
111.37(b)(3)
and (c),
111.40(a)(3)
and (b)(2),
111.50(d)(1)
, 111.65(d),
and
111.70(c))
111.117
(formerly
proposed
Sec. Sec.
111.30(b)(4)
and
111.37(b)(6)
through
(b)(8))
111.120
(formerly
proposed
Sec. Sec.
111.35(i)(4)
(i) and
(i)(4)(ii),
111.37(b)(2)
and (b)(10),
111.40(a)(3)
and (b)(2),
and
111.50(e)(1)
)
111.123
(formerly
proposed
Sec. Sec.
111.35(e)(2)
, (f),
(i)(2), and
(o)(2)
111.37(a),
(b)(2),
(b)(4),
(b)(5), and
(b)(11),
111.45(c),
and
111.50(d)(1)
, (d)(2),
and (g))
111.127
(formerly
proposed
Sec. Sec.
111.37(b)(2)
, (b)(10),
and (b)(11),
111.40(a)(2)
and (a)(3),
and
111.70(c),
(d) and (e))
111.130
(formerly
proposed
Sec. Sec.
111.37(b)(2)
and (b)(15),
and
111.85(a))
111.135 (new)
111.140
(formerly
proposed
Sec. Sec.
111.35(j)
and
111.37(c)
and (d)
------------------------------------------------------------------------
....................... G--Productio 111.153 (new)
n and 111.155
Process (formerly
Control proposed
System: Sec. Sec.
Requirement 111.35(d)(1)
s for through
Components, (d)(5) and
Packaging, 111.40(a)(1)
and Labels through
and for (a)(5))
Product 111.160
That You (formerly
Receive for proposed
Packaging Sec. Sec.
or Labeling 111.35(e)(4)
a Dietary , and
Supplement 111.40(a)(2)
and (b)(1)
through
(b)(4))
111.165
(formerly
proposed
Sec.
111.40(a)(1)
through
(a)(5))
111.170
(formerly
proposed
Sec.
111.74)
111.180
(formerly
proposed
Sec. Sec.
111.35(d)(4)
, and
111.40(c)(1)
(i) through
(c)(1)(iv)
and (c)(2))
------------------------------------------------------------------------
....................... H--Productio 111.205
n and (formerly
Process proposed
Control Sec.
System: 111.45(a)(1)
Requirement , (a)(2),
s for the and (d))
Master 111.210
Manufacturi (formerly
ng Record proposed
Sec.
111.45(b))
------------------------------------------------------------------------
[[Page 34760]]
....................... I--Productio 111.255
n and (formerly
Process proposed
Control Sec.
System: 111.50(a),
Requirement (b), and
s for the (i))
Batch 111.260
Production (formerly
Record proposed
Sec. Sec.
111.35(i)(2)
, (j), (m),
and (o)(2),
111.37(b)(3)
, (b)(5),
(b)(9) and
111.50(c)(1)
through
(c)(11),
(c)(13),
(c)(14),
(d)(2), (e),
and (g), and
111.70(b)(6)
and (g))
------------------------------------------------------------------------
....................... J--Productio 111.303 (new)
n and 111.310
Process (formerly
Control proposed
System: Sec.
Requirement 111.60(a))
s for 111.315
Laboratory (formerly
Operations proposed
Sec.
111.60(b)(1)
)
111.320
(formerly
proposed
Sec.
111.60(c)
and (d))
111.325
(formerly
proposed
Sec.
111.60(b)(2)
and (b)(3))
------------------------------------------------------------------------
....................... K--Productio 111.353 (new)
n and 111.355
Process (formerly
Control proposed
System: Sec.
Requirement 111.65(a))
s for 111.360
Manufacturi (formerly
ng proposed
Operations Sec.
111.65(b))
111.365
(formerly
proposed
Sec.
111.65(c))
111.370
(formerly
proposed
Sec.
111.74)
111.375 (new)
------------------------------------------------------------------------
....................... L--Productio 111.403 (new)
n and 111.410
Process (formerly
Control proposed
System: Sec.
Requirement 111.70(a),
s for (b)(6), and
Packaging (f))
and 111.415
Labeling (formerly
Operations proposed
Sec.
111.70(b))
111.420
(formerly
proposed
Sec.
111.70(d)
and (e))
111.425
(formerly
proposed
Sec.
111.74)
111.430
(formerly
proposed
Sec.
111.70(g)
and (h))
------------------------------------------------------------------------
F--Holding and 111.80 M--Holding 111.453 (new)
Distributing 111.82 and 111.455
111.83 Distributin (formerly
111.85 g proposed
111.90 Sec.
111.80)
111.460
(formerly
proposed
Sec.
111.82)
111.465
(formerly
proposed
Sec.
111.83(b)(1)
and (b)(2))
111.470
(formerly
proposed
Sec.
111.90)
111.475 (new)
------------------------------------------------------------------------
[[Page 34761]]
....................... N--Returned 111.503 (new)
Dietary 111.510
Supplements (formerly
proposed
Sec.
111.85(a))
111.515
(formerly
proposed
Sec.
111.85(b)
and (c))
111.520
(formerly
proposed
Sec.
111.37(b)(15
))
111.525
(formerly
proposed
Sec.
111.50(g))
111.530
(formerly
proposed
Sec.
111.85(d))
111.535
(formerly
proposed
Sec. Sec.
111.50(g)
and
111.85(e)
and (f))
------------------------------------------------------------------------
G--Consumer 111.95 O--Product 111.553 (new)
Complaints Complaints 111.560
(formerly
proposed
Sec.
111.95(a)
through (d))
111.570
(formerly
proposed
Sec.
111.95(e)
and (f))
------------------------------------------------------------------------
H--Records and 111.125 P--Records 111.605
Recordkeeping and (formerly
Recordkeepi proposed
ng Sec.
111.125((a)
and (b))
111.610
(formerly
proposed
Sec.
111.125(b)
and (c))
------------------------------------------------------------------------
\1\The reference to (d) is the second (d) in the proposed rule in this
section due to a misnumbering in the proposed rule.
We discuss all subparts and sections, and our reasons for amending
or creating subparts and sections, in our discussion of the comments to
the proposal.
III. What Does the Final Rule Do?
A. Overview of CGMP
In considering the specific requirements necessary for dietary
supplement CGMPs, we considered information from a variety of sources.
We considered information from our outreach activities, as described in
section I of this document; comments to the 2003 CGMP Proposal; our own
knowledge and expertise about CGMP for foods, including dietary
supplements; and characteristics of CGMP that apply to manufacturing,
labeling, packaging, and holding operations.
The general food CGMPs in part 110 (21 CFR part 110) largely
address practices designed to ensure that food is manufactured,
processed, packed, and held under sanitary conditions and that the food
is safe, clean, and wholesome. Although the general food CGMPs in part
110 apply to a variety of food products, including dietary supplements,
they do not address the unique characteristics of certain specific
types of food products. The agency has implemented separate, and more
specific, CGMPs for various types of food products to provide for
process controls in manufacturing that are not captured by the more
general part 110 food CGMPs. (See discussion in section V of this
document (``Legal Authority'') on product specific CGMP requirements).
At the time DSHEA was enacted, there were four such additional,
specific food CGMP regulations: Those for infant formula (part 106 (21
CFR part 106)), thermally processed low-acid canned food (part 113 (21
CFR part 113)), acidified food (part 114 (21 CFR part 114)), and
bottled water (part 129 (21 CFR part 129)).
Dietary supplements are a type of food product for which specific
food CGMPs also are needed. Manufacturing process controls are needed
to ensure that a dietary supplement contains what the manufacturer
intends. Unlike most foods, the majority of dietary supplements are
packaged into tablets, gelcaps, and capsules. Some dietary supplements
may contain bioactive ingredients for which certain, controlled amounts
are intended to be in each tablet or capsule. The process controls that
must be in place to ensure the tablet or capsule contains what it
purports to contain are different than those that must be in place to
ensure a food is manufactured, processed, packed, and held under
sanitary conditions. Process controls for dietary supplement
manufacture include establishing and meeting specifications to ensure
the finished dietary supplement contains the correct ingredient,
purity, strength, and composition intended.
Vitamins can present a concentrated source of biologically active
components. A vitamin, for example, that contains too high a
concentration, such as vitamin D at levels that are many times greater
than intended, can lead to illness and hospitalization (Refs. 7 and 8).
A manufacturer must establish a process for manufacturing a dietary
supplement product in order to produce the product consistently and
reliably each time. In order to achieve consistency and reliability,
there must be process controls in place to ensure, for example, that
appropriate tests and examinations are conducted, a master
manufacturing record is prepared, each batch production follows the
master manufacturing record, and the finished tablet or capsule is
placed in the intended package with the intended label.
These same types of controls are needed for herbal and botanical
dietary supplements. Botanicals are often complex mixtures that can
vary in
[[Page 34762]]
composition depending on factors such as the part of the plant used,
the location of harvesting and growing conditions that can vary from
year to year even in the same location. It can be difficult to
distinguish between closely related species of botanicals, and the
biological activity of components of an incorrectly identified species
can lead to adverse consequences. In addition, different species may be
present in different ratios or blends in a particular product. Various
products might contain different parts of the plant--flower, leaf,
root, stem, extract--and the test methods for each can vary in the
nature, sensitivity, and specificity of the test.
Well-established principles of CGMP require process controls at
each step of the manufacturing process as early in the production
process as possible. Quality cannot be tested into the product only at
the end (Ref. 9). Instead, the quality of the dietary supplement must
be built into the product throughout the manufacturing process; quality
begins with the starting material and continues with the product being
manufactured in a reproducible manner according to established
specifications. It is not sufficient, nor effective, to rely solely on
end product testing to assure the quality of the individual dietary
supplement product sold to the consumer.
CGMPs are intended to establish a comprehensive system of process
controls, including documentation of each stage of the manufacturing
process, that can minimize the likelihood of, or detect, problems and
variances in manufacturing as they occur and before the product is in
its finished form. These process controls that are a part of CGMPs are
essential to ensure that the dietary supplement is manufactured,
packaged, held, and labeled in a consistent and reproducible manner.
Manufacturing according to CGMP means that the manufacturing
process incorporates a set of controls in the design and production
processes to assure a quality finished product. CGMPs specific to
dietary supplements are necessary to help ensure that these products
have the identity, purity, strength, and composition that meet
specifications established in the master manufacturing record and that
they are not adulterated.
Many comments stressed that the most critical aspect of a
successful CGMP system is effective process control. Comments asserted
that, with effective process control, quality is built into a product
throughout the entire production process. The term ``quality'' came up
repeatedly in comments as the desired outcome of the dietary supplement
manufacturing process.\1\ In fact, several comments asked us to define
``quality'' and suggested various definitions, each of which related to
a dietary supplement having the identity, purity, strength, and
composition intended (see comment 49 in section VI of this document).
Some comments distinguished the concept of quality from that of
preventing adulteration. These comments objected to our statement that
dietary supplement CGMP requirements are needed to prevent adulteration
and stated that CGMP is focused on assuring that finished products are
manufactured using quality procedures, but are not related to
preventing adulteration. Other comments asked us to define
``adulteration.''
---------------------------------------------------------------------------
\1\ Throughout this final rule, we refer to the ``manufacture''
or ``manufacturing process'' of dietary supplements. We use these
terms in the broad sense, i.e., the terms refer to those activities
that may be done from receipt of raw ingredients through the
distribution of a finished dietary supplement, including labeling,
packaging, and holding activities. We discuss the various roles and
responsibilities of those who ``manufacture'' dietary supplements in
the context of final Sec. 111.1 ``Who is subject to this part?'' We
also sometimes use the terms to apply to only part of the process,
i.e., those operations other than labeling, packaging, and holding.
---------------------------------------------------------------------------
We agree that a critical aspect of CGMP is achieving control over
manufacturing processes. Controls are necessary to ensure that you
manufacture what you intend so that the characteristics and/or
attributes desired in a final product will be consistently and reliably
achieved. We disagree with the comments to the extent that they were
suggesting that quality is not related to preventing contamination in
the manufacturing process that may adulterate the finished product.
However, we have reconsidered, as discussed in this section, what types
of adulteration and misbranding are necessary to control for in this
dietary supplement CGMP rule.
To clarify what dietary supplement CGMP requirements are intended
to achieve, we have added a definition of quality in the final rule. As
defined, quality means ``that the dietary supplement consistently meets
the established specifications for identity, purity, strength, and
composition and has been manufactured, packaged, labeled, and held
under conditions to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the Federal Food, Drug, and Cosmetic
Act.'' Ensuring the quality of the dietary supplement means that you
consistently and reliably manufacture what you intend and that you
establish manufacturing controls to prevent the dietary supplement from
being adulterated under section 402(a)(1) of the act due to the
presence of contaminants, under section 402(a)(2) of the act, for
example, if it bears or contains any unintentionally added poisonous or
deleterious substance, under section 402(a)(3) of the act if the
dietary supplement consists in whole or in part of any filthy, putrid,
or decomposed substance, or if it is otherwise unfit for food, or under
section 402(a)(4) of the act if the dietary supplement has been
prepared, packed, or held under insanitary conditions whereby it may
have become contaminated with filth, or whereby it may have been
rendered injurious to health. The definition of quality limits to
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act the types of
adulteration that you must control for in this CGMP final rule. The
definition applies to the controls that are designed to prevent
contamination of the product that you intend to manufacture.
In the 2003 CGMP Proposal, we said that our purpose was to present
a broad enough scope to the proposed rule so that we could receive the
depth and breadth of comment needed to develop a final rule that would
provide the proper balance of regulation (68 FR 12157 at 12161). We
asked for comment on whether each of the provisions proposed was
necessary to ensure the safety and quality of the dietary supplement
and was adequate to protect the public health (id.). We stated that the
proposed rule ``would establish the minimum CGMPs necessary to ensure
that, if you engage in activities related to manufacturing, packaging,
or holding dietary ingredients or dietary supplements, you do so in a
manner that will not adulterate and misbrand such dietary ingredients
or dietary supplements'' (68 FR 12157 at 12158). For example, we stated
that the proposed rule would require the manufacturer to test for toxic
compounds in botanicals that may likely be present to ensure that no
such compounds are present that may adulterate the dietary supplement
(68 12157 FR at 12162). Further, we included a requirement that the
ingredients, other than dietary ingredients under section 201(ff) of
the act, be lawful under the applicable food additive regulations or be
generally recognized as safe (GRAS) (proposed Sec. 111.35(d).
The approach that we set forth in the 2003 CGMP Proposal was
designed to prevent a manufacturer, under CGMP regulations, from using
an ingredient, whether a dietary ingredient or another
[[Page 34763]]
component, in the manufacture of a dietary supplement that would
adulterate the product under relevant provisions of the act, such as
section 402(a)(1) or (a)(2)(C). The manufacturer would have been
required to establish specifications at any point, step, or stage in
the manufacturing process where control is necessary to prevent
adulteration (proposed Sec. 111.35(e)). Thus, the manufacturer would
not have been able to establish a specification, consistent with
proposed Sec. 111.35(e), for the use of an unlawful ingredient because
such use would not prevent adulteration. In addition, the manufacturer
would have to establish specifications for contaminants that may
adulterate or that could lead to adulteration of the dietary
supplement. The manufacturer would have to take necessary precautions
to prevent the presence or level of contaminants, that would otherwise
adulterate the dietary supplement under another provision of the act,
from being present in the dietary supplement. The specifications were
intended to ensure that adulterated and misbranded dietary supplements
would not reach the marketplace (68 FR 12157 at 12197).
In addition to the general specifications established under
proposed Sec. 111.35(e), the proposed rule would have required the
manufacturer to establish specifications for the identity, purity,
quality, strength, and composition of the components received (proposed
Sec. 111.35(e)(1)) and for the finished batch of dietary supplement
(proposed Sec. 111.35(e)(3)). Although we stated that the proposed
rule did not address questions related to the safety of dietary
ingredients used (68 FR 12157 at 12172), if a dietary ingredient was
deemed to be unsafe under the act--under section 402(a)(1) or another
provision--a specification could not have been established for that
dietary ingredient, consistent with proposed Sec. 111.35(e). Thus, a
manufacturer would not be able to use, under dietary supplement CGMP, a
dietary ingredient, or other component, that would otherwise adulterate
the product under another provision of the act.
Further, the proposed rule was designed to ensure that the correct
label was applied during manufacture so that the dietary supplement
label would accurately identify the dietary supplement (proposed
Sec. Sec. 111.45(b)(7), 111.50(c)(12), and 111.70(b)(7)). The proposed
rule also would have required the master manufacturing record to
contain the identity of each ingredient that is required to be declared
on the ingredient list in section 403 of the act (21 U.S.C. 343)
(proposed Sec. 111.45(b)(4)).
Several comments seemed to question why the dietary supplement CGMP
rule would require that a manufacturer use lawful ingredients when
other provisions of the act would require such use. In fact, some
comments objected to the proposed requirement in the rule that required
that a component, other than a dietary ingredient, be approved for use
as a food additive or be GRAS. The comments stressed that such a
provision was not necessary because the statute already requires that
such an ingredient be approved as a food additive or be GRAS. In light
of these comments, we reconsidered our interpretation of the scope of
``prevent adulteration'' in the proposed rule and whether that
interpretation should be narrowed. We also considered whether to
require, as part of a CGMP requirement, that the label that accurately
reflects the ingredients in the product be applied or whether such a
requirement was not necessary, given our existing authority in section
403 of the act.
We determined that ensuring quality in dietary supplement CGMP, in
part, means that you produce what you intend to produce. As stated in
section V of this document, manufacturers must plan what they intend to
produce, institute adequate controls to achieve the desired outcome,
and ensure that the controls work so that the desired outcome is
consistently achieved. Thus, for example, the manufacturer decides on
the identity, purity, strength, and composition of the dietary
supplement it manufactures. The focus of CGMP is on process controls to
ensure that the desired outcome is consistently achieved, and not on
the inherent safety of the ingredients used (which is addressed by
other statutory prohibitions).
We agree with the comments that the safety of a particular
ingredient is governed by other provisions of the act. If you
manufacture a dietary supplement, you have a responsibility as a
manufacturer to evaluate the safety of the ingredients under, for
example, section 402(f) of the act.\2\ Dietary supplement CGMP would
require you to establish the identity, purity, strength, and
composition specifications for the product and ensure that such
specifications are met in the finished batch of dietary supplement.
Nothing in the dietary supplement CGMPs relieves manufacturers from
complying with any other substantive provisions of the act relating to
the safety of ingredients and other components.
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\2\Under section 402(f) of the act, a dietary supplement is
deemed to be adulterated if it is or contains a dietary ingredient
that presents a significant or unreasonable risk of illness or
injury under conditions of use recommended or suggested in labeling
or, if no such conditions, under ordinary conditions of use.
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Quality not only means that you produce what you intend, but that
you prevent contamination in your manufacturing process that could
adulterate your product. Food CGMP regulations, after which the dietary
supplement CGMP rule is modeled, require that the manufacturer take
precautions to ensure that the manufacturer does not adulterate the
product under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
For example, under Sec. 110.5 (food CGMP), the criteria and
definitions apply in determining whether a food is adulterated under
section 402(a)(3) and (a)(4) of the act. Specifically, Sec.
110.80(a)(2) states that raw materials shall not contain levels of
microorganisms that may produce food poisoning or other disease in
humans, unless otherwise treated during manufacturing operations so
that they no longer contain levels that would adulterate the product
within the meaning of the act. In addition, Sec. 110.80(a)(3) states
that raw materials and other ingredients susceptible to contamination
with natural toxins must comply with current FDA regulations and action
levels for poisonous or deleterious substances before such materials
are incorporated into finished food. Under dietary supplement CGMP, we
believe it is appropriate to require you to establish specifications
that are designed to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act from contamination during the
manufacturing, packaging, labeling, and holding operations. For
example, if you are manufacturing a dietary supplement that you know is
likely to contain a contaminant, you would need to establish limits on
the contaminant in your supplement, and you must design these limits to
prevent the dietary supplement from being adulterated under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
Quality, as the term is used for the purposes of this final rule,
relates both to producing what is intended (i.e., establishing and
ensuring that specifications for the identity, purity, strength, and
composition are met) and to ensuring that the dietary supplement that
you intend to produce has been manufactured, packaged, labeled, and
held under conditions to prevent adulteration within the meaning of
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. Thus, this
final rule is not designed to specifically prevent all
[[Page 34764]]
types of adulteration that may occur under the act. Rather, this final
rule is designed to prevent adulteration from those types of
contamination that are commonly controlled in other food CGMP
regulations. We do expect, however, that compliance with CGMP
requirements in the final rule will help to avoid other types of
adulteration. Also, nothing in this rule exempts a manufacturer from
compliance with other relevant adulteration provisions of the act.
We are replacing the phrase ``prevent adulteration'' in the
codified with words that relate to ensuring the quality of the dietary
supplement. Thus, for example, we have modified proposed Sec.
111.35(e) (now final Sec. 111.70(a)) to read, ``You must establish a
specification for any point, step, or stage in the manufacturing
process where control is necessary to ensure the quality of the
finished dietary supplement and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record'' instead
of ``* * * necessary to prevent adulteration.'' This phrase is replaced
in several codified provisions and an explanation of this change is not
provided in the preamble of this document each time it is made.
Moreover, you have a responsibility under CGMP to ensure that the
label you specify in the master manufacturing record is applied to the
product. Under section 403 of the act, you are required to ensure that
your label accurately reflects the ingredients in the product. Because
section 403 of the act provides that food, including dietary
supplements, is misbranded if a label that does not contain accurate
statements is applied, we do not need to impose the same requirement in
this final rule. Thus, if the representative label in the master
manufacturing record for the product does not identify the correct
dietary ingredients and the label that lists inaccurate information is
applied, that dietary supplement would be misbranded under section 403
of the act. Such labeling would not be a violation of dietary
supplement CGMP unless there is a mixup in your process control and you
do not put the representative label specified in the master
manufacturing record on the product. Such a mixup would be a violation
of dietary supplement CGMP requirements (see e.g., final Sec. Sec.
111.127(d), 111.160(e), 111.410(c), 111.415).
Thus, in addition to stating ``ensure the quality of the dietary
supplement,'' in the codified instead of ``prevent adulteration,'' we
are adding the language ``and that the dietary supplement is packaged
and labeled as specified in the master manufacturing record.'' Such
change is intended to clarify that the use of the packaging and
labeling that is stated in the master manufacturing record is what is
required in this final rule.
A failure to follow the requirements in this final rule, including
a failure to establish required specifications, could result in an
enforcement action by the agency under section 402(g) of the act
because the dietary supplement is adulterated in that it was prepared,
packed, labeled, or held under conditions that do not meet CGMPs for
dietary supplements. The act establishes certain prohibited acts and
enforcement mechanisms to remove adulterated product from the market
and prevent manufacturers from continuing to manufacture adulterated
product. Enforcement mechanisms currently available to us under the act
are not affected by this final rule.
Finally, we have included in this final rule the existing
requirements in part 110 that we believe are common to dietary
supplement manufacturing. For example, the requirements in subpart C,
Physical Plant and Grounds, are similar to those in Sec. 110.20. We
recognize that there may be operations related to the manufacturing of
dietary supplements for which certain provisions in part 110 apply, but
that we did not determine to be common to most dietary supplement
manufacturing operations. For example, there may be some dietary
supplements that are dehydrated and rely on the control of moisture
consistent with Sec. 110.80(b)(14). A manufacturer would be expected
to comply with the regulations in part 110 in addition to the
regulations in part 111, unless the regulations conflict. To the extent
that the regulations conflict, the dietary supplement manufacturer must
comply with the regulation in part 111.
B. Highlights of the Final Rule
The final rule:
Applies to persons who manufacture, package, label, or
hold dietary supplements unless subject to an exclusion in Sec. 111.1;
Establishes minimum requirements for personnel, physical
plant and grounds, and equipment and utensils;
Requires the establishment and use of written procedures
for certain operations, including those related to equipment, physical
plant sanitation, certain manufacturing operations, quality control,
laboratory testing, packaging and labeling, and product complaints;
Requires the establishment of specifications in the
production and process control system that will ensure dietary
supplements meet the identity, purity, strength, and composition
established in specifications and are properly packaged and labeled as
specified in the master manufacturing record;
Provides for the option to use a certificate of analysis
(for specifications other than the identity of a dietary ingredient)
from a component supplier instead of having manufacturers conduct tests
or examinations on the components they receive;
Requires testing of a subset of finished batches of
dietary supplements based on a sound statistical sampling or,
alternatively, testing all finished batches;
Requires implementation of quality control operations to
ensure the quality of a dietary supplement;
Requires the preparation and use of a written master
manufacturing record for each unique formulation of manufactured
dietary supplement, and for each batch size, to ensure your
manufacturing process is performed consistently and to ensure
uniformity in the finished batch from batch to batch;
Requires the preparation of a batch production record
every time a dietary supplement batch is made. The batch production
record must accurately follow the appropriate master manufacturing
record;
Requires the establishment and use of laboratory control
processes related to establishing specifications and to the selection
and use of testing and examination methods;
Requires reserve samples of dietary supplements to be held
in a manner that protects against contamination and deterioration;
Requires identification and quarantine of returned dietary
supplements until quality control personnel conduct a material review
and make a disposition decision;
Requires quality control personnel to conduct a material
review and make a disposition decision under certain circumstances;
Requires a qualified person to investigate any ``product
complaint'' that involves a possible failure of a dietary supplement to
meet any CGMP requirement, with oversight by quality control personnel;
and
Requires records associated with the manufacture,
packaging, labeling, or holding of a dietary supplement to be kept for
1 year beyond the shelf life dating (when such dating is used, such as
expiration dating, shelf life dating, or ``best if used by'' dating),
or if shelf life dating is not used, for 2 years beyond the date of
distribution of the last batch
[[Page 34765]]
of dietary supplements associated with those records.
IV. What General Comments Did We Receive?
We received approximately 400 comments on the proposed rule.
Although most comments support CGMP requirements for dietary
supplements and dietary ingredients, others question the need for a
regulation and many sought changes to the rule. We describe, in this
section, comments on general aspects of the final rule. We include
comments related to the structure and organization of the final rule,
comments we received on why CGMP requirements are needed, and comments
on written procedures. In addition, we describe some general comments
we received on multiple sections of the proposed rule that we believe
are better addressed in one response.
To make it easier to identify comments and our responses, the word
``comment,'' in parentheses, will appear before each comment, and the
word ``response'' will appear before each response. We also have
numbered the comments to make it easier to distinguish between
comments; the numbers are for organizational purposes only and do not
reflect the order in which we received the comments or any value
associated with the comment.
A. What Comments Did We Receive on the Structure and Organization of
the Rule?
(Comment 1) Several comments seek to restructure or reorganize the
rule. For example, one comment states we should simplify the entire
section on production and process controls. The comment asserts it
would be more logical to list contaminants that may adulterate a
dietary supplement or lead to adulteration as part of the requirements
for specifications (proposed Sec. 111.35(e)) than to list such
contaminants as part of the testing requirements (proposed Sec.
111.35(k)). Other comments say it would be more logical to list the
tests that are considered appropriate as part of proposed Sec.
111.35(h) (concerning appropriate tests or examinations to determine
whether specifications are met) than to have a separate requirement for
appropriate tests in proposed Sec. 111.35(l) (which listed the types
of analyses that should be part of a test).
Another comment claims the rule is too complex, asserting it would
create chaos. Other comments say that the proposal's degree of detail
required is unrealistic for small dietary supplement firms, and we
should rewrite the rule to be more user friendly.
Yet another comment says that any final rule we issue must clearly
set forth CGMP requirements. This comment seems to suggest the
requirements need to be more detailed in describing what is required.
The comment asserts that ambiguities in interpretation could result in
economic disadvantage for small businesses because they typically do
not have in-house legal counsel and, thus, must be more conservative in
interpreting ambiguous regulatory provisions.
(Response) In response to these comments, as well as comments on
specific subparts and provisions, we have reorganized the final rule
and have re-phrased or introduced concepts in a ``user-friendly'' or
plain language format. We also have eliminated certain redundant
regulatory requirements and combined similar requirements. For example,
rather than put all production and process control system requirements
in a single subpart, we have reorganized the final rule to create a
series of subparts that first describe the requirements for the overall
design and implementation of the production and process control system
and then describe the requirements of the individual operations
associated with that system. We also present each requirement as a
question rather than as a paragraph within a section. This question
format will help readers focus on the subparts or sections that apply
to specific operations.
As another example, we reduced the redundancy associated with the
interrelated nature of the proposed rule by combining most similar
requirements. Both proposed Sec. Sec. 111.35(m) and 111.60(b)(2) would
require you to keep testing and examination results. The final rule
places this requirement in a single section (Sec. 111.325(b)(2)(ii)).
The final rule also shortens the construction ``includes, but is
not limited to'' to ``includes.'' We did this because the use of the
word ``includes'' indicates that the specified list that follows is not
exclusive. The phrase ``but is not limited to'' is unnecessary.
Finally, some changes we have made to one specific section have an
impact on other sections. For example, after considering the comments,
we revised subpart B to require you to establish and follow written
procedures to fulfill the requirements of subpart B. Those written
procedures are records you must make and keep in accordance with the
recordkeeping requirements of subpart P, thus we made changes to
include that requirement of making and keeping records.
B. What Comments Did We Receive on the Need for Dietary Supplement CGMP
Requirements?
(Comment 2) Some comments state that dietary supplement CGMP
requirements will protect consumers from supplements that contain
inherently unsafe dietary ingredients. Other comments request that we
take additional action to ensure the safety of dietary ingredients.
(Response) This final rule focuses on the manufacturing practices
of dietary supplements and not on whether certain dietary ingredients
are or are not safe. Therefore, comments related to whether certain
dietary ingredients are inherently unsafe and any request to take
actions related to the inherent safety of dietary ingredients are
outside the scope of this rule.
(Comment 3) Some comments support the rule, explaining that it will
address current problems with superpotent and subpotent dietary
supplements, undeclared ingredients, and varying levels of ingredients.
Others indicate the rule will better protect consumers and increase
consumer confidence. One comment states that CGMP requirements for
dietary supplements are not needed for responsible manufacturers
because they already manufacture safe dietary supplements. Some
comments state that dietary supplement CGMP requirements are not needed
because the dietary supplements have a track record of safety. Other
comments say there were more adverse events reported from drug use than
from dietary supplement use and that a large number of Americans take
dietary supplements, and on that basis suggested that dietary
supplements are safer than foods or drugs.
(Response) We agree the final rule will better protect consumers
and help address the types of manufacturing problems identified in the
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162 through
12163) through consistent use of established production processes and
controls.
However, we disagree with the comments asserting dietary
supplements have a track record of safety such that dietary supplement
CGMP requirements are unnecessary. Section 402(g) of the act does not
require us to establish a ``bad'' track record of safety in the
manufacture of dietary supplements before we may issue a dietary
supplement CGMP rule. Furthermore, we disagree with the comments
comparing dietary supplement safety to drug safety; there
[[Page 34766]]
are different statutory requirements, different regulatory
requirements, and different safety evaluations for dietary supplements
and drugs.
We also disagree that the final rule should apply only to
manufacturers who cannot manufacture dietary supplements responsibly.
Establishing who is or is not a responsible manufacturer is not a
threshold requirement in section 402(g) of the act, and it would be
impractical to regulate dietary supplement CGMP in such a manner,
because parties may differ as to whether a particular manufacturer
acted ``responsibly'' in a particular situation. All dietary supplement
manufacturers are subject to this final rule, just as all dietary
supplement manufacturers are subject to section 402(g) of the act. We
therefore are not persuaded that dietary supplement CGMP requirements
are not needed, or should only be applied to manufacturers who have not
acted ``responsibly.''
(Comment 4) Some comments state that our authority under the
current food CGMP regulation in part 110 and our authority to take
actions against adulterated and misbranded products generally are
sufficient. Other comments state that DSHEA gives us the necessary
legal authority to protect the public health and that additional
regulatory requirements are unnecessary. Several comments object to our
statement that dietary supplement CGMP requirements are needed to
prevent adulteration. These comments suggest dietary supplement CGMP is
focused on ensuring finished products are manufactured using quality
procedures, but are not related to preventing adulteration. Other
comments state we should enforce current food CGMP regulations rather
than adopt new regulations.
(Response) We disagree that dietary supplement CGMP requirements
are not related to preventing adulteration. In fact, under the
statutory scheme a dietary supplement is deemed to be adulterated under
section 402(g)(1) of the act if it fails to meet CGMP requirements we
promulgate by regulation. As we discussed in section III of this
document, dietary supplement CGMP requirements are necessary to ensure
the quality of the dietary supplement; ensuring quality includes
ensuring that the dietary supplement has been manufactured, packaged,
labeled, and held under conditions to prevent adulteration under
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
We also disagree with those comments stating that the requirements
in part 110 are adequate and that no additional requirements are
necessary. The comments do not explain why the specific requirements
set forth in the proposed rule that are not also in part 110 are
unnecessary. As discussed in greater detail in response to comments on
our legal authority in section V of this document, the particular
characteristics and hazards of dietary supplements call for CGMP
requirements tailored to dietary supplements. Congress specifically
provided independent authority under section 402(g) of the act for us
to promulgate CGMP requirements for dietary supplements. That authority
would have been unnecessary if Congress had concluded that part 110 was
adequate.
We also disagree that enforcement of part 110 would eliminate a
need for dietary supplement CGMP requirements. The dietary supplement
CGMP requirements include practices specifically tailored to the
characteristics and hazards of dietary supplements and their
manufacturers. The comments asserting that current food CGMP
requirements in part 110 are sufficient provided no persuasive or
compelling reasons for that assertion, or for why we should not
implement dietary supplement CGMP requirements under section 402(g) of
the act. For these reasons, we are not persuaded by the comments that
these dietary supplement CGMP requirements are not needed.
(Comment 5) Some comments object to the examples of manufacturing
problems that we used to support the need for CGMP requirements.
Specifically, some comments object to the Prevention magazine citation
and also object to the nine examples we presented in the preamble to
the 2003 CGMP Proposal (see 68 FR 12157 at 12161 through 12163). We
cited the Prevention magazine survey on consumer use of dietary
supplements to show that only 41 percent of surveyed consumers who use
vitamins and minerals think those products are very safe, and only 50
percent think the products are somewhat safe; among those using herbal
products, only 24 percent thought the products were very safe, and only
53 percent thought the products were somewhat safe. We noted that 74
percent supported increased government regulation of dietary
supplements (see, id.). As one example of adulterated dietary
supplements caused by manufacturing practices, the preamble to the 2003
CGMP Proposal mentioned an instance where a young woman suffered a
life-threatening abnormal heart function that was traced to a
mislabeled or contaminated dietary ingredient (68 FR 12157 at 12162).
Another example involved recalls of super- and subpotent dietary
supplements (id.).
Comments objecting to the Prevention survey said it provided no
rationale for why CGMP requirements are needed. Other comments said the
nine examples we provided represent a failure to conform to an existing
regulation and do not demonstrate a need for a new CGMP regulation for
dietary supplements. One comment disagrees that the CGMP requirements
would prevent adverse reactions, as one example suggested in the
preamble to the 2003 CGMP Proposal (see 68 FR 12157 at 12162) because,
the comment claims, most adverse reactions are not the result of
manufacturing problems. Another comment states the example involving
plantain (68 FR 12157 at 12162), where a raw material was labeled as
``plantain'' when it was, in fact, Digitalis lanata (a plant that can
cause life-threatening heart reactions), shows that, had there been a
system in place to test finished product for purity and identity or to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place. The
comment states identity testing is necessary in the final rule.
Another comment objects to the example of ``non-food grade
chemicals'' (id.) because the reference supporting the example involved
Gamma-Butyrolactone, a substance we have stated is an unapproved new
drug and not a dietary supplement. Some comments say the risks cited in
the justification for these regulations are hypothetical or theoretical
and current statutory or regulatory authority is adequate.
(Response) We disagree, in most part, with the comments. We cited
the Prevention survey to illustrate consumer perception and support for
increased government involvement in dietary supplement regulation. We
did not describe the survey as illustrating CGMP problems associated
with dietary supplements.
We also disagree that the risks cited in the preamble to the 2003
CGMP Proposal are merely hypothetical or theoretical. We provided
actual examples of failures in the manufacturing of products marketed
as dietary supplements. The comments may have misunderstood what the
CGMP requirements for dietary supplements are intended to accomplish. A
principal goal of the CGMP requirements is to have those who
manufacture, package, label, or hold dietary supplements do so in a
manner that ensures the quality of the
[[Page 34767]]
dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. It is the
manufacturer who needs to establish procedures for its manufacturing
operations to ensure, for example, the final product is produced
according to its specifications in the master manufacturing record,
meets limits on contaminants, and is a quality dietary supplement. If a
product does not meet its specifications, a manufacturer who observes
the CGMP requirements should know that and be able to take corrective
action before the dietary supplement enters the marketplace. The onus
is on the manufacturer, and not simply on us, to take action to prevent
the adulterated product from entering the market or, if the product has
already been released, to remove the product from the market. The
umbrella food CGMP requirements in part 110 do not contain specific
provisions establishing specifications, requiring identity testing, or
requiring in-process and/or finished product testing. Through this
final rule, we are establishing a new CFR part regarding CGMP
requirements specifically for dietary supplements.
The examples we used in the preamble to the 2003 CGMP Proposal
included adverse event reports associated with contamination with
Digitalis lanata, the possible contamination of botanical ingredients
with toxic compounds, the use of non-food grade chemicals, the
manufacture of super- and subpotent dietary supplements, the presence
of undeclared ingredients, and the variability of ingredients from what
is declared on the label (Refs. 7, 8, and 10; see, also, 68 FR 12157 at
12162 through 12163). These were all examples where products were
manufactured, labeled, and sold to the consumer as dietary supplements.
We disagree with the comments' assertions that all these problems can
be adequately dealt with by the food CGMP requirements in part 110, but
agree with the comment that, had there been a system in place ``to
perform identity testing upon receipt, the manufacturer could have
prevented that adulterated product from entering the market place.''
Most of these examples present situations in which the manufacturer
could have identified these problems through the dietary supplement
CGMP requirements for specifications and testing or examination, such
as identity verification, and could have prevented such products from
entering the market or at least provided a greater assurance that such
products would not make it into the marketplace. The dietary supplement
CGMP requirements ensure adequate controls are in place to identify
many of these types of manufacturing errors before the product is in
the marketplace and not through postmarketing adverse event reports or
consumers' illnesses.\3\
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\3\Mandatory reporting to FDA of serious adverse events is now
required as a result of the enactment of the ``Dietary Supplement
and Non-Prescription Drug Consumer Protection Act'' (Public Law 109-
462) signed into law on December 22, 2006 (see discussion in section
XX of this document).
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The dietary supplement industry is diverse, as are the number and
types of products marketed as dietary supplements. As we stated in the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12163), given the
wide range of public health concerns presented by the manufacturing
practices for dietary supplements, a comprehensive system of controls
is necessary. This final rule will set the standards for CGMP for
dietary supplements that, if followed, will help ensure the quality of
the dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. The
establishment of production and process controls and adherence to these
and other CGMP requirements of this final rule will help to prevent the
types of events (and others) we described in the nine examples
presented in the preamble to the 2003 CGMP Proposal.
(Comment 6) Several comments suggest that dietary supplements are
no different in safety or physiologic effect and require no different
requirements than conventional food with respect to CGMP. One comment
disagrees with us that dietary supplements require different
requirements than conventional food because dietary supplements are
ground up or in powder form and may not be easily recognized or
differentiated; the comment says the same is true of many food
ingredients as well.
(Response) We disagree with the suggestions by these comments that
dietary supplement CGMP requirements need not differ from those for
conventional foods. By definition, a dietary supplement is in a
category of food separate and distinct from the category of
conventional food. The definition of dietary supplement in section
201(ff) of the act, in part, essentially describes a dietary supplement
as a type of food that differs from conventional food. The definition
refers to section 411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act (21
U.S.C. 350(c)(1)(B)(i) and (c)(1)(B)(ii)), which describes the forms
that dietary supplements intended to be ingested may take, i.e.,
tablet, capsule, powder, softgel, gelcap, or liquid form, and if not in
such a form, limitations on how dietary supplements can be represented,
i.e., not as conventional food or as a sole item of a meal or the diet.
Congress included separate additional provisions under section 402
of the act (see section 402(f) and (g) of the act) for when a dietary
supplement may be adulterated. Congress considered that dietary
supplements may warrant CGMP requirements that are different than those
for conventional food. Although dietary supplements may include
substances that are used as ingredients in conventional foods, the
amounts consumed as a dietary supplement and as a conventional food
product may not be the same and, in fact, may be more concentrated, and
in higher amounts, when taken as a dietary supplement. The forms in
which dietary supplements are consumed differ (e.g., capsule, tablet),
as may the frequency, when compared to conventional foods. The uses of
dietary supplements also differ from use as conventional food.
Consequently certain manufacturing practices considered to be a part of
CGMP for dietary supplement manufacturing may not be necessary for all
types of food.
C. What Comments Did We Receive on Written Procedures?
1. Overview
In the 2003 CGMP Proposal (68 FR 12157 at 12165), we stated that
written procedures were included in the dietary supplement CGMP outline
submitted to us by industry, namely, the National Nutritional Foods
Association standards (NNFA), the NSF International draft standards,
and the United States Pharmacopoeia (USP) draft manufacturing
practices. We also stated that, to limit the burden to manufacturers,
we were not proposing to require written procedures for all the
requirements. We invited comment on whether we should require written
procedures for a variety of operations; specifically, for complying
with the CGMP requirements, under proposed Sec. 111.10 for personnel
hygiene and for preventing microbial contamination due to personnel (68
FR 12157 at 12182); maintenance, cleaning, and sanitation for the
physical plant under proposed Sec. 111.15 (68 FR 12157 at 12187);
calibrating instruments and controls under proposed Sec. 111.25(b),
(c), and (d) (68 FR 12157 at 12191); maintaining, cleaning, and
sanitizing equipment and utensils under proposed Sec. 111.25(e) (68
[[Page 34768]]
FR 12157 at 12192); calibrating, inspecting, and checking automatic
equipment under proposed Sec. 111.30 (68 FR 12157 at 12193); the
duties of the quality control unit under proposed Sec. 111.37 (68 FR
12157 at 12201); implementing the proposed requirements for receipt of
components, dietary supplements, packaging, and labels under proposed
Sec. 111.40(a) and (b) (68 12157 at FR 12203); preparing the master
manufacturing record under proposed Sec. 111.45 (68 FR 12157 at
12205); laboratory operations under proposed Sec. 111.60 (68 FR 12157
at 12209); manufacturing operations under proposed Sec. 111.65 (68 FR
12157 at 12211); packaging and labeling operations under proposed Sec.
111.70 (68 FR 12157 at 12213); holding components, dietary supplements,
packaging, labels, and in-process materials under proposed Sec. Sec.
111.80 and 111.82 (68 FR 12157 at 12214); identifying, quarantining,
and salvaging returned dietary supplements under proposed Sec. 111.85
(68 FR 12157 at 12216); and receiving, reviewing, and investigating
consumer complaints under proposed Sec. 111.95 (68 FR 12157 at 12217).
We stated that if comments assert that written procedures are
necessary, comments should include an explanation of why the
requirement is necessary to prevent adulteration including how such a
requirement would ensure the identity, purity, quality, strength, and
composition of the dietary supplement. Conversely, if comments assert
that written procedures are not necessary, we asked for an explanation
of why and how, in the absence of the requirement, one can prevent
adulteration and ensure the identity, purity, quality, strength, and
composition of the dietary supplement.
(Comment 7) Many comments stress the most critical aspect of a
successful CGMP system is effective process control, which requires
conducting key operations using written procedures. Several comments
assert that written procedures are an important part of manufacturing
operations to ensure uniform practices in production operations, from
receiving through final operations. Several comments assert written
procedures provide a sound basis for employee training and supervision.
Several comments state that without a written training program, it is
very likely that some employees may not receive sufficient training, or
in some cases, any CGMP training at all. One comment specifically
suggests that companies develop written procedures for the minimum CGMP
training common to all departments.
One comment points out that all well-recognized quality systems
require establishment of written procedures to ensure consistent
process control, and cites examples such as the International
Organization for Standardization, the American National Standards
Institute (ANSI), and the Malcolm Baldridge National Quality Award
criteria. Other comments state that written procedures are necessary
for the definition, operation, and documentation of a process control
system, and that without such procedures it would be virtually
impossible for any company, regardless of size, to consistently
manufacture products that meet established requirements for identity,
purity, quality, strength, and composition. The comments note that
written procedures contain the necessary instructions for all employees
to successfully execute their respective functions. Another comment
supports a requirement for conducting key operations using written
procedures and states that records document that operations were
performed, but that written procedures show how the task is to be
performed and at what frequency it should be performed. One comment
states effective communication is essential to build quality into a
process, and written procedures provide that throughout all levels of
an organization. Another comment states it is difficult to imagine how
the quality control unit could carry out its obligations under proposed
Sec. 111.37(b)(1) to ``approve or reject all processes,
specifications, controls, tests, and examinations, and deviations from
or modifications to them * * *'' if these are not subject to written
procedures.
Many comments which present one or more of these general reasons
for requiring written procedures also list operations that they believe
should be conducted using written procedures. The operations that one
or more comments list as key operations are:
Employee training;
Cleaning the physical plant, including pest control;
Maintenance, cleaning, and sanitizing of equipment and
utensils;
Calibration of equipment used in manufacturing or testing;
All aspects of the production process, including a general
procedure to document the minimum investigation, review, and approval
requirements for failures in manufacturing or packaging operations;
All quality control operations;
Reprocessing of batches or start-up materials that do not
conform to specifications;
Receipt, identification, examination, handling, sampling,
testing, and approval or rejection of components, packaging, and
labels;
Laboratory operations, including the establishment of
specifications and descriptions of laboratory test methods used to
ensure that components, in-process materials, and finished product meet
established specifications;
Packaging and labeling operations, including issuance and
use of appropriate labels, labeling, and packaging materials;
Holding and distribution procedures, including procedures
for quarantine and parameters for storage;
Return and salvage operations;
Handling of consumer complaints; and
Procedures for product recall.
Many comments assert an effective process control system that
includes extensive written procedures would justify a decreased testing
burden with respect to the finished product. One comment suggests we
exempt manufacturers from the requirement to test each finished batch
of product if they have a qualified manufacturing process that meets
certain basic criteria, including a requirement for written procedures
for each stage of the process. One comment notes it would be clearer to
all parties if specific written procedures were listed as required and
stresses the importance of having all companies know exactly what is
procedurally expected of them.
In addition to these general reasons for requiring that key
operations be conducted using written procedures, several comments
provide specific reasons for requiring that specific operations be
conducted using written procedures. In response to our request for
comment on whether written procedures should be required for complying
with proposed Sec. 111.10 (personnel hygiene and for preventing
microbial contamination due to personnel), one comment states that
written procedures help to ensure compliance with the proposed hygiene
requirements by clearly listing the requirements and requiring the
employees to follow them on a consistent basis.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for maintenance, cleaning, and sanitation for the physical
plant under proposed Sec. 111.15, one comment states that having
written procedures in place to clean the physical plant will ensure
that there is no cross-contamination. Another comment states utility
areas such as effluent treatment, boilers, cooling towers, and water
[[Page 34769]]
treatment plants also should have documented procedures for cleaning in
order to create a general awareness of cleanliness throughout the
plant. Other comments state that such written procedures should not be
required because they would not directly prevent contamination or
ensure the identity, purity, quality, strength, and composition of the
dietary supplement if, as the ``bottom line,'' a manufacturer maintains
the physical plant in a clean and sanitary condition.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
calibrating instruments and controls under proposed Sec. 111.25(b),
(c), and (d), several comments assert we should require manufacturers
to establish and follow written procedures for calibrating equipment
and controls. According to these comments, such procedures would
provide us with a written record that is sufficient to evaluate the
adequacy of the company's calibration procedures and would provide the
necessary controls to meet the underlying intent of the rule. These
comments assert that written procedures will lessen the risk that
adulterated products will be produced.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for maintaining, cleaning, and sanitizing equipment and
utensils under proposed Sec. 111.25(e), several comments assert such
written procedures are crucial. These comments claim that written
procedures promote consistency, clearly lay out expectations for
employees, facilitate training, and provide a reference for individuals
in performing their job functions. One comment states that written
procedures for maintaining, cleaning, and sanitizing equipment are an
industry standard.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for preparing the master manufacturing record under
proposed Sec. 111.45, one comment states that written procedures for
in-process control and quality checks should ensure the addition of the
proper ingredients in the proper amount, and proper blending and
control of other critical points. Another comment states written
procedures are a critical element for ensuring consistent
implementation of proper corrective action. Other comments state they
do not support a requirement for written procedures for preparing the
master manufacturing record; and one comment suggests such a written
procedure is not necessary because the proposed regulations for
preparing the master manufacturing record already delineate the
requirements for what information must be included in the master
manufacturing record.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for laboratory operations under proposed Sec. 111.60,
some comments specifically note the need for written procedures for the
laboratory test methods used to ensure that components, in-process
materials, and finished product meet established specifications. Some
comments emphasize written procedures would create a standard for
testing of products or groups of products and establishing parameters
for passing or failing products.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for manufacturing operations under proposed Sec. 111.65,
one comment asserts this is an effective way to train personnel and a
means to hold operators accountable to a quality standard. Another
comment states written procedures can improve quality and consistency
in a manufacturing operation.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for packaging and labeling operations under proposed Sec.
111.70, one comment asserts this is an effective way to train personnel
and a means to hold operators accountable to a quality standard.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
holding components, dietary supplements, packaging, labels, and in-
process materials under proposed Sec. Sec. 111.80 and 111.82, one
comment asserts this is an effective way to train personnel and a means
to hold operators accountable to a quality standard. Another comment
states a company cannot be considered to be a CGMP operation without
having written procedures for every product manufacturing activity,
including holding and distributing. This comment states mixups and
adulterations will be more likely to occur if there are no written
procedures for control of storage locations, manner of storage, and
container and storage location identification codes.
In response to our request for comment on whether written
procedures should be required for complying with the proposed
requirements for returned dietary supplements, one comment states
written procedures should govern all return and salvage operations to
create a standard for quarantine and salvage and to establish
parameters for proper salvage conditions.
Responding to our request for comment on whether written procedures
should be required for complying with the proposed requirements for
handling consumer complaints, some comments state written procedures
will encourage companies to handle consumer complaints in a uniform
manner. One comment asserts written procedures should be required for
handling consumer complaints because some complaints could relate to
serious illness or injury. The comment states that written procedures
would set out exactly what steps need to be taken when complaints are
reviewed, and are the best way to ensure the essential information is
captured.
(Response) We agree with the comments that effective process
control, using written procedures, is an important aspect of a
successful CGMP program. We also agree requiring written procedures
will help to ensure consistent practices in operations i.e., help to
ensure the operation is conducted in the same manner regardless of who
conducts the operation or when the operation is conducted. We also
agree that written procedures provide a sound basis for employee
training and supervision, are an effective communication tool, and
enable quality control personnel to carry out the responsibility to
approve or reject all processes, specifications, controls, tests, and
examinations, and deviations from or modifications to them. In
addition, written procedures establish expectations for each covered
operation so the operation does not proceed in an ad-hoc manner.
Written procedures provide specific guidance if there is an
unanticipated occurrence and, thus, can play a key role in ensuring a
quality product, because actions to correct the unanticipated
occurrence can take place swiftly and with confidence in the outcome.
This final rule establishes the minimum CGMPs necessary for
activities related to manufacturing, packaging, labeling, and holding
dietary supplements to ensure a quality
[[Page 34770]]
product. The operations required by this final rule must be conducted
in a consistent manner, regardless of who is conducting an operation or
when the operation is conducted. As discussed in the following
paragraphs, with a few exceptions, we are requiring that you establish
and follow written procedures to fulfill the requirements for the
operations covered by this final rule. The exceptions include final
subpart A, which addresses the scope of the rule, rather than
operations covered by the rule; final subparts E, H, and I, in which we
conclude that a requirement for written procedures would be redundant
to other requirements; and final subpart P, which establishes
requirements for making and keeping records, rather than for conducting
operations.
We believe requiring you to establish and follow written procedures
to fulfill the requirements of subparts B through D, F, G, and J
through O, when combined with other requirements of this final rule,
justifies reduced requirements for testing finished batches of product
compared to the proposed requirements for such testing as found in
proposed Sec. 111.35. By establishing and following written
procedures, you will focus your production and process control system
on ensuring the quality of the finished product at each stage in the
production process, rather than relying entirely on testing at the end
of the process.
2. Written Procedures That Are Required by This Final Rule
a. Written procedures for personnel (final subpart B). We believe
that successful programs for process control are directly connected to
appropriate training programs. Employee training must be conducted in a
consistent manner, regardless of who conducts the training or when it
is conducted. Failure to conduct employee training in a consistent
manner could lead to a failure in ensuring product quality. For
example, an employee who has not received appropriate training on how
to conduct a specific physical examination to verify the identity of a
dietary ingredient may erroneously report that the correct ingredient
was received when, in fact, the received dietary ingredient is related
to, but different from, the ingredient that is specified in the master
manufacturing record.
We also believe the requirements that apply to preventing microbial
contamination due to sick or infected personnel and that apply to
proper hygienic practices must be conducted in a consistent manner. For
example, it is well known that foodborne illness can be transmitted by
workers who are sick. For example, volunteer food workers at an outdoor
music festival were found to be the source of contamination for an
outbreak of Shigellosis (Ref. 11).
We include in final subpart B a requirement (final Sec. 111.8)
that you establish and follow written procedures for fulfilling the
requirements of subpart B.
b. Written procedures for cleaning the physical plant, including
pest control (final subpart C). We agree with the comments that written
procedures for cleaning the physical plant would reduce the potential
for cross-contamination and that such written procedures must include
written procedures for pest control. Cleaning operations and pest
control must be conducted in a consistent manner, regardless of who
conducts the operation or when it is conducted. Failure to conduct
cleaning operations and pest control in a consistent manner could lead
to failure in ensuring product quality. For example, application of a
chemical such as a fumigating agent or rodenticide in a production area
must be performed correctly to avoid contaminating dietary supplements.
Therefore, we disagree that written procedures would not directly
prevent contamination or ensure the identity, purity, strength, and
composition of the dietary supplement even if a manufacturer maintains
the physical plant in a clean and sanitary condition.
We include in final subpart C a requirement that you establish and
follow written procedures for cleaning the physical plant and for pest
control (final Sec. 111.16).
c. Written procedures for calibrating instruments and controls and
for calibrating, inspecting, and checking automated, mechanical, or
electronic equipment (final subpart D). Calibrating instruments and
controls, and calibrating, inspecting, and checking automated,
mechanical, or electronic equipment must be conducted in a consistent
manner, regardless of who conducts the operation or when it is
conducted. Without a consistent approach, the performance of these
operations could lead to equipment that produces inaccurate results.
For example, if a scale is out of calibration, the wrong amounts of
components could be added to a mixer. We include in final subpart D a
requirement that you establish and follow written procedures for
calibrating instruments and controls that you use in manufacturing or
testing a component or dietary supplement (final Sec. 111.25(a)) and
for calibrating, inspecting, and checking automated, mechanical, and
electronic equipment (final Sec. 111.25(b)). We note that the
manufacturers of equipment often provide written procedures for
calibrating equipment. Depending on your circumstances and
applications, you may be able to rely on written procedures provided by
the manufacturer of the equipment with little or no modification.
Final Sec. 111.25(a), pertaining to establishing and following
written procedures for calibrating instruments and controls used in
manufacturing or testing components or dietary supplements, is similar
to proposed Sec. 111.25(c)(1) which would provide an option, in
relevant part, that you establish written procedures for calibrating
such instruments and controls in addition to requiring you to document
that the procedure was followed each time a calibration is performed.
d. Written procedures for maintaining, cleaning, and sanitizing
equipment and utensils (final subpart D). Maintaining, cleaning, and
sanitizing equipment and utensils must be conducted in a consistent and
appropriate manner, regardless of who conducts the operation or when it
is conducted. Failure to clean and sanitize equipment and utensils in a
consistent and appropriate manner could lead to a product that is
adulterated because, for example, equipment and utensils that are not
properly cleaned and sanitized could be a source of microorganisms, or
could lead to cross-contamination of products. In addition, failure to
maintain equipment in a consistent manner could lead to the failure to
ensure product quality. For example, equipment that is properly
maintained is less likely to malfunction than equipment that is not
maintained, and using equipment that malfunctions could lead to errors
in production, such as dispensing an incorrect amount of each
ingredient.
We include in final subpart D a requirement that you establish and
follow written procedures for maintaining, cleaning, and sanitizing
equipment and utensils (final Sec. 111.25(c)). Final Sec. 111.25(c)
applies to equipment, utensils, and any other contact surfaces used in
labeling operations as well as in manufacturing, packaging, and holding
operations. Although the factors you must consider for maintaining,
cleaning, and sanitizing equipment used for labeling operations likely
are different from those for equipment used in manufacturing or
packaging operations, you nevertheless must determine the appropriate
steps to take to ensure that labeling equipment is appropriately
maintained and does not become a source of contamination
[[Page 34771]]
for dietary supplements. For example, equipment used for labeling
operations has a greater potential to contaminate a dietary supplement
when labeling operations are carried out in concert with packaging
operations, because the dietary supplement could be exposed to one or
more contact surfaces during the packaging operations.
Final Sec. 111.25(c) requires you to establish and follow written
procedures for maintaining, cleaning, and sanitizing, as necessary, all
equipment, utensils, and any other contact surfaces used to
manufacture, package, label, or hold components or dietary supplements.
Final Sec. 111.25(c) relates to proposed Sec. 111.25(e)(1) which
would, in relevant part, require you to maintain, clean, and sanitize
as necessary, all equipment, utensils, and contact surfaces used to
manufacture, package, label, or hold components, dietary ingredients,
or dietary supplements.
(Comment 8) Some comments suggest that written procedures for
maintaining, cleaning, and sanitizing equipment require visual
inspection of equipment when more than one product is manufactured
using the same equipment, and that the presence of residual components
from one product in a different product could be harmful. The comments
also suggest the written procedures include residual limits of
components from different product lines to guarantee the safety of the
dietary supplement.
(Response) The final rule gives you flexibility to develop written
procedures appropriate to your products and equipment. Consequently,
final Sec. 111.25(c) neither requires nor prohibits any specific
procedure, such as the visual inspection suggested by the comment.
As for the residual limits, the comment provides no data or other
information that would provide a basis for setting residual limits for
any particular components. However, as we discuss more fully in the
discussion of final Sec. 111.70(e) in section X of this document, the
final rule requires you to establish and meet specifications for the
identity, purity, strength, and composition of dietary supplements and
for limits on contamination for dietary supplements that you
manufacture. When considering the specifications you must establish to
ensure the quality of the dietary supplements, you must take into
account the need to ensure that components or dietary supplements are
not contaminated as a result of using the same equipment. Such
equipment could be a source of contamination if more than one product
is manufactured using the equipment and it is not properly cleaned and/
or sanitized.
e. Written procedures for quality control operations, including
written procedures for conducting a material review and making a
disposition decision and written procedures for approving or rejecting
reprocessing (final subpart F). Quality control operations must be
conducted in a consistent manner. Failure to carry out quality control
operations in a consistent and appropriate way could lead to failure to
ensure product quality and to ensure the dietary supplement is packaged
and labeled as specified in the master manufacturing record. For
example, you could use a component that should not have been released
for use in manufacturing, or you could distribute a packaged and
labeled dietary supplement that should not have been released for
distribution.
We include in final subpart F a requirement that you establish and
follow written procedures for quality control operations (final Sec.
111.103). We agree with the comments that there should be written
procedures for investigating failures in manufacturing operations. In
the 2003 CGMP Proposal, we referred to the process of investigating
such failures as a ``material review'' and proposed a series of
requirements related to a material review and the disposition decision
that follows a material review. The review must be conducted in a
consistent manner, and the criteria for making a disposition decision
must be consistent, regardless of who is conducting the material review
or when it is conducted, and regardless of who makes the disposition
decision and when the decision is made. For example, if you do not have
written criteria for determining whether a deviation from
specifications has resulted in, or could lead to, adulteration,
different individuals who conduct a material review could reach
different decisions regarding the appropriate disposition of the
affected dietary supplement, including decisions that incorrectly
result in the release of an adulterated product. As discussed more
fully in sections X and XI of this document, the final rule requires
that quality control personnel conduct all required material reviews
and make all required disposition decisions. Therefore, we are
requiring that the written procedures for quality control operations
include written procedures for conducting a material review and making
a disposition decision (final Sec. 111.103).
We considered the comments that suggest that there should be a
requirement for you to establish and follow written procedures for
reprocessing from two perspectives: (1) Determining whether
reprocessing should be approved or rejected and (2) performing the
reprocessing. In general, reprocessing is performed when there is a
problem with the manufacturing process, such as when a specification is
not met or any step in the master manufacturing record is omitted.
Depending on the nature of the dietary supplement, the manufacturing
process, and the problem, reprocessing may or may not be able to
correct the problem. From the perspective of determining whether
reprocessing should be approved or rejected, under the final rule it is
quality control personnel who must approve or reject any reprocessing
(see final Sec. Sec. 111.90, 111.113, 111.120, 111.123, and 111.130).
The decision to approve reprocessing must be made in a consistent
manner, regardless of who conducts the operation or when it is
conducted. For example, if it is not possible to test the product at
the finished batch stage to determine whether the reprocessing
corrected the problem (because, for example, there is no scientifically
valid method available to test for a specification that is directly
related to the reason for reprocessing), you must have a clear basis to
decide that reprocessing will actually correct the problem or you will
not know if all required specifications can be met. Without written
procedures for approving reprocessing, different individuals who
approve or reject any reprocessing could make very different decisions
on when reprocessing can correct a problem and when it cannot.
Therefore, we are specifically requiring that the written procedures
for quality control operations include written procedures for approving
or rejecting any reprocessing.
From the perspective of performing the reprocessing, we agree that
any procedure for reprocessing must be written because, for example,
quality control personnel may need to rely on the procedure that you
followed to determine whether all specifications are met for the
reprocessed material. However, the final rule requires you to document
any reprocessing in the batch record (final Sec. 111.260(n)) rather
than establishing and following written procedures to conduct
reprocessing, because the actual procedure you follow to reprocess a
dietary supplement likely will be different depending on the
circumstances.
f. Written procedures for components, packaging, labels, and
product that is received for packaging and labeling as a dietary
supplement (final subpart G). We agree with the comments that the
[[Page 34772]]
receipt, examination, quarantine, and release from quarantine of
components, packaging, labels, and product that are received for
packaging and labeling as dietary supplements must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to carry out these operations in a consistent way
could lead to failure to ensure product quality if, for example, you
use a component that should not have been released for use in
manufacturing.
We include in final subpart G a requirement that you establish and
follow written procedures for fulfilling the requirements of subpart G
(final Sec. 111.153).
g. Written procedures for laboratory operations (final subpart J).
Testing and examination of components, packaging, labels, and product
that are received for packaging or labeling as a dietary supplement, or
packaged and labeled dietary supplements, must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. The reason a firm conducts these tests and examinations
is to ensure that a dietary supplement meets established
specifications. Failure to conduct tests and examinations in a
consistent manner could lead to failure in ensuring the quality of the
dietary supplement. For example, a test designed to determine the
concentration of a product before it is diluted to the appropriate
concentration could provide different results if it is conducted in a
different manner by different individuals.
In addition, laboratory operations such as use of criteria for
establishing appropriate specifications and use of sampling plans for
obtaining representative samples must be conducted in a consistent
manner, regardless of who conducts the operation or when it is
conducted. For example, failure to consider that specifications are
needed to ensure that a dietary supplement derived from a botanical
source does not contain contaminants, such as an unlawful pesticide,
could result in a dietary supplement that contains unsafe levels of a
contaminant.
We include in final subpart J a requirement that you establish and
follow written procedures for laboratory operations, including written
procedures for the tests and examinations that you conduct to determine
whether specifications are met (final Sec. 111.303).
h. Written procedures for manufacturing operations (final subpart
K). We agree with the comments that written procedures for
manufacturing operations would be an effective way to train personnel,
provide a means to hold operators accountable to a quality standard,
and improve quality and consistency in a manufacturing operation. The
final provisions for manufacturing operations require you to design or
select manufacturing processes to ensure that dietary supplement
specifications are consistently achieved, conduct all manufacturing
operations in accordance with adequate sanitation principles, and take
all necessary precautions to prevent contamination of components and
dietary supplements. These manufacturing operations must be conducted
in a consistent manner, regardless of who conducts the operation or
when it is conducted. Failure to perform these operations in a
consistent way could lead to failure to ensure the quality of the
dietary supplement. For example, surfaces that come in contact with a
dietary supplement are potential sources of microbial contamination if
consistent procedures are not in place to ensure good sanitary
practices. We are including in final subpart K a requirement that you
establish and follow written procedures for manufacturing operations
(final Sec. 111.353).
i. Written procedures for packaging and labeling operations (final
subpart L). We agree with the comments that written procedures for
packaging and labeling operations are an effective means to hold
operators accountable to ensure the quality of the dietary supplement
and that the dietary supplement is packaged and labeled as specified in
the master manufacturing record. The final provisions for packaging and
labeling operations require that you fill, assemble, package, label,
and perform other related operations in a way that ensures the quality
of the finished product, including practices such as cleaning and
sanitizing all filling and packaging equipment, utensils, and
containers; protecting manufactured dietary supplements against
airborne contamination, using sanitary handling procedures; taking
actions to prevent mixups; and suitably disposing of obsolete packaging
and labels. These packaging and labeling operations must be conducted
in a consistent manner, regardless of who conducts the operation or
when it is conducted. Failure to perform these operations in a
consistent way could lead to a failure to ensure the quality of the
dietary supplement and that the dietary supplement is labeled and
packaged as specified in the master manufacturing record. For example,
if you do not have procedures for identifying filled, but unlabeled,
containers of dietary supplements, mixups could occur before the labels
are applied. The final product could contain ingredients other than
those identified on the label specified in the master manufacturing
record. Therefore, we include in final subpart L a requirement that you
establish and follow written procedures for packaging and labeling
operations (final Sec. 111.403).
j. Written procedures for holding and distributing operations
(final subpart M). We agree with the comments that written procedures
for holding and distributing operations are an effective means to hold
operators accountable to CGMP standards, and that mixups and other
problems that affect the final product will be more likely to occur if
there are no written procedures for operations such as control of
storage locations, manner of storage, and container and storage
location identification codes. The final provisions for holding and
distributing operations require, among other things, that you hold
components and dietary supplements under appropriate conditions of
temperature, humidity, and light so that the identity, purity,
strength, and composition of the components and dietary supplements are
not affected; that you hold components, dietary supplements, and in-
process materials under conditions that do not lead to the mixup,
contamination, or deterioration of components or dietary supplements;
and that you distribute dietary supplements under conditions that will
protect them against contamination and deterioration.
These holding and distributing operations must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to follow these requirements for holding and
distributing in a consistent manner could lead to a failure to ensure
the quality of the dietary supplement product. For example, if
employees do not know how to store an in-process batch of a botanical
dietary supplement to control humidity, the growth of mold could be
promoted. Furthermore, if a distributor does not refrigerate a dietary
supplement that requires refrigeration to ensure its strength, the
dietary supplement may not meet its specification for strength.
Therefore, we include in final subpart M a requirement that you
establish and follow written procedures for holding
[[Page 34773]]
and distributing operations (final Sec. 111.453).
k. Written procedures for returned dietary supplements (final
subpart N). We agree with the comments that written procedures for
returned dietary supplements would help to ensure appropriate handling
of such supplements prior to a disposition decision. The final rule
requires you, among other things, to identify and quarantine returned
dietary supplements until quality control personnel conduct a material
review and make a disposition decision. You must destroy, or otherwise
suitably dispose of, any returned dietary supplement that quality
control personnel do not approve for salvage or reprocessing. These
operations for returned dietary supplements must be conducted in a
consistent manner, regardless of who conducts the operation or when it
is conducted. Failure to comply with these requirements for quarantine,
salvage, and disposition in a consistent way could lead to a failure to
ensure the quality of the dietary supplement. For example, if an
investigation leads to a conclusion that a dietary supplement requiring
refrigeration to ensure its strength was not refrigerated while held at
a customer's warehouse, and this dietary supplement was not quarantined
while quality control personnel conducted a material review, the
dietary supplement could be inadvertently co-mixed with other
containers of that same lot of product and then inadvertently
redistributed. Therefore, we are including in final subpart N a
requirement that you establish and follow written procedures to fulfill
the requirements of subpart N (final Sec. 111.503).
l. Written procedures for product complaints (final subpart O). We
agree with the comments that written procedures for handling consumer
complaints (now called product complaints) will encourage companies to
handle product complaints in a consistent manner and help ensure the
essential information is captured during investigation of a product
complaint. The final rule requires you, among other things, to review
all product complaints to determine whether the product complaint
involves a possible failure of a dietary supplement to meet any of its
specifications; investigate any product complaint that involves a
possible failure of a dietary supplement to meet any of its
specifications; and extend the review and investigation of the product
complaint to all relevant batches and records. These operations must be
conducted in a consistent manner, regardless of who conducts the
operation or when it is conducted. Failure to comply with these
requirements for review and investigation of a product complaint in a
consistent way could lead to a failure to ensure the quality of the
dietary supplement. For example, if you do not have a procedure in
place to determine whether the product complaint involves a possible
failure of a dietary supplement to meet any of its specifications, you
may not recognize that a particular product complaint is indicative
that a problem has occurred with one of your manufacturing processes.
That undiscovered problem may lead to continued distribution of product
that is contaminated or otherwise not consistent with your
specifications in the master manufacturing record. Therefore, we
include in final subpart O a requirement that you establish and follow
written procedures to fulfill the requirements of subpart O (final
Sec. 111.553).
3. Written Procedures That Are Not Required by This Final Rule
a. Written procedures for final subpart E (``Requirement to
Establish a Production and Process Control System''). In the CGMP
proposal, we did not specifically request comments on whether we should
require that you establish and follow written procedures to fulfill the
requirements of proposed Sec. 111.35 (``What Production and Process
Controls Must You Use?''), and we received no specific comments
regarding whether we should establish and follow such written
procedures. Given the strong support in the comments for the use of
written procedures in a production and process control system, we
nonetheless considered whether the requirements that we establish in
final subpart E, Requirement to Establish a Production and Process
Control System, would require written procedures.
Final subpart E requires that you implement a system of production
and process controls that covers all stages of manufacturing,
packaging, labeling, and holding of the dietary supplements and that
your system be designed to ensure the quality of the dietary supplement
and that the dietary supplement is packaged and labeled as specified in
your master manufacturing record (final Sec. Sec. 111.55 and 111.60);
implement quality control operations to ensure the quality of dietary
supplements and that the dietary supplement is packaged and labeled as
specified in your master manufacturing record (final Sec. 111.65);
establish specifications (final Sec. 111.70); determine whether
specifications are met (final Sec. Sec. 111.73 and 111.75); collect
representative samples (final Sec. 111.80); hold reserve samples of
packaged and labeled dietary supplements (final Sec. 111.83); have
quality control personnel conduct all required material reviews and
make all required disposition decisions (final Sec. 111.87); and
adhere to certain requirements for treatment, in-process adjustments,
and for reprocessing (final Sec. 111.90).
In considering whether we should require that you establish and
follow written procedures to fulfill the requirements of final subpart
E, we evaluated whether requirements in other subparts that address
specific operations for the production and process control system
substitute for the requirement of written procedures in final subpart
E.
Final subparts F through M establish specific requirements for
manufacturing, packaging, labeling, and holding dietary supplements,
including requirements for quality control operations (final subpart
F); components, packaging, labels, and product that is received for
packaging and labeling as a dietary supplement (final subpart G);
establishing a written master manufacturing record and batch record
(final subparts H and I); laboratory operations (final subpart J);
manufacturing operations (final subpart K); packaging and labeling
operations (final subpart L); and holding operations (final subpart M).
We require you to establish and follow written procedures to fulfill
the requirements of final subparts F, G, J, K, L, and M. Given these
requirements, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill the requirements of
final Sec. Sec. 111.55, 111.60, and 111.65 in subpart E.
Final subpart J requires you to establish and follow laboratory
control processes that include the use of criteria for establishing
appropriate specifications (final Sec. 111.315(a)); use of sampling
plans for obtaining representative samples (final Sec. 111.315(b));
use of criteria for selecting appropriate examination and testing
methods (final Sec. 111.315(c)); use of criteria for selecting
standard reference materials used in performing tests and examinations
(final Sec. 111.315(d)); and use of test methods and examinations in
accordance with established criteria (final Sec. 111.315(e)). In
addition, under final Sec. 111.303 you must establish and follow
written procedures for laboratory operations. Given the requirements of
final subpart J, we conclude it would be redundant to require you to
establish and follow written procedures to fulfill
[[Page 34774]]
the requirements of final Sec. Sec. 111.70, 111.75, and 111.80 in
subpart E.
Final subpart M establishes requirements for holding reserve
samples. Under final Sec. 111.453, you must establish and follow
written procedures for holding operations. Given the requirements of
final subpart M, we conclude that it would be redundant to require you
to establish and follow written procedures to fulfill the requirements
of final Sec. 111.83 in subpart E for reserve samples.
Final subpart F establishes requirements for quality control
personnel to conduct a material review and make a disposition decision
(final Sec. 111.113); approve any reprocessing (final Sec.
111.123(a)(5)); and document any material review and disposition (final
Sec. 111.140(b)(3)). In addition, as discussed, under final Sec.
111.103 you must establish and follow written procedures for quality
control operations. Given the requirements of final subpart F, we
conclude that it would be redundant to require that you establish and
follow written procedures to fulfill the requirements of final
Sec. Sec. 111.87 and 111.90 in subpart E.
We conclude that it would be redundant to require you to establish
and follow written procedures for each of the requirements established
in final subpart E. We, therefore, do not require you to establish and
follow written procedures to fulfill the requirements established in
subpart E.
b. Written procedures for preparing the master manufacturing record
(final subpart H) and for preparing the batch record (final subpart I).
As discussed in the 2003 CGMP Proposal (68 FR 12157 at 12203), a master
manufacturing record is analogous to a recipe that sets forth the
ingredients to use, the amounts of ingredients to use, the tests to
perform, and the instructions for preparing the quantity the recipe
calls for. This master manufacturing record helps ensure that you
manufacture each ingredient or dietary supplement in a consistent and
uniform manner. If you neglect to follow the master manufacturing
record, you might not add all of the necessary components in the
appropriate strength or amount, and this could result in a final
product not consistent with the master manufacturing record. Thus, you
must follow a written master manufacturing record in a consistent
manner, regardless of who conducts the operation or when it is
conducted.
However, we agree with the comments that the specific requirements
for what must be in the master manufacturing record make it unnecessary
to require written procedures for preparing the master manufacturing
record. Under final subpart H, the master manufacturing record must
include written instructions, including specifications for each point,
step, or stage in the manufacturing process where control is necessary
to ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record; procedures for sampling, testing, and
examinations; specific actions necessary to perform and verify points,
steps, or stages in the manufacturing process where control is
necessary to ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record; special notations and precautions to be followed;
and corrective action plans for use when a specification is not met.
With all of this detail specified for the written instructions the
master manufacturing record must include, we believe a written
procedure for developing a master manufacturing record can be optional.
Therefore, we do not require you to establish and follow written
procedures for preparing the master manufacturing record.
A batch is prepared by following the written instructions provided
in the master manufacturing record. The master manufacturing record
functions as a written procedure for the production of the batch.
Therefore, we do not require you to establish and follow written
procedures for the batch production record because such practices would
be redundant to the requirements for the master manufacturing record in
final subpart H.
c. Written procedures for records and recordkeeping (final subpart
P). Final subpart P establishes general requirements for making and
keeping records required in other subparts. We did not request comments
on written procedures, nor did we receive any comments that supported
such a requirement. Because we believe that requiring written
procedures to fulfill subpart P requirements would be redundant or
unnecessary, we do not require such written procedures.
d. Written procedures for product recalls. We acknowledge that a
product recall by persons who manufacture, package, label, or hold
dietary supplements must be conducted in a consistent manner,
regardless of who conducts the operation or when it is conducted.
However, the final rule does not establish any requirements for product
recalls. Therefore, we do not require you to establish and follow
written procedures for product recalls. However, we encourage you to
refer to our ``Guidance for Industry: Product Recalls, Industry
Removals and Corrections'' (Ref. 12) (available at http://www.fda.gov/opacom/7alerts.html).
D. Other Comments on Written Procedures
(Comment 9) One comment stresses the need for flexibility in
requiring written procedures, based on differences between individual
activities and companies. The comment suggests companies should be
required to review and determine the need for written procedures at
each critical step of their operations and be prepared to defend those
determinations as necessary.
(Response) To the extent the comment suggests we do not require any
written procedures specific to a particular function or requirement,
and allow firms to decide when and when not to include them, we
disagree. We believe that written procedures for the specific
operations we have identified should not be optional. We have no
objection if firms decide to establish and follow additional written
procedures, beyond those we require in this final rule. Although we
require written procedures for entire subparts, or specific
requirements within certain subparts, we provide flexibility for firms
to establish those written procedures that will ensure the requirements
are met.
(Comment 10) Some comments stress the importance of written
procedures in enabling FDA to ensure compliance with the dietary
supplement CGMP requirements.
(Response) We believe written procedures will help us to ensure
compliance with these CGMP requirements because they will clearly
communicate the steps the firm must take to satisfy the requirements.
During an inspection, we observe the practices that employees follow.
However, to ensure that a firm is consistently complying with CGMP
requirements, our investigators need access to records that both
describe a firm's processes and procedures and demonstrate whether the
firm has been following them. Under the final rule, we require you to
make and keep records of the written procedures in each applicable
subpart. Such records would be available to us under the requirements
of final subpart P, Records and Recordkeeping.
(Comment 11) Many comments object to FDA's stated reasons for not
requiring written procedures for most activities, including concerns
about cost control and burden reduction. The comments contend that
written procedures
[[Page 34775]]
actually save time and other resources because they greatly facilitate
employee training and ensure that activities are performed consistently
and correctly. Some comments assert most companies already have written
procedures in place, so start-up costs associated with such
requirements would be minimal. One comment notes written procedures
would be among the least costly of all the procedural requirements
proposed by FDA.
(Response) We agree that requiring that operations be conducted
using written procedures can save time and other resources by
facilitating employee training and ensuring operations are performed
consistently and correctly. Because following written procedures can
help ensure uniformity in the process and ensure the quality of the
dietary supplement at every step, periodic end product testing can be
sufficient to determine whether your manufacturing process is
controlled. CGMP is premised upon quality assurance at every step of
the process. It is less costly to establish and follow written
procedures than it would be to test each finished batch for conformance
with specifications. As suggested by these comments, our analysis
(section XXIV of this document) shows that the overall costs are
reduced, in part, because requiring that certain operations be
conducted using written procedures enables us to reduce requirements
for testing at the finished batch stage.
(Comment 12) One comment states training employees on the required
hygienic practices prior to their first day of handling product is
critical to ensuring product safety.
(Response) The requirement to establish and follow written
procedures to fulfill the requirements of subpart B does not establish
any fixed requirement for when an employee must receive such training
relative to when the employee handles product. However, final Sec.
111.12(c) requires that any person engaged in manufacturing, packaging,
labeling, or holding, or in performing any quality control operations,
must have the education, training, or experience to perform the
person's assigned functions. We therefore assume that employees will
have the necessary education, training, or experience for each
operation that they perform before they perform it.
(Comment 13) Some comments make recommendations for what written
procedures should contain, including general parameters that should be
included in all written procedures and specific parameters that should
be included in specific written procedures. The general parameters
include identification of the company; title that reflects the
activities to be performed; identification or control number with a
revision level code; effective date; the number of pages in the
procedure (e.g., by a procedure such as listing page numbers using a
convention such as ``page 1 of 4''); approval date and signature(s);
references to linked or related procedures or forms; definitions of
technical terms and acronyms; list of equipment, materials, and
supplies needed in performing the task; who has the responsibility for
performing each task; when and where a task is to be performed; concise
step-by-step instructions for performing the task; the expected results
from performing the task; what data to collect; and how to analyze,
file, or report the collected data. In the specific case of written
procedures for cleaning equipment and utensils, some comments suggest
the written procedures include descriptions of appropriate cleaning
agents, methods of cleaning, and the intervals and schedules for
cleaning equipment.
(Response) We agree the suggestions provided by these comments are
useful to include in any written procedures. However, to provide the
flexibility necessary to address diverse dietary supplement
manufacturing processes, we are leaving details such as these to the
judgment of the company rather than prescribing them within the final
rule.
(Comment 14) Some comments request the final rule include
requirements for managing changes to written procedures. One comment
states changes to written procedures should be reviewed, justified,
documented, approved, and implemented in a defined manner. The comments
explain that ``Change control procedures'' define what is and what is
not covered by the written procedure and how proposed changes will be
identified or recommended, processed, reviewed, and approved.
(Response) As discussed in final subpart F, the final rule requires
that quality control personnel approve all written procedures. ``All''
written procedures includes revisions to written procedures. As
discussed in this section, the final rule requires you to establish and
follow written procedures for quality control operations. We believe
that procedures for managing changes to written procedures can be
addressed within the written procedures for quality control operations.
(Comment 15) Some comments assert the final rule should not require
written procedures for key operations because the rule should stay
focused on end results and not process.
(Response) We disagree. The essence of good manufacturing practice
that is established by this final rule is a production and process
control system that is designed to ensure the quality of the dietary
supplement.
E. What Other General Comments Did We Receive?
(Comment 16) Some comments say any final rule should not require
written procedures, should not propose a definition of appropriate
tests, and generally should not include requirements for procedures
better left to ``normal business practices.'' The comments cited
Executive Order 12866 and the Small Business Regulatory Enforcement
Flexibility Act (SBREFA). The comment added that there is no such
requirement in the food CGMPs or in the 1997 ANPRM.
(Response) We disagree the final rule violates either Executive
Order 12866 or SBREFA and discuss this in section XXIV of this
document. We address SBREFA's regulatory flexibility issues by
staggering compliance dates so that certain businesses would have 24
and 36 months, respectively, to comply with the final rule. As for the
assertion that food CGMPs do not require written procedures, we discuss
the requirements of food CGMPS in relation to the requirements of these
dietary supplement CGMPs in section V of this document. The comment's
assertion that the 1997 ANPRM did not contain written procedures is
incorrect. The industry draft that we published in the 1997 ANPRM had
multiple written procedures, including written procedures for:
Cleaning and maintaining equipment and utensils used in
the manufacture of products;
The receipt, identification, examination, handling,
sampling, testing, and approval or rejection of raw materials;
Appropriate tests and/or examinations to be conducted to
assure the purity, composition, and quality of the finished product;
The method for reprocessing batches or operational start-
up materials that do not conform to finished goods standards or
specifications;
The control procedures employed for the receipt, storage,
handling, sampling, examination, and/or testing that may be necessary
to assure the identity of labeling and the appropriate identity,
cleanliness, and quality characteristics of packaging materials for
dietary products;
[[Page 34776]]
Ensuring correct labels, labeling, and packaging materials
are issued and used for dietary products; and
Describing the handling of all written and oral complaints
regarding a product.
(62 FR 5700 at 5704 through 5706).
(Comment 17) In the analysis of impacts in the 2003 CGMP Proposal
(68 FR 12157 at 12222), we stated that we had considered imposing fewer
CGMP requirements for the manufacture of vitamins and minerals.
Although this issue arose as a discussion of regulatory options that we
had considered and rejected, we received several comments on this
subject. Some comments state we should not create different CGMP
standards based upon the type of dietary ingredient. These comments
state that one set of appropriately flexible standards would be more
efficient and less confusing to industry than separate standards for
each portion of the industry. Some comments say that different
requirements for vitamins and minerals would cause problems because
most people who use these products take a multivitamin/mineral
preparation as their primary and sole dietary supplement, so the risk
of adverse events arising from adulteration, misidentification, or
misformulation of products would be much higher if vitamins and
minerals were subject to fewer requirements compared to other dietary
supplements. Other comments supported the concept of differing
standards. Some comments assert, in order for the CGMP regulations to
set minimum quality standards for all dietary supplements, we would
have to regulate each facet of the manufacture, packaging, and storage
of a dietary supplement independently of product type. These comments
state reducing the requirements for vitamin and mineral manufacturers
would not allow the development of minimum quality standards across the
entire dietary supplement industry.
(Response) The concept of fewer requirements for vitamins and
minerals was simply one regulatory option we considered as part of the
2003 CGMP Proposal's analysis of impacts (see 68 FR 12157 at 12220
through 12223). We rejected it (id.). We disagree with the comments
that there should be fewer CGMP requirements for vitamins and minerals.
Neither the 2003 CGMP Proposal, nor this final rule, imposes fewer
requirements on vitamin or mineral firms compared to firms that make
other types of dietary supplements.
V. What Legal Authority Comments Did We Receive?
Many comments were submitted from individuals, companies, and trade
groups concerning our legal authority for this rule. Most of the
comments question the scope of the rule based on the language in
section 402(g) of the act (21 U.S.C. 342(g)) stating that ``regulations
shall be modeled after current good manufacturing practice regulations
for food.'' Other comments question our authority for records access.
Some comments assert that certain provisions of the proposed rule are
unconstitutionally vague, and therefore violate the Fifth Amendment. A
few comments disagree with our rationale for why dietary supplements
are different than conventional food and need separate CGMP
requirements. We address these comments immediately below in this
section.
A. Modeled After CGMP for Food
(Comment 18) Some comments support our approach of proposing
requirements that are more comprehensive than the CGMP requirements for
food. One comment states that the current requirements for food CGMP
are less comprehensive than the CGMP requirements in current use by
both the food and dietary supplement industries and the current ``best
practices'' should be incorporated into the dietary supplement CGMP
rule. Several comments state that the requirements for dietary
supplement CGMP do not need to be identical to the requirements in
existing food CGMP regulations, that appropriate manufacturing controls
are needed for dietary ingredients contained in dietary supplements to
protect the public health, that some borrowing of drug CGMP concepts
may be necessary, and that we should balance effective control with
necessary flexibility in the dietary supplement CGMP rule. In addition,
one comment states that the USP manufacturing guidelines, which contain
wording from the drug CGMP requirements, are a model for dietary
supplement CGMP for many in industry.
Several comments express concern about not deviating too
drastically from the requirements in existing food CGMP regulations.
Although several comments recognize that additional CGMP provisions for
dietary supplements, such as those related to identity, purity,
strength, quality, and composition, are needed, the comments say that
we should not regulate dietary supplement manufacturing in the same
manner as drug manufacturing because it would entail overly burdensome
methods for production and process controls. Some comments contend that
some of the proposed rule requirements exceed the drug CGMP
requirements.
Most of the comments assert that the proposed dietary supplement
CGMP requirements are not modeled after the CGMP regulations for food.
The reasons for this assertion vary. Some assert that certain
provisions in the proposed rule were not found in, or differ from, the
provisions in part 110. Examples of proposed requirements that comments
indicate exceeded food CGMP included batch testing, packaging and
labeling, recordkeeping, consumer complaints, and the use of validated
methods. Other comments state that the proposed requirements exceeded
those for food because the proposed rule provided for finished testing
of certain substances when used as dietary supplements, such as garlic
and ginger, whereas no such testing is required under existing food
CGMP regulations when those same substances are used as conventional
food. One comment says the rule was modeled after juice hazard analysis
and critical control point (HACCP) and therefore goes beyond existing
food CGMP regulations.
Some comments assert that the proposed requirements exceed the
existing food CGMP regulations because certain proposed provisions
contained a level of detail that is not in the food or the drug CGMP
regulations, or because elements of a provision in the proposed rule
were similar to a provision in part 210 (21 CFR part 210) (drug CGMP
regulation). Other comments disagree with our rationale that the
proposed rule was designed on the same principles as the existing food
CGMP regulations to address the characteristics and hazards specific to
dietary supplements, or to prevent adulteration in preparing,
packaging, or holding dietary supplements. The comments also disagree
that we may include provisions in the dietary supplement CGMP final
rule that were not found in the food CGMP regulations at the time DSHEA
was enacted.
Several comments state that we exceed our legal authority for the
proposed rule because it used too broad a definition of ``modeled
after.'' Some comments offer their own definitions of ``model;'' others
object to the use of the noun form ``model'' and provide dictionary
definitions of the verb form ``modeled.'' A few comments assert that
the meaning of ``model'' is clear, despite different dictionary
meanings, and that the statute is not ambiguous under Chevron U.S.A.
Inc. v. Natural Resources Defense Council, 467 U.S.
[[Page 34777]]
837 (1984) (``Chevron''). One comment states that, even if the language
is ambiguous and our interpretation merits deference, our
interpretation is too expansive and not based on a permissible
construction of the statute. Another comment states that we did not
explain why our interpretation was consistent with our congressional
mandate.
(Response) We agree with the comments stating that the dietary
supplement CGMP requirements in this final rule need not be identical
to the existing food CGMP regulations and that a system of
manufacturing controls specific to dietary supplements is needed. We do
not agree that we exceeded the scope of our authority under section
402(g) of the act in issuing the proposed requirements for dietary
supplement CGMP or these final requirements. Our interpretation of the
language in section 402(g) of the act, including the ``modeled after''
language, as to what requirements of the act we have authority to
issue, is based on a permissible construction of the statute.
The comments present the following general questions: (1) Whether
the statute gives us authority to promulgate CGMP requirements for
dietary supplements that are not identical to the requirements in
existing CGMP regulations for food and (2) if so, whether the
requirements in this final rule that differ from those in existing CGMP
regulations for food are fairly encompassed within Congress' direction
that the dietary supplement regulations shall be ``modeled after'' food
regulations and, therefore, are based on a permissible construction of
the statute.
Under section 402(g)(1) of the act, a dietary supplement is deemed
to be adulterated if it has ``been prepared, packed, or held under
conditions that do not meet current good manufacturing practice
regulations, including regulations requiring, when necessary,
expiration date labeling, issued by the Secretary under subparagraph
(2).'' Section 402(g)(2) of the act authorizes the Secretary, by
regulation, to ``prescribe good manufacturing practices for dietary
supplements.'' Congress further provided that such regulations ``shall
be modeled after current good manufacturing practice regulations for
food'' and ``may not impose standards for which there is no current and
generally available analytical methodology.''
In construing the meaning of section 402(g) of the act, and, in
particular, the language in that section stating that such regulations
shall be ``modeled after current good manufacturing practice
regulations for food,'' we are confronted with two questions. First,
has Congress directly and unambiguously spoken to the precise question
at issue? (``Chevron step one'') (see Chevron, 467 U.S. at 842.) To
find no ambiguity, Congress must have clearly manifested its intention
with respect to the particular issue (see Young v. Community Nutrition
Institute, 476 U.S. 974, 980 (1986)). If Congress has spoken directly
and plainly, we must implement Congress's unambiguously expressed
intent (see Chevron, 467 U.S. at 842-843). Second, if the act is silent
or ambiguous with respect to a particular issue in section 402(g) of
the act, is our interpretation based on a permissible construction of
the statute (``Chevron step two'') (Chevron, 467 U.S. at 843; FDA v.
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000))? When
Congress leaves a gap for the agency to fill by regulation, the
regulation will pass muster so long as it is not ``arbitrary,
capricious, or manifestly contrary to the statute'' (Chevron, 467 U.S.
at 843-844).
We believe that the language in section 402(g) of the act provides
an express delegation of authority to us to promulgate a regulation to
``prescribe good manufacturing practices for dietary supplements'' so
long as those regulations are ``modeled after the current good
manufacturing practice regulations for food.'' The express language in
section 402(g) of the act contemplates broad, but not unlimited, agency
discretion as to what to include in a dietary supplement CGMP
regulation.
Congress has also spoken to the precise question of whether the
dietary supplement CGMP requirements must be identical to the
requirements in existing food CGMP regulations. If Congress had wanted
dietary supplement CGMP to be identical to food CGMP, it easily could
have required that by statute. Indeed, if Congress had intended for
CGMPs for dietary supplements to be the same as food CGMPs, there would
have been no need for Congress to have addressed the issue at all; as a
type of food, dietary supplements would otherwise be governed by the
food CGMPs. See section (ff) of the act (21 U.S.C. 321(ff)). Instead,
the statute calls for us to issue regulations that are ``modeled
after'' CGMP regulations for food. The plain meaning of a ``model'' or
``modeled after,'' as discussed in the 2003 CGMP Proposal (68 FR 12157
at 12165) and in the comments, relates to a pattern, plan,
representation, or simulation. The use of the term ``modeled after''
makes it clear that the regulations need not be identical to the
original, but instead are contemplated to differ from the original.
Thus, the additional, independent authority to promulgate CGMP
regulations for dietary supplements that Congress provided in section
402(g) of the act, without delineating what requirements such a
regulation could or could not include, left us with considerable
authority to fill in the gaps in ways that recognize the differences
between dietary supplements and other foods that warrant different
manufacturing controls. A contrary interpretation, as some comments
suggested, that the ``modeled after'' language means the requirements
for dietary supplement CGMP must be precisely found in current part
110, or other food CGMP regulations, would so narrowly circumscribe our
discretion as to make it impossible to tailor the regulation to fit the
products it is designed to address. Such an interpretation would lead
to a rule that would ``frustrate the success of the regulation
undertaken by Congress'' because it would not take into consideration
the characteristics, hazards, and manufacturing practices specific to
dietary supplements (American Trucking Ass'ns v. U.S., 344 U.S. 298,
311 (1953)).\4\
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\4\The Senate Report on DSHEA states that Congress inserted
section 402(g) because it recognized that ``dietary supplements may
require different manufacturing and quality controls'' when compared
to food CGMP (S. Rep. No. 140, 103rd Cong., 2d Sess., at 31 (1994)).
However, the report is not considered legislative history. Congress
issued a Statement of Agreement (140 Cong. Rec. S14801 (Oct. 7,
1994), reprinted in 1994 U.S.C.C.A.N. 3523) that stated ``it is the
intent of the chief sponsors of the bill * * * that no other reports
or statements be considered as legislative history for the bill'').
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Congress has also spoken to the precise question of which
requirements CGMP ``regulations for food.'' The plain meaning of
``regulations'' is plural (more than one), and the plain meaning of
``food'' is as Congress defined in section 201(f) of the act, including
articles ``used for food or drink.'' At the time DSHEA was enacted,
there were five food CGMP regulations: Those for infant formula (part
106), thermally processed low-acid canned food (part 113), acidified
food (part 114), bottled water (part 129), and general food (part 110,
often referred to as the ``umbrella'' regulations). All of these
regulations appear in Subchapter B of Chapter 1 of Title 21 of the Code
of Federal Regulations, entitled ``Food for Human Consumption.''
Nothing in the language of section 402(g) or elsewhere suggests that
Congress meant to limit the term CGMP ``regulations for food'' to only
the regulation in part 110. Thus, it is
[[Page 34778]]
consistent with our statutory authority for us to look to all of our
food CGMP regulations--including infant formula, low-acid canned foods,
acidified foods, and bottled water, as well as our general food CGMP
regulations--after which to model our dietary supplement CGMP
regulations.
Congress has not spoken to the precise question of what specific
requirements for dietary supplements may be imposed under the ``shall
be modeled after'' language. Given this ambiguity, therefore, under
Chevron step two, we may determine what requirements to include in this
final rule for dietary supplement CGMP, provided that our
interpretation is not arbitrary, capricious, or manifestly contrary to
the statute (Chevron, 467 U.S. at 844).
Accordingly, we considered the types of requirements in the
existing food CGMP regulations and used those as models for the dietary
supplement CGMP requirements. We considered both the objectives and the
means of achieving the objectives in the existing food CGMP
regulations. These CGMP food regulations include those for infant
formula (part 106), general food (``umbrella'' regulations) (part 110),
thermally processed low-acid canned food (part 113), acidified food
(part 114), and bottled water (part 129). Each of these food CGMP
regulations provides objectives and means upon which we modeled the
dietary supplement CGMP regulations. Just as the precise requirements
of the other food CGMP regulations are tailored to the particular
characteristics and hazards of the foods and manufacturing processes
being addressed, the dietary supplement CGMP requirements are also so
tailored.
For example, the infant formula CGMP regulation is intended to
ensure that the ``safety and nutritional potency'' of a formula are
``built into the manufacturing process'' in order to establish a
quality control system to make sure that infant formula products are
properly manufactured (47 FR 17016 at 17017, April 20, 1982). The
specific criteria in the regulations apply in determining whether the
infant formula meets the safety, quality, and nutrient requirements of
the act (Sec. 106.1(a)). The means to achieving the objectives in the
infant formula regulations include, for example, requirements for
ingredient control (through a supplier's guarantee or certification or
through analysis of the ingredient) (Sec. 106.20); preparation of a
master manufacturing order and a system to assure and verify the
addition of each ingredient (Sec. 106.25); either in-process batch
testing (Sec. 106.25(b)) or sampling and testing of each batch to
ensure nutrient requirements are met (Sec. 106.30); and coding to
enable ready identification of lots during their sale and distribution
(Sec. 106.90).
The infant formula CGMP regulation also includes numerous
requirements that manufacturers maintain records, e.g., records on
certain food-packaging materials; records on nutrient premix testing;
certificate and guarantees from premix suppliers for required
nutrients; records of results of testing conducted by suppliers;
records of tests to establish the purity of each nutrient, the weight,
and amounts of nutrients; records to ensure proper nutrient quality
control; records to ensure required nutrient control at the final
product stage; distribution records; records on microbiological quality
and purity of raw materials; and records of audits (Sec. 106.100). The
infant formula CGMP regulation also requires manufacturers to maintain
procedures describing how complaints will be handled, to follow those
procedures, and to investigate when a complaint shows a possible health
hazard (Sec. 106.100(k)). Quality control records must contain enough
information to permit a public health evaluation of any batch of infant
formula (Sec. 106.100(o)). All required records must be available for
authorized inspection (Sec. 106.100(l)).
Many provisions of the dietary supplement CGMP final rule are
similar in objective and means and are ``modeled after'' the provisions
of the infant formula CGMP regulation. For example, like the infant
formula regulation, the dietary supplement CGMP regulation is designed
to establish a quality control system to make sure that dietary
supplements are properly manufactured. The dietary supplement
regulation uses similar means to ensure this goal, such as requirements
for ingredient control (through supplier's certificate of analysis or
testing or examination) (final Sec. 111.75(a)); preparation of a
master manufacturing record (final Sec. 111.205); in-process batch
monitoring (final Sec. 111.75(b)) or batch testing or examination
(final Sec. 111.75(c)); and coding to provide a batch, lot, or control
number (final Sec. 111.260(a)). Like the infant formula CGMP
regulations, the dietary supplement CGMP final rule contains
recordkeeping requirements related to packaging materials; certificates
of analysis from suppliers; results of tests that you conduct, for
example, on ingredients or the finished batch; and results of chemical,
microbiological, or other tests that you conduct as necessary to
prevent the use of contaminated components (final Sec. Sec. 111.95,
111.180(b)(2), 111.260(h), 111.325(b)(2), and 111.365(d)). Also similar
to the infant formula CGMP regulation, the dietary supplement CGMP
final rule requires manufacturers to maintain procedures for handling
complaints (final Sec. Sec. 111.553 and 111.570(b)(1)); to investigate
certain complaints (final Sec. 111.560(a)(2)); and to keep records of
complaints (final Sec. 111.570(b)(2)). Required dietary supplement
records must also, as with infant formula records, be available for
inspection by FDA (final Sec. 111.610(a)).
The ``umbrella'' food CGMP regulation in part 110 details practices
to ensure ``(1) that food is manufactured, processed, packed, and held
under conditions that are sanitary, and (2) that such food is safe,
clean, and wholesome'' (44 FR 33238 at 33239, June 8, 1979).
Promulgated primarily under the adulteration provisions of section
402(a)(3) and (a)(4) of the act, as well as section 361 of the Public
Health Service Act (the PHS Act) (42 U.S.C. 264), the umbrella CGMP
food regulation requires a quality control operation whose main purpose
is ``to provide a systematic procedure for taking all actions necessary
to prevent food from being adulterated within the meaning of the act''
(51 FR 22458 at 22461, June 19, 1986), as well as to prevent the spread
of food-borne communicable diseases (44 FR 33239, June 8, 1979) (see
Sec. 110.5(a)). Part 110 also ``specifies requirements that must be
met to produce safe and wholesome food'' (51 FR 22461). These umbrella
food CGMP requirements not only pertain to food safety, but also are
``concerned with contamination by filth or decomposition which may or
may not raise safety concerns'' (51 FR 22458 at 22462).
The detailed requirements of the umbrella food CGMP regulation
accomplish these objectives through a variety of means. For example,
there are specific personnel provisions requiring employees who may be
sources of microbial contamination to be excluded from certain
operations (Sec. 110.10(a)); persons working in contact with food,
food-contact surfaces, and food-packaging materials to follow hygienic
practices (Sec. 110.10(b)); and that certain personnel have sufficient
education or experience to produce clean and safe food (Sec.
110.10(c)). The umbrella food CGMP regulation also includes detailed
requirements concerning the grounds surrounding a food plant and the
design of buildings and structures to protect against contamination or
to maintain sanitary operations and produce safe food (Sec. 110.20).
Detailed provisions also require that physical facilities be
[[Page 34779]]
maintained in sanitary condition and in sufficient repair to prevent
food from being adulterated (Sec. 110.35). Any water that contacts
food or food-contact surfaces must be ``safe and of adequate sanitary
quality'' (Sec. 110.37(a)); plumbing, sewage, and other disposal, as
well as toilet facilities, must also protect against contamination
(Sec. 110.37(b), (c), and (d)). Similarly, equipment and utensils must
be designed and maintained to preclude adulteration and food contact
surfaces must be maintained to protect food from being contaminated by
any source, including unlawful indirect food additives (Sec.
110.40(a)). All operations for receiving, inspecting, transporting,
segregating, preparing, manufacturing, packaging, and storing food must
be conducted using adequate sanitation principles (Sec. 110.80).
Appropriate quality control operations must be used to ensure that food
is suitable for human consumption and that food-packaging materials are
safe and suitable (Sec. 110.80). Foods must be stored and transported
under conditions to protect against physical, chemical, and microbial
contamination, as well as against deterioration of the food and the
container (Sec. 110.93).
The provisions of the umbrella food CGMP regulation serve as the
model for many dietary supplement CGMP provisions. For example, the
dietary supplement CGMP requirements concerning personnel and microbial
contamination (final Sec. 111.10(a)); hygienic practices (final Sec.
111.10(b)); and education, training, or experience (final Sec. 111.12)
are very similar to provisions in part 110. In addition, the dietary
supplement CGMP requirements concerning the grounds, physical plant
facilities, cleaning materials, pest control, water supply, plumbing,
sewage disposal, bathrooms, and trash disposal (final Sec. Sec. 111.15
and 111.20) closely resemble the analogous part 110 requirements.
Because of the particular hazards associated with low-acid canned
foods and with acidified foods, the CGMP regulations for these foods
contain detailed provisions to ensure safe manufacturing. Specifically,
the CGMP regulations for these foods protect the public health against
microbial contamination from these foods. Part 113 sets out safe
manufacturing, processing, and packaging procedures for low-acid foods
in hermetically sealed containers. The CGMP criteria in this part apply
in determining whether the facilities, methods, practices, and controls
used by commercial processors of such foods are operated ``in a manner
adequate to protect the public health'' (Sec. 113.5). Processors of
low-acid canned foods must have a ``scheduled process'' that is
established by a qualified person and is ``adequate under the
conditions of manufacture for a given product to achieve commercial
sterility'' (Sec. Sec. 113.3 and 113.83). ``Commercial sterility'' of
thermally processed food means a condition achieved by applying heat to
render the food free of certain microorganisms (Sec. 113.3). Part 113
requires that supervisors satisfactorily complete training at a school
approved by FDA (Sec. 113.10).
Part 113 also contains extremely detailed requirements on equipment
and procedures. For example, each vessel used for pressure processing
in steam must be equipped with a mercury thermometer that is tested for
accuracy at least once a year, or more frequently if necessary, to
ensure its accuracy (Sec. 113.40(a)(1)). Critical factors (variation
of which may affect the attainment of commercial sterility) must be
specified in the scheduled process and must be measured and recorded on
processing records frequently enough to ensure that the factors are
within the specified limits (at least every 15 minutes) (Sec. Sec.
113.40(a)(13) and 113.83). Observations and measurements of certain
operating conditions must be made and recorded at intervals of
sufficient frequency to ensure that commercial sterility of the food
product is being achieved (at least every hour) (Sec.
113.40(g)(2)(ii)(c)). There must also be a system to stop packaging
operations (or to segregate products) when the packaging conditions
fall below scheduled processes (Sec. 113.40(g)(2)(ii)(b)). Regular
observations of container closures are required to be made and recorded
(Sec. 113.60). Each container must be coded ``to enable ready
identification of lots during their sale and distribution'' (Sec.
113.60(c)).
Before using raw materials and ingredients susceptible to
microbiological contamination, the low-acid food processor must ensure
that they are ``suitable for use in processing low-acid food'' (Sec.
113.81(a)). Complete records covering all aspects of the establishment
of the scheduled process and of certain confirmation tests must be
maintained permanently (Sec. 113.83). Scheduled processes must be
readily available to any duly authorized FDA employee (Sec.
113.87(a)). Whenever any process is less than the scheduled process or
when critical factors are not in control, the low-acid food must be
reprocessed or set aside for further evaluation as to public health
significance (Sec. 113.89). Unless the evaluation demonstrates that
the product is free of microorganisms of potential public health
significance, the product either must be reprocessed to render it
commercially sterile or destroyed (Sec. 113.89).
All process deviations involving a failure to satisfy the minimum
requirements of the scheduled process must be recorded and kept in a
separate file detailing the deviations and actions taken (Sec.
113.89). Detailed information on processing and production must be
entered on forms (Sec. 113.100(a)). Not later than 1 working day after
the actual process, and before the food is shipped or released for
distribution, a qualified representative of management must review all
processing and production records for completeness and to ensure that
the product was subjected to the scheduled process (Sec. 113.100(b)).
Records to identify the initial distribution of the finished product
must be kept to facilitate segregation of lots that may have become
contaminated or otherwise rendered unfit for their intended use (Sec.
113.100(d)). Records must be maintained at the processing plant for at
least 1 year after the date of manufacturing and at a reasonably
accessible location for another 2 years (Sec. 113.100(e)).
Similarly, the CGMP regulation for acidified food in part 114
requires supervision by personnel trained at an FDA-approved school
(Sec. 114.10); manufacturing in accordance with a scheduled process
established by a qualified person (Sec. Sec. 114.80 and 114.83);
processing sufficient to destroy the vegetative cells of certain
microorganisms (Sec. 114.80(a)(1)); sufficient control, including
frequent testing and recording of results, to ensure that the finished
hydrogen-ion concentration (pH) values are not higher than 4.6 (Sec.
114.80(a)(2)); testing and examinations of containers to ensure that
the food is suitably protected from leakage or contamination (Sec.
114.80(a)(4)); and coding to enable ready identification of lots during
their sale and distribution (Sec. 114.80(b)).
Whenever any acidified food process operation deviates from the
scheduled process or the pH of the finished product exceeds 4.6, the
processor must reprocess it, process it under part 113 requirements, or
set it aside for evaluation as to any potential public health
significance (Sec. 114.89). Unless the evaluation demonstrates that
the food has undergone a process that has rendered it safe, the food
must be fully reprocessed to render it safe or be destroyed (Sec.
114.89).
A record must be made of the procedures used in the public health
[[Page 34780]]
evaluation and the results of the evaluation (Sec. 114.89). Records
must be kept of examinations of raw materials, packaging materials, and
finished products, and of suppliers' guarantees or certifications that
verify compliance with our regulations (Sec. 114.100(a)). Processing
and production records showing adherence to scheduled processes must be
maintained and must have sufficient additional information such as
product code, date, container size, and product, to permit a public
health hazard evaluation of the processes applied to each lot, batch,
or other portion (Sec. 114.100(b)). Departures from scheduled
processes having a possible bearing on public health or the safety of
the food must be recorded and kept in a separate file or log, along
with the action taken to rectify the departure and the product
disposition (Sec. 114.100(c)). Records must be kept identifying
initial distribution of the finished product to facilitate segregation
of lots that may have become contaminated or otherwise unfit for their
intended use. Copies of certain required records must be kept at a
reasonably accessible location for 3 years from the date of manufacture
(Sec. 114.100). The criteria in the part 114 regulation, as well as
those in part 110, apply in determining whether an article of acidified
food is adulterated under section 402(a)(3) of the act in that it has
been manufactured under such conditions that it is unfit for food or
under section 402(a)(4) of the act in that it has been prepared,
packed, or held under insanitary conditions whereby it may have become
contaminated with filth, or whereby it may have been rendered injurious
to health (Sec. 114.5).
Many provisions of parts 113 and 114 also serve as models for
provisions in the dietary supplement final rule. In many instances, the
analogous provision in the dietary supplement final rule allows more
flexibility in the means to achieve the goal. For example, under final
Sec. 111.13 qualified personnel must be assigned to supervise the
manufacturing, packaging, labeling, or holding of dietary supplements.
Although the supervisor must be qualified by education, training, or
experience to supervise, the more restrictive requirement of parts 113
and 114 to attend an FDA-approved school is not included. The
``scheduled process'' for low-acid and acidified food manufacturing,
processing, and packing is analogous to the required ``system of
production and process controls'' that dietary supplement manufacturers
must design and implement (final Sec. Sec. 111.55 and 111.60(a)).
Similarly, the ``critical factors'' required to be specified in the
scheduled process for low-acid and acidified foods are akin to the
``specifications'' that dietary supplement manufacturers must establish
for certain points in the manufacturing process (final Sec. 111.70).
Just as low-acid food processors must establish procedures to ensure
that ingredients are suitable for use, so too must dietary supplement
manufacturers establish component and finished product specifications
(final Sec. 111.70(b) and (e)). Just as containers for acidified food
must ensure suitable protection from contamination, packaging that
comes into contact with dietary supplements must be safe and suitable
for use (final Sec. 111.70(d)). Dietary supplement in-process points,
like the ``critical factors'' for low-acid and acidified food, must be
monitored to detect any deviation or unanticipated occurrence that may
result in adulteration (final Sec. 111.75(b)(2)).
Rejected dietary supplements must also be held under quarantine
(final Sec. Sec. 111.370 and 111.425); dietary supplements which have
been reprocessed, treated, or which have had in-process adjustments
must meet all established product specifications and be approved before
release (final Sec. 111.90(c)). Similar to coding low-acid or
acidified foods, dietary supplements must have assigned batch, lot, or
control numbers (final Sec. 111.415(f)). The design, calibrations, and
cleaning of equipment and utensils must also result in the equipment
and utensils being suitable for their intended uses and not result in
contamination of components or dietary supplements (final Sec.
111.27). Written procedures for the various controls are required (see,
e.g., final Sec. Sec. 111.8, 111.25, and 111.103), and required
written records (see, e.g., final Sec. Sec. 111.14, 111.23, 111.35,
and 111.95) must be kept for 1 year past the shelf life date, if shelf
life dating is used, or 2 years after the date of distribution of the
last associated batch of dietary supplement (final Sec. 111.605). All
required dietary supplement CGMP records must be readily available for
inspection and copying by FDA (final Sec. 111.610(a)).
Finally, the bottled water CGMP regulation was promulgated to
ensure the safety and sanitary quality of these products, which include
all water processed and bottled for human consumption (38 FR 32563,
November 26, 1973). The criteria in part 129, as well as in part 110,
apply in determining whether the facilities, methods, practices, and
controls used to process, bottle, hold, and ship bottled drinking water
conform with good manufacturing practice ``to assure that bottled
drinking water is safe and that it has been processed, bottled, held,
and transported under sanitary conditions'' (Sec. 129.1). Part 129
requires plant construction and design features, such as a separate
bottling room and an enclosed room for washing and sanitizing
containers, to protect against contamination (Sec. 129.20). All plant
equipment and utensils must be suitable for their intended use (Sec.
129.40(a)).
Both the product water supply and the operations water supply must
be of a ``safe, sanitary quality'' in conformance with ``the applicable
laws and regulations of the government agency or agencies having
jurisdiction'' (Sec. 129.35(a)). Samples of source water must be
analyzed at least once a year for chemical contaminants and once every
4 years for radiological contaminants (Sec. 129.35(a)(3)). Source
water from other than a public water system must be sampled and
analyzed for microbiological contaminants at least once a week (id.).
The product water-contact surfaces of all containers and equipment must
be clean and adequately sanitized and protected from contamination
(Sec. 129.37(a) and (b)). Filling, capping, closing, sealing, and
packaging of containers must be done so as to preclude contamination of
the water (Sec. 129.37(d)). All product water contact surfaces must be
nontoxic and in compliance with section 409 of the act (21 U.S.C. 348)
(concerning food additives) (Sec. 129.40(a)(2)).
Numerous production processes and controls for bottled water are
also required. For example, all treatment of product water must be
effective in accomplishing its intended purpose and in accordance with
section 409 of the act (Sec. 129.80(a)). The treatment processes must
be performed with equipment and substances that will not adulterate the
product (Sec. 129.80). Product water samples must be taken before
bottling and analyzed as often as necessary to assure uniformity and
effectiveness of the processes performed by the plant (Sec.
129.80(a)). Cleaning and sanitizing solutions must be sampled and
tested to assure adequate performance (Sec. 129.80(c)).
Each unit package from a batch or segment of continuous production
run must be identified by a production code (Sec. 129.80(e)). The
plant must maintain information on the kind of product, volume, date,
lot code, and distribution of finished product to wholesale and retail
outlets (id.). During the process of filling, capping, or sealing the
containers, performance must be monitored and the filled containers
inspected to assure that they are sound, properly capped or sealed, and
coded
[[Page 34781]]
and labeled (Sec. 129.80(f)). All containers and closures must be
sampled and inspected to ascertain that they are free from
contamination (id.).
To assure that the plant's production of bottled water complies
with applicable standards, laws, and regulations, the plant must
analyze product samples at specified intervals (Sec. 129.80(g)). The
methods used to analyze the samples must be approved by the government
agency with jurisdiction (Sec. 129.80(g)(3)). Records of the date of
sampling, type of product sampled, production code, and results of
analysis must be maintained (Sec. 129.80(g)(3)). All required records
must be maintained at the plant for at least 2 years (Sec. 129.80(h))
and be available for official review by FDA at reasonable times (id.).
Provisions of the bottled water CGMP regulation also serve as a
model for provisions of the dietary supplement CGMP regulation. For
example, water that is used in a manner such that the water may become
a component of a dietary supplement must at a minimum comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplements (final Sec. Sec. 111.15(e)(2) and 111.365(c)).
Precautions that must be taken to prevent contamination of components
or dietary supplements include performing chemical, microbiological, or
other testing (final Sec. 111.365(d)). Filling, assembling, packaging,
labeling, and related operations must be performed to protect the
dietary supplement against adulteration (final Sec. 111.415).
Equipment and utensils must be suitable for their intended use (final
Sec. 111.27(a)). Safe and adequate cleaning compounds and sanitizing
agents must be used (final Sec. 111.15(c)(1)). Representative samples
of each batch must be examined to ensure that the product meets
established specifications (final Sec. 111.415(g)). Each lot of
packaged and labeled dietary supplement must be assigned a batch, lot,
or control number (final Sec. 111.415(f)).
Moreover, our interpretation of permissible requirements for the
dietary supplement CGMP regulation is also consistent with the use of
the terms ``good manufacturing practice'' and ``current good
manufacturing practice'' in section 402(g) of the act. Although these
terms are not defined in the act, GMP is generally used to refer to
methods used in, and the facilities and controls used for, product
manufacturing and related activities.\5\ The umbrella food CGMP
regulation, for example, defines the ``plant'' covered by the
requirements of that regulation as the facility used for, or in
connection with, ``the manufacturing, packaging, labeling, or holding
of human food'' (Sec. 110.3(k)). As we have described in detail, the
objectives of the existing food CGMP regulations and the precise means
(or requirements) used to achieve the objectives vary depending on the
particular hazards and characteristics of the products and their
manufacturing. For example, the umbrella food CGMP regulation is
specifically designed to ensure that food is manufactured, processed,
packed, and held under sanitary conditions and that the food is safe,
clean, and wholesome. Low-acid and acidified food CGMP requirements
focus on facilities, methods, practices, and controls to protect the
public health against the particular risks of microbial contamination
from these foods. The infant formula CGMP regulation is aimed at
ensuring both the safety and nutritional potency of these special
foods. Infant formula is often the sole item in the diet. An infant
formula that does not meet the requirements for nutritional potency may
cause a hazard to the health of the infant (see 61 FR 36154, July 9,
1996). The bottled water CGMP regulation embodies requirements for
facilities, methods, practices, and controls used in processing,
bottling, holding, and shipping of bottled water to ensure its safety
and sanitary quality.
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\5\Although the act does not define ``current good manufacturing
practice,'' the term is used elsewhere in the statute (see, e.g.,
sections 501(a)(2)(B) (drug CGMP) and 520(f)(1)(A) of the act
(device CGMP) (21 U.S.C. 351(a)(2)(B) and 21 U.S.C. 360j(f)(1)(A),
respectively). Case law supports the agency's view that ``current''
does not mean ``actually prevailing manufacturing practice'' in an
industry and that such a practice need not be accepted by a majority
of manufacturers (National Ass'n of Pharmaceutical Mfr's v.
Department of Health and Human Services, 586 F. Supp. 740, 752
(S.D.N.Y. 1984)). Nevertheless, the requirements of this final rule
embody current practices of many food and dietary supplement
manufacturers, as reflected in the comments supporting the
provisions of the proposed rule.
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Like the food CGMP regulations after which they are modeled, the
dietary supplement CGMP final rule contains criteria for facilities,
methods, practices, and controls used in manufacturing, packaging,
labeling, or holding dietary supplements to ensure the quality of the
dietary supplement. Quality includes consistently meeting the
established specifications for identity, purity, strength, and
composition of the dietary supplement and limits on contaminants, in
addition to manufacturing the dietary supplement under conditions to
prevent adulteration. As Congress recognized in DSHEA, identity,
purity, strength, and composition are essential characteristics for
dietary supplements (see, e.g., section 403(s)(2) of the act (a dietary
supplement is misbranded if its labeling fails to list the name and
quantity of each dietary ingredient and if it fails to have the
identity and strength or the quality, purity, or compositional
specifications it is represented to meet)). Yet without information
about the identity, purity, strength, or composition, the manufacturer
could not know the final contents of the dietary supplements it
manufactures or whether its processes are reliably and consistently
producing the correct combination and amounts of ingredients in a
dietary supplement. Accordingly, the final rule requires a manufacturer
to establish specifications for the identity, purity, strength, and
composition and for limits on contaminants of the dietary supplements
it manufactures and ensure that such specifications are consistently
met in the finished batch of dietary supplement (Sec. 111.75(e)).
Dietary supplements, like infant formula, are relied upon by consumers
not only to be safe, but also in many instances to provide specific and
important claimed health benefits (see, e.g., section 403(r) of the
act). In the preamble to the 2003 CGMP Proposal, we discussed a number
of examples illustrating adulteration and improper formulation of
dietary supplements caused by manufacturing, packaging, or holding
practices (68 FR 12157 at 12162 and 12163). These dietary supplement
CGMP requirements will help to protect consumers against similar types
of adulteration and against reliance on products that are not properly
formulated.
Generally recognized principles underlying CGMP also support our
interpretation of section 402(g) of the act. Our interpretation of
permissible CGMP regulations is reasonable based on recognized
principles for controlling the quality of manufactured products in
general (Ref. 9). As many comments asserted, if the dietary supplement
CGMP requirements are to be meaningful, they must ensure quality in the
finished product (see, for example, the discussion in section X of this
document of comments regarding the production and process control
system). Controls to ensure quality include planning processes to
determine desired product features or characteristics, a system of
controls to ensure that the desired product will be consistently
produced, and making necessary improvements to the process (section 2.6
of Ref. 9). Manufacturers must plan what they intend to produce,
institute adequate controls to achieve the desired outcome, and ensure
that the controls
[[Page 34782]]
work so that the desired outcome is consistently achieved. If the
outcome is not consistently achieved, corrective actions need to be
implemented in order to reach the desired outcome.
This final rule, like the other food CGMP regulations, embodies the
basic concepts of controlling quality, i.e., planning, control, and
improvement. As discussed earlier in the ``Overview of CGMP'' (section
III.A of this document), we have defined the term ``quality'' for this
dietary supplement CGMP regulation to mean ``that the dietary
supplement consistently meets the established specifications for
identity, purity, strength, and composition and has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the Federal
Food, Drug, and Cosmetic Act.'' Identifying the desired characteristics
of identity, purity, strength, and composition of a dietary supplement,
as required in this final rule, is an essential part of the planning
process to manufacture a dietary supplement. Without identifying
specifications for each of these characteristics of a dietary
supplement, it is not possible to control for, and repeatedly and
reliably produce, the desired end product. Similarly, requirements for
batch testing ensure that there is consistency from batch to batch.
Packaging and labeling requirements ensure that suitable packaging is
used and that the label identified in the master manufacturing record
for the product is placed on the finished product. In addition,
requirements related to consumer complaints help to ensure that
manufacturers are made aware of problems related to their manufacturing
processes, including those that may result in illness or injury, so
that they can take corrective actions to prevent any future problems
from occurring. The procedures for production and process control in
this final rule also include as key elements measures to prevent
contamination that could adulterate the product. Requirements to
protect against contamination during the manufacturing, packaging,
labeling, and holding operations help ensure that this aspect of
``quality'' is also achieved for dietary supplements. In sum, this
final rule embodies principles for controlling quality through
requirements designed to ensure both that the dietary supplement meets
its established specifications for identity, purity, strength, and
composition and that it is not adulterated.
The dietary supplement CGMP requirements are also reasonable
because they take into consideration the different product forms in
which these products will be manufactured. Unlike conventional foods,
such as fruit, vegetables, cereals, and dairy products, dietary
supplements will be sold in tablet, capsule, powder, or softgel form.
They may also be sold as a concentrate, metabolite, constituent, or
extract of a vitamin, mineral, herb, botanical, or dietary substance.
Because dietary supplements are often sold in different forms than
conventional foods, different processes and controls are needed to
manufacture dietary supplements than to manufacture conventional foods.
For example, equipment must be able to manufacture dietary supplements
in tablet or softgel form. Therefore, the final rule requires that
controls be established to ensure that the equipment functions in
accordance with its intended use (final Sec. 111.30(e)) and will
consistently manufacture a product in whatever form is desired.
Consistent with basic CGMP principles, ensuring the quality of the
dietary supplement product requires that the manufacturer establish
precisely what it will produce (specifications for its product), how it
will make the product (processes), and which process controls and tests
it will use to ensure reliable, reproducible results. These CGMP
requirements will help to achieve these results.
The dietary supplement CGMP requirements are also reasonable when
viewed in the context of the act as a whole. See Brown & Williamson,
529 U.S. at 133. Our mission is, in part, to protect the public health
by ensuring that foods are safe, wholesome, sanitary, and properly
labeled (section 903(b)(2)(A) of the act) (21 U.S.C. 393(b)(2)(A))).
Section 701(a) of the act (21 U.S.C 371(a)) gives us the authority to
promulgate regulations for the efficient enforcement of the act in
order to ``effectuate a congressional objective expressed elsewhere in
the Act'' (Association of American, Physicians and Surgeons, Inc. v.
FDA, 226 F. Supp. 2d 204 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v.
FDA, 484 F. Supp. 1179, 1183 (D. Del. 1980)). The final rule is
designed to help ensure that dietary supplements consistently are
manufactured to produce the product established by the manufacturer, to
bear the label identified in the master manufacturing record, and to
prevent adulteration. The requirements are written to facilitate
efficient and effective action to enforce their terms when necessary.
Some provisions of the dietary supplement CGMP final rule may be
similar to the existing drug CGMP regulations. However, we have not
modeled these regulations after the drug CGMP regulations. Controls
that relate to certain product forms (e.g., tablets, capsules, powder,
softgel) are required in this final rule based on the specific
characteristics of dietary supplements and the hazards associated with
these forms, not, as some comments imply, based on a desire to emulate
drug CGMP requirements. The act does not state that there may not be
similarities between the dietary supplement CGMP requirements and the
CGMP requirements for drugs or other non-food products. Inasmuch as
food CGMP regulations and other CGMP regulations are all based on CGMP
principles, it is neither surprising nor impermissible that there are
similarities between the dietary supplement CGMP requirements and drug
or device CGMP requirements. Although we do not agree that any of the
CGMP requirements exceed drug GCMP requirements, even if a particular
requirement did, it is not prohibited under the statute. As long as the
CGMP final rule is ``modeled after'' the food CGMP regulations, we have
satisfied the statutory requirements. As noted, our interpretation of
``modeled after'' means that the dietary supplement CGMP final rule
provisions share similar objectives and/or use similar means as the
existing food CGMP regulations. To the extent that there are
similarities to drug CGMP regulations, those similarities are
appropriate and not prohibited by section 402(g) of the act.
Consistent with our role ``to fill in, through interpretation,
matters of detail related to [the statute's] administration,'' Barnhart
v. Walton, 535 U.S. 212, 225 (2002), we applied our scientific
expertise, policy judgment, and experience to promulgate dietary
supplement CGMP requirements that will protect the public health and
effectively implement our statutory authority to prescribe dietary
supplement CGMP. See United States v. Mead, 533 U.S. 218, 227-228
(2001); Nationsbank of North Carolina v. Variable Annuity Life Ins.
Co., 513 U.S. 251, 256-58 (1995); Chevron, 467 U.S. at 844; Forester v.
Consumer Product Safety Com., 559 F.2d 774, 783 (D.C. Cir. 1977).
B. Records Authority
(Comment 19) Some comments state that requirements related to
record keeping and access to such records are necessary to allow our
inspectors to assess the adequacy of a dietary supplement
manufacturer's practices. Additional comments state that access to
records is necessary to ensure that CGMP requirements are followed and
to protect the public health. Several comments identify specific types
of
[[Page 34783]]
records we should require in a final rule, including written
procedures, batch and master manufacturing records, distribution
records, and lot numbers. Another comment states that training records
should be required because the qualifications and training of employees
affects product quality.
Other comments, however, state that the record retention and access
requirements seem to be modeled after drug CGMP and not food CGMP.
Other comments state that, even though records may be necessary to
ensure that CGMP requirements are followed, we do not have authority to
require access to and copying of such records. Some comments assert the
authority to establish regulations for dietary supplement CGMP does not
imply there is authority to inspect records. Several comments state we
cannot rely on section 701 of the act because there is not another
section of the act that authorizes us access to company records for
dietary supplement CGMP and section 701(a) of the act does not itself
give us the authority we need to require records inspection. Another
comment suggests that the absence of an express grant of records
inspection authority means that records inspection is not necessary for
the efficient enforcement of the act.
Some comments assert that we have no record inspection authority
under section 704(a) of the act (21 U.S.C 374(a)). A few comments
suggest that, because records inspection authority was not expressly
granted in DSHEA's statutory language, as it was for OTC drugs and
medical devices, Congress provided no authority for records inspection
for dietary supplement CGMP. The comments state that we have a
longstanding interpretation that section 704 of the act does not give
us access to a food manufacturer's records. Several comments state that
it was sufficient to have voluntary records access, stating that many
companies are willing to provide access to records.
Other comments say that our record inspection authority for dietary
supplement CGMP is limited to that under section 306(a) of the Public
Health Security and Bioterrorism Preparedness and Response Act of 2002
(Bioterrorism Act) (21 U.S.C. 350(c)), i.e., when we have a
``reasonable belief that an article of food is adulterated and presents
a threat of serious adverse health consequences * * *'' Another comment
suggests an alternative standard to that in section 306(a) of the
Bioterrorism Act of a ``reasonable belief that there is a public health
hazard'' for when we may access records.
One comment cites In the Matter of Establishment Inspection of
Medtronic, Inc., 500 F. Supp 536 (D. Minn. 1980), to support its
assertion that we exceeded our statutory inspection authority in the
dietary supplement CGMP record requirements. One comment states that a
warrantless inspection of dietary supplement CGMP records and criminal
consequences that may be imposed under the act for failure to comply
with the act provide a ``powerful argument against expanding the
Agency's inspection authority any further'' and raise ``serious
constitutional concerns.'' Several comments ask us to clarify our
jurisdiction for records inspection requirements or delete proposed
Sec. 111.125(c).
Still other comments seek confirmation that the confidential and
trade secret information obtained by us under the rule would be
protected from disclosure under applicable statutes. Among other
things, the comments cite the Trade Secrets Act, 18 U.S.C. 1905, and
the Freedom of Information Act (FOIA), 5 U.S.C. 552(b)(4). Some
comments express concern that records inspection would violate ``rights
to privacy of corporate manpower'' or would compromise trade secrets.
The comments request the rule specifically reconfirm our obligations
under these laws.
(Response) We disagree with the comments suggesting that we have no
authority to require dietary supplement manufacturers to maintain
records to comply with CGMP under section 402(g) of the act; that the
absence of an express grant of records authority means records are not
needed for the efficient enforcement of the act; and that Congress
meant, by its silence, that we have no authority to issue records
requirements. Clearly, just as Congress is not expected to express
``every single evil sought to be corrected'' in a grant of authority to
promulgate a rule, it can not be expected to articulate every
requirement that is within an agency's delegated authority (American
Trucking Assoc. v. United States, 344 U.S. 298, 309-10 (1953)).
Agencies are expected to bring their expertise to bear on what
requirements are necessary that will not ``directly frustrate the
success of the regulation undertaken by Congress'' (id. at 311). In
this instance, Congress has not expressed any specific intent regarding
recordkeeping for dietary supplements but has directed FDA to use other
food CGMP regulations, which require recordkeeping and FDA access to
records, as models for these regulations. Congress has delegated
substantial and sufficiently specific authority to us to promulgate
recordkeeping and access regulations (Cf. United States v. Storer
Broadcasting, 351 U.S. 192, 202-03 (1956) (upholding a rule that
established limitations on broadcast licensing that were ``not
specifically authorized by statute'')). As stated earlier in this
section, the ``modeled after'' language in section 402(g) of the act is
ambiguous with respect to what specific CGMP requirements we are to
include in this final rule. At the time Congress enacted section 402(g)
of the act there were several food regulations that contained
recordkeeping and record access requirements. We included records
requirements in the food CGMP regulations for infant formula (part
106), low acid food (part 113), acidified food (part 114), and bottled
water (part 129). Accordingly, the directive in section 402(g) of the
act is sufficient authority for our recordkeeping requirements in this
final rule. In addition, our authority to establish records
requirements has been upheld under other provisions of the act, which
lacked explicit recordkeeping authority for FDA, where we have found
records to be necessary (National Confectioners Assoc. v. Califano, 569
F.2d 690, 693-94 (D.C. Cir. 1978) (upholding requirements for source
coding and distribution records based on the statutory scheme as a
whole)).
Moreover, records are an indispensable component of CGMP. The
records required by this final rule provide the foundation for the
planning, control, and improvement processes that constitute a quality
control system. Implementation of these processes in a manufacturing
operation serves as the backbone to CGMP. The records will show what is
to be manufactured; what was, in fact, manufactured; and whether the
controls that the manufacturer put in place to control the identity,
purity, strength, and composition and limits on contaminants and to
prevent adulteration were effective. Further, records will show whether
and what deviations from control processes occurred, facilitate
evaluation and corrective action concerning these deviations
(including, where necessary, whether associated batches of product
should be recalled from the marketplace), and enable a manufacturer to
assure that the corrective action was effective. Written procedures
also will help ensure that personnel follow hygienic practices; permit
evaluation of whether equipment, including software that may run the
equipment, performs as it is intended; and help ensure that the
[[Page 34784]]
equipment is properly maintained and adequately cleaned.
The CGMP final rule establishes the parameters for the production
and process control system in which dietary supplements are to be
manufactured. The dietary supplement manufacturer establishes the
identity, strength, purity, and composition of the supplement it
manufactures (final Sec. 111.70); determines whether the established
specifications are met (final Sec. 111,73); uses the tests it needs to
ensure that those characteristics are consistently met (final
Sec. Sec. 111.75 and 111.315); and identifies the steps necessary to
ensure that any necessary tests or examinations are completed,
reviewed, and recorded in a timely fashion before the dietary
supplement is released for distribution to the public (final Sec. Sec.
111.110 and 111.325(b)(2)). The CGMP final rule also requires that the
manufacturer establish written procedures for its quality control
operations to ensure the personnel performing this function provide
proper review and oversight of the production and process control
system, have the knowledge and experience to identify and anticipate
possible problems in the manufacturing of the dietary supplement, and
ensure corrective measures are taken promptly when problems occur
(final Sec. Sec. 111.103 through 111.140). The final rule also
requires that the manufacturer establish the ``master recipe(s)'' for
the dietary supplement(s) it manufactures so that such recipe(s) can be
followed for each batch produced (final Sec. Sec. 111.205 through
111.210). In sum, manufacturers cannot operate without records because
critical elements in a manufacturing process are entirely dependent on
information written or captured in the form of a record.\6\ Such
records are also necessary to protect consumers by enabling
manufacturers to identify and recall problematic products as necessary
and make necessary corrections to deviations in their processes.
---------------------------------------------------------------------------
\6\It is also worth noting that standard references used in many
industries establish clear expectations for documentation and
recordkeeping practices for assuring quality control in
manufacturing operations (Refs. 9 and 13).
---------------------------------------------------------------------------
The authority granted us under sections 402(g) and 701(a) of the
act not only includes the authority to establish record requirements,
but also includes access to such records. Without such authority, the
dietary supplement CGMP requirements are, practically speaking, not
enforceable. Under section 402(g)(1) of the act, the failure to meet
any CGMP requirements, including the failure to have a record that is
required by this final rule, renders a dietary supplement so
manufactured to be adulterated as a matter of law. The introduction or
delivery for introduction into interstate commerce of an adulterated
dietary supplement is a prohibited act under section 301(a) of the act
(21 U.S.C. 331(a)), and acts done to an ingredient in a dietary
supplement, or to a dietary supplement, while held for sale after
shipment in interstate commerce that result in the ingredient or
dietary supplement being adulterated violates section 301(k) of the act
(21 U.S.C. 331(k)). Thus, in order for us to determine whether the
dietary supplement product is adulterated and whether a manufacturer
has committed a prohibited act, we must have access to the
manufacturer's records that we are requiring to be kept under section
402(g) of the act.
In light of the foregoing, without access to such records, we would
not know whether a manufacturer was complying with the procedures and
processes required in this final rule. For example, our investigator
must have access to the test results for the identity of a dietary
ingredient to determine whether such ingredient meets the
manufacturer's specification for identity. The investigator needs to
understand, by reviewing a record, what the software that runs a
production operation is set up to do and whether it performs those
functions to achieve the desired product characteristics. Observation
of these processes alone, by an investigator, would not allow that
investigator to evaluate compliance with this final rule. Moreover,
records often cannot be thoroughly evaluated by the investigator on
site. In such cases, records must be readily available to food experts
at the Center for Food Safety and Applied Nutrition (CFSAN) and agency
consultants. We must have accurate, reliable, and objective data about
the manufacturing specifications to be able to achieve an enforceable
rule.
We also disagree with comments stating our records inspection
authority is limited to that provided by section 306(a) of the
Bioterrorism Act. There is no basis to conclude that Congress intended
to limit our authority to inspect records, to enforce section 402(g) of
the act, to the records inspection authority under the Bioterrorism
Act. The Bioterrorism Act, enacted almost 8 years after section 402(g),
to address credible threats of serious adverse health consequences or
death to humans and animals, required recordkeeping to identify the
immediate previous sources and the immediate subsequent recipients of
food (21 U.S.C. 350c).
There is nothing in the Bioterrorism Act that reflects any
Congressional intent to modify section 402(g) of the act. In fact,
section 414(d)(1) of the act (21 U.S.C. 350c(d)(1)), added by section
306(a) of the Bioterrorism Act, shows a contrary intent. Section
414(d)(1) provides that ``This section shall not be construed--(1) to
limit the authority of the Secretary to inspect records or to require
establishment and maintenance of records under any other provision of
this Act.'' Moreover, Congress, in the legislative history to the
Bioterrorism Act, supported our general approach of requiring
recordkeeping pursuant to authority in section 701(a) of the act in
combination with other provisions.\7\ We are not relying on section 704
of the act for its underlying authority to require recordkeeping and
records access in this final rule. Those comments asserting that we do
not have such authority and the underlying references, for example, to
past hearings on records inspection authority under section 704 of the
act, are not controlling with regard to the action we are taking under
sections 402(g) and 701(a) of the act. When there are other bases for
jurisdiction and tools to protect the public interest, we may use what
``will be the most effective in advancing the Congressional objective''
(U.S. v. Midwest Video Corp., 406 U.S. 649, 656 (1972)).
---------------------------------------------------------------------------
\7\In discussing section 306 of the Bioterrorism Act
(Maintenance and Inspection of Records for Foods), Congress stated,
``The managers did not adopt a Senate proposal to authorize the
Secretary to require the maintenance and retention of other records
for inspection relating to food safety, because the Secretary has
authority under section 701(a) of the [act] to issue regulations for
the `efficient enforcement of this Act' and this authority, in
combination with other provisions (such as section 402 [of the
act]), gives the Secretary the authority to require appropriate
record keeping in food safety regulations.'' (H.R. Conf. Rep. No.
107-481, at 135 (2002), (Ref. 14)).
---------------------------------------------------------------------------
Some comments stated that our access to dietary supplement records
is not consistent with constitutional jurisprudence. We disagree. The
comment which expressed concern about ``constitutional issues'' in the
context of an FDA inspection of records during a warrantless FDA
inspection expressed concern about the criminal liability that could be
imposed on a manufacturer under the act (citing United States v.
Dotterweich, 320 U.S. 277 (1944) and United States v. Park, 421 U.S.
658 (1975)). To the extent that the comment asserts that the records
access established in this final rule constitutes an improper search
and seizure under the Fourth Amendment, we disagree.
The dietary supplement industry, as the food industry as a whole,
is a
[[Page 34785]]
pervasively regulated industry that is subject to warrantless
inspections (see, e.g., United States v. Biswell, 406 U.S. 311, 315
(1972) (``In the context of a regulatory inspection system of business
premises * * * the legality of the search depends not on consent but on
the authority of a valid statute.''); United States v. New England
Grocers Supply Co., 488 F. Supp. 230, 238 (D. Mass. 1980) (holding that
a warrantless inspection under 21 U.S.C. 374 is ``fully consistent with
the Fourth Amendment''); United States v. Acri Wholesale Grocery Co.,
409 F. Supp. 529, 533 (S.D. Iowa 1976) (holding that a warrantless
inspection, which includes photographic activities, conducted under 21
U.S.C. 374 does not violate the Fourth Amendment); United States v.
Business Builders, Inc., 354 F. Supp. 141, 143 (N.D. Okla. 1973) (``the
statute takes the place of a valid search warrant''); United States v.
Del Campo Baking Mfg. Co., 345 F. Supp. 1371 (D. Del 1972) (finding
warrantless inspection of food establishment lawful under 21 U.S.C.
374)).
As explained earlier in this section, we have ample authority,
under sections 402(g) and 701(a) of the act, to require that certain
records be kept and accessible to us upon inspection. Records access is
imperative to the efficient enforcement of the dietary supplement CGMP
final rule, and we are not prohibited from requiring access to these
records under sections 402(g) and 701(a) of the act (See Permian Basin
Area Rate Cases, 390 U.S. 747, 780 (1968) (``in the absence of
compelling evidence that such was Congress' intention * * * [the court
should not] prohibit administrative action imperative for the
achievement of an agency's ultimate purposes.'')).
We also disagree with the comment suggesting that voluntary records
access is sufficient. In our experience, many manufacturers are not
willing, as the comments suggest, to provide records voluntarily to us
(Ref. 15). Moreover, it is often the case that the most uncooperative
manufacturers are the very ones whose records and processes are
deficient. Without mandatory requirements for agency access to records
required by the final rule, we could not enforce and there would be
minimal incentives for manufacturers to comply with the rule, which
would frustrate Congressional intent in enacting section 402(g) of the
act.
We also disagree with the comment that cited In the Matter of
Establishment Inspection of Medtronic, Inc., 500 F. Supp. 536 (D. Minn.
1980), to suggest that our proposed recordkeeping requirements exceed
our statutory inspection authority. As already discussed, we are not
relying on section 704 of the act for our authority to require access
to dietary supplement CGMP records. Thus, to the extent the comment
cited to Medtronic as an example of the statutory authority for
inspection of device records under section 704 of the act, Medtronic is
not pertinent to our authority for records access in this final rule.
Finally, we disagree that the records access in this final rule
will violate any protection a manufacturer has with respect to
protection of confidential commercial or financial information or trade
secrets. Trade secrets and commercial or financial information that is
privileged or confidential are protected from disclosure under FOIA and
other laws (see, e.g., 21 U.S.C. 331(j), 18 U.S.C. 1905). Further, our
FOIA regulations set forth the specific procedures for assuring such
protection.
It was not clear from the comments what was meant by ``rights to
privacy of corporate manpower.'' We note that Sec. Sec. 20.63 and
20.64 contain provisions for the protection of personal privacy.
C. Public Health Service Act Authority
(Comment 20) One comment acknowledges that we have authority under
the PHS Act to regulate intrastate activities that may cause the spread
of communicable diseases. The comment states that, in any situation in
which we need to exercise our authority over any disease-causing
substance within the State where a component or dietary supplement is
manufactured, packed, or held, we can and should exercise our authority
under the PHS Act. However, the comment asserts that nothing in the
preamble clearly states whether we believe that the final rule will be,
in its entirety, binding on manufacturers, packers, and holders of
dietary supplements who are engaged solely in intrastate commerce, and
that we have not requested comment on this specific issue. The comment
requests that we clearly state that the final rule applies only to
interstate commerce, except for activities that may spread communicable
diseases.
(Response) We address each of these issues in turn.
1. The Communicable Disease Risk Posed by Dietary Supplements
There are communicable disease risks related to the manufacture of
dietary supplements that are appropriately addressed not only under the
act, but, as the comment acknowledges, also under the PHS Act.
Microorganisms, including Salmonella enterica (Salmonella),
Campylobacter jejuni, and enterohemorrhagic Escherichia coli 0157:H7
(EHEC), are well-known causes of communicable diseases, and may be
present in dietary supplements and their components. There are a number
of microorganisms that cause communicable diseases and that may be
found in components or dietary supplements. These microorganisms cause
serious effects and symptoms. For example, Salmonella causes
salmonellosis, which affects the gastrointestinal (GI) tract and is
characterized by diarrhea, fever, abdominal cramps, headache, nausea,
and vomiting (Ref. 16). In a small portion of healthy people (1 to 4
percent), infection spreads from the GI tract into the blood stream,
which can be life-threatening. Persons with immune compromising
conditions (such as cancer, Acquired Immunodeficiency Syndrome (AIDS),
autoimmune disorders) are at greater risk of blood stream infection
(Ref. 16).
Campylobacteriosis, often due to infection with Campylobacter
jejuni, is characterized by diarrhea, fever, and abdominal cramps,
which can be severe (Ref. 17). These symptoms frequently relapse, and
the disease may become chronic in immune compromised persons. People
with campylobacteriosis are also at increased risk of developing
certain post-infectious complications, which will prolong their
recovery.
EHEC may cause infections with a very low infectious dose (as low
as 2 to 45 organisms), and may result in non-bloody and bloody
diarrhea, hemolytic-uremic syndrome (a cause of red blood cell
destruction, damage of blood vessel walls, and, in severe cases, kidney
failure (especially in young children)), thrombotic thrombocytopenic
purpura (i.e., a blood disorder characterized by low platelets, low red
blood cell count, abnormalities in kidney function, and neurological
abnormalities (especially in adults)), and death (Ref. 18).
Animal tissues (e.g., organs from livestock), as well as
botanicals, used as components in dietary supplements may contain EHEC,
Salmonella, and Campylobacter jejuni. In addition, because the same
microorganisms are also present in the environment, they may
contaminate components during manufacturing activities. Moreover,
people who harbor those pathogens could transmit them to components and
dietary supplements during processing. Therefore, components and
dietary supplements, as potential sources of communicable diseases, may
be regulated under the PHS Act.
For these microorganisms (e.g., EHEC, Salmonella, and Campylobacter
jejuni)
[[Page 34786]]
humans carry and transmit infections through their feces or by direct
contact with other persons. For other microorganisms, domestic and wild
animals serve as the reservoir, and humans become infected when
contaminated tissues of infected animals are used in dietary
supplements. For both categories of microorganisms, dietary supplements
can also become contaminated indirectly by human and animal fecal
contamination of water or through the production or processing
environment.
Dietary supplements may contain a variety of components derived
from domestic and wild animals, such as powders prepared from whole or
partial gecko, deer antler velvet, and organs, such as cow liver and
brain, pork stomach, or sheep spleen from common domestic livestock.
Each of these tissues may be contaminated with microorganisms such as
Salmonella, Campylobacter jejuni, and EHEC. Even clinically normal
animals obtained from safe sources may harbor these communicable
pathogens and result in contaminated products (Ref. 19). (Information
on these animals and potential pathogens can be accessed at http://www.fsis.usda.gov/Science/Microbiology/index.asp). Dietary supplements
also may contain crustacean or molluscan shellfish or components
prepared from them, such as glucosamine from shrimp exoskeletons and
oyster extract, that may be contaminated with Vibrio species, including
V. parahaemolyticus. Vibrio species are natural inhabitants of
shellfish harvest waters, and shellfish are commonly naturally
contaminated, especially during times of the year when harvest waters
are warm (Refs. 20 through 23). V. parahaemolyticus most often causes
gastroenteritis characterized by diarrhea, abdominal cramps, nausea,
vomiting, and fever (Ref. 24).
Dietary supplements may also contain botanicals (plants) that may
harbor microorganisms, including organisms from animal feces
(Salmonella and Shigella spp., Escherichia coli), and organisms arising
from handling (Staphylococcus aureus), harvesting, processing, and
transportation.
Components contaminated with microorganisms must be treated to
prevent the finished dietary supplements from being contaminated. The
processes used to manufacture dietary supplements do not, by
themselves, always eliminate the microorganisms. Studies show, for
example, that microorganisms, such as EHEC and Salmonella, can even
survive the tablet production process and thereby expose consumers
(Ref. 25).
The industry is aware of the dangers of using components
contaminated with Salmonella and other microorganisms. For example, in
2001, a component manufacturer recalled 2,400 pounds of pepsin
contaminated with Salmonella. As a result, a number of dietary
supplement manufacturers issued recalls for their dietary supplements
that contained the pepsin. In the press releases accompanying the
recalls, the dietary supplement manufacturers warned consumers of the
possible dangers of Salmonella contamination, and encouraged consumers
to either destroy or return the supplements (Ref. 26).
Therefore, because of the communicable disease concerns associated
with dietary supplements, we are asserting legal authority under the
PHS Act in support of the final rule. As discussed in the following
section of this document, our authority under the PHS Act is not
limited to interstate activities. It also covers intrastate activities.
2. Activities For Which We Are Asserting Legal Authority Under the PHS
Act
There are many opportunities for components and dietary supplements
to become contaminated with microorganisms that spread communicable
diseases. The final rule requires firms to take all the necessary
precautions during the manufacture of a dietary supplement to prevent
such contamination.
These precautions, for example, include: Performing manufacturing
operations under conditions and controls that protect against potential
microorganism growth; washing or cleaning components that contain soil
or other contaminants; performing microbiological testing, as
necessary, to prevent the use of contaminated components;
sterilization, pasteurization, freezing, refrigeration, and controlling
pH, humidity, and water activity (aw), or using other
effective means to remove, destroy, or prevent the growth of
microorganisms and decomposition; and holding components and dietary
supplements that can support the growth of infectious microorganisms of
public health significance in a manner that prevents them from becoming
adulterated.
Failure to properly clean components, or take any other appropriate
steps, such as those listed in the previous paragraph, could lead to
pathogen growth and the spread of communicable diseases. If, for
example, a dietary supplement manufacturer purchased an animal-derived
ingredient that harbored Salmonella enterica, but failed to take the
steps necessary to inactivate the pathogen, the consumption of the
dietary supplement could lead to the spread of salmonellosis.
The final rule also requires firms to take measures to exclude from
certain operations any sick persons who might contaminate material,
including components, dietary supplements, and contact surfaces used to
manufacture, package, label, or hold a dietary supplement.
D. The Interstate Commerce Nexus for the Final Rule
1. The PHS Act
(Comment 21) Several comments assert that, although the PHS Act may
extend to some intrastate activities, its reach is very limited. The
comments appear to conclude that the reach of the PHS Act and the act
extends only to situations in which the finished dietary supplement is
shipped in interstate commerce.
(Response) We do not agree that this view is correct. The PHS Act
extends to intrastate commerce. Under section 361 of the PHS Act (42
U.S.C. 264), we may ``make and enforce such regulations as in [our]
judgment are necessary to prevent the introduction, transmission, or
spread of communicable diseases from foreign countries into the States
or possessions, or from one State or possession into any other State or
possession.''
In Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977), the
court upheld FDA's regulation that banned the sale of small turtles to
prevent the spread of disease caused by turtles harboring Salmonella
and Arizona microorganisms. The ban covered both interstate and
intrastate sales. The court held that the intrastate ban is not only
authorized by the law, but, under modern conditions of transportation
and commerce ``is clearly reasonable to prevent the interstate spread
of disease'' (id.).
We are authorized under the PHS Act to regulate conduct that occurs
within a State to the extent necessary to prevent the interstate spread
of communicable diseases. Such is the present case with respect to the
provisions of the dietary supplement CGMP final rule for which section
361 of the PHS Act provides authority.
2. The Act
The act extends to the sale of a dietary supplement that was
manufactured and
[[Page 34787]]
distributed entirely in one State, if the supplement contains any
ingredient or uses any component that came from outside of that State.
Such a dietary supplement is subject to section 301(k) of the act,
which prohibits ``[t]he alteration, mutilation, destruction,
obliteration, or removal of the whole or any part of the labeling of,
or the doing of any other act with respect to, a food, drug, device, or
cosmetic, if such act is done while such article is held for sale
(whether or not the first sale) after shipment in interstate commerce
and results in such article being adulterated or misbranded.''
(emphasis added). See also 21 U.S.C. 321(b)(3) (defining food to
include articles used as components of food).
The interstate commerce prerequisite under section 301(k) or
section 304(a) (21 U.S.C. 334(a)) of the act is established when one or
more components used in the manufacture of the product have crossed
State lines. This principle is known as ``component jurisdiction''
(See, e.g., Baker v. United States, 932 F.2d 813, 814-15 (9th Cir.
1991); United States v. Article of Food * * * Coco Rico, Inc., 752 F.2d
11, 14 (1st Cir. 1985); United States v. Dianovin Pharmaceuticals,
Inc., 475 F.2d 100, 103 (1st Cir.), cert. denied, 414 U.S. 830 (1973)
(``appellants' use of components shipped in interstate commerce to make
vitamin K for injection brought their activities within Sec.
331(k)''); United States v. Cassaro, Inc., 443 F.2d 153, 155-56 (1st
Cir. 1971); United Statesv. Detroit Vital Foods, Inc., 330 F.2d 78, 81-
82 (6th Cir.), cert. denied, 379 U.S. 832 (1964); United States v.
Allbrook Freezing & Cold Storage, Inc., 194 F.2d 937, 939 (5th Cir.
1952); United States v. Varela-Cruz, 66 F.Supp.2d 274, 277-281 (D. P.R.
1999)).
Nor does it matter that the interstate product component comprises
only a minute part of the article, United States v. Miami Serpentarium
Laboratories, [1981--1982 Transfer Binder] Food Drug Cosm. L.Rep. (CCH)
paragraph 38,164 at 38,930 (S.D. Fla. 1982); United States v. 14 Cases
* * * Naremco, 374 F.Supp. 922, 925 (W.D. Mo. 1974), or if the
interstate ingredient combines with others to form a different product.
Detroit Vital Foods, 330 F.2d at 81; United States v. 40 Cases * * *
Pinocchio Brand * * * Oil, 289 F.2d 343, 346 (2d Cir.), cert. denied,
368 U.S. 831 (1961).
Finally, we note that section 709 of the act creates a presumption
of interstate commerce (see 21 U.S.C. 379a (``In any action to enforce
the requirements of this Act respecting a device, food, drug, or
cosmetic the connection with interstate commerce required for
jurisdiction in such action shall be presumed to exist.'')).
In conclusion, the final rule covers not only finished products
that have moved in interstate commerce but also products made from
ingredients or components that have moved in interstate commerce. This
is true regardless of the amount of the ingredient or component in the
product and regardless of whether the finished dietary supplement has
itself moved in interstate commerce. The final rule also covers
products, components, and ingredients that may contribute to the spread
of communicable disease, regardless of whether the component,
ingredient, or product has itself moved in interstate commerce.
3. Commerce Clause
(Comment 22) One comment states that we must be ``mindful of the
limits'' imposed on the regulation of intrastate commerce by the
Supreme Court in United States v. Lopez, 514 U.S. 549 (1995). The
comment asserts that we may only regulate intrastate activity that has
a ``substantial effect'' on interstate commerce and activity that
``exerts a substantial economic effect on interstate commerce.''
(Response) The final rule is consistent with the Lopez decision.
Among the cases cited by the Court in Lopez as support for its decision
is Wickard v. Filburn, 317 U.S. 111 (1942), which involved the
production and consumption of homegrown wheat. In that case, the Court
explained: ``although Filburn's own contribution to the demand for
wheat may have been trivial by itself, that was not enough to remove
him from the scope of federal regulation where, as here, his
contribution, taken together with that of many others similarly
situated, is far from trivial'' (Lopez, 514 U.S. at 556). The same is
true for dietary supplement manufacturers. Therefore, the requirements
of the final rule are consistent with the Commerce Clause of the
Constitution.
E. Fifth Amendment
(Comment 23) Several comments allege a number of the sections of
the proposed regulation are unconstitutionally vague and violate the
Administrative Procedure Act (APA) because the rule would be ``contrary
to constitutional right, power, privilege, or immunity.'' The comments
express concern that if such terms are not defined or deleted, there
would be no fair notice on what conduct is prohibited and would result
in ``unbridled discretion'' in how the rule will be enforced. The
comments focus on provisions containing words such as ``adequate,''
``qualified,'' ``readily accessible,'' ``convenient,'' ``suitable,''
``appropriate,'' and ``necessary.'' For example, one comment notes that
proposed Sec. 111.15(e) would require physical plant plumbing to be of
an adequate size and design and to be adequately installed and
maintained. The comment objects to the section on the ground that
``what constitutes `adequate' in those contexts is left undefined.''
(Response) We disagree these terms are vague or that the identified
terms should be deleted from the final rule. The qualifying terms
objected to in the comments have been in use since the umbrella food
CGMP rule (part 110) was first promulgated in 1969. For example, this
regulation included requirements that: ``[p]lant buildings and
structures shall be suitable in size;'' there must be ``sufficient
space'' for equipment and storage materials; there must be ``adequate
lighting;'' and protection against pests must be provided ``where
necessary'' (see 34 FR 6977 at 6978, April 26, 1969). The court in
National Association of Pharmaceutical Manufacturers. v. Department of
Health & Human Services, 586 F.Supp. 704 (S.D.N.Y 1986), addressed the
very question of whether terms such as ``adequate,'' ``appropriate,''
``proper,'' ``sufficient,'' and ``suitable,'' in the drug CGMP
regulation were vague. The court found that the drug CGMP regulation
containing such terms was ``sufficiently definite to give notice of the
required conduct to one who would avoid [their] penalties, and to guide
the judge in [their] application * * *'' (Id. at 753). The court so
held, in part, in light of the fact that the drug CGMP statute was
upheld against a constitutional vagueness attack in United States v.
Bel-Mar Laboratories, Inc., 284 F. Supp. 875, 883 (E.D.N.Y. 1968)
(``the phrase `current good manufacturing practice' is not strange to
those in the trade to whom the subject section is directed.'').
Furthermore, the use of such ``ordinary terms to express ideas which
find adequate interpretation in common usage and understanding'' are
not the types of terms that have been held to be unconstitutionally
vague (Boyce Motor Lines v. United States, 342 U.S. 337, 342 (1952)).
Some of these very terms have been in use for over 30 years in food
CGMP regulations.
No comments were submitted objecting to the use of such terms, when
the umbrella food CGMP rule was revised in 1986 (see 51 FR 22458, June
19, 1986). Also, when we began work on the dietary supplement CGMP
rule, we
[[Page 34788]]
received and published for comment an industry draft of a CGMP
regulation for dietary supplements. The industry draft used many of the
same terms. For example, it provides in part: ``Plumbing shall be of
adequate size and design and adequately installed and maintained'' (62
FR 5700 at 5703, February 6, 1997). Thus, there has been sufficient
common usage of these terms in the food industry and, in particular,
the dietary supplement industry to enable manufacturers, and those who
enforce the requirements, to comprehend and apply such terms ``with a
reasonable degree of certainty'' to their particular operations (Boyce
Motor Lines v. United States, 342 U.S. at 340 (``[F]ew words possess
the precision of mathematical symbols, most statutes must deal with
untold and unforeseen variations in factual situations, and the
practical necessities of discharging the business of government
inevitably limit the specificity with which legislators can spell out
prohibitions [and therefore] no more than a reasonable degree of
certainty can be demanded.'')). The same reasoning applies here. It
addresses ``untold and unforeseen variations in factual situations''
and, as such, ``no more than a reasonable degree of certainty can be
demanded.''
Agencies are permitted to, and indeed must, use such qualifying
terms to address the variety of conditions that exist at different
companies. We do not need to, nor could we, predict with mathematical
precision how many inches or feet, for example, would be ``adequate
space'' to allow for cleaning a particular piece of equipment that
could be applied to every size of facility and every operation (id.).
Moreover, defining such terms too precisely would unduly restrict the
application of the regulation to a very narrow, limited set of
circumstances and not provide industry with the needed flexibility to
address the number and variety of types of manufacturing operations
that Congress intended for this rule to cover (see Freeman United Coal
Mining Company v. Federal Mine Safety and Health Review Commission, 108
F.3d 358, 363 (D.C. Cir. 1997) (citations omitted) (upholding a
regulation that required equipment to be ``maintained in good repair,''
the court rejected the vagueness challenge: ``specific regulations
cannot begin to cover all of the infinite variety of [conditions at
firms and that] * * * [b]y requiring regulations to be too specific
[courts] would be opening up large loopholes allowing conduct which
should be regulated to escape regulation.''); United States v. Bel-Mar
Laboratories, Inc., 284 F. Supp. at 883 (rejecting a vagueness
challenge to the CGMP requirements for drugs, noting that ``[a]s a
matter of fact, there are responsible segments of opinion within the
industry itself which oppose a greater degree of specificity in this
area.'').
Finally, it is important to understand that rules are not
unconstitutionally vague simply because they require interpretation by
regulated persons. For example, courts have held that the term
``insanitary conditions'' in the act is not unconstitutionally vague
(See Golden Grain Macaroni Co. v. United States, 209 F.2d 166, 168 (9th
Cir. 1953) (citing Boyce Motor Lines, supra); Berger v. United States,
200 F.2d 818 (8th Cir. 1952)). In Berger, the court rejected the claim
that the term ``insanitary condition'' is unconstitutionally vague on
the ground that it does not specify the ``degree of insanitation''
required for a violation (id. at 822). A law may require a person to
make ``estimates of the degree of dirtiness and lack of sanitation''
which may result in a violation (id., see alsoBoyce Motor Lines v.
United States, 342 U.S. at 340 (It is not ``unfair to require that one
who deliberately goes close to an area of proscribed conduct shall take
the risk that he may cross the line'')). There are sufficient
protections under the act to overcome any concerns related to how it
will be criminally enforced. We disagree that such terms will lead to
``unbridled discretion'' on how the rule is enforced.
In short, we find that the rule is not unconstitutionally vague,
and does not violate section 706(2)(B) of the APA (5 U.S.C. 706(2)(B)).
F. Miscellaneous
(Comment 24) One comment states that the proposed rule violates
section 402(f)(1)(A)(i) and (f)(1)(A)(ii) of the act (21 U.S.C. 342
(f)(1)(A)(i) and (f)(1)(A)(ii)), which deems a dietary supplement
adulterated if it contains a dietary ingredient that presents an
unreasonable risk of illness or injury under conditions of use in
labeling or ordinary conditions of use, if none are suggested or
recommended in labeling. Under section 402(f) of the act, the
Government bears the burden of proof to show that a dietary supplement
is adulterated. The comment states that the proposed rule reversed the
presumption under section 402(f) of the act, and would revise the rule
to require us to first show a violation under section 402(f) of the act
before we could take any enforcement action under section 402(g).
Another comment states that, because the rule was intended to enable
manufacturers to be able to detect and avoid adulteration through CGMP,
the proposed rule created a presumption that dietary supplements are
adulterated until proven otherwise.
(Response) The final rule does not violate section 402(f) of the
act. Section 402(f) and (g) of the act provide two independent bases
under which we may take enforcement action against dietary supplements.
A dietary supplement may be adulterated either because a manufacturer
has failed to follow a CGMP requirement, or because a dietary
supplement presents an unreasonable risk of illness or injury, or both.
There would be no reason to assert a second basis for adulteration
under section 402(g) of the act if one always had to demonstrate
adulteration under section 402(f) of the act as a prerequisite.
We also disagree with the comment that the proposed rule creates a
presumption that the dietary supplement is adulterated simply because
the proposed requirements would enable a manufacturer to detect and
avoid adulteration. The requirements for CGMP are prophylactic and are
designed in part to ensure that all aspects of manufacturing, from
receipt through distribution, provide the necessary controls and
monitoring to ensure the quality of the dietary supplement, including
that it is manufactured, packaged, labeled, and held in a manner to
prevent adulteration.
(Comment 25) One comment states that, if there is reduced
competition through the enforcement of the rule, there will be a
secondary effect of elimination of speech on dietary supplement
innovative uses.
(Response) The comment seems to conclude that, if a dietary
supplement manufacturer is not able to stay in business due to adverse
enforcement actions against it by us, or elects to not go into business
based on the possibility of enforcement action by us, there will be
reduced competition due to fewer products, less labeling, and
``elimination of speech on innovative uses.'' To the extent that the
comment is suggesting that the dietary supplement CGMP requirements are
unconstitutionally overbroad, this argument is wholly without merit
(Cf. Wisconsin v. Mitchell, 508 U.S. 476, 488-89 (1993) (finding no
merit to an overbreadth argument that the possibility of enhanced
sentences based on prior racially motivated speech or associations
constitutes an impermissible chill on free speech)). Manufacturing a
dietary supplement in a manner that violates the CGMP requirements
causes the product to be adulterated, and therefore, unlawful.
[[Page 34789]]
The fact that a manufacturer may not stay in business, or elects not
to enter business, due to: (1) Our implementation of CGMP requirements
or (2) our enforcement against a product that violates CGMP
requirements, does not mean that we are somehow prohibiting speech. In
any event, there is no First Amendment protection for speech that
concerns unlawful activity under the first prong of the test set out in
Central Hudson Gas & Electric Corp. v. Public Service Commission, 447
U.S. 557 (1980). Therefore, the comment's suggestion that there is
elimination of speech based on the rulemaking is not supportable. The
requirements in the final rule do not infringe on a manufacturer's
right to lawfully label and market a dietary supplement.
VI. What Comments Did We Receive on the General Provisions? (Subpart A)
A. Organization of Final Subpart A
Proposed subpart A contained five provisions regarding the scope of
the proposed rule, definitions, and exclusions. Table 2 of this
document lists the sections in final subpart A and identifies the
proposed sections that form the basis of the final rule.
Table 2.--Derivation of Sections in Final Subpart A
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.1 Who is subject to this part? Sec. 111.1
------------------------------------------------------------------------
Sec. 111.3 what definitions apply to this Sec. 111.3
part?
------------------------------------------------------------------------
Sec. 111.5 Do other statutory provisions Sec. 111.5
and regulations apply?
------------------------------------------------------------------------
B. Who Is Subject to This Part? (Final Sec. 111.1)
Section 111.1 explains who is subject to the dietary supplement
CGMP requirements. In brief, final Sec. 111.1(a) states that you are
subject to the dietary supplement CGMP requirements if you manufacture,
package, label, or hold a dietary supplement. This requirement includes
a dietary supplement you manufacture but that is packaged or labeled by
another person, and a dietary supplement that is imported, offered for
import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico. Final Sec. 111.1(b),
however, excludes certain persons from the rule. Specifically, Sec.
111.1(b) states that the requirements pertaining to holding dietary
supplements do not apply to you if you are holding those dietary
supplements at a retail establishment for the sole purpose of direct
retail sale to individual consumers. This section also states that a
retail establishment does not include a warehouse or other storage
facility for a retailer or a warehouse or other storage facility that
sells directly to individual consumers.
This exclusion represents specific changes sought by the comments.
We provide detail on the comments and our reasons for revising final
Sec. 111.1 in the following paragraphs.
(Comment 26) Some comments interpret the proposal as not applying
to persons who perform labeling operations. For example, one comment
claims that proposed Sec. 111.35(e), which would require
manufacturers, packagers, and persons who hold dietary supplements to
establish specifications, did not apply to ``labelers'' because the
proposed definition of ``you'' did not expressly mention persons who
label dietary supplements.
(Response) We disagree with the comments. Various provisions in the
proposal expressly mentioned or pertained to labels and labeling
operations (see, e.g., proposed Sec. Sec. 111.20(c)(6) (which would
require your physical plant to have separate or defined areas for
packaging and label operations), 111.30(a) (which would impose certain
requirements on automatic, mechanical, or electronic equipment used to
``manufacture, package, label, and hold'' a dietary supplement),
111.35(a) (which would require you to implement a system of production
and process controls that cover, among other things, all stages of
labeling dietary supplements), 111.37(a) (which would require you to
use a quality control unit to ensure, among other things, your label
operations are performed in a manner that prevents adulteration and
misbranding), 111.40(b) and (c) (which would impose certain
requirements on packaging and labels you receive and on persons who
perform label requirements), and 111.70 (which would impose various
requirements on packaging and label operations)). Although the proposed
definition of ``you'' and proposed Sec. 111.1 did not include the word
``label'' or ``labeling,'' we considered label operations to be part of
a broader manufacturing process, and it would be illogical to interpret
the proposal's specific references to label operations as somehow being
inapplicable to labelers simply because a proposed definition of
``you'' or a general ``scope'' provision did not mention labels or
otherwise distinguish label operations from the broader context of
manufacturing.
In any case, to correct such misinterpretation, we have revised
Sec. 111.1 to include the word ``label.'' Thus, under final Sec.
111.1(a), you are subject to the dietary supplement CGMP requirements
if you ``manufacture, package, label, or hold a dietary supplement.''
We also have made corresponding changes to other sections in this final
rule; for example, we have revised the definition of ``you'' in final
Sec. 111.3 to state that ``you'' means ``a person who manufactures,
packages, labels, or holds'' a dietary supplement, and we also have
inserted the word ``labeling'' in the title to this final rule. We have
not explained this change in the preamble each time it is made in the
codified provision.
In addition, we refer to ``label'' and ``labeling'' in the context
of CGMP requirements related to operations for ensuring the correct
label is on the product. To help clarify that we are referring to
labeling requirements in this final rule for labeling operations and
not, for example, to the labeling requirements in part 101, we inserted
the word ``operations'' in the title of part 111 to read ``Current Good
Manufacturing Practice in Manufacturing, Packaging, Labeling, or
Holding Operations for Dietary Supplements.''
(Comment 27) Several comments ask for clarification about the
rule's applicability to different types of businesses and practices.
Some comments ask for a clear listing of who is subject to the rule,
stating that it is difficult to apply the rule's specific provisions.
According to these comments, the rule's level of detail and
inflexibility does not account for variations in manufacturing needs
within the entire industry.
Several comments on various proposed sections ask who would be
responsible for complying with CGMP requirements if more than one party
was involved in the manufacturing, packaging, labeling, or holding of
the dietary supplement. For example, some comments ask whether
consultants are subject to a specific proposed section; others ask who
would be responsible if a firm employed another firm to handle
packaging or labeling operations.
Other comments request clarification regarding the rule's
applicability to distributors. Some comments claim that a person who
holds and sells packaged products should not be subject to dietary
supplement CGMP requirements. Other comments state that dietary
supplement CGMPs should apply to distributors as well as
[[Page 34790]]
manufacturers. These comments assert many supplement distributors are
merely marketers who employ contract manufacturers. The comments said
that, because marketers are the parties providing supplements to
consumers, we should hold marketers responsible for their products and
require marketers to ensure that their contract manufacturers adhere to
CGMP requirements. These comments argue we should not permit marketers
to transfer their responsibilities in delivering safe supplements.
Other comments assert questions about the rule's applicability are
underscored by typical dietary supplement labeling practices where the
contact information listed on the product label pertains to the
distributor/marketer instead of the actual manufacturer.
Collectively, these comments raise a basic question as to which
party or parties are responsible for complying with the dietary
supplement CGMP requirements where more than one party is involved in
the manufacture, packaging, labeling, or holding of that dietary
supplement.
(Response) In the 2003 CGMP Proposal, we stated that it would apply
to a wide variety of activities associated with the manufacture,
packaging, and holding of a dietary supplement, including labeling,
testing, quality control, holding, and distribution (68 FR 12157 at
12175). We stated under proposed part 111 you would need to comply with
those regulations directly applicable to the operations that you
perform and provided examples (id.). All activities may not be
performed by the same person. For example, a manufacturer may contract
with another firm to package and label the dietary supplement in the
containers used for distribution to consumers. Alternatively, a
distributor may contract with one firm to manufacture a dietary
supplement, and another firm to package and label the dietary
supplement that the distributor ultimately distributes under its own
name.
Under this final rule, you must comply with the CGMP requirements
that apply to your operations related to the manufacture, packaging,
labeling, and holding of dietary supplements. It is not practical to
list all possible contractual relationships that persons may enter into
in the manufacture of a dietary supplement, or to list all businesses
or practices that may be subject to the requirements of this final rule
in order for persons to know whether they are subject to requirements
of this final rule. To provide additional clarity about how this rule
may apply to various persons, we provide some examples in the following
paragraphs.
A manufacturer that manufactures a dietary supplement, and then
packages and labels and distributes the dietary supplement, is subject
to all the requirements in this final rule. If that manufacturer
contracts with another person to package and label the dietary
supplement, then the packager/labeler is responsible for complying with
the requirements for packaging and labeling operations, in addition to
other relevant requirements. The packager/labeler, in this example,
would need to comply, not only with the specific requirements related
to packaging and labeling operations in subpart L, but also with the
general requirements related to personnel, physical plant, quality
control, and other requirements that apply to that firm's operations.
However the packager/labeler would not need to comply with requirements
that do not apply to it; for example, the packager/relabeler would not
have to conduct testing on the finished batch of dietary supplement
since it does not manufacture the finished batch of dietary supplement.
A manufacturer who contracts with a person to do packaging and
labeling, but who later distributes the packaged and labeled product,
is ultimately responsible for the dietary supplement it releases for
distribution. The manufacturer would be responsible for the CGMP
requirements for the operations that it performs, including those
related to the release of the product for distribution. For example,
the manufacturer must determine whether the packaged and labeled
dietary supplement it receives from the packager/labeler conforms to
applicable specifications (final Sec. 111.127(d)), and must approve
the release of the packaged and labeled dietary supplement for
distribution (final Sec. 111.127(h)). Although the manufacturer is not
performing the specific activities related to the packaging and
labeling operations done by another person, the manufacturer has an
obligation to know what and how such activities are performed so that
it can make decisions related to whether the packaged and labeled
product conforms to applicable specifications and whether to approve
and release the product for distribution.
Some manufacturers may sell their finished batch of dietary
supplement to a packager/labeler that the packager/labeler may package,
label, and then hold and distribute. The manufacturer and packager/
labeler would each be responsible for complying with the applicable
CGMP requirements related to the operations that they perform. The
manufacturer would not be responsible for the oversight of the
packager/labeler, since the packager/labeler is not under the control
of the manufacturer and has control over the release of the packaged
and labeled dietary supplement.
A manufacturer may decide to hire a contractor or a consultant for
specific operations within the scope of the manufacturer's
responsibilities under the final rule. For example, a manufacturer may
hire a person to calibrate its equipment. The manufacturer is
responsible for complying with the requirements related to its
responsibilities, e.g., calibration requirements in this example, even
though the manufacturer has hired another person to perform that job
task.
In another example, a distributor who purchases a packaged and
labeled dietary supplement and who then holds the product in a
warehouse for distribution to another physical location is subject to
the requirements related to its operations. The codified uses the word
``hold'' since it is a broad term which encompasses the activities of a
distributor. Thus, the distributor would be responsible for complying
with requirements in subpart M, Holding and Distributing, in addition
to other requirements related to its operations (e.g., Personnel,
Physical Plant and Grounds).
In cases where a distributor contracts with a manufacturer to
manufacture a dietary supplement that the distributor then distributes
under its own label, the distributor has an obligation to know what and
how manufacturing activities are performed so that the distributor can
make decisions related to whether the packaged and labeled product
conforms to its established specifications and whether to approve and
release the product for distribution.
(Comment 28) Some comments state that the proposed rule
requirements would require the manufacturer to report adverse events to
us, but would not require those who distribute the product and whose
name is likely to be on the product label, to report adverse events to
us. The comments state that reports of adverse events submitted by
consumers to those who distribute, but do not make, dietary supplements
could be hidden from the public if such persons are not required to
submit those reports to us.
(Response) The comments may have misinterpreted the proposed rule.
The requirement to review and investigate a product complaint is
distinct from any report about the product complaint to
[[Page 34791]]
us. Reporting a complaint to us is not covered by these CGMP
requirements and would be voluntary, unless the complaint is subject to
the statutorily mandated reporting requirements for ``significant
adverse events'' pursuant to the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462),
signed into law on December 22, 2006 (see discussion in section XX of
this document).
Under the procedures that are set forth in subpart O, Product
Complaints (see section XX of this document), a distributor and a
manufacturer are both subject to the requirements related to the review
and investigation of a product complaint that they receive.
(Comment 29) Some comments argue against including minimum CGMPs
necessary for activities related to manufacturing, packaging, labeling,
or holding dietary ingredients in the final rule. Several comments
argue the proposed rule is overly broad and inconsistent with
congressional intent. These comments question whether Congress intended
that CGMP apply to persons involved in the manufacture, packaging,
labeling, and holding of dietary ingredients. The comments also argue
that, if the rule applies to dietary ingredient manufacturers, we would
be establishing precedent and that we lack legal authority to regulate
ingredients rather than the finished products themselves. The comments
state that neither food CGMP nor drug CGMP offers precedent or guidance
on regulating ingredients. The comments argue those who provide dietary
ingredients should be subject to the existing general food CGMP
requirements in part 110 rather than to the dietary supplement CGMP
requirements.
Several comments argue that many dietary ingredients are used in
regular foods and in drugs as well as in dietary supplements. The
comments argue, for some dietary ingredients, their use in dietary
supplements represents a very small percentage of the dietary
ingredient's worldwide usage. The comments say we should allow those
who deal only with dietary ingredients to operate under one set of
regulations, such as the general food CGMP requirements in part 110.
According to these comments, we have not demonstrated either a failure
of the current system or a compelling need to create different
regulations for raw materials common to both the food and dietary
supplement industries. The comments would revise the title of part 111
and proposed Sec. 111.1 and make conforming revisions throughout the
proposed rule to limit the rule's applicability to dietary supplements.
In contrast, other comments say the rule should apply to dietary
ingredient manufacturers as well as to dietary supplement
manufacturers. The comments state that excluding those who provide or
supply dietary ingredients would mean those who have the greatest
expertise in these goods would not be subject to dietary supplement
CGMP requirements and thus fail to cover a crucial step in preventing
the adulteration or contamination of dietary supplements. The comments
argue that, for some dietary ingredients (especially raw botanical and
agricultural goods), the most critical point in ensuring an
ingredient's quality and purity is at time of harvest or creation, and
that this is particularly true with new or original ingredients.
The comments state problems with dietary supplements often arise
from substandard ingredients, and the difficulty in testing the
properties of some botanical and other dietary ingredients at the in-
process or finished product stage makes it necessary to include dietary
ingredient manufacturers in the final rule. Furthermore, these comments
assert a flexible testing scheme that they recommend (which emphasizes
establishing specifications for components, relying on certificates of
analysis from qualified suppliers, qualifying component suppliers, and
establishing written procedures, with testing of finished batches
serving as a check on the overall manufacturing process) makes it
important to regulate dietary ingredient manufacturers.
Other comments suggest we issue a separate or modified set of CGMP
requirements that would apply to persons who manufacture, package,
label, or hold dietary ingredients. These comments say the proposed
rule does not work for all dietary ingredients, especially those
converted from non-food grade to food grade during the manufacturing
process. These comments said the rule should be modified for dietary
ingredients.
(Response) Two issues seem to be raised by these comments: (1)
Whether dietary ingredients are within the scope of this final rule and
(2) whether dietary ingredient manufacturers are subject to this final
rule. Dietary ingredients are included within the scope of this final
rule but dietary ingredient manufacturers are not necessarily subject
to this rule. The definition of ``component'' in this final rule
includes ``any substance intended for use in the manufacture of a
dietary supplement including those that may not appear in the finished
batch of the dietary supplement. Component includes dietary ingredients
(as described in section 201(ff) of the act) and other ingredients''
(final Sec. 111.3). The proposed rule, Sec. 111.3, recognized that
``dietary ingredients'' are ``components'' (68 FR 12157 at 12176)
(describing how dietary ingredients would fall within the proposed
definition of ``component'').
There are specific requirements in this final rule that relate to
components, and thus dietary ingredients, that are used in the
manufacture of a dietary supplement. For example, final Sec. 111.70(b)
requires you to establish certain component specifications. Such
requirements would include specifications for dietary ingredients as
``components.'' It is important to control the components used in the
manufacture of dietary supplements to ensure consistency and to ensure
the quality of the dietary supplement. Since dietary ingredients are
considered components, the various requirements apply to dietary
ingredients as part of the production and process control. Therefore,
we disagree to the extent comments were suggesting that there should be
no CGMP requirements related to the dietary ingredients used by a
manufacturer in the manufacture of dietary supplements.
Dietary ingredients are included within the meaning of
``component.'' In those requirements in the proposed rule where
``component'' encompasses ``dietary ingredient'' we are, in the final
rule, removing ``dietary ingredient'' in those requirements and only
refer to ``component.'' Given the scope of the final rule, it is
redundant to refer to both ``component'' and ``dietary ingredient''
where the latter is subsumed in the former.
In response to comments that questioned the need to include
manufacturers of dietary ingredients within the scope of part 111, we
have made changes to the scope of the rule, as applied to dietary
ingredient manufacturers. As we explain more fully in our discussion of
final Sec. Sec. 111.70, 111.73, 111.75, and 111.77 (see section X of
this document), after considering comments about the overall production
and process control system, we revised the final rule's approach to
ensuring product quality. This approach emphasizes that it is important
to ensure the quality of the dietary supplement throughout the
production and process control system. This approach emphasizes
establishing specifications for components and ensuring those
specifications are met.
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You may rely on a certificate of analysis for specifications (except
for the identity of the dietary ingredient) only if you satisfy certain
criteria, which include qualifying the supplier of the components. With
this approach, the goal of ensuring the quality of dietary supplements
can be achieved without applying the rule specifically to persons who
manufacture, package, label, or hold dietary ingredients that will be
further processed as a dietary supplement by other persons.
Consequently, we revised Sec. 111.1 by deleting ``dietary
ingredient.'' Therefore, those who manufacture, package, label, or hold
dietary ingredients are not subject to the final rule. To illustrate,
assume you manufacture a dietary ingredient and sell that bulk dietary
ingredient to Company X. Company X then utilizes the bulk dietary
ingredient in a dietary supplement. Under final Sec. 111.1(a), you
would not be subject to these dietary supplement CGMP requirements
because you are not manufacturing a dietary supplement, rather you are
manufacturing a dietary ingredient for further incorporation into a
dietary supplement by Company X. If, however, you sell herbs in bulk to
Company X, and Company X simply packages the herbs into smaller units
for sale as a dietary supplement, you would be subject to the dietary
supplement CGMP requirements because you are manufacturing a dietary
supplement that Company X is simply packaging and labeling, and not
further processing into a dietary supplement. In other words, in the
latter example, you would have acted as a manufacturer whose finished
product is simply repackaged or relabeled.
Under final Sec. 111.1(a) persons engaged solely in activities
relating to the harvesting, storage, or distribution of raw
agricultural commodities that will be incorporated into a dietary
supplement by others are not included within the scope of the rule as a
dietary supplement manufacturer. This is because those persons simply
``supply'' a component (i.e., the raw agricultural commodity) that
another person will process into a dietary supplement; thus you do not
manufacture, package, label, or hold a dietary supplement.
Note, too, that if you manufacture and supply a component directly
to consumers as a dietary supplement, you would be considered a dietary
supplement manufacturer within the scope of final Sec. 111.1(a).
Likewise, if you manufacture a component and sell part of the batch to
another person who, in turn, will further process the component as a
dietary supplement and sell the remainder of the batch to consumers as
a dietary supplement, you would be subject to the dietary supplement
CGMP requirements, as a manufacturer, for the product sold to consumers
and not subject to an exclusion under final Sec. 111.1(b), discussed
in this section. In other words, final Sec. 111.1(a) refers to the
nature of your activity, and simply engaging in some activities that do
not bring you within the scope of the final rule does not necessarily
mean that all your activities are outside the scope of the final rule.
We do not agree, as some comments suggested, that we need to issue
a separate or modified set of CGMP requirements for dietary
ingredients. That is because there are adequate controls established in
this final rule for the use of dietary ingredients used by the
manufacturer of a dietary supplement. However, if you manufacture,
package, label, or hold dietary ingredients that will be further
processed as a dietary supplement by another person, you must comply
with food CGMP requirements in part 110. A dietary ingredient is a food
under section 201(f) of the act, as a food, or as a component of food.
Because the final rule gives manufacturers an incentive to qualify
suppliers of dietary ingredients, persons who manufacture, package,
label, or hold dietary ingredients may wish to familiarize themselves
with these dietary supplement CGMP requirements and use them in
manufacturing, packing, labeling, or holding operations for dietary
ingredients.
(Comment 30) Some comments argue if the final rule ultimately
covers dietary ingredient suppliers then we should clarify what
constitutes a ``consumer.'' According to these comments, dietary
ingredient suppliers do not typically supply their products directly to
those individuals who will ultimately consume or ingest them. Thus,
``consumers'' of dietary ingredients are other companies, not
individuals. The comments express concern about the possible
application of proposed Sec. 111.95 which would require procedures for
handling complaints.
(Response) The final rule applies only to persons who manufacture,
package, label, or hold dietary supplements and are not subject to an
exclusion in final Sec. 111.1. However, as explained in the previous
response to comment 29, if a dietary ingredient manufacturer also
supplies or sells a dietary ingredient as a dietary supplement, such a
manufacturer would be subject to final Sec. 111.1(a) and subject to
all relevant dietary supplement CGMP requirements.
Some comments expressed concern about dietary ingredient
manufacturers having to comply with proposed Sec. 111.95 on product
complaints. If a dietary ingredient manufacturer receives a product
complaint, we encourage the manufacturer to evaluate the complaint to
determine if it may involve a problem with the manufacture of the
dietary ingredient. In addition, we encourage the dietary ingredient
manufacturer to notify the dietary supplement manufacturer so that it
can review the complaint and investigate, as needed.
(Comment 31) Several comments question the proposal's applicability
to persons who sell packaged products or seek clarification as to
whether the rule applies to dietary supplement manufacturers that
operate from homes and those that distribute product to other
distributors.
(Response) To the extent that the comments question whether
retailers or individuals who sell dietary supplements directly to
individual consumers are subject to the dietary supplement CGMP
requirements, we have revised the final rule by creating a new Sec.
111.1(b) which states that: ``The requirements pertaining to holding
dietary supplements do not apply to you if you are holding those
dietary supplements at a retail establishment for the sole purpose of
direct retail sale to individual consumers. A retail establishment does
not include a warehouse or other storage facility for a retailer or a
warehouse or other storage facility that sells directly to individual
consumers. '' This means, for example, if you operate a storefront
retail establishment where you stock dietary supplements on your
shelves for purchase by individual consumers, we do not consider you to
be ``holding'' those dietary supplements in a manner that would require
you to comply with the holding provisions in this final rule. Sale to
individual consumers, where you are not storing bulk dietary
supplements as one would in a warehouse or storage facility, does not
fall within the manufacturing, packaging, labeling, or holding
activities that would subject you to dietary supplement CGMP
requirements.
However, if you operate storefront retail establishments, and those
retail establishments obtain their stocks from your warehouse, we would
consider your warehouse operations to be ``holding'' dietary
supplements and expect your warehouse operations to comply with the
rule's holding requirements. Such distribution is no different than
other warehouse operations that are normally subject to CGMP
requirements. Consequently, to
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distinguish between ``holding'' dietary supplements for retail sale to
consumers and ``holding'' dietary supplements in a warehouse for
further distribution, final Sec. 111.1(b) limits the exclusion to
persons holding dietary supplements ``at a retail establishment for the
sole purpose of direct retail sale to individual consumers.'' Final
Sec. 111.1(b) also makes it clear that a retail establishment does not
include a warehouse or other storage facility that a retailer uses to
hold the dietary supplements or an operation that sells directly to
consumers, but that itself distributes the product to the consumer from
a warehouse or storage facility and not from a storefront retail
establishment.
(Comment 32) Many comments question the rule's applicability to
various practitioners such as herbalists, acupuncturists, naturopaths,
and other health care providers who prepare individualized herbal
formulas for specific individuals on a case-by-case basis. Most
comments say such practitioners should not be covered by the rule.
These comments give various reasons to justify their position,
including:
These practitioners do not broadly sell products;
These practitioners make very small quantities of
individualized formulas, and can therefore be very selective as to the
quality of ingredients used;
The testing and storage requirements of each finished
batch cannot apply to a small dispensary where several different
modified herbal formulas are prepared each day;
Based on the projected costs to implement CGMPs, it would
be virtually impossible for an individual practitioner or university
clinic to develop the necessary quality control unit, maintain reserve
samples, maintain the required paperwork, or retrofit clinics to comply
with the rule;
Many States regulate or license these practitioners, so
further Federal regulation is unnecessary;
Some practitioners do not consider themselves to be
manufacturers;
In an analogous situation, compounding pharmacists are not
required to comply with drug CGMPs; and
Despite the growing number of such practitioners, there is
no proof that greater harm has occurred to the general public from the
herbs these practitioners sell.
(Response) We stated in the 2003 CGMP Proposal (68 FR 12157 at
12175) that we declined to exempt herbalist practitioners from the
proposed rule. We continue to believe that the risks of adulteration
are not eliminated just because the practitioner is an herbalist, and
therefore, such an exemption should not be included in this final rule.
However, after further consideration, we have determined that it would
be appropriate for us to consider the exercise of our enforcement
discretion in deciding whether to apply the requirements of this final
rule to certain health care practitioners, such as herbalists,
acupuncturists, naturopaths, and other related health care providers.
We find it noteworthy that the comments identified two potential
safeguards that could support the exercise of our enforcement
discretion on whether to apply the requirements of the final rule to
certain practitioners: (1) Adequate training in the professional
practice and (2) an individual client and practitioner relationship.
For example, comments claimed that the practitioners receive adequate
training to formulate dietary supplements and that they provide the
dietary supplements to individuals in the course of a one-on-one
consultation on the premises of the practitioner. One comment from a
practitioner states that she received her training from an accredited
4-year university and it included didactic and clinical training in
acupuncture and Chinese herbs. Another comment from an organization
provides detailed training guidelines for practitioners, including
1,600 hours of training, 400 hours of which should include clinical
work. Moreover, many comments also assert that the practitioners are
different from dietary supplement manufacturers because they formulate
the dietary supplements in the course of a one-on-one consultation at
their premises. That enables them to ensure the formulations are made
to meet the specific needs of the individuals.
We believe that a one-on-one consultation by a practitioner who is
adequately trained in their profession may not necessitate the same
types of controls as we are establishing in this final rule for
manufacturing activities that are on a larger scale. Such a
practitioner may make some formulations in advance of the consultation
and still make the formulations in very limited quantities for the
individual client. We believe that it would be appropriate to consider
the exercise of our enforcement discretion, on a case-by-case basis, to
determine whether to apply the requirements of this final rule to such
persons.
We do not expect the number of those subject to the consideration
of our enforcement discretion to be very large. Many products that are
manufactured by practitioners would not necessarily be considered to be
dietary supplements (e.g., certain products used by traditional Asian
medicine practitioners). Further, we are not considering exercising our
enforcement discretion with respect to practitioners who prepare
batches of herbs and sell them to individual consumers without
determining whether the dietary supplement is appropriate for each
consumer's needs in a one-on-one personal consultation, or those that
prepare batches of a dietary supplement for which there is a known or
suspected safety concern.
(Comment 33) Several comments asked us to exempt academic
institutions that provide training for therapeutic disciplines that
use, for example, herbal formulas in their practice regardless of
whether the dietary supplements they produce enter into interstate
commerce. Specifically, these comments would revise the final rule to
state that it does not apply ``to academic institutions that provide
training in dispensing of nutritional or herbal products and formulas
related to courses in therapeutic disciplines that provide such
products and formulas as a part of their therapy, for example,
naturopathy, herbalism, traditional Chinese medicine, and
acupuncture.''
(Response) Similar to what we stated in response to comment 32, we
believe that it may be appropriate to consider the exercise of our
enforcement discretion in circumstances where an academic institution's
actions are similar to those of a practitioner who is adequately
trained in their profession and who provides dietary supplements within
the context of an individual client and practitioner relationship. In
general, it is not our policy to inspect an academic institution that
provides training for therapeutic disciplines that use, for example,
dietary supplements in their practice. We intend to consider the
exercise of our enforcement discretion in those situations where there
is a one-on-one consultation that includes a practitioner with adequate
training. We intend to issue guidance to further clarify how the agency
intends to exercise its enforcement discretion on the application of
this final rule to certain academic institutions.
(Comment 34) Several comments discuss the position taken by certain
nations, notably Australia and Canada, that have developed CGMP
requirements and related guidance for botanicals. According to these
comments, these nations recognize that there are various types of
practitioners who sell herbs and herbal preparations in a clinical
setting, and do not consider such persons to be manufacturers. The
[[Page 34794]]
comments ask us to follow the example of these nations.
(Response) We intend to consider the positions taken by other
nations to inform us in our decisionmaking in any future guidance on
how we intend to exercise our enforcement discretion on the application
of this final rule to certain practitioners.
(Comment 35) Many comments say we should define when a dietary
supplement will be said to have entered interstate commerce. The
comments state herbal practitioners (and academic institutions) often
purchase source herbs from outside their State, even if they prepare
these herbs for their specific customers within the State. These
comments request we clarify that the rule does not apply to herbs
purchased out of State if prepared for local use. Other comments
request clarification regarding clients who have moved across State
lines, yet maintain a relationship with an herbalist practitioner.
(Response) In section V of this document we explain the interstate
and intrastate issue related to the final rule.
(Comment 36) A few comments assert individual practitioners and
practitioner organizations often are unaware of the opportunity to
comment on CGMP or regulatory issues. Therefore, the comments say these
practitioners and organizations often fail to provide comment or
otherwise participate in rulemaking and say we should give these
practitioners and practitioner organizations a chance to comment.
(Response) We provided many opportunities for comment and,
therefore, we decline to adopt the comments' suggestion. As we discuss
in section I of this document, we published an ANPRM concerning dietary
supplement CGMPs on February 6, 1997 (62 FR 5700); the 1997 ANPRM
provided an opportunity for public comment. On March 7, 2003, we issued
a Talk Paper, along with other background documents, announcing the
issuance of a proposed dietary supplement CGMP rule. We made the
proposed rule available when it went on display (before it published)
in the Federal Register on March 13, 2003 (68 FR 12157), and, again,
provided an opportunity for public comment. We also held public
meetings on April 29, 2003, in College Park, MD and on May 6, 2003, in
Oakland, CA. We also held a public meeting (via satellite downlink) on
May 9, 2003, with viewing sites at our district and regional offices
throughout the country. Thus, we provided numerous opportunities for
interested persons to learn about the rule and to submit comments or
otherwise participate in the rulemaking process. Consequently, we
decline to provide yet another opportunity for comment.
(Comment 37) The preamble to the 2003 CGMP Proposal noted that
comments submitted in response to our 1997 ANPRM state we should not
distinguish between dietary supplements made in the United States and
those made in a foreign country (68 FR 12157 at 12174). Although we
agreed with the comments and made no distinction between foreign and
domestic firms in the proposed rule, we invited comment on how we might
ensure dietary ingredients and dietary supplements exported to the
United States have been manufactured, packaged, labeled, and held
consistent with part 111 (68 FR 12157 at 12175).
Several comments argue the rule should apply to foreign firms as
well as domestic manufacturers to ensure a ``level playing field'' and
to protect American consumers. Some comments say we should work with
foreign countries to harmonize our requirements and thus avoid
potential trade disputes under international trade agreements such as
the General Agreement on Tariffs and Trade. Other comments suggest
compliance by foreign firms could be achieved through the use of third
party certification programs, such as the dietary supplement
verification program administered by USP, or the adoption of importer
verification provisions similar to those used in our HACCP requirements
for seafood (see Sec. 123.12).
In contrast, another comment says we should inspect foreign firms
to ensure compliance, whereas other comments claim we lack jurisdiction
over foreign firms.
(Response) We are amending proposed Sec. 111.1 to clarify the
regulation's applicability to foreign firms. We explain in this section
how we may enforce the rule against foreign firms. We, however, are not
making any changes in response to the comments calling for the
harmonization of the rule with foreign rules because this request is
beyond the scope of the final rule.
In response to comments, and for clarification, we have revised
final Sec. 111.1(a) to clarify that the regulation applies to the
extent that you manufacture, package, label, or hold a dietary
supplement, including a dietary supplement imported or offered for
import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico.
With respect to the comments requesting that we make clear our
position for enforcing the rule against foreign firms, we explain our
position as follows. Section 801(a) of the act (21 U.S.C. 381a)
authorizes us to refuse admission of an imported food if it appears
from the examination of such samples or otherwise that such article is,
among other things, adulterated. A foreign firm's refusal to allow us
to obtain records via an inspection for CGMP purposes, as required by
final Sec. 111.610 (for the dietary supplements the foreign firm
offers for import into the United States), would create the appearance
that such imported dietary supplements are adulterated under section
402(g) of the act, and thus, could lead to a refusal of admission under
section 801(a) of the act.
Foreign firms who ship to the United States must operate under
conditions that satisfy our regulations, including the requirement that
records be made available during the course of an FDA inspection. We
note that except in circumstances where there is a public health
emergency or we receive information that would indicate the appearance
of adulteration of products shipped to the United States, foreign
inspections are generally scheduled well, e.g., weeks, in advance.
Thus, we believe that taking action under section 801 of the act is
appropriate if companies do not accommodate our inspectional request.
C. What Definitions Apply to This Part? (Final Sec. 111.3)
Section 111.3 defines various terms that we use in the final rule
and notes that definitions or interpretations of terms in section 201
of the act also apply. In general, we adopted the definitions that we
proposed, although, in some cases, we deleted words or concepts as a
result of other changes we made to the final rule. We have added a
definition of ``quality'' for purposes only of this final rule.
A recurring change we made is the deletion of the words ``dietary
ingredient'' in several definitions. In some cases, the use of the
words ``dietary ingredient'' was redundant to the use of ``component''
and thus not necessary in the final rule. Because a ``dietary
ingredient'' is subsumed within the definition of ``component,'' as
explained in our response to comment 29, we deleted ``dietary
ingredient'' in those definitions where ``component'' was used to avoid
redundancy.
In other provisions, we deleted ``dietary ingredient'' from the
definition because the use of those words was no longer necessary given
the narrowing of the scope of the rule as it applies to dietary
ingredient manufacturers (explained in the response to comments
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29 and 30). For example, we deleted ``dietary ingredient'' from the
proposed definition of ``ingredient'' that referred to the
``manufacture of a dietary ingredient or dietary supplement'' and the
``finished batch of the dietary ingredient or dietary supplement.'' We
did not need to state ``manufacture of the dietary ingredient'' or
refer to ``finished batch of dietary ingredient'' because dietary
ingredient manufacturers that only supply such ingredients to other
persons for processing into a dietary supplement are not subject to the
final rule.
We discuss changes to the definitions, other than the changes we
have made globally such as the deletion of ``dietary ingredients,'' the
change from ``include, but not limited to'' to ``includes'' or
``include,'' the addition of labels and labeling, and the deletion of
the word ``quality'' from the phrase ``identity, purity, quality,
strength, and composition,'' as well as comments asking us to define
more terms or to delete certain definitions, in more detail in the
following paragraphs.
1. Actual Yield
The final rule defines ``actual yield'' as ``the quantity that is
actually produced at any appropriate step of manufacture or packaging
of a particular dietary supplement.''
We received no substantive comments to the proposed definition.
2. Batch
The final rule defines ``batch'' as ``a specific quantity of a
dietary supplement that is uniform, that is intended to meet
specifications for identity, purity, strength, and composition, and
that is produced during a specified time period according to a single
manufacturing record during the same cycle of manufacture.''
This definition differs from the proposed definition of ``batch''
by stating that a batch is a specific quantity of a dietary supplement
that is ``uniform.''
We inserted the word ``uniform'' in response to comments asking
that we define ``lot'' to be consistent with ``batch.'' We explain our
reasons for harmonizing the definitions and for inserting ``uniform''
into the definition of ``batch'' in the response to comment 42 of this
document.
We discuss the comments on our proposed definition of ``batch'' and
our changes to the definition in our responses to the following
comments.
(Comment 38) Several comments ask us to clarify what the ``same
cycle of manufacture'' is in the definition of ``batch.'' One comment
asks if it meant the same product made with the same lot(s) of raw
materials regardless of how many days it took to produce the batch, or
if it meant a quantity produced in 1 day. The comment also asks whether
batches produced on consecutive days, using the same formula, can be
considered to be the same batch with respect to the proposed testing
requirements if the quality control unit determined that different lots
of raw materials are equivalent (e.g., by meeting all specifications).
(Response) The ``same cycle of manufacture'' refers to a process
during which equipment remains dedicated to the manufacture of the
batch. The terms do not limit you to any particular time period or
require you to operate equipment continuously until you have completed
the ``same cycle of manufacture.'' The ``same cycle of manufacture''
also does not limit the number of lots of components you use.
You may consider, as one batch, a product produced using different
lots of raw materials where the production of the batch is a continuous
process on a dedicated line. However, for each component that you use
in the manufacture of the batch of dietary supplement, you would need
to establish specifications under final Sec. 111.70, determine whether
these specifications are met under final Sec. 111.73, and ensure that
these component specifications are met using the criteria under final
Sec. 111.75. Further, you may not consider different batches of
product produced on consecutive days using the same formula to be the
same batch for purposes of testing requirements. The term ``different
batches'' suggests that the production is not a continuous process on a
dedicated line.
3. Batch Number, Lot Number, or Control Number
The final rule defines these terms as ``any distinctive group of
letters, numbers, or symbols, or any combination of them, from which
the complete history of the manufacturing, packaging, labeling, and/or
holding of a batch or lot of dietary supplements can be determined.''
We received no substantive comments on the definition. We added the
word ``and'' before ``or'' to emphasize that the history of each
activity must be able to be determined.
4. Component
The final rule defines ``component'' as ``any substance intended
for use in the manufacture of a dietary supplement, including those
that may not appear in the finished batch of the dietary supplement.
Component includes dietary ingredients (as defined in section 201(ff)
of the act) and other ingredients.''
The definition of component now refers only to the manufacture of a
dietary supplement (whereas the proposal also referred to the
manufacture of dietary ingredients). We also made a nonsubstantive,
editorial revision in the last sentence to put parentheses around the
reference to section 201(ff) of the act and to change the word order so
that ``component'' includes ``dietary ingredients * * * and other
ingredients.'' (The proposed definition had ``components'' including
``ingredients and dietary ingredients.'')
(Comment 39) Some comments would distinguish among ``raw
material,'' ``components,'' and ``starting material'' because the
comments said that defining ``component'' to include all these
materials is confusing. One comment adds that many starting materials
are not food grade or approved food ingredients until they have been
processed. One comment states the term ``raw material'' is typically
used to describe the materials (such as dietary ingredients, fillers,
and processing aids) that will be used to make the final product. The
comment further states ``component'' is typically used to describe the
specific items used to assemble the finished product for the end user.
The components would include packaging components such as bottles,
caps, and labels, as well as the bulk dietary supplement. This comment
also suggests that we use the term ``starting material'' to distinguish
substances used in the manufacture of dietary ingredients from
substances used in the manufacture of dietary supplements.
(Response) We decline to revise the rule as suggested by the
comments. There may be differences in how components are referred to by
certain manufacturers and how we refer to it in this final rule.
However, for purposes of this final rule we refer to all substances
used in the manufacture of dietary supplements as ``components,''
whether or not those substances appear in the finished product.
Please note that, although ingredients are ``components'' under our
definition, not all components are ingredients. For example, a solvent
used to make an herbal extract is not an ingredient when it is removed
from the extract by a process such as drying, because the solvent was
not intended to be present in the finished dietary supplement. However,
the solvent would be a ``component'' because it was used in the
manufacture of the dietary supplement.
[[Page 34796]]
As for materials that might not be food grade or approved food
ingredients until processing, see the discussion in response to comment
240 in section XII of this document.
(Comment 40) Several comments express concern that ``component''
could be interpreted to mean any constituent present in a botanical
extract or other natural product. The comments say a single botanical
can contain tens of thousands of constituents or metabolites and that
chemists have not identified all constituents of a single botanical.
According to the comments, the cost of testing for all constituents
would exceed a product's total annual revenues.
(Response) In general, we would consider the botanical extract or
the other natural product to be the ``component'' as defined in this
final rule rather than consider that all the various chemical
substances contained in the botanical extract or other natural product
are components. Thus, if you are manufacturing a dietary supplement
that is intended to provide a certain substance (e.g., vitamin C ) and
you add a natural product which is intended to supply the vitamin C
(e.g., vitamin C in the form of rosehips), we would consider the
natural product (e.g. rosehips that contain a certain amount of vitamin
C) to be a component which must be listed in the master manufacturing
record. The component specifications for the rosehips must include a
specification for the strength of the substance (e.g., vitamin C) in
whatever amount you determine is necessary to meet the specification
for the strength of the vitamin C in the finished batch of dietary
supplement. Under final Sec. 111.70, we expect you to establish
specifications for the natural product and ensure that the
specifications are met. As an example relevant to an extract, if you
are manufacturing a dietary supplement that is intended to provide a
certain amount of vitamin C that derives from the natural product
rosehips, and the substance that you purchase from a supplier to add as
a component is a purified extract of rosehips (rather than rosehips
themselves), we would consider the purified extract to be a component
(as an ingredient). The component specifications for the purified
extract must include a specification for the strength of the substance
(i.e., vitamin C) in whatever amount you determine is necessary to meet
the specification for the strength of the vitamin C in the finished
batch of dietary supplement. However, in this example ``rosehips''
would not be considered a component, because ``rosehips'' is not what
you added.
5. Contact Surface
The final rule defines ``contact surface'' as ``any surface that
contacts a component or dietary supplement, and those surfaces from
which drainage onto the component or dietary supplement, or onto
surfaces that contact the component or dietary supplement, occurs
during the normal course of operations.'' The final rule lists
containers, utensils, tables, contact surfaces of equipment, and
packaging as examples of ``contact surfaces.''
We did not receive any substantive comments on the proposed
definition. We deleted ``ordinarily'' from ``ordinarily occurs during
the normal course of operations'' because ``ordinarily'' is redundant
to ``normal.''
6. Ingredient
The final rule defines ``ingredient'' as ``any substance that is
used in the manufacture of a dietary supplement and that is intended to
be present in the finished batch of the dietary supplement. An
ingredient includes, but is not necessarily limited to, a dietary
ingredient as defined in section 201(ff) of the act.'' We did not
receive any substantive comments on this definition. We made a
nonsubstantive, editorial change to replace ``finished dietary
supplement'' with ``finished batch of the dietary supplement.''
(Comment 41) One comment says we should define ``ingredient''
better to ensure consistent interpretation of CGMP at all levels
throughout the dietary supplement industry.
(Response) We disagree with the comment. We believe the definition
is adequate, including as it does both dietary ingredients as described
in section 201(ff) of the act and other ingredients that do not fit
that description, such as an emulsifier used to establish a uniform
dispersion in a liquid dietary supplement or a color additive used to
color a capsule. Moreover, the comment did not explain or specify which
aspects of the proposed definition should be revised or explain why the
proposed definition would lead to inconsistent interpretations of CGMP.
7. In-Process Material
The final rule defines ``in-process material'' as ``any material
that is fabricated, compounded, blended, ground, extracted, sifted,
sterilized, derived by chemical reaction, or processed in any other way
for use in the manufacture of a dietary supplement.''
We did not receive any substantive comments on the proposed
definition.
8. Lot
The final rule defines ``lot'' as ``a batch, or a specific
identified portion of a batch, that is uniform and that is intended to
meet specifications for identity, purity, strength, and composition;
or, in the case of a dietary supplement produced by continuous process,
a specific identified amount produced in a specified unit of time or
quantity in a manner that is uniform and that is intended to meet
specifications for identity, purity, strength, and composition.''
The final rule differs from the proposed definition in that the
proposed definition of ``lot'' would have the batch or specific
identified portion of a batch be intended to have ``uniform identity,
purity, quality, strength, and composition.''
(Comment 42) One comment agrees with the proposed definition for
``lot,'' but several other comments would revise the definition to be
more consistent with the proposed definition of ``batch.''
Specifically, the comments note the proposed definition of ``batch''
would refer to a quantity of dietary supplement that is ``intended to
meet specifications for identity, purity, quality, strength and
composition,'' whereas the proposed definition of ``lot'' would refer
to a batch or specific identified portion of a batch that is ``intended
to have uniform identity, purity, quality, strength, and composition.''
The comments would revise the definition of ``lot'' by deleting the
phrase ``intended to have uniform'' and inserting the phrase ``intended
to meet specifications for'' in order to make the definitions of
``batch'' and ``lot'' consistent.
(Response) We agree that the definitions for ``batch'' and ``lot''
should be consistent, but we disagree with the comments' suggestion to
delete the term ``uniform'' from the definition of ``lot.'' The
attributes of a lot or batch should be uniform throughout the lot or
batch and meet established specifications for those attributes. If
samples from a lot or batch were tested for appropriate specifications
of identity, purity, strength, and composition, the attributes should
be consistent throughout the sample and be uniform from sample to
sample regardless of whether the test samples are taken from the
beginning, middle, or end of the lot or batch. Consequently, we revised
the definition of ``lot'' to state, in relevant part, that a ``lot'' is
a batch or specific identified portion of a batch that ``is uniform and
that is intended to meet specifications
[[Page 34797]]
for identity, purity, strength, and composition'' or, for dietary
supplements produced by a continuous process, a specific identified
amount produced in a specified unit of time or quantity in a manner
that is uniform and that is intended to meet specifications for
identity, purity, strength, and composition.''
Similarly, we revised the definition of ``batch'' so that it
states, in relevant part, that a ``batch'' is a specific quantity of a
dietary supplement ``that is intended to meet specifications for
identity, purity, strength, and composition.''
These revisions make the definitions of ``batch'' and ``lot''
consistent.
9. Microorganisms
The final rule defines ``microorganisms'' as ``yeasts, molds,
bacteria, viruses, and other similar microscopic organisms having
public health or sanitary concern.'' It adds that the definition
includes species that: (1) May have public health significance; (2) may
cause a component or dietary supplement to decompose; (3) indicate that
the component or dietary supplement is contaminated with filth; or (4)
otherwise may cause the component or dietary supplement to be
adulterated.
(Comment 43) One comment would revise the definition to identify
specific microorganisms that have public health or sanitary concern
(i.e., Salmonella species, Escherichia coli, Pseudomonas aeruginosa,
and Staphylococcus aureus). The comment says this would be consistent
with USP requirements.
(Response) We disagree with the comment. A list of specific
microorganisms could easily become outdated as new pathogens emerge,
and constantly issuing new rules to revise the list would be both
inefficient and impractical.
(Comment 44) One comment expresses concern that the proposed
definition for microorganisms would include microorganisms that are a
natural part of the ecology of all natural products. The comment says
certain levels of microorganisms are expected on botanical raw
materials (i.e., those naturally occurring or introduced through
organic cultivation techniques) and that many do not present a public
health risk. The comment expresses concern that nonpathogenic
microorganisms that are not a public health risk would be a
``sanitary'' concern that would render a product adulterated. The
comment argues there should be little concern about the presence of
microorganisms that present no public health consequence, and so we
should revise the definition accordingly. The comment further discusses
the difficulties in ``sterilizing'' botanicals to render them free of
microorganisms associated with insanitary conditions. The comment notes
that some international organizations have established ``upper limits''
for these organisms for botanical supplements, which, in the comment's
opinion, represent more realistic standards than trying to attain a
``sterile'' botanical supplement.
(Response) We disagree with the comment. We do not interpret the
definition of ``microorganism'' as making the presence of nonpathogenic
microorganisms that are not a public health risk a ``sanitary concern''
that would render a product adulterated. Instead, we interpret the
definition as saying that microorganisms of public health significance
and microorganisms presenting sanitary concerns are ``microorganisms''
under this rule. These are the types of microorganisms that may cause a
component or dietary supplement to become adulterated.
As for upper limits on microbial contamination, the comment offered
no suggested limits, and we decline to establish such limits in this
rule. The final rule requires manufacturers to establish limits for
those types of contamination that may adulterate or lead to
adulteration of components or dietary supplements. Thus, for example, a
manufacturer of a botanical dietary supplement would have to determine
what, if any, microorganisms are likely or certain to be present and
establish limits, as appropriate to prevent adulteration of the
finished batch of the dietary supplement.
We have modified the word ``have'' with the word ``may'' to
indicate that the determination or evaluation of whether there is a
``public health significance'' is not made after the fact. There does
not have to be a factually established determination of public health
significance for you to conclude that the microorganisms ``may
adulterate'' the dietary supplement. The change from ``could cause'' to
``may cause'' is to be consistent with the previous change to ``may
have.''
10. Must
The final rule explains that the word ``must'' is ``used to state a
requirement.''
(Comment 45) One comment would revise the definition to say that
the term ``must'' be used to state mandatory requirements ``unless
shown to be inapplicable or replaced by an alternative demonstrated to
provide at least an equivalent level of quality assurance.''
(Response) We decline to revise the rule as suggested by the
comment. The comment's revision would undermine the reasons for issuing
a rule. Rules create enforceable requirements. It is not clear, nor did
the comment discuss, how we could enforce the requirements in this
final rule if firms were able to avoid a particular requirement by
declaring them to be ``inapplicable'' or substituting alternatives
which they felt they had demonstrated were ``at least an equivalent
level of quality assurance.'' There would be inconsistency in the
general CGMP practices used within the dietary supplement industry and
uncertainty as to whether the process and production controls ensure
the quality of the dietary supplement. Consequently, we decline to
revise the rule as suggested by the comment.
We have, however, made a nonsubstantive, editorial change to the
definition so that ``must'' is used to state ``a requirement.'' The
proposed definition had referred to ``mandatory requirements.'' Since a
requirement by its nature is mandatory, the word ``mandatory'' is
unnecessary.
11. Pest
The final rule defines ``pest'' as ``any objectionable insect or
other animal, including birds, rodents, flies, mites, and larvae.''
We did not receive any substantive comments on this definition.
However, on our own initiative, we made nonsubstantive, editorial
changes to delete the words, ``but not limited to'' after ``including''
and to place the word ``animals'' in the singular.
12. Physical Plant
The final rule defines ``physical plant'' as ``all or any part of a
building or facility used for or in connection with manufacturing,
packaging, labeling, or holding a dietary supplement.''
We received no substantive comments on this definition. The final
rule is substantially similar to the proposed rule's definition of
``physical plant.'' We added ``any'' and placed ``part'' in the
singular to clarify that individual parts of a building or facility are
subject to the CGMP requirements.
13. Product Complaint
The final rule defines ``product complaint'' as ``any communication
that contains any allegation, written, electronic, or oral, expressing
concern, for any reason, with the quality of a dietary supplement, that
could be related to current good manufacturing practice. Examples of
product complaints are: Foul odor, off taste, illness or injury,
disintegration time,
[[Page 34798]]
color variation, tablet size or size variation, under-filled container,
foreign material in a dietary supplement container, improper packaging,
mislabeling, or dietary supplements that are superpotent, subpotent, or
contain the wrong ingredient, or contain a drug or other contaminant
(e.g., bacteria, pesticide, mycotoxin, glass, lead).''
This definition modifies the proposed rule's definition of
``consumer complaint,'' which would define such a complaint as any
``communication that contains any allegation, written or oral,
expressing dissatisfaction with the quality of a dietary supplement
related to good manufacturing practices. Examples of product quality
related to good manufacturing practices are: Foul odor, off taste,
superpotent, subpotent, wrong ingredient, drug contaminant, other
contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead),
disintegration time, color variation, tablet size or size variation,
under-filled container, foreign material in a dietary supplement
container, improper packaging, or mislabeling. For the purposes of this
regulation, a consumer complaint about product quality may or may not
include concerns about a possible hazard to health. However, a consumer
complaint does not include an adverse event, illness, or injury related
to the safety of a particular dietary ingredient independent of whether
the product is produced under good manufacturing practices.''
We explain the reasons for revising the proposed definition in our
response to the following comments.
(Comment 46) Some comments would broaden the definition of consumer
complaint to include complaints from dietary ingredient suppliers. One
comment would change ``consumer complaint'' to ``customer complaint.''
(Response) As discussed in section VI of this document, the final
rule does not apply to those who only manufacture dietary ingredients.
However, we encourage such firms that receive complaints about a
dietary supplement to share those complaints with those in the
manufacturing chain associated with that dietary supplement's
manufacture so others may take corrective action as needed. Those who
engage in the manufacture of a dietary supplement, including
manufacturing, packaging, labeling, and holding operations, are
responsible for complying with this final rule's product complaint
requirements.
Furthermore, we encourage packagers, labelers, and distributors who
receive a product complaint to notify those in a dietary supplement's
manufacturing chain about product complaints they receive or they,
themselves, generate that may relate to operations outside the
packagers', labelers', or distributors' control. For example, a
distributor who purchases a dietary supplement in bulk for packaging
and labeling may complain about product quality to the dietary
supplement manufacturer. The manufacturer who receives the complaint
must then take appropriate action to determine whether the complaint
involves a possible failure of a dietary supplement to meet any CGMP
requirements. Thus, the final rule revises the term ``consumer
complaint'' to ``product complaint'' to emphasize that the complaint is
about the product regardless of the complaint's source.
(Comment 47) One comment disagrees that ``disintegration time'' and
``tablet size'' are appropriate examples of complaints about product
quality specifications.
(Response) We disagree with this comment. Complaints about
disintegration time or tablet size could indicate a problem with the
production and process control system that may affect the quality of
the dietary supplement.
(Comment 48) Some comments disagree with the proposed definition of
``consumer complaint'' because it excluded an adverse event, illness,
or injury related to the safety of a particular dietary ingredient. The
comments say there should be a consistent approach for handling all
complaints, including adverse events. One comment states consumers will
not be able to determine whether a product quality issue related to
CGMP caused an adverse event. This comment expresses concern that not
classifying adverse events as consumer complaints could lead
manufacturers to avoid investigating certain adverse events and,
therefore, prevent them from determining the appropriate cause and
implementing the associated corrective action. The comments stress we
should not treat complaints related to CGMP issues differently from
other complaints and urged us to classify all adverse events as
consumer complaints, whether or not they might have been caused by a
particular dietary ingredient.
A few comments state the proposal, which did not specifically
address adverse event reporting, but did address the broader category
of consumer complaints and would require companies to investigate
``adverse event reports,'' may simply create more confusion and may
contradict the overall objective of a comprehensive adverse event
reporting system. The comments also state neither the food CGMP
regulations nor the 1997 ANPRM defined ``consumer complaints.'' The
comments say we should delete this definition and deal with consumer
complaints separately as part of the new CFSAN Adverse Event Reporting
System (CAERS).
One comment states we should define the term ``serious adverse
dietary supplement experience.'' The comment would define a ``serious
adverse dietary supplement experience'' as ``any adverse dietary
supplement experience occurring at any dose that results in any of the
following outcomes: death, a life-threatening adverse dietary
supplement experience, inpatient hospitalization or prolongation of
existing hospitalization, a persistent or significant disability/
incapacity, or a congenital anomaly/birth defect. Important medical
events that may not result in death, be life-threatening, or require
hospitalization may be considered a serious adverse dietary supplement
experience and, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in this
definition.''
(Response) We decline to include in the definition of ``product
complaint'' an adverse event related to the safety of a particular
dietary ingredient. The final rule establishes CGMP requirements for
dietary supplements and does not focus on whether dietary ingredients
that manufacturers may use in their dietary supplements are inherently
safe. Nevertheless, we encourage firms to investigate all complaints,
regardless of whether the complaints relate to CGMP. Furthermore,
mandatory reporting to FDA of serious adverse events is now required as
a result of the enactment of the ``Dietary Supplement and Non-
Prescription Drug Consumer Protection Act'' (Public Law 109-462),
signed into law on December 22, 2006. In any event, consistent with
these CGMP requirements, manufacturers must establish limits on
contamination, as needed, for all ingredients or any component they use
in manufacturing a dietary supplement.
We agree it may be unclear whether a particular product complaint
is related to CGMP. Final Sec. 111.560, relating to product
complaints, applies in situations where the product complaint involves
a ``possible failure of a dietary supplement to meet any of its
specifications or any other requirements of this part.'' Thus, if a
firm is unclear whether a particular complaint it receives relates to a
CGMP issue, we would consider that complaint to be related to a
``possible failure'' to meet CGMP. Consequently, the firm must
[[Page 34799]]
comply with the requirements in subpart O, unless the firm
affirmatively determines that the complaint is not related to a
``possible failure'' to meet CGMP, and therefore, is not a ``product
complaint.'' To make this clear, we revised the definition so that it
applies to any ``communication * * * that could be related to good
manufacturing practice'' rather than to be any ``communication * * *
that is related to good manufacturing practice.''
We disagree with comments that suggested that the requirements for
product complaints would somehow contradict the overall objective of
the CAERS. This final rule has no effect on the mandatory or voluntary
reporting of adverse events. We agree some adverse events may be
related to a failure to ensure the quality of the dietary supplement as
required by the final rule. To the extent that an adverse event is
associated with CGMP, it would be considered a ``product complaint''
under the final rule. The fact that it is considered a product
complaint does not mean that such complaint could not be voluntarily
reported as an adverse event through CAERS. Such a complaint may be
required to be reported under the mandatory reporting requirements of
the ``Dietary Supplement and Non-Prescription Drug Consumer Protection
Act'' (Public Law 109-462), signed into law on December 22, 2006. We
have added ``illness or injury'' to the final rule's definition of
``product complaint'' as an example of a product problem relating to
CGMP to help clarify that there may be some overlap in the type of
complaints related to product quality that may also be considered an
adverse event.
As for defining ``serious adverse dietary supplement experience,''
we decline to add such a definition to the final rule. We define
certain terms in a rule to give those terms a clear and consistent
meaning. None of the provisions in this rule addresses or even mentions
``serious adverse dietary supplement experiences,'' so there would be
no advantage in codifying a definition for the term in this final rule.
If, however, the comment meant to narrow the definition of ``consumer
complaint'' to ``serious'' illness, or injury, we decline to do so. If
a consumer reports an illness or injury, which he or she attributes to
consuming a dietary supplement, the report may indicate a problem with
the production and process control system for that dietary supplement,
even if the injury or illness is not ``serious'' or severe.
We have, however, decided to delete the last two sentences in the
proposed definition of ``consumer complaint'' (now ``product
complaint'' in the final rule). These sentences explained, in part,
that a consumer complaint does not include an adverse event, illness,
or injury related to the safety of a particular dietary ingredient
independent of whether the product is produced under CGMP. We deleted
those sentences because they are unnecessary to include in the
definition and can be included as further explanation of what the
definition of ``product complaint'' means in the preamble discussion.
The proposed definition of ``consumer complaint'' used the phrase
``expressing dissatisfaction with the quality of a dietary * * *
supplement;'' the final rule uses the phrase ``expressing concern, for
any reason, with the quality of a dietary supplement.'' This change is
to ensure that even if the consumer is not actually dissatisfied with
the product, but has a concern with the product, this is still handled
as a product complaint.
We made several editorial or grammatical changes to the definition
of product complaint in this final rule for simplicity and revised the
order of the listed examples of product complaints. For example, the
proposed definition of ``consumer complaint'' states the term ``means
communication that contains any allegation * * *.'' The final rule
defines ``product complaint'' as meaning ``any communication that
contains any allegation * * *.'' Another nonsubstantive change was to
insert the words ``dietary supplements that are'' before ``superpotent,
subpotent'' to give the reader a clear understanding as to the article
that is superpotent or subpotent.
Finally, we added ``electronic'' as an example of how a product
complaint could be communicated to ensure that all forms of
communication are included and added ``current'' to modify ``good
manufacturing practice'' for consistency.
We discuss in section V of this document, our general response to
the comment that stated that neither the food CGMP regulations nor the
1997 ANPRM contains a definition of ``consumer complaint,'' is in our
discussion of whether this final rule exceeds our authority or it has
to be identical to the food CGMP regulations. More specifically, we
acknowledge that the industry draft that we published in the 1997 ANPRM
did not define ``consumer complaint.'' The industry draft did contain
provisions that would be directed to ``complaint files.'' The
provisions for complaint files would require the use of written
procedures to handle complaints, retention of records of complaints for
a certain time period, and the inclusion of specific information in the
record of a complaint.
14. Quality
For purposes solely of this final rule we have decided to define
``quality.'' Quality means that the dietary supplement consistently
meets the established specifications for identity, purity, strength,
and composition and limits on contaminants and has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
(Comment 49) Some comments asked that we define ``quality.'' Some
comments claimed the proposal described ``quality'' in terms of
``identity,'' ``purity,'' and ``composition.'' One comment would define
``quality'' as ``the total characteristics of a product that bear on
its ability to satisfy stated (i.e., labeled) or implied needs of
identity, purity, strength and composition.'' Another comment would
define ``quality'' as ``having the appropriate identity, purity, and
strength for the intended purpose.'' Another comment would define
quality using all the other attributes of identity, purity, strength
and composition.
(Response) For purposes only of this final rule, we have added a
definition of quality. This definition is not intended to apply to CGMP
requirements other than those that apply to dietary supplements. In
section III of this document, in the overview discussion, we discuss
the concept of ``quality'' as it applies to these dietary supplement
CGMP requirements and the distinction between the use of the term in
the final rule and in the proposed rule.
Because we have defined ``quality'' as encompassing identity,
purity, strength, and composition, we have revised each section with
requirements for the ``identity, purity, quality, strength, and
composition'' to remove the word ``quality.'' The affected sections in
this final rule are: Sec. 111.3 (definition of batch); Sec. 111.3
(definition of lot); Sec. 111.65 (``What are the requirements for
quality control operations?''); Sec. 111.70 (``What specifications
must you establish?''); Sec. 111.75 (``What must you do to determine
whether specifications are met?''); Sec. 111.80 (``What representative
samples must you collect?''); Sec. 111.95 (``Under this subpart E,
what records must you make and keep?''); Sec. 111.105 (``What must
quality control personnel do?''); Sec. 111.455 (``What requirements
apply to holding components, dietary supplements, packaging, and
labels?''); and Sec. 111.515
[[Page 34800]]
(``When must a returned dietary supplement be bestroyed, or otherwise
suitably disposed of?'').
15. Quality Control
The final rule defines ``quality control'' as ``a planned and
systematic operation or procedure for ensuring the quality of a dietary
supplement.'' The proposed rule defined ``quality control'' as ``a
planned or systematic operation for preventing a dietary ingredient or
dietary supplement from being adulterated.''
(Comment 50) One comment suggests revising the definition to use
more positive language. Specifically, the comment would define
``quality control'' as ``a planned and systematic operation or
procedure for ensuring the quality of dietary supplement products.''
(Response) We agree that the comment's suggested language conveys a
positive concept about quality control's role and value and adopt the
language in part. The final rule's quality control requirements will
help ensure compliance with other CGMP requirements and, therefore,
will help ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record. We have defined the term ``quality'' in this
final rule as including preventing a dietary supplement from being
adulterated. Consequently, we revised the definition of ``quality
control'' to state that ``quality control'' means a planned and
systematic operation or procedure ``for ensuring the quality of a
dietary supplement.'' We deleted ``for preventing a dietary ingredient
or dietary supplement from being adulterated'' in the proposed
definition since the concept of quality includes preventing
adulteration.
16. Quality Control Personnel
The final rule defines ``quality control personnel'' as ``any
person, persons, or group, within or outside your organization, who you
designate to be responsible for your quality control operations.''
(Comment 51) Some comments seem to suggest that the reference in
the 2003 CGMP Proposal to a ``quality control unit'' mandates a
separate unit or department with responsibility for all quality control
operations. One comment explains many companies do not have one quality
control unit with oversight of all operations within the facility. This
comment states companies commonly have each separate section of an
operation perform both its function and its own quality control. A few
comments would clarify the definition by indicating that a distinct or
separate unit need not perform the quality control function. These
comments say the quality control function is best performed by a person
or persons qualified by training, education, or experience in the
different processing areas.
Many comments say we should consider any individual carrying out a
quality control function to be part of the quality control unit for
purposes of this rule.
(Response) We agree that the quality control function is best
performed by a person or persons qualified by training, education, or
experience in relevant areas. To the extent that the comments
interpreted the proposed definition as requiring firms to have a
separate person or group whose sole function in the company is to
perform quality control operations or that the quality control
functions are limited to those who are employed within the firm, we
disagree. As discussed in the preamble to the proposal, the quality
control unit should consist of as many people as necessary to perform
the quality control operations (68 FR 12157 at 12252). We have
reconsidered the use of the term ``unit.'' In order to clarify that we
do not intend to require a separate division or office be created, we
instead use the term ``personnel.'' Although we have eliminated
references to ``unit,'' we still agree that personnel can be a person,
persons, or a group, and as many persons as necessary, who perform the
quality control operations. The manufacturer must identify the
appropriate person or persons to be responsible for the quality control
operations associated with a particular manufacturing operation. For
example, the manufacturer may designate one individual as a packaging
expert who is responsible for the quality control operations related to
packaging, designate a second individual as an expert in deciding
whether to accept or reject incoming components, and designate a third
individual as an expert in deciding whether in-process specifications
are met at certain control points. The definition does not limit the
other activities that these designated individuals may perform within
the manufacturing operations; thus, for example, the packaging expert
who performs the quality control function for packaged dietary
supplements could also have responsibilities in the actual packaging
operation. Quality control responsibilities and specific activities are
distinct and separate from any other responsibilities and specific
activities that an employee might perform for any other operation. In
addition, the quality control operations may be performed by someone
outside the organization (such as a contractor).
To clarify these points and to prevent potential misinterpretation
of quality control operations, we revised the definition of ``quality
control unit.'' Instead of a unit, quality control personnel who
perform quality control operations may be a person, persons, or group
and may be ``within or outside of your organization.'' We also added a
new Sec. 111.12(b) to require you to identify who is responsible for
your quality control operations. Under final Sec. 111.12(b) each
person who is identified to perform quality control operations must be
qualified to do so and have distinct and separate responsibilities
related to performing such operations from those responsibilities that
the person otherwise has when not performing such operations.
Throughout the codified, we use the term ``quality control personnel''
when referring to the performance of specific quality control
operations. The term ``quality control personnel'' refers to the person
or persons designated to perform the particular quality control
operation.
17. Representative Sample
The final rule defines ``representative sample'' as ``a sample that
consists of an adequate number of units that are drawn based on
rational criteria, such as random sampling, and that are intended to
ensure that the sample accurately portrays the material being
sampled.'' This definition is similar to the proposed definition of
``representative sample.'' We have added ``an adequate'' before
``number'' to emphasize that the sample must be sufficient for its
purpose. We also made nonsubstantive grammatical changes to insert
``that are'' between ``and'' and ``intended.''
(Comment 52) Some comments note the proposed rule would use the
terms ``representative sample,'' ``reserve sample,'' and
``representative reserve sample'' but would only define
``representative sample.'' The comments ask us to clarify the
distinction, if any, between these terms.
(Response) A ``reserve sample'' is a sample that is to be held or
kept for a designated time. It differs from a ``representative sample''
in the sense that a representative sample is not always kept; for
example, one might take a representative sample to test product
quality, but one would not necessarily keep every tested sample.
To clarify this distinction, the final rule now defines a ``reserve
sample'' as ``a representative sample of product that
[[Page 34801]]
is held for a designated period of time.'' We also revised the rule to
refer solely to a ``reserve sample'' rather than use both ``reserve
sample'' and ``representative reserve sample.''
18. Reprocessing
The final rule defines ``reprocessing'' as ``using, in the
manufacture of a dietary supplement, clean, uncontaminated components
or dietary supplements that have been previously removed from
manufacturing and that have been made suitable for use in the
manufacture of a dietary supplement.'' We modified the definition that,
in part, read ``* * * dietary supplements that have been previously
removed from manufacturing for reasons other than insanitary
conditions'' by removing ``for reasons other than insanitary
conditions'' to expand the scope of what may be reprocessed. We explain
the reason for the latter change in our response to the following
comments. We also changed ``unadulterated'' to ``uncontaminated'' to be
consistent with the revisions we have made in other sections, including
the definition of quality.
(Comment 53) Some comments ask us to clarify whether components or
dietary supplements that have been successfully treated to reduce
microbial levels to acceptable levels can be reprocessed. Some comments
object to the proposed definition of ``reprocessing'' because it did
not include components or dietary supplements removed for insanitary
conditions, and several comments object to the restrictions to
reprocessing described in proposed Sec. Sec. 111.35(i)(4)(iii) and
111.50(f), because, they argue, the definition and sections associated
with reprocessing would not permit the reprocessing of previously
insanitary ingredients even if there are processes available that are
safe and effective in removing foreign matter, microorganisms, or
chemicals that may have rendered the ingredient ``insanitary.'' One
comment would revise the definition as follows: ``Reprocessing means
using, in the manufacture of a dietary supplement, clean, unadulterated
components * * * or dietary supplements that have been previously
removed from manufacturing for reasons other than insanitary conditions
or that have been successfully reconditioned so that they are suitable
for use.''
(Response) We agree that materials can be treated, subjected to in-
process adjustments, or reprocessed when there are suitable processes
available, and we revised the definition of ``reprocessing'' to reflect
this. However, there must be appropriate oversight of the treatment,
in-process adjustments, and reprocessing so the dietary supplement will
still meet required specifications. Therefore, we added a conforming
requirement to final Sec. Sec. 111.90(b) and 111.140(b)(3)(vi) to
require oversight by quality control personnel for any reprocessing,
treatment, or in-process adjustment of a dietary supplement that have
been previously removed from manufacturing and that have been made
suitable for use in the manufacture of a dietary supplement (see
sections X and XI of this document).
19. Reserve Sample
The final rule contains a new definition of ``reserve sample.''
``Reserve sample'' is defined as ``a representative sample of product
that is held for a designated period of time.'' We explain our reasons
for creating this definition in this section under the definition of
``representative sample.''
20. Sanitize
The final rule defines ``sanitize'' as ``to adequately treat
cleaned equipment, containers, utensils, or any other cleaned contact
surface by a process that is effective in destroying vegetative cells
of microorganisms of public health significance, and in substantially
reducing numbers of other microorganisms, but without adversely
affecting the product or its safety for the consumer.''
The final rule's definition of ``sanitize'' differs from the
proposal in that the proposed definition would have specified a
reduction of 5 logs or 99.999 percent reduction of ``representative
disease microorganisms of public health significance'' and ``other
undesirable microorganisms'' and would have specified the use of heat
or chemicals. The preamble to the 2003 CGMP Proposal explained that we
based the proposed definition of ``sanitize'' on the definition of
``sanitization'' in the ``Food Code'' (which is a model that gives food
control authorities a scientifically sound technical and legal basis
for regulating the retail and food service segment of the industry)
because dietary supplements are often consumed without further
processing, similar to foods consumed in retail outlets (68 FR 12157 at
12179). The preamble to the 2003 CGMP Proposal also explained that, to
achieve the reduction levels in the proposed definition, one would need
to validate control measures to ensure they are both appropriate to
their operation and scientifically sound. The preamble explained that
in many cases, manufacturers may rely on a written certification from
the equipment manufacturer or may obtain a written scientific
evaluation of a process, especially in cases where two or more control
measures are used to accomplish the 99.999 percent reduction in the
target pathogen, to ensure the process is adequate to destroy
microorganisms of public health significance or to prevent their
growth.
(Comment 54) Many comments object to the proposed text concerning
the application of heat or chemicals to a food contact surface to yield
a reduction of 5 logs or 99.999 percent of representative disease
organisms of public health significance. The comments state the aspect
of the proposed definition is overly prescriptive, beyond our legal
authority, and would not provide additional public health benefits.
Many comments say it is inappropriate to use the definition of
sanitization from our Food Code because retail and manufacturing
operations are distinct. A few comments assert the process of
manufacturing dietary supplements shares more in common with food or
drug manufacturing than with retail operations. Most comments recommend
that we define ``sanitize'' in the manner that was presented in the
1997 ANPRM and consistent with the current food CGMP definition at
Sec. 110.3 so that ``sanitize'' means ``to adequately treat dietary
product contact surfaces by a process that is effective in destroying
vegetative cells of microorganisms of public health significance, and
in substantially reducing numbers of other undesirable microorganisms,
but without adversely affecting the product or its safety for the
consumer.''
One comment states that consistently validating the effectiveness
of the sanitizing procedure is impractical and recommended we state
instead that equipment, utensils, etc., should be cleaned and sanitized
in a manner that keeps undesirable microorganisms and other adulterants
from contaminating all components, ingredients, in-process materials,
and finished product. The comment claims that, by this approach, the
microbial and analytical test results of product produced on a
facility's equipment, coupled with random testing of final rinse water
after cleaning and sanitizing equipment and utensils, would provide
sufficient and continuous evidence of a proper and effective cleaning
and sanitizing plan.
Two comments claim that the proposed definition for sanitize
denotes ``validation methodology'' found in drug CGMP, and that we must
base dietary supplement CGMP on food rather than on drug standards.
[[Page 34802]]
Other comments express concern about validating control measures to
ensure that they are scientifically sound and appropriate to operations
and the economic burden to do the testing. A few comments state it
would be difficult to show a 100,000-fold reduction on an already
cleaned surface, particularly if the pre-sanitization level is at or
near the lower limit of the test method employed.
One comment states the definition required the manufacturer to
demonstrate a 100,000-fold reduction in microbial count every time a
food contact surface is sanitized. A few comments express concern that
processing lines would have to be closed down each time they are
sanitized in order to test them, creating a financial hardship
especially on smaller operations. Other comments ask us to give
companies the flexibility necessary to monitor sanitation needs based
on individual products and manufacturing operations to be consistent
with existing industry practices and food and drug CGMPs.
One comment requests we clarify that a sanitizing agent for use on
food processing equipment must be approved in accordance with part 178,
Indirect Food Additives: Adjuvants, Production Aids, and Sanitizers (21
CFR part 178) and our expectations with respect to what documentation
would be necessary to prove the effectiveness of the sanitizer used.
Two comments say the proposed definition of sanitize means that
manufacturers must perform validation studies to demonstrate that the
sanitizers they are using reduce the microbial load on equipment by
100,000-fold, a requirement for a ``sanitizer'' under regulations
issued by the Environmental Protection Agency. The comments say a
sanitizer should not be held to this standard for the purpose of
reducing microbial loads on food product contact surfaces, and that
manufacturers of a solid dosage form may not need to ``sanitize'' their
equipment because the processing environment is not suitable for
microbial growth due to the low water activity. One comment recommended
using the approach in the Food Code, which specifies conditions under
which chemical sanitizers listed in Sec. 178.1010 may be used,
including the requirement that they be used in accordance with the
Environmental Protection Agency-approved manufacturer's label use
instructions, and be used for dietary supplements rather than imposing
a validation requirement on manufacturers.
Some comments would divide the definition of ``sanitize'' by
creating separate definitions for ``sanitize'' and ``sanitizing
agent.'' The comments would define ``sanitize'' as meaning ``to
adequately treat equipment, containers, utensils, or any other dietary
product contact surface by applying a sanitizing agent on cleaned food
contact surfaces.'' One comment would define ``sanitizing agent'' as
``cumulative heat or chemicals that, when evaluated for efficacy, yield
a reduction of 5 logs, which is equal to 99.999 percent reduction, of
representative disease microorganisms of public health significance and
substantially reduce the numbers of other undesirable microorganisms,
but without adversely affecting the product or its safety for the
consumer.'' Another comment would define ``sanitizing agent'' in a
similar manner, except it would omit references to a 5-log reduction.
(Response) The proposed definition of ``sanitize'' was intended to
give firms the flexibility to monitor sanitation needs based on their
products and operations. We did not intend to suggest that
manufacturers had to demonstrate a 100,000-fold reduction in microbial
count every time they sanitized a contact surface, nor did we intend,
as some comments claimed, to have firms close down processing lines
every time they were sanitized to test them for microbial reduction.
Rather, the language of the proposed rule was intended to make it clear
that processes used to sanitize contact surfaces should be effective.
However, we recognize that the proposed definition caused confusion as
to our intent. The proposed definition may have been interpreted as
proposing validation to ensure an area was sanitized; however our
intent was simply to require that effective sanitizers and sanitizing
processes be used, just as in food establishments. Therefore, in order
to clarify the provision, we have revised the definition of
``sanitize'' to be consistent with Sec. 110.3(o). The final rule
defines ``sanitize'' as adequately treating ``cleaned equipment,
containers, utensils, or any other cleaned contact surface by a process
that is effective in destroying vegetative cells of microorganisms of
public health significance, and in substantially reducing numbers of
other microorganisms, but without adversely affecting the product or
its safety for the consumer.'' The final definition of sanitize does
not include any statements about mechanisms that you may use to achieve
compliance because including such nonbinding information is
inconsistent with our current practices for establishing regulations.
We note that the Environmental Protection Agency has regulatory
authority over certain uses of sanitizers as pesticide chemicals and we
have regulatory authority over certain uses of sanitizers as food
additives. Under section 201(q)(1)(B) of the act, as amended by the
Food Quality Protection Act (FQPA) (Public Law 104-170) and the
Antimicrobial Regulation Technical Corrections Act (ARTCA) (Public Law
105-324), certain substances used as food contact surface sanitizing
solutions are subject to the Environmental Protection Agency's
regulatory authority as pesticide chemicals. The Environmental
Protection Agency recently codified tolerance exemptions under section
408 of the act (21 U.S.C. 346a) for those food contact surface
sanitizing solutions that were previously subject to our authority at
Sec. 178.1010 and transferred to the Environmental Protection Agency's
authority under FQPA and ARTCA (see 40 CFR 180.940 (69 FR 23113, April
28, 2004). Such pesticide chemicals must comply with the Pesticide
Tolerance regulations in 40 CFR 180.940. Sanitizers used on food
packaging must comply with our regulations at Sec. 178.1010. For an in
depth discussion of appropriate sanitizers for food contact surface
use, see the Environmental Protection Agency's Pesticides; Tolerance
Exemptions for Active and Inert Ingredients for Use in Antimicrobial
Formulations (Food Contact Surface Sanitizing Solutions) (69 FR 23113,
April 28, 2004) and DIS/TSS-4 Efficacy Data Requirements Sanitizing
Rinses (for previously cleaned food-contact surfaces) (January 30,
1979) (Ref. 27) (available on the Internet at http://www.epa.gov/oppad001/dis_tss_docs/dis-04.htm).
21. Theoretical Yield
The final rule defines ``theoretical yield'' as ``the quantity that
would be produced at any appropriate step of manufacture or packaging
of a particular dietary supplement, based upon the quantity of
components or packaging to be used, in the absence of any loss or error
in actual production.''
We received no substantive comments on the proposed definition.
22. Water Activity
The final rule defines ``water activity'' as ``a measure of the
free moisture in a component or dietary supplement and is the quotient
of the water vapor pressure of the substance divided by the vapor
pressure of pure water at the same temperature.''
We received no substantive comments on the proposed definition.
[[Page 34803]]
23. We
The final rule explains that ``we'' means the United States Food
and Drug Administration.
The final rule's definition is identical to the proposed
definition. We received no substantive comments on the proposed
definition.
24. You
The final rule defines ``you'' as a ``person who manufactures,
packages, labels, or holds dietary supplements.''
25. What Other Terms Did the Comments Want Defined?
(Comment 55) Some comments ask us to define ``adulteration'' (based
on the provisions of section 402 of the act), ``dietary ingredient,''
and ``dietary supplement'' (based on the definition in section 201(ff)
of the act).
(Response) We decline to revise the rule as suggested by the
comments. The terms have meaning within the context of the act and case
law. Further, under final Sec. 111.3 the act's definitions and
interpretations ``apply to such terms when used in this part.'' Thus,
there is no need for us to define the terms as requested by the
comments.
(Comment 56) Proposed Sec. 111.35(e)(2) would require a person to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration, and proposed Sec. 111.35(f) would require monitoring of
the in-process control points, steps, or stages to ensure these
established specifications are met and to detect any unanticipated
occurrence that may result in adulteration. Some comments ask us to
define the term ``control point'' as ``any point, step or stage in the
manufacturing process where control is necessary to prevent
adulteration.''
(Response) We decline to add a definition of ``control point'' as
requested by the comments. Instead, we revised final Sec. 111.75(b)
(formerly proposed Sec. 111.35(f)) to state that you must monitor the
in-process points, steps, or stages where control is necessary to
ensure the quality of the finished batch of dietary supplement; this
revision eliminates the need to define ``control point.''
(Comment 57) Several comments would have us define one or more of
the following terms: Identity, purity, strength, and composition. Some
comments suggest specific text for the definitions.
Similarly, some comments suggest codifying the preamble description
that we used for these terms, i.e., the phrase ``identity, purity,
quality, strength, and composition'' means that the production on a
batch-by-batch basis is consistent with the master manufacturing record
and is what it is represented on the label to be (identity); is without
impurities and is the desired product (purity); is the identity,
purity, and strength for its intended purpose (quality); is the
concentration, that is, the amount per unit of use intended (strength);
and is the intended mix of product and product-related substances
(composition) (68 FR 12157 at 12176). One comment says ``identity''
should mean ``a substance or product is what it is represented on the
label to be.''
One comment says that it does not seem appropriate to define the
term ``purity'' to mean ``without impurities.'' The comment states it
would be difficult to consider an herbal extract as being ``pure''
because it is a mixture of naturally occurring compounds in a solvent.
Another comment suggests the term ``purity'' be defined to mean ``free
from objectionable and/or deleterious levels of impurities including,
but not limited to, heavy metals, pesticides, mycotoxins,
radioactivity, filth, extraneous material, molds, yeasts and
bacteria.'' Another comment suggests defining the term ``purity'' as
``having the intended identity and composition and being without
significant impurities.'' However, the comment does not explain what is
meant by ``without significant impurities.''
One comment suggests defining the term ``strength'' as ``having the
intended concentration, that is, the amount of the dietary ingredient
per unit of use (tablet, capsule, soft gel, teaspoon, or other unit).''
Another comment expresses concern about the use of the term
``strength'' in relationship to nonstandardized herbals because there
are no current industry standards for these products. This comment
suggests we clarify the term ``strength'' so it refers to having the
correct amount of a stated ingredient. One comment notes St. Johns wort
has a composition of approximately 40 different constituents in
addition to the essential oil that contains numerous constituents. The
comment asks which constituent it should use to determine ``strength.''
Another comment would use the term ``quantity'' instead of
``strength.''
One comment would define ``composition'' as ``having the intended
mix of components or ingredients, including dietary ingredients.''
Another comment would delete ``composition'' from the rule because, the
comment claimed, an FDA investigator might conclude that
``composition'' refers to every constituent of every botanical.
According to this comment, there are many tests that could be used to
identify the botanical constituents, but that it would be economically
exhausting considering the number of botanical constituents, and it
would not contribute to quality or safety.
(Response) We decline to revise the rule to define identity,
purity, strength, or composition. The exact way in which the dietary
supplement industry uses these terms may vary, and defining these terms
could limit the flexibility that is needed to accommodate such
variations.
Nevertheless, to elaborate on our interpretation of identity,
purity, strength, and composition, and to respond to the particular
concerns raised by some comments, we provide the following information.
a. Identity. The ``identity'' of a dietary supplement refers to the
dietary supplement's consistency with the master manufacturing record
and/or that it is the same as described in the master manufacturing
record.
b. Purity. The ``purity'' of a dietary supplement refers to that
portion or percentage of a dietary supplement that represents the
intended product. For example, amino acids generally can exist in two
forms (i.e., dextro (D-, or right) and levo (L-, or left) forms) called
enantiomers. Enantiomers have the same chemical formula and the same
chemical structure, but differ in their three-dimensional orientation.
If you manufacture a dietary supplement to provide the amino acid L-
arginine, and you determine that 90 percent of the manufactured product
is L-arginine and 10 percent of the manufactured product is D-arginine,
you could describe your L-arginine product as ``90 percent pure.'' As
another example, if you manufacture a mixture of triglycerides that
provides polyunsaturated fatty acids in the diet, the manufactured
triglycerides may contain small amounts of free fatty acids and
sterols. The free fatty acids and sterols could derive, for example,
from the source of the triglycerides or could be byproducts of the
manufacturing process. If you determine that 95 percent of the
manufactured product is the mixture of the triglycerides that provides
the polyunsaturated fatty acids, and 5 percent of the product is free
fatty acids and sterols, you could describe the purity of your product
as ``95 percent pure.''
Just as we use the term ``purity'' to refer to the identity and
amount of a dietary supplement that is the desired product, we use
``impurity'' to refer to the identity and amount of a dietary
supplement that is not the desired product. In the previous examples,
we
[[Page 34804]]
view the D-arginine that is present in the product that is intended to
be L-arginine as an ``impurity,'' and we view the free fatty acids and
sterols that are present in the product that is intended to be a
mixture of triglycerides that provide polyunsaturated fatty acids in
the diet as ``impurities.'' For the purposes of these examples, we do
not view these ``impurities'' as ``contaminants.''
If the comments were concerned that the dietary supplement CGMP
requirements regarding a dietary supplement's ``purity'' mean that we
expect you to characterize each constituent of a natural product to
determine whether each constituent is present in a certain pre-
established quantity (i.e., purity specification) to determine whether
it contributes to the ``purity'' of the dietary supplement or would be
considered as an ``impurity,'' we do not consider such constituents to
be ``components'' of a dietary supplement (see discussion of the
definition of component in this section). For example, if you
manufacture a dietary supplement containing fish oil, we would not
consider the triglycerides, which are constituents of the fish oil, to
be components. Likewise, we would not consider particular fatty acids
(such as the polyunsaturated fatty acids docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA)), which are constituents of the
triglycerides, to be components of the dietary supplement. In this
example, you would be required to establish a purity specification for
the amount of triglycerides in the fish oil. (Note that if you are
manufacturing fish oil to provide the fatty acids DHA and EPA in the
dietary supplement, the component specifications for the fish oil must
include a strength specification for DHA and EPA in whatever amount you
determine is necessary to meet the specification for strength of DHA
and EPA in the dietary supplement.) We do, however, expect you to set
appropriate limits on contaminants (e.g., toxic substances) that are
known to be constituents of botanical extracts or other natural
products that are likely or certain to contain constituents that are
harmful.
c. Strength. The strength of a dietary supplement relates to its
concentration. By concentration, we mean the quantitative amount per
serving (for example, weight/weight, weight/volume, or volume/volume).
Therefore, for purposes of this final rule, strength does not refer
simply to the quantity of an ingredient, rather it refers to the amount
of a stated ingredient per a specified unit of measure.
If the comments were concerned that the ``strength'' of a dietary
supplement meant that you need to establish the quantitative amount per
unit of measure of each constituent in a dietary ingredient, such as a
botanical extract or natural product, we do not consider such
constituents to be ``components'' of a dietary supplement, unless you
add such constituents as components (as in an extract) (see discussion
of the definition of component in this section).
We do not consider the rule's requirements on dietary supplement
strength as necessarily relating to the individual constituents of such
products. Whether the requirements regarding dietary supplement
strength apply to one or more constituents of dietary ingredients in a
dietary supplement depends on what you are manufacturing. For example,
if you are manufacturing vitamin C, and your source of vitamin C is
rosehips, you would establish a strength specification for vitamin C in
the finished batch of the dietary supplement (e.g., ``x milligrams (mg)
of vitamin C per tablet''). You are required to ensure that the dietary
supplement does in fact contain ``x mg of vitamin C per tablet.''
Alternatively, if you are manufacturing rosehips and not vitamin C from
rosehips, the strength specification that you establish for the
finished batch of the dietary supplement is the strength of the
rosehips themselves (i.e., the concentration of rosehips in the final
product, such as ``x mg of rosehips per tablet''). You are required to
ensure that the product does in fact contain ``x mg of rosehips per
tablet.''
We discuss the requirements to establish and meet specifications in
our discussion of subpart E (see section X of this document).
d. Composition. A dietary supplement's ``composition'' refers to
the specified mix of product and product-related substances in a
dietary supplement. For example, a dietary supplement manufactured to
provide vitamin C may contain, in addition to vitamin C, a tablet
coating agent and substances used as binders. The composition could be
described as the percent of the dietary supplement that is vitamin C,
the tablet-coating agent, and each binder.
e. Other terms.
(Comment 58) Several comments would revise the rule to define
``manufacturer.'' Many comments ask whether the rule applies to certain
types of companies or professionals and said a definition of
``manufacturer'' would clarify the rule's applicability.
Some comments suggest specific text for a definition. For example,
one comment would define ``manufacturer'' as ``a person who formulates
or changes the composition or physical characteristics of a dietary
supplement or who packages or labels the product in a container for
distribution'' to clarify that a company that does not manufacture a
specific dietary supplement, but purchases a dietary supplement in bulk
and then packages or labels the bulk dietary supplement for sale to
consumers, is still subject to dietary supplement CGMP requirements.
The comment cites our proposed definition of ``manufacturer'' in our
infant formula CGMP proposal (see 61 FR 36154 at 36209, July 9, 1996
(proposing to define a ``manufacturer'' as ``a person who prepares, re-
constitutes or otherwise changes the physical or chemical
characteristics of an infant formula or packages or labels the product
in a container for distribution'')).
Other comments would define ``manufacturer'' to exclude a health
care practitioner or herbalist and noted the Canadian Natural Health
Product regulations do not apply to health care practitioners.
(Response) We decline to define ``manufacturer'' in the final rule.
In section III, footnote 1 of this document, we explain that
``manufacture'' is a broad term and is not limited to production,
packaging, or labeling activities. Consequently, we prefer to explain
our interpretation of the final rule in this preamble and to have the
codified provisions state general principles rather than attempt to
capture subtleties in a definition of ``manufacturer.''
(Comment 59) Proposed Sec. 111.35(e)(1) through (e)(3) would
require you to establish specifications for identity, purity, quality,
strength, and composition at receipt, in-process, and finished batch
stages, while proposed Sec. 111.35(g)(1) would require you to test
each dietary supplement at the finished batch stage before release for
distribution to confirm that specifications are met, provided that
there are scientifically valid analytical methods available to perform
such testing. If your quality control unit determined that finished
batch testing could not be completed for any specification because a
scientifically valid analytical method was not available, proposed
Sec. 111.35(g)(2) and (g)(3) would require you to perform testing on
components and at the in-process stage to determine whether that
specification is met. The preamble to the 2003 CGMP Proposal explained
that a scientifically valid analytical method is one that is based on
scientific data or
[[Page 34805]]
results published in, for example, scientific journals, references,
text books, or proprietary research (68 FR 12157 at 12198).
Several comments agree that scientifically valid analytical methods
are those that are based on scientific data or results published in
scientific journals, references, textbooks, or proprietary research.
However, several comments ask us to define or better explain the terms
``test'' or ``scientifically valid analytical method'' as used in the
dietary supplement CGMP final rule. One comment argues that, because of
the evolving nature of methodology for ingredients used in dietary
supplements, we should give the industry more guidance as to what can
be considered authoritative for the purpose of compliance with CGMP.
Some comments state we should acknowledge methods from the Institute
for Nutraceutical Advancement (INA), American Herbal Pharmacopoeia
(AHP), European Pharmacopoeia, and the World Health Organization (WHO)
as scientifically valid analytical methods. One comment notes the USP
establishes scientifically valid procedures in its compendia and
encouraged us to designate compendial procedures as ``scientifically
valid'' by defining ``scientifically valid'' to include compendial
procedures. The comment further argues that failure to acknowledge
compendial procedures as scientifically valid would be inconsistent
with section 403(s)(2)(D) of the act, which acknowledges the role of
compendia, by considering a dietary supplement misbranded if the
supplement is covered by the specifications of an official compendium,
is represented as conforming to the specifications of an official
compendium, and fails to so conform.
Other comments would define ``validation'' and ``verification'' and
directed us to ``ANSI Standard A8402-1994'' (a description of
validation and verification standards).
(Response) We decline to define ``test,'' ``scientifically valid
analytical method,'' or ``scientifically valid method'' in this final
rule. As the comments recognized, the analytical methods for components
are evolving. A regulatory definition for ``test,'' ``scientifically
valid analytical method,'' or ``scientifically valid method'' could
become obsolete if we based it on specific sources such as INA, AHP, or
USP that may or may not themselves stay current or that may be modified
in a manner that did not enjoy widespread support.
The preamble to the 2003 CGMP Proposal acknowledged that compendia
can have a role in establishing tests used to determine whether
specifications are met. For example, we noted that compendial standards
may be appropriate reference materials for use in conducting tests or
examinations (68 FR 12157 at 12208). However, we did not list specific
compendia that would be suitable sources or scientifically valid
analytical tests, and are not listing such compendia in this final
rule. The compendia identified in the comments, i.e., INA, ANSI, AHP,
and USP, may include some methods that are based on scientific data or
results published in scientific journals, references, textbooks, or
proprietary research, but also contain some methods that are not based
on such data or results. Thus, whether or not a method is
scientifically valid is not determined solely by its inclusion in a
compendium. Rather, it is the responsibility of quality control
personnel to approve the use of those scientifically valid tests that
will ensure a product's identity, purity, strength, and composition
whether or not such tests are contained in a particular compendium.
We also decline to define ``validation'' and ``verification''
because the final rule does not establish any requirements that use
these terms.
(Comment 60) One comment asks us to define the terms ``adequate,''
``sufficient,'' and ``qualified'' and argues that, without these
definitions, an FDA investigator may assert that something or someone
is not adequate, sufficient, or qualified.
(Response) We decline to define ``adequate,'' ``sufficient,'' or
``qualified'' in this final rule. Deciding what is ``adequate'' or
``sufficient,'' or who is ``qualified'' must be done on a case-by-case
basis, depending on the operations and the particular facts. As
explained in section V of this document, we do not need to, nor could
we, predict with mathematical precision how many inches or feet, for
example, would be ``adequate space'' to allow for cleaning a particular
piece of equipment that could be applied to every size of facility and
every operation. Furthermore, defining ``adequate,'' as defined in part
110, as ``that which is needed to accomplish the intended purpose in
keeping with good public health practice'' would still require context
to determine whether, in a particular operation and based on a
particular set of facts the particular practice was ``adequate.''
Moreover, for terms such as ``adequate,'' ``sufficient,'' and
``qualified,'' where there has been common usage in the food industry
to enable manufacturers and FDA investigators to comprehend and apply
such terms to a particular operation, we do not believe a definition
for these terms is necessary.
(Comment 61) Several comments would define the terms ``certificate
of analysis,'' ``certificate of compliance/conformance,'' and
``continuing product guarantee.'' Most comments include these terms in
a list of terms that they want us to define to ensure consistent
interpretation of the rule throughout the industry. One comment says a
standard for documentation, such as a certificate of analysis, would
put greater emphasis on the firm's responsibility to comply with CGMP.
(Response) We decline to define these terms as suggested by the
comments. We have included, in the codified, the use of a certificate
of analysis as an option to determine whether certain specifications
have been met. The final Sec. 111.75(a)(2)(ii)(B) requires that
certain information be provided in a ``certificate of analysis.'' This
provision states that the certificate of analysis must include a
description of the test or examination method(s) used, limits of the
test or examinations, and actual results of the tests or examinations,
provided you satisfy certain other criteria.
As for the claim that a standard for documentation, such as a
certificate of analysis, would emphasize a firm's responsibility to
comply with CGMP, we encourage firms who are excepted from the scope of
the rule in final Sec. 111.1 and who supply dietary ingredients and
other components to follow dietary supplement CGMP requirements.
We decline to define ``certificate of compliance/conformance'' or
``continuing product guarantee'' because the final rule does not
establish any requirements that use these terms.
26. What Definitions Did the Comments Want Us to Delete?
(Comment 62) Some comments would delete certain definitions (e.g.,
``component'' and ``ingredient'') because these terms do not appear in
the food CGMP, the 1997 ANPRM, or both.
(Response) We decline to delete any definition for the reasons
stated by the comments. As discussed in section V of this document,
Congress did not require dietary supplement CGMP requirements to be
identical to the food CGMP requirements, so the mere fact that a
definition may not appear in a food CGMP regulation does not mean we
must delete that definition from this final rule, especially when the
comments offered no other justification for deleting the definition.
Definitions
[[Page 34806]]
provide clarity and consistency in interpreting various terms in a
rule.
D. Do Other Statutory Provisions and Regulations Apply? (Final Sec.
111.5)
Final Sec. 111.5 states: ``In addition to this part, you must
comply with other applicable statutory provisions and regulations under
the act related to dietary supplements.'' Proposed Sec. 111.5 stated
that, in addition to the dietary supplement CGMP requirements, ``you
must comply with other applicable statutory provisions and regulations
under the act related to the manufacturing, packaging or holding of
dietary ingredients or dietary supplements.''
Section 111.5 reminds you that other statutory or regulatory
requirements, not included in the dietary supplement CGMP requirements,
may apply to your particular products, operations, or activities. In
our further review of this provision, we determined that we do not need
to elaborate on the individual operations and have shortened the
provision to eliminate the references to particular operations. You are
required to comply with other applicable statutory and regulatory
requirements, and we have retained this provision to ensure you
understand that this final rule does not relieve you of your
responsibilities to comply with other applicable statutory and
regulatory requirements related to dietary supplements.
E. What Sections Did We Remove From the Rule, and Why?
The final rule omits sections that were in the proposed rule.
Proposed Sec. 111.2, ``What Are These Regulations Intended to
Accomplish,'' would have described the rule's purpose as establishing
the minimum CGMP you must use to the extent that you manufacture,
package, or hold a dietary supplement. Proposed Sec. 111.6,
``Exclusions,'' would have excluded ``persons engaged solely in
activities related to the harvesting, storage, or distribution of raw
agricultural commodities that will be incorporated into a dietary
supplement by other persons'' from the dietary supplement CGMP
requirements.
1. ``What Are These Regulations Intended to Accomplish?'' (Proposed
Sec. 111.2)
We elected to remove proposed Sec. 111.2 from the final rule
because we realized that it created no enforceable obligations and
provided little, if any, helpful information. The few comments that
address proposed Sec. 111.2 either disagreed with its general
statement or sought to weaken the provision; the comments' arguments
prompted us to reconsider whether proposed Sec. 111.2 was necessary at
all, and, in the end, we decided to delete the proposed section. We
describe the comments on proposed Sec. 111.2 in the following
paragraphs.
(Comment 63) Several comments argue the proposed rule went beyond
the ``minimum standards'' mentioned in proposed Sec. 111.2. These
comments also assert the proposed rule lacked flexibility.
(Response) We disagree with the comments. In several instances, the
proposed requirement is practically identical to requirements in the
umbrella food CGMP regulations. For example, most of the proposed
requirements for personnel, physical plants, and equipment and utensils
correspond to long-established, similar requirements in the umbrella
food CGMP regulations in part 110. In other instances, the proposed
rule would require a particular action or result (such as establishing
specifications for components, in-process controls, manufactured
dietary supplements, and packaged and labeled dietary supplements under
proposed Sec. 111.35(e)), but gave firms the flexibility and the
responsibility to decide what those specifications will be. We have
included flexibility where it is appropriate to do so, and, after we
revised parts of the rule in response to the comments, the final rule
provides more flexibility than the proposal. For example, final Sec.
111.75 sets forth criteria for relying on a certificate of analysis to
ensure that certain specifications for components are met and for when
you can test a subset of finished batches for a select number of
specifications; this differs considerably from the proposal which would
have required testing all batches for all specifications.
(Comment 64) One comment would revise proposed Sec. 111.2 to read
as follows: ``These regulations recommend general minimum current good
manufacturing practices that, when modified by manufacturer product
specifications, will extend to the manufacture, package, or holding of
dietary ingredients or dietary supplements for that manufacturer.''
(Response) We decline to revise the rule as suggested by the
comment. Section 402(g) of the act states that ``The Secretary may by
regulation prescribe good manufacturing practices for dietary
supplements.'' If a dietary supplement has been prepared, packaged,
labeled, or held under conditions that do not meet the final rule's
requirements, the dietary supplement is deemed to be adulterated under
section 402(g)(1) of the act. Here, the comment's suggestion that
dietary supplement CGMP requirements could be ``modified by
manufacturer product specifications'' would create uncertainty over
whether manufacturers could unilaterally ``modify'' their product
specifications to fit a batch that failed to meet specifications or
claim that a violation was ``cured'' by a manufacturer's new product
specification. In any event, given that we decided to omit proposed
Sec. 111.2 altogether, the change sought by the comment is moot.
2. ``Exclusions'' (Proposed Sec. 111.6)
As we stated earlier in this section, proposed Sec. 111.6 would
exclude from the dietary supplement CGMP requirements persons who
engage solely in activities related to the harvesting, storage, or
distribution of raw agricultural commodities that would be incorporated
into a dietary supplement by other persons. However, as we explained in
our response to comment 27 of this document, we decided that the
exclusion was not necessary, given the changes that we made to final
Sec. 111.1(a).
Nevertheless, we received several comments on proposed Sec. 111.6,
and we address those comments here.
(Comment 65) One comment would revise the rule to exclude or use
different requirements for small businesses. The comment suggested we
categorize small businesses by employment levels or dollar sales and
adopt a tiered enforcement strategy similar that used in other
government programs, such as those under the Occupational Safety and
Health Act, the Americans with Disabilities Act, and the Family Leave
Act. Another comment would exempt small businesses from the specific
requirements for testing if those businesses produce annual batch runs
of 25,000 capsules and tablets.
(Response) We decline to exclude small businesses from the final
rule or to have different criteria for such businesses. As we stated in
our response to comments 1, 3, and 16, there is no reason to assume
that Congress meant to apply different or lesser CGMP requirements, or
no CGMP requirements at all, to dietary supplements made by small
businesses. Dietary supplement CGMP requirements help to ensure the
quality of the dietary supplement and, among other things, that a
dietary supplement meets its specifications, that it contains the
ingredients specified in its master manufacturing record, and that it
is not contaminated. Consumers should be able to expect that the
dietary supplements they purchase meet CGMP requirements regardless of
the manufacturer's size. However, to help
[[Page 34807]]
businesses comply with dietary supplement CGMPs, we are giving
businesses with fewer than 500 employees but 20 or more employees a
compliance date of 24 months after the date of publication of this
final rule, and we are giving businesses with fewer than 20 employees a
compliance date of 36 months after the date of publication of this
final rule.
We carefully considered the size of a business when developing
these regulations. The most common Small Business Association size
standard applicable to manufacturers covered by this final rule is 500
employees. Based on comments and our knowledge of the dietary
supplement industry, we know that there are a number of dietary
supplement manufacturers who fall significantly below the standard of
500 employees. To accommodate these manufacturers, we have established
different compliance dates as noted.
(Comment 66) One comment would exempt ``consolidators'' (whom it
described as individuals who purchase raw agricultural commodities for
sale to raw ingredient manufacturers) from the rule. Some comments
suggest expanding the exclusion pertaining to harvesting, storage, and
distribution of raw agricultural commodities to include other common
and basic raw botanical processing activities, such as drying,
chopping, cutting, size reduction, sifting, grinding, and storage. One
comment would delete the word ``solely'' to make the rule more flexible
and make it possible to exclude producers, who do not manufacture a
distinct product, from the CGMP rule. Another comment expresses concern
about potential safety issues that can arise from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration; the comment says businesses
involved in producing or distributing raw agricultural commodities
should be subject to some requirements under the rule. A few comments
ask us to draft guidance documents to address activities such as
wildcrafting, plant identification, good agricultural practices, and
good hygienic practices for wildcrafters (persons who harvest plants
grown in the wild), and growers and brokers and specific service
providers (millers, extractors). Some comments would exempt individual
wildcrafters because wildcrafters deal in relatively small amounts of
material at a time and sell their material to larger brokers who
combine materials from different pickers together.
(Response) As explained in our responses to comments 29 and 30,
persons who only manufacture or supply a component that will be further
processed as a dietary supplement by another person are not within the
scope of this final rule. Thus, a ``consolidator'' who simply buys raw
agricultural commodities and then sells them to dietary ingredient
manufacturers would not be subject to this final rule. Similarly,
persons engaged in drying, chopping, cutting, size reduction, sifting,
and grinding of raw agricultural commodities which they then sell to
others for processing into a dietary supplement would not be subject to
this final rule. We note, however, that such persons are not exempt
from other regulatory requirements. We remind readers that a dietary
ingredient is a food under section 201(f)(3) of the act. Consequently,
a raw agricultural commodity that is a dietary ingredient is still
subject to the umbrella food CGMP requirements in part 110, and
activities such as drying, chopping, and cutting are what we have long
considered to be types of food processing.
As for ``wildcrafters,'' if they package and label raw agricultural
commodities as dietary supplements or sell them to consumers for use as
a dietary supplement, we would consider them to be manufacturers of a
dietary supplement and subject to the rule. If, however, the
wildcrafter simply sells the raw agricultural commodity to another for
incorporation into a dietary supplement, it would not be subject to
this final rule, but might be subject to the CGMP requirements in part
110. Persons engaged in the harvesting, storage, or distribution of raw
agricultural commodities, whether for distribution as a dietary
supplement or for distribution as a dietary ingredient to a dietary
supplement manufacturer, may want to read our guidance entitled ``Guide
to Minimize Microbial Food Safety Hazards for Fresh Fruits and
Vegetables'' available at http://www.cfsan.fda.gov/~dms/prodguid.html
(Ref. 28). This guidance addresses common areas of food safety concern
in the growing, harvesting, sorting, packing, and distribution of fresh
produce, and contains principles that would apply to raw agricultural
commodities, such as herbs and botanicals.
As for the comment that would delete the word ``solely'' from
proposed Sec. 111.6, we note that such a change is no longer necessary
since we are deleting Sec. 111.6. However, we caution that only those
persons or entities that manufacture or supply components that will be
further processed as a dietary supplement by others are not subject to
the final rule. If you manufacture and sell dietary supplements, in
addition to supplying components to others, you would be subject to
this final rule under Sec. 111.1(a).
As for potential safety issues arising from the early stages of
manufacturing, such as the use of improper handling of agricultural
commodities and the risk of adulteration, the final rule, at Sec.
111.75, describes criteria that enable a manufacturer of a dietary
supplement to rely on a certificate of analysis. One criterion is that
the manufacturer must first qualify the firm providing the component by
establishing the reliability of the firm's certificate of analysis
through confirmation of the results of the firm's tests or
examinations. Firms that improperly handle raw agricultural
commodities, such that the commodities that they provide are
adulterated, are not likely to be qualified as suppliers of those
commodities.
In the future, we will consider the requests to develop guidance
for subsets of agricultural and post-harvest activities (such as for
hygienic practice for wildcrafters, identifying botanicals) associated
with dietary supplement manufacturing, along with other guidance we may
find useful as they relate to certain CGMP requirements for dietary
supplements.
VII. Comments on Personnel (Final Subpart B)
A. Organization of Final Subpart B
Proposed subpart B contained three provisions regarding personnel.
Table 3 of this document lists the sections in final subpart B and
identifies the proposed sections that form the basis of the final rule.
Table 3.--Derivation of Sections in Final Subpart B
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.8 What are the requirements under N/A
this subpart B for written procedures?
------------------------------------------------------------------------
Sec. 111.10 What requirements apply for Sec. 111.10
preventing microbial contamination from sick
or infected personnel and for hygienic
practices?
------------------------------------------------------------------------
[[Page 34808]]
Sec. 111.12 What personnel qualification Sec. 111.12
requirements apply?
------------------------------------------------------------------------
Sec. 111.13 What supervisor requirements Sec. 111.13
apply?
------------------------------------------------------------------------
Sec. 111.14 Under this subpart B, what N/A
records must you make and keep?
------------------------------------------------------------------------
B. Highlights of Changes to the Proposed Requirements for Personnel
1. Revisions
The final provisions in subpart B include revisions that clarify
that the final rule applies only to persons who manufacture, package,
label, or hold dietary supplements unless subject to an exclusion in
Sec. 111.1.
The final provisions also include revisions that clarify the
applicability of the rule to persons who perform labeling operations
for dietary supplements.
2. Changes After Considering Comments
The final rule:
Requires you to establish and follow written procedures to
fulfill the requirements of subpart B;
Provides flexibility regarding the requirement to exclude
personnel who might be a source of microbial contamination (e.g., due
to illness or open lesions) so that such personnel must be excluded
only from operations where such contamination may occur;
Clarifies that the qualification of personnel and
supervisors may be done through education, training, or experience;
Sets forth a new requirement that you identify qualified
personnel to perform quality control operations and requires that such
personnel have distinct and separate responsibilities related to
performing quality control operations from those responsibilities that
the person otherwise has when not performing quality control
operations; and
Sets forth a new requirement to make and keep records that
document training of personnel.
C. General Comments on Proposed Subpart B
(Comment 67) Some comments assert one or more proposed requirements
are unconstitutionally vague under the Fifth Amendment and arbitrary
and capricious under section 706(2)(B) of the Administrative Procedure
Act (APA) and therefore should be deleted. The comments focus on:
Proposed Sec. 111.12(a) which would require ``qualified
employees'' and
Proposed Sec. 111.13(a) which would require ``qualified
personnel to supervise.''
In general, these comments say the proposal's failure to define the
term ``qualified'' means that persons who are subject to the rule could
not discern the meaning of the term. These comments also say the
proposal imposes no limits on enforcement officers as to what would
satisfy the requirements and, thus would represent an exercise of
unbridled discretion and disparate decisionmaking. These comments argue
proposed Sec. 111.12(b), which would require employees to have ``the
training and experience to perform the person's duties,'' and proposed
Sec. 111.13(b), which would require supervisors to be ``qualified by
training and experience to supervise,'' would suffice.
(Response) We are not deleting Sec. Sec. 111.12(a) and 111.13(a)
as requested by these comments. As discussed in section V of this
document, we disagree that the terms in question are unconstitutionally
vague, need to be defined, or may result in discriminatory enforcement.
There has been sufficient common usage of these terms in the food
industry to enable manufacturers, and those who enforce the
requirements, to comprehend and apply such terms ``with a reasonable
degree of certainty'' to their particular operations (see Boyce Motor
Lines v. United States 342 U.S. at 340). Further, agencies are
permitted to use qualifying terms to enable them to address a wide
variety of conditions at companies. For these reasons, we have retained
the use of the terms in the final rule. The provisions at issue also
give firms the flexibility to determine how to comply with the
regulations. We also explain in section V of this document that the
final rule does not violate the APA.
D. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.8)
We received many comments that recommended written procedures for
various provisions. We address the need for written procedures
generally in section IV. We also respond to individual comments on
specific provisions in the same section. Final Sec. 111.8 requires you
to establish and follow written procedures to fulfill the requirements
of subpart B. Additionally, to ensure that we can evaluate firms'
compliance with their written procedures, final Sec. 111.14 requires
that a person who manufactures, packages, labels, or holds dietary
supplements make and keep records of such procedures. Such records
would be available to us under subpart P.
E. What Requirements Apply for Preventing Microbial Contamination From
Sick or Infected Personnel and for Hygienic Practices? (Final Sec.
111.10)
The title of this provision has been changed from proposed Sec.
111.10 to clarify that the requirements are related to the prevention
of microbial contamination due to the health condition of personnel and
not other sources.
1. Final Sec. 111.10(a)
Final Sec. 111.10(a) requires you to take measures to exclude from
any operations any person who might be a source of microbial
contamination, due to a health condition, where such contamination may
occur, of any material including components, dietary supplements, and
contact surfaces used in the manufacture, packaging, labeling, or
holding of a dietary supplement. This provision is similar to proposed
Sec. 111.10. We added ``due to a health condition'' for clarity.
(Comment 68) Several comments suggest that employees who are sick
should be allowed to work in areas where they will not come into
contact with components, dietary supplements, or contact surfaces, and
that the requirements of proposed Sec. 111.10 are too strict. These
comments say proposed Sec. 111.10(a) is too broad in stating that such
persons be excluded ``from working in any operation.'' These comments
explain that such persons may be suitable for performing other tasks,
such as warehouse functions or administrative work. These comments
would revise proposed Sec. 111.10(a) so that it is acceptable for such
persons to work so long as they will not be a vessel for microbial
contamination.
Other comments agree with proposed Sec. 111.10(a), and state that
employees who are sick should be excluded from the plant, even from
areas where products are not processed. These comments state excluding
such personnel should be mandatory as the microbes from an open sore,
wound, or other source of contamination could contaminate the
surrounding air, personnel, etc. For example, if the production area is
a closed loop air handling system, then contamination could spread to
the other areas through the common air handling units/ducts.
[[Page 34809]]
(Response) We agree that some tasks may be suitable for a person
who might be a source of microbial contamination. Certain warehouse
functions or administrative tasks may be appropriate for such a person
to do, provided that these functions or tasks do not expose components,
dietary supplements, or contact surfaces to microbial contamination
from the person, and provided that the person would not infect others
who would then expose components, dietary supplements, or contact
surfaces to microbial contamination.
A requirement to exclude employees from being present at work would
limit potential microbial contamination, which is the basis of the
point made by some comments that employees who are sick should be
excluded from the plant. However, the comments do not persuade us to
deny firms the flexibility to determine whether it would be appropriate
for an employee who may be a source of microbial contamination to work
in some areas of the physical plant that are sufficiently separated
from areas where product contamination could occur. When considering
whether an employee may be permitted to work and whether he/she
represents a potential source of microbial contamination, one should
look beyond the obvious potential sources of contamination, and
consider possibilities such as the forms of indirect contamination
discussed by the comments. Therefore, we are revising proposed Sec.
111.10(a) to require you to take measures to exclude ``from any
operations any person who might be a source of microbial contamination,
due to a health condition, where such contamination may occur, of any
material including components, dietary supplements, and contact
surfaces used in the manufacture, packaging, labeling, or holding of a
dietary supplement.''
As one measure to reduce potential microbial contamination, final
Sec. 111.10(a)(1) requires you to exclude, from working in any
operations that may result in contamination, any person who, by medical
examination, the person's acknowledgement, or supervisory observation,
is shown to have, or appears to have an illness, infection, open
lesion, or any other abnormal source of microbial contamination, that
may result in microbial contamination of components, dietary
supplements, or contact surfaces, until the health condition no longer
exists. Final Sec. 111.10(a)(1) is similar to proposed Sec.
111.10(a)(1). We have added that the person can acknowledge that he or
she may be a source of microbial contamination. We are moving and
modifying the prepositional phrase concerning ``working in any
operation.'' We also have added the word ``infection'' to clarify the
sources of potential abnormal contamination.
(Comment 69) Several comments suggest employees who may be the
source of microbial contamination should be permitted to work in areas
of the plant where they pose no risk of contamination, and therefore
should not be excluded unless they pose such a risk.
(Response) We agree with the comments and are revising proposed
Sec. 111.10(a)(1) accordingly. Therefore, you may allow persons with
certain health conditions to work in areas of a plant where they pose
no risk of contamination even though they must be excluded from other
areas where they would pose such a risk.
Final Sec. 111.10(a)(2) requires you to instruct your employees to
notify their supervisor(s) if they have, or if there is a reasonable
possibility that they have, a health condition stated in Sec.
111.10(a)(1) that could contaminate any components, dietary
supplements, or any contact surface.
We did not receive comments specific to proposed Sec.
111.10(a)(2).
2. Final Sec. 111.10(b)
Final Sec. 111.10(b) requires, if you work in an operation during
which adulteration of the component, dietary supplement, or contact
surface may occur, you to use hygienic practices to the extent
necessary to protect against contamination of components, dietary
supplements, or contact surfaces. Final Sec. 111.10(b) lists nine
hygienic practices, such as wearing outer garments in a manner that
protects against contamination, washing hands thoroughly, and wearing,
where appropriate, hair nets, caps, beard covers, or other effective
hair restraints.
We did not receive any comments concerning proposed Sec.
111.10(b)(1) (wearing outer garments in a manner that protects against
contamination), Sec. 111.10(b)(2) (maintaining adequate personal
cleanliness), Sec. 111.10(b)(3) (washing hands thoroughly), Sec.
111.10(b)(4) (removing all unsecured jewelry and other objects that
might fall into components, dietary supplements, equipment, or
packaging and removing hand jewelry that cannot be adequately
sanitized), Sec. 111.10(b)(6) (wearing, where appropriate, hair nets,
caps, beard covers, and other effective hair restraints), Sec.
111.10(b)(7) (not storing clothing or other personal belongings where
components, dietary supplements, or contact surfaces are exposed or
where contact surfaces are washed), and Sec. 111.10(b)(9) (taking any
other precautions necessary to protect against contamination).
Proposed Sec. 111.10(b)(5) would require the hygienic practices
that you use to include maintaining gloves used in handling components,
dietary ingredients, or dietary supplements in an intact, clean, and
sanitary condition and ensuring that gloves be of an impermeable
material.
(Comment 70) One comment asks us to clarify the requirements for
the use of gloves in proposed Sec. 111.10(b)(5). The comment says
there are situations in which gloves are ineffective or cumbersome. The
comment provides as an example, if a person is packaging a bulk
material in fiber packs with metal ring lids, bulky gloves can
interfere with the finer work such as attaching security tabs, and
thin, flexible gloves can be easily damaged by the sharp edges of the
metal rings on the lid.
(Response) Final Sec. 111.10(b)(5) requires you to maintain gloves
in an intact, clean, and sanitary condition; it does not require you to
use gloves in any specific situation. Although there is no requirement
for wearing gloves while performing specific operations, you must wear
gloves when they are necessary to protect against contamination of any
components, dietary supplements, or contact surfaces.
(Comment 71) Proposed Sec. 111.10(b)(8) would require that the
hygienic practices that you use, to the extent necessary to protect
against contamination, include not eating food, chewing gum, drinking
beverages, or using tobacco products in areas where components, dietary
ingredients, dietary supplements, or any contact surfaces are exposed,
or where contact surfaces are washed.
One comment would substitute the word ``processed'' for the word
``exposed'' in proposed Sec. 111.10(b)(8). The comment says, although
areas where components, dietary supplements, and contact surfaces are
exposed pose the greatest risk, adulteration is also possible where
these items are held (i.e., stored in containers and, thus, not
exposed). Furthermore, the comment explains the use of the word
``processed,'' rather than ``exposed,'' would cover all areas intended
to be covered by CGMPs and would alleviate the need to specify that the
requirement applies to areas where contact surfaces are washed.
(Response) We decline to revise the rule as suggested by the
comment. We believe the word ``exposed'' covers all areas intended to
be covered by the
[[Page 34810]]
requirement, including areas where contact surfaces are washed. We
consider an area where contact surfaces are washed to ``expose'' the
contact surface. To avoid any confusion, we are modifying Sec.
111.10(b)(8) to say ``* * * any contact surfaces are exposed, or where
contact surfaces are washed.'' As written, the requirement to not eat,
chew gum, drink, or use tobacco products in areas where components,
dietary supplements, and contact surfaces are exposed gives firms
appropriate flexibility to determine areas where employees may or may
not eat, chew gum, drink, or use tobacco products.
F. What Personnel Qualification Requirements Apply? (Final Sec.
111.12)
Final Sec. 111.12(a) requires you to have qualified employees who
manufacture, package, label, or hold dietary supplements. Final Sec.
111.12(a) is similar to proposed Sec. 111.12(a), except that the final
rule includes an editorial change to clarify that the requirement is to
have the qualified employees do the work rather than merely to have
qualified employees.
(Comment 72) The 2003 CGMP Proposal invited comment on whether
there is a minimum number of employees needed to manufacture dietary
supplements (68 FR 12157 at 12183). Several comments state the final
rule should not include such a minimum number because firms should be
able to decide for themselves how many qualified personnel they need.
(Response) The final rule does not stipulate a minimum number of
employees. However, there should be enough employees to manufacture,
package, label, and hold dietary supplements to ensure compliance with
the final rule. In general, CGMP suggests the need for a minimum of two
persons: One to perform the work, and a second to check the work
performed to ensure that a manufacturing deviation or an unanticipated
occurrence is not overlooked.
(Comment 73) Some comments about the proposed definition of
``quality control unit'' say the quality control function need not be
performed by a distinct or separate unit. These comments say the
quality control function is best performed by a person or persons
qualified by training, education, or experience in the different
processing areas.
(Response) As discussed, we have revised the proposed definition
and substituted the term ``personnel'' for ``unit.'' (For the
definition of quality control personnel, see section VI of this
document.) We agree the quality control functions do not need to be
performed by a distinct or separate unit or person and that a person
who is qualified by training, education, or experience can serve a
quality control function. Therefore, we are adding a new Sec.
111.12(b) to clarify that you must identify who is responsible for
quality control operations. Under final Sec. 111.12(b) each person
identified must be qualified to perform such operations, and must have
distinct and separate responsibilities related to performing such
operations from those responsibilities that the person otherwise has
when not performing such operations. The quality control personnel can
have dual functions within the facility but should separately perform
the different responsibilities.
Final Sec. 111.12(c) requires that each person engaged in
manufacturing, packaging, labeling, or holding, or in performing any
quality control operations, have the education, training, or experience
to perform the person's assigned functions. Final Sec. 111.12(c)
includes a revision associated with final Sec. 111.12(b) by including
persons who perform quality control operations as persons who also need
to have the education, training, or experience for the assigned
functions.
(Comment 74) Several comments state we should revise the rule to
allow for any combination of ``training or experience.'' These comments
explain it is not always possible for an employee to have both
``training and experience.'' These comments would revise proposed Sec.
111.12(b) to read, ``each person engaged in the manufacture of a
dietary product should have the proper education, training, and
experience (or any combination thereof) needed to perform the assigned
functions. Training should be in the particular operations(s) that the
employee performs as they relate to the employee's functions.'' Another
comment asks for guidance as to what type of education, training, or
experience is required for an employee to be considered qualified.
(Response) We agree with the point made by the comments. We
acknowledge that some positions will require an appropriate educational
background in addition to any on-the-job training. In the preamble to
the 2003 CGMP Proposal (68 FR 12157 at 12183) we noted ``training'' may
be considered a form of ``education'' and elected to require that
employees be qualified by ``training and experience'' rather than
``education, training, and experience.'' The 2003 CGMP Proposal used
the conjunction ``and'' because we considered ``experience'' to be
different from training, in that ``experience'' is knowledge that a
person gains over time, e.g., as he or she becomes increasingly
familiar with a particular action or piece of equipment.
These comments persuade us that the rule would be clearer if we
added ``education'' to the list of attributes that are used to qualify
an employee. We also agree there are some employees who could be
qualified based solely on their education or experience and other
employees who would become qualified through, for example, on-the-job
training before they are left on their own to perform their assigned
duties. Rather than revise the rule to list all three attributes and
then explain that an employee can be qualified by any combination of
the attributes, we have changed the conjunction from ``and'' to ``or.''
Additionally, on our own initiative, we have replaced ``person's
duties'' with ``person's assigned functions.'' This change reinforces
the principle that the employee's training relates to the functions
that he or she is assigned to perform.
We will consider whether it would be useful to provide guidance on
what type of education, training, or experience would be sufficient for
an employee to be properly qualified. We believe that such education,
training, or experience may vary by job function and that it would be
difficult to provide generic guidance that would be sufficient for all
specific job tasks. We decline to suggest that training should be
limited, as the comments suggest, to the particular operation(s) that
the employee performs as they relate to the person's functions. These
CGMP requirements apply to many types of manufacturing operations of
various size and complexity, so the training may vary depending on the
circumstances and may include more than the employee's assigned
functions.
(Comment 75) One comment states we should provide training
materials such as texts, videos, Internet training, or seminars, to
help companies properly train their employees.
(Response) We have no plans at this time to provide companies with
training materials for their employees. We expect that most companies
already have trained or will train their employees and that where
additional training is needed to comply with these regulations,
companies will develop the training materials that are appropriate for
the functions their employees perform. We may consider providing
guidance in the future if circumstances warrant such guidance.
[[Page 34811]]
G. What Supervisor Requirements Apply? (Final Sec. 111.13)
Final Sec. 111.13(a) requires you to assign qualified personnel to
supervise the manufacturing, packaging, labeling, or holding of dietary
supplements. Final Sec. 111.13(a) derives from proposed Sec.
111.13(a).
We did not receive comments specific to proposed Sec. 111.13(a).
Final Sec. 111.13(b) requires each supervisor you use to be
qualified by education, training, or experience to supervise. Final
111.13(b) derives from proposed Sec. 111.13(b) which would require you
and your supervisors to be qualified by training and experience to
supervise.
(Comment 76) Several comments ask us to revise the rule so that
supervisors may be qualified by any combination of training or
experience. These comments would revise proposed Sec. 111.13(b) to
read, ``supervisors must be qualified by education, training, and
experience (or any combination thereof) to supervise the manufacturing,
packaging, or holding of dietary ingredients and dietary supplements in
compliance with this rule.'' One comment, however, would make an
exception for quality control and sanitation supervisors, stating we
should require these supervisors to have both training and experience.
(Response) Consistent with the change we made to proposed Sec.
111.12(c), we are revising proposed Sec. 111.13(b) to require the
supervisors you use to be qualified by ``education, training, or
experience.'' We acknowledge that some supervisory personnel may need a
different range of education, training, or experience than others, and
expect firms to determine the appropriate balance of education,
training, and experience.
(Comment 77) Several comments say our use of the phrase ``you and
the supervisors you use'' in proposed Sec. 111.13(b) was unclear.
According to these comments, the term ``you'' as defined in the
proposal, is quite expansive and could be read so broadly as to require
the Chief Executive Officer (CEO) of a company be ``qualified'' to
supervise.
(Response) We agree that the phrase ``you and the supervisors you
use'' could be clearer. Therefore, we are revising proposed Sec.
111.13(b) to say that ``each supervisor whom you use'' must be
qualified to supervise. Section 111.13(b) applies to any person who
supervises the manufacturing, packaging, labeling, or holding of
dietary supplements, even if that person also is an executive such as
the CEO. Thus, final Sec. 111.13(b) states, ``Each supervisor whom you
use must be qualified by education, training, or experience to
supervise.''
(Comment 78) Several comments say the term ``to supervise'' is
ambiguous and would revise the rule to clarify what a supervisor must
be qualified to supervise: The manufacture, packaging, or holding of
dietary ingredients and dietary supplements. Another comment would
revise proposed Sec. 111.13(b) to clarify what type of training and
experience are required so that firms would have more guidance as to
what is expected to confirm that personnel are qualified.
(Response) We decline to revise the rule as suggested by the
comments. We disagree that the term ``to supervise,'' which is commonly
used in the industry, is ambiguous. These CGMP requirements apply to
many types of manufacturing operations of various size and complexity,
and the training must be suited to the circumstances.
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.14)
As discussed in this section, the final rule contains a new Sec.
111.8 requiring you to establish and follow written procedures to
fulfill the requirements of subpart B. Those written procedures are
records. Therefore, we are adding a new Sec. 111.14(a) requiring you
to make and keep records in accordance with subpart P. Final Sec.
111.14(b)(1) requires you to make and keep a record of the written
procedures for fulfilling the requirements of subpart B.
The preamble to the 2003 CGMP Proposal invited comment on whether
we should require documentation and records regarding each employee's
training (68 FR 12157 at 12183). After considering comments and for the
reasons discussed in the following paragraphs, Sec. 111.14(b)(2)
requires you to make and keep documentation of training, including the
date of training, the type of training, and the person(s) trained.
We also invited comment on whether the final rule should contain
requirements for documentation about consultants that you use (68 FR
12157 at 12183). We specifically suggested any such requirement include
the consultant's name, address, qualifications, and a description of
services provided. After considering the comments and for the reasons
discussed in the following paragraphs, the final rule does not include
any requirements to make and keep records regarding consultants.
(Comment 79) Several comments state employee training records are
critical and should be required under the final rule. The comments
explain that these records should show the content of the training, the
date of the training, and the signature of the employee trained. These
comments assert that a formal (written) GMP training program is
necessary to track which employees have been trained in the CGMP
requirements. These comments add, without a written and documented
training program, it is likely that some employees may not receive
sufficient training, or in some cases, any CGMP training at all. These
comments say successful quality control programs are inextricably
connected to appropriate training programs, and written documentation
of employee training is an important safeguard to ensuring safe and
accurately labeled dietary supplements. These comments also state it is
already an industry standard to document training.
Other comments question our ability to evaluate whether a firm's
employees have been adequately trained without written documentation of
the training.
(Response) As discussed more fully in the discussion of subpart E
in section X of this document, the final rule focuses on ensuring the
quality of the dietary supplement at every stage of the production and
process control system. Such a system begins with the proper training.
We agree that documentation of employee training is necessary to track
which employees have been trained in which operations. Therefore, final
Sec. 111.14(b)(2) requires you to keep documentation of training,
including the date of the training, the type of training, and the
person(s) trained.
(Comment 80) One comment says we should not require manufacturers
to document and keep records regarding each employee's training. The
comment says the rule should focus on end results and not on process.
(Response) We disagree with the comment. As we have explained in
this section, each person engaged in an activity covered by these CGMP
regulations must have the education, training, or experience to perform
the person's assigned functions. Some employees will be considered
qualified based in part on training taken as company employees. To show
that such training is appropriate to the employee's functions and has
in fact occurred, the training must be properly documented. This
documentation is an important aspect of ensuring adequate training and,
therefore, helping to ensure the result of having qualified employees
who perform their functions properly.
[[Page 34812]]
(Comment 81) Several comments state the documentation of the
training program should include the title of the person doing the
training, an evaluation of the employee's understanding of the
training, and recommendations for the frequency of refresher training.
One comment describes a specific method for training and for tracking
training. The comments state an evaluation of the employee's
understanding of the training would ensure that employees who receive
training understand what they have been taught.
(Response) We decline to require specific additional documentation
of employee training. We believe a firm should have some flexibility in
how it wants to document training.
(Comment 82) Several comments respond to our question as to whether
the final rule should require documentation about consultants,
including each consultant's name, address, qualifications, and a
description of services provided. Several comments say that documenting
this information is useful and could be done on a voluntary basis, but
that such information is not necessary to ensure safe and accurately
labeled supplements and, thus, should not be required. One comment
notes that recommendations from consultants may or may not be used, and
that a company should not have to explain at a later date why such
decisions were made. Another comment asserts that we and the company
may have different opinions on whether a consultant is qualified and
that the consultant's qualification is not our concern if a product is
not adulterated. One comment says documenting the name and services of
the GMP consultants should be required to facilitate contact in case of
need.
(Response) The proposal noted documentation of the name, address,
qualifications, and services rendered for each consultant may help you
know whom to contact and if questions arise concerning the advice that
the consultant has given. Thus, our intent in suggesting such
documentation was to help you rather than to make the information
available for us to determine whether we agreed with you that a
particular individual was qualified to be a consultant. However, the
comments persuade us that such information is not necessary to help
ensure dietary supplement quality. Therefore, the final rule does not
require documentation regarding consultants.
VIII. Comments on Physical Plant and Grounds (Final Subpart C)
A. Organization of Final Subpart C
Proposed subpart C contained two provisions regarding physical
plants. Table 4 of this document lists the sections in final subpart C
and identifies the corresponding proposed sections that form the basis
of the final rule.
Table 4.--Derivation of Sections in Final Subpart C
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.15 What sanitation requirements Sec. 111.15
apply to your physical plant and grounds?
------------------------------------------------------------------------
Sec. 111.16 What are the requirements N/A
under this subpart C for written
procedures?
------------------------------------------------------------------------
Sec. 111.20 What design and construction Sec. 111.20
requirements apply to your physical
plant?
------------------------------------------------------------------------
Sec. 111.23 Under this subpart C, what Sec. 111.15(d)(3) and
records must you make and keep? (e)(2)
------------------------------------------------------------------------
B. Highlights of Changes to the Proposed Requirements for Physical
Plant and Grounds
1. Revisions
The final rule:
Reflects that the rule applies to persons who manufacture,
package, label, or hold dietary supplements unless subject to an
exclusion in Sec. 111.1.
Requires you to have documentation or otherwise be able to
show that water that is used in a manner such that the water may become
a component of the dietary supplement, e.g., when such water contacts
components, dietary supplements, or any contact surface, meets
applicable Federal, State, and local requirements and does not
contaminate the dietary supplement.
2. Changes After Considering Comments
The final rule:
Includes requirements similar to the food CGMP
requirements in Sec. 110.20(a) for keeping the grounds bordering your
physical plant in a condition that protects against contamination.
Clarifies that sanitation supervisors can be qualified by
education, training, or experience.
Modifies the minimum requirements for water that is used
in a manner such that the water may become a component of the dietary
supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface. Such water must, at a minimum,
comply with applicable Federal, State, and local requirements and not
contaminate the dietary supplement.
Simplifies the sanitation requirements for toxic
materials, bathroom facilities, and hand-washing facilities.
Simplifies and clarifies the design requirements for
floors, walls, and ceilings; fans and other air-blowing equipment;
equipment that controls temperature and humidity; and the use of
safety-type glass or glass-like materials.
Requires written procedures for cleaning the physical
plant and for pest control.
Requires that you make and keep records of the written
procedures.
C. General Comments on Proposed Subpart C
(Comment 83) Several comments say we should have different
sanitation requirements for dietary ingredient manufacturers than for
dietary supplement manufacturers. These comments state that the
manufacture of synthetic or highly processed dietary ingredients
includes extensive purification steps, especially toward the end of the
manufacturing process, and that these steps remove contaminants that
may have been introduced at earlier stages in the manufacturing
process. These comments consider some stages of the dietary ingredient
manufacturing process to not be subject to the same strict controls as
those used for manufacturing finished dietary supplements.
(Response) As discussed in section VI of this document (subpart A),
the final rule applies to persons who manufacture, package, label, or
hold dietary supplements and who are not subject to an exclusion in
Sec. 111.1, and does not apply to establishments that only manufacture
dietary ingredients. We addressed this comment in the response to
comment 29.
(Comment 84) Some comments assert that one or more proposed
requirements are unconstitutionally vague under the Fifth Amendment and
are arbitrary and capricious under section 706(2)(B) of the APA. The
comments would delete the following proposed requirements:
Sec. 111.15(e), which would require plumbing to be ``of
an adequate size and
[[Page 34813]]
design and be adequately installed and maintained;''
Sec. 111.15(g), which would require bathrooms to be
``adequate'' and ``readily accessible; ''
Sec. 111.15(h), which would require hand-washing
facilities ``to be adequate, convenient, and furnish running water at a
suitable temperature;''
Sec. 111.15(h)(i), which would require hand-washing and,
where appropriate, hand-sanitizing facilities ``at each location in
your physical plant'' where good hygienic practices require employees
to wash or to sanitize or both wash and sanitize their hands;
Sec. 111.20(a), which would require your physical plant
to ``be suitable in size, construction, and design to facilitate
maintenance, cleaning, and sanitizing operations;'' and
Sec. 111.20(d)(6), which would require aisles or working
spaces between equipment and walls to be adequately unobstructed and of
adequate width.
In general, these comments assert the 2003 CGMP Proposal did not
define terms or phrases (such as ``adequately'' or ``at each
location'') in a way that persons who are subject to the rule can
discern the meaning of the term or phrase. These comments argue that
the proposed rule imposes no limitations on enforcement officers on the
exercise of their discretion and, thus, invites exercise of unbridled
discretion and disparate decisionmaking.
(Response) As discussed in section V of this document, we disagree
that the terms that the comments objected to in the 2003 CGMP Proposal
are unconstitutionally vague, need to be defined, or may result in
discriminatory enforcement. We are retaining the terms in the final
rule.
D. What Sanitation Requirements Apply to Your Physical Plant and
Grounds? (Final Sec. 111.15)
1. Final Sec. 111.15(a)
The preamble to the 2003 CGMP Proposal (68 FR 12157 at 12184)
stated that we were not proposing requirements similar to the food CGMP
requirements found in Sec. 110.20(a) for keeping the grounds bordering
your physical plant in a condition that protects against contamination
of components or dietary supplements in order to limit the burden to
manufacturers. However, we invited comment on whether we should include
such requirements in a final rule. After considering the comments, we
have drafted final Sec. 111.15(a) to require you to keep the grounds
of your physical plant in a condition that protects against the
contamination of components, dietary supplements, or contact surfaces.
The methods for adequate ground maintenance include:
Properly storing equipment, removing litter and waste, and
cutting weeds or grass within the immediate vicinity of the physical
plant so that it does not attract pests, harbor pests, or provide pests
a place for breeding;
Maintaining roads, yards, and parking lots so that they do
not constitute a source of contamination in areas where components,
dietary supplements, or contact surfaces are exposed;
Adequately draining areas that may contribute to the
contamination of components, dietary supplements, or contact surfaces
by seepage, filth or any other extraneous materials, or by providing a
breeding place for pests;
Adequately operating systems for waste treatment and
disposal so that they do not constitute a source of contamination in
areas where components, dietary supplements, or contact surfaces are
exposed; and
If your plant grounds are bordered by grounds not under
your control, and if those other grounds are not maintained in the
manner described in this section, you must exercise care in the plant
by inspection, extermination, or other means to exclude pests, dirt,
and filth or any other extraneous material that may be a source of
contamination.
(Comment 85) Several comments say the final rule should require the
maintenance of external areas similar to the food CGMP requirement at
Sec. 110.20(a) for keeping the grounds outside the facility adequately
maintained. These comments state that such a requirement is basic, is
equally important to facilities that manufacture conventional foods and
to facilities that manufacture dietary supplements, and that there is
no reason why this requirement should differ from food CGMPs. One
comment asserts such a requirement is basic to the industry and it
should not be dismissed as a burden to the industry. Some comments also
assert that a provision similar to Sec. 110.20(a) would help train
staff and would explain to plant maintenance personnel what is required
and why.
One comment says there should be some minimum requirement for
sanitation and cleanliness in the area surrounding the plant and that
requirements for drainage and trash removal should be adequate.
(Response) We agree that a requirement to maintain grounds is
equally important for facilities that manufacture conventional foods
and for facilities that manufacture dietary supplements. Although some
requirements in Sec. 110.20(a) are not strictly limited to drainage
and trash disposal, the comment suggesting the requirements to maintain
grounds be limited to drainage and trash disposal did not explain why,
for example, it would not be as important for a facility that
manufactures dietary supplements to maintain roads, yards, and parking
lots so that they do not become a source of contamination as it already
is for facilities that manufacture conventional foods. Therefore, the
final rule is adding Sec. 111.15(a), which is similar to Sec.
110.20(a) with editorial revisions consistent with the rest of this
final rule.
2. Final Sec. 111.15(b)(1)
Final Sec. 111.15(b)(1) (proposed Sec. 111.15(a)) requires you to
maintain your physical plant in a clean and sanitary condition. Final
Sec. 111.15(b)(2) requires you to maintain your physical plant in
repair sufficient to prevent components, dietary supplements, or
contact surfaces from becoming contaminated.
We did not receive comments specific to proposed Sec. 111.15(a).
3. Final Sec. 111.15(c)
Final Sec. 111.15(c) (proposed Sec. 111.15(b)) sets forth
requirements for cleaning compounds, sanitizing agents, pesticides, and
other toxic materials.
Final Sec. 111.15(c) includes changes that we are making for
clarity and consistency. We added other ``toxic'' materials because
some paragraphs within final Sec. 111.15(c) simply refer to the
cleaning compounds, sanitizing agents, and pesticides as ``toxic
materials,'' and because proposed Sec. 111.15(b)(2) addressed the use
and storage of toxic materials that are not within the general category
of cleaning compounds, sanitizing agents, or pesticides.
Final Sec. 111.15(c)(1) requires you to use cleaning compounds and
sanitizing agents that are free from microorganisms of public health
significance and that are safe and adequate under the conditions of
use. Final Sec. 111.15(c)(1) is similar to proposed Sec.
111.15(b)(1), except that we inserted ``that are'' before ``safe and
adequate.'' We consider this to be a nonsubstantive, editorial change.
Proposed Sec. 111.15(b)(1) was, itself, patterned after Sec.
110.35(b)(1), which: (1) Requires cleaning compounds and sanitizing
agents used in cleaning and sanitizing procedures to be free from
undesirable microorganisms and safe and adequate under the conditions
of use and (2) provides that compliance may be verified by any
effective means including purchase of these substances
[[Page 34814]]
under a supplier's guarantee or certification or examination of these
substances for contamination.
(Comment 86) Several comments ask us to clarify our expectations
with respect to substantiating that a cleaning compound or sanitizing
agent is free from microorganisms of public health significance and is
safe and adequate under conditions of use. Some comments suggest
proposed Sec. 111.15(b)(1) provide for the use of certifications or
guarantees from a supplier because our investigators otherwise may not
recognize such documents as evidence of compliance. Several comments
say it is not necessary for a manufacturer to test these types of
products, and that a continuing product guarantee, combined with a
statement of intended use from the manufacturer of the cleaning
compound or sanitizing agent, should satisfy the requirements.
(Response) When assessing compliance with final Sec. 111.15(c)(1),
we would not treat a firm that manufactures, packages, labels, or holds
a dietary supplement differently than we would treat a facility that
manufactures, packages, labels, or holds conventional foods. Therefore,
we intend to accept, as the comments request, a supplier's guarantee or
certification that a cleaning compound or sanitizing agent is free from
microorganisms of public health significance and is safe and adequate
under the conditions of use for the purpose of determining compliance
with final Sec. 111.15(c)(1).
Final Sec. 111.15(c)(2) requires you to not use or hold toxic
materials in a physical plant in which components, dietary supplements,
or contact surfaces are manufactured or exposed, unless those materials
are necessary: (1) To maintain clean and sanitary conditions, (2) for
use in laboratory testing procedures, (3) for maintaining or operating
the physical plant or equipment, or (4) for use in the plant's
operations.
We did not receive comments specific to proposed Sec.
111.15(b)(2). We have made a nonsubstantive edit to Sec. 111.15(c)(2)
by moving ``contact surfaces'' to be the last item on the list.
Final Sec. 111.15(c)(3) requires you to identify and hold cleaning
compounds, sanitizing agents, pesticides, pesticide chemicals, and
other toxic materials in a manner that protects against contamination
of components, dietary supplements, or contact surfaces. Final Sec.
111.15(c)(3) is similar to proposed Sec. 111.15(b)(3).
We did not receive comments specific to proposed Sec.
111.15(b)(3), but replaced ``toxic cleaning compounds'' with ``cleaning
compounds,'' and added ``other toxic materials.''
4. Final Sec. 111.15(d)
Final Sec. 111.15(d) (proposed Sec. 111.15(c)) sets forth
requirements for pest control. Section Sec. 111.15(d) is almost
identical to proposed Sec. 111.15(c).
Final Sec. 111.15(d)(1) requires you to not allow animals or pests
in any area of your physical plant. Final Sec. 111.15(d)(1) allows
guard or guide dogs in some areas of your physical plant if the
presence of the dogs will not result in contamination of components,
dietary supplements, or contact surfaces. Final Sec. 111.15(d)(2)
requires that you take effective measures to exclude pests from your
physical plant and to protect against the contamination of components,
dietary supplements, and contact surfaces on the premises by pests.
Final Sec. 111.15(d)(3) requires that you not use insecticides,
fumigants, fungicides, or rodenticides unless you take precautions to
protect against the contamination of your components, dietary
supplements, or contact surfaces.
(Comment 87) Several comments claim proposed Sec. 111.15(c) would
require that sealed equipment outside of the plant (e.g. storage tanks,
vessels, piping) be enclosed to prevent pests from roaming around these
areas. The comments say there is no need to shelter outdoor equipment
if it is properly sealed. These comments state that dietary supplements
are sometimes manufactured in extensive, highly automated facilities in
which large tanks and vessels are interconnected via piping, and that
in these cases ``the physical plant'' and ``the equipment in the
plant'' converge so that some or much of the equipment is effectively
located outdoors. Thus, the comments ask us to revise proposed Sec.
111.15(c) to clarify that it applies only to interior areas of the
physical plant.
(Response) Equipment such as that described by the comments, if
properly sealed, should protect components, dietary supplements, and
contact surfaces from contamination with pests. Final Sec. 111.15(d)
does not require that sealed equipment outside of the plant, such as
storage tanks, vessels, or piping, be enclosed, e.g., inside a
building. Final Sec. 111.15(d)(2) requires that you take effective
measures to exclude pests from your physical plant and to protect
against the contamination of components, dietary supplements, or
contact surfaces on the premises by pests. Moreover, final Sec.
111.15(a) includes several requirements designed to limit or exclude
pests around all parts of the exterior of your physical plant.
Therefore, although you do not have to enclose your outside equipment,
you must take measures to exclude pests from areas outside of the
plant.
5. Final Sec. 111.15(e)
Final Sec. 111.15(e) (proposed Sec. 111.15(d)) sets forth
requirements for the water supply of your physical plant.
Final Sec. 111.15(e)(1) requires that you must provide water that
is safe and sanitary at suitable temperatures and under pressure as
needed for all uses where water does not become a component of the
dietary supplement.
We did not receive comments specific to proposed Sec.
111.15(d)(1). We have modified the phrase ``safe and of adequate
sanitary quality'' to read ``safe and sanitary.'' To avoid confusion
with the definition of ``quality'' we have adopted solely for purposes
of this final rule, we deleted the references to ``quality'' as it
applies to water standards. We consider this change to be
nonsubstantive and still require water that is not a component of a
dietary supplement to meet a safe and sanitary standard.
Final Sec. 111.15(e)(2) requires that water used in a manner such
that the water may become a component of the dietary supplement, e.g.,
when such water contacts components, dietary supplements, or any
contact surface, must, at a minimum, comply with applicable Federal,
State, and local requirements and not contaminate the dietary
supplement. Final Sec. 111.15(e)(2) derives from proposed Sec.
111.15(d)(2) which would require that water that contacts components,
dietary supplements, or any contact surfaces must, at a minimum, comply
with the applicable National Primary Drinking Water (NPDW) regulations
and any State and local government requirements. Final Sec.
111.15(e)(2) includes changes we are making after considering comments
discussed in the following paragraphs.
(Comment 88) Several comments state the water quality that is
required for conventional foods is sufficient for dietary supplements.
The comments argue that no additional water standards are listed in the
CGMPs for low-acid canned foods in part 113 or in the CGMPs for
acidified foods in part 114. These comments argue that, if ``safe and
of adequate sanitary quality'' is sufficient to ensure the quality of
the water used in most food products, then it is also adequate to
ensure the quality of the water used in dietary supplements.
Other comments would revise the final rule to allow different
standards and requirements for water that contacts or is used in
dietary supplements
[[Page 34815]]
compared to water that contacts components, including dietary
ingredients. These comments state current food CGMP regulations require
only that water supplies that contact food (defined to include
ingredients and raw materials) be ``safe and of adequate sanitary
quality.'' These comments say that this would be consistent with the
act's basis for CGMP requirements for foods, i.e., that food is not
prepared ``under unsanitary conditions whereby it may have become
contaminated with filth, or whereby it may have been rendered injurious
to health'' (section 402(a)(4) of the act). Several comments state the
final rule should adopt a similar rationale for components, including
dietary ingredients. These comments explain that components, including
dietary ingredients, are not in a form in which they will be consumed
and are subject to further processing prior to consumption.
Several comments say that requiring water used for cleaning contact
surfaces to meet Environmental Protection Agency regulations is an
unnecessary burden for companies that do not have access to municipal
water. According to these comments, potable water should be sufficient.
(Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12185), we stated that water should, at a minimum, be potable and
that water that is ``safe and of adequate sanitary quality'' should be
potable. We also said water that contacts components, dietary
supplements, or contact surfaces should, at a minimum, meet the
Environmental Protection Agency's NPDW regulations and State, and local
requirements. We proposed to require that water used in operations
where water contacts components, dietary supplements, or any contact
surfaces meet the NPDW regulations because of the potential for
contamination if water were used that did not adhere to the microbial
standards, for example, in the NPDW regulations. Finally, we stated
these requirements were minimum requirements and that water that is
more pure than that required under the NPDW regulations may be desired.
The comments stated some manufacturers may not have access to
municipal water, and therefore, that meeting the NPDW regulations for
cleaning contact surfaces would be too burdensome. These comments
asserted that potable water would be sufficient. The comments do not
provide a definition of ``potable water.'' We have defined ``potable
water,'' in the regulations on interstate conveyance sanitation in 21
CFR part 1250 to be, in part, water that meets the standards prescribed
in the Environmental Protection Agency's NPDW regulations in 40 CFR
part 141.
We would consider it to be a rare situation where a dietary
supplement manufacturer uses well water and has no access to municipal
water. Nonetheless, to the extent that a manufacturer uses water that
is not subject to Federal oversight, the manufacturer would have to
comply with any State or local regulations that apply to food
manufacturing facilities using such water in food processing.
Manufacturers that use water from a municipal source, which is
subject to the Environmental Protection Agency NPDW regulations, should
not be subject to a lesser standard in this final rule than what is
already required of them by the Environmental Protection Agency. Thus,
to accommodate manufacturers subject to the Environmental Protection
Agency's NPDW regulations for the water that they use in the
manufacture of dietary supplements, as well as those dietary supplement
manufacturers who are not subject to the Environmental Protection
Agency's NPDW regulations, we are modifying the rule to state water
that is used in a manner such that the water may become a component of
the dietary supplement, e.g., when such water contacts components,
dietary supplements, or any contact surface, must, at a minimum, comply
with applicable Federal, State, and local requirements and not
contaminate the dietary supplement. We decline to use ``safe and of
adequate safety'' that some comments state is sufficient because it is
for conventional foods. We believe that requiring that water comply
with Federal, State and local requirements and not contaminate dietary
supplements provides a clear standard as to what is required.
(Comment 89) Some comments assert that water that is used to
manufacture components or dietary ingredients where such components or
dietary ingredients are subject to further processing prior to
consumption, should be subject to the ``safe and of adequate sanitary
quality'' standard in Sec. 110.37.
(Response) We acknowledge that such components and dietary
ingredients are subject to the requirement in Sec. 110.37. If the
manufacturers do not fall within the scope of final Sec. 111.1, such
manufacturers would be subject to the CGMP requirements in part 110.
To the extent that such comments request the ``safe and of adequate
sanitary quality'' language apply to water used in the manufacture of a
dietary supplement, we decline to make that change. Water that is safe
and sanitary would not necessarily comply with, for example, the NPDW
regulations. A requirement stating ``safe and of adequate sanitary
quality'' or, as stated in the final rule, the requirement of ``safe
and sanitary'' could be seen as a lesser standard than water that
complies with ``applicable Federal, State, and local requirements.'' We
want to make clear that you must comply with applicable Federal, State,
and local requirements related to the water that you use for food
processing that would otherwise be required of you, and not to some
lesser standard that you may consider is ``safe and sanitary'' when
water is used in a manner such that the water may become a component of
the dietary supplement, e.g., when such water contacts a component,
dietary supplement, or any contact surface. Foreign manufacturers would
need to comply with the water standard required in this final rule and
achieve the same level of performance as is required of domestic
manufacturers. The water used in domestic or foreign manufacturing must
not contaminate the dietary supplement. To clarify that the water used,
whether by a domestic or foreign manufacturer, must not be a source of
contamination, we are adding the words ``and not contaminate the
dietary supplement'' in final Sec. 111.15(e)(2). We also want to make
it clear that water includes what is in the water, e.g., any of its
contaminants in addition to H2O. For example, when we speak
of drinking water, we do not just mean the H2O, we mean the
iron, lead, sulfur, and any other contaminants contained in the water.
(Comment 90) Several comments suggest water should meet some or all
standards of the USP monograph for sterile, purified water and say that
the standard in the USP monograph is a higher, and presumably safer,
standard than the NPDW standard. The comments state the USP's water
deionization and purification systems requirements are already common
in the industry.
(Response) We do not discourage firms from using water in dietary
supplement manufacturing that meets USP standards, including deionized
or purified water, but we do not require, as a CGMP, the use of USP
standards. This final rule sets forth minimum requirements for persons
who manufacture, package, label, or hold a dietary supplement. Thus,
firms may use water that exceeds our minimum requirements.
(Comment 91) The preamble to the 2003 CGMP Proposal recognized that
foreign firms might not be subject to Environmental Protection Agency
water
[[Page 34816]]
requirements or adhere to such requirements, but also stated that water
quality is an important part of CGMP (68 FR 12157 at 12185). Thus, in
the preamble to the 2003 CGMP Proposal, we invited comment on how we
might ensure that foreign firms meet the same water quality
requirements as domestic firms. Several comments respond to our request
for comments specific to the applicability of the water standards to
foreign firms. Several comments recommend we not distinguish between
domestic and foreign firms with regard to water quality. The comments
claim all firms must compete on a ``level playing field.'' These
comments state water quality standards vary from country to country,
and many countries do not have requirements that are comparable to
those in the United States. The comments say foreign manufacturers
should not be permitted to import products into the United States that
do not meet the same safety standards as domestic goods.
Other comments ask us to consider the water quality requirement to
be met if the water complies with the NPDW standard or any equivalent
water quality standard that is ensured by a foreign public agency.
(Response) We agree that foreign firms should be required to meet
the water safety and sanitary requirements required of domestic firms
and achieve the same level of performance of domestic firms. As
discussed in this section, foreign firms are required to meet all
requirements and would need to comply with their own national or local
water safety requirements and not contaminate the dietary supplement.
(Comment 92) One comment would combine proposed Sec. 111.15(d)(1)
and (d)(2) into a single paragraph. The comment says the two proposed
paragraphs are redundant. Proposed Sec. 111.15(d)(1) would require
that you provide water that is safe and of adequate sanitary quality,
at suitable temperatures, and under pressure as needed, in all areas
where water is necessary for: (1) Manufacturing dietary ingredients or
dietary supplements; (2) making ice that comes in contact with
components, dietary ingredients, dietary supplements, or contact
surfaces; (3) cleaning any surface; and (4) employee bathrooms and
hand-washing facilities. Proposed Sec. 111.15(d)(2) would require that
water that contacts components, dietary ingredients, dietary
supplements, or any contact surface must at a minimum comply with the
NPDW regulations prescribed by the Environmental Protection Agency
under 40 CFR part 141 and any State and local government requirements.
(Response) We disagree that proposed Sec. 111.15(d)(1) and (d)(2)
were redundant. For example, as described in the proposed sections,
nonpotable water that would have been ``safe and of adequate sanitary
quality'' for use in flushing toilets may not have been ``safe and of
adequate sanitary quality'' for use in the manufacture of a liquid
dietary supplement.
Final Sec. 111.15(e)(1) requires that you provide water that is
safe and sanitary, at suitable temperatures, and under pressure as
needed, for all uses where water does not become a component of the
dietary supplement. Final Sec. 111.15(e)(2) requires that water that
is used in a manner such that the water may become a component of the
dietary supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface, must, at a minimum, comply with
applicable Federal, State, and local requirements and not contaminate
the dietary supplement. As an example of how the requirements would
apply, water that contains lead at a level that is 20 times higher than
the maximum accepted level in the Environmental Protection Agency's
NPDW standards for lead may not be safe for use in the manufacture of
dietary supplement that is consumed in four 2-ounce portions per day,
but may be safe for use in cleaning the floors of the physical plant.
Therefore, to emphasize that water that is ``safe and sanitary'' may be
different depending on its use, the final rule continues to separate
Sec. 111.15(e)(1) and (e)(2) (formerly proposed Sec. 111.15(d)(1) and
(d)(2)).
Additionally, to emphasize the importance of the water that is used
in the manufacture of a dietary supplement, where the water is used in
a manner such that the water may become a component of the dietary
supplement, final Sec. 111.23(c) (proposed Sec. 111.15(d)(3))
requires you to have documentation and keep records that such water
meets the requirements of final Sec. 111.15(e)(2). In contrast, there
is no corresponding requirement for documentation in final Sec. 111.23
that other water, such as water that is used to clean floors or used in
employee bathrooms, meets requirements of final Sec. 111.15(e)(1).
(Comment 93) Several comments state, if we retain a water standard
requirement based on the Environmental Protection Agency NPDW standard,
then it is important to include provisions recognizing the
acceptability of municipal water sources and the frequency of testing
required for other water sources. Some comments recommend water should
meet the USP standard for purified water and point out that the USP
standard provides an assurance of the water's consistency and provides
a system that can be monitored.
Several comments suggest we include timetables for water testing or
describe water testing frequency requirements. These comments state we
should apply something analogous to the proposed requirements for
infant formula which would require manufacturers to conduct the tests
with sufficient frequency to ensure that the water meets the
Environmental Protection Agency's NPDW standard, but not less
frequently than annually for chemical contaminants, every 4 years for
radiological contaminants, and weekly for bacteriological contaminants.
Other comments refer to the amendments to the bottled water regulations
at Sec. 165.110 which require a minimum yearly monitoring of source
water and finished bottled water products for chemical contaminants for
which allowable levels have been established in the bottled water
quality standard.
(Response) Final Sec. 111.23(c) requires you to have documentation
that water, when used in a manner such that the water may become a
component of the dietary supplement, e.g., when such water contacts a
component, dietary supplement, or contact surface, meets the
requirements of final Sec. 111.15(e)(2). You must meet the requirement
for final Sec. 111.15(e)(2) at the point of use, rather than at the
point of delivery, i.e., at the point the water may become a component
of the dietary supplement, such as when the water contacts components,
dietary supplements, or any contact surface (such as when the water
comes out of the faucet or comes out of a spigot from a holding tank
where you store water). Thus, you must ensure that the water used in a
manner such that the water may become a component of the dietary
supplement, not the water source before it enters your facility, meets
the NPDW regulations, or if not subject to the NPDW regulations, that
it meets any other applicable Federal, State, and local requirements
and does not contaminate the dietary supplement.
For example, if the water that enters your facility is subject to
the Environmental Protection Agency NPDW regulations, then the water
must comply with such requirements at the point of use, i.e., when it
contacts the components, dietary supplement, or any contact surface
(such as when the water comes out of the faucet or out of a spigot from
a holding tank where you store water). You could rely on a certificate
of analysis under final Sec. 111.75(a)(2)(ii)
[[Page 34817]]
from the supplier of the water (e.g., the municipality) to ensure that
the water entering your facility complies the applicable Federal,
State, and local requirements. However, you must ensure that nothing
happens to the water that may contaminate the water once it enters your
facility and before the water may become a component of the dietary
supplement at the point of use. Certain contaminants or microorganisms
may be introduced into the water from the facility. Thus, you may need
to establish specifications and procedures to prevent contamination
from pipes through which the water travels in the facility or from
vessels in which the water is held in the facility prior to use. You
may need to test for certain contaminants, e.g., lead or
microorganisms, at point of use to ensure there is no contamination of
the water within your facility. Such tests may not need to include all
of the chemical, microbiological, or contaminant testing already
certified by the supplier to determine whether the water entering your
facility complies with Federal, State and local requirements. Rather,
you would need to evaluate what, if any, introductions of contaminants
are likely to occur within your facility and determine whether
additional tests are needed to verify that the water, at point of use,
will comply with Federal, State, and local requirements and not
contaminate the dietary supplement. Alternatively, you may decide not
to rely on a certificate of analysis and instead conduct your own
testing at point of use to determine if the water complies with
applicable Federal, State, and local requirements. We decline to set
out testing requirements or frequency of testing in this final rule in
lieu of giving manufacturers the flexibility to decide on the
appropriate testing and frequency of such testing to ensure that the
water meets the requirements in final Sec. 111.15(e)(2). We may
consider issuing guidance, as needed, on our recommendation for testing
based on water sources and the purposes for which the water is used. If
you rely on a certificate of analysis from the supplier of the water,
we recommend that you qualify your facility by conducting appropriate
tests at the point of use to verify that no other tests are necessary
or that any additional tests you have chosen are sufficient to
establish that the water that is used in a manner such that the water
may become a component of the dietary supplement, e.g., when such water
contacts components, dietary supplements or any contact surface, meets
the requirements of final Sec. 111.15(e)(2). We also recommend that
you requalify your facility at the point of use at appropriate
intervals.
If you use water from a private source, you must use water that
complies with any State and local requirement and does not contaminate
the dietary supplement. You may need to perform appropriate water
treatment procedures, including filtration, sedimentation, and
chlorination to satisfy final Sec. 111.15(e)(2).
(Comment 94) Several comments would delete proposed Sec.
111.15(d)(2), arguing that it is unnecessary to state a requirement
that water meet the Environmental Protection Agency's NPDW standards.
These comments state that if water is used in processing or at critical
points in the cleaning process, then a manufacturer will already have
established specifications for its appropriate use.
(Response) We agree that a manufacturer will need to establish
specifications, under final Sec. 111.70(a), for any point, step, or
stage in the manufacturing process where control is necessary to ensure
the quality of the dietary supplement, and for water that is used in a
manner such that the water may become a component of the dietary
supplement. For reasons set forth in response to comment 88, final
Sec. 111.15(e)(2) establishes the minimum standards for water that
will be used in a manner such that the water may become a component the
dietary supplement, e.g., when such water contacts components, dietary
supplements, or any contact surface. Thus, we disagree that proposed
Sec. 111.15(e)(2) be eliminated.
6. Final Sec. 111.15(f)
Final Sec. 111.15(f) (proposed Sec. 111.15(e)) sets forth
requirements for the plumbing of your physical plant.
Final Sec. 111.15(f) requires your plumbing to be of an adequate
size and design and be adequately installed and maintained to: (1)
Carry sufficient amounts of water to required locations throughout the
physical plant; (2) properly convey sewage and liquid disposable waste
from your physical plant; (3) avoid being a source of contamination to
components, dietary supplements, water supplies, or any contact
surface, or creating an unsanitary condition; (4) provide adequate
floor drainage in all areas where floors are subject to flooding-type
cleaning or where normal operations release or discharge water or other
liquid waste on the floor; and (5) not allow backflow from, or cross-
connection between, piping systems that discharge waste water or sewage
and piping systems that carry water used for manufacturing dietary
supplements, for cleaning contact surfaces, or for use in bathrooms and
hand-washing facilities.
We did not receive comments specific to proposed Sec. 111.15(e),
other than comments arguing that certain text was unconstitutionally
vague and arbitrary and capricious. We address those comments in
section V of this document.
7. Final Sec. 111.15(g)
Final Sec. 111.15(g) (proposed Sec. 111.15(f)) sets forth
requirements for sewage disposal and requires you to dispose of sewage
into an adequate sewage system or through other adequate means.
We did not receive comments specific to proposed Sec. 111.15(f).
8. Final Sec. 111.15(h)
Final Sec. 111.15(h) (proposed Sec. 111.15(g)(1)) sets forth
requirements for the bathrooms of your physical plant. Final Sec.
111.15(h) requires you to provide your employees with adequate, readily
accessible bathrooms, and that the bathrooms be kept clean and not be a
potential source of contamination to your components, dietary
supplements, or contact surfaces.
(Comment 95) Several comments state companies should be given
flexibility in designing their bathrooms. These comments assert the
food CGMP requirements allow flexibility in bathroom design, so the
dietary supplement CGMP rule should do the same. The comments would
delete proposed Sec. 111.15(g)(1) through (g)(3), which pertained to:
(1) Keeping the bathrooms in good repair at all times; (2) providing
self-closing doors; and (3) providing doors that do not open into areas
where components, dietary ingredients, dietary supplements, or contact
surfaces are exposed to airborne contamination, except where alternate
means have been taken to protect against contamination.
(Response) We agree that it is unnecessary to require specific
bathroom features such as those in proposed Sec. 111.15(g)(1) through
(g)(3) because you may be able to achieve compliance through other
means better suited to your operations. Accordingly, we are revising
the rule by deleting proposed Sec. 111.15(g)(1) through (g)(3) as
requested by the comments. However, we continue to believe that
mechanisms such as self-closing doors and doors that do not open onto
areas where components, dietary supplements, or contact surfaces are
exposed to
[[Page 34818]]
contamination will help protect against contamination.
9. Final Sec. 111.15(i)
Final Sec. 111.15(i) (proposed Sec. 111.5(h)) sets forth
requirements for the hand-washing facilities of your physical plant.
Final Sec. 111.15(i) requires you to provide hand-washing facilities
that are designed to ensure that an employee's hands are not a source
of contamination of components, dietary supplements, or any contact
surface, by providing facilities that are adequate, convenient, and
furnish running water at a suitable temperature.
Final Sec. 111.15(i) differs from the proposal in that the
proposal would list six specific features of a hand-washing facility,
such as effective hand-cleaning and sanitizing preparations (proposed
Sec. 111.15(h)(2)), air driers, sanitary towel service, or other
suitable drying devices (proposed Sec. 111.15(h)(3)), and trash bins
that are constructed to protect against recontamination (proposed Sec.
111.15(h)(4)).
(Comment 96) Several comments state we should give firms the
flexibility to design their hand-washing facilities. According to these
comments, substituting the word ``may'' for the word ``must'' would
accomplish this. The comments argue that, as with bathrooms, an overall
sanitation requirement should be sufficient, and that, as long as there
is a strong and enforceable standard, firms should have the flexibility
to adopt only those measures that are needed to meet the underlying
requirement.
(Response) We agree that it is unnecessary to require specific
hand-washing mechanisms because you may be able to achieve compliance
through other means better suited to your operations. However, we
disagree that an overall sanitation requirement would be sufficient,
because such a requirement would not clearly state the purpose of the
requirement, which is to ensure that an employee's hands are not a
source of contamination of components, dietary supplements, or any
contact surface.
We are revising proposed Sec. 111.15(h) (final Sec. 111.15(i)) in
the final rule in two respects. First, the final rule states that the
hand-washing facilities are to be designed to ensure that an employee's
hands are not a source of contamination. Second, final Sec. 111.15(i)
states that the hand-washing facilities are to be adequate, convenient,
and furnish running water at suitable temperatures but does not provide
the specific hand-washing mechanisms detailed in the 2003 CGMP
Proposal.
10. Final Sec. 111.15(j)
Final Sec. 111.15(j) (proposed Sec. 111.15(i)) sets forth
requirements for trash disposal at your physical plant. Final Sec.
111.15(j) requires that you convey, store, and dispose of trash to: (1)
Minimize the development of odors; (2) minimize the potential for trash
to attract, harbor, or become a breeding place for pests; (3) protect
against contamination of components, dietary supplements, any contact
surface, water supplies, and grounds surrounding your physical plant;
and (4) control hazardous waste to prevent contamination of components,
dietary supplements, and contact surfaces.
(Comment 97) One comment suggests deleting proposed Sec.
111.15(i)(1) concerning minimizing the development of odors, because,
the comment claimed, minimizing odors is not a ``true'' CGMP
requirement.
(Response) We disagree that minimizing the development of odors is
not part of CGMP. Odor from trash is often an indication of problems
with microbial contamination, such as decomposition, decay, and the
growth of harmful bacteria. In addition, odor from trash can attract
pests. By conveying, storing, and disposing of trash to minimize the
development of odors, you will help reduce the potential for problems
with microbial contamination and pests.
11. Final Sec. 111.15(k)
Final Sec. 111.15(k) (proposed Sec. 111.15(j)) sets forth
requirements for sanitation supervisors at your physical plant. Final
Sec. 111.15(k) requires that you assign one or more employees to
supervise overall sanitation. Each supervisor must be qualified by
education, training, or experience to develop and supervise sanitation
procedures. Final Sec. 111.15(k) differs from proposed Sec. 111.15(j)
in that the proposal would require that each supervisor be qualified by
training and experience.
(Comment 98) Several comments suggest revising proposed Sec.
111.15(j) to state that sanitation supervisors may be qualified by
education, training, or experience (or any combination thereof) to
develop and supervise sanitation procedures. In contrast, several
comments say that sanitation supervisors should be qualified by both
training and experience.
(Response) Consistent with our response to comment 76 in section
VII of this document, final Sec. 111.15(k) provides that sanitation
supervisors, like other supervisors, must be qualified by education,
training, or experience to develop and supervise sanitation procedures.
As we also stated in response to comment 76, we acknowledge that some
supervisory personnel may need a different range of education,
training, or experience than others. However, we have decided to give
firms the flexibility to decide the appropriate amount of education,
training, or experience for a given job function. If that includes a
combination of attributes, the firm should select and train employees
accordingly.
E. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.16)
We received many comments that recommend written procedures for
various provisions. We address the need for written procedures
generally in section IV of this document. We also respond to comments
on specific provisions in the same section.
We are adding a new final Sec. 111.16 entitled ``What Are the
Requirements Under This Subpart for Written Procedures?,'' to require
you to establish and follow written procedures for fulfilling certain
requirements of subpart C. You must establish and follow written
procedures for cleaning the physical plant and for pest control.
F. What Design and Construction Requirements Apply to Your Physical
Plant? (Final Sec. 111.20)
Final Sec. 111.20 addresses physical plant design and construction
requirements.
1. Final Sec. 111.20(a) and (b)
Final Sec. 111.20(a) and (b) require that any physical plant that
you use in the manufacturing, packaging, labeling, or holding of
dietary supplements: (1) Be suitable in size, construction, and design
to facilitate maintenance, cleaning, and sanitizing operations and (2)
have adequate space for the orderly placement of equipment and holding
of materials as is necessary for maintenance, cleaning, and sanitizing
operations and to prevent contamination and mixups of components and
dietary supplements during manufacturing, packaging, labeling, or
holding.
We did not receive comments specific to proposed Sec. 111.20(a) or
(b), other than comments arguing that certain text in proposed Sec.
111.20(b) was unconstitutionally vague and arbitrary and capricious. We
address those comments in this section and section V of this document.
[[Page 34819]]
2. Final Sec. 111.20(c)
Final Sec. 111.20(c) requires that any physical plant you use in
the manufacturing, packaging, labeling, or holding of dietary
supplements provide for the use of proper precautions to reduce the
potential for mixups or contamination of components, dietary
supplements, or contact surfaces, with microorganisms, chemicals,
filth, or other extraneous material.
Under final Sec. 111.20(c) your physical plant must have, and you
must use, separate or defined areas of adequate size or other control
systems, such as computerized inventory controls or automated systems
of separation, to prevent contamination and mixups of components and
dietary supplements during the following operations: (1) Receiving,
identifying, holding, and withholding from use, components, dietary
supplements, packaging, and labels that will be used in or during the
manufacturing, packaging, labeling, or holding of dietary supplements;
(2) separating, as necessary, components, dietary supplements,
packaging, and labels that are to be used in manufacturing from
components, dietary supplements, packaging, or labels that are awaiting
material review and disposition decision, reprocessing, or are awaiting
disposal after rejection; (3) separating the manufacturing, packaging,
labeling, and holding of different product types including different
types of dietary supplements and other foods, cosmetics, and
pharmaceutical products; (4) performing laboratory analyses and holding
laboratory supplies and samples; (5) cleaning and sanitizing contact
surfaces; (6) packaging and label operations; and (7) holding
components or dietary supplements.
(Comment 99) Several comments would change ``computerized inventory
controls'' to ``adequate inventory controls'' in proposed Sec.
111.20(c). The comments say that a requirement to use a computerized
system is too prescriptive and that inventory controls that are not
computerized may be equally effective in achieving compliance with
proposed Sec. 111.20(c).
(Response) These comments may have misinterpreted proposed Sec.
111.20(c). Computerized inventory controls are an example of the type
of system that may be appropriate; Sec. 111.20(c) does not require you
to have a computerized system in the first instance. Thus, final Sec.
111.20(c) continues to use computerized inventory controls as an
example of a central system.
(Comment 100) Several comments ask us to clarify the degree of
separation that is intended under proposed Sec. 111.20(c) when it
referred to ``separate or defined areas'' of a physical plant. These
comments state that it is unclear if we expect a firm not to
manufacture multiple products in a single room or area. The comments
state that, if this is the case, this would be equivalent to the drug
CGMP requirements and would be excessive. The comments argue that, if
the proper controls are in place, manufacturing and packaging of
multiple products is possible in a single room or area without
compromising product identity, quality, strength, purity, and
composition.
(Response) Final Sec. 111.20(c) states that you must have and use
separate or defined areas of adequate size or other control systems,
such as computerized inventory controls or automated systems of
separation. The preamble of the 2003 CGMP Proposal explained that if
your physical plant does not allow for physically separate areas, you
could develop an alternative approach for segregating components and
dietary supplements at points when they are received, stored, and
rejected (68 FR 12157 at 12188). We interpret the comments as asking
whether alternative approaches for segregating products could be used,
even if physically separate areas were available in a facility, so that
different materials could be processed in the same area. Final Sec.
111.20(c) allows you to use ``separate or defined areas of adequate
size or other control systems;'' thus, you can comply with this
requirement by manufacturing multiple products in the same room or area
instead of using a physically separate location, as long as you have
systems in place to prevent contamination and mixups of components and
dietary supplements.
3. Final Sec. 111.20(d)
Final Sec. 111.20(d) requires that any physical plant you use in
the manufacturing, packaging, labeling, or holding of dietary
supplements be designed and constructed in a manner that prevents
contamination of components, dietary supplements, or contact surfaces.
Final Sec. 111.20(d)(1) requires the design and construction to
include: (1) Floors, walls, and ceilings that can be adequately cleaned
and kept clean and in good repair; (2) fixtures, ducts, and pipes that
do not contaminate components, dietary supplements, or contact surfaces
by dripping or other leakage or condensate; (3) adequate ventilation or
environmental control equipment, such as air flow systems, including
filters, fans, and other air-blowing equipment, that minimize odors and
vapors (including steam and noxious fumes) in areas where they may
contaminate components, dietary supplements, or contact surfaces; (4)
equipment that controls temperature and humidity, when such equipment
is necessary to ensure the quality of the dietary supplement; and (5)
aisles or working spaces between equipment and walls that are
adequately unobstructed and of adequate width to permit all persons to
perform their duties and to protect against contamination of
components, dietary supplements, or contact surfaces with clothing or
personal contact.
Final Sec. 111.20(d)(1)(i) through (d)(1)(v) is similar to
proposed Sec. 111.20(d)(1), (d)(2), (d)(3), (d)(5), and (d)(6),
respectively. Additionally, as explained in the following paragraphs,
we have made other changes to proposed Sec. 111.20(d)(1) (final Sec.
111.20(d)(1)(i)) and proposed Sec. 111.20(d)(5) (final Sec.
111.20(d)(1)(iv)).
(Comment 101) Several comments argue that the requirement of
proposed Sec. 111.20(d)(1) that floors, walls, and ceilings be made of
``smooth and hard surfaces,'' if read literally, could be interpreted
to prohibit the use of ceilings with drop-in tiles. These comments
assert that, while there may be areas in a manufacturing plant where
drop-in ceilings are inappropriate given the height of the ceiling, the
nature of the product, or the type of operation conducted in that area,
such ceilings are adequate in many areas of a manufacturing facility,
and certainly are appropriate in places where product is labeled or
stored. The comments argue that replacing such ceilings with surfaces
that are ``smooth and hard'' is unnecessary. Several other comments
argue that they could find no precedent in any food CGMP regulations
for a provision specifying ``smooth and hard surfaces'' for ceilings,
but did identify a precedent in the section of drug CGMP requirements
relating to ``aseptic processing.'' The comments state that adopting
such a drug CGMP requirement is inappropriate for dietary supplements.
The comments say the overall purpose of proposed Sec. 111.20(d)(1)
should be to ensure that facilities can be kept in a clean and sanitary
condition. The comments would revise proposed Sec. 111.20(d)(1) to
require physical plants to have surfaces that can be adequately
cleaned, but would give manufacturers the flexibility to use
appropriate surfaces in different parts of a plant.
The comments also argue that the rule's specificity establishes a
conundrum for certain manufacturers to conform to other Federal
regulations,
[[Page 34820]]
e.g., Occupational Safety and Health Administration (OSHA) noise
levels. The comments argue that firms should be allowed to
simultaneously conform to both OSHA and FDA requirements.
(Response) We agree that a smooth and hard surface may not be
necessary in every case to prevent contamination of the dietary
supplement. However, you may need floors, walls, and ceilings that are
constructed of smooth and hard surfaces to prevent contamination of the
dietary supplement when, for example, physical attributes of components
(e.g., particle size or electrostatic charge) would make it difficult
to keep floors, walls, and ceilings clean. Consequently, we conclude
that a requirement that the physical plant have floors, walls, and
ceilings that can be adequately cleaned and kept clean and in good
repair to prevent contamination of the dietary supplement is
sufficient. We are revising final Sec. 111.20(d)(1) to remove the
language concerning smooth and hard surfaces. The final rule gives you
the flexibility to determine how best to construct your facility in
order to prevent contamination and to ensure the quality of the dietary
supplements you manufacture, package, label, or hold.
Section 111.20(d)(1)(ii) of the final rule (proposed Sec.
111.20(d)(2)) requires your physical plant design and construction to
have fixtures, ducts, and pipes that do not contaminate components,
dietary supplements, or contact surfaces by dripping or other leakage,
or condensate. Final Sec. 111.20(d)(1)(iii) (proposed Sec.
111.20(d)(3)) pertains to adequate ventilation or environmental control
equipment. We added ``or other leakage'' to clarify that the
requirement relates to ``leakage'' regardless of whether the leakage is
in the form of ``dripping.''
(Comment 102) Proposed Sec. 111.20(d)(5) would require your
physical plant design and construction to include equipment that
controls temperature and humidity. Several comments suggest adding a
qualifier to the temperature and humidity control requirements so that
controls are only required as necessary to prevent adulteration. The
comments state there is adequate evidence that temperature and humidity
do not stimulate reproduction of microorganisms and pests in dietary
supplements. The comments also argue that retesting older ingredients
stored in an uncontrolled environment and subjected to heat, cold, and
ambient humidity produced no evidence of reproduction of
microorganisms. According to the comments, temperature and humidity may
present issues with raw, unprocessed botanical ingredients or animal-
derived ingredients, but there is no proven issue with the powdered
botanical and animal derived ingredients used by the dietary supplement
industry.
Several comments argue against requiring temperature and heat
controls, asserting that most equipment used to manufacture dietary
supplements is often cleaned with large amounts of hot water, and
therefore temperature and humidity controls are not practical.
(Response) We agree that controls for temperature and humidity
should only be required when necessary to ensure the quality of the
dietary supplement, and we are revising final Sec. 111.20(d)
accordingly. However, we disagree that there is adequate evidence that
temperature and humidity do not stimulate reproduction of
microorganisms in dietary supplements. It is well-recognized that
microorganisms such as bacteria will grow in a warm environment and
that microorganisms, such as molds, will grow in a moist environment.
In addition, if the comments are suggesting that this final rule should
only include requirements that derive from specific, already known
examples that the absence of a requirement directly led to a problem
with a dietary supplement, we disagree. CGMP requirements can help
prevent products from becoming adulterated during the manufacturing
process, and, in certain cases, controlling temperature and humidity
may be necessary to ensure the quality of the dietary supplement.
With respect to the comments stating that using hot water to clean
equipment makes control of temperature and humidity impractical, we
advise that a firm unable to control temperature and humidity in those
parts of its facility where control is necessary to ensure the quality
of the dietary supplement because it uses hot water to clean equipment
would not be in compliance with final Sec. 111.20(c). The provision
requires that your physical plant have, and that you use, separate and
defined areas of adequate size, or other control systems, to prevent
contamination during operations such as cleaning contact surfaces
(final Sec. 111.20(c)(5)).
Final Sec. 111.20(d)(2) (proposed Sec. 111.20(d)(4)) requires
that, when fans and other air-blowing equipment are used, such fans and
equipment be located and operated in a manner that minimizes the
potential for microorganisms and particulate matter to contaminate
components, dietary supplements, or contact surfaces.
(Comment 103) Several comments interpret proposed Sec.
111.20(d)(4) as requiring fans and air-blowing equipment. These
comments state this type of equipment is not always needed and may, in
some instances, be more likely to cause adulteration than prevent it.
The comments ask us to clarify that fans and other air-blowing
equipment are only required when they are necessary to prevent
adulteration.
(Response) Proposed Sec. 111.20(d)(4) was intended to require that
any fans and other air-blowing equipment you use be located and
operated in a manner that minimizes the potential for microorganisms
and particulate matter to contaminate components, dietary supplements,
or contact surfaces.
Nevertheless, given the comments' misinterpretation, we are
revising proposed Sec. 111.20(d)(4) (final Sec. 111.20(d)(2)) to
state that, ``When fans and other air-blowing equipment are used,''
those fans and equipment must be located and operated in a manner that
minimizes the potential for contamination by microorganisms and
particulate matter. This should clarify that the rule does not mandate
the use of fans and air-blowing equipment.
(Comment 104) Some comments state that exhaust and venting
equipment can, under certain circumstances, be a source of microbial
contamination. The comments would revise proposed Sec. 111.20(d)(4) to
read: ``Fans and other air-blowing or exhaust and venting equipment
located and operated in a manner that minimizes the potential for
microorganisms and particulate matter to contaminate components,
dietary ingredients, dietary supplements, or contact surfaces.''
(Response) We decline to revise the rule as suggested by these
comments as there is no need to do so. We consider exhaust equipment
and venting equipment to be types of fans or air-blowing equipment and
therefore covered by the term ``fans and other air-blowing equipment.''
4. Final Sec. 111.20(e)
Final Sec. 111.20(e) (proposed Sec. 111.20(e)) requires that any
physical plant that you use in the manufacturing, packaging, labeling,
or holding of dietary supplements provide adequate light in: (1) All
areas where components or dietary supplements are examined, processed,
or held; (2) all areas where contact surfaces are cleaned; and (3)
hand-washing areas, dressing and locker rooms, and bathrooms.
We did not receive any comments specific to proposed Sec.
111.20(e).
5. Final Sec. 111.20(f)
Final Sec. 111.20(f) (proposed Sec. 111.20(f)) requires that any
physical
[[Page 34821]]
plant you use in the manufacturing, packaging, labeling, or holding of
dietary supplements use safety-type light bulbs, fixtures, skylights,
or other glass or glass-like materials when the light bulbs, fixtures,
skylights, or other glass or glass-like materials are suspended over
exposed components or dietary supplements in any step of preparation,
unless your physical plant is otherwise constructed in a manner that
will protect against contamination of components or dietary supplements
in case of breakage of glass or glass-like materials.
We did not receive any comments specific to proposed Sec.
111.20(f). On our own initiative, we are making clarifying changes to
final Sec. 111.20(f) by:
Adding ``or glass-like materials'' after the word
``glass.'' Although proposed Sec. 111.20(f) only specified glass, its
intent was to cover any material that could shatter and contaminate
components, dietary supplements, or contact surfaces. Therefore, we are
adding glass-like material to final Sec. 111.20(f) to cover fixtures
and skylights that use non-glass materials (such as acrylic and
polycarbonate materials) but could still contaminate components,
dietary supplements, or contact surfaces if shattered or broken.
Further, we are stating that the requirement applies when the light
bulbs, fixtures, skylights, or other glass or glass-like materials are
suspended over exposed components or dietary supplements in any step of
preparation. We made this change to prevent the rule from being
misinterpreted as requiring firms to suspend light bulbs, fixtures,
skylights, or other glass over components or dietary supplements in
every step of preparation.
6. Final Sec. 111.20(g)
Final Sec. 111.20(g) (proposed Sec. 111.20(g)) requires that any
physical plant you use in the manufacturing, packaging, labeling, or
holding of dietary supplements provide effective protection against
contamination of components and dietary supplements in bulk
fermentation vessels. Such protection includes: (1) Use of protective
coverings; (2) placement in areas where you can eliminate harborages
for pests over and around the vessels; (3) placement in areas where you
can check regularly for pests, pest infestation, filth or any other
extraneous materials; and (4) use of skimming equipment.
We did not receive comments specific to proposed Sec. 111.20(g).
We have made nonsubstantive, grammatical changes to the provision by
replacing ``by any effective means'' with ``effective'' before the word
protection and ``including consideration of'' with ``by, for
example:''.
7. Final Sec. 111.20(h)
Final Sec. 111.20(h) (proposed Sec. 111.20(h)) requires that any
physical plant you use in the manufacturing, packaging, labeling, or
holding of dietary supplements use adequate screening or other
protection against pests, where necessary.
(Comment 105) One comment argues that proposed Sec. 111.20(h)
should be deleted because it is redundant when compared to proposed
Sec. 111.15(c) which would require you to not allow animals or pests
in any area of your physical plant, except for guard or guide dogs in
certain circumstances.
(Response) We disagree that final Sec. 111.20(h) is redundant to
proposed Sec. 111.15(c) (final Sec. 111.15(d)). Although both
paragraphs deal with pests, final Sec. 111.20(h) establishes a design
requirement (i.e., a specific requirement to use adequate screening or
other protection), while final Sec. 111.15(d) sets forth a sanitation
requirement (i.e., to not allow animals or pests in your physical
plant). Therefore, we are retaining Sec. 111.20(h) in the final rule.
G. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.23)
Final Sec. 111.23(a) requires you to make and keep records
required under this subpart in accordance with subpart P.
Final Sec. 111.23(b) requires that you make and keep records of
the written procedures for cleaning the physical plant and for pest
control. This provision was added to ensure that the written procedures
now required under final Sec. 111.16 are maintained as required under
subpart P.
Final Sec. 111.23(c)(1) (proposed Sec. 111.15(d)(3)) requires
that you make and keep records that water, when used in a manner such
that the water may become a component of the dietary supplement, meets
the requirements of final Sec. 111.15(e)(2).
(Comment 106) Several comments state there is no documentation
requirement for water in the food or drug CGMPs. The comments,
therefore, say there should be not be such a requirement in this final
rule for dietary supplements.
(Response) To the extent that the comments assert we cannot include
such a requirement for documentation in the dietary supplement CGMP
because there is no corollary requirement in part 110, we have
responded to this issue in section V of this document. The absence of a
provision in drug CGMP requirements does not preclude us from requiring
it in this final rule establishing CGMP requirements for dietary
supplements for which we have no pre-approval scheme for ingredients
used in such a product.
(Comment 107) Several comments ask us to clarify that, if a
municipal water supply is used in a facility, the municipal water
report is acceptable documentation of water quality. These comments say
that a city's yearly report of its municipal water quality should be
sufficient documentation, and that independent testing should not be
required. Several comments claim that our officials made statements to
this effect during a public meeting held on May 6, 2003.
The comments also assert that water quality in a community is
typically well known due to public notification that is required by the
Environmental Protection Agency or due to other resources. These
comments say that municipal water supplies are also well controlled as
a result of Environmental Protection Agency regulations, and that, if
water quality in a community or country is suspect, we can move
aggressively to enforce the standards. The comments argue that,
overall, our enforcement burden would be less than requiring every
company in the industry to maintain and produce documentation related
to water quality.
(Response) A yearly municipal report is a good starting point for
documenting water meets the requirements of final Sec. 111.15(e),
however, such a report cannot stand on its own as the only assurance
that the water of the regulated body (such as persons subject to this
final rule) complies with these regulations. A municipal water report
offers reasonable assurance that the water entering your plant
satisfies the requirements of the Environmental Protection Agency's
NPDW regulations. However, as discussed previously, the requirement to
show that the water that is used in a manner such that the water may
become a component of the dietary supplement, e.g., when such water
contacts components, dietary supplements, or any contact surface, meets
the requirements of Sec. 111.15(e)(2), applies to water at the point
of use, i.e., after it has passed through your plumbing system.
If you use a municipal water supply, you should take steps to
ensure that you are at all times aware of problems, such as an acute
problem with microbial contamination or a long-term problem associated
with lead pipes that are present in some parts of the city water
[[Page 34822]]
supply, that may not be reflected in the municipal water report.
IX. Comments on Requirements Related to Equipment and Utensils (Subpart
D)
A. Organization of Final Subpart D
Proposed subpart D contained two provisions regarding equipment,
utensils, and automatic, mechanical, or electronic equipment. Table 5
of this document lists the sections in the final rule and identifies
the corresponding sections in the 2003 CGMP Proposal that form the
basis of the final rule.
Table 5.--Derivation of Sections in Subpart D
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.25 What are the requirements Sec. 111.25(c)(1)
under this subpart D for written Sec. 111.25(e)(1)
procedures?
------------------------------------------------------------------------
Sec. 111.27 What requirements apply to Sec. 111.25(a), (b), (d),
the equipment and utensils that you use? and (e)
------------------------------------------------------------------------
Sec. 111.30 What requirements apply to Sec. 111.30
automated, mechanical, or electronic
equipment?
------------------------------------------------------------------------
Sec. 111.35 Under this subpart D, what Sec. Sec. 111.25(c)(1),
records must you make and keep? (c)(2), (d), and (f),
Sec. 111.30(b)(2), (b)(5),
and (c)
Sec. 111.50(c)(4)
------------------------------------------------------------------------
B. Highlights of Changes to the Proposed Requirements for Equipment and
Utensils
1. Revisions
The final rule includes revisions that reflect the final rule
applies to persons who manufacture, package, label, or hold dietary
supplements unless subject to an exclusion in Sec. 111.1.
2. Revisions Associated With the Reorganization
The revisions associated with the reorganization include:
Renumbering proposed Sec. 111.25 as final Sec. 111.27
and correcting the numbering of the sections misnumbered in the 2003
CGMP Proposal;
Requiring documentation and backup files in a separate
section for recordkeeping requirements; and
A nonsubstantive editorial change to refer to ``automated
equipment'' rather than ``automatic equipment.'' Although there is no
practical difference between these two terms, the term ``automated'' is
the customary term.
3. Changes After Considering Comments
The final rule:
Requires you to establish and follow written procedures to
fulfill the requirements of subpart D, including written procedures
for:
[cir] Calibrating instruments and controls;
[cir] Calibrating, inspecting, and checking automated, mechanical,
and electronic equipment; and
[cir] Maintaining, cleaning, and sanitizing, as necessary,
equipment, utensils, and other contact surfaces;
Requires you to keep records of the maintenance, cleaning,
and sanitizing of equipment either in equipment logs or in batch
records;
Requires that quality control personnel periodically
review records of calibrations, inspections, or checks of automated,
mechanical, or electronic equipment rather than approve such records
when they are made;
Specifies that software for a computer controlled process
is included under automated, mechanical, or electronic equipment; and
Clarifies that the requirement to retain backup files of
software programs and of data entered into computer systems is for
computer systems that you use in the manufacture, packaging, labeling,
or holding of dietary supplements.
C. General Comments on Proposed Subpart D
(Comment 108) Some comments claim one or more proposed requirements
are unconstitutionally vague under the Fifth Amendment and arbitrary
and capricious under Sec. 706(2)(B) of the APA. These proposed
requirements include:
Sec. 111.25(a)(1), which would require that equipment and
utensils be ``of appropriate design, construction, and workmanship to
enable them to be suitable for their intended use and to be adequately
cleaned and properly maintained''; and
Sec. 111.25(a)(2), which would require you to ``use
equipment and utensils of appropriate design and construction so that
use will not result in the contamination of components, dietary
ingredients, or dietary supplements.''
In general, these comments assert the proposed sections did not
define terms or phrases (such as ``suitable'' or ``appropriate
design'') in a way that persons who are subject to the rule can discern
the meaning of the term. These comments also assert the proposed
sections do not limit enforcement officers' exercise of their
discretion as to what will satisfy the requirements and, thus, invite
exercise of unbridled discretion and disparate decisionmaking.
(Response) As discussed in section V of this document, we disagree
that the terms are unconstitutionally vague, need to be defined, may
result in discriminatory enforcement, or violate the APA. There has
been sufficient usage of these terms in the food industry to enable
manufacturers, and those who enforce the requirements, to comprehend
and apply such terms. Agencies are permitted to use qualifying terms to
enable them to address a wide variety of conditions at companies.
D. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.25)
We received many comments that recommend written procedures for
various provisions. We address the need for written procedures
generally in section IV of this document. We also respond to comments
on specific provisions in the same section. We are adding final Sec.
111.25 that requires you to establish and follow written procedures for
certain requirements.
E. What Requirements Apply to the Equipment and Utensils That You Use?
(Final Sec. 111.27)
Final Sec. 111.27 (proposed Sec. 111.25) sets forth various
requirements for equipment and utensils.
1. Final Sec. 111.27(a)
a. Final Sec. 111.27(a). Final Sec. 111.27(a) (proposed Sec.
111.25(a)(1)) requires you to use equipment and utensils that are of
appropriate design, construction, and workmanship to enable them to be
suitable for their intended use and to be adequately cleaned and
properly maintained. In order to correct the misnumbering of this
provision in the 2003 CGMP Proposal, this general requirement has been
broken out from the remaining requirements of final Sec. 111.27(a).
Final Sec. 111.27(a)(1)(i) through (a)(1)(v) provide examples of
such equipment, such as equipment used to hold or convey (Sec.
111.27(a)(1)(i)), equipment using compressed air or gas (Sec.
111.27(a)(1)(iii)), and equipment used in automated, mechanical, or
electronic systems (Sec. 111.27(a)(1)(v)).
Final Sec. 111.27(a)(1) is similar to proposed Sec. 111.25(a)(1)
except for two, nonsubstantive editorial changes. The first change
replaces ``automatic equipment'' with ``automated equipment'' in what
is now Sec. 111.27(a)(1)(v) (proposed Sec. 111.25(a)(1)(5)). Although
there is no practical difference between
[[Page 34823]]
``automatic'' and ``automated,'' the latter is the customary term.
(Comment 109) Some comments argue that the proposal's use of terms
such as ``appropriate design, construction, and workmanship to enable
them to be suitable for their intended use'' and ``adequately cleaned
and properly maintained'' are unconstitutionally vague under the Fifth
Amendment and arbitrary and capricious under the APA.
(Response) We discuss those comments generally in section V of this
document and, because we disagree that the final rule violates either
the Fifth Amendment of the Constitution or the APA, we have not revised
Sec. 111.27(a)(1) except for the changes mentioned in the previous
paragraphs.
b. Final Sec. 111.27(a)(2). Final Sec. 111.27(a)(2) (proposed
Sec. 111.25(a)(2)) requires you to use equipment and utensils of
appropriate design and construction so that use will not result in the
contamination of components or dietary supplements with: (1)
Lubricants, (2) fuel, (3) coolants, (4) metal or glass fragments, (5)
filth or any other extraneous material, (6) contaminated water, or (7)
any other contaminants.
(Comment 110) Several comments state we should recognize that
lubricants are an integral part of the encapsulation of gelatin-enrobed
products and other dosage forms. These comments state lubricants are
not potential contaminants, and in fact, help move gelatin ribbons
through encapsulating machines. The comments would revise proposed
Sec. 111.25(a)(2) to read, ``lubricants not intended for product
contact,'' to clarify the rule's intent.
(Response) We decline to revise the final rule as suggested by the
comments. Final Sec. 111.27(a)(2) states that the use of equipment and
utensils must not result in the contamination of components or dietary
supplements with lubricants. If a lubricant used for encapsulation does
not result in contamination of the components or dietary supplements
then the encapsulating machine complies with final Sec. 111.27(a)(2).
c. Final Sec. 111.27(a)(3). Final Sec. 111.27(a)(3) (proposed
Sec. 111.25(a)(3)) requires all equipment and utensils you use to be:
(1) Installed and maintained to facilitate cleaning the equipment,
utensils, and all adjacent spaces; (2) corrosion-resistant if the
equipment or utensils contact components or dietary supplements; (3)
made of nontoxic materials; (4) designed and constructed to withstand
the environment in which they are used, the action of components or
dietary supplements, and, if applicable, cleaning compounds and
sanitizing agents; and (5) maintained to protect components and dietary
supplements from being contaminated by any source.
We did not receive comments specific to proposed Sec.
111.25(a)(3). We have substituted the phrase ``in which they are used''
for ``of their intended use'' to make clear the requirement applies to
equipment actually used in the manufacture, packaging, labeling, or
holding of dietary supplements.
d. Final Sec. 111.27(a)(4). Final Sec. 111.27(a)(4) (proposed
Sec. 111.25(a)(4)) requires that the equipment and utensils you use
have seams that are smoothly bonded or maintained to minimize
accumulation of dirt, filth, organic material, particles of components
or dietary supplements, or any other extraneous materials or
contaminants. Final Sec. 111.27(a)(4) is similar to proposed Sec.
111.25(a)(4) and is analogous to Sec. 110.40(b) which requires that
seams on food-contact surfaces be smoothly bonded or maintained so as
to minimize accumulation of food particles, dirt, and organic matter
and thus minimize the opportunity for growth of microorganisms. We have
deleted the phrase ``to minimize the opportunity for growth of
microorganisms'' as unnecessary in this context as the remaining
wording of the provision encompasses this concept. In nonsubstantive
editorial changes to final Sec. 111.27(a)(4) we substitute ``particles
of components or dietary supplements'' for ``component or dietary
supplement particles'' to improve clarity, and re-order the list of
extraneous materials or contaminants.
(Comment 111) Several comments argue that proposed Sec.
111.25(a)(4) is overly restrictive by requiring equipment and utensils
to ``have seams that are smoothly bonded or maintained'' to minimize
contamination. The comments would revise the rule as follows:
``Equipment and utensils you use must be of proper design and
maintained to minimize accumulation * * *.''
(Response) We disagree that proposed Sec. 111.25(a)(4) (final
Sec. 111.27(a)(4)) is overly restrictive or that it requires a
particular design. Final Sec. 111.27(a)(4) requires seams that are
smoothly bonded or maintained to minimize accumulation of dirt and
gives firms the flexibility to use any design they choose, provided
that the seams, by design or maintenance, minimize accumulation of
contaminants.
e. Final Sec. 111.27(a)(5). Final Sec. 111.27(a)(5) (proposed
Sec. 111.27(a)(5)) requires that each freezer, refrigerator, and other
cold storage compartment you use to hold components or dietary
supplements: (1) Be fitted with an indicating thermometer, temperature-
measuring device, or temperature-recording device that indicates, and
records, or allows for recording by hand, the temperature accurately
within the compartment and (2) have an automated device for regulating
temperature or an automated alarm system to indicate a significant
temperature change in a manual operation.
(Comment 112) The preamble to the 2003 CGMP Proposal invited
comment as to whether we should require specific target temperatures
for dietary ingredients or dietary supplements held in freezers or cold
storage (68 FR 12157 at 12190). Several comments assert there is no
need for us to specify storage temperatures for dietary ingredients or
dietary supplements. The comments state most dietary supplements and
dietary ingredients are shelf stable based on their low water activity
control, which limits and slows chemical degradation and
microbiological growth. Other comments say target temperatures are not
required where freezing is used only to enhance the milling properties
(fracturing) of dried botanicals and not to prevent microbial
contamination.
(Response) We have not included any specific target temperature
requirements in the final rule. Consequently, firms should determine
for themselves what temperatures are needed to ensure that the their
dietary supplements are not adulterated (see final Sec. 111.70
regarding the specifications you must establish).
f. Final Sec. 111.27(a)(6). Final Sec. 111.27(a)(6) (proposed
Sec. 111.25(a)(6)) requires the instruments or controls you use in the
manufacturing, packaging, labeling, or holding of a dietary supplement,
and instruments or controls that you use to measure, regulate, or
record temperatures, pH, aw, or other conditions, to control
or prevent the growth of microorganisms or other contamination, be
accurate and precise, adequately maintained, and adequate in number for
their designated uses.
(Comment 113) One comment states that proposed Sec.
111.25(a)(6)(i)'s requirements that instruments and controls be
``accurate and precise'' goes beyond ``typical'' calibration, and would
require full validation of all instruments and controls. The comment
argues that it is unnecessary to require both accuracy and precision
for all instruments and controls, and would require precision only when
necessary to prevent contamination. The comment states calibration to
ensure accuracy of instruments and controls is usually sufficient to
ensure control or prevention of the growth of
[[Page 34824]]
microorganisms or other contaminants in most situations. The comment
gives an example where thermometers are used to monitor temperature in
a warehouse where dietary supplements are stored.
(Response) We disagree that proposed Sec. 111.27(a)(6) requires
full validation of all equipment and controls. As discussed in the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12190), accuracy
means that the recorded measurements are equal to the (true value) of
the thing being measured and precision means that individual
measurements should be close to each other when made under the same
conditions.
We also disagree that instruments need not be precise. An
instrument that gives widely varying readings from one use to the next
cannot ensure product quality over time. The degree of accuracy and
precision is determined by the nature of the instrument or control and
the process to which it relates. We have, however, made several
nonsubstantive, editorial changes to Sec. 111.27(a)(6) as well as
other edits to conform to changes made throughout the final rule. These
are the nonsubstantive editorial changes:
Inserting a hyphen between ``hydrogen'' and ``ion'' and
Revising the end of the paragraph so that it discusses
``instruments and controls that you use * * * to control or prevent the
growth of microorganisms or other contamination * * *.'' The proposal
stated ``instruments and controls that you use * * * that control or
prevent the growth of microorganisms or other contamination * * *''.
(In other words, the final rule replaces ``that'' with ``to''.)
g. Final Sec. 111.27(a)(7). Final Sec. 111.27(a)(7) (proposed
Sec. 111.25(a)(7)) requires that the compressed air or other gases you
introduce mechanically into or onto a component, dietary supplement, or
contact surface or you use to clean any contact surface be treated in
such a way that the component, dietary supplement, or contact surface
is not contaminated.
We received no comments specific to proposed Sec. 111.25(a)(7).
2. Final Sec. 111.27(b)
Final Sec. 111.27(b) (proposed Sec. 111.25(b)(1)) requires you to
calibrate instruments and controls that you use in manufacturing or
testing a component or dietary supplement. In order to correct the
misnumbering of this provision in the 2003 CGMP Proposal, this general
requirement has been broken out from the remaining requirements of
final Sec. 111.27(b) and now has paragraphs (b) and (b)(1) through
(b)(3).
Final Sec. 111.27(b)(1) through (b)(3) (proposed Sec.
111.25(b)(1) and (b)(2)) requires you to calibrate before first use,
and at the frequency specified in writing by the manufacturer of the
instrument or control, or at routine intervals, or as otherwise
necessary to ensure the accuracy and precision of the instrument and
control.
(Comment 114) Several comments object to the level of detail
regarding the proposed calibration. Specifically, the comments object
to requiring that manufacturers calibrate instruments and controls ``as
specified in writing by the manufacturer of the instrument and
control.'' The comments say this requirement is more prescriptive than
drug CGMP requirements. The comments acknowledge that following
manufacturer specifications is likely to be part of the calibration
procedure, but state that firms should have the flexibility to modify
their procedures as necessary. These comments would couple proposed
Sec. 111.25(b) with a requirement to establish and follow written
procedures for calibrating instruments and controls and redraft
proposed Sec. 111.25(b) to mirror the drug CGMP requirements, using
language such as ``You must routinely calibrate instruments and
controls that control or monitor critical parameters that you use in
manufacturing or testing a component or dietary supplement.''
(Response) We disagree that proposed Sec. 111.25(b) is overly
prescriptive, exceeds drug CGMP requirements, or requires what is
claimed by the comments. We discuss, generally, the issue of whether
this final rule ``exceeds drug CGMPs'' in section V of this document.
It is standard practice to calibrate an instrument before using it for
the first time. A requirement that you calibrate as specified by the
manufacturer of the equipment, or at routine intervals, or as otherwise
necessary to ensure the accuracy and precision of the instrument and
control, provides ample flexibility. Calibration, whether for
instruments and controls used in manufacturing or testing drugs,
devices, conventional foods, or dietary supplements, helps ensure the
accuracy and precision of the instrument and control. We do not
prescribe how frequently such calibration must be done, but it must be
done often enough to ensure that instruments and controls are operating
within the correct parameters. We are revising the 2003 CGMP Proposal
(at Sec. 111.27(b)(2)) to clarify that the requirement relates to the
frequency of calibration.
(Comment 115) Several comments claim requirements relating to
calibration of instruments and controls should be limited to those
instruments and controls that directly affect the identity, purity,
quality, strength, and composition of a dietary supplement. According
to the comments, in most manufacturing facilities, there are many
instruments and controls that do not directly affect identity, purity,
quality, strength, and composition, and that calibrating all
instruments and controls could easily become unduly burdensome. The
comments also would limit the requirement for periodic calibration of
instruments and controls to those instruments and controls directly
involved in the critical control parameters of the process, i.e., those
parameters needed to meet specifications or to ensure identity, purity,
quality, strength, and composition. The comments suggest that critical
control parameters would have to be established.
(Response) We decline to revise the rule as suggested by the
comments. The requirement to calibrate instruments and controls is
limited to those instruments and controls that you use in testing a
component or dietary supplement or in manufacturing a dietary
supplement. Any such equipment has the potential to affect, directly or
indirectly, the quality of the dietary supplement.
(Comment 116) Some comments would revise proposed Sec.
111.25(b)(1) to state that ``calibration should be done, where
standards are available or where it is necessary to meet product
specifications.''
(Response) We decline to revise the rule as suggested by the
comments. It would be customary for an equipment manufacturer to have
standards that can be used to calibrate the equipment, irrespective of
the specific composition of the dietary supplement that is manufactured
using that equipment. Equipment that is not or cannot be calibrated is
unlikely to be in compliance with the requirement of final Sec.
111.27(a)(6)(i) which requires instruments used in the manufacturing,
packaging, labeling, and holding of dietary supplements, and
instruments and controls that you use to perform certain operations, be
accurate and precise.
(Comment 117) Some comments would revise proposed Sec. 111.25 from
the active voice to the passive voice. These comments claim that the
active voice--i.e., requiring that ``you'' calibrate instruments and
controls--requires that the dietary supplement manufacturer perform the
calibration,
[[Page 34825]]
when in fact such calibrations are often performed by an outside
service.
(Response) You may use an outside service. We would not consider
that calibration done for you by an outside service is any different
than calibration done by your employees, and it is you (rather than an
outside service) whom we will hold responsible to ensure that the
calibration is performed. Accordingly, we decline to revise the
provisions as suggested.
(Comment 118) Several comments say calibration before first use
should not be required for certified, precalibrated instrumentation.
The comments state precalibrated instrumentation is much more expensive
than noncalibrated instrumentation, with the additional expense
attributed to the precalibration. Several comments would revise
proposed Sec. 111.25(b)(2) to read, ``you must calibrate, or be able
to verify that the calibration has been completed, before first use,''
instead of ``you must calibrate before first use.'' The comments state
that performance test results could be made available for this
verification.
(Response) As written, the requirement that equipment be calibrated
before first use includes calibration performed by a third party as a
precalibration because we would consider that calibration performed by
a third party as no different from calibration performed by one of your
own employees. Under final Sec. 111.35(b)(3) you must have
documentation of the calibration.
If you purchase a precalibrated instrument, we strongly recommend
that the vendor conduct the certification onsite after installation. If
not, we strongly recommend that you verify that the instrument remains
calibrated after it has been installed.
(Comment 119) Several comments ask whether the proposed requirement
to calibrate ``before first use'' refers to the first use after
installation or the first use after each start-up.
(Response) Final Sec. 111.27(b)(1) refers to the first use after
installation and does not require calibration after each start-up.
(Comment 120) Some comments would require that instruments and
controls be calibrated, but argue that the final rule should not
include detailed procedures specifying calibration methods. The
comments said the rule should stay focused on end results and not
process.
(Response) We disagree that the regulations should not focus on
process. The essence of the CGMP requirements established by these
regulations is a production and process control system, i.e., a
process, that is designed to ensure the quality of the dietary
supplement. The final rule gives firms the flexibility to use different
calibration methods as long as the method used is established in a
written procedure.
3. Final Sec. 111.27(c)
Final Sec. 111.27(c) (proposed Sec. 111.25(d)) requires that you
repair or replace instruments or controls that cannot be adjusted to
agree with the reference standard.
We received no comments specific to proposed Sec. 111.25(d).
4. Final Sec. 111.27(d)
Final Sec. 111.27(d) (proposed Sec. 111.25(e)) requires you to
maintain, clean, and sanitize, as necessary, all equipment, utensils,
and any other contact surfaces used to manufacture, package, label, or
hold components or dietary supplements. In order to correct the
misnumbering of this provision in the 2003 CGMP Proposal, this general
requirement has been broken out from the remaining requirements of
final Sec. 111.27(d) and now has paragraphs (d) and (d)(1) through
(d)(7).
a. Final Sec. 111.27(d)(1). Final Sec. 111.27(d)(1) requires that
the equipment and utensils be taken apart as necessary for thorough
maintenance, cleaning, and sanitizing.
(Comment 121) Some comments argue that individual manufacturing
operations will determine when sanitizing agents are needed after
cleaning because of the wide variety of processes in the industry. The
comments also say widespread use of sanitizing agents is creating
resistant microbial strains, and incorporating unnecessary sanitization
processes would contribute to this health concern.
Some comments recommend manufacturers calibrate sanitizing
procedures to the particular process in a declared fashion depending
upon the risk factors of their process and materials. The comments set
out several standards for sanitation procedures.
(Response) Final Sec. 111.27(d) requires you to maintain, clean,
and sanitize, as necessary, equipment, utensils, and any other contact
surfaces, used to manufacture, package, label, or hold dietary
supplements. The final rule thus gives you discretion to decide when
sanitizers or sanitizing treatments, such as heat, are necessary and
does not mandate the incorporation of unnecessary sanitization
processes.
Additionally, under final Sec. 111.27(d) you have flexibility to
determine when sanitizing is appropriate and to sanitize only as
necessary. We note that this flexibility was also present in proposed
Sec. 111.25(e)(1). Some comments suggested calibrating sanitation
operations based on risk. The final rule largely leaves it up to firms
to decide whether to sanitize or to just clean without sanitizing,
based on the risks associated with the materials and process used.
However, under final Sec. 111.27(d)(3), if you use wet processing, if
you determine that it is necessary to clean a contact surface, you must
also sanitize that surface.
(Comment 122) Several comments state the final rule should include
a requirement for validating cleaning procedures. The comments argue
that testing requirements for finished dietary supplements might not
test for certain contaminants that could arise as a result of cleaning.
One comment asserts these potential contaminants would be discovered in
a properly designed and executed cleaning validation protocol, and that
including these written cleaning procedures in the final rule would
help prevent adulteration and help ensure the identity, purity,
quality, strength, and composition of dietary supplements.
(Response) We decline to require specific cleaning validation
procedures in the final rule. Final Sec. 111.27(d) and the
requirements for written procedures under final Sec. 111.25(c) are
sufficient to ensure the use of cleaning procedures to ensure the
quality of the dietary supplement.
b. Final Sec. 111.27(d)(2). Final Sec. 111.27(d)(2) (proposed
Sec. 111.25(e)(2)) requires you to ensure that all contact surfaces,
used for manufacturing or holding low-moisture components or dietary
supplements, are in a dry and sanitary condition when in use. When the
surfaces are wet-cleaned, you must sanitize them, when necessary, and
allow them to dry thoroughly before you use them again.
We received no comments specific to proposed Sec. 111.25(e)(2). We
have substituted the phrase ``when in use'' for ``at the time of use''
for clarity.
c. Final Sec. 111.27(d)(3). Final Sec. 111.27(d)(3) (proposed
Sec. 111.25(e)(3)) requires you, if you use wet processing during
manufacturing, to clean and sanitize all contact surfaces, as
necessary, to protect against the introduction of microorganisms into
components or dietary supplements. Final Sec. 111.27(d)(3) also
requires that:
When cleaning and sanitizing is necessary, you clean and
sanitize all contact surfaces before use and after any interruption
during which the contact surface may become contaminated and
If you use contact surfaces in a continuous production
operation or in consecutive operations involving
[[Page 34826]]
different batches of the same dietary supplement, you must adequately
clean and sanitize the contact surfaces, as necessary. In this
provision, we substituted ``consecutive'' for ``back-to-back,'' a
nonsubstantive change. We also inserted ``adequately'' to make clear
that cleaning and sanitizing must be adequate.
(Comment 123) Several comments argue against using the term
``sanitize'' in proposed Sec. 111.25(e)(3). The comments state that,
based on the proposed definition of ``sanitize,'' Sec. 111.25(e)(3)
would require evaluation of any sanitation steps to ensure that the
level of log reduction is reached, for example, by taking ``before and
after'' swab samples. The comments would revise proposed Sec.
111.25(e)(3) to state that equipment, utensils, etc. shall be cleaned
and sanitized in a manner that keeps microorganisms and other
adulterants from contaminating all components, ingredients, in-process
materials, and finished goods.
(Response) The final rule now defines ``sanitize'' as ``to
adequately treat cleaned equipment, containers, utensils, or any other
cleaned product contact surface by a process that is effective in
destroying vegetative cells of microorganisms of public health
significance, and in substantially reducing numbers of other
microorganisms, but without adversely affecting the product or its
safety for the consumer.'' The definition no longer specifies a level
of log reduction, so the revised definition should eliminate the
comments' concern as to any possible need for ``before and after''
samples.
d. Final Sec. 111.27(d)(4). Final Sec. 111.27(d)(4) (proposed
Sec. 111.25(e)(4)) requires you to clean surfaces that do not come
into direct contact with components or dietary supplements as
frequently as necessary to protect against contamination. Final Sec.
111.27(d)(4) relates to final Sec. 111.27(d)(2) and (d)(3). For
example, you would not have to clean your ceilings as often as you
clean your contact surfaces because your ceilings normally do not touch
components or dietary supplements. However, you would have to clean
your ceilings as frequently as necessary to prevent dust or other
contaminants from falling onto your components, dietary supplements,
and contact surfaces.
We received no comments specific to proposed Sec. 111.25(e)(4). We
substituted ``do not come into direct contact with'' for ``do not
touch'' as a nonsubstantive editorial revision.
e. Final Sec. 111.27(d)(5). Final Sec. 111.27(d)(5) (proposed
Sec. 111.25(e)(5)) requires that single-service articles (such as
utensils intended for one-time use, paper cups, and paper towels) be:
(1) Stored in appropriate containers and (2) handled, dispensed, used,
and disposed of in a manner that protects against contamination of
components, dietary supplements, or any contact surface.
We received no comments specific to proposed Sec. 111.25(e)(5).
f. Final Sec. 111.27(d)(6). Final Sec. 111.27(d)(6) (proposed
Sec. 111.25(e)(6)) requires your cleaning compounds and sanitizing
agents to be adequate for their intended use and safe under their
conditions of use.
(Comment 124) One comment would delete proposed Sec. 111.25(e)(6),
stating it is redundant to proposed Sec. 111.15(b), which would
require you to use cleaning compounds and sanitizing agents that are
free from microorganisms of public health significance and safe and
adequate under the conditions of use.
(Response) We disagree with this comment. Proposed Sec. Sec.
111.15(b)(1) and 111.25(e)(6) (now final Sec. Sec. 111.15(b)(1) and
111.27(d)(6), respectively) differed in their requirements and their
applicability. Proposed Sec. 111.15(b)(1) would apply to cleaning
compounds and sanitizing agents used in the physical plant and would
require them to be ``safe and adequate under the conditions of use.''
In contrast, proposed Sec. 111.25(e)(6) would apply to cleaning
compounds and sanitizing agents used on equipment, utensils, and
contact surfaces used to manufacture, package, or hold components,
dietary ingredients, or dietary supplements, and it would require such
cleaning compounds or sanitizing agents to be ``adequate for intended
use and safe under condition [sic] of use.'' By using the phrase
``adequate for intended use,'' proposed Sec. 111.25(e)(6) would have
you consider whether a particular cleaning compound or sanitizing agent
was appropriate for the particular use to which it was being applied.
Furthermore, depending on the situation, a cleaning compound or
sanitizing agent that is appropriate for use on a physical plant may be
inappropriate for use on equipment, utensils, and contact surfaces. For
example, a powdered cleaning compound might be suitable for cleaning
your physical plant's floors, but inappropriate for cleaning equipment
that mixes components. In other words, the ``conditions of use'' can
also vary between final Sec. Sec. 111.15(e)(1) and 111.27(d)(6) and
lead to different conclusions regarding use of the same cleaning
compound.
Additionally, on our own initiative, we have made two editorial,
nonsubstantive changes to final Sec. 111.27(d)(6). The final rule now
states that the cleaning compounds and sanitizing agents must be
adequate for ``their'' intended use and safe under ``their conditions''
of use.
g. Final Sec. 111.27(d)(7). Final Sec. 111.27(d)(7) (proposed
Sec. 111.25(e)(7)) requires you to store cleaned and sanitized
portable equipment and utensils that have contact surfaces in a
location and in a manner that protects them from contamination. We
received no comments specific to proposed Sec. 111.25(e)(7).
F. Reorganization of Certain Paragraphs in Proposed Sec. 111.25
Proposed Sec. 111.25 would impose certain requirements relating to
written procedures for calibrating instruments and controls (proposed
Sec. 111.25(c) and (d)) and keeping calibration records (proposed
Sec. 111.25(f)). The final rule now contains a new recordkeeping
section (Sec. 111.35) that combines elements of proposed Sec.
111.25(c), (d), and (f), as well as other sections. We discuss comments
on proposed Sec. 111.25(c), (d), and (f) and describe final Sec.
111.35 in this section.
G. What Requirements Apply to Automated, Mechanical, or Electronic
Equipment? (Final Sec. 111.30)
Final Sec. 111.30 sets forth requirements for automated,
mechanical, or electronic equipment that you use to manufacture,
package, label, or hold a dietary supplement.
1. Comments on the Organization and Framework of Proposed Sec. 111.30
(Comment 125) Some comments would revise proposed Sec. 111.30(a)
to replace ``equipment to manufacture, package, label, and hold'' with
``equipment to manufacture, package, label, or hold.'' The comments
said that the same piece of equipment will not serve to manufacture,
package, label, and hold components or dietary supplements.
(Response) We agree, and have revised Sec. 111.30 accordingly.
Final Sec. 111.30 also contains the following changes:
``Automatic'' (as in ``automatic equipment'') is replaced
with ``automated'' as an editorial, nonsubstantive change;
The phrase ``determine the suitability of your equipment''
has been revised to read ``determine the suitability of the equipment *
* *'' in Sec. 111.30(b) and has no substantive impact; and
[[Page 34827]]
We have substituted the word ``met'' for ``achieved'' to
comply with ``plain language'' initiatives and to be consistent with
other provisions.
We describe other changes to proposed Sec. 111.30 in the following
paragraphs.
(Comment 126) Several comments support proposed Sec. 111.30
particularly with respect to computers. The comments state computers
are susceptible to erroneous data input, are subject to malfunctions
and software problems, and thus should be regulated under the final
rule.
One comment questions why we organized proposed Sec. 111.30 into
two paragraphs (a) and (b). The comment claims there was no meaningful
difference between the two paragraphs.
Other comments say some proposed requirements for automatic,
mechanical, and electronic equipment, such as the proposed requirement
for maintaining backup files of data entered into computer systems,
would apply to automatic, mechanical, and electronic equipment that are
not related to CGMPs. The comments argue that proposed Sec. 111.30(b)
would apply to computers on which payroll records are maintained, and
that such a requirement does not belong in these CGMPs.
(Response) We agree, in part, and disagree, in part, with the
comments. We agree that computers used in the manufacture, packaging,
labeling, or holding of dietary supplements should be, and are, subject
to final Sec. 111.30.
We disagree, however, with those comments that interpreted proposed
Sec. 111.30(a) and (b) as being the same or interpreted proposed Sec.
111.30 as applying to equipment that has no direct bearing on dietary
supplements. Proposed Sec. 111.30(a) differed from proposed Sec.
111.30(b) in that paragraph (a) would pertain to the operation and
suitability of your equipment within your manufacturing process. In
contrast, proposed Sec. 111.30(b) would apply to calibration of your
equipment and controls you establish for your equipment.
We disagree with those comments that would interpret proposed Sec.
111.30(b) as applying to payroll computers or other equipment that has
no CGMP function. To prevent misinterpretations of final Sec. 111.30,
we have revised it to apply to equipment ``that you use to manufacture,
package, label, or hold a dietary supplement'' and renumbered proposed
Sec. 111.30(a)(1), (a)(2), (b)(1), (b)(3), and (b)(4) as Sec.
111.30(a) through (e), respectively. Proposed Sec. 111.30(b)(2) which
would require you to make and keep written records of equipment
calibrations, inspections, and checks, and proposed Sec. 111.30(b)(5)
which would require you to make and keep backup files of software
programs and data, are now incorporated into final Sec. 111.35, and we
discuss these provisions later in this section.
(Comment 127) Several comments would limit proposed Sec. 111.30(a)
and (b) to automatic, mechanical, or electronic equipment that actually
affects product specifications. The comments argue that, in a modern
manufacturing facility, most, if not all, equipment used to
manufacture, package, label, or hold any food product is automatic,
mechanical, or electronic. The comments say that equipment, such as
forklifts, should not be required to be designed or selected in a
manner that ensures that product specifications are met, as would be
required in proposed Sec. 111.30(a)(1), or to be calibrated, as would
be required in Sec. 111.30(b)(1).
(Response) As we stated previously, we have revised Sec. 111.30 so
that it applies to equipment ``that you use to manufacture, package,
label, or hold a dietary supplement.'' This revision should prevent the
rule from being interpreted as applying to forklifts or other equipment
that have no bearing on the manufacture, packaging, labeling, or
holding of dietary supplements.
(Comment 128) Several comments argue that proposed Sec. 111.30 is
redundant to proposed Sec. 111.25 and could be removed without
meaningful effect. One comment argues that proposed Sec. 111.30(a) and
(b) (i.e., that all automatic, mechanical, and electronic equipment be
designed or selected to ensure that product specifications are
consistently achieved and operate satisfactorily within operating
limits required by the process) are redundant to proposed Sec.
111.25(a)(1) (which would require that all equipment be of appropriate
design, construction, and workmanship to enable them to be suitable for
their intended use) and proposed Sec. 111.25(a)(1)(v) (which would
state that ``equipment'' includes automatic, mechanical, or electronic
systems). The comment states that, for equipment to be suitable for its
intended use, the equipment must operate satisfactorily within
operating limits and, by extension, ensure that product specifications
are consistently achieved. The comment states the separate regulations
for automatic equipment in the drug CGMPs is less detailed despite our
efforts to present the 2003 CGMP Proposal in ``simplified language.''
(Response) We disagree that proposed Sec. 111.30 is redundant to
proposed Sec. 111.25 (final Sec. 111.27). Although both proposed
Sec. Sec. 111.25 and 111.30 pertained to equipment, they differed in
their focus. Proposed Sec. 111.25 would focus on equipment design,
construction, maintenance, cleaning, sanitizing, and calibration. In
contrast, proposed Sec. 111.30 would focus on the equipment's
operation or suitability within your manufacturing process. For
example, proposed Sec. 111.30(a)(2) would require you to determine the
suitability of your equipment by ensuring that your equipment is
capable of operating satisfactorily ``within the operating limits
required by the process.'' In contrast, proposed Sec. 111.25 had no
comparable suitability requirement insofar as your manufacturing
processes were concerned. Thus, the proposed sections are not
redundant, and the final rule retains both Sec. 111.27 (proposed Sec.
111.25) and Sec. 111.30.
2. Comments Specific to Proposed Sec. 111.30
a. Final Sec. 111.30(a) and (b). Final Sec. 111.30(a) (proposed
Sec. 111.30(a)(1)) requires you, for any automated, mechanical, or
electronic equipment you use to manufacture, package, label, or hold a
dietary supplement, to design or select the equipment to ensure that
dietary supplement specifications are consistently met.
Final Sec. 111.30(b) (proposed Sec. 111.30 (a)(2)) requires you,
for any automated, mechanical, or electronic equipment that you use to
manufacture, package, label, or hold a dietary supplement, to determine
the suitability of the equipment by ensuring that the equipment is
capable of operating satisfactorily within the operating limits
required by the process.
(Comment 129) Some comments argue that the requirements of proposed
Sec. 111.30(a) might be impossible to meet because, in many instances,
dietary supplement manufacturers cannot predict, at the time of
purchase, the entire range of ingredients and products for which a
particular piece of equipment might be used. The comments argue that a
particular piece of equipment's suitability for a particular ingredient
or product must be evaluated at the time the need arises. The comments
would revise proposed Sec. 111.30(a)(1). The words ``Design and select
equipment to ensure'' would be replaced with the words ``Use equipment
that ensures;'' and proposed Sec. 111.30(a)(2) would be revised to
replace the words ``is capable of operating'' with the word,
``operates.''
(Response) We disagree with the comments. Although a company may
not know the entire range of products that a machine may be used for,
[[Page 34828]]
proposed Sec. 111.30(a)(1) and (a)(2) would neither require you to
determine all uses of equipment at the time of purchase nor prevent you
from evaluating an old machine for a new use (these provisions are
renumbered as final Sec. 111.30(a) and (b), respectively). Thus, even
if you chose to use old equipment for a new use, you still must select
that equipment to ensure that dietary supplement specifications are
consistently met with the new equipment use and determine the
suitability of the new equipment use by ensuring that the equipment is
capable of operating satisfactorily within the operating limits
required by the new process.
(Comment 130) Several comments express concern that facilities and
much equipment in the industry are old and lack historical
documentation. These comments ask us to clarify whether manufacturers
would have to establish baseline information for old facilities and
equipment.
(Response) All equipment that you use, regardless of whether it is
old or new, must be capable of doing what you intend it to do. Just as
you could evaluate old equipment for a new use, you can demonstrate
that old equipment does, in fact, do what you intend it to do for uses
that you developed before these CGMP requirements were established, and
thereby comply with final Sec. 111.30(a) and (b).
(Comment 131) Several comments argue that our statement in the
preamble to the 2003 CGMP Proposal that ``systems need to be installed
in a manner that takes into account the inherent limitations of the
system, tested under conditions that reflect actual conditions of use''
(68 FR 12157 at 12193) is vague and subject to multiple
interpretations.
(Response) We disagree with the comment. The statement in question
should be read in context because the preamble to the 2003 CGMP
Proposal described several conditions for consideration. The preamble
to the 2003 CGMP Proposal stated, in relevant part: ``Some systems may
work properly only within a narrow range of environmental conditions,
such as temperature and humidity, and some might be particularly
sensitive to electromagnetic interference. The actual conditions of use
of a system should be considered as early as possible in its design and
development. Systems need to be installed in a manner that takes into
account the inherent limitations of each system, tested under
conditions of use, and properly maintained to ensure that they continue
to function as expected during their lifetime'' (68 FR 12157 at 12193.)
Thus, suitability under final Sec. 111.30(b) involves considerations
of how the equipment would be affected by environmental conditions,
whether the equipment is appropriate for its intended use, and whether
the equipment can be maintained properly to ensure satisfactory
operation.
(Comment 132) Several comments argue that the requirement of
proposed Sec. 111.30(a)(2) to ``determine the suitability of your
equipment by ensuring that your equipment is capable of operating
satisfactorily within the operating limits required by the process'' is
vague and subject to many interpretations. These comments assert that
this may cause an uneven playing field among companies as they apply
differing standards to this requirement. The comments also argue that
the vagueness of this requirement could potentially cause uneven
enforcement, depending on the experience and understanding of
individual inspectors.
(Response) We disagree that proposed Sec. 111.30(a)(2) (final
Sec. 111.30(b)) is vague or may result in uneven enforcement. There
has been sufficient common usage of terms such as ``suitable,''
``capable,'' and ``satisfactorily'' in the industry to enable firms,
and those who enforce the requirements, to comprehend and apply such
terms to particular operations. Agencies may use qualifying terms to
enable them to address a wide variety of conditions, and such terms
provide the flexibility needed for various operations.
(Comment 133) Several comments assert that proposed Sec.
111.30(a)(2) is without justification and overly prescriptive when
compared to conventional food CGMPs.
(Response) As discussed in section V of this document, the mere
fact that a dietary supplement CGMP requirement has no counterpart in
the food CGMP regulations, or has more detail than a counterpart in
such regulations, does not mean that it is overly prescriptive. Rather,
what is important is whether proposed Sec. 111.30(a)(2) (final Sec.
111.30(b)) is necessary to ensure the quality of the dietary
supplements. For example, the preamble to the 2003 CGMP Proposal (68 FR
12157 at 12193) discussed how the incorporation of software into the
operation of automatic equipment has both increased the complexity of
such equipment and resulted in a process that may operate differently
for each execution, because a software-based control system can be
configured at will by the operator or by the system itself. Therefore,
it is essential that you ensure that automated equipment is capable of
operating satisfactorily within the operating limits required by the
process.
(Comment 134) Several comments urge us to develop a separate
guidance document with respect to determining the suitability and
capability of equipment used in the manufacture of dietary supplements.
(Response) We believe that firms have sufficient experience to
determine whether equipment is suitable and capable of performing its
intended function. However, if we find that guidance will be helpful,
we will consider whether to issue guidance at a later date.
b. Final Sec. 111.30(c). Final Sec. 111.30(c) (proposed Sec.
111.30(b)(1)) requires you, for any automated, mechanical, or
electronic equipment you use to manufacture, package, label, or hold a
dietary supplement, to routinely calibrate, inspect, or check the
equipment to ensure proper performance. Final Sec. 111.30(c) also
requires quality control personnel to periodically review these
calibrations, inspections, or checks.
(Comment 135) Several comments claim the requirement for the
quality control unit to approve calibrations, inspections, or checks of
equipment is too prescriptive and that qualified persons outside of the
quality control unit should be able to approve these calibrations,
inspections, or checks. The comments also state the quality control
unit should perform audits of the records generated to ensure the
appropriate calibrations, inspections, or checks are being adequately
performed at the required intervals.
Other comments refer to related requirements in proposed Sec.
111.37(b)(8) that the quality control unit review all records for
equipment calibrations, inspections, or checks. The comments state the
requirements for oversight by the quality control unit in proposed
Sec. 111.37(b)(8) are excessive and go beyond requirements for both
the drug CGMPs and food CGMPs. One comment would revise proposed Sec.
111.37(b)(8) to require a review of all records when there is a
negative impact on the dietary supplement due to a calibration failure.
(Response) Final Sec. 111.12(b) requires that you identify who is
responsible for your quality control operations, and each person who is
designated to perform quality control operations must be qualified to
do so and have distinct and separate responsibilities related to
performing such operations from those responsibilities that the person
otherwise has when not performing such operations. Thus, you may
identify any person whom you believe is qualified to approve
calibrations, equipments, or checks to perform quality control
operations.
[[Page 34829]]
We disagree that the review by quality control personnel should be
limited to circumstances when there has been a calibration failure. One
function of quality control personnel is to provide oversight to
prevent problems with the product that you distribute by finding any
problems with the equipment that you use to produce the product rather
than to investigate the cause of a problem with a product that you
already distributed. However, we agree that it is sufficient to
periodically review the records of calibrations, inspections, or checks
of automated, mechanical, or electronic equipment, for example, on an
annual basis, rather than to approve each record when it is made. A
periodic review can uncover trends in the performance of the equipment
that have the potential to adversely affect the quality of the dietary
supplement and that may not be obvious by merely approving each record
when it is made. Seeing such trends would enable quality control
personnel to recommend corrective actions. This periodic review is
consistent with proposed Sec. 111.37(b)(8) which would require the
quality control unit to ``review'' all records for equipment
calibration, inspections, or checks rather than ``approve'' these
records. Therefore, we have revised the requirement that the quality
control unit approve calibrations, inspections, or checks of automatic,
mechanical or electronic equipment so that final Sec. 111.30(c)
requires that quality control personnel periodically review such
operations rather than approve them when they are made.
Additionally, we have made a minor change to Sec. 111.30(c). The
change inserts the words ``the equipment'' after ``Routinely calibrate,
inspect, or check * * *.'' This insertion simply reiterates that ``the
equipment'' must be routinely calibrated, inspected, or checked.
c. Final Sec. 111.30(d). Final Sec. 111.30(d) (proposed Sec.
111.30(b)(3)) requires you, for any automated, mechanical, or
electronic equipment you use to manufacture, package, label, or hold a
dietary supplement, to establish and use appropriate controls for the
equipment (including software for a computer-controlled process) to
ensure that any changes to the manufacturing, packaging, labeling,
holding, or other operations are approved by quality control personnel
and instituted only by authorized personnel.
(Comment 136) The preamble to the 2003 CGMP Proposal invited
comment on whether we should regulate computerized systems separately
from other automatic equipment, given the broad range in
sophistication, complexity, and computerization in manufacturing
equipment (68 FR 12157 at 12194).
Several comments state that computers are susceptible to erroneous
data input and subject to malfunctions and software problems and, thus,
should be regulated under the final rule.
(Response) We agree that computers used in the manufacturing
processes should be regulated under the final rule. As the preamble to
the 2003 CGMP Proposal stated the incorporation of software into the
operation of automatic equipment has increased the complexity of such
equipment and resulted in a process that may operate differently for
each execution, because a software-based control system can be
configured at will by the operator or by the system itself (68 FR 12157
at 12193). Additionally, final Sec. 111.35(b)(5) requires you to make
and keep backup files of software programs and data to keep them secure
from alterations, inadvertent erasures, or loss. The issue in the
preamble to the 2003 CGMP Proposal, however, was whether computerized
systems should be regulated separately from other equipment; in the
absence of comments supporting separate treatment for computerized
systems, we have included computerized systems as ``equipment'' in
final Sec. 111.30(d).
We are, however, revising final Sec. 111.30(d) in the following
manner:
We are inserting the words ``for automated, mechanical,
and electronic equipment (including software for a computer controlled
process)'' after ``Establish and use appropriate controls.'' This
change simply reiterates the types of equipment for which appropriate
controls must be established and used, and makes it clear that software
is included under the rule and
We are rephrasing the purpose of Sec. 111.30(d). The
proposal stated that you must establish and use appropriate controls
``to ensure that your quality control unit approves changes in the
master manufacturing record batch control records, packaging
operations, and label operations, or changes to other operations
related to the equipment that you use and that only authorized
personnel institute the changes.'' The final rule states that you must
establish and use appropriate controls for your equipment ``to ensure
that any changes to the manufacturing, packaging, labeling, holding, or
other operations are approved by quality control personnel and
instituted only by authorized personnel.''
As revised, final Sec. 111.30(d) shifts its emphasis from the
person(s) who must approve or institute the changes to the types of
changes that must be approved and instituted. This shift in emphasis is
appropriate given that the final rule addresses responsibilities of the
quality control personnel elsewhere.
d. Final Sec. 111.30(e). Final Sec. 111.30(e) (proposed Sec.
111.30(b)(4)) requires you, for any automated, mechanical, or
electronic equipment you use to manufacture, package, label, or hold a
dietary supplement, to establish and use appropriate controls to ensure
that the equipment functions in accordance with its intended use.
Quality control personnel must approve these controls.
We did not receive comments specific to proposed Sec.
111.30(b)(4).
3. Reorganization of Certain Paragraphs in Proposed Sec. 111.30
As we explained earlier in this section, proposed Sec. 111.30
would impose certain requirements relating to written records of
equipment calibrations, inspections, or checks (proposed Sec.
111.30(b)(2)) and making and keeping backup files of software programs
and data (proposed Sec. 111.30(b)(5)). The final rule now contains a
new recordkeeping section, final Sec. 111.35, that combines elements
of proposed Sec. 111.30(b)(2) and (b)(5), as well as other sections.
Additionally, proposed Sec. 111.30(c) would require you to keep
records in accordance with the written procedure and recordkeeping
requirements in proposed Sec. 111.125. Section 111.35 of the final
rule now incorporates proposed Sec. 111.30(c) as well. We discuss
final Sec. 111.35 in the following paragraphs.
H. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.35)
Final Sec. 111.35 describes the recordkeeping requirements. It
represents a combination of proposed Sec. Sec. 111.25(c)(1) through
(c)(2), (d)(1) through (d)(7), and (f); 111.30(b)(2), (b)(5), and (c);
and 111.50(c)(4).
1. Final Sec. 111.35(a)
Final Sec. 111.35(a) states that you must make and keep records
required under subpart D in accordance with subpart P. Subpart P deals
with records and recordkeeping.
Final Sec. 111.35(a) is broader than proposed Sec. 111.25(f),
which stated that you ``must keep calibration records as required by
this section in accordance with'' the 2003 CGMP Proposal's
recordkeeping section, and compared to proposed Sec. 111.30(c), which
stated that you must keep ``automatic, mechanical, or electronic
equipment records required by this section in accordance
[[Page 34830]]
with'' the 2003 CGMP Proposal's recordkeeping section. However, final
Sec. 111.35(a) has the same effect as proposed Sec. Sec. 111.25(f)
and 111.30(c).
We did not receive any substantive comments on proposed Sec. Sec.
111.25(f) or 111.30(c).
2. Final 111.35(b)(1) and (b)(2)
Final Sec. 111.35(b) combines the various recordkeeping
requirements that were in proposed Sec. Sec. 111.25(c) (written
procedures for calibrating instruments and controls and documentation
that those procedures were followed and that the calibration was
performed), 111.25(d) (written procedures or documentation for
calibration, such as the instrument or control calibrated and the
calibration date), 111.30(b)(2) and (b)(5) (written records of
equipment calibrations, inspections, or checks, and backup files of
software and data, respectively), and 111.50(b)(4) (inclusion of date
and time of maintenance, cleaning, and sanitizing of equipment and
processing lines in the batch record).
Specifically, final Sec. 111.35(b)(1) states that you must make
and keep records of ``written procedures for fulfilling the
requirements of this subpart,'' including written procedures for:
Calibrating instruments and controls that you use in
manufacturing or testing a component or dietary supplement. This
paragraph is similar to proposed Sec. 111.25(c). Although we did not
receive any substantive comment on proposed Sec. 111.25(c), we are
rephrasing the paragraph due to its reorganization as part of final
Sec. 111.35. Additionally, although proposed Sec. 111.25(c) would
require you to document that the written procedures for calibration
were followed each time a calibration is performed, we are moving the
documentation requirement to final Sec. 111.35(b)(3) which we discuss
later in this section.
Calibrating, inspecting, and checking automated,
mechanical, and electronic equipment. This paragraph is similar to
proposed Sec. 111.30(b)(2), although we are rephrasing the paragraph
due to its reorganization as part of final Sec. 111.35.
Maintaining, cleaning, and sanitizing, as necessary, all
equipment, utensils, and any other contact surfaces that are used to
manufacture, package, label, or hold components or dietary supplements.
This paragraph relates to final Sec. 111.25(c) which requires you to
establish and follow written procedures for such activities.
We did not receive any comments specific to proposed Sec. Sec.
111.25(c) or 111.30(b)(2).
Final Sec. 111.35(b)(2) (proposed Sec. 111.50(c)(4)) requires you
to make and keep documentation, in individual equipment logs, of the
date of the use, maintenance, cleaning, and sanitizing of equipment,
unless such documentation is kept with the batch record.
(Comment 137) Proposed Sec. 111.50(c)(4) would require that the
batch record include the date and time of the maintenance, cleaning,
and sanitizing of the equipment and processing lines used in producing
the batch. The preamble to the 2003 CGMP Proposal also invited comment
on whether the person performing the maintenance, cleaning, and
sanitizing of portable equipment and utensils should document at the
time of performance the maintenance, cleaning, and sanitizing (68 FR
12157 at 12192\8\). Several comments argue that the final rule should
require documentation at the time of performance of equipment, utensil,
and contact surface maintenance, cleaning, and sanitation and should
also require this documentation to be kept as records. The comments
explain that such recordkeeping is common practice in the industry, is
an important part of batch history, and omitting such a requirement
would diminish the industry standard. In addition, the comments state
that written records are an effective way to ensure that there is
consistency in how employees are trained and to assess compliance.
---------------------------------------------------------------------------
\8\Although the preamble to the 2003 CGMP Proposal discussed
this issue in relation to proposed Sec. 111.25 (``What Requirements
Apply to the Equipment and Utensils You Use?''), the same principle
applies to proposed Sec. 111.50(c)(4).
---------------------------------------------------------------------------
Several comments agree that equipment maintenance, cleaning, and
sanitizing records should be kept and state that this information
should be kept with individual pieces of equipment, rather than in the
batch record as proposed Sec. 111.50(c)(4) would require. The comments
say it is easier and more efficient for some companies to maintain
equipment logs that can be referenced when necessary.
Other comments say manufacturers should have flexibility to design
a recordkeeping program suited to their operations, and should have the
option of using an equipment log as it provides an efficient way to
document, trace, and review equipment use, maintenance, cleaning, and
sanitization of equipment. According to these comments, because the
2003 CGMP Proposal would require batch production records to identify
all equipment used during production, this will allow for cross-
referencing with the equipment log, should the need occur. The comments
argue that the proposed approach will be awkward for some companies to
comply with and would not result in collection of information in a
logical order or location where it can be easily referenced and
reviewed, such as on the production floor, or to provide data for trend
analysis. The comments also contend requiring all information to be
maintained in the batch record will be difficult in practice and place
an enormous burden on companies.
(Response) We agree that documenting the cleaning, sanitizing, and
maintenance of equipment is important. However, we have revised the
provision so that these records need not be part of the batch record.
Instead, final Sec. 111.35(b)(2) requires you to make and keep
documentation of the date of use, maintenance, cleaning, and sanitizing
of equipment in individual equipment logs, unless such documentation is
kept with the batch record. By ``equipment log,'' we mean a written
record that includes information about the history of a piece of
equipment. This history includes items such as date of installation,
routine maintenance, repairs, and cleaning.
Additionally, final Sec. 111.260 requires you to identify the
equipment and processing lines used in producing the batch and either
provide a cross-reference that will make it possible to find the
applicable equipment log as needed or include documentation that
equipment was cleaned, sanitized, or maintained (we discuss final Sec.
111.260 in section XIV of this document). For example, you may keep
records documenting that you cleaned containers you will use for
holding a finished batch either in records associated with the
equipment you use for cleaning, or with the applicable batch record,
depending on what is most convenient and practical for your operations.
(Comment 138) Several comments state documenting the cleaning of
contact surfaces would be unnecessarily labor-intensive because the
term is so broadly defined. Other comments argue that documenting the
cleaning of utensils is unnecessary and inappropriate. These comments
support requiring documentation for the cleaning of large equipment,
but claim that requiring manufacturers to uniquely identify each spoon,
spatula, container, and hose (or other general cleaning) in order to
document each cleaning would be inappropriate and create an enormous
burden on the manufacturer. According to these comments, such a
requirement would slow and complicate the cleaning process, making
proper cleaning more cumbersome. The comments assert that
[[Page 34831]]
contamination from these sources has not caused any recalls and is not
justified.
(Response) We disagree with these comments. The final rule requires
you to document the work that was done, but gives you the flexibility
to decide how to document that work was done. For contact surfaces such
as containers you use to hold a finished batch, you could, for example,
record the cleaning either on a single line that you provide in your
batch record, or as a line entry in the log of the equipment that you
use to clean the containers, or in some other way that suits your
needs. These are not labor-intensive requirements.
It is important that you have procedures in place to know that
small items, such as spatulas, are clean when you use them. For
example, if you have a log where you designate equipment that has been
cleaned, your batch record could simply have a place to check that you
used equipment designated as clean.
3. Final Sec. 111.35(b)(3)
Final Sec. 111.35(b)(3) (proposed Sec. 111.25(d)(1) through
(d)(7)) requires you to make and keep documentation of any calibration,
each time the calibration is performed, for instruments and controls
that you use in manufacturing or testing a component or dietary
supplement. In the documentation you must: (1) Identify the instrument
or control calibrated; (2) provide the calibration date; (3) identify
the reference standard used, including the certification of accuracy of
the known reference standard and a history of recertification of
accuracy; (4) identify the calibration method used, including
appropriate limits for accuracy and precision of instruments and
controls when calibrating; (5) provide the calibration reading or
readings found; (6) identify the recalibration method used, and reading
or readings found, if accuracy or precision or both accuracy and
precision limits for instruments and controls were not met; and (7)
include the initials of the person who performed the calibration and
any recalibration.
(Comment 139) Some comments support proposed Sec. 111.25(d).
However, other comments argue that the documentation requirements are
unduly prescriptive. Some comments would revise proposed Sec.
111.25(d) to more closely mirror the requirements in drug CGMPs. Some
comments suggest the requirement to maintain written records of
calibrations should simply state ``You must maintain written records of
calibrations according to Sec. 111.125.'' Other comments suggest
detailed calibration requirements would not be needed if the final rule
included requirements to establish and follow written procedures.
(Response) The information required under final Sec. 111.35(b)(3)
(proposed Sec. 111.25(d)) is the minimum amount necessary to provide
sufficient information concerning equipment calibration. For example,
some firms may have more than one machine to perform a given function;
in those situations, documentation that identified the exact machine
that was calibrated would distinguish it from other, seemingly
identical, but noncalibrated machines. Likewise, if the maintenance
instructions for a machine called for calibration checks every month,
documenting the date of calibration would show you whether calibrations
were done on schedule. As another example, if a machine required
calibration according to a particular standard, identifying the
reference standard would help verify that the calibration was done
correctly.
Thus, we disagree with those comments claiming that proposed Sec.
111.25(d) was too prescriptive. If, for example, the final rule simply
directed you to document calibration, without specifying what
information should be contained in that documentation, then the
resulting documentation could have little or no value. For example,
assume that you have two identical pieces of equipment, but only one
had been calibrated. If the documentation simply said, ``machine was
calibrated,'' you would not know which machine had been calibrated. As
another example, if you had a machine that had to be recalibrated every
year, and the documentation merely said, ``recalibration completed,''
you would not know whether the machine had been recalibrated yesterday,
last month, last year, or 4 years ago.
With respect to the argument that proposed Sec. 111.25(d) should
be revised to resemble the drug CGMPs, we disagree. We recognize that
the drug CGMPs are less detailed with respect to documentation; for
example, 21 CFR 211.68(a), ``Automatic, mechanical, and electronic
equipment,'' simply states, in relevant part, ``If such equipment is so
used, it shall be routinely calibrated, inspected, or checked according
to a written program designed to assure proper performance'' and
``Written records of those calibration checks and inspections shall be
maintained.'' However, the comments overlook the fact that, from 1993
to 2003, the Center for Drug Evaluation and Research (CDER) issued
periodic guidance, in the form of ``Human Drug CGMP Notes,'' and those
guidances offered advice on various drug CGMP issues. With respect to
calibration, for example, the December 1997 edition dealt with the
question of whether the drug CGMP regulations require equipment to be
labeled with calibration dates. The guidance identified various
regulations that would be applicable and also said that: ``During an
inspection a firm should be able to document when a specific piece of
equipment was last calibrated/maintained, the results or action, and
when its next calibration/maintenance is scheduled. The absence of such
documentation is a CGMP deviation'' (see CDER, ``Human Drug CGMP
Notes,'' December 1997, at page 3 (Ref. 29)).
This advice is comparable, in several respects, to the information
required by final Sec. 111.35(b)(3). For example, it refers to a
``specific piece of equipment,'' which is similar to final Sec.
111.35(b)(3)(i)'s requirement to identify the instrument or control
calibrated. It refers to the time when calibration occurred; this is
similar to final Sec. 111.35(b)(3)(ii)'s requirement to provide the
calibration date. Although public distribution of ``Human Drug CGMP
Notes'' ended in 2003, and the document was circulated only within FDA
from 2001 to 2003 (but was available through FOIA), the guidances
offered the drug industry advice on complying with the drug CGMPs, and
we have retained the guidances on our Internet site. In other words,
the drug CGMP regulations did not have to be as ``prescriptive''
because the drug industry learned about our interpretations or
expectations of the drug CGMPs through guidance.
Here, in contrast, there is no comparable history of issuing
periodic guidance to inform the dietary supplement industry about
specific CGMP issues.
Yet, even if final Sec. 111.35 is more ``prescriptive'' than the
drug CGMPs, that difference does not mean that we must revise the rule
to ``mirror'' the drug CGMPs. The dietary supplement industry is more
diverse compared to the drug industry, and so, at least with respect to
documenting calibration, more--rather than less--detail is appropriate.
We do note, however, that final Sec. 111.35(b)(3) differs from
proposed Sec. 111.25(d) in the following respects:
Sec. 111.25(d) would require you to identify specific
calibration-related information ``in any written procedure or at the
time of performance,'' final Sec. 111.35(b)(3) requires documentation
``each time the calibration is performed.'' Final section 111.35(b)(1)
[[Page 34832]]
requires you to have records of the written procedures for calibrating
instruments and controls, but does not specify the contents of such
written procedures;
Sec. 111.25(d) would refer to ``instruments and
controls.'' Final Sec. 111.35(b)(3) now refers to ``instruments and
controls that you use in manufacturing or testing a component or
dietary supplement.'' This change clarifies the instruments and
controls that are subject to final Sec. 111.35(b)(3) and is consistent
with final Sec. 111.27(b), which requires you to calibrate instruments
and controls;
The type of information that must be documented under
Sec. 111.35(b)(3)(i) through (b)(3)(vii) is essentially identical to
that in proposed Sec. 111.25(d)(1) through (d)(7), but we revised the
sentence structure due to the manner in which we reorganized final
Sec. 111.35;
Sec. 111.25(d)(6) would have you identify the
recalibration method used. Final Sec. 111.35(b)(3)(vi) requires you to
identify the recalibration method used ``and reading or readings
found.'' The addition of ``reading or readings found'' is consistent
with the remainder of proposed Sec. 111.25(d)(6) (final Sec.
111.35(b)(3)(vi)) which is a simplification of the phrase ``accuracy or
precision or both accuracy and precision limits for instruments and
controls were not met.'' One would only know that limits were not met
based on a reading or readings; and
Sec. 111.25(d)(7) would require the initials of the
person who performed the calibration. Final Sec. 111.35(b)(3)(vii)
requires the initials of the person who performed the calibration and
any recalibration. Arguably, recalibration is a type of calibration,
but we have added ``any recalibration'' to final Sec.
111.35(b)(3)(vii) to ensure that recalibrations are included in the
rule.
(Comment 140) Several comments would revise proposed Sec.
111.25(d) to read, ``The following must be identified * * *'', rather
than ``you must identify.'' The comments explain that calibrations and
recalibrations are often performed by the equipment manufacturer,
vendor, or other outside service, rather than by the dietary supplement
manufacturer. The comments argue that the proposal requires that the
calibration or recalibration must be performed onsite (i.e., at the
plant manufacturing the dietary ingredient or supplement) when in fact
many calibrations can, or even must, be performed offsite.
(Response) We decline to revise the paragraph as requested. As we
discuss in section VI of this document, the term ``you'' can refer to
someone with whom you contract, but you are responsible for ensuring
that the calibration requirements are met, and to have documentation of
the calibration, even though the steps may be performed offsite.
4. Final Sec. 111.35(b)(4)
Final Sec. 111.35(b)(4) (proposed Sec. 111.30(b)(2)) requires you
to make and keep written records of calibrations, inspections, and
checks of automated, mechanical, and electronic equipment that is used
to manufacture, package, label, or hold a dietary supplement.
We did not receive comments specific to proposed Sec.
111.30(b)(2). We have made nonsubstantive editorial changes to the
rule. For example, proposed Sec. 111.30(b)(2) would require you to
``make and keep'' written records; final Sec. 111.35(b)(4) omits the
words `` make and keep'' because that requirement appears earlier in
Sec. 111.35.
5. Final Sec. 111.35(b)(5)
Final Sec. 111.35(b)(5) (proposed Sec. 111.30(b)(5)) requires you
to make and keep backup file(s) of current software programs (and of
outdated software that is necessary to retrieve records that you are
required to keep in accordance with subpart P, when current software is
not able to retrieve such records) and of data entered into computer
systems that you use to manufacture, package, label, or hold dietary
supplements. Under final Sec. 111.35(b)(5)(i), your backup file (e.g.,
a hard copy of data you have entered, diskettes, tapes, microfilm, or
compact disks) must be an exact and complete record of the data you
entered. Under final Sec. 111.35(b)(5)(ii), you must keep your backup
software programs and data secure from alterations, inadvertent
erasures, or loss.
(Comment 141) Several comments would limit the requirement for
maintaining backup files of data entered into computer systems to those
data entered into computer systems that are relied upon for compliance
with CGMPs. These comments argue that the paragraph, as written, calls
for a firm to make and keep backup files of data entered into computers
on which personnel payroll records are maintained, and state that no
such requirement should be imposed. Therefore, these comments would
replace the words ``your computer system'' with the words ``any of your
computer systems that are relied upon for compliance with this part.''
(Response) We have modified the provision to clarify that the
requirement is for computer systems that you use to manufacture,
package, label, or hold dietary supplements.
(Comment 142) Several comments argue that many software programs
are in a near constant state of revision and that it is not a common
business practice for a firm in any industry to maintain records of
outdated software programs, at least if the firm is still able to use a
revised program to access data it entered using an outdated program.
The comments assert that, although the drug CGMPs require the
maintenance of certain backup files of data entered into computer
systems, they do not require the maintenance of backup files of
software programs.
(Response) Keeping backup copies of software helps ensure that data
can be retrieved if the primary software develops a problem. When we
use the term ``backup,'' we mean a second copy of the software in
question rather than a copy of previous versions of the software that
are outdated, provided that data can be retrieved. However, if the data
collected using outdated software cannot be retrieved by the newer
software, there would still be a need to maintain a primary copy and a
backup copy of the outdated software used to collect or manage the
data.
We have narrowed the requirement to retain backup files of software
to current software and of outdated software that is necessary to
retrieve records that you are required to keep in accordance with
subpart P, when current software is not able to retrieve such records.
(Comment 143) Some comments claim that, although the drug CGMPs
require the maintenance of certain backup files of data entered into
computer systems, they do not require the maintenance of backup files
of software programs. Several comments also assert that it is not
always possible to keep backup files of the software programs used in
certain pieces of equipment, because the equipment manufacturer may be
the only one having access to the programming of its equipment. The
comments would delete the words ``software programs and'' from proposed
Sec. 111.30(b)(5).
(Response) In most cases, we anticipate that firms will have access
to backup copies of their software programs. We acknowledge that in
rare instances, backup copies may not be available and in these
situations, we will take that into account in reviewing compliance with
this provision. We decline to revise the provision as suggested.
6. Final Sec. 111.35(b)(6)
Final Sec. 111.35(b)(6) states that you must make and keep
``documentation of
[[Page 34833]]
the controls that you use to ensure that equipment functions in
accordance with its intended use.''
The preamble to the 2003 CGMP Proposal stated that we were not
proposing verification requirements for automatic, mechanical, or
electronic equipment (68 FR 12157 at 12194). However, we invited
comment on whether the final rule should require such verification
(id.). Verification would ensure that the processes using automatic,
mechanical, and electronic equipment consistently produce an outcome
that meets a predetermined specification and any predetermined quality
characteristics. Verification would show whether your automatic,
mechanical, or electronic processes will consistently operate as they
should.
(Comment 144) Several comments argue against including equipment
verification requirements. The comments argue that the verification
discussion in the preamble to the 2003 CGMP Proposal is difficult to
distinguish from drug validation. The comments argue that validation
should be allowed to evolve in the dietary supplement industry as it
evolved in drug CGMPs. According to these comments, the dietary
supplement industry, being largely self regulated in CGMPs to date and
not generally practicing verification, would be more readily adaptable
to, and better controlled by, strict operating controls and quality
control checks including sufficient input and output checks on computer
operated systems, than having to digest the concept of verification and
implement verification processes. The comments state that, in the
future, verification may be a means of offsetting some of the extensive
testing of finished products.
Other comments state we should not require verification of
processes that use automatic, mechanical, or electronic equipment given
the different processes that dietary supplement manufacturers use. The
comments argue that although dietary supplement manufacturers,
depending on the unique circumstances of a particular manufacturing
process, may choose to verify processes using a sound verification
system, we should not require verification.
Several comments ask us to clarify whether we intended to require
full validation of equipment used to process dietary supplements
because terms such as ``suitability'' and ``capable,'' which we used in
proposed Sec. 111.30(a)(1) and (a)(2), might be interpreted to require
validation. These comments state validation is unnecessary and overly
burdensome for equipment used in manufacturing dietary supplements.
Several comments argue that proposed Sec. 111.30(a)(1) and (a)(2)
have the effect of establishing unnecessarily formal, stringent, and
expensive validation requirements on equipment design, selection, and
capability. The comment states that this language represents a de facto
``IQ/OQ/PQ'' (installation qualification/operational qualification/
performance qualification) requirement. According to these comments,
emphasis should instead be directed to actual use and operation.
In contrast, several comments argue we should require manufacturers
to develop and maintain data that demonstrate that equipment is
suitable and that the production process consistently delivers expected
results. The comments argue that one key CGMP element is the
requirement for systems to operate consistently and to produce an
outcome that meets a predetermined specification. According to these
comments, demonstration of system capability is best achieved through
systems verification. The comments explain that, in an industry where
the complexity of finished products often precludes finished product
testing, the capability of the systems employed is of paramount
importance. The comments state if the processes used fail to produce a
product meeting predetermined specifications and quality
characteristics, then the product should not be sold. The comments add
that, although verification imposes additional costs on manufacturers,
frequently rejected product, adequate rework procedures, and extensive
in-process and finished product testing also would be costly.
Several comments also claim the use of an appropriate verification
system may, under certain circumstances, allow for lot testing as
opposed to batch testing. These comments state that, with process
verification and an appropriate testing scheme, a manufacturer could
demonstrate that lot testing provides sufficient assurance of quality
and lack of adulteration. The comments ask us to address these
alternatives in the final rule. Many comments said written records of
verification should be maintained. The comments offer several
suggestions on how this could be accomplished, including using
statistical process control techniques or other appropriate statistical
tools.
(Response) We used the term ``verification'' rather than
``validation'' to signal that we did not expect that a final rule would
include requirements for formal process validation requirements, such
as an IQ/OQ/PQ requirement, for equipment. Regardless, several comments
interpreted our request for comments as a suggestion that we were
considering such formal validation requirements. At this time, we are
not requiring formal process validation for equipment. However, we will
monitor the development of systems that evolve within this diverse
industry.
We disagree that proposed Sec. 111.30(a)(1) and (a)(2) would have
the effect of establishing unnecessarily formal, stringent, and
expensive validation requirements on equipment design, selection, and
capability, and that the language would represent a de facto ``IQ/OQ/
PQ'' requirement for equipment. Final Sec. 111.30(e) requires you to
ensure equipment operates in accordance with its intended use. We agree
with the comments that argued that data demonstrating that equipment is
suitable, and that the production process consistently delivers
expected results, are a key element of CGMP. Therefore, final Sec.
111.35(b)(6) requires you to make and keep documentation of the
controls that you use to ensure that the equipment functions in
accordance with its intended use. Examples of such controls include
temperature settings, fill rates, and blending times that must be set,
checked, and adjusted as necessary.
X. Comments on Requirement to Establish a Production and Process
Control System (Final Subpart E)
A. Reorganization of Proposed Sec. 111.35 Into Final Subpart E
In the 2003 CGMP Proposal, the requirements for a production and
process control system were set forth in Sec. 111.35. As shown in
table 6 of this document, we are reorganizing proposed Sec. 111.35
into subpart E. Table 6 lists the sections in final subpart E and
identifies the sections in the 2003 CGMP Proposal that form the basis
of the final rule.
Table 6.--Derivation of Sections in Final Subpart E
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.55 What are the requirements Sec. 111.35(a)
to implement a production and process
control system?
------------------------------------------------------------------------
Sec. 111.60 What are the design Sec. 111.35(b)
requirements for the production and
process control system?
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[[Page 34834]]
Sec. 111.65 What are the requirements Sec. 111.35(c)
for quality control operations?
------------------------------------------------------------------------
Sec. 111.70 What specifications must Sec. 111.35(e), (f), (g),
you establish? and (k)
------------------------------------------------------------------------
Sec. 111.73 What is your responsibility Sec. 111.35 (f), (g), and
for determining whether established (h)
specifications are met?
------------------------------------------------------------------------
Sec. 111.75 What must you do to Sec. 111.35(e), (f), (g),
determine whether specifications are (h), (i), (k), and (l)
met? Sec. 111.37 (b)(11)(iv)
Sec. 111.40(a)(2)
------------------------------------------------------------------------
Sec. 111.77 What must you do if Sec. 111.50(d)(2), (f), and
established specifications are not met? (g)
Sec. 111.35(i)(4)(i) and
(i)(4)(ii)
------------------------------------------------------------------------
Sec. 111.80 What representative samples Sec. 111.37(b)(11)
must you collect?
------------------------------------------------------------------------
Sec. 111.83 What are the requirements Sec. 111.37(b)(12)
for reserve samples? Sec. 111.50(h)
Sec. 111.83(b)(2)
------------------------------------------------------------------------
Sec. 111.87 Who conducts a material Sec. 111.35(i) and (n)
review and makes a disposition decision? Sec. 111.37(b)(5) and
(b)(14)
Sec. 111.40(a)(3)
Sec. 111.50(d)(1)
Sec. 111.85(a) and (c)
------------------------------------------------------------------------
Sec. 111.90 What requirements apply to Sec. 111.35(i)(4)
treatment, in-process adjustments, and Sec. 111.50(d)(1), (f), and
reprocessing when there is a deviation (g)
or unanticipated occurrence or when a Sec. 111.65(d)
specification established in accordance
with Sec. 111.70 is not met?
------------------------------------------------------------------------
Sec. 111.95 under this subpart E, what Sec. 111.35(m) and (o)
records must you make and keep?
------------------------------------------------------------------------
B. General Comments on Proposed Sec. 111.35
(Comment 145) Several comments emphasize the first step in ensuring
safe, high quality products is to use high quality components that meet
well-defined specifications. Some of these comments assert the 2003
CGMP Proposal does not encourage development of such specifications.
Several comments assert that a more appropriate balance is needed
between an effective process control system and a reasonable testing
scheme that is calculated to confirm the quality of dietary
supplements, and that it is important to provide companies with more
flexibility in developing a specific CGMP program that satisfies the
requirements. The comments stress it is important to build quality into
a product throughout the entire production process by relying on strong
process controls rather than by testing at the finished batch stage.
One comment asserts that, in an appropriate process control system,
testing is a means to monitor and ensure that the control system is
functioning as intended. Many comments recommend the final rule include
rigorous in-process controls plus a requirement for one identity test
of incoming components to ensure quality and safety.
Many comments assert a certificate of analysis can be a key element
of the manufacturing process provided that a manufacturer certifies
that a vendor consistently supplies suitable product through a
combination of vendor audits and product testing. (A certificate of
analysis is a document, provided by the supplier of a component prior
to or upon receipt of the component, that documents certain
characteristics and attributes of the component.) Comments also assert
that, with use of a certificate of analysis from a properly qualified
supplier, the amount of required testing could be reduced. One comment
notes that, although a certificate of analysis may not be relied upon
completely to forgo testing of a received ingredient, the extent of
testing could be reduced to take into account the history of the
supplier in providing quality ingredients. This and other comments
recommend the dietary supplement manufacturer conduct identity tests to
ensure that the correct component has been received. A few comments
note that the drug CGMP regulations permit the use of a supplier's
certificate of analysis based upon certification of the supplier by a
program of complete testing for conformance with the certificate of
analysis.
Several comments support the use of a qualified supplier's
certificate of analysis in lieu of testing at the finished batch stage.
One comment recommends testing be strategically employed to verify that
other control procedures have accomplished their intended result; if
other controls are adequate, a statistically-based testing program
should be permitted for finished batches rather than the proposed
requirement for testing every batch for every specification.
Many comments note that section 402(g)(2) of the act directs us to
develop dietary supplement CGMP requirements that are modeled after the
CGMP regulations for food. These comments point out that, because the
food CGMPs allow the use of a verified certificate of analysis, it is
unfair and illogical to disallow a certificate of analysis in the
dietary supplement CGMP final rule. One comment states the proposed
requirements for production and process controls are more stringent
than the requirements for drug products.
Several comments stress that the most critical aspect of a
successful CGMP system is effective process control, which includes a
requirement for written procedures and documentation for all key
processing operations. Many comments argue that effective process
control, including extensive written procedures, should allow for a
decreased testing burden with respect to the finished product. One
comment suggests we exempt manufacturers from the requirement to test
each batch of finished product if they have a qualified manufacturing
process that meets certain basic criteria, including a requirement for
written procedures for each stage of the process and a written plan for
qualifying this process.
Several comments urge us to build more flexibility into the testing
requirements, in both the type and number of tests required and the
point(s) in the supply chain at which they would be required. Some
comments recommend that the frequency of testing be established under a
statistically valid method to ensure that in-process controls are
adequate to guarantee production of a safe and effective dietary
supplement or ingredient. Several comments recommend we require
manufacturers to test incoming ingredients and raw materials, in lieu
of testing each finished batch of product. These comments state it is
more prudent to test to ensure that the materials used in formulating a
product are appropriate and safe than to risk making an adulterated
product and, in so doing, contaminate manufacturing equipment.
Several comments recommend we allow manufacturers to employ skip-
lot testing as an alternative to testing each finished batch of
product. One comment states that, with adequate process controls in
place, periodic or skip-lot testing is sufficient, and notes that skip-
lot testing is acceptable under the regulatory frameworks for herbal
[[Page 34835]]
products in other countries, including Canada and countries in the
European Union.
In summary, the comments suggest an approach that stresses the
importance of establishing specifications for components, relying on a
certificate of analysis from a qualified supplier for certain
specifications with qualification of the suppliers, and establishing
and following written procedures. This overall approach would focus on
building quality into a dietary supplement throughout the production
and process control system. The role of testing at the finished batch
stage would become a check on whether the overall manufacturing process
is, in fact, under control.
(Response) Based upon a review of the comments, we have
reconsidered the approach taken in the 2003 CGMP Proposal. The 2003
CGMP Proposal would require that all finished batches of dietary
supplements be tested at the finished batch stage to ensure that the
products met specifications for identity, purity, strength, and
composition. The 2003 CGMP proposal recommended, but would not require,
testing of incoming components to ensure that component specifications,
including identity, were met. However, if a specification (such as
identity) could not be tested at the finished batch stage, the proposed
rule would require a firm to test incoming components for that
specification and to test for that specification at the in-process
stage as necessary to ensure that products met specifications. We are
persuaded that, as an alternative to testing each finished batch of
product, we can allow for the use of a statistically sound sampling and
testing program for finished batches of dietary supplements unless a
manufacturer chooses to test every batch. Such a sampling and testing
program is feasible when controls are implemented earlier than the
final product stage in the manufacturing process. Controls include the
use of a certificate of analysis from a qualified supplier for
specifications other than the identity of a dietary ingredient, and the
establishment and monitoring of in-process manufacturing controls. We
agree with the comments that if we reduce the requirements for testing
at the finished batch stage, then it is critical that you determine
whether components meet specifications. We address this issue in the
following two ways: (1) Each manufacturer must confirm the identity of
each component prior to use (you must test or examine dietary
ingredients to verify the identity, but may rely on a certificate of
analysis to confirm the identify of components other than dietary
ingredients) and (2) each company must confirm other required
specifications for components prior to use, either by relying upon a
certificate of analysis or by testing or examining the component.
As the comments have suggested, specifications for the ``identity''
of components of dietary supplements are critically important. These
comments included references to industry proposals that supported
identity testing. The 1997 ANPRM (62 FR 5700) included an industry
proposed outline of CGMP provisions which contained a provision that
required identity testing as follows: ``(iv) Each lot of raw material
shall undergo at least one test by the manufacturer to verify its
identity. Such tests may include any appropriate test with sufficient
specificity to determine identity, including chemical and laboratory
tests, gross organoleptic analysis, microscopic identification, or
analysis of constituent markers.'' (60 FR 5700 at 5705).
In January 2004, a group of trade associations representing dietary
supplement manufacturers and others submitted text of proposed CGMP
requirements to the docket as an alternative to the 2003 CGMP Proposal.
This submission also included a provision which required identity
testing as follows:
(1) For components, dietary ingredients, or dietary supplements
that you receive, you must:
(i) conduct at least one test or examination to verify that the
specifications for identity are met; * * *
(1996N-0417, EMC000261-02 at 20).
Both the 1997 ANPRM industry outline and the January 2004 industry
docket submission included provisions that allowed certificates of
analysis to establish specifications other than for identity for
ingredients and components.
In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12162) we
discussed a case in which Digitalis lanata was labeled as plantain and,
as a result, a young woman experienced a life-threatening abnormal
heart function after consuming a dietary supplement containing D.
lanata in lieu of plantain. The problem occurred notwithstanding the
fact that certificates of analysis furnished by the supplier provided
assurances that the component was indeed plantain.
Because of the critical importance of ensuring the proper identity
of dietary ingredients--they are the central defining ingredients of a
dietary supplement--we are requiring each firm that uses a dietary
ingredient to perform its own testing or examination for identity of
each dietary ingredient prior to use. This requirement is similar to
the proposed requirement set forth by industry in both the 1997 ANPRM
and in the January 2004 industry comment to the proposed rule. Firms
may not rely upon a certificate of analysis provided by suppliers to
determine the identity of a dietary ingredient before use. We
recognize, however, that it may be possible for a manufacturer to
demonstrate, through various methods and processes in use over time for
its particular operation, that a system of less than 100 percent
identity testing would provide no material diminution of assurance of
the identity of the dietary ingredient as compared to the assurance
provided by 100 percent identity testing. To provide an opportunity for
a manufacturer to make such a showing and reduce the frequency of
identity testing of components that are dietary ingredients from 100
percent to some lower frequency, we decided to provide, in an interim
final rule published elsewhere in this issue of the Federal Register, a
procedure that allows for submission to, and review by, FDA of an
alternative to the required 100 percent identity testing of components
that are dietary ingredients, provided certain conditions are met.
In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12198),
we explained that we would not permit firms to rely upon supplier
certifications. The decision was based, in large part, on problems that
have occurred with faulty certificates in the past. We have, however,
reconsidered our position on certificates for specifications, other
than for the identity of the dietary ingredients, based on comments
discussing how firms have taken steps to ensure that their certificates
are reliable. We believe that the minimum criteria that we are
establishing for a certificate of analysis, together with the
requirement that a firm relying on a certificate of analysis must
qualify a supplier and periodically repeat that qualification process,
can prevent the problems that have occurred with faulty certificates in
the past. Therefore, for component specifications, other than the
identity of a dietary ingredient, including confirming the identity of
components that are not dietary ingredients, we are permitting firms to
rely upon certificates of analysis provided by suppliers, if the
certificates meet the requirements of the final rule. Under final Sec.
111.75(a), a firm may rely upon a certificate of analysis from its
supplier of a component, provided that certain criteria are met which
include the following: (1) The
[[Page 34836]]
firm first qualifies the supplier by establishing the reliability of
the supplier's certificate of analysis through confirmation of the
results of the supplier's tests or examinations; (2) the certificate of
analysis includes a description of the test or examination method(s)
used, limits of the test or examinations, and actual results of the
tests or examinations; (3) the firm maintains documentation of how it
qualified the supplier; (4) the firm periodically reconfirms the
supplier's certificate of analysis; and (5) the firm's quality control
personnel review and approve the documentation setting forth the basis
for qualification (and requalification) of any supplier.
As we discussed in the preamble to the 2003 CGMP Proposal, in-
process controls are necessary to ensure that dietary supplements are
manufactured in accordance with their specifications (68 FR 12157 at
12197). Under final Sec. 111.75(b), firms must monitor the in-process
points, steps, or stages where control is necessary to ensure the
quality of the finished batch of the dietary supplement to: (1)
Determine whether the in-process specifications are met and (2) detect
any deviation or unanticipated occurrence that may result in a failure
to meet specifications. In addition, we have strengthened the
requirements for in-process controls by requiring that quality control
personnel conduct all required material reviews and make all required
disposition decisions using written procedures to ensure that
deviations or unanticipated occurrences that occur are consistently
handled.
Because of the strengthened requirements regarding component and
in-process specifications, the final rule permits testing of a subset
of finished batches rather than requiring testing of each finished
batch. Consistent with several suggestions in the comments, we built
more flexibility into the testing requirements so that a firm may test
a subset of finished dietary supplement batches that the firm
identifies through a sound statistical sampling plan for selected
specifications rather than test every batch of the finished dietary
supplement for every specification. Finally, quality control personnel
must review and approve any exceptions from testing requirements that
are allowed under the rule and the basis for such exceptions. This
approach is consistent with the comments that we received and will
achieve a high degree of integrity in the manufacturing process, while
at the same time provide flexibility to the industry.
Additional discussion on the requirements for identity testing of
dietary ingredients and the appropriate reliance on a certificate of
analysis for components other than dietary ingredients is found in this
section in response to comment 174.
C. Final Subpart E and Highlights of Changes to the Proposed
Regulations
The provisions in final subpart E reflect that the final rule
applies only to persons who manufacture, package, label, or hold a
dietary supplement unless subject to an exclusion in final Sec. 111.1.
The approach that we are incorporating into the final rule requires
changes in most of the individual paragraphs of proposed Sec. 111.35.
D. What Are the Requirements to Implement a Production and Process
Control System? (Final Sec. 111.55)
Final Sec. 111.55 requires you to implement a system of production
and process controls that covers all stages of manufacturing,
packaging, labeling, and holding of the dietary supplement to ensure
the quality of the dietary supplement and that the dietary supplement
is packaged and labeled as specified in the master manufacturing
record. Final Sec. 111.55 derives from proposed Sec. 111.35(a).
(Comment 146) A few comments say the production and process
controls outlined in proposed Sec. 111.35 are critical in ensuring
that dietary supplements meet specifications for identity, purity,
quality, strength, and composition. One comment recommends proposed
Sec. 111.35(a) be revised to state ``* * * that covers all stages of
manufacturing, packaging, labeling, and holding of * * * dietary
supplements that occur in your facility or for which you otherwise have
responsibility.'' This comment explains that the production of dietary
supplements is often broken up into several stages which are under the
control of different entities. The comment gives the following
examples: A marketing company may manufacture and package a product
itself; or it may contract with one company to manufacture and package
the product; or it may contract with one company to manufacture the
product and another company to package the product; and contract
manufacturers and packagers may subcontract portions of the
manufacturing or packaging.
(Response) We decline to revise the rule as suggested by the
comments. As we discussed in response to comment 37 in section VI of
this document, you must comply with the CGMP requirements that apply to
your operations related to the manufacturing, packaging, labeling, and
holding of dietary supplements. We decline to include codified language
that may not capture all of the possible relationships that exist in a
given operation.
E. What Are the Design Requirements for the Production and Process
Control System? (Final Sec. 111.60)
Final Sec. 111.60(a) requires that your production and in-process
control system be designed to ensure that the dietary supplement is
manufactured, packaged, labeled, and held in a manner that will ensure
the quality of the dietary supplement and that the dietary supplement
is packaged and labeled as specified in the master manufacturing
record. Final Sec. 111.60(b) requires that the production and in-
process control system include all requirements of subparts E through L
of part 111 and be reviewed and approved by quality control personnel.
Final Sec. 111.60(a) and (b) derive from proposed Sec. 111.35(b).
As discussed in section III of this document, we are clarifying a
number of provisions that did not explicitly identify labeling as an
operation that is covered by the rule. Final Sec. 111.60 is one such
provision. Under proposed Sec. 111.35(a) we would require that you
implement a system of production and process controls that covers all
stages of manufacturing, packaging, labeling, and holding of the
dietary supplements. In an oversight, proposed Sec. 111.35(b) would
require your production and in-process control system to be designed to
ensure that the dietary supplement is manufactured, packaged, and
held--but not labeled--in a manner that would prevent adulteration of
the dietary supplement. To correct this oversight, final Sec. 111.60
explicitly identifies labeling as an operation that the design of your
production and process control system must address.
(Comment 147) A few comments recommend that the phrase ``designed
to ensure'' in proposed Sec. 111.35(b) be deleted because it requires
that formal, prospective studies (similar to a process validation) must
be performed and such a requirement would be unduly burdensome.
(Response) We disagree with the comments' interpretation of the
proposed regulation and decline the request. Final Sec. 111.60(a)
relates to the overall design of your production and process control
system. It does not require validation based on scientific studies, but
rather that your process contain all the controls necessary to ensure
the quality of your dietary supplements and that the dietary supplement
is packaged and labeled as specified in the master manufacturing
record. The process, for example, must
[[Page 34837]]
ensure that the dietary supplement meets all specifications established
under Sec. 111.70(e).
F. What Are the Requirements for Quality Control Operations? (Final
Sec. 111.65)
Final Sec. 111.65 requires that you implement quality control
operations in your manufacturing, packaging, labeling, and holding
operations for producing the dietary supplement to ensure that these
operations are performed in a manner that ensures the quality of the
dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. Final Sec.
111.65 derives from proposed Sec. 111.35(c).
Proposed Sec. 111.35(c) referred to the role of the quality
control unit in manufacturing, packaging, and label operations--but not
in holding operations. This was an oversight. We, therefore, revised
proposed Sec. 111.35(c) to include ``holding'' as an operation that is
subject to the oversight of quality control personnel for consistency
with final Sec. 111.105 (proposed Sec. 111.37(a)), which provides for
the performance of quality control operations to ``ensure that your
manufacturing, packaging, label, and holding operations ensure the
quality of the dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record.''
(Comment 148) One comment recommends proposed Sec. 111.35(c) be
revised to state ``ensures that the * * * dietary supplement meets
manufacturing specifications for identity, purity, quality, strength,
and composition.''
(Response) We are not making this change because it is unnecessary
in the context of the provisions of final Sec. 111.65.
(Comment 149) One comment argues that proposed Sec. 111.35(c) is
too wordy and needs clarification. The comment recommends it be revised
to state ``You must use a quality control unit to ensure that the
dietary supplement meets specifications for identity, purity, quality,
strength, and composition.''
(Response) We disagree with this comment. The change requested by
the comment would emphasize a single responsibility of quality control
personnel (i.e., releasing final product) and would obscure the fact
that quality control personnel have a role in the design and conduct of
most of your operations.
(Comment 150) One comment recommends proposed Sec. 111.35(c) be
revised to state ``ensures that the * * * dietary supplement meets
specifications for identity, purity, quality, strength, and composition
as appropriate to protect the public health; and quality, strength, and
composition as appropriate for the * * * product.'' This comment states
it is confusing and unnecessary to require that all five of these
attributes be addressed for all dietary supplements. The comment also
states the term ``purity'' requires explanation because not all
ingredients or supplements are subject to the same types of
contamination.
(Response) We are not making any changes in the provision as
suggested by this comment. The comment provides no basis for the
assertion that the proposed requirement to use a quality control unit
to ensure that a dietary supplement meets specifications for identity,
purity, strength, and composition is confusing and unnecessary. In
section VI of this document, we explain that purity means that portion
or percentage of a dietary supplement that represents the intended
product.
G. What Specifications Must You Establish? (Final Sec. 111.70)
Final Sec. 111.70 derives from proposed Sec. Sec. 111.35(e), (f),
(g), and (k), 111.37(b)(11)(iv), and 111.70(c).
(Comment 151) Some comments state proposed Sec. 111.35(k), which
would require that you test or examine components and dietary
supplements for those types of contamination that may adulterate or
lead to adulteration, is more appropriate for, and should be
incorporated into, proposed Sec. 111.35(e) which would require, in
part, that you establish specifications for the identity, purity,
quality, strength, and composition of components that you receive and
of dietary supplements that you manufacture. The comments note this
suggestion would help simplify and eliminate some redundancy in
proposed Sec. 111.35. One comment would revise proposed Sec.
111.35(k) to state ``Purity specifications for purchased or
manufactured components and dietary supplements must be established for
those types of contamination which can reasonably be expected to affect
the component, ingredient, or supplement in question * * *.'' According
to the comment not all ingredients or supplements are subject to the
same types of contamination, and it would be unduly burdensome to
require that all ingredients and supplements be tested for all possible
contaminants (as opposed to all likely contaminants).
(Response) We agree that not all ingredients or dietary supplements
are subject to the same types of contamination. It would not be
practicable or necessary to require testing for all possible
contaminants for every dietary supplement, or for every component used
to manufacture a dietary supplement. As we explained in the 2003 CGMP
Proposal (68 FR 12157 at 12199 through 12200), the manufacturer has the
responsibility to determine what types of contamination are likely or
certain to contaminate a given product and to determine what types of
tests to conduct and when to test for such contamination. We explained
that botanicals are likely or certain to contain filth and
microorganisms of public health significance based on the areas in
which they are harvested (id.). As another example, fungal growth on a
botanical component can provide the environment for mycotoxin
production, especially aflatoxin (id.). If fungal growth is present,
the manufacturer would need to perform an appropriate test that can
detect the toxic substance. We stated that the manufacturer must be
aware of potential contamination, regardless of whether due to filth,
insects, microorganisms, or toxins and to test or examine, as
appropriate, the components and dietary supplements for those types of
contamination that may adulterate or that may lead to adulteration
(id.). Thus, the types of contamination that we were referring to in
proposed Sec. 111.35(k) are those that are likely or certain to be
present in or on components received, based on the nature of the
product, its source, handling prior to receipt by the facility, or
other reason, and not due to poor manufacturing practices that resulted
in their presence in the first instance.
It is the responsibility of the manufacturer to identify those
contaminants and to establish limits to prevent adulteration under
section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. For example,
if you manufacture a polysaccharide that derives from seaweed, it is
likely that you would include a limit on cadmium, because cadmium is a
common contaminant that can be present in marine-derived ingredients.
If you manufacture a polysaccharide that has a composition similar to
seaweed-derived polysaccharide, but derives from a land-based plant, it
is not likely that you would include a limit on cadmium, because
cadmium is not a common contaminant of land-based plants. Likewise, if
you manufacture a mineral that contains phosphates, it is likely that
you would include a limit on arsenic, because phosphates are generally
mined and arsenic is a common contaminant that can be present in
ingredients that
[[Page 34838]]
are mined. If you manufacture a mineral that does not include
ingredients that are mined, it is not likely that you would include a
limit on arsenic.
We agree that controlling contamination is critical to the quality
of the dietary supplement. However, we do not agree that the types of
contamination addressed by proposed Sec. 111.35(k) should be
considered as a purity specification. We have described purity in this
final rule to mean something that you intend to be present in the final
product. As explained in section VI of this document, purity means that
portion or percentage of a dietary supplement that represents the
intended product. For example, you may manufacture a dietary supplement
that uses a natural product such as fish oil to provide triglycerides
that are a source of the polyunsaturated fatty acids DHA and EPA. The
purity refers to the percent of the fish oil that is triglycerides.
(Note that if you are manufacturing fish oil to provide the fatty acids
DHA and EPA in the dietary supplement, the component specifications for
the fish oil must include a strength specification for DHA and EPA in
whatever amount you determine is necessary to meet the specification
for strength of DHA and EPA in the dietary supplement.) If the natural
product also contains lead, or other unwanted ingredients that may
adulterate or may lead to adulteration, you would have to establish
limits for such contaminants. Thus, to distinguish the proposed
requirement in Sec. 111.35(k), which relates to contaminants that may
be present on or in the components that you receive, from the
requirements related to specifications for desired characteristics of
identity, purity, strength, and composition, we are including a
separate requirement on establishing limits on such contaminants for
components that you receive (final Sec. 111.70(b)). We also include a
requirement for establishing an in-process specification for any point,
step, or stage in the master manufacturing record where control is
necessary to help ensure that specifications are met, as necessary, for
limits on contamination. In addition, we are including a requirement
for such limits on contaminants in the finished batch of dietary
supplement (or subset of finished batches) (final Sec. 111.70(e)) to
ensure that the manufacturing process has not adversely affected such
levels, e.g., has not contributed an additional source of such
contaminant or failed to remove the contaminant, when necessary. Such
limits would need to ensure the quality of the dietary supplement,
i.e., to ensure that the dietary supplement has been manufactured,
packaged, labeled, and held under conditions to prevent adulteration
under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
Thus, in addition to the presence of contaminants that may be in or
on components that you receive, there may be sources of contamination
that you need to control for in your facility. As discussed in this
section, you must establish specifications under final Sec. 111.70(a)
and (c) to prevent adulteration from such sources. The specifications
established under final Sec. 111.70(a) and (c) may or may not include
limits on such contaminants. By ``limits on those types of
contamination'' in final Sec. 111.70, we do not mean contamination
from, for example, the presence of rodent pellets or other filth that
would constitute an insanitary condition under section 402(a)(3) or
(a)(4) of the act, if such filth was present in your facility. You are
not allowed to establish specifications for limits on contaminants that
would otherwise adulterate your product under the act if such
contaminants were present.
Further, in proposed Sec. 111.35(k), we included a listing of the
types of contamination we considered to be applicable to dietary
supplements (68 12157 FR at 12258). We stated that the types of
contamination include: (1) Filth, insects, or other extraneous
material; (2) microorganisms; and (3) toxic substances. We have deleted
the listing of the types of contamination in the final rule because the
listing is simply informative and establishes no independent
requirement. We received several comments, discussed in the following
paragraphs, on the types of contamination that may be present, some
which were solicited by us in the 2003 CGMP Proposal (68 FR 12157 at
12179 through 12181).
In the 2003 CGMP Proposal, we solicited comment on whether we
should include in the final rule specific requirements for
manufacturing, packaging, or holding animal-derived dietary
ingredients, because animal-derived dietary ingredients present
important public health and safety issues.
In the 2003 CGMP Proposal, the example we used was an animal-
derived dietary ingredient potentially contaminated with the agent that
causes bovine spongiform encephalopathy (BSE), which is a type of
transmissible spongiform encephalopathy (TSE). TSEs are fatal,
neurodegenerative disorders, which have been identified in humans and a
number of animal species (e.g., cattle, sheep, goats, elk, deer, cats,
and mink), but primarily in ruminants (cattle, sheep, elk, deer) (69 FR
42256, July 14, 2004). Most scientists believe that variant Creutzfeldt
Jakob Disease (vCJD), a progressive neurological disease in humans, is
caused by consumption of cattle products contaminated with the agent
that causes BSE (69 FR 42256 at 42257).
In the 2003 CGMP Proposal (68 FR 12157 at 12180), we stated that we
had communicated with the public and manufacturers of FDA-regulated
products about appropriate steps to increase product safety and
minimize the risk of products contaminated with the BSE agent. We
referenced a notice in the Federal Register of August 29, 1994 (59 FR
44591), entitled ``Bovine-Derived Materials; Agency Letters to
Manufacturers of FDA-Regulated Products.'' We sent letters to dietary
supplements manufacturers to alert them to the developing concern about
TSEs in animals and Creutzfeldt-Jakob Disease in humans. We recommended
they investigate the source of any bovine and ovine material used in
their products. We suggested that manufacturers develop plans to
ensure, with a high degree of certainty, that bovine and ovine
materials used in their products were not from BSE countries or from
sheep flocks (foreign or domestic) infected with scrapie. We stated
that our Center for Biologics Evaluation and Research (CBER) had
developed guidances for industry that describe steps manufacturers
should take to ensure the safety and suitability for human use of
animal-derived biologics. We also stated that we were considering
whether the procedures that CBER recommends for a product with animal-
derived materials, substances, or tissues would be appropriate for
dietary ingredients and dietary supplements that contain animal-derived
materials, substances, or tissues. We believed that the use of an
animal-derived material, substance, or tissue in a dietary supplement
may raise many of the same serious public health and safety issues as
animal-derived materials, substances, or tissues, in a biologic. We
invited comment on whether there is a scientific basis for us to treat
animal-derived dietary ingredients in a manner different from, or that
would offer less protection than, what is recommended for animal-
derived biologics when the same public health and safety risks may be
present.
(Comment 152) Several comments state there should not be specific
requirements for manufacturing, packaging, or holding animal-derived
dietary ingredients because BSE issues
[[Page 34839]]
are not specific to dietary supplements, and because other guidance and
regulations, issued by FDA and by the U.S. Department of Agriculture
(USDA), already address BSE and public health. Other comments state it
would be appropriate to include specific CGMP requirements for BSE as
long as the requirements reflect the thinking in currently existing
regulations and guidance.
Several comments do not support the need for additional provisions
regarding the handling of imported animal-derived ingredients because
the industry has already taken steps to comply with the requirements or
recommendations issued by either USDA or FDA. The comments state that
the regulations issued by USDA for meat related products in the food
industry provide adequate control over the use of animal tissues that
might contain microorganisms, specifically viruses, of public health
concern.
One comment argues that if purchases of domestic raw tissues have
been inspected by USDA, it is unfair to impose additional regulations
simply because these tissues are included in dietary supplements. This
comment asserts it would be unfair to require testing of animal-derived
products given the fact that there are no tests for BSE available, and
that reliance on USDA and FDA is the best way to stop the spread of
BSE.
Another comment states that industry trade associations have been
working actively with their member companies to ensure adherence to the
requirements set forth in our various letters regarding the need to
develop plans ``that ensure, with a high degree of certainty'' that
animal-derived ingredients are used only in accordance with FDA and
USDA policies designed to protect against BSE. The comment states that
a summary of industry procurement and handling practices regarding
animal-derived ingredients (submitted to us) contains lists of animal-
derived ingredients used by various companies, with examples of the
certificates of origin and other documentation required for import of
any animal-derived materials. One comment states that industry members
who handle animal-derived ingredients already have implemented many of
the controls that originated either from USDA or the dietary ingredient
suppliers in response to demands by various governments or consumers,
and that such matters should remain with USDA to avoid duplication of
effort.
Some comments oppose any recommendation that guidance issued by
CBER for ensuring the safety and suitability for human use of animal-
derived biologics apply to dietary supplement products. One comment
includes a review of literature on BSE and claims the review justifies
not applying the CBER guidances on BSE to dietary supplement products
under part 111.
(Response) For cattle derived materials, you must comply with the
requirements of the interim final rule on BSE set forth in Sec. 189.5
(see 70 FR 53063, September 7, 2005) and any subsequent modifications.
Under the interim final rule, no human food, including dietary
supplements, shall be manufactured from, processed with, or otherwise
contain, prohibited cattle materials as defined in the rule. In
addition, manufacturers and processors of such food that is
manufactured from, processed with, or otherwise contains, cattle
material must make existing records relevant to compliance available to
us for inspection and copying. For both cattle-derived and other
animal-derived materials, you must comply with all applicable
provisions of this final rule. For example, under final Sec. 111.70,
you must establish specifications for any point, step, or stage in the
manufacturing process where control is necessary to ensure the quality
of the dietary supplement. Thus, you must establish specifications for
your animal-derived materials that are necessary to ensure the quality
of the dietary supplement. Ensuring quality includes preventing
contamination that may adulterate the product under section 402(a)(1),
(a)(2), (a)(3), or (a)(4) of the act. In addition, you must take
actions to determine whether the specifications are met (final Sec.
111.73). Therefore, if you used animal-derived materials other than
prohibited cattle materials subject to the BSE interim final rule, you
would need to establish specifications necessary to ensure the quality
of the dietary supplement.
The guidances issued by CBER are still in effect for animal-derived
biologics, and we continue to recommend that you use them as
appropriate for your products that contain animal-derived ingredients.
(Comment 153) One comment agrees with the provisions of proposed
Sec. 111.35(k) but requests that we provide guidance to the industry
on allowable limits for the types of contamination listed. Another
comment asks us to develop specific defect action levels (DALs) for
dietary supplements as more information becomes available, rather than
rely on existing DALs from the food industry.
(Response) In the 2003 CGMP Proposal (68 FR 12157 at 12163), we
stated that we were not identifying DALs for the types of contaminants
for dietary ingredients because there are not enough data available to
identify an appropriate DAL for most dietary ingredients. These
comments do not provide data, or evidence that data are available, to
enable us to issue guidance for DALs for specific contamination.
Therefore, we are not taking the action requested by these comments. We
discuss DALs in this section in response to comment 156.
(Comment 154) Some comments suggest the provisions in proposed
Sec. 111.35(k), testing for contamination that could adulterate a
product, would be more appropriate to include in proposed Sec.
111.35(e), which concerns the establishment of specifications.
(Response) We agree with these comments and are including
requirements to include limits on contamination in final Sec. 111.70.
The requirements set forth in final Sec. Sec. 111.70 and 111.75 are
consistent with this comment. Under final Sec. 111.70(b) you must
establish limits on those types of contamination that may adulterate or
may lead to adulteration of the finished batch of the dietary
supplement to ensure the quality of the dietary supplement. Under final
Sec. 111.70(c) you must establish in-process specifications for any
point, step, or stage in the master manufacturing record where control
is necessary to help ensure that specifications are met for the
identity, purity, strength, and composition of the dietary supplements,
and as necessary, limits on contamination for those types of
contamination that may adulterate or may lead to adulteration of the
finished batch of the dietary supplement. Under final Sec. 111.70(e),
you must establish product specifications for the identity, purity,
strength, and composition of the finished batch of the dietary
supplement, and for limits on those types of contamination that may
adulterate, or that may lead to adulteration of, the finished batch of
the dietary supplement to ensure the quality of the dietary supplement.
As we explained in the response to comment 151, by ``limits on those
types of contamination'' in final Sec. 111.70, we do not mean
contamination from, for example, the presence of rodent pellets or
other filth that would constitute an insanitary condition under section
402(a)(3) or (a)(4) of the act, if such filth was present in your
facility. You are not allowed to establish specifications for limits on
contaminants that would otherwise adulterate your product under the act
if such contaminants were present.
(Comment 155) Several comments object to proposed Sec. 111.35(k)
because
[[Page 34840]]
the provision would be more stringent than the food or drug CGMP
requirements. Some point out that the consumption levels for food are
higher than for dietary supplements. A few comments argue that proposed
Sec. 111.35(k) is too broad as it requires testing or examination for
those contaminants that ``may'' adulterate or ``may lead to''
adulteration, which could be interpreted to mean testing for unknown
contaminants of every description. The comments suggest that this
provision be revised to require testing or examination for those types
of contamination that ``may be present in an amount or at a level''
that may adulterate or lead to adulteration or that ``may reasonably be
expected'' to adulterate or lead to adulteration. Other comments agree
that to test for all possible contaminants would be burdensome.
Several comments state that manufacturers should be allowed to rely
on a supplier's certificate of analysis and that testing should not be
required for every potential contaminant. One comment recommends that
CGMPs should be specific to the source and that testing should depend
on the nature of the material.
Some comments note that for botanicals it is sometimes nearly
impossible to identify and analyze all naturally occurring substances.
(Response) The final rule does not include any specific
requirements to test or examine components or dietary supplements for
contamination. Rather, under final Sec. 111.70(b), (c), and (e), you
are required to establish specifications for limits on those types of
contamination that may adulterate or may lead to adulteration of the
finished batch of the dietary supplement. Under final Sec. 111.73, you
must determine whether the specifications established under Sec.
111.70 are met. Final Sec. 111.75(a) through (d) sets forth the
criteria you must use to determine whether the specifications that you
establish under final Sec. 111.70(b), (c), and (e) are met. Consistent
with these comments, under final Sec. 111.75(a) you may rely on a
certificate of analysis (other than for the identity of a dietary
ingredient) from a qualified supplier of components to ensure that
specifications that include limits on contamination are met, provided
you satisfy the criteria set forth in final Sec. 111.75(a). This would
include, for example, relying on a certificate of analysis to ensure
that the level of lead in each of your components would not adulterate
the dietary supplement.
In determining compliance with the requirements to set limits for
those types of contamination that may adulterate the dietary supplement
or lead to adulteration for received components, we would not expect
you to set limits for every potential contaminant or for every
naturally occurring constituent of a botanical. Rather, we agree with
the comments that the substances you would consider when determining
whether to set limits for particular types of contamination would vary
depending on the source of a component, such as a plant source, an
animal source, a microbial source, or a marine source.
(Comment 156) Some comments point out that some compounds, such as
mycotoxins, that are toxic at higher levels are detectable in nearly
all plant ingredients and are found in the food supply. A few comments
assert that dietary ingredients should not contain levels of certain
toxic compounds that are higher than reasonable or higher than
recognized maximum allowable limits as opposed to the zero tolerance
for toxic compounds contained in the 2003 CGMP Proposal.
One comment requests clarification of the term ``toxic
substances.'' One comment points out that information for identifying
potential adulterants is provided in monographs. Another comment
requests clarification on whether dietary supplement manufacturers will
be required to test for toxins while food manufacturers, who may use
some of the same ingredients, will not.
(Response) As the comments point out, the food supply does contain
some degree of contaminants such as mycotoxins that can be found, for
example, in certain grain. We do not have a ``zero tolerance'' policy
for such unavoidable contaminants but we have issued some regulations
and guidance to address certain common contaminants. We also have
issued a booklet entitled ``Action Levels For Poisonous Or Deleterious
Substances In Human Food And Animal Feed'' (Ref. 30; available at
http://www.cfsan.fda.gov). The booklet is a useful resource for
manufacturers who seek information about common contaminants that may
adulterate a dietary supplement product or lead to adulteration.
Another resource is the Foods Chemical Codex,\9\ which includes
monographs on many substances, such as salts that are used as sources
of minerals used in both dietary supplements and conventional food.
These monographs include limits on common contaminants, such as lead or
other heavy metals. In addition, the regulations in 21 CFR part 109
provide information about certain contaminants.
---------------------------------------------------------------------------
\9\The Food Chemicals Codex (FCC) project is an activity of the
Food and Nutrition Board of the Institute of Medicine. The FCC was
intended to provide standards for the purity of food chemicals and
thus promote uniform quality and ensure safety in the use of such
chemicals. The First Edition of the resulting FCC, published in
1966, was limited to chemicals added directly to foods to achieve a
desired technological function. Succeeding editions upgraded the
specifications for these substances and added specifications for
substances that come into contact with foods and some that are
regarded as foods, rather than as additives. The FCC is available
for purchase at 1-800-624-6242 or at http://www.nap.edu.
---------------------------------------------------------------------------
(Comment 157) One comment recommends that all finished products be
tested for microorganisms. Another comment contends the manufacturer
should be allowed to restrict testing to the raw material if the
facility and equipment are monitored for contamination. Some comments
point out that contaminants may be detectable in raw materials but not
in the finished product.
(Response) We disagree that all finished products must, as a matter
of course, be tested for contamination with microorganisms. Whether it
is necessary to test the finished product for microorganisms would
depend, for example, on the characteristics of your product, the nature
and source of your components, the specifications you establish for
microbial contaminants in your components and whether these
specifications are addressed in a certificate of analysis, the in-
process specifications you establish, and the nature of your
manufacturing process. However, these comments raise an important
point--i.e., that microbial contamination could occur at your facility
even if an incoming component is free of microorganisms. Final subpart
K discussed in section XVI of this document, sets forth requirements
for your manufacturing operations. Many of these requirements are
designed to limit the potential for contamination with microorganisms.
(Comment 158) Some comments would revise the requirements for
establishment of specifications for in-process controls (proposed Sec.
111.35(e)(2)) and the finished batch of dietary supplements (proposed
Sec. 111.35(e)(3)), so that specifications for attributes of quality,
strength, and composition are not required for a product that does not
purport to possess such attributes.
(Response) We decline to reword the provision as requested by these
comments. The requirement to establish specifications for strength and
composition relate to the manufacturers' responsibility to know what
their finished dietary supplement is
[[Page 34841]]
composed of so that their products are consistently manufactured.
Establishing specifications and following these CGMP requirements will
help ensure the quality of the dietary supplement. The requirement to
establish specifications is not limited to when a manufacturer purports
that its product possesses attributes of strength and composition on
the label. As discussed in the 2003 CGMP Proposal (68 FR 12157 at
12162), the absence of minimum standards has contributed to the
adulteration and misbranding of dietary supplements because of
contaminants or because manufacturers do not set and meet
specifications for their products, including specifications for
identity, purity, strength, and composition and do not set and meet
limits on contaminants, when necessary. The comment does not persuade
us otherwise. We note, however, that the final rule's requirements to
establish specifications for components do, in fact, provide
flexibility so that you are not required to establish a component
specification for certain attributes, such as the strength of a tablet
coating agent (see the discussion of final Sec. 111.70(b) in this
section).
(Comment 159) One comment asks for guidance as to what constitutes
an official or scientifically valid standard for specifications.
(Response) We are not aware of any officially recognized standard
for specifications. Specifications are critical standards that are
proposed and justified by the manufacturer for each product that the
manufacturer produces. The manufacturer establishes the set of criteria
to which a product should conform to be considered acceptable for its
intended use. In general, a specification may include a list of tests,
references to analytical procedures, and appropriate acceptance
criteria that are numerical limits, ranges, or other criteria for the
tests described.
(Comment 160) One comment asks that we clarify whether every
specification sheet must include separate, specific qualitative or
quantitative standards, and tests to be established for each attribute,
or whether a specification sheet can be modeled after a compendial
monograph. Some comments state that product specification sheets should
be modeled after pharmacopoeia monographs other than those listed in
the preamble to the 2003 CGMP Proposal.
(Response) These CGMP requirements do not establish any
requirements to have a ``specification sheet.'' Rather, the final rule
(final Sec. 111.70(a)) requires you to establish a specification for
any point, step, or stage in the manufacturing process where control is
necessary to ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record. We require that you establish specifications for
components (final Sec. 111.70(b)), in-process production (final Sec.
111.70(c)), labels and packaging (final Sec. 111.70(d)), the finished
batch of dietary supplement (final Sec. 111.70(e)), product that you
receive from a supplier for packaging and labeling (final Sec.
111.70(f)), and the packaging and labeling for the finished packaged
and labeled dietary supplement (final Sec. 111.70(g)). The general
requirement for establishing specifications in final Sec. 111.70(a)
includes specifications, not otherwise required in final Sec.
111.70(b) through (g), that the manufacturer determines are necessary
to achieve quality, i.e., that are necessary to meet the identity,
purity, strength, or composition of the dietary supplement or that are
necessary to prevent adulteration under section 402(a)(1), (a)(2),
(a)(3), and (a)(4) of the act.
Requirements to establish specifications to control for
contamination are included in final Sec. 111.70(a), (b), (c), and (e).
As discussed earlier, the specifications for contaminants in final
Sec. 111.70(b) refer to those types of contamination of a component or
dietary supplement that may adulterate or that may lead to adulteration
that are due to contaminants that may be present in or on the
components that you receive, based on the nature of the product, its
source, its handling prior to receipt, or other reason. Limits are
established by the manufacturer for such contaminants at receipt.
The requirement to establish specifications to control for
contamination under final Sec. 111.70(a) and (c) include
specifications necessary to prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act as a result of what
the manufacturer may do or fail to do in its manufacturing operation,
and not as a result of contaminants that are in or on the components
received. For example, it may be critical that a certain piece of
equipment be cleaned and/or sanitized after handling certain raw
materials to ensure that there is no microbial contamination from
microorganisms of public health significance to components processed on
the equipment. If the manufacturer failed to establish a specification
for cleaning and/or sanitizing after handling those raw materials
before processing components, the manufacturer would have failed to
establish a specification required by final Sec. 111.70(a) or (c)
necessary to prevent a type of contamination that may lead to
adulteration under section 402(a)(4) of the act. We would consider it a
failure to follow CGMP requirements if a manufacturer allowed
conditions in the manufacture of a dietary supplement that would not
ensure the quality of the dietary supplement.
We have specified in final Sec. 111.70(b) that you must establish
certain types of specifications that are critical to ensuring that you
know what the components are that you use in manufacturing a dietary
supplement and that are necessary to ensure that the dietary
supplements you manufacture meet their specifications for identity,
purity, strength, composition, and do not exceed their limits for
contaminants. The identity, purity, strength, and composition, and the
limits that you establish for contaminants, for a finished batch of
dietary supplement are what we call ``product specifications'' in final
Sec. 111.70(e). These product specifications must be met in order for
you to ensure the quality of your finished batch of dietary supplement.
A specification may include a list of tests, references to analytical
procedures, and appropriate acceptance criteria that are numerical
limits, ranges, or other criteria for the tests described. For example,
a specification for a component may include information about the test
used to verify the identity of the component and the range of test
results that are acceptable. Under final Sec. 111.70(c), a
specification for an in-process control may include information about
the viscosity that must be achieved during a batch production of a
liquid product and information about the test or equipment used to
measure the viscosity. Under final Sec. 111.70(d), a specification for
packaging may include the specific type or grade of plastic. Under
final Sec. 111.70(e), a specification for the finished batch may
include the quantitative amount of a dietary ingredient, such as
vitamin C.
Under this final rule, the manufacturer has the flexibility--and
the responsibility--to develop specifications that are appropriate to
the circumstances, including whether information in any particular
monograph is an appropriate model for a given dietary supplement.
1. Final Sec. 111.70(a)
Final Sec. 111.70(a) requires you to establish a specification for
any point, step, or stage in the manufacturing process where control is
necessary to
[[Page 34842]]
ensure the quality of the dietary supplement and that the dietary
supplement is packaged and labeled as specified in the master
manufacturing record. Final Sec. 111.70(a) derives from the opening
statement in proposed Sec. 111.35(e).
As we discussed in the preamble to the 2003 CGMP Proposal (68 FR
12157 at 12196), the points, steps, or stages where specifications must
be established may include heating steps, cooling steps, points where
specific sanitation procedures are needed, product formulation control
steps, points where cross-contamination may occur, and steps where
employee and environmental hygiene are necessary to ensure the quality
of the dietary supplement. These specifications are regulatory
specifications addressed by these CGMP regulations. The final rule does
not prevent you from establishing additional, nonregulatory
specifications that are not at points, steps, or stages where control
is necessary to ensure the quality of the dietary supplement. For
example, you could establish specifications that largely address the
appearance of the dietary supplement in an aesthetic sense. Such
nonregulatory specifications are not addressed by the final rule.
(Comment 161) One comment notes that labelers would not be subject
to proposed Sec. 111.35(e).
(Response) Consistent with final Sec. 111.1, persons who perform
labeling operations are, in fact, subject to the final rule, including
the requirements to establish specifications. As discussed in this
section, the final rule includes an explicit requirement that, if you
receive a product from a supplier for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier), you must establish specifications to ensure that the product
that you receive is adequately identified and is consistent with your
purchase order (final Sec. 111.70(f)).
(Comment 162) One comment asks whether the manufacturer determines
where control is ``necessary'' to prevent adulteration.
(Response) In accordance with the changes made to the section, the
manufacturer does determine where control is necessary to ensure the
quality of the dietary supplement.
(Comment 163) Some comments express concern that manufacturers who
must confirm the validity of subjective criteria established as
specifications may set the specifications as low as possible or set
meaningless specifications.
(Response) The specifications you must establish under this final
rule are designed to ensure the quality of the dietary supplement that
you manufacture. It is not meaningless to establish requirements that
will ensure, for example, the product meets the established
specifications for identity, purity, strength, and composition, and is
within specified limits on contaminants to prevent adulteration.
(Comment 164) Some comments express concern that the language of
proposed Sec. 111.35(e) may require specifications beyond those
already required in the master manufacturing record, as stated in
proposed Sec. 111.45(a)(1), to identify specifications for the points,
steps, or stages in the manufacturing process where control is
necessary to prevent adulteration, or may require specifications for
attributes that are not present at all stages. These comments urge us
to be flexible during inspections as to what specifications are
appropriate.
(Response) Final Sec. 111.70(a) provides the manufacturer with
flexibility in determining what specifications may be necessary for its
operation. Moreover, final Sec. 111.70(a) through (g) provide the
manufacturer with flexibility to determine what the specifications
require in order to ensure the quality of the dietary supplement.
2. Final Sec. 111.70(b)
Final Sec. 111.70(b) requires you to establish component
specifications for each component you use in the manufacture of a
dietary supplement. Under final Sec. 111.70(b)(1), you must establish
an identity specification for each component that you use in the
manufacture of a dietary supplement. A specification for identity may
include more than one attribute. For example, a specification for the
identity of a salt used in the manufacture of a vitamin and mineral
supplement may include the physical characteristics of the solid (e.g.,
as a crystal or as a powder), the color, and the state of hydration
(e.g., with two or three molecules of water). A specification for the
identity of a botanical may include the part of the plant (e.g., roots
or leaves), the color, and whether the part of the plant is in a native
state or has been ground. Under final Sec. 111.70(b)(2), you must
establish component specifications that are necessary to ensure that
specifications for the purity, strength, and composition of dietary
supplements manufactured using the components are met. Under final
Sec. 111.70(b)(3) you must establish limits on those types of
contamination that may adulterate or may lead to adulteration of the
finished batch of the dietary supplement to ensure the quality of the
dietary supplement. Final Sec. 111.70(b) derives from proposed Sec.
111.35(e)(1) and (k). Final Sec. 111.70(b) is consistent with
comments, already discussed, that recommended the provisions of
proposed Sec. 111.35(k), regarding contaminants that could adulterate
a product, be incorporated into proposed Sec. 111.35(e). In addition,
as discussed previously with respect to final Sec. 111.55, final Sec.
111.70(b) provides that the required component specifications you must
establish for a dietary supplement include identity, purity, strength,
and composition.
(Comment 165) A few comments state it is appropriate and acceptable
to establish a requirement for a specification for the identity and
purity of components, insofar as such specifications are necessary to
ensure that components are not contaminated with substances having
public health significance. However, these comments argue that
specifications for quality, strength, and composition of components
should only be required for the quality, strength, and composition that
a component is purported to possess. One comment notes this would
provide the same requirement that is currently established for drug
products and processing. Some comments recommend that specifications
should be established ``as appropriate'' or ``where control is
necessary to assure production of a quality product.''
(Response) After considering the comments that questioned the need
to establish specifications for the identity, purity, quality,
strength, and composition of components, as well as the general
comments that led to the overall approach that focuses on building
quality into a dietary supplement at every stage of the production and
process control system (see discussion in section IV of this document),
we are requiring in final Sec. 111.70(b)(1) that you establish an
identity specification for components that you use. This identity
specification is necessary to ensure that the finished dietary
supplement meets its specification for identity because you could not
know what your final product contains if you do not know what you put
into it. In addition, final Sec. 111.70(b)(2) requires you to
establish those component specifications for purity, strength, and
composition that are necessary to ensure that specifications for the
purity, strength, and composition of dietary supplements manufactured
using the components are met.
Final Sec. 111.70(b)(2) provides flexibility for you to determine
which component specifications other than identity are, or are not,
necessary to
[[Page 34843]]
ensure that the final dietary supplement meets its specifications. For
example, it is likely that you will need to establish a specification
for the strength of vitamin C added as a component, that you use to
make a multivitamin supplement, so that you will know how much vitamin
C to add to satisfy the specification for the strength of the vitamin C
in the final product. Thus, if you are manufacturing a vitamin C tablet
with a strength of 50 milligrams (mg) per tablet, you must determine
how much vitamin C, of a given strength, you must add in order to
produce tablets that will contain 50 mg, after accounting for the
theoretical yield at each step in the manufacturing process. However,
you may not need to establish a specification for the strength of the
tablet coating agent for that multivitamin supplement, if your final
specifications include the amount of the tablet coating agent as part
of the specifications for the composition, but not the strength of the
multivitamin supplement. In most cases, a specification for the
composition of the dietary supplement would be sufficient to ensure
that the tablet coating agent is used within the established level.
(Comment 166) A few comments express concern about how to determine
certain specifications for botanicals, such as the strength of
peppermint leaf. The comments explain that a specification for strength
of peppermint leaf could be based on a number of different attributes.
One comment argues that establishing specifications for all dietary
ingredients may not contribute to any assurance of product quality and
will not protect public health. Some comments assert that ``quality,
strength, and composition'' are subjective with respect to botanical
ingredients for which no potency claim is made, and, thus, these
attributes should not be included in the rule. Another comment asserts
proposed Sec. 111.35(e)(1) goes beyond either food or drug CGMPs and
that the composition of approximately 1,200 botanicals used in the
industry will be impossible to determine in an economically feasible
manner.
(Response) To the extent that these comments assert that this final
rule should not require you to establish specifications for the
strength and composition of botanical ingredients, we disagree. As
explained in response to comment 145, it is fundamental to CGMPs that
you know what components are used to manufacture your dietary
supplement and to ensure that the finished batch of dietary supplement
contains the established identity, purity, strength, and composition.
As explained in response to comment 40, this final rule does not
require that you establish specifications for the identity, purity,
strength, or composition of the various constituents that are
inherently present in a natural product such as a botanical. However,
as previously discussed in section VI of this document, depending on
what you are manufacturing, the product specifications for the finished
batch of a dietary supplement may include a specification, for example,
of the strength of a substance that is present in the dietary
supplement because it is a constituent of a natural product that you
add as a component. For example, you may establish a specification for
the amount of vitamin C in a dietary supplement that you manufacture by
adding the component rose hips. If this is the case, then the component
specifications for the natural product must include a specification for
the strength of the constituent (e.g., vitamin C) in whatever amount
you determine is necessary to meet the specification for the
constituent (vitamin C) in the finished batch of dietary supplement.
(Comment 167) One comment asserts it would be more appropriate for
proposed Sec. 111.35(e)(1) to address components ``that you purchase''
than to address components ``that you receive,'' because customers
sometimes provide the ingredient or product to be processed and the
customer, rather than the manufacturer, establishes the specifications.
(Response) Final Sec. 111.70(b) (derived from proposed Sec.
111.35(e)(2)) requires that component specifications be established for
each component that you use in the manufacture of a dietary supplement.
Thus, the firm must establish specifications for the components it uses
to manufacture a dietary supplement, regardless of whether it
manufactures the components itself or contracts with another firm to
manufacture the components. The firm that conducts the manufacturing
operations, as explained in section VI of this document, would be
responsible for complying with all relevant CGMP requirements in this
final rule related to its operations.
(Comment 168) One comment asserts that proposed Sec. 111.35(e)(1)
is unnecessary because the requirements for testing to meet the
manufacturer's specifications are described elsewhere.
(Response) We disagree. The requirements to establish
specifications are distinct from what you must do to determine whether
specifications are met. Under the final rule (Sec. 111.73), you have a
responsibility to determine whether the established specifications are
met. What criteria you must use in order to determine whether
specifications are met are set forth in final Sec. 111.75.
3. Final Sec. 111.70(c)
Final Sec. 111.70(c)(1) requires you, for in-process production,
to establish in-process specifications for any point, step, or stage in
the master manufacturing record where control is necessary to help
ensure that specifications are met for the identity, purity, strength,
and composition of the dietary supplements and, as necessary, for
limits on those types of contamination that may adulterate or may lead
to adulteration of the finished batch of the dietary supplement. Final
Sec. 111.70(c)(1) derives from proposed Sec. 111.35(e)(2). Final
Sec. 111.70(c)(1) includes a nonsubstantive, editorial change that we
are making for consistency with other regulations in part 111. This
change is to refer to ``in-process specifications for any point, step,
or stage in the master manufacturing record where control is
necessary'' rather than ``in-process controls in the master
manufacturing record where control is necessary.''
We also have added that you must establish in-process
specifications, as necessary, for limits on those types of
contamination that may adulterate or may lead to adulteration of the
finished batch of the dietary supplement. This clarifies that if it is
necessary to establish limits on contaminants in-process, due to
contamination that may occur in the facility you do so under final
Sec. 111.70(c)(1). With a requirement to set, as necessary, limits on
contamination in-process, aspects of the production and process system
from receipt to finished product are covered with respect to
contamination. For example, under final Sec. 111.70(e) you may
determine that you need to establish a microbiological specification
that the aerobic plate count of your finished batch of the dietary
supplement will not exceed a certain number of colony forming units per
gram of product. Under the written instructions in your master
manufacturing record (final Sec. 111.210(h)) and your written
procedures for manufacturing operations (final Sec. 111.353), you
would establish controls to prevent microbial contamination at each
point, step, or stage in the manufacturing process where control is
necessary to prevent microbial contamination. To ensure that you will
meet the microbiological specification that you set for the finished
batch of the dietary supplement, you may determine that it is necessary
to establish a specification
[[Page 34844]]
for the aerobic plate count at an intermediate stage of the in-process
production.
Final Sec. 111.70(c)(2) requires you, for in-process production,
to provide adequate documentation of your basis for why meeting the in-
process specifications, in combination with meeting component
specifications, will help ensure that the specifications are met for
identity, purity, strength, and composition of the dietary supplements
and for limits on those types of contamination that may adulterate or
may lead to adulteration of the finished batch of the dietary
supplement. Final Sec. 111.70(c)(3) requires that quality control
personnel review and approve the documentation you provide under final
Sec. 111.70(c)(2). Final Sec. 111.70(c)(3) also derives in part from
proposed Sec. 111.37(b)(1) which would require the quality control
unit to approve or reject all processes that may affect the identity,
purity, strength, or composition of a dietary supplement.
In final Sec. 111.70(c)(2), we are requiring documentation that
includes the basis for why meeting the in-process specifications, in
combination with meeting the component specifications will help ensure
the specifications for the identity, purity, strength, and composition
of the dietary supplement and limits on contamination are met. Meeting
in-process specifications alone may not ensure the identity, purity,
strength, or composition of the dietary supplement, but information
about the component specification may be needed in order to put the
results from the in-process specification in perspective. For example,
if the manufacturer establishes a component specification for lead that
it not be greater than ``x'' mg and establishes a specification that
all piping that comes into contact with the component be lead free in
the facility, and there are no other components or equipment that would
be a source of lead, then there should be no added lead from
processing, provided that the material only came in contact with the
lead-free pipes and only the other lead-free components and equipment
are used. Thus, we would not know by looking solely at the in-process
specification whether the lead in the final product is not greater than
``x'' mg. We would need to evaluate the component specification, in
addition to the in-process specification, to ensure that the final
product contains no greater than ``x'' mg lead. To emphasize the
interplay of the specifications and component specifications in
ensuring the specifications are met for the identity, purity, strength,
and composition of dietary supplements, and, as necessary, for limits
on contamination, final Sec. 111.70(c)(1) and (c)(2) state ``help
ensure'' rather then ``ensure'' the identity, purity, strength, and
composition of dietary supplements and for limits on contamination.
(Comment 169) One comment asserts monitoring and process controls
are more practical and effective than the proposed requirements for in-
process testing, which the comment asserts are overly broad and could
impose an undue burden on small businesses.
(Response) The comment's objection is unclear. The final rule
requires that you establish in-process specifications for any point,
step, or stage in the master manufacturing record where control is
necessary in the manufacturing process to help ensure that
specifications are met for the identity, purity, strength, and
composition of the dietary supplement and, as necessary, for limits on
contamination. You must monitor the in-process points, steps, or
stages, where control is necessary to ensure the quality of the
finished batch of dietary supplement, to determine whether the in-
process specifications are met and to detect any deviation or
unanticipated occurrence that may result in a failure to meet
specifications (see final Sec. 111.75(b)). The final rule does not
establish specific requirements for in-process monitoring. The
manufacturer must determine any in-process monitoring that is necessary
to ensure that the specifications are met for the finished batch.
Examples of such monitoring include measuring pH or viscosity.
4. Final Sec. 111.70(d)
Final Sec. 111.70(d) requires you to establish specifications for
dietary supplement labels (label specifications) and for packaging that
may come in contact with dietary supplements (packaging
specifications). Final Sec. 111.70(d) derives from proposed Sec.
111.35(e)(4). Further, Sec. 111.70(d) requires that packaging that may
come into contact with dietary supplements must be safe and suitable
for its intended use and must not be reactive or absorptive or
otherwise affect the safety or quality of the dietary supplements,
consistent with proposed Sec. 111.35(e)(4). We deleted the phrase
``comply with other statutory and regulatory provisions'' from proposed
Sec. 111.35(e)(4) because the requirement was redundant to final Sec.
111.5.
5. Final Sec. 111.70(e)
Final Sec. 111.70(e) requires you, for each dietary supplement
that you manufacture, to establish product specifications for the
identity, purity, strength, and composition of the finished batch of
the dietary supplement, and for limits on those types of contamination
that may adulterate or may lead to adulteration of the finished batch
of the dietary supplement, all to ensure the quality of the dietary
supplement. Final Sec. 111.70(e) derives from proposed Sec.
111.35(e)(3) and (k). Final Sec. 111.70(e) is consistent with
comments, already discussed, recommending that the provisions of
proposed Sec. 111.35(k) regarding contaminants that could adulterate a
product be incorporated into proposed Sec. 111.35(e).
6. Final Sec. 111.70(f)
Final Sec. 111.70(f) requires you, if you receive a product from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier), to establish
specifications to provide sufficient assurance that the product you
receive is adequately identified and is consistent with your purchase
order. Final Sec. 111.70(f) derives from proposed Sec. 111.35(e)(1)
which would, in part, require you to establish specifications for
dietary supplements that you receive. Final Sec. 111.70(f) includes
changes we are making after considering comments.
(Comment 170) One comment notes that labelers would not be subject
to proposed Sec. 111.35(e). Other comments request we clarify the
roles of the various parties in the ``pre-consumer supply chain'' for
dietary supplements. One comment suggests that manufacturers and
packagers be responsible for establishing specifications only for the
operations occurring in their own facility or for which they are
otherwise responsible (e.g., subcontracted operations), not for
upstream or downstream operations over which they may not have any
control. This comment states that we intended to relieve packagers from
establishing specifications for the dietary supplements that they
package, and also states that such requirements should not be in the
CGMP regulations.
(Response) We have discussed, in section VI of this document, who
is subject to the final rule under Sec. 111.1 in what the comment
describes as the ``pre-consumer supply chain'' and do not repeat that
discussion. We agree that packagers and labelers must establish
specifications for the dietary supplements that they package and did
not intend to relieve them of complying with relevant CGMP
requirements. We recognize that a firm that only packages and labels a
product may rely on
[[Page 34845]]
information about the content of the product that it receives from the
manufacturer. The information may consist of an invoice, certificate,
guarantee, or other form of verification as to what the product
consists of so that the packager or labeler has adequate information
about the dietary supplement it receives to label the product and to
ensure that the product is consistent with its purchase order.
Therefore, we are setting forth certain requirements that distinguish a
product you receive for packaging or labeling as a dietary supplement
(and for distribution rather than for return to the supplier) from a
product you manufacture. One such requirement is final Sec. 111.70(f)
which requires you to establish specifications for a product you
receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier).
The inclusion of final Sec. 111.70(f), or any other provision that
relates explicitly to a product you receive for packaging or labeling
as a dietary supplement, does not alter the fact that such a product is
no different from any other dietary supplement as far as the
applicability of these CGMP requirements.
Under final Sec. 111.70(f), the specifications you establish for a
product you receive for packaging or labeling as a dietary supplement
must provide sufficient assurance that the received product is
adequately identified and is consistent with your purchase order. For
example, you may be purchasing tablets that provide 500 mg (strength)
(quantitative amount per serving) of vitamin C (identity). Therefore,
your purchase order would need to include the identity and amount of
vitamin C per tablet to distinguish it from other tablets of vitamin C
that may contain only 60 mg, or from other vitamin tablets of 500 mg
that you may also purchase.
Final Sec. 111.70(f) sets forth a requirement for a product you
receive for packaging or labeling as a dietary supplement that will be
distributed by you, rather than returned to the firm from which you
receive the product. Thus, Sec. 111.70(f) applies to product that has
left the control of the person who manufactured the batch.
If you are a packager or labeler who packages and labels for the
manufacturer and you will return the packaged and labeled dietary
supplement to the manufacturer, we would not consider that you are
``receiving'' product within the meaning of final Sec. 111.70(f).
Thus, you would not be subject to final Sec. 111.70(f).
(Comment 171) Some comments assert that ``packaging'' should be
included with ``manufacturing process,'' but that a firm involved only
in ``holding'' a product should not have to set specifications.
(Response) Under final Sec. 111.70(a), a person who holds packaged
and labeled dietary supplements for distribution and who does no
manufacturing, packaging, or labeling, would be required to establish a
specification for any point, step, or stage in the manufacturing
process where control is necessary to ensure the quality of the dietary
supplement. For example, a person may need to establish a specification
for the temperature at which the product will be held. However, a
person who only holds packaged and labeled dietary supplements for
distribution is not required to establish component specifications
(final Sec. 111.70(b)), in-process specifications (final Sec.
111.70(c)), specifications for labels and for packaging (final Sec.
111.70(d)), product specifications (final Sec. 111.70(e)),
specifications for product received from a supplier for packaging as a
dietary supplement (and for distribution rather than for return to the
supplier) (final Sec. 111.70(f)), or specifications for the packaging
and labeling of the finished packaged and labeled dietary supplements
(final Sec. 111.70(g)) because the person does not engage in any of
those activities. This is consistent with the views expressed by the
comments regarding the applicability of proposed Sec. 111.35(e) to
persons who only hold packaged and labeled dietary supplements for
distribution.
7. Final Sec. 111.70(g)
Final Sec. 111.70(g) requires you to establish specifications for
the packaging and labeling of the finished packaged and labeled dietary
supplements, including specifications that ensure you used the
specified packaging and you applied the specified label.
Final Sec. 111.70(g) is a new provision we are adding for clarity
and consistency. We had proposed to require that you conduct a material
review and make a disposition decision of any packaged and labeled
dietary supplements that do not meet specifications (proposed Sec.
111.70(c)). We proposed minimum standards for packaged and labeled
dietary supplements--i.e., we would require that the quality control
unit collect representative samples of each batch of packaged and
labeled dietary supplements to determine whether you used the packaging
specified in the master manufacturing record and applied the label
specified in the master manufacturing record (proposed Sec.
111.37(b)(11)(iv)). Final Sec. 111.70(g) includes the minimum
standards that we proposed to establish for packaged and labeled
dietary supplements in proposed Sec. 111.37(b)(11)(iv).
To make clear that the use of packaging and labels for a final
packaged and labeled product must be that which is specified in the
master manufacturing record, we have created a separate provision
(under final Sec. 111.70(g)) requiring you to create the relevant
specifications to be met.
Final Sec. 111.70(g) requires you to establish specifications that
ensure you use the ``specified packaging'' and to apply the ``specified
label'' as we proposed under proposed Sec. 111.37(b)(11)(iv). We
removed the words ``specified in the master manufacturing record'' as
an editorial change that we are making to simplify the language of the
requirement.
As already explained (see discussion of final Sec. 111.70(a)), the
specifications you establish under final Sec. 111.70 are regulatory
specifications required by these final CGMP requirements. The final
rule would not prevent you from establishing additional, nonregulatory
specifications, such as specifications that largely address the
appearance of the dietary supplement in an aesthetic sense.
H. What is Your Responsibility for Determining Whether Established
Specifications Are Met? (Final Sec. 111.73)
Final Sec. 111.73 requires you to determine whether all
specifications you establish under final Sec. 111.70 are met. The
criteria for determining whether the specifications that you establish
under final Sec. 111.70 are met are set forth in final Sec. 111.75.
The oversight by quality control personnel for determining whether
specifications established under final Sec. 111.70 are met in
accordance with the criteria established under final Sec. 111.75 and
under what conditions quality control personnel can approve deviations
from specifications are set forth in final Sec. 111.77 and final
subpart F. Although final Sec. 111.73 requires you to determine
whether specifications are met, it is the responsibility of quality
control personnel to conduct a material review and make a disposition
decision if a specification established in accordance with final Sec.
111.70 is not met.
Final Sec. 111.73 derives, in part, from proposed Sec. 111.35(f),
(g), and (h). Final Sec. 111.73 includes changes associated with
reorganization, and other revisions associated with final Sec. 111.70.
Final Sec. 111.73 neither includes any finished
[[Page 34846]]
batch testing requirements that derive from proposed Sec. 111.35(g)(3)
nor specifies what you must do to determine whether all specifications
are met because the requirements for what means and methods you must
use to determine whether specifications are met, including certain
requirements for testing, are set forth in final Sec. 111.75.
The comments relevant to final Sec. 111.73 are the general
comments that recommend an overall approach that focuses on building
quality into a dietary supplement throughout the production and process
control system. Because the primary focus of the relevant comments is
on the proposed requirements for testing, we discuss those comments
when we describe the derivation of the testing requirements in final
Sec. 111.75.
I. What Must You Do to Determine Whether Specifications Are Met? (Final
Sec. 111.75)
Final Sec. 111.75 derives from proposed Sec. Sec. 111.35(f), (g),
(h), (k), and (l); 111.37(b)(11); and 111.40(a) and (b). Final Sec.
111.75 describes the steps you must take to determine whether
specifications are met.
(Comment 172) Many comments assert that the CGMPs for dietary
supplements should place greater emphasis on in-process controls and
HACCP principles. The comments state FDA's narrow focus on finished
product testing is not in line with the philosophy of HACCP, in which
manufacturing steps are controlled and verified so as to result in end
products that are safe, with minimal finished product testing. One
comment cites a 1997 document entitled ``Hazard Analysis and Critical
Control Point Principles and Application Guidelines'' in which we state
that ``[A]n effective HACCP system requires little end-product testing,
since sufficient validated safeguards are built-in early in the
process.'' (Ref. 31).
(Response) In the 1997 ANPRM, we asked for comments on whether
certain, or all, of the requirements for manufacturing and handling
dietary ingredients and dietary supplements may be more effectively
addressed by a regulation based on the principles of HACCP, rather than
the system outlined in the industry submission (62 FR 5700 at 5708).
HACCP is a science-based, systematic approach to preventing food safety
problems by anticipating how such problems are most likely to occur and
by installing effective measures to prevent them from occurring. The
HACCP concept is a systematic approach to the identification and the
assessment of risk (likelihood of occurrence and severity), and control
of the biological, chemical, and physical hazards associated with a
particular food production process or practice. HACCP is a preventive
strategy. It is based on development by the food producer of a plan
that anticipates food safety hazards and identifies the points in the
production process where a failure would likely result in a hazard
being created or allowed to persist; these points are referred to as
critical control points (CCPs).
Under HACCP, identified CCPs are systematically monitored, and
records kept of that monitoring. Corrective actions are taken when
control of a CCP is lost, including proper disposition of the food
produced during that period, and these actions are documented. Thus,
the focus of a HACCP-based approach is to anticipate food safety
hazards, take actions to prevent them, and keep records of both the
actions taken to prevent problems and the actions taken if a problem
nonetheless occurs.
As discussed in the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12174), most of the comments that we received to the ANPRM opposed
basing a CGMP regulation for dietary supplements on HACCP principles.
Consistent with those comments, we proposed certain requirements that,
although consistent with a HACCP-based approach, did not require a
HACCP-based approach. For example, proposed Sec. 111.65 would
establish requirements for manufacturing operations, including several
proposed requirements to prevent contamination of components or dietary
supplements, but would not require that you develop a specific plan for
the precautions that you would take, or that you keep records of any
monitoring that was directed solely at preventing specific types of
contamination.
In contrast to the specific focus of HACCP to anticipate food
safety hazards, take actions to prevent them, and keep records of both
the actions taken to prevent problems and the actions taken if a
problem nonetheless occurs, CGMP requires that you take all necessary
steps to both prevent hazards and ensure that the product that you
manufacture is what you established in your specifications. The
proposed testing requirements were directed at ensuring that a dietary
supplement meets all of its established specifications, including
specifications for the identity, purity, strength, and composition,
rather than on ensuring only that specific food safety hazards that you
take steps to prevent are not, in fact, present in the dietary
supplement. The comments that assert that the CGMP requirements should
place greater emphasis on HACCP principles and, in so doing, reduce the
requirements to test product at the finished batch stage, did not
explain how the preventive measures that are associated with a HACCP
plan would be effective at ensuring that a dietary supplement is what
you established it to be in your specifications. Therefore, we are not,
as the comments request, including additional HACCP requirements as
part of the overall approach set forth in this final rule.
In the 2003 CGMP Proposal, we noted that you may voluntarily choose
to implement a HACCP plan that meets the requirements of the National
Advisory Committee on Microbiological Criteria for Foods, but that
proposed part 111 would still apply to you (68 FR 12157 at 12174). We
also noted that any HACCP plans that are intended to meet the records
requirements under proposed part 111 would be treated as records under
the CGMP regulations.
(Comment 173) One comment states that it supports a requirement
that a firm ensure that specifications have been met and asserts that
the 2003 CGMP Proposal failed to do so. This comment asserts the
specific testing requirements in proposed Sec. 111.35(g)(1) and (g)(2)
must be significantly modified and suggests that a more effective
approach would be to establish separate requirements for ensuring that
specifications are met in each of the four categories addressed by
proposed Sec. 111.35(e): Goods received (Sec. 111.35(e)(1)), in-
process controls (Sec. 111.35(e)(2)), manufactured goods (Sec.
111.35(e)(3)), and labels and packaging (Sec. 111.35(e)(4)).
(Response) The final rule is consistent with this comment. Final
Sec. 111.70 requires you to establish certain specifications
(including specifications for components, in-process controls, the
finished batch and packaging and labels), and final Sec. 111.75 sets
forth the requirements for what you must do to determine whether those
specifications are met.
1. Final Sec. 111.75(a)
Final Sec. 111.75(a)(1) requires you, before you use a component
that is a dietary ingredient, to conduct at least one appropriate test
or examination to verify the identity of the dietary ingredient. We
recognize, however, that it may be possible for a manufacturer to
demonstrate, through various methods and processes in use over time for
its particular operation, that a system of less than 100 percent
identity testing would provide no material diminution
[[Page 34847]]
of assurance of the identity of the dietary ingredient as compared to
the assurance provided by 100 percent identity testing. To provide an
opportunity for a manufacturer to make such a showing and reduce the
frequency of identity testing of components that are dietary
ingredients from 100 percent to some lower frequency, we decided to
provide, in an interim final rule published elsewhere in this issue of
the Federal Register, a procedure that allows for submission to, and
review by, FDA of an alternative to the required 100 percent identity
testing of components that are dietary ingredients, provided certain
conditions are met.
Final Sec. 111.75(a)(2) requires you, before you use a component,
to confirm the identity of other components and determine whether other
applicable component specifications established in accordance with
Sec. 111.70(b) are met. To do so, final Sec. 111.75(a)(2) requires
you to either conduct appropriate tests or examinations (final Sec.
111.75(a)(2)(i)); or rely on a certificate of analysis from the suppler
of the component that you receive (final Sec. 111.75(a)(2)(ii)). Final
Sec. 111.75(a)(2)(ii) sets forth the criteria that you must satisfy in
order to rely on a certificate of analysis from a supplier:
You must first qualify the supplier by establishing the
reliability of the supplier's certificate of analysis through
confirmation of the results of the supplier's tests or examinations;
The certificate of analysis must include a description of
the test or examination method(s) used, limits of the test or
examinations, and actual results of the tests or examinations;
You must maintain documentation of how you qualified the
supplier;
You must periodically re-confirm the supplier's
certificate of analysis; and
Quality control personnel must review and approve the
documentation setting forth the basis for qualification (and re-
qualification) of any supplier.
Final Sec. 111.75(a)(1) and (a)(2) derive, in part, from proposed
Sec. 111.35(g) and (h) and proposed Sec. 111.40(a)(2) and (a)(3).
Final Sec. 111.75(a)(1) and (a)(2) include changes that we are making
after considering comments to proposed Sec. Sec. 111.35 and 111.40(a).
(Comment 174) Many comments assert that a certificate of analysis
from a properly certified supplier can be a key element of the
manufacturing process, and reduce the need for testing at the finished
batch stage. Some comments specifically recommend the dietary
supplement manufacturer conduct identity tests to ensure that the
correct component has been received (also, see comment 145 of this
document).
Some comments recommend an appropriate vendor qualification
program, including a combination of vendor audits and product testing,
to alleviate the need for complete testing of every lot of incoming
components.
Several comments stress that a meaningful certificate of analysis
must be based on the results of actual analytical testing. One comment
adds that reliance on a supplier's certificate of analysis should be
conditioned on a qualification program whereby the recipient
independently verifies the supplier's ability to conduct tests and
verifies test results through confirmatory testing.
Many comments provide suggestions for ways in which manufacturers
could demonstrate the reliability of a certificate of analysis, which
include the following: (1) Identity testing of ingredients and
components, (2) maintenance of documentation of appropriate test
results, (3) appropriate verification of the information provided
initially and at appropriate intervals, and (4) documentation that any
suppliers have adequate CGMP programs in place.
Some comments recommend that vendor certification programs include
plant visits and inspections, while other comments do not believe
manufacturers should be required to conduct plant inspections. Other
comments recommend that vendor certification programs include CGMP
audits or process reviews at supplier facilities; verification of
laboratory test results against a certificate of analysis; and 100
percent inspection and testing of incoming materials for a specified
period of time while reliability is being assessed.
Some comments provide suggestions for the types of information that
should be included on an acceptable certificate of analysis, such as
moisture, sieve analysis, identity, and results of tests against
established raw material specifications and specifications of any
compendia referenced on the label. One comment suggests that a
certificate of analysis could be converted into sworn affidavits to
guarantee their reliability. Some comments suggest that a system of
testing one batch for agreement with the certificate of analysis, and
then relying on this information for future purchases, would work well
if the suppliers are required to provide reliable and valid certificate
of analysis documents. One comment suggests we issue guidelines as to
what should be included in a properly verified certificate of analysis.
Some comments address the requirement in proposed Sec.
111.40(a)(2) to ``Visually examine the suppliers invoice, guarantee, or
certification * * * and perform testing, as needed, to determine
whether specifications are met.'' One comment agrees with this proposed
requirement and asserts that the supplier's certification is not
sufficient to ensure that appropriate standards are met. Other
comments, however, disagree with this aspect of the proposed
requirement or ask for further clarification. A few comments assert
that manufacturers should not have to retest material already tested by
a supplier. Some comments note that a certificate of analysis can be
used for ensuring received materials are consistent with the purchase
order, and assert the certificate of analysis can be an appropriate way
to ensure specifications are met without requiring testing. One comment
suggests the phrase ``perform testing, as needed'' be replaced with
``perform testing, if necessary'' and that the CGMP regulations allow
for the use of a certificate of analysis that has been verified through
a vendor certification process. Another comment states that the
provisions requiring testing in proposed Sec. 111.40(a)(2) are more
burdensome than those required of food and pharmaceutical products and
cites the drug CGMP provision that permits the use of certificates of
analysis in lieu of testing for conformity with written specifications.
One comment supports the idea of testing upon receipt in the specific
circumstance when testing cannot be performed on the finished product.
Several comments contend that there is a conflict between the 2003
CGMP Proposal and our position during our stakeholder meetings. The
comments assert that, at the meetings, FDA representatives recognized
that a verified certificate of analysis is acceptable, provided it is
based on appropriate testing from suppliers who are audited by their
customers as to their testing and manufacturing practices.
A few comments say the 2003 CGMP Proposal should allow more
reliance on strict chain of custody and documentation requirements.
Other comments recommend that manufacturers not be required to retest
previously tested incoming ingredients if they arrive with the vendor's
seal intact. Rather, the purchaser should be able to rely on the
vendor's test results, as presented in a verified certificate of
analysis, unless there has been a breach in quality control during
distribution and subsequent manufacture. One
[[Page 34848]]
comment notes the Canadian regulations for Natural Health Products
allow periodic testing of ingredients if a manufacturer has
satisfactory evidence that the raw materials sold to him/her are
consistently manufactured in compliance with established
specifications.
(Response) We agree that CGMP requires that a person who
manufactures a dietary supplement conduct at least one appropriate test
or examination to verify the identity of each dietary ingredient that
will be used in the manufacture of the dietary supplement. For example,
because some botanicals require microscopic examination and comparison
to a reference to be distinguished, and because suppliers of such
botanicals may manufacture several of these botanicals, it is important
to verify that a botanical that you receive from a supplier is the
correct botanical. In some cases, a single test or examination may be
all that is needed to verify the identity of a dietary ingredient; in
other cases, it may be necessary to conduct more than one test or
examination. It is the responsibility of the manufacturer to determine
the appropriate test(s) or examination(s) necessary to verify the
identity of a dietary ingredient.
The comments discussed the importance of testing all components for
identity and did not appear to limit their recommendation for
conducting identity tests to those components that are dietary
ingredients. Based on the comments, we conclude that many firms would
conduct an identity test for most ingredients and other components
rather than limit identity testing to dietary ingredients. However,
because dietary ingredients are the central defining ingredient of a
dietary supplement, final Sec. 111.75(a) only requires you to conduct
tests or examinations to verify the identity of any component that is a
dietary ingredient. As discussed previously in this section, we
recognize, however, that it may be possible for a manufacturer to
demonstrate, through various methods and processes in use over time for
its particular operation, that a system of less than 100 percent
identity testing would provide no material diminution of assurance of
the identity of the dietary ingredient as compared to the assurance
provided by 100 percent identity testing. To provide an opportunity for
a manufacturer to make such a showing and reduce the frequency of
identity testing of components that are dietary ingredients from 100
percent to some lower frequency, we decided to provide, in an interim
final rule published elsewhere in this issue of the Federal Register, a
procedure that allows for submission to, and review by, FDA of an
alternative to the required 100 percent identity testing of components
that are dietary ingredients, provided certain conditions are met. For
components other than dietary ingredients you must confirm the identity
of the component and you have the flexibility of relying on a
certificate of analysis, in lieu of conducting a test or examination,
to confirm identity. The preamble to the 2003 CGMP Proposal discussed
why we were not proposing that you could rely on a certificate of
analysis, but did not express a view as to whether the establishment of
minimum criteria for how you would qualify the supplier, and for what
must be included on the certificate of analysis, could alleviate our
concerns about whether the certificate of analysis could ensure certain
attributes of dietary supplements.
After considering the comments, we also are persuaded that it is
possible to rely on a certificate of analysis from the supplier, for
attributes other than identity of the dietary ingredient, provided you
satisfy certain minimum criteria set forth in final Sec.
111.75(a)(2)(ii). These criteria include qualifying the supplier,
maintaining documentation of how you qualified the supplier,
periodically reconfirming the supplier's certificate of analysis, and
having quality control personnel review and approve the documentation
setting forth the basis for qualifying the supplier. These criteria
also require that the certificate of analysis, at a minimum, includes a
description of the test or examination method(s) used, limits of the
tests or examinations, and the actual results of the tests or
examinations. Under final Sec. 111.75(a)(2)(ii)(A), to qualify the
supplier you must establish the reliability of the supplier's
certificate of analysis through confirmation of the supplier's tests or
examinations.
Certain comments request that we provide guidance on what should be
included in a certificate of analysis. As stated earlier in this
section, a certificate of analysis is a document, provided by the
supplier of a component prior to or upon receipt of the component, that
documents certain characteristics and attributes of the component.
Instead of guidance, we are establishing, in final Sec.
111.75(a)(2)(ii)(B), minimum criteria that a certificate of analysis
must meet to satisfy these CGMP requirements. As we gain experience in
applying the CGMP regulations, we will consider whether it is
appropriate to provide guidance on certificates of analysis.
(Comment 175) One comment asks if a raw material contains an
unknown amount of excipients, is it necessary to quantify the
excipients or can a company simply assess the active material and rely
on a vendor's specification for the excipient content?
(Response) To the extent that this comment is asking whether it is
necessary to set a component specification for the strength of
excipients that are present in a dietary supplement, the final rule
does not require you to do so provided that such a component
specification is not necessary to ensure that the specifications for
the purity, strength, composition, or contamination limit for the
dietary supplement manufactured using the excipients are met (final
Sec. 111.70(b)(2)). If such a strength specification for an excipient
is necessary to ensure that the purity, strength, or composition
specifications are met, or that a contamination limit is met for the
dietary supplement, you could, as the comment suggested, rely on a
certificate of analysis for that quantitative information provided that
you satisfy the criteria set forth in final Sec. 111.75(a).
2. Final Sec. 111.75(b)
Final Sec. 111.75(b) requires that you monitor the in-process
points, steps, or stages where control is necessary to ensure the
quality of the finished batch of dietary supplement, to determine
whether the in-process specifications are met, and to detect any
deviation or unanticipated occurrence that may result in a failure to
meet specifications. Final Sec. 111.75(b) derives from proposed Sec.
111.35(f) with revisions associated with final Sec. 111.70(c)(1).
(Comment 176) A few comments argue that it is not possible to
monitor in-process for those specifications required under proposed
Sec. 111.35(e). One comment states that a specification such as
identity is no longer identifiable at an in-process stage. This comment
also notes any such requirement in proposed Sec. 111.35(e) would be
redundant, because proposed Sec. 111.35(h) requires a firm to ensure,
through testing or examination, that all established specifications are
met. Another comment contends that some specifications are not met
until processing is complete, such as with liquid extracts. A few
comments recommend that the requirement for monitoring be limited to
ensuring that specifications established for in-process controls under
proposed Sec. 111.35(e)(2) and finished product under proposed Sec.
111.35(e)(3) are met.
[[Page 34849]]
One comment states it is not always possible for a manufacturer to
monitor for strength and purity of raw materials during in-process
steps. The comment suggests this proposed requirement be removed or
revised.
(Response) The comments may have misunderstood what we refer to as
``in-process'' specifications. Under final Sec. 111.75(b), you must
monitor the in-process points, steps, or stages where control is
necessary to ensure the quality of the finished batch of dietary
supplement, to determine whether the in-process specifications are met,
and to detect any deviation or occurrence that may result in a failure
to meet specifications. The in-process specifications that you
establish ensure that, for example, the specification for strength is
achieved. If you must deliver a certain amount of powdered vitamin C to
a mixture at a certain point in the process in order to achieve a final
product that contains 60 mg of vitamin C, a critical point in the
process is where ``x'' mg of vitamin C is added to ensure that the
final product contains 60 mg of vitamin C. You would monitor the
operation to ensure that ``x'' mg of vitamin C is added. Your strength
specification may be tested at the end of the process as a product
specification, but your in-process specification to ensure the addition
of ``x'' mg of vitamin C is a specification that is separate and
distinct from the specification that you establish for strength, i.e.,
60 mg vitamin C. You may determine that in-process specifications are
met through a test or examination. You could monitor for the vitamin C
product by checking the equipment you use to mix the vitamin C-
containing product to ensure that the mixing process was carried out
during the time period specified in the master manufacturing record to
ensure uniformity in the finished batch. Other examples could include a
measurement, such as checking pH during the course of a process, or
removing samples during the course of a process to conduct a test for
viscosity. There may be no need for certain in-process specifications
to ensure that specifications for identity, purity, strength, and
composition of the finished batch of dietary supplement are met. If
there are no in-process points, steps, or stages at which any test or
examination is needed to ensure that the identity specification for the
finished batch of dietary supplement is met, then you would not need to
establish an in-process specification to ensure identity in the
finished batch, and, therefore, would not need to conduct in-process
monitoring for identity.
(Comment 177) One comment requests clarification on what would be
considered ``in-process'' for materials that are simply blended
together to form a final product. The comment asks how a firm would
test the samples if a final material cannot be tested due to
interferences or lack of an available method.
(Response) Examples of in-process specifications when materials are
simply blended together are the mixing time and speed.
(Comment 178) One comment points out that in-process testing for
``unanticipated occurrences'' required under proposed Sec. 111.35(f)
would be difficult, because the manufacturer would not know what to
test for.
(Response) This comment may have misunderstood the provision, which
did not propose to require that you test for an unanticipated
occurrence. Rather, proposed Sec. 111.35(i)(2) would require you to
review the results of any monitoring, and conduct a material review and
make a disposition decision, if there is any unanticipated occurrence
that adulterates or could result in adulteration of a component or
dietary supplement. An example of such an occurrence is leakage of
extraneous material from a pipe onto a component. Quality control
personnel, under final Sec. 111.113(a)(3), must conduct a material
review and make a disposition decision if there is such an
unanticipated occurrence during the manufacturing operations.
(Comment 179) One comment suggests that the provision is a HACCP
requirement and is unnecessary for dietary supplements whose production
generally does not involve bacterial contamination.
(Response) We disagree. It is not a HACCP requirement because the
provisions deal with unanticipated occurrences. Dietary supplement
production can involve bacterial contamination as discussed in section
V of this document. The purpose of final Sec. 111.75(b) is to ensure
that the product meets all specifications, which include specifications
associated with contamination, and, therefore, is a necessary
provision.
3. Final Sec. 111.75(c) and (d)
Final Sec. 111.75(c) requires you, for a subset of finished
dietary supplement batches, which you identify through a sound
statistical sampling plan (or for every finished batch), to verify that
your finished batch of the dietary supplement meets product
specifications for identity, purity, strength, composition, and limits
on those types of contamination that may adulterate or that may lead to
adulteration of the finished batch of the dietary supplement. Final
Sec. 111.75(c) also sets forth the following verification
requirements:
You must select one or more established specifications for
identity, purity, strength, composition, and limits on those types of
contamination that may adulterate or that may lead to adulteration of
the dietary supplement that, if tested or examined on the finished
batch of the dietary supplement, would verify that the production and
process control system is producing a dietary supplement that meets all
product specifications (or only those product specifications not
otherwise exempted from this provision by quality control personnel
under final Sec. 111.75(d));
You must conduct appropriate tests or examinations on the
specifications selected in final Sec. 111.75(c)(1);
You must provide adequate documentation of your basis for
why meeting the specification(s) selected under final Sec.
111.75(c)(1), through the use of appropriate tests or examinations
conducted under final Sec. 111.75(c)(2), will ensure that your
finished batch of the dietary supplement meets all product
specifications for identity, purity, strength, composition, and the
limits on those types of contamination that may adulterate, or that may
lead to the adulteration of, the dietary supplement; and
Quality control personnel must review and approve the
documentation that you provide under final Sec. 111.75(c)(3).
Final Sec. 111.75(c) requires you to verify that your finished
batch of dietary supplement meets specifications for identity, purity,
strength, composition, and limits that you established for those types
of contamination that may adulterate or that may lead to adulteration
of the finished batch. You may verify this by either testing or
examining: (1) Every finished batch for each of these specifications or
(2) a subset of finished batches for the dietary supplement. The subset
of batches tested must be identified using a sound statistical sampling
plan.
If you choose to test or examine a subset of finished batches of
dietary supplement, you may test or examine each subset of batches for
identity, purity, strength, composition, and limits on contamination
that you established. Alternatively, you may determine that you can
select one, two, or three, or other number of these specifications
that, if determined to be in compliance
[[Page 34850]]
with specifications, would be able to verify that the other untested
specifications are met. For example, you may be able to substantiate
that, if you determine compliance with the specification for the
identity and composition of a product for which no contamination limits
are needed, the system is adequately controlling for the purity and
strength of the product, without the need to test for compliance with
the specifications for purity and strength. If so, you must document,
under final Sec. 111.75(c)(3) your basis for why this is so. Quality
control personnel must review and approve such documentation under
final Sec. 111.75(c)(4).
Under final Sec. 111.75(d), you may determine, in the previous
example, that you could not verify, by testing for compliance with the
specifications for identity and composition, that the purity
specification is met, and there may be no scientifically valid method
for testing or examining the finished batch to evaluate the purity in
the finished batch of dietary supplement. In that case, you could
exempt the specification for purity from the requirement in final Sec.
111.75(c)(1) if you can document why the purity specification is met
without such testing or examination. You could do so through, for
example, documentation that meeting component and specifications for
strength is sufficient, or through documentation that in-process
monitoring is sufficient. Quality control personnel must review and
approve such documentation (final Sec. 111.75(d)).
Final Sec. 111.75(c) and (d) derive from proposed Sec. 111.35(g)
and (h) and include changes that we are making after considering
comments.
(Comment 180) Several comments assert that a more appropriate
balance is needed between an effective process control system and a
reasonable testing scheme calculated to confirm the quality of dietary
supplements. The comments stress it is important to build quality into
a product throughout the entire production process by relying on strong
process controls rather than by testing at the finished batch stage.
One comment asserts that in an appropriate process control system,
testing is a means to monitor and ensure that the control system is
functioning as intended. Several comments make a specific
recommendation that the final rule include rigorous controls.
Some comments support the requirement under proposed Sec.
111.35(g) to test each batch of finished product when possible, and to
perform testing of components and in-process testing when testing the
finished product is not possible. Other comments object to the proposed
requirements for finished product testing on the grounds that they are
overly burdensome, duplicative, and unnecessary.
Some comments suggest that a more practical approach to finished
product testing would be to conduct identity testing of each component,
combined with certification of the vendor by a program of complete
testing for conformance with a certificate of analysis, as is allowed
under the drug CGMP regulations. Some comments suggest manufacturers
that have written procedures for each stage of their process, including
raw material certification, production, and finished product analysis,
and a written plan for qualifying the process, should be exempt from
the proposed requirements to test each finished batch. Some comments
urge us to give companies the flexibility to devise testing procedures.
(Response) The approach in final Sec. 111.75(c) and (d) is
consistent with these comments and is part of the overall approach of
this final rule, which focuses on ensuring the quality of the dietary
supplement throughout the production and process control system.
The concept behind final Sec. 111.75(c) and (d) is analogous to
the overall concept of proposed Sec. 111.35(g). Under proposed Sec.
111.35(g) you could rely on a combination of meeting component
specifications and in-process specifications when you are unable to
test for a specification, provided you satisfied certain criteria.
Under the final rule, you may rely on a combination of meeting
component specifications and in-process specifications to verify that
your product meets specifications, rather than test every batch to
determine whether specifications are met, regardless of whether a test
is available, provided you satisfy certain criteria. Thus, the final
rule provides flexibility that is needed to build adequate controls
early in the process to reduce the need for end product testing on
every batch of finished dietary supplement.
(Comment 181) One comment expresses concern that the requirement to
use appropriate tests to determine compliance with specifications could
be interpreted as requiring companies to test dietary supplements not
only for compliance with company specifications, but also for
compliance with any labeled specifications of the ingredient suppliers,
such as for contaminants. The comment believes this would be redundant
and overly burdensome.
(Response) As we explain in section XXIV of this document, we have
made changes to reduce the testing burden on companies while still
requiring steps necessary to ensure the quality of dietary supplements.
For example, under final Sec. 111.75(a), instead of testing or
examination (other than for identity of the dietary ingredients), firms
may rely upon supplier certificates of analysis in certain
circumstances. Also, we recognize, however, that it may be possible for
a manufacturer to demonstrate, through various methods and processes in
use over time for its particular operation, that a system of less than
100 percent identity testing would provide no material diminution of
assurance of the identity of the dietary ingredient as compared to the
assurance provided by 100 percent identity testing. To provide an
opportunity for a manufacturer to make such a showing and reduce the
frequency of identity testing of components that are dietary
ingredients from 100 percent to some lower frequency, we decided to
provide, in an interim final rule published elsewhere in this issue of
the Federal Register, a procedure that allows for submission to, and
review by, FDA of an alternative to the required 100 percent identity
testing of components that are dietary ingredients, provided certain
conditions are met. In addition, under final Sec. 111.75(c), testing
or examination for a portion of the finished batches is an option, and
exemptions are provided for in final Sec. 111.75(d).
(Comment 182) One comment points out that, if a product cannot be
tested for technical reasons at the final product stage, then it also
cannot be tested at the final blending stage in the process, because
the nature and composition of the product at both stages are virtually
the same. Another comment asks whether a verification of content in the
final product will suffice if there is no valid testing procedure.
(Response) Under final Sec. 111.75(c), you have flexibility to
select one or more established specifications for identity, purity,
strength, composition, and limits on those types of contamination that
may adulterate or that may lead to adulteration of the dietary
supplement that, if tested or examined on the finished batch of the
dietary supplement, would verify that the production and process
control system is producing a dietary supplement that meets all product
specifications. Under final Sec. 111.75(d), you have flexibility to
exempt one or more product specifications from verification
requirements, provided that
[[Page 34851]]
you satisfy the criteria established under final Sec. 111.75(d).
(Comment 183) Some comments request that the rule include
requirements for dissolution, disintegration, and bioavailability
testing for dietary supplements. These comments note that, although a
product may contain the labeled amount, it may not dissolve readily in
the body or be available for absorption.
(Response) We decline to revise the rule as suggested by the
comments. As discussed in the preamble to the 2003 CGMP Proposal (68 FR
12157 at 12163), tests for dissolution, disintegration, and
bioavailability of dietary supplements are examples of areas where
scientific study is still evolving; thus it is premature to impose
requirements for such tests. The comments provide no specific
information that would alter this view or support the technical
feasibility of conducting such tests for all types of dietary
supplement products. However, nothing in this final rule would preclude
a manufacturer from establishing such requirements. A manufacturer
should have data to support any specifications it establishes for
parameters such as dissolution, disintegration, and bioavailability.
(Comment 184) One comment questions the requirements in the 2003
CGMP Proposal that all manufacturers quantify certain marker compounds
in their products. The comment offers two reasons why such testing
should not be required for botanical products: Their food-like
composition and legal status, and the assertion that scientifically
valid analytical methods may prove to be irrelevant or even hinder the
development of superior products.
(Response) The final rule does not require any specific testing
requirements, such as testing for marker compounds. You would determine
the specific testing requirements, and whether to use a marker compound
in those tests, depending on your product and process. In the 2003 CGMP
Proposal (68 FR 12157 at 12172), we merely discussed how a marker
compound could help you identify whether you have a particular species
of an herb to differentiate, for example, between a poisonous and
nonpoisonous species.
4. Final Sec. 111.75(e)
Final Sec. 111.75(e) requires you, before you package or label a
product you receive for packaging or labeling as a dietary supplement
(and for distribution rather than for return to the supplier), to
visually examine the product and have documentation to determine
whether the specifications that you established under final Sec.
111.70(f) are met. Final Sec. 111.75(e) derives from proposed Sec.
111.35(e)(1) and (g) and from proposed Sec. 111.40(a)(2).
(Comment 185) Some comments request we clarify the roles and
testing obligations of the various parties in the ``pre-consumer supply
chain'' for dietary supplements. Some comments argue that redundant
tests should not be required at every transaction point in the pre-
consumer supply chain. The comments contend that any testing already
performed by a supplier, manufacturer, or packager should suffice, so
long as other CGMP certification, and chain of custody standards, are
met. Other comments urge us to give companies the flexibility to devise
testing procedures and point out that different testing is needed for
different roles in the supply chain.
One comment requests clarification of the testing requirements
applicable to packagers/labelers. The comment states it is unclear how
a packager or labeler/distributor could conduct testing of component
ingredients if all the firm receives is a finished product for which
there is no scientifically valid testing method.
(Response) As discussed in section VI of this document, you are
responsible for the CGMP requirements that are applicable to your
operations. We agree that redundant tests should not be required.
Further, we agree that it is the responsibility of the manufacturer to
do component testing. The packager or labeler does not need to do any
required component testing because the packager or labeler does not
receive components, rather it receives a finished dietary supplement.
Under final Sec. 111.70(f) if you receive a product from a supplier
for packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier), you must establish
specifications to provide sufficient assurance that the product you
receive is adequately identified and is consistent with your purchase
order.
Under final Sec. 111.75(e), before you package or label such a
product, you must visually examine the product and have documentation
to determine whether the specifications that you established under
final Sec. 111.70(f) are met. Your documentation may consist of an
invoice, certificate, guarantee, or other documentation from the
supplier to ensure that the product is adequately identified and is the
product that you ordered. Final Sec. 111.75(e) does not require that
the documentation consist of the result of testing or examination by
the packager or labeler of such a product.
As with final Sec. 111.70(f), final Sec. 111.75(e) applies to
``product that you receive for * * * for distribution rather than for
return to the supplier'' and, thus, applies to product that has left
the control of the person who manufactured the batch. If you are a
packager or labeler who packages and labels a dietary supplement for
the manufacturer, and you will return the packaged and labeled dietary
supplement to the manufacturer, we would not consider that you are
``receiving'' product within the meaning of final Sec. 111.75(e).
Thus, you would not be subject to final Sec. 111.70(f).
5. Final Sec. 111.75(f)
Before you use packaging, final Sec. 111.75(f)(1) requires you, at
a minimum, to conduct a visual identification of the containers and
closures and review the supplier's invoice, guarantee, or certification
to determine whether packaging specifications are met. Before you use
labels, final Sec. 111.75(f)(2) requires you, at a minimum, to conduct
a visual examination of the label and review the supplier's invoice,
guarantee, or certification to determine whether labeling
specifications are met. Final Sec. 111.75(f)(1) and (f)(2) derive from
proposed Sec. 111.40(b)(2) which, in part, would require you, for
packaging and labels you receive, to conduct at least a visual
identification on the containers and closures. Proposed Sec.
111.40(b)(2) also would require you, in part, for packaging and labels
you receive, to quarantine the packaging and labels until your quality
control unit tests or examines a representative sample to determine
whether specifications are met. Consistent with changes that we are
making to the requirements for packaging and labels that you receive
(see discussion of final Sec. 111.160 in section XII of this
document), final Sec. 111.75(f)(1) and (f)(2) include a requirement
analogous to proposed Sec. 111.40(a)(2) which would require you to
visually examine the supplier's invoice, guarantee, or certification to
determine whether the components, dietary ingredients, or dietary
supplements you receive are consistent with your purchase order and to
perform testing, as needed, to determine whether specifications are
met.
6. Final Sec. 111.75(g)
Final Sec. 111.75(g) requires you, at a minimum, to conduct a
visual examination of the packaging and labeling of the finished
packaged and labeled dietary supplements to determine whether you used
the specified packaging and applied the specified label. Final Sec.
111.75(g) derives from proposed Sec. 111.37(b)(11)(iv) which
[[Page 34852]]
would require the quality control unit to collect representative
samples of each batch of packaged and labeled dietary ingredients or
dietary supplements to determine whether you used the packaging
specified in the master manufacturing record and applied the label
specified in the master manufacturing record. Final Sec. 111.75(g) is
associated with final Sec. 111.70(g) which requires you to establish
specifications for the packaging and labeling for the finished packaged
and labeled dietary supplements, including specifications that ensure
you used the specified packaging and applied the specified label.
7. Final Sec. 111.75(h)
Final Sec. 111.75(h)(1) requires you to ensure that the tests and
examinations you use to determine whether the specifications are met
are appropriate and scientifically valid methods. Final Sec.
111.75(h)(1) derives from proposed Sec. 111.35(h). Final Sec.
111.75(h)(1) includes editorial changes associated with the
reorganization and changes that we are making after considering
comments.
Final Sec. 111.75(h)(2) requires that the tests and examinations
you use include at least one of the following: Gross organoleptic
analysis, macroscopic analysis, microscopic analysis, chemical
analysis, or other scientifically valid methods. Final Sec.
111.75(h)(2) derives from proposed Sec. 111.35(l).
(Comment 186) Some comments suggest that the tests listed in
proposed Sec. 111.35(l) be incorporated into proposed Sec. 111.35(h),
relating to appropriate test methods.
(Response) We agree with the comment, and final Sec. 111.75(h)(2)
combines these requirements as requested.
(Comment 187) One comment states that the list of tests should be
deleted because it is not sufficient to cover the types of testing that
will be required for compliance with proposed Sec. 111.35(g).
(Response) The comment does not identify the types of tests that
would not be covered. We believe that final Sec. 111.75(h)(2)(v)'s
``catch-all'' provision, which requires that one of the tests that you
use be an ``other scientifically valid method'' is sufficient to cover
all other types of testing required under this final rule.
(Comment 188) One comment states that the final rule should make
clear that organolepsis is an acceptable method for identity testing.
The comment contends it is imperative for the survival of small
businesses that organolepsis be allowed, coupled as necessary with
macroscopic and morphological examination and comparison with voucher
specimens or photographs. Another comment requests clarification of
whether gross organoleptic analysis alone can be a test for releasing
finished products. Some comments assert that several organizations have
published relevant methods that include macroscopic methods that can be
used in identifying herbal ingredients.
(Response) Organolpetic analysis would be an acceptable method
under the 2003 CGMP Proposal and remains an acceptable method under the
final rule, which clarifies that the method you use, including
organoleptic analysis, must be appropriate. Organoleptic analysis may
not be an appropriate method of testing for certain substances. This is
particularly true when the nature of the substance decreases the
reliability of organoleptic analysis. For example, while organoleptic
analysis may be an appropriate identity test for whole or coarsely-cut
botanical parts, it may not be an appropriate identity test for
powdered or extracted botanicals because of decreased reliability, or
in those instances where misidentification of botanicals is known to
occur. Additionally, we recognize ``macroscopic analysis'' is one of
the tests or examinations you may select to determine whether
specifications are met.
(Comment 189) One comment remarks that the appropriateness of the
test depends on the material being tested, and the method selected by
the manufacturer may be inappropriate. One comment believes the methods
stated in proposed Sec. 111.35(l) (organoleptic, microscopy, chemical)
for establishment of identity and purity would not be applicable to
animal products. This comment suggests that a separate list of test
methods should be identified for those materials.
(Response) We agree that the appropriateness of the test depends on
the material being tested. However, we are not revising the rule to
identify methods that are, or are not, appropriate for specific
circumstances (such as the case of animal-derived ingredients). There
are so many distinct circumstances that such a list would be neither
practical nor useful. Beyond that, the manufacturer is responsible for
choosing the appropriate test.
(Comment 190) One comment asks us to clarify in the final rule the
requirement that methods be scientifically valid applies only to
quantitative methods.
(Response) In proposed Sec. 111.35(h), we did not intend that the
proposed requirement that you use scientifically valid methods apply
only to quantitative methods, because we also proposed that tests in
accordance with proposed Sec. 111.35 must include at least one of the
following: (1) Gross organoleptic analysis, (2) microscopic analysis,
(3) chemical analysis, or (4) other appropriate test. To clarify that
the requirement that methods be scientifically valid applies to all the
tests and examinations you use, rather than to quantitative tests
alone, final Sec. 111.75(h)(1) does not use the term ``analytical.''
(Comment 191) One comment states that the proposed definition of
``appropriate test'' (i.e., ``a scientifically valid analytical
method'') is extremely onerous and violates congressional intent. The
comment believes that mandating specific methods is inappropriate, and
dietary supplement CGMPs should comply with Executive Order 12866 and
not impose additional requirements on small businesses that are better
left to normal business practices.
Several comments take issue with our statement that we were not
aware of a situation where an appropriate scientifically valid method
is not available when, in fact, valid test methods are not always
available for testing dietary ingredients or dietary supplements. One
comment contends the 2003 CGMP Proposal contains conflicting
information about available test methods. For example, the preamble to
the 2003 CGMP Proposal states that we are ``not aware of a situation
where an appropriate scientifically valid analytical method is not
available,'' and our cost analysis does not address costs of method
development. At the same time, however, we set out alternatives to
finished product testing in cases where adequate methods are
unavailable, and we decline to require expiration dating because there
may not be adequate methods available for assessing the strength of a
dietary ingredient. The comment cites numerous ongoing efforts in
methods development by both industry and government that illustrate the
lack of existing methods necessary to confirm compliance with all
quality specifications.
(Response) These comments appear to take our statements out of
context. In the 2003 CGMP Proposal, we stated: ``If an AOAC or FDA
method is not available, a scientifically valid analytical method is
one that is based on scientific data or results published in, for
example, scientific journals, references, text books, or proprietary
research. Although there may not be an Association of Official
Analytical
[[Page 34853]]
Chemist (AOAC) or FDA method available, we are not aware of a situation
where an appropriate scientifically valid analytical method is not
available'' (68 FR 12157 at 12198). We also stated: ``We recognize that
certain tests for identity, purity, quality, strength, or composition
for certain finished product may not be available due to complex
finished matrices that would make such testing impracticable'' (68 FR
12157 at 12197). We disagree that our statement acknowledging that the
available tests may not be practicable in certain matrices is
inherently inconsistent with our statement that we are not aware of a
situation where an appropriate scientifically valid analytical method
is not available. One statement relates to the availability of methods,
the other relates to the practicality of using an available method in
particular circumstances.
In any case, under final Sec. 111.75(d)(1) you may exempt a
product specification from the verification requirements of final Sec.
111.75(c)(1) if you show that: (1) The specifications selected to
verify that the product meets all product specifications are not able
to verify that the control system is producing a dietary supplement
that meets the exempted product specification and (2) there is no
scientifically valid method for testing or examining the exempted
product specification at the finished batch stage. Final Sec.
111.75(c)(1) also requires you to document why other information, such
as component and in-process testing, will determine whether the
exempted product specification is met without finished batch testing.
Although we agree that there may be some circumstances where there is
not a scientifically valid method available for finished product
testing, we believe that there would be some scientifically valid
method available for component or in-process testing.
(Comment 192) One comment encourages flexibility toward the
development of a quality system that is based on a balance of
prevention, appraisal, and process verification activities. Another
comment asks whether the industry should use industry standards and
tests now used.
A few comments request that we clarify proposed Sec. 111.35(h) to
make it clear whether the section recommends or requires the use of
available USP, AOAC International (formerly Association of Official
Analytical Chemists) or FDA methods. One comment recommends that the
final rule give companies flexibility to use the method(s) most
suitable to the ingredient they are testing and the specification they
have set. The comment adds that companies should then be required to
ensure, through appropriate rationale and data, that the method is
indeed suitable and produces accurate and reproducible results.
(Response) We agree that companies should have the flexibility to
adopt the method most suitable to the ingredient they are testing. As
discussed in the preamble to the proposal (68 FR 12157 at 12163 and
12208), official methods, such as AOAC International methods, are
validated in collaborative studies using several laboratories under
identical conditions and the AOAC International methods are often cited
as ``official validated methods.'' Other method validations are
conducted in a single laboratory by repeating the same test multiple
times. In the case of methods used to support specific regulatory
applications to FDA, data and information about methods that are
developed and conducted in a single laboratory by repeating the test
multiple times are sent to us, together with appropriate samples and
reference materials so the test can be repeated in an agency
laboratory. Typical validation characteristics include accuracy,
precision, specificity, detection limit, quantitation limit, linearity,
range, and robustness.
The process of method validation discussed in the previous
paragraph is a formal process for demonstrating that procedures are
suitable for their intended use. Although many methods that are
scientifically valid have been formally validated, other methods may
not have been subject to the formal validation process, e.g., by
collaborative studies using multiple laboratories, but nonetheless
remain scientifically valid because they are, in fact, suitable for
their intended use. For this reason, we stated that the 2003 CGMP
Proposal would permit tests using methods other than those that are
officially validated (68 FR 12157 at 12163). Consistent with the view
that we expressed in the 2003 CGMP Proposal, we believe a
scientifically valid method is one that is accurate, precise, and
specific for its intended purpose. In other words, a scientifically
valid test is one that consistently does what it is intended to do.
Under final Sec. 111.75(h)(1), you must ensure the tests and
examinations you use to determine whether the specifications are met
are appropriate, scientifically valid methods. Under final Sec.
111.75(h)(2) the tests and examinations you use must include at least
one of the following: (1) Gross organoleptic analysis, (2) macroscopic
analysis, (3) microscopic analysis, (4) chemical analysis, or (5) other
scientifically valid methods.
(Comment 193) One comment questions how a company would know of all
the available scientifically valid methods when it deals with hundreds
of items. The comment states it cannot be expected to have expertise in
the assay methodology for so many different ingredients.
Several comments suggest we make fuller use of available monographs
and other resources on test methods and method development. These
sources include USP and AHP monographs, AOAC International, the
European Pharmacopoeia, and the WHO. The comments urge us to
disseminate information on these additional resources.
Many comments assert that several organizations have published
relevant analytical methods, such as macroscopic, microscopic, and
chemical methods, that can be used in identifying herbal ingredients.
These comments suggest that we should acknowledge those methods and
organizations as authoritative sources of quality standards.
(Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12209), we acknowledged that validated methods exist in official
compendia for vitamins, minerals, and several botanicals, and we
recommended you use validated methods whenever such methods are
available. We explicitly stated that you may use validated methods that
can be found in official references, such as AOAC International, USP,
and others.
As discussed in this section (see response to comment 196), we
believe that it is sufficient to provide in this preamble general
guidance on what we consider to be scientifically valid tests, such as
those based on scientific data or results published in, for example,
scientific journals, references, text books, or proprietary research,
and leave it to the manufacturer to decide what scientifically valid
tests or examinations to use in a given operation. In the future, we
may consider issuing guidance as to sources of appropriate tests or
examinations, along with other guidances that we may find useful that
relate to certain dietary supplement CGMP.
(Comment 194) One comment states the act prohibits us from imposing
testing requirements for which scientifically valid methods are not
generally available, and other comments believe that not all components
have scientifically valid identification tests. Given the substantial
ongoing efforts towards method development, the
[[Page 34854]]
comments believe that the proposed requirements for testing would
impose standards on many products and ingredients that cannot be met
through current and generally available methods.
(Response) We disagree that the statute prohibits us from imposing
testing requirements. Section 402(g)(2) of the act states that dietary
supplement CGMP regulations ``may not impose standards for which there
is no current and generally available analytical methodology.'' We are
not imposing such standards. The manufacturer must establish
specifications for its product and components, and we have provided
flexibility for how the manufacturer can determine whether those
specifications are met. The manufacturer can test, examine, rely on a
certificate of analysis (other than to verify the identity of dietary
ingredients), or, in the case of a specification that is exempted from
periodic testing of a finished batch, rely on other information that
ensures that such an exempted product specification is met.
(Comment 195) One comment requests clarification on the definition
of ``examination'' and asks whether it includes monitoring of process
parameters as established in the master manufacturing record. If so,
the comment questions whether this practice would satisfy the
requirement now in final Sec. 111.75(h)(1).
(Response) Under final Sec. 111.75(h), scientifically valid tests
and examinations include techniques such as gross organoleptic
analysis, macroscopic analysis, chemical analysis, and other
scientifically valid methods. As discussed in the response to comment
169, monitoring in-process parameters could encompass tests such as
measuring pH or viscosity. Such tests would fall under ``other
scientifically valid methods.''
(Comment 196) One comment contends that botanical identification is
largely ignored in the 2003 CGMP Proposal. The comment states that
botanical identification forms the basic foundation for botanical
authenticity and that manufacturers have a legal responsibility to
ensure the authenticity of claimed ingredients. The comment recommends
that specific requirements for authentication of botanical ingredients
be included in the final rule.
One comment points out the difficulty in identifying and analyzing
all naturally occurring ingredients in herbs and plants and suggests
several alternatives to testing for all such ingredients. Another
comment requests that an herbal product containing 20 percent or more
ethanol have relaxed testing requirements due to the bacteriostata
properties of ethanol. One comment lists some alternatives for testing
naturally occurring ingredients.
One comment requests clarification on the testing requirements for
bovine cartilage products. The comment states there is no published
method for extracting chondroitin sulfate from bovine cartilage. As a
result, the comment assumes that testing for chondroitin sulfate would
not be required for these products.
(Response) We believe that it is sufficient to provide in this
preamble general guidance about testing, such as our discussion that
scientifically valid tests include official, validated methods as well
as tests based on scientific data or results published in, for example,
scientific journals, references, text books, or proprietary research.
It is the manufacturer's responsibility to choose which scientifically
valid tests or examinations to use in a given operation. Therefore, the
final rule does not address the specific testing circumstances
described in these comments, such as testing requirements for an herbal
product that contains 20 percent or more ethanol, or for bovine
cartilage products. The manufacturer is responsible for establishing
specifications and meeting such specifications, consistent with the
requirements in this final rule. In the future, we may consider issuing
detailed guidance as to specific tests or examinations, along with
other guidances that may be useful that relate to certain dietary
supplement CGMP.
With respect to the comments that discuss botanical identification,
we note that the 2003 CGMP Proposal referred to the draft report of the
Dietary Supplement Working Group of FDA's Food Advisory Committee (68
FR 12157 at 12161) (Ref. 32). The draft report discusses the selection
of the most appropriate and reliable identity test and the general
principles for consideration in setting performance standards for such
tests (Ref. 32). This report may provide useful guidance.
8. Final Sec. 111.75(i)
Final Sec. 111.75(i) requires you to establish corrective action
plans for use when an established specification is not met. Final Sec.
111.75(i) derives from proposed Sec. 111.35(i)(1).
(Comment 197) One comment asks whether the proposed requirement to
establish corrective action plans for use when an established
specification is not met (proposed Sec. 111.35(i)(1)) would apply to
specifications for raw materials and finished goods as well as to in-
process specifications.
(Response) The requirement to establish corrective action plans
(final Sec. 111.75(i)) applies to components, in-process
specifications, and to the finished batch.
(Comment 198) One comment states that corrective action plans would
be difficult to prepare for a variety of situations, such as for
complex multivitamin and mineral formulas. One comment recommends this
requirement be deleted. Another comment asserts that establishment of
corrective action plans should be at the manufacturer's discretion.
(Response) We disagree that the final rule should not require you
to establish corrective plans or that having such plans should be at
the manufacturer's discretion. The purpose of having corrective action
plans in place before a problem occurs is to help you to deal quickly
and efficiently with problems as they arise.
You may have a corrective action plan to determine the steps to
take if something goes wrong such as not meeting a specification.
Moreover, a corrective action plan may include steps not only for
dealing with an acute problem, but also for dealing with steps you
would take to followup after the acute problem is resolved. For
example, after you resolve an acute problem, such as a failure to meet
an in-process specification, your corrective action plan may include
testing of every finished batch, rather than a subset of finished
batches, for some period of time to verify that the problem is
resolved.
We acknowledge that it may not be practical to establish a
corrective action plan for all circumstances, because not all
circumstances are foreseeable. However, the comment asserting that it
would be difficult to establish corrective action plans for the variety
of situations that could come up for complex multivitamin and mineral
formulas provided no basis for why manufacturers of such formulas could
not anticipate specific situations that present potential problems.
(Comment 199) Some comments recommend that proposed Sec.
111.35(i)(1) state ``Establish procedures,'' rather than ``Establish
corrective action plans.''
(Response) The comments did not explain what, if any, practical
difference would exist between ``procedures'' and ``corrective action
plans.'' A corrective action plan is a procedure for which you must
have a record in the master manufacturing record (final Sec.
111.210(h)(5)). Because ``corrective action plans'' is a term that is
commonly used in the industry, we have retained it in the final rule.
[[Page 34855]]
J. What Must You Do if Established Specifications Are Not Met? (Final
Sec. 111.77)
1. Final Sec. 111.77
As we explain in section II of this document, we reorganized the
final rule to make it more ``user-friendly'' and to clarify the rule's
applicability to certain persons, items, or activities. Final Sec.
111.77 is a new provision that clarifies your responsibilities and
identifies those responsibilities in a more ``user-friendly'' fashion.
We have identified in final Sec. 111.77 the consequences of not
meeting the specifications you establish under subpart E and when you
can consider a treatment, in-process adjustment, or reprocessing to
correct a failure to meet and established specification for a
component, dietary supplement, packaging, or label. Subpart F does
identify these consequences in several provisions which deal with the
responsibility of quality control personnel to review and approve or
reject components, dietary supplements, packaging, and labels. We
determined it would add clarity to state the consequences for not
meeting a specification in the same subpart in which the requirements
to establish specifications are located.
2. Final Sec. 111.77(a)
Final Sec. 111.77(a) requires that for specifications established
under Sec. 111.70(a), (b)(2), (b)(3), (c), (d), (e), and (g) that you
do not meet, quality control personnel, in accordance with the
requirements in subpart F of this part, must reject the component,
dietary supplement, package, or label unless it approves a treatment,
an in-process adjustment, or reprocessing that will ensure the quality
of the finished dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record.
No finished batch of dietary supplements may be released for
distribution unless it complies with final Sec. 111.123(b).
This provision identifies those specifications, if not fully met,
that may be able to be corrected by treatment, in-process adjustment,
or reprocessing and approved by quality control personnel. We
emphasize, however, that even if, for example, corrections are
approved, the finished batch of dietary supplement can not be released
for distribution unless it is compliance with the requirements of final
Sec. 111.123(b) (discussed in section XI of this document).
Final Sec. 111.77(a) derives from the following proposed
provisions:
Proposed Sec. 111.50(d)(2), which would require the
quality control unit not to approve and release for distribution any
batch of dietary supplement that does not meet all specifications;
Proposed Sec. 111.50(f), which would require you to not
reprocess a batch that deviates from the master manufacturing record
unless approved by the quality control unit.
Proposed Sec. 111.50(g), which would require that a
reprocessed batch of dietary supplement meet all specifications and
that the quality control unit approve its release for distribution.
Proposed Sec. 111.35(i)(4)(i), which would require you,
for any deviation or unanticipated occurrence which resulted in or
could lead to adulteration of the component, dietary supplement,
packaging, or label, to reject the component, dietary supplement,
packaging, or label, unless the quality control unit determines that
in-process adjustments are possible to correct the deviation or
occurrence.
Proposed Sec. 111.35(i)(4)(ii), which would require you,
for any deviation or unanticipated occurrence which resulted in or
could lead to adulteration of the component, dietary supplement,
packaging, or label, to not reprocess a rejected component or dietary
supplement unless approved by the quality control unit.
3. Final Sec. 111.77(b)
Final Sec. 111.77(b) requires that for specifications established
under final Sec. 111.70(b)(1) that you do not meet, quality control
personnel must reject the component and the component must not be used
in manufacturing the dietary supplement. Final Sec. 111.77(b)
complements final Sec. 111.70(b)(1) which requires you to establish an
identity specification for components; final Sec. 111.75(a)(1) which
requires you to conduct at least one appropriate test or examination to
verify the identity of any component that is a dietary ingredient; and
final Sec. 111.75(a)(2) which requires you to confirm the identity of
all other components. As discussed earlier in this section, many
comments recommended the final rule include a requirement for an
identity test of incoming components to ensure quality and safety. We
agree with these comments and earlier comments that point out it may
not be possible to confirm the identity of some components after they
have been processed into the finished batch of the dietary supplement.
For these reasons, we have concluded that, if the component
specification for identity is not met, you may not use the component in
the manufacture of the dietary supplement. This component specification
must be met and quality control personnel are restricted in what action
must be taken if this specification is not met.
4. Final Sec. 111.77(c)
Final Sec. 111.77(c) requires that if you do not meet the
specifications established under Sec. 111.70(f), quality control
personnel must reject the product and the product must not be packaged
or labeled for distribution as a dietary supplement. As with final
Sec. 111.77(b), final Sec. 111.77(c) limits the actions you can take
to package and label product you receive for packaging and labeling
from a supplier for packaging or labeling as a dietary supplement (and
for distribution rather than for return to the supplier). Final Sec.
111.77(c) complements final Sec. 111.70(f), which requires you to
establish a specification for such received product and final Sec.
111.75(e), which requires you to visually examine the product, before
you package or label it, and have documentation to determine whether
the specifications that you established under Sec. 111.70(f) are met.
If you do not meet the specifications under final Sec. 111.70(f), you
must reject the product and not package or label the product for
distribution as a dietary supplement.
K. Comments on Shelf Life
In the preamble to the 2003 CGMP Proposal (68 FR 12157 at 12203),
we stated that we had considered whether to propose requirements for
expiration dating, shelf life dating, or ``best if used by'' dating
(referred to in this preamble as shelf life or expiration dating). We
recognized that there are current and generally available methods to
determine the expiration date of some dietary ingredients, such as
vitamin C. However, we were uncertain whether there are current and
generally available methods to determine the expiration dating of other
dietary ingredients, especially botanical dietary ingredients. We did
not propose to require expiration dating because we had insufficient
scientific information to determine the biological activity of certain
dietary ingredients used in dietary supplements, and such information
would be necessary to determine an expiration date. Further, because
official validated testing methods (e.g., AOAC International or FDA)
for dietary supplements are evolving, especially for botanical dietary
ingredients, such methods are not always available to assess the
strength of
[[Page 34856]]
a dietary ingredient in a dietary supplement.
The preamble to the 2003 CGMP Proposal emphasized that, if you use
an expiration date on a product, you should have data to support that
date (68 FR 12157 at 12204). We recommended that you have a written
testing program designed to assess the stability characteristics of the
dietary supplement, and that you use the results of the stability
testing to determine appropriate storage conditions and expiration
dates.
In the 2003 CGMP Proposal (68 FR 12157 at 12204), we invited
comment on whether any final rule should contain provisions regarding
expiration dating and the feasibility of conducting tests needed to
support such dates. We also invited comment on whether to require
expiration dating on certain dietary ingredients and not others, for
example, require expiration dating of vitamin, mineral, and amino acid,
but not of botanical dietary ingredients.
(Comment 200) Several comments agree with our decision not to
require expiration dating on labels for dietary supplements at this
time, because of the wide range of products and the need for additional
data. Most of these comments state, however, that manufacturers should
be allowed to include a ``best if used by'' date. One comment suggests
addressing the issue in a separate rulemaking. Other comments support
an expiration date because consumers and retailers expect one, and some
markets require one. Some comments state that the expiration date or
statement of product shelf life will help ensure that the product meets
its label claims and potency.
Many comments state an expiration date on a label must be supported
by a rationale or data on stability testing. Some of those comments
suggest that manufacturers should have flexibility in the type of
supporting data used. Although label claims should be confirmed by
shelf life testing when analytical methods exist, data could come from
a manufacturer's experience with the product or accelerated stability
testing on similar products with the same storage container. One
comment points out that some manufacturers already use stability
testing. Another comment recommends that we provide a guidance document
on supporting data.
One comment suggests stringent supporting data are not needed for a
``best if used by'' date, because that date provides a recommended time
frame to ensure the best quality. Another comment asserts that the
discussion about expiration dates in the 2003 CGMP Proposal gives the
impression that the required level of supporting data is similar to the
requirements for drug labeling, rather than the requirements for food
shelf life labeling. Another comment recommends that a general maximum
shelf life of 4 or 5 years should be included in the rule, with
shortened or lengthened shelf lives for individual products as data
become available.
(Response) These comments do not provide data or information that
would reduce the uncertainty about the feasibility of conducting tests
to support an expiration date and, thus, do not persuade us to alter
our position not to require that you establish an expiration date for
your product. Indeed, the comments generally concur with that position.
Because the final rule does not require that you establish an
expiration date, we decline to offer guidance on the type of data that
are acceptable to support an expiration date, other than to repeat that
any expiration date that you place on a product label (including a
``best if used by'' date) should be supported by data.
L. What Representative Samples Must You Collect? (Final Sec. 111.80)
Final Sec. 111.80 sets forth requirements to collect
representative samples of components, packaging, and labels (final
Sec. 111.80(a)); in-process materials (final Sec. 111.80(b)); the
finished batch of dietary supplement (final Sec. 111.80(c)); product
you receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) (final Sec.
111.80(d)); and packaged and labeled dietary supplements (final Sec.
111.80(e)). Final Sec. 111.80(a) through (e) derive from proposed
Sec. 111.37(b)(11)(i) through (b)(11)(iv).
1. Final Sec. 111.80(a)
Final Sec. 111.80(a) requires you to collect representative
samples of each unique lot of components, packaging, and labels that
you use to determine whether the components, packaging, and labels meet
specifications established in accordance with Sec. 111.70(b) and (d),
and as applicable, final Sec. 111.70(a) (and, when you receive
components, packaging, or labels from a supplier, representative
samples of each unique shipment, and of each unique lot within each
unique shipment). Final Sec. 111.80(a) derives from proposed Sec.
111.37(b)(11)(i). Final Sec. 111.80(a) includes changes related to our
review of the proposed requirements for clarity. We had used the term
``shipment lot'' in several proposed requirements, including Sec.
111.35(g)(1)(i) (requirement to test components that you receive),
Sec. 111.37(b)(11)(i) (requirement to collect representative samples
of components that you receive), Sec. 111.40(a)(4) (requirements for
components that you receive), Sec. 111.40(b)(5) (requirements for
packaging and labels that you receive), and Sec. 111.50(c)(5)
(requirement to identify materials that you use in the batch production
record). Some of these proposed requirements (e.g., those in Sec. Sec.
111.40(a)(4) and (b)(3) and 111.50(b)(5)) make clear that you must be
able to trace each lot of materials you receive to each separate
shipment that contains that lot. To clarify and emphasize this meaning
of shipment lot, we are revising proposed Sec. 111.37(b)(11)(i) so
that the representative samples you collect must come from ``each
unique shipment, and of each unique lot within each unique shipment.''
We make analogous revisions throughout the final rule as necessary.
As discussed in this section, final Sec. 111.70(b) sets forth the
requirements to establish specifications for components, final Sec.
111.73 requires you to determine if the specifications established are
met, and final Sec. 111.75(a) sets forth the criteria you use to
determine whether these specifications are met. Likewise, final Sec.
111.70(f) sets forth the requirements to establish specifications for
product that you receive from a supplier for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier), final Sec. 111.73 requires you to determine if
specifications established are met, and final Sec. 111.75(e) sets
forth the criteria to use to determine whether these specifications are
met.
For consistency with the regulations in final Sec. Sec. 111.70 and
111.75, we are separating the requirement to collect representative
samples of components (final Sec. 111.80(a)) from the requirement to
collect representative samples of product that you receive from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) (final Sec.
111.(80)(d)).
We did not receive comments specific to proposed Sec. 111.37(b).
2. Final 111.80(b)
Final Sec. 111.80(b) requires you to collect representative
samples of in-process materials for each manufactured batch at points,
steps, or stages, in the manufacturing process as specified in the
master manufacturing record, where control is necessary to ensure the
identity, purity, strength, and composition of dietary supplements, to
[[Page 34857]]
determine whether the materials meet specifications established under
final Sec. 111.70(c), and, as applicable, final Sec. 111.70(a). Final
Sec. 111.80(b) derives from proposed Sec. 111.37(b)(11)(ii).
We did not receive comments specific to proposed Sec.
111.37(b)(11)(ii).
3. Final 111.80(c)
Final Sec. 111.80(c) requires you to collect representative
samples of a subset of finished batches of each dietary supplement you
manufacture, which you identify through a sound statistical sampling
plan (or otherwise every finished batch), before releasing for
distribution, to verify that the finished batch of dietary supplement
meets product specifications established in accordance with final Sec.
111.70(e), and, as applicable, final Sec. 111.70(a). Final Sec.
111.80(c) derives from proposed Sec. 111.37(b)(11)(iii). Final Sec.
111.80(c) includes changes associated with final Sec. 111.75(c) which
provides flexibility for you to test or examine a subset of finished
batches you select through a sound statistical sampling plan rather
than to test or examine all finished batches. Under final Sec.
111.75(c) the tests or examinations you conduct at the finished batch
stage verify that your process is in control.
We did not receive comments specific to proposed Sec.
111.37(b)(11)(iii).
4. Final Sec. 111.80(d)
Final Sec. 111.80(d) requires you to collect representative
samples of each unique shipment, and of each unique lot within each
unique shipment, of product you receive for packaging or labeling as a
dietary supplement (and for distribution rather than for return to the
supplier) to determine whether the received product meets the
specifications established under final Sec. 111.70(f), and, as
applicable, final Sec. 111.70(a). Final Sec. 111.80(d) derives from
proposed Sec. 111.37(b)(11)(i). We did not receive comments specific
to this proposed requirement. However, we are making changes to final
Sec. 111.80(d) consistent with those described for final Sec.
111.80(a).
5. Final Sec. 111.80(e)
Final Sec. 111.80(e) requires you to collect representative
samples of each lot of packaged and labeled dietary supplements to
determine whether the packaging and labeling of the packaged and
labeled dietary supplements meet specifications established in
accordance with final Sec. 111.70(g), and, as applicable, final Sec.
111.70(a). Final Sec. 111.80(e) derives from proposed Sec.
111.37(b)(11)(iv). Final Sec. 111.80(e) includes revisions associated
with final Sec. 111.70(g), which requires you to establish
specifications for the packaging and labeling of the finished packaged
and labeled dietary supplements. Final Sec. 111.70(g) includes
specifications that determine whether you used the packaging specified
in the master manufacturing record and you applied the label specified
in the master manufacturing record. Under final Sec. 111.70(a) and (g)
the parameters that we proposed to specify under proposed Sec.
111.37(b)(11)(iv) are the required specifications for packaged and
labeled dietary supplements.
Final Sec. 111.80(e) includes a change to clarify the exact
specifications by citing the relevant sections. Final Sec. 111.80(e)
also includes an editorial change in that you are required to
``determine whether'' specifications are met rather than to ``determine
that'' specifications are met. We are making this change because
``determine that specifications are met'' may be interpreted as a
predetermined outcome, i.e., that specifications will, in fact, be met.
We did not receive comments specific to proposed Sec.
111.37(b)(11)(iv).
M. What Are the Requirements for Reserve Samples? (Final Sec. 111.83)
Final Sec. 111.83 sets forth requirements to collect and hold
reserve samples of dietary supplements. Final Sec. 111.83 derives from
proposed Sec. Sec. 111.37(b)(12), 111.50, and 111.83(b)(2).
Under proposed Sec. 111.37(b)(12) we would require holding reserve
samples as an operation performed by the quality control unit. Under
proposed Sec. 111.50(h), we proposed that you collect representative
reserve samples of each batch of dietary supplement. Consistent with
the changes that we are making to final Sec. 111.80, final Sec.
111.83 does not specify who must collect and hold the required reserve
samples. However, under final Sec. 111.105(g), quality control
personnel retain oversight of the collection and holding of the
required reserve samples. Because the requirement to collect and hold
reserve samples is not an operation that must be performed by quality
control personnel, we are including the requirement to collect reserve
samples in subpart E as part of the elements of a production and
process control system rather than in subpart F as part of the
requirements for quality control personnel.
For consistency with terms used elsewhere in the final rule, final
Sec. 111.83 requires that you ``hold'' reserve samples rather than
``keep'' them.
1. Final Sec. 111.83(a)
Final Sec. 111.83(a) requires you to collect and hold reserve
samples of each lot of packaged and labeled dietary supplements that
you distribute. Final Sec. 111.83(a) derives, in part, from proposed
Sec. 111.37(b)(12), which would require the quality control unit to
keep the reserve samples and, in part, from proposed Sec. 111.50(h),
which would require you to collect representative reserve samples from
each batch of dietary supplement.
(Comment 201) Several comments ask for clarification of the
requirements for representative and reserve samples as proposed in
Sec. 111.37(b)(11) and (b)(12). One comment notes that proposed Sec.
111.37(b)(11) does not indicate whether representative samples are also
collected to serve as the reserve samples described in proposed Sec.
111.37(b)(12) and asks whether the items in proposed Sec.
111.37(b)(11)(i) through (b)(11)(iv) are to be kept as reserve samples.
(Response) As discussed in section VI of this document, we are
adding a definition of ``reserve sample'' to reduce the potential for
confusion between requirements for reserve samples and requirements for
representative samples. A reserve sample is a representative sample
that is held for a designated period of time.
2. Final Sec. 111.83(b)(1)
Final Sec. 111.83(b)(1) requires the reserve samples to be held
using the same container-closure system in which the packaged and
labeled dietary supplement is distributed, or if distributing dietary
supplements to be packaged and labeled, using a container-closure
system that provides essentially the same characteristics to protect
against contamination or deterioration as the one in which it is
distributed for packaging and labeling elsewhere. Final Sec.
111.83(b)(1) derives from proposed Sec. 111.83(b)(2) which we proposed
to include with the requirements for holding and distributing. The
final sections that derive from proposed Sec. 111.83(b)(2) are in
subpart M (final Sec. 111.465). However, we are duplicating these
requirements in final Sec. 111.83(b)(1) for clarity and ease of use,
so that you have information about the requirements for the container-
closure system for holding reserve samples of packaged and labeled
dietary supplements in the same section as the requirements to collect
the samples.
3. Final Sec. 111.83(b)(2)
Final Sec. 111.83(b)(2) requires that reserve samples be
identified with the batch, lot, or control number. Final
[[Page 34858]]
Sec. 111.83(b)(2) derives from proposed Sec. 111.37(b)(12)(i) with
editorial changes associated with the reorganization. We have added
``control number'' to the provision for consistency with other
provisions of the final rule which refer to a ``control number'' in
addition to a ``batch or lot number.''
We did not receive comments specific to proposed Sec.
111.37(b)(12)(i).
4. Final Sec. 111.83(b)(3)
Final Sec. 111.83(b)(3) requires that reserve samples be retained
for 1 year past the shelf life date (if shelf life dating is used), or
for 2 years from the date of distribution of the last batch of dietary
supplements associated with those reserve samples, for use in
appropriate investigations. Final Sec. 111.83(b)(3) derives from
proposed Sec. 111.37(b)(12) which would require the quality control
unit to keep the reserve samples for 3 years from the date of
manufacture for use in appropriate investigations including, but not
limited to, consumer complaint investigations to determine, for
example, whether the dietary supplement associated with a consumer
complaint failed to meet any of its specifications for identity,
purity, quality, strength, and composition, as well as from proposed
Sec. 111.50(h) which would require reserve samples to be kept for 3
years from the date of manufacture. We discuss the change from 3 years
to 2 years and the change from ``date of manufacture'' to ``the date of
distribution'' in connection with the recordkeeping requirements in
subpart P, in section XXI of this document.
Final Sec. 111.83(b)(3) thus provides flexibility in determining
how long you must hold reserve samples of packaged and labeled dietary
supplements.
Final Sec. 111.83(b)(3) does not include the proposed examples of
investigations that may require the use of reserve samples because
these examples are not requirements.
(Comment 202) Many comments address the requirement to keep the
reserve samples after manufacture and recommend that expiration dates
be a factor when determining the amount of time reserve samples should
be kept and maintained. Most of the comments recommend holding reserve
samples of packaged and labeled dietary supplements for 3 years from
the date of manufacture or, when an expiration date has been
established by the manufacturer, for 1 year after the expiration date.
Other comments recommend holding reserve samples for time periods
ranging from 6 months to 2 years after the expiration date.
(Response) The final rule contains requirements similar to the
suggestions made by the comments. The final rule provides flexibility
to hold reserve samples for 1 year past the shelf life date, when such
dating is used. Any shelf life date that you include on the label of
the product should be supported by data.
5. Final Sec. 111.83(b)(4)
Final Sec. 111.83(b)(4) requires that reserve samples consist of
at least twice the quantity necessary for all tests or examinations to
determine whether or not the dietary supplement meets product
specifications. Final Sec. 111.83(b)(4) derives from proposed Sec.
111.37(b)(12)(ii) which would require that the reserve samples consist
of at least twice the quantity necessary for tests.
Final Sec. 111.83(b)(4) provides that the reserve samples may be
used for examinations or tests and to determine whether or not the
dietary supplement meets product specifications, as a revision
associated with final Sec. 111.75.
(Comment 203) One comment agrees that twice the quantity necessary
for testing should be collected and held.
(Response) The final rule is consistent with this comment.
N. Who Conducts a Material Review and Makes a Disposition Decision?
(Final Sec. 111.87)
Final Sec. 111.87 requires quality control personnel to conduct
all required material reviews and make all required disposition
decisions. Final Sec. 111.87 derives from a number of proposed
requirements for conducting a material review and making a disposition
(Sec. Sec. 111.35(i) and (n), 111.37(b)(5) and (b)(14), 111.40(a)(3),
111.50(d)(1), and 111.85(a) and (c)). Under each of these provisions,
the quality control unit would have an oversight role and would review
and approve all material reviews and all disposition decisions. Under
some of these provisions (i.e., Sec. Sec. 111.50(d)(1) and 111.85(a)
and 85(c)) the quality control unit would conduct the material review
itself and make the disposition decision.
(Comment 204) One comment disagrees that the quality control unit
must conduct the material review and make the disposition decision. The
comment argues that manufacturing personnel are better qualified to
conduct the review and make disposition decisions because they are
often engineers and have the relevant expertise regarding the use of
machinery and people to produce a product. In contrast, the comment
asserts that quality control unit personnel generally are chemists with
expertise only in testing and little expertise in manufacturing. The
comment asserts that the quality control unit should not be expected to
make decisions concerning manufacturing operations; however, it should
be informed of changes so it can evaluate the results of reprocessing
on the finished product.
(Response) We agree, in part, with the comments and the final rule
simplifies the provisions regarding a material review and disposition
decision. Quality control personnel can conduct the material review and
disposition decision by reviewing the underlying information gathered
or obtained by other qualified personnel and then making the final
decision. Under the final rule, we retain the principle that qualified
individuals other than quality control personnel can contribute to the
quality control personnel's material review and disposition decision.
The final rule sets forth the following requirements:
Under final Sec. 111.87, quality control personnel must
conduct all required material reviews and make all required disposition
decisions;
Under final Sec. 111.103, you must establish and follow
written procedures for conducting a material review and making a
disposition decision; and
Under final Sec. 111.140(b)(3)(vii), documentation of a
material review and disposition decision and followup must include the
signature of the individual(s) designated to perform the quality
control operations, who conducted the material review and made the
disposition decision, and of any qualified individual who provided
information relevant to that material review and disposition decision.
Taken in total, the final rule establishes a system in which you
have flexibility to develop procedures that suit your organization,
including having qualified individuals, other than the designated
quality control personnel, provide information relevant to the material
review and disposition decision. For example, under final Sec.
111.140(b)(3), you could have a qualified individual in the production
department prepare a report that includes all the required
documentation and information and provide a signed copy of that report
to designated quality control personnel. An individual designated to
perform quality control operations would then read that report, add to
it if necessary, conduct any additional investigations if necessary,
and if he or she agrees with the report, co-sign the report or an
amended report that includes additional documentation or information,
thus completing a material review and disposition decision.
[[Page 34859]]
The final rule provides for the participation of qualified
individuals, other than those designated to perform quality control
operations, in conducting the material review. In addition, as already
discussed, under final Sec. 111.12(b) you may assign a qualified
individual who has responsibilities for operations other than quality
control to perform quality control operations, provided that the
individual has distinct and separate responsibilities related to
performing quality control operations.
O. What Requirements Apply to Treatments, In-Process Adjustments, and
Reprocessing When There is a Deviation or Unanticipated Occurrence or
When a Specification Established in Accordance with Sec. 111.70 Is Not
Met? (Final Sec. 111.90)
1. Final Sec. 111.90
Final Sec. 111.90 is a unified provision that clarifies your
responsibilities regarding treatment or in-process adjustments to a
component, and in-process adjustments or reprocessing of a dietary
supplement, in a more ``user-friendly'' fashion. We have identified in
one provision the restrictions that apply to these operations. Final
Sec. 111.90 derives from proposed Sec. Sec. 111.35(i)(4)(i),
(i)(4)(ii), and (i)(4)(iii); 111.50(d)(1), (f), and (g); and 111.65(d).
Final Sec. 111.90 includes the following changes we are making to
the proposed provisions for consistency and clarity:
We are making revisions to make the section consistent
with the definition of ``reprocessing'' in final Sec. 111.3, which
refers only to ``components or dietary supplements that have been
previously removed from manufacturing.''
We are adding ``treatments'' as a step that quality
control personnel could approve, because that term better describes
actions that could be taken to correct a deviation or unanticipated
occurrence with a component, packaging, or label.
We are clarifying that it is quality control personnel who
reject components, packaging, or labels.
We are clarifying that quality control personnel approve
the treatment, in-process adjustment, or reprocessing rather than
determine whether the treatment, in-process adjustment, or reprocessing
is possible.
We are clarifying that, with respect to labels, the
provision applies to the potential that a label not specified in the
master manufacturing record could be used.
We are making changes to be consistent with the new
provision, final Sec. 111.77.
(Comment 205) One comment recommends deletion of proposed Sec.
111.35(i)(4) and (i)(4)(i), arguing that the principles of those
sections are covered under proposed Sec. 111.35(i)(2) and (i)(3).
(Response) We disagree with the comment's assertion. The
requirements of proposed Sec. 111.35(i)(4) and (i)(4)(i) are not
covered by proposed Sec. 111.35(i)(2) and (i)(3). All the sections are
related, but deal with different aspects of corrective action. Proposed
Sec. 111.35(i)(2) and (i)(3) would require the firm to conduct a
material review and make a disposition decision, while proposed Sec.
111.35(i)(4) would prohibit the use of rejected ingredients unless the
quality control unit determines that in-process adjustments are
possible to correct the deviations or occurrence. We are making no
changes as suggested by this comment and the primary elements of
proposed Sec. 111.35(i)(4) are retained in final Sec. 111.90.
(Comment 206) A few comments state their support for the
requirement that the quality control unit have the authority to
determine whether adjustments are possible to correct a deviation.
(Response) We are retaining the proposed requirement for quality
control personnel in final Sec. 111.90.
2. Final Sec. 111.90(a)
Final Sec. 111.90(a) requires that you must not reprocess a
rejected dietary supplement or treat or provide an in-process
adjustment to a component, packaging, or label to make it suitable for
use in the manufacture of a dietary supplement, unless: (1) Quality
control personnel conduct a material review and make a disposition
decision to approve the reprocessing, treatment, or in-process
adjustment and (2) the reprocessing, treatment, or in-process
adjustment is permitted by Sec. 111.77.
Final Sec. 111.90(a) derives from proposed Sec. Sec.
111.35(i)(4)(ii) and 111.50(d)(1). We revised this provision to be
consistent with the changes in final Sec. 111.77.
(Comment 207) Several comments state their support for proposed
Sec. 111.35(i)(4)(ii), which would require the quality control unit to
approve the reprocessing of any rejected component, dietary ingredient,
or dietary supplement. However, not all comments agree that the quality
control unit should have to conduct (under proposed Sec.
111.50(d)(1)), rather than review and approve, a material review and
disposition decision.
(Response) As discussed in this section, by ``conduct a material
review and make a disposition decision,'' we do not intend to limit
those who may participate in a material review and disposition decision
to only those persons acting in their capacity as designated quality
control personnel. Others may assist quality control personnel in
gathering and considering information relevant to the review and
decision, however the quality control personnel have the responsibility
to conduct a material review and make disposition decisions. Thus, we
are retaining in final Sec. 111.90(a) the requirements in proposed
Sec. Sec. 111.25(i)(4)(ii) and 111.50(d)(1).
3. Final Sec. 111.90(b)
Final Sec. 111.90(b) requires that you must not reprocess any
dietary supplement or treat or provide an in-process adjustment to a
component to make it suitable for use in the manufacture of a dietary
supplement, unless: (1) Quality control personnel conduct a material
review and make a disposition decision based on a scientifically valid
reason and approve the reprocessing, treatment, or in-process
adjustment and (2) the reprocessing, treatment or in-process adjustment
is permitted by Sec. 111.77. Final Sec. 111.90(b) derives from
proposed Sec. Sec. 111.35(i)(4)(iii), 111.50(f), and 111.65(d). We
revised this provision to be consistent with the changes in final Sec.
111.77.
(Comment 208) As discussed in section VI of this document
(discussion of the definition of ``reprocessing''), some comments
object to the restrictions in the definition of reprocessing in
proposed Sec. 111.3 because the definition would not permit the
reprocessing of ingredients that may have been removed because of
insanitary conditions even if there are processes available that are
safe and effective in removing foreign matter, microorganisms, or
chemicals that may have rendered the ingredient ``insanitary.'' These
comments also object to proposed Sec. 111.35(i)(4)(iii) for the same
reasons. A few comments argue that a manufacturer should be able to
reprocess a component or dietary supplement if it has been rejected
because of contamination with microorganisms or types of contamination,
such as heavy metals, if the quality control unit approves the
reprocessing. These comments indicate this is the industry practice,
one based on a scientific rationale for doing the reprocessing and that
ensures other quality attributes of the product are not affected.
Some comments state that the requirement is more strict than the
food or drug CGMP requirements, noting that
[[Page 34860]]
reprocessing is widely accepted and allowed in the food CGMPs. Other
comments believe that the prohibition in proposed Sec.
111.35(i)(4)(iii) against reprocessing materials contaminated with
microorganisms should be limited to materials contaminated with health-
hazardous microorganisms.
(Response) As we discussed in the response to comment 53 for the
definition of ``reprocessing,'' we agree with the comments that state
that in-process materials can be reprocessed when there are suitable
processes available. However, as noted by the comments, it is critical
that there be appropriate oversight of the reprocessing so the quality
of the dietary supplement is not compromised. Final Sec. 111.90(b)
provides for the flexibility requested by the comments, provided that
there is oversight by quality control personnel.
(Comment 209) Proposed Sec. 111.35(i)(4)(iii) mentions
``microorganism or other contaminants, such as heavy metals.'' One
comment proposes that other contaminants, such as pesticides and
aflatoxin, should be mentioned. Another comment suggests that the final
rule should specify limits for heavy metals in dietary supplements.
(Response) We decline to revise the final rule as suggested by the
comments. It is impractical to provide an exhaustive list of relevant
types of contamination, and a list that is longer, but not exhaustive,
is more likely to be misunderstood as suggesting that the only types of
contamination that are significant are the types of contamination in
the list. For that reason, we have eliminated the reference to
contamination to clarify that in any instance where it is appropriate
quality control personnel must ensure that the disposition decision is
based on a scientifically valid reason and also approve the
reprocessing.
(Comment 210) One comment notes that in the May 9, 2003, satellite
broadcast concerning the 2003 CGMP Proposal, we indicated that treating
a component or dietary supplement with irradiation as a means to reduce
or eliminate the microbial load was acceptable as long as the treatment
was part of the process for producing that material. The comment asks
for confirmation that irradiation of components or dietary supplements
is allowed under part 179 (21 CFR part 179), even though such
treatments are not listed in the table provided in Sec. 179.26(b).
(Response) We are unable to provide the requested confirmation.
Under section 201(s) of the act, irradiation intended for use in
producing, manufacturing, packing, processing, preparing, treating,
packaging, transporting, or holding food is a food additive that
requires premarket review and approval before it can be used in food.
Our Office of Food Additive Safety is currently reviewing a food
additive petition for the use of irradiation on dietary ingredients and
dietary supplements. Until that review process is completed and we have
authorized this use of irradiation through a final rule codified in
part 179, irradiation of dietary ingredients and dietary supplements as
a means to reduce or eliminate microbial loads is not permitted.
However, you may use an irradiated component (such as a spice that is
used to flavor a dietary supplement) when the irradiation of that
component is allowed under Sec. 179.26.
4. Final Sec. 111.90(c)
Final Sec. 111.90(c) requires that any batch of dietary supplement
that is reprocessed, that contains components that you have treated, or
to which you have made in-process adjustments to make them suitable for
use in the manufacture of the dietary supplement must be approved by
quality control personnel and comply with final Sec. 111.123(b) before
releasing for distribution. Final Sec. 111.90(c) derives from proposed
Sec. 111.50(g).
Final Sec. 111.90(c) also includes conforming revisions to clarify
that a dietary supplement that contains a component treated before use
or adjusted in-process, or that has had in-process adjustments to make
it suitable for use in the manufacture of a dietary supplement, must be
approved by quality control personnel and comply with final Sec.
111.123(b) before releasing for distribution. We revised this provision
to be consistent with the changes in final Sec. Sec. 111.77 and
111.123(b).
Final Sec. 111.90(c) also includes revisions to reflect the final
provisions that relate to reprocessing and in-process adjustments (see
final Sec. Sec. 111.113, 111.120, and 111.155).
(Comment 211) One comment asserts that a reprocessed product should
be retested to confirm that it meets product specifications.
(Response) Under final Sec. 111.75(c) and (d) quality control
personnel have flexibility to determine whether tests or examinations
are necessary to ensure that a reprocessed product meets product
specifications.
P. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.95)
1. Final Sec. 111.95(a)
Final Sec. 111.95(a) requires you to make and keep records
required under this subpart in accordance with subpart P. Final Sec.
111.95(a) derives from proposed Sec. 111.35(o). Some of the records
required under subpart E are set forth as recordkeeping requirements in
other subparts of this final rule, such as those related to receiving
records for components, packaging, and labels in subpart G, and the
results of testing or examination in subpart J. The record requirements
not specifically required in other related subparts are listed in
subpart E.
(Comment 212) One comment supports the recordkeeping requirements,
states that the records provide a valuable paper trail that will allow
manufacturers to identify and fix problems in the process, and suggests
the requirements protect consumers from adulterated and misbranded
products.
(Response) We agree. Under final Sec. 111.95(a), a firm must make
and keep records required by subpart E in accordance with subpart P. As
discussed in this section, firms are required to keep the records
necessary for determining whether their products are made in accordance
with specifications. This will help them identify and correct any
problems. In addition, under subpart P, the records must be kept for 1
year past the shelf life date (if shelf life dating is used) or 2 years
beyond the date of distribution of the last batch of dietary
supplements associated with those records. Moreover, firms must make
their records available to us for inspection and copying, which will
permit us to determine whether firms are manufacturing, packaging,
labeling, and holding dietary supplements in accordance with the
requirements of this rule.
2. Final Sec. 111.95(b)
Final Sec. 111.95(b) specifies the records you must make and keep
under subpart E. Under the reorganization several recordkeeping
requirements of proposed Sec. 111.35 are set forth in other subparts.
Final Sec. 111.95(b)(1) requires you to make and keep records of
the specifications established. Final Sec. 111.95(b)(1) derives from
proposed Sec. 111.35(o)(1).
Final Sec. 111.95(b)(2) requires you to make and keep records of
your qualification of a supplier for the purpose of relying on the
supplier's
[[Page 34861]]
certificate of analysis. Final Sec. 111.95(b)(2) is a record that is
required under final Sec. 111.75(a)(2)(B).
Final Sec. 111.95(b)(3) requires you to make and keep
documentation for why meeting in-process specifications, in combination
with meeting component specifications, helps ensure that the dietary
supplement meets the specifications for identity, purity, strength, and
composition and for limits on those types of contamination that may
adulterate or may lead to adulteration of the finished batch of the
dietary supplement. Final Sec. 111.95(b)(3) refers to records required
under final Sec. 111.70(c)(2).
Final Sec. 111.95(b)(4) requires you to make and keep
documentation for why the results of appropriate tests or examinations
for the product specifications selected under final Sec. 111.75(c)(1)
ensures that the dietary supplement meets all product specifications.
Final Sec. 111.95(b)(4) is a record that is required under final Sec.
111.75(c)(3).
Final Sec. 111.95(b)(5) requires you to make and keep
documentation for why any component and in-process testing,
examination, or monitoring, and any other information, will ensure that
a product specification that is exempted under final Sec. 111.75(d) is
met without verification through periodic testing of the finished
batch, including documentation that the selected specifications tested
or examined under final Sec. 111.75(c)(1) are not able to verify that
the production and process control system is producing a dietary
supplement that meets the exempted product specification and there is
no scientifically valid method for testing or examining such exempted
product specification at the finished batch stage. Final Sec.
111.95(b)(5) refers to a record required under final Sec.
111.75(d)(1). As previously discussed in this section, we are issuing
an interim final rule, published elsewhere in this issue of the Federal
Register, that sets forth a procedure for requesting an exemption from
the requirement that the manufacturer conduct at least one appropriate
test or examination to verify the identity of any component that is a
dietary ingredient. Included in the interim final rule is an amendment
to final Sec. 111.95(b) adding a new paragraph (b)(6) requiring the
retention of FDA's response to a petition submitted under Sec.
111.75(a)(1)(ii) that provides for an exemption from the provision of
Sec. 111.75(a)(1)(i).
(Comment 213) One comment recommends the recordkeeping requirements
of proposed Sec. 111.35(m) be moved to follow the requirements for
appropriate test methods because these requirements are related and
probably best understood without intervening information.
(Response) Consistent with this comment, the recordkeeping
requirements of proposed Sec. 111.35(m) are set forth in final subpart
J instead of subpart E.
XI. Comments on Requirements for Quality Control (Final Subpart F)
A. Organization of Final Subpart F
Proposed Sec. 111.37 set forth requirements for quality control
operations. Other proposed requirements related to quality control
operations were set forth in other sections. For example, proposed
Sec. 111.40(a) would require the quality control unit to perform
operations associated with components that you use in the manufacturing
process. Proposed Sec. 111.45 would establish requirements for the
master manufacturing record and would have the quality control unit
review and approve each master manufacturing record. Proposed Sec.
111.50 would have the quality control unit review batch production
records.
As shown in table 7 of this document, the final rule reorganizes
the requirements related to quality control operations into a distinct
subpart (final Subpart F--Production and Process Control System:
Requirements for Quality Control Operations). Table 7 lists the
sections in final subpart F and identifies the proposed sections that
form the basis for the sections in the final rule.
Table 7.--Derivation of Sections in Final Subpart F
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.103 What are the requirements N/A
under this subpart F for written
procedures?
------------------------------------------------------------------------
Sec. 111.105 What must quality control Sec. 111.37(a), (b)(1),
personnel do? (b)(11), and (b)(12)
------------------------------------------------------------------------
Sec. 111.110 What quality control Sec. 111.37(b)(9) and
operations are required for laboratory (b)(13)
operations associated with the
production and process control system?
------------------------------------------------------------------------
Sec. 111.113 What quality control Sec. 111.35(i)(2), (i)(3),
operations are required for a material (i)(4)(i), (i)(4)(ii), (j),
review and disposition decision? and (n)
Sec. 111.37(b)(3)
Sec. 111.37(c)
Sec. 111.40(a)(3) and
(b)(2)
Sec. 111.50(d)(1)
Sec. 111.65(d)
Sec. 111.70(c)
------------------------------------------------------------------------
Sec. 111.117 What quality control Sec. 111.30(b)(4), (b)(6),
operations are required for equipment, (b)(7), and (b)(8)
instruments, and controls?
------------------------------------------------------------------------
Sec. 111.120 What quality control Sec. 111.35(i)(4)(i) and
operations are required for components, (i)(4)(ii)
packaging, and labels before use in the Sec. 111.37(b)(2) and
manufacture of a dietary supplement? (b)(10)
Sec. 111.40(a)(3) and
(b)(2)
Sec. 111.50(e)(1)
------------------------------------------------------------------------
Sec. 111.123 What quality control Sec. 111.35(e)(2), (f),
operations are required for the master (i)(2), and (o)(2)
manufacturing record, the batch Sec. 111.37(b)(2), (b)(4),
production record, and manufacturing (b)(5), and (b)(11)(iii)
operations? Sec. 111.45(c)
Sec. 111.50(d)(1) and
(d)(2)
Sec. 111.50(g)
------------------------------------------------------------------------
Sec. 111.127 What quality control Sec. 111.37(b)(2) and
operations are required for packaging (b)(10)
and labeling operations? Sec. 111.40(a)(2) and
(a)(3)
Sec. 111.70(c), (d), and
(e)
------------------------------------------------------------------------
Sec. 111.130 What quality control Sec. 111.37(b)(2) and
operations are required for returned (b)(15)
dietary supplements? Sec. 111.85(a)
------------------------------------------------------------------------
Sec. 111.135 What quality control Sec. 111.95
operations are required for product
complaints?
------------------------------------------------------------------------
Sec. 111.140 Under this subpart F, what Sec. 111.35(j)
records must you make and keep? Sec. 111.37(c) and (d)
------------------------------------------------------------------------
B. Highlights of Changes to the Proposed Requirements for Quality
Control Operations
1. Revisions
The final rule:
Reflects that the rule applies to persons who manufacture,
package, label, or hold dietary supplements
[[Page 34862]]
unless subject to an exclusion under Sec. 111.1;
Changes the requirement for a quality control unit to a
requirement for quality control operations performed by quality control
personnel;
Requires quality control personnel to review and approve
documentation for why meeting in-process specifications will ensure the
specifications for identity, purity, strength, and composition of a
dietary supplement are met;
Requires quality control personnel to review and approve
documentation setting forth the basis for qualifying a supplier of a
component;
Requires quality control personnel to review and approve
documentation of your basis for why meeting certain selected
specifications in a subset of finished batches will ensure your
finished batch of the dietary supplement meets all product
specifications for identity, purity, strength, and composition and
limits on those types of contamination that may adulterate, or that may
lead to the adulteration of, the dietary supplement; and
Requires quality control personnel to review and approve
documentation for why a product specification exempted from the
verification requirements in final subpart E is met without
verification through periodic testing of the finished batch.
2. Changes Associated With the Reorganization
The final rule:
Reduces redundant provisions and
Combines parts of various proposed requirements that were
scattered throughout the 2003 CGMP Proposal.
3. Changes After Considering Comments
The final rule:
Incorporates a new requirement to establish, and keep as a
record, written procedures for quality control operations;
Simplifies the requirements associated with conducting a
material review and making a disposition decision;
Requires quality control personnel to ensure that
representative samples are collected rather than collecting these
samples;
Requires quality control personnel to ensure that reserve
samples are held rather than quality control personnel holding these
samples;
Requires quality control personnel to ensure tests or
examinations are appropriate rather than conduct these tests or
examinations; and
Requires review by quality control personnel of all
records for calibration of instruments, and for calibrations,
inspections, and checks of automatic, mechanical, or electronic
equipment to be performed on a periodic basis rather than at the time
the record is made.
C. General Comments on Proposed Sec. 111.37 (Final Subpart F)
(Comment 214) Some comments support the use of a quality control
unit and recognize it as an important need in manufacturing operations.
Some comments assert the quality control unit may not have all the
responsibilities listed in proposed Sec. 111.37 because there may be
some duties contracted out to someone else, such as testing that could
be sent to a contract laboratory, or some duties that may be better
suited for employees in other organizational units. As an example, a
few comments note that the instrument and equipment calibration
functions in proposed Sec. 111.37 may be better performed by
individuals responsible for the equipment in their particular
operational area, by those in a unit dedicated to equipment maintenance
and calibration, or possibly by a third party, who is qualified by
training and/or experience, to do these functions. Similarly, other
comments note that other groups with the appropriate expertise may be
assigned or required to review and approve proposed changes or
procedures in manufacturing operations or to conduct material reviews
and make disposition decisions. These comments assert the quality
control unit should have overall responsibility and oversight for
quality control functions but also should be able to rely on the
expertise of other persons in the organization to accomplish the tasks.
(Response) As already discussed with respect to the definition of
quality control personnel in section VI of this document, these
comments may have misunderstood the quality control unit's role under
the proposed rule. Consequently, we have added final Sec. 111.12(b) in
subpart B, discussed in section VII of this document, to state you must
identify who is responsible for your quality control operations. Each
person who is designated to perform quality control operations must be
qualified to do so and have distinct and separate responsibilities
related to performing such operations from those responsibilities that
the person otherwise has when not performing such operations.
The final rule requires quality control personnel to ensure all
appropriate tests and examinations are conducted, and review and
approve the results of all tests and examinations, but does not require
that quality control personnel conduct the tests or examinations. Thus,
you would not need to consider that an individual who conducts tests or
examinations at a laboratory under contract to your organization is
performing a quality control operation that must be performed by
quality control personnel. However, you may choose to designate that
individual as part of your quality control personnel and require that
the tests or examinations conducted by that individual be quality
control operations. Importantly, however, for the purposes of this
final rule, we consider that a quality control operation performed by
an individual under contract to you or by another third party is no
different than a quality control operation performed by your employees
who are designated to perform such operation. If, during the course of
an inspection, we find the requirements of this final rule were not
followed, we will hold you, rather than the contractor or other third
party, responsible. The applicability of this final rule to contractors
is discussed in detail in section VI of this document.
(Comment 215) Several comments request that the quality control
unit focus on reviewing tasks performed by others rather than on
performing the tasks itself.
(Response) We agree with these comments and have revised several
provisions accordingly. For example, in the 2003 CGMP Proposal we would
require the quality control unit to perform appropriate tests and
examinations of incoming materials, in-process materials, each finished
batch of dietary supplements, and each batch of packaged and labeled
dietary supplements (proposed Sec. 111.37(b)(13)). Under the final
rule, quality control operations include ensuring appropriate tests and
examinations are conducted (final Sec. 111.110(b)) but do not include
conducting these tests and examinations.
(Comment 216) One comment asks whether we expect the quality
control unit to approve operational activities as soon as they occur or
collectively at the end of the process. This and other comments argue
the quality control function is usually accomplished by a team of
qualified persons with the quality control unit having the overall
responsibility and authority to perform a collective, post-processing,
final approval.
(Response) The time at which quality control personnel conduct
assigned duties will vary by the specific operation, the size and
complexity of the operation, and how quality control functions are
assigned to qualified
[[Page 34863]]
persons. For example, the final rule requires quality control personnel
to determine whether components conform to specifications, and to
release components from quarantine before you use them in the
manufacture of a dietary supplement (final Sec. 111.120). However,
this final rule does not require, for example, that quality control
personnel determine whether components conform to specifications as
soon as you receive them, although it may be common business practice
to do so.
Regardless of when quality control personnel perform their
operations, quality control personnel have the ultimate responsibility
for ensuring manufacturing, packaging, labeling, and holding operations
are performed in a manner that will ensure the quality of the dietary
supplement and that the dietary supplement is packaged and labeled as
specified in the master manufacturing record.
D. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.103)
We received many comments that recommend written procedures for
various provisions. We address the need for written procedures
generally in section IV of this document. We also respond to comments
on specific provisions in the same section.
Final Sec. 111.103 requires that you establish and follow written
procedures for the responsibilities of the quality control operations.
Final Sec. 111.103 specifically identifies two of the written
procedures you must establish and follow, i.e., written procedures for
conducting a material review and making a disposition decision and for
approving or rejecting any reprocessing.
E. What Must Quality Control Personnel Do? (Final Sec. 111.105)
Final Sec. 111.105 broadly captures the responsibility of quality
control personnel to provide oversight for manufacturing, packaging,
labeling, and holding operations. It requires quality control personnel
to ensure that your manufacturing, packaging, labeling, and holding
operations ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record. Final Sec. 111.105 derives from proposed Sec.
111.37(a) which would require you to use a quality control unit to
ensure your manufacturing, packaging, labeling, and holding operations
in the production of dietary supplements are performed in a manner that
prevents adulteration and misbranding, including ensuring dietary
supplements meet specifications for identity, purity, quality,
strength, and composition.
This final rule focuses on ensuring that the manufacturer
establishes specifications for its dietary supplements; includes those
specifications in the master manufacturing record; meets those
specifications and manufactures, packages, labels, and holds the
product in a manner that will ensure the quality of the dietary
supplement; and that the dietary supplement is packaged and labeled as
specified in the master manufacturing record. Because of that focus,
the labeling requirements of the final rule address the operation of
putting the label that is specified in the master manufacturing record
on the product rather than the content of a product label that meets
all of the labeling requirements of the act and our implementing
regulations. The failure to put the label identified in the master
manufacturing record on the finished product would be a violation of
this final rule. In addition, if the label on the product does not
correctly reflect the ingredients, the label would misbrand the product
under section 403 of the act. For purposes of this final rule, the
labeling operations are CGMP requirements and relate to the label
identified in the master manufacturing record. Therefore, we are
deleting ``misbranding'' from proposed Sec. 111.37(a) (final Sec.
111.105) since the act of misbranding other than applying a label
different from the one identified in the master manufacturing record is
not considered a CGMP violation in the context of this final rule. Any
misbranding is still a violation of the act, however, and manufacturers
must comply with all applicable statutory and regulatory requirements
in addition to the requirements of this final rule.
This series of changes emphasizes the need to ensure the quality of
a dietary supplement and that the dietary supplement is packaged and
labeled as specified in the master manufacturing record. As discussed
in detail in the rest of this section, final Sec. 111.105 also
requires that quality control personnel perform certain operations and
groups of operations.
1. Final Sec. 111.105(a)
Final Sec. 111.105(a) requires that quality control personnel
approve or reject all processes, specifications, written procedures,
controls, tests, and examinations, and deviations from or modifications
to them, that may affect the identity, purity, strength, or composition
of a dietary supplement. Final Sec. 111.105(a) derives from proposed
Sec. 111.37(b)(1).
(Comment 217) One comment recommends revising proposed Sec.
111.37(b)(1) by replacing ``* * * identity, purity, quality, strength,
and composition'' with ``* * * identity, purity, quality, strength, or
composition.'' The comment asserts the quality control unit must be
responsible for approving or rejecting anything that may affect one of
these attributes.
(Response) We agree with this comment. Under proposed Sec.
111.37(b)(1) we had intended that the quality control unit be
responsible, for example, for approving a test that would establish the
identity of a component even if that test did not also establish the
strength of that component. Final Sec. 111.105(a) changes ``and'' to
``or'' as requested by this comment.
(Comment 218) One comment recommends the quality control unit be
responsible for maintaining the master copies of all current and
approved written procedures, for distributing copies of approved
written procedures to relevant personnel, and for collecting and
destroying outdated Standard Operating Procedures (SOPs) (except
designated historical SOP files).
(Response) This comment is consistent with the underlying principle
that quality control personnel oversee the design and conduct of the
operations associated with the production of a dietary supplement.
After considering these comments, final Sec. 111.105(a) requires
quality control personnel to approve all written procedures that may
affect the identity, purity, strength, or composition of a dietary
supplement. With respect to the other suggested duties of quality
control personnel, we are leaving the decision as to who performs them,
up to the individual firm to best suit its overall operations.
2. Final Sec. 111.105(b), (c), d), and (e)
Final Sec. 111.105(b) requires quality control personnel to review
and approve the documentation setting forth the basis for qualification
of any supplier. Final Sec. 111.105(c) requires quality control
personnel to review and approve the documentation setting forth the
basis for why meeting in-process specifications, in combination with
meeting component specifications, will help ensure that specifications
for the identity, purity, strength, and composition of the dietary
supplement are met. Final Sec. 111.105(d) requires quality control
personnel to review and approve the documentation setting forth the
basis for why the results of appropriate tests or examinations for each
product specification selected under final Sec. 111.75(c)(1) will
ensure
[[Page 34864]]
that the finished batch of the dietary supplement meets product
specifications. Final Sec. 111.105(e) requires quality control
personnel to review and approve the basis and documentation for why any
product specification is exempted from the verification requirements in
final Sec. 111.75(c)(1), and for why any component and in-process
testing, examination, or monitoring, or other methods will ensure that
such exempted product specification is met without verification through
periodic testing of the finished batch.
Final Sec. 111.105(b), (c), (d), and (e) are requirements
associated with the requirements established in final Sec. Sec.
111.70(c)(3) and 111.75(a)(ii)(2)(E), (c)(4), (d)(1) and (d)(2).
3. Final Sec. 111.105(f)
Final Sec. 111.105(f) requires quality control personnel to ensure
that required representative samples are collected. Final Sec.
111.105(f) differs slightly from proposed Sec. 111.37(b)(11)(i)
through (b)(11)(iv) which would require the quality control unit to
collect representative samples of incoming materials, in-process
materials, each finished batch of dietary supplements, and each batch
of packaged and labeled dietary supplements.
After considering comments requesting the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks themselves, the final rule does not specify that quality
control personnel must collect representative samples. Under final
Sec. 111.105(f), however, quality control personnel retain oversight
of sample collection.
4. Final Sec. 111.105(g)
Final Sec. 111.105(g) requires quality control personnel to ensure
that required reserve samples are collected and held. Final Sec.
111.105(g) derives from proposed Sec. 111.37(b)(12) which would
require the quality control unit to keep reserve samples.
After considering comments requesting the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks themselves, the final rule does not specify that quality
control personnel must keep reserve samples. Under final Sec.
111.105(g), however, quality control personnel retain oversight of
sample collection and holding.
5. Final Sec. 111.105(h)
Final Sec. 111.105(h) requires that quality control operations for
the master manufacturing record, the batch production record, and
manufacturing operations include determining whether all specifications
established in accordance with final Sec. 111.70(a) are met. Final
Sec. 111.105(h) derives from proposed Sec. 111.37(b)(2) which would
require that the quality control unit determine whether all components,
dietary supplements, packaging, and labels conform to specifications.
Under the final rule, we are identifying each of the specifications
subject to review by quality control personnel under final Sec.
111.77. The requirement for quality control personnel to determine
whether specifications established under final Sec. 111.70(a) are met
is included for consistency. This requirement is also consistent with
final Sec. 111.73 which requires that the production and process
control system must include a determination of whether all of the
established specifications under final Sec. 111.70(a) are met.
6. Final Sec. 111.105(i)
Final Sec. 111.105(i) requires quality control personnel to
perform other operations required under subpart F. Final Sec.
111.105(i) is associated with the reorganization. Under the 2003 CGMP
Proposal, proposed Sec. 111.37(a) broadly captured the responsibility
of the quality control unit to provide oversight for your
manufacturing, packaging, labeling, and holding operations. Proposed
Sec. 111.37(b) listed specific operations that we would require the
quality control unit to perform. Final Sec. 111.105 now captures the
responsibility of quality control personnel to provide oversight for
your manufacturing, packaging, labeling, and holding operations. The
specific operations that quality control personnel must perform to
provide that oversight are set forth in final Sec. 111.105(a) through
(h) and in final Sec. Sec. 111.110, 111.113, 111.117, 111.120,
111.123, 111.127, 111.130, 111.135, and 111.140.
F. What Quality Control Operations Are Required for Laboratory
Operations Associated With the Production and Process Control System?
(Final Sec. 111.110)
Final Sec. 111.110 sets forth the minimum required operations that
quality control personnel must perform with respect to laboratory
operations associated with the production and process control system.
1. Final Sec. 111.110(a)
Final Sec. 111.110(a) requires that quality control operations for
laboratory operations include reviewing and approving all laboratory
control processes associated with the production and process control
system. Final Sec. 111.110(a) derives, in part, from proposed Sec.
111.37(b)(9) which would require that the quality control unit review
and approve all laboratory control processes. For clarity, we are
adding that the laboratory operations covered by final Sec. 111.110
are those associated with the production and process control system. We
want to make clear that laboratory operations such as those in your
research and development department are not subject to final Sec.
111.110.
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(9).
2. Final Sec. 111.110(b)
Final Sec. 111.110(b) requires that quality control operations for
laboratory operations associated with the production and process
control system include ensuring all tests and examinations required
under final Sec. 111.75 are conducted. Final Sec. 111.110(b) derives,
in part, from proposed Sec. 111.37(b)(13) which would require the
quality control unit to perform appropriate tests and examinations of
incoming materials, in-process materials, each finished batch of
dietary supplements, and each batch of packaged and labeled dietary
supplements.
Proposed Sec. 111.37(b)(13) would list the types of materials that
must be tested, including components, packaging, labels, dietary
ingredients, and dietary supplements that you receive; the batch
production at the in-process and finished batch stages; and packaged
and labeled dietary supplements. This list would include materials
that, at a minimum, would be tested under the 2003 CGMP Proposal. Under
the final rule, the minimum requirements for testing or examination of
the materials listed in proposed Sec. 111.37(b)(13) are set forth in
final Sec. 111.75. To simplify and clarify proposed Sec.
111.37(b)(13), final Sec. 111.110(b) replaces this list with ``all
tests and examinations required under Sec. 111.75.''
3. Final Sec. 111.110(c)
Final Sec. 111.110(c) requires that quality control operations for
laboratory operations associated with the production and process
control system include reviewing and approving the results of all tests
and examinations required under final Sec. 111.75. Final Sec.
111.110(c) derives from proposed Sec. 111.37(b)(9), which would
require, in part, that the quality control unit review and approve all
testing results. Final Sec. 111.110(c) requires that quality control
[[Page 34865]]
personnel review and approve the results of examinations as well as
tests. This revision reflects the flexibility provided in the final
rule to use either tests or examinations to determine whether
specifications are met, provided that the test or examination is an
appropriate, scientifically valid method.
As with final Sec. 111.110(b), we provide in final Sec.
111.110(c) that the tests and examinations are those required under
final Sec. 111.75.
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(9).
G. What Quality Control Operations Are Required for a Material Review
and Disposition Decision? (Final Sec. 111.113)
Final Sec. 111.113 derives from several proposed provisions,
including Sec. Sec. 111.35(i), (j), and (n); 111.37(b)(3);
111.40(a)(3) and (b)(2); 111.50(d)(1); 111.65(d); and 111.70(c). All
these proposed requirements are related to one or more aspects
associated with a material review and disposition, including the
circumstances that require a material review and disposition decision,
the documentation that must be included in a material review and
disposition decision, any restrictions on who must conduct the material
review and make the disposition decision, and the need for oversight by
the quality control unit. As discussed in section X of this document,
we simplified the provisions regarding a material review and
disposition decision (final Sec. 111.87), emphasizing the importance
of oversight by quality control personnel and retaining the principle
that qualified individuals other than those who are designated quality
control personnel can contribute to the material review and disposition
decision. The final rule sets forth the following requirements for
quality control personnel that relate to final Sec. 111.113:
Under final Sec. 111.87, quality control personnel must
conduct all required material reviews and make all required disposition
decisions;
Under final Sec. 111.103, you must establish and follow
written procedures for conducting a material review and making a
disposition decision; and
Under final Sec. 111.140(b)(3)(vii), documentation of a
material review and disposition decision and followup must include the
signature of the individual, designated to perform the quality control
operation, who conducted the material review and made the disposition
decision and of any qualified individual who provided information
relevant to that material review and disposition decision.
The final rule establishes a system in which you have the
flexibility to develop procedures that suit your organization,
including having qualified individuals, who are not designated to
perform the quality control operation, provide information relevant to
the material review and disposition decision. For example, under final
Sec. 111.140(b)(3), you could have a qualified individual in the
production department assist quality control personnel in conducting a
material review by preparing a report that includes all the required
documentation and information and providing a signed copy of that
report to quality control personnel. An individual who is designated to
perform the quality control operation could then use that report as
part of the material review, conduct any further investigations, as
necessary, and decide to accept, amend, or reject the report.
1. Final Sec. 111.113(a)
Under final Sec. 111.113(a) quality control personnel must conduct
a material review and make a disposition decision if:
A specification established in accordance with Sec.
111.70 is not met;
A batch deviates from the master manufacturing record,
including when any step established in the master manufacturing record
is not completed and including any deviation from specifications;
There is any unanticipated occurrence during the
manufacturing operations that adulterates or may lead to adulteration
of the component, dietary supplement, or packaging, or could lead to
the use of a label not specified in the master manufacturing record;
Calibration of an instrument or control suggests a problem
that may have resulted in a failure to ensure the quality of a batch or
batches of a dietary supplement; or
A dietary supplement is returned.
Final Sec. 111.113(a) is substantially similar to proposed Sec.
111.35(i)(3), which would require, in part, that you make a material
disposition decision for any component, dietary supplement, packaging,
or label:
If a component, dietary supplement, packaging, or label
fails to meet established specifications;
If any step established in the master manufacturing record
is not completed;
If there is any unanticipated occurrence during the
manufacturing operations that adulterates or may lead to adulteration
of the component, dietary supplement, packaging, or label;
If calibration of an instrument or control suggests a
problem that may have caused batches of a dietary supplement to become
adulterated; or
If a dietary supplement is returned.
Final Sec. 111.113(a) also incorporates elements from other
proposed sections regarding the circumstances that require a material
review and disposition decision as follows:
Proposed Sec. 111.35(n), which would require you, for any
specification that is not met, to conduct a material review and
disposition decision under proposed Sec. 111.35(i);
Proposed Sec. 111.40(a)(3), which would require you, for
components, dietary ingredients, or dietary supplements you receive, to
conduct a material review and make a disposition decision if
specifications are not met;
Proposed Sec. 111.40(b)(2), which would require that for
packaging and labels you receive, you must conduct a material review
and make a disposition decision if specifications are not met;
Proposed Sec. 111.50(d)(1), which would require that if a
batch deviates from the master manufacturing record, including any
deviation from specifications, the quality control unit must conduct a
material review and make a disposition decision and record any decision
in the batch production record;
Proposed Sec. 111.65(d), which would require you to
conduct a material review and make a disposition decision in accordance
with proposed Sec. 111.35(i) for any component, dietary ingredient, or
dietary supplement that fails to meet specifications or that is or may
be adulterated; and
Proposed Sec. 111.70(c), which would require you to
conduct a material review and make a disposition decision of any
packaged and labeled dietary supplements that do not meet
specifications.
In final Sec. 111.113(a) we are incorporating, into a single
unified provision, the various proposed circumstances that would
require a material review and disposition decision under the 2003 CGMP
Proposal. We included revisions associated with final Sec. 111.87
which requires quality control personnel to conduct any required
material review and make any required disposition decision. We also
included revisions associated with final Sec. 111.90 that relate to
the impact on labeling operations due to deviations and unanticipated
occurrences.
In establishing final Sec. 111.113(a)(1), we are deleting the
specific reference to the articles (components, dietary supplements,
packaging, and labels)
[[Page 34866]]
required to undergo a material review. We are deleting these
references, in part, to simplify the provision. Under final Sec.
111.113(a) quality control personnel must conduct a material review and
make a disposition decision if any specification established in
accordance with final Sec. 111.70 is not met. It is not necessary to
repeat, in final Sec. 111.113, the list of specifications that is
clearly set forth in final Sec. 111.70.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.35(i)(3) and (n), 111.40(a)(3) and
(b)(2), 111.50(d)(1), 111.65(d), or 111.70(c).
2. Final Sec. 111.113(b)
Final Sec. 111.113(b)(1) requires that, when there is a deviation
or unanticipated occurrence during the production and in-process
control system that results in or could lead to adulteration of a
component, dietary supplement, or packaging, or could lead to the use
of a label not specified in the master manufacturing record, quality
control personnel must reject the component, dietary supplement, or
packaging, or label unless it approves a treatment, an in-process
adjustment, or reprocessing to correct the applicable deviation or
occurrence.
Final Sec. 111.113(b)(1) derives from the following proposed
provisions:
Proposed Sec. 111.35(i)(4)(i) which, in part, would
require that, for any deviation or unanticipated occurrence which
resulted in or could lead to adulteration of the component, dietary
ingredient, dietary supplement, packaging, or label, you reject the
component, dietary ingredient, dietary supplement, packaging, or label,
unless the quality control unit determines that in-process adjustments
are possible to correct the deviation or occurrence;
Proposed Sec. 111.35(i)(4)(ii) which, in part, would
require that, for any deviation or unanticipated occurrence which
resulted in or could lead to adulteration of the component, dietary
ingredient, dietary supplement, packaging, or label, you not reprocess
a rejected component or dietary supplement unless approved by the
quality control unit; and
Proposed Sec. 111.37(b)(3) which, in part, would require
the quality control unit to approve or reject all dietary ingredients,
dietary supplements, components, packaging, and labels.
For consistency with other provisions in final subpart F, final
Sec. 111.113(b)(1) requires that quality control personnel ``reject''
a component, dietary supplement, packaging, or label. We also included
revisions that are associated with final Sec. 111.90.
Final Sec. 111.113(b)(2) requires that when a specification
established in accordance with Sec. 111.70 is not met, quality control
personnel must reject the component, dietary supplement, package, or
label, unless quality control personnel approve a treatment, an in-
process adjustment, or reprocessing, as permitted in final Sec.
111.77. This provision has been added as a result of the new provision,
final Sec. 111.77 which provides for what happens when certain
specifications are not met, the responsibilities of quality control
personnel, and the changes made to final Sec. 111.90.
(Comment 219) Several comments request that the quality control
unit focus on reviewing tasks performed by others rather than on
performing the tasks itself.
(Response) We agree, and final Sec. 111.113(b) provides that
quality control personnel ``approve'' an in-process adjustment rather
than ``determine whether'' the in-process adjustment is possible.
3. Final Sec. 111.113(c)
Final Sec. 111.113(c) requires the person who conducts a material
review and makes the disposition decision, at the time of performance,
to document that material review and disposition decision. Final Sec.
111.113(c) derives from proposed Sec. 111.35(j) which, in part, would
require that the person who conducts the material review and makes the
disposition decision must, at the time of performance, document every
material review and disposition decision in proposed Sec. 111.35(i).
As an editorial revision, final Sec. 111.113(c) requires
documentation of ``that'' decision rather than ``every'' decision. As a
practical matter, under final Sec. 111.113(c) every material review
and disposition decision is documented.
We did not receive comments specific to quality control operations
under proposed Sec. 111.35(j).
H. What Quality Control Operations Are Required for Equipment,
Instruments, and Controls? (Final Sec. 111.117)
Final Sec. 111.117 (proposed Sec. 111.37(b)(6) through (b)(8))
sets forth the minimum required operations that quality control
personnel must perform with respect to equipment, instruments, and
controls.
1. Final Sec. 111.117(a) through (c)
Final Sec. 111.117(a) through (c) requires the quality control
operations for equipment, instruments, and controls to include:
Reviewing and approving all processes for calibrating
instruments and controls;
Periodically reviewing all records for calibration of
instruments and controls; and
Periodically reviewing all records for calibrations,
inspections, and checks of automated, mechanical, or electronic
equipment.
Final Sec. 111.117(a), (b), and (c) derive from proposed Sec.
111.37(b)(6), (b)(7), and (b)(8) which would require the quality
control unit to:
Review and approve all processes for calibrating
instruments or controls;
Review all records for calibration of instruments,
apparatus, gauges, and recording devices; and
Review all records for equipment calibrations,
inspections, and checks.
Final Sec. 111.117 includes the following changes we are making
for consistency with the requirements, set forth in subpart D, for
equipment and utensils:
We have deleted the terms ``apparatus,'' ``gauges,'' and
``recording devices'' from proposed Sec. 111.37(b)(7) as they would
fall under the terms ``instruments and controls'' in final Sec.
111.117, and because subpart D does not use the terms ``apparatus,''
``gauges,'' or ``recording devices.''
We are characterizing the records for equipment
calibrations, inspections, and checks as records for calibrations,
inspections, and checks of ``automated, mechanical, or electronic
equipment,'' because final Sec. 111.30(c) requires you to calibrate,
inspect, or check ``automated, mechanical, or electronic equipment.''
(Comment 220) One comment argues the requirements for oversight by
the quality control unit in proposed Sec. 111.37(b)(7) and (b)(8) are
excessive and go beyond requirements for both the drug CGMPs and food
CGMPs. The comment recommends revising proposed Sec. 111.37(b)(7) and
(b)(8) to require a review of all records when there is a negative
impact on the product due to a calibration failure.
Other comments refer to the related requirements in proposed Sec.
111.30(b)(1) that the quality control unit approve calibrations,
inspections, or checks of automatic, mechanical, or electronic
equipment. These comments assert the requirement for the quality
control unit to approve such calibrations, inspections, and checks of
equipment is too prescriptive and that qualified persons outside of the
quality control unit should be able to approve these calibrations,
inspections, or checks. These comments also assert the quality control
unit should perform audits of the records generated to ensure the
appropriate calibrations, inspections,
[[Page 34867]]
and checks are being adequately performed at the required intervals.
(Response) As already discussed with respect to proposed Sec.
111.30(b)(1) (final Sec. 111.30(c)), we disagree that the review by
quality control personnel should be limited to circumstances when there
has been a calibration failure. One of the oversight functions of
quality control personnel is to prevent problems with the product you
distribute by finding any problems with the equipment you use to
produce the product rather than to investigate the cause of a problem
with a product that you already distributed. However, we agree it is
sufficient to review the records of calibrations, inspections, and
checks of automated, mechanical, or electronic equipment periodically,
for example, on an annual basis, rather than to approve each record
when it is made. A periodic review can uncover trends in the
performance of the equipment that have the potential to adversely
affect the quality of the dietary supplement and that may not be
obvious by merely approving each record when it is made. Seeing such
trends would enable quality control personnel to recommend actions to
correct the trend. Therefore, we have revised the proposed requirement
so that under final Sec. 111.117(c) quality control personnel must
review all records of calibrations, inspections, and checks of
automatic, mechanical, or electronic equipment on a periodic basis.
Likewise, we have revised the rule so that the quality control
personnel's review of all records of equipment calibrations also is on
a periodic basis.
(Comment 221) A few comments argue the review of calibration
records may be conducted by a qualified person other than the quality
control unit, such as by a supervisor or by a separate department
dedicated to equipment maintenance and calibration. These comments
assert the quality control unit should approve calibration processes,
but review of completed calibration records by the dedicated department
is sufficient to assure compliance with the approved process.
(Response) As already discussed, many comments about the quality
control unit may have misunderstood the proposed definition of
``quality control unit'' (now replaced by ``quality control
personnel''). Under final Sec. 111.12(b), you must identify who is
responsible for your quality control operations. Each person who is
identified to perform quality control operations must be qualified to
do so and have distinct and separate responsibilities related to
performing such operations from those responsibilities that the person
otherwise has when not performing such operations. Thus, in the
situation described by these comments, you could identify a qualified
person in a department dedicated to equipment maintenance and
calibration to perform quality control operations for equipment
calibration. Neither the definition of ``quality control personnel,''
nor the requirements of final Sec. 111.12(b), would preclude a person
who performs ``Operation X'' from being identified as the person who
performs quality control operations for ``Operation X.'' However, we
strongly recommend that the person you identify to perform a given
quality control operation be a different person than the person who
performed the operation that is subject to quality control oversight.
2. Final Sec. 111.117(d)
Final Sec. 111.117(d) requires that quality control operations for
equipment, instruments, and controls include reviewing and approving
controls to ensure automated, mechanical, or electronic equipment
functions in accordance with its intended use. Final Sec. 111.117(d)
derives, in part, from proposed Sec. 111.30(b)(4) (final Sec.
111.30(e)) which would require that, for any automated, mechanical, or
electronic equipment you use, you must establish and use appropriate
controls and the controls are approved by your quality control unit to
ensure that the equipment functions in accordance with its intended
use. We are clarifying the proposed requirement related to quality
control personnel in final Sec. 111.117(d).
We did not receive comments specific to this responsibility of the
quality control unit in proposed Sec. 111.30(b)(4).
I. What Quality Control Operations Are Required for Components,
Packaging, and Labels Before Use in the Manufacture of a Dietary
Supplement? (Final Sec. 111.120)
Final Sec. 111.120 sets forth the minimum required operations that
quality control personnel must perform with respect to components,
packaging, and labels before use in the manufacture of a dietary
supplement. Some of the proposed provisions that form the basis for
final Sec. 111.120 included requirements for ``dietary supplements
that you receive.'' For example, proposed Sec. 111.40(a) would require
you, for components or dietary supplements you receive, to visually
examine containers and documentation provided by the supplier,
quarantine the materials until they are released by the quality control
unit, and identify the materials in a manner that allows you to trace
the shipment you receive to the product that you manufacture and
distribute. The final rule separates these and other requirements for
quality control operations for ``product that you receive from a
supplier'' for packaging or labeling as a dietary supplement from the
analogous requirements for components. Thus, the requirements for
quality control operations for product you receive for packaging and
labeling as a dietary supplement (and for distribution rather than for
return to the supplier) are found in final Sec. 111.127 rather than
final Sec. 111.120.
1. Final Sec. 111.120(a)
Final Sec. 111.120(a) requires that quality control operations for
components, packaging, and labels include reviewing all receiving
records for components, packaging, and labels before use. Final Sec.
111.120(a) derives from the following proposed provisions:
Proposed Sec. 111.37(b)(10) which, in part, would require
the quality control unit to review and approve all packaging and label
records which include, but are not limited to, cross-referencing
receiving and batch production records;
Proposed Sec. 111.40(a)(3) which, in part, would require
that you quarantine dietary supplements until your quality control unit
reviews the supplier's invoice, guarantee, or certification; and
Proposed Sec. 111.50(e)(1) which, in part, would require
the quality control unit to document its review of component receiving
records.
(Comment 222) One comment asserts that the proposed requirement
that the review of the batch record by the quality control unit include
cross-referencing of receiving records with the batch production record
is redundant and should be mandatory only in cases where a
specification has not been met. This comment asserts the quality
control unit has already reviewed and approved components, packaging,
and labels prior to their release and has used unique identifiers for
these raw materials as they are recorded on related documentation and
records, which allow traceability back to this documentation for review
when necessary. This comment also asserts all material review and
disposition decisions must be documented and these will include the
unique identifiers that tie them to particular raw or in-process
materials.
Another comment asserts that the quality control unit should only
need to repeat a review of the receiving records as a result of
conducting an investigation or a material review, as is required for
drugs, and to require
[[Page 34868]]
otherwise would be redundant. This comment also states requiring the
quality control unit to repeat its review of the receiving records
places a fairly large burden on the quality control unit because this
re-review must be performed for each and every batch production record.
The comments assert the requirement should be completed properly and
only once.
(Response) In the preamble to the 2003 CGMP Proposal (68 FR 12157
at 12200), we stated that cross-referencing receiving and batch
production records means the quality control unit must verify that the
batch record includes certain documentation of the receiving records
for the components such as the unique identifier assigned to the
shipment lot of components, testing results, a material review and
disposition decision, if conducted, and approval for use by the quality
control unit. We agree with the comments that the review of records
such as receiving records (including proper documentation of a unique
identifier for components, packaging, and labels), if done properly the
first time it is performed, need not be repeated. Therefore, the final
rule does not include any requirement for cross-referencing receiving
records with the batch production record as we would require under
proposed Sec. 111.37(b)(10). As noted, we have changed ``quality
control unit'' to ``quality control personnel.'' We agree that cross-
referencing receiving and batch production records is an appropriate
step to take when conducting a material review and making a disposition
when, for example, a specification is not met. We encourage firms to
include this activity in the written procedures for conducting a
material review and making a disposition decision.
2. Final Sec. 111.120(b)
Final Sec. 111.120(b) requires that quality control operations for
components, packaging, and labels include determining whether all
components, packaging, and labels conform to specifications established
under Sec. 111.70(b) and (d) before use. Final Sec. 111.120(b)
derives from proposed Sec. 111.37(b)(2).
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(2). For clarity, we have identified the
specifications as those required under final Sec. 111.70(b) and (d).
3. Final Sec. 111.120(c)
Final Sec. 111.120(c) requires that quality control operations for
components, packaging, and labels include conducting any required
material review and making any required disposition decision before
use. Final Sec. 111.120(c) derives from the following proposed
provisions:
Proposed Sec. 111.40(a)(3) which, in part, would require
you to conduct a material review and make a disposition decision if
specifications are not met for components; and
Proposed Sec. 111.40(b)(2) which, in part, would require
you to conduct a material review and make a disposition decision if
specifications are not met for packaging and labels.
Final Sec. 111.120(c) includes revisions associated with final
Sec. 111.87 which requires quality control personnel to conduct any
required material review and make any required disposition decision.
(Comment 223) One comment recommends the quality control unit have
authority to allow usage of material that has failed to meet
specifications if the defect will not significantly affect the overall
quality of the finished product even if reprocessing is not an option.
The comment gives an example of a material that fails to meet particle
size specifications designed to maximize the efficiency of processing
of the material, but ultimately does not impair strength, and asserts
the quality unit should have the authority to release the material for
use.
(Response) The final rule provides for a process in which quality
control personnel determine whether a component meets specifications
and conduct a material review and make a disposition decision if a
component does not meet one or more specifications. The final rule does
not prohibit the use of a component that does not meet all component
specifications other than the identity specification. For example,
under final Sec. 111.120(d) quality control personnel may approve an
in-process adjustment of a component to make it suitable for use in the
manufacture of a dietary supplement (see discussion of final Sec.
111.120(d) in the following paragraphs). Under final Sec. 111.123(b)
quality control personnel must not approve and release for distribution
any batch of dietary supplement, including any reprocessed batch, that
does not meet all product specifications or is not a quality product.
Thus, although a disposition decision could be made under final Sec.
111.120(c) to use a component even if it does not meet certain
specifications, that decision should take into account whether the
failure for the component to meet specifications will ultimately cause
the dietary supplement to fail to meet product specifications.
4. Final Sec. 111.120(d)
Final Sec. 111.120(d) requires that quality control operations for
components, packaging, and labels include approving, or rejecting, any
treatment and in-process adjustments of components, packaging, or
labels to make them suitable for use in the manufacture of a dietary
supplement. Final Sec. 111.120(d) derives from the following proposed
provisions:
Proposed Sec. 111.35(i)(4)(i) which, in part, would
require that you reject the component, packaging, or label, unless the
quality control unit determines that in-process adjustments are
possible to correct the deviation or occurrence and
Proposed Sec. 111.35(i)(4)(ii) which would have
prohibited you from reprocessing a rejected component unless approved
by the quality control unit.
Final Sec. 111.120(d) includes a revision associated with final
Sec. 111.90(c), and refers to ``treatment and in-process adjustments
to make them suitable for use in the manufacture of a dietary
supplement'' (see discussion of final Sec. 111.90(c) in section X of
this document).
(Comment 224) Several comments request the quality control unit
focus on reviewing tasks performed by others rather than on performing
the tasks itself.
(Response) Final Sec. 111.120(d) includes a revision that quality
control personnel ``approve'' a treatment rather than ``determine
that'' the treatment is possible.
(Comment 225) A few comments support the proposed requirement that
the quality control unit have the authority to approve reprocessing
measures.
(Response) These comments are consistent with proposed Sec.
111.35(i) and (i)(4)(ii) and final Sec. 111.120(d), as applicable to
quality control personnel.
(Comment 226) One comment states that the decision to reprocess a
material belongs within the particular operational unit, and that the
role of the quality control unit should be to approve the results of
the reprocessing.
(Response) We disagree that the role of quality control personnel
should be limited to approving the results of reprocessing or, in this
case, of the treatment or in-process adjustments of components,
packaging, or labels. An underlying principle of these CGMP
requirements is that quality control personnel oversee the design and
conduct of manufacturing, packaging, labeling, and holding operations.
A
[[Page 34869]]
decision about when reprocessing is, or is not, appropriate requires
oversight.
As already discussed, under final Sec. 111.12(b) you must identify
who is responsible for your quality control operations. Each person who
is identified to perform quality control operations must be qualified
to do so and have distinct and separate responsibilities related to
performing such operations from those responsibilities that the person
otherwise has when not performing such operations.
5. Final Sec. 111.120(e)
Final Sec. 111.120(e) requires that quality control operations for
components, packaging, and labels include approving and releasing from
quarantine all components, packaging, and labels before they are used.
Final Sec. 111.120(e) derives from the following proposed provisions:
Proposed Sec. 111.40(a)(3) which, in part, would require
that you quarantine components until your quality control unit approves
the components and releases them from quarantine and
Proposed Sec. 111.40(b)(2) which, in part, would require
that you quarantine packaging and labels until your quality control
unit approves the packaging and labels and releases them from
quarantine.
We did not receive comments specific to quality control operations
under proposed Sec. 111.40(a)(3) or (b)(2).
J. What Quality Control Operations Are Required for the Master
Manufacturing Record, the Batch Production Record, and Manufacturing
Operations? (Final Sec. 111.123)
Final Sec. 111.123 sets forth the minimum required operations that
quality control personnel must perform with respect to the master
manufacturing record, the batch production record, and manufacturing
operations.
1. Final Sec. 111.123(a)(1)
Final Sec. 111.123(a)(1) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include reviewing and approving all master
manufacturing records and all modifications to the master manufacturing
records. Final Sec. 111.123(a)(1) derives from duplicate proposed
requirements, in proposed Sec. Sec. 111.37(b)(4) and 111.45(c), with
no changes other than the editorial changes associated with the
reorganization.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.37(b)(4) or 111.45(c), but have combined
them as final Sec. 111.123(a)(1).
2. Final Sec. 111.123(a)(2)
Final Sec. 111.123(a)(2) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include reviewing and approving all batch
production-related records. Final Sec. 111.123(a)(2) derives from
proposed Sec. 111.37(b)(5), which would require, in part, the quality
control unit to review and approve all batch production-related
records. Proposed Sec. 111.37(b)(5) explicitly stated, in part, that
the batch record would include, but not be limited to, cross-
referencing receiving and batch production records.
(Comment 227) One comment expresses concern that proposed Sec.
111.37(b) does not state specifically that the complete batch history,
including batch record, analytical records, quality control records,
yields, and packaging records should be reviewed and approved by the
quality control unit before the batch is shipped. The comment believes
these are important requirements that should be clearly stated.
(Response) Proposed Sec. 111.37(b)(5) would require that the
quality control unit ``review and approve all batch production-related
records, including but not limited to * * *'' We disagree with the
comment that this proposed provision would not include what the comment
describes. To the extent that the comments interpreted the list of
records to mean that only the partial listing of records was required,
we have modified final Sec. 111.123(a)(2) to require quality control
personnel to review all batch production-related records. We do not
emphasize any particular aspect of the batch production record. This
reduces the potential to misinterpret the requirement as being limited
to the specific items cited.
(Comment 228) As already discussed in detail with respect to final
Sec. 111.120(a), some comments assert the proposed requirement that
the review of the batch record by the quality control unit include
cross-referencing of receiving records with the batch production record
is redundant to other requirements that the quality control unit review
receiving records for components, packaging, and labels. In general,
these comments assert the requirement should be completed properly and
only once.
(Response) We agree with the comments that the review of records,
such as receiving records, if done properly the first time that it is
performed, need not be repeated. Therefore, the final rule does not
include any requirements for cross-referencing receiving records with
the batch production record as we would require under proposed Sec.
111.37(b)(5).
3. Final Sec. 111.123(a)(3)
Final Sec. 111.123(a)(3) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include reviewing all monitoring required
under subpart E. Final Sec. 111.123(a)(3) derives from the following
proposed provisions:
Proposed Sec. 111.35(f) which would require you to
monitor the in-process control points, steps, or stages to ensure that
specifications established under proposed Sec. 111.35(e) are met and
to detect any unanticipated occurrence that may result in adulteration;
Proposed Sec. 111.35(e)(2) which would require you to
establish a specification for any point, step, or stage in the
manufacturing process where control is necessary to prevent
adulteration, including the in-process controls in the master
manufacturing record where control is necessary to ensure the identity,
purity, quality, strength, and composition of dietary supplements;
Proposed Sec. 111.35(i)(2) which would require you to
review the results of the monitoring required under proposed Sec.
111.35(f) and conduct a material review if an established specification
is not met or if there is any unanticipated occurrence that adulterates
or could result in adulteration;
Proposed Sec. 111.35(o)(2) which would require you to
make and retain records to ensure you follow the requirements of
proposed Sec. 111.35, including the actual results obtained during the
monitoring operation; and
Proposed Sec. 111.37(b)(5) which would require the
quality control unit to review and approve all batch production-related
records.
Under the final rule, the results of the monitoring required under
proposed Sec. 111.35(f) must be kept in the batch record (see the
discussion of the batch record in section XIV of this document).
Quality control personnel must review the results of the required
monitoring.
(Comment 229) One comment suggests the phrase ``review the results
of the monitoring required by this section'' be deleted from proposed
Sec. 111.35(i)(2) because it is unnecessary and can be read as
narrowing any final rule. This comments points out the only required
monitoring in the proposal appears in Sec. 111.35(f) related to
[[Page 34870]]
monitoring of in-process control points, steps, or stages, and that
such monitoring would not necessarily find all failures in
specifications, for example, specifications related to raw materials or
labels.
(Response) We disagree with the comment that the quoted language
narrows the final rule. Monitoring that relates to in-process control
points, steps, or stages would be required under proposed Sec.
111.35(f) and is now required in final Sec. 111.123(a)(3). However, in
practice, a manufacturer must monitor its entire operation to ensure
that the requirements of the final rule are met. For example, under
final Sec. 111.73, a manufacturer must determine whether
specifications established under final Sec. 111.70 are met and under
final Sec. 111.75(a) and (f) a manufacturer must use certain criteria
to determine whether specifications for components and labels,
respectively, are met. Thus, there are sufficient controls in other
requirements to ensure the entire production and process controls are
functioning as intended.
4. Final Sec. 111.123(a)(4)
Final Sec. 111.123(a)(4) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include conducting any required material
review and making any required disposition decision. Final Sec.
111.123(a)(4) derives from the following proposed provisions:
Proposed Sec. 111.37(b)(5) which, in part, would require
the quality control unit to approve a material review and disposition
decision related to batch production records; and
Proposed Sec. 111.50(d)(1) which, in part, would require,
if a batch deviates from the master manufacturing record, including any
deviation from specifications, the quality control unit to conduct a
material review and make a disposition decision.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.37(b)(5) or 111.50(d)(1).
5. Final Sec. 111.123(a)(5)
Final Sec. 111.123(a)(5) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include approving or rejecting any
reprocessing. Final Sec. 111.123(a)(5) derives from proposed Sec.
111.37(b)(5) which would require the quality control unit to approve
any reprocessing. For consistency with other provisions in this final
rule (such as final Sec. 111.90), final Sec. 111.123(a)(5) includes a
revision that quality control personnel must approve--or reject--any
reprocessing.
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(5).
6. Final Sec. 111.123(a)(6)
Final Sec. 111.123(a)(6) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include determining whether all in-process
specifications established in accordance with Sec. 111.70(c) are met.
Final Sec. 111.123(a)(6) derives from the following proposed
provisions:
Proposed Sec. 111.35(f) which would require you to
monitor the in-process control points, steps, or stages to ensure
specifications are met (including the in-process specifications
required under proposed Sec. 111.35(e)(2)) and
Proposed Sec. 111.37(a) which, in part, would require the
quality control unit to ensure your manufacturing, packaging, labeling,
and holding operations are performed in a manner that prevents
adulteration, including that such operations ensure the dietary
supplement meets its specifications for identity, purity, quality,
strength, and composition.
Final Sec. 111.123(a)(6) is consistent with the overall approach,
set forth in final Sec. Sec. 111.70, 111.73, and 111.75, that focuses
on ensuring the quality of the dietary supplement throughout the
production and process control system.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.35(e)(2) or (f), or 111.37(a).
7. Final Sec. 111.123(a)(7)
Final Sec. 111.123(a)(7) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include determining whether each finished
batch conforms to product specifications established in accordance with
final Sec. 111.70(e). Final Sec. 111.123(a)(7) derives from proposed
Sec. 111.37(b)(2) which, in part, would require the quality control
unit to determine whether all dietary supplements conform to
specifications.
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(2).
8. Final Sec. 111.123(a)(8)
Final Sec. 111.123(a)(8) requires that quality control operations
for the master manufacturing record, the batch production record, and
manufacturing operations include approving and releasing, or rejecting,
each finished batch for distribution, including any reprocessed
finished batch. Final Sec. 111.123(a)(8) derives from the following
proposed provisions:
Proposed Sec. 111.37(b)(5) which, in part, would require
the quality control unit to approve batch production records for
releasing finished batches for distribution;
Proposed Sec. 111.50(d)(2) which would require the
quality control unit to not approve and release for distribution any
batch that does not meet all specifications; and
Proposed Sec. 111.50(g) which would require the quality
control unit to not approve and release for distribution any
reprocessed batch of dietary supplement that does not meet all
specifications.
We did not receive comments specific to the proposed provisions
cited above.
9. Final Sec. 111.123(b)
Final Sec. 111.123(b) requires that quality control personnel must
not approve and release for distribution:
any batch of dietary supplement for which any component in
the batch does not meet its identity specification;
any batch of dietary supplement, including any reprocessed
batch, that does not meet all product specifications established in
accordance with Sec. 111.70(e);
any batch of dietary supplement, including any reprocessed
batch, that has not been manufactured, packaged, labeled, and held
under conditions to prevent adulteration under section 402(a)(1),
(a)(2), (a)(3), and (a)(4) of the act; and
any product received from a supplier for packaging or
labeling as a dietary supplement (and for distribution rather than for
return to the supplier) for which sufficient assurance is not provided
to adequately identify the product and to determine that the product is
consistent with your purchase order.
Final Sec. 111.123(b) derives from the following proposed
provisions:
Proposed Sec. 111.50(d)(2) which would require the
quality control unit to not approve and release for distribution any
batch of dietary supplement that does not meet all specifications;
Proposed Sec. 111.50(g) which would require that a
reprocessed batch of dietary supplement meet all specifications and
that the quality control unit approve its release for distribution; and
Proposed Sec. 111.37(b)(11)(iii) which would require the
quality control unit to collect representative samples of each batch of
dietary supplement manufactured to determine, before releasing for
distribution, whether the dietary supplement meets its
[[Page 34871]]
specifications for identity, purity, quality, strength, and
composition.
The final provision clarifies all of the responsibilities of
quality control personnel and includes provisions consistent with
changes made to final Sec. Sec. 111.73, 111.77, and 111.90.
We did not receive comments specific to those aspects of proposed
Sec. Sec. 111.50(g) and 111.37(b)(11)(iii) that are relevant to final
Sec. 111.123(b). We discuss in the following paragraphs comments we
received to proposed Sec. 111.50(d)(2).
(Comment 230) Several comments object to proposed Sec.
111.50(d)(2) because it would prohibit the release of any batch that
does not meet all specifications. Other comments suggest the
prohibition should apply to meeting ``release specifications'' or
``essential manufacturer specifications'' rather than ``all
specifications'' because in-process deviations and minor deviations may
not affect product quality.
(Response) A finished dietary supplement that is ready for release
for distribution must meet component specifications for identity
established under final Sec. 111.70(b) and all product specifications
established for the batch under final Sec. 111.70(e) and must be
manufactured in a manner to prevent adulteration under section
402(a)(1), (a)(2), (a)(3), and (a)(4) of the act. The final rule does
not prevent you from establishing additional specifications that do not
affect the identity, purity, strength, composition, or contaminant
levels of your finished dietary supplement. Such a specification is not
a component specification for identity or a product specification that
is required under the final rule. Final Sec. 111.123(b) would not
preclude you from releasing a product that fails to meet a
specification that is not a component specification for identity or a
product specification established under final Sec. 111.70 provided
quality control personnel approve such release. Final Sec. 111.123(b)
would not preclude you from releasing a product that you are permitted
to release under final Sec. 111.77.
(Comment 231) Some comments note that proposed Sec. 111.50(d)(2)
would not allow the quality control unit to conduct an investigation,
and make a disposition decision, of the failure of a batch to meet
specifications. These comments assert proposed Sec. 111.50(d)(2)
therefore restricts the provision in proposed Sec. 111.50(d)(1) which
would require that, if a batch deviates from the master manufacturing
record, including any deviation from specifications, the quality
control unit must conduct a material review and make a disposition
decision. The comments argue the quality control unit should have the
authority to release products with minor deviations.
(Response) As discussed previously (see discussion of final Sec.
111.90 in subpart E in section X of this document), we acknowledge that
some specifications, such as component, other than for identity, and
in-process specifications, that are not met may be able to be corrected
by a treatment or an in-process adjustment. Quality control personnel
would need to conduct a material review and disposition decision for
any such specification not met. If there are specifications for any
point, step, or stage in the manufacturing process where control is
necessary to ensure the quality of the dietary supplement and that the
dietary supplement is packaged and labeled as specified in the master
manufacturing record (final Sec. 111.70(a)), you must determine
whether these specifications are met (final Sec. 111.73).
Final Sec. 111.123(b) does not preclude you, for example, from
releasing a product that was the subject of a material review because
sampling procedures had not been followed if, as a corrective action,
the appropriate samples were collected and subjected to appropriate
tests and examinations.
K. What Quality Control Operations Are Required for Packaging and
Labeling Operations? (Final Sec. 111.127)
Final Sec. 111.127 sets forth the required operations that quality
control personnel must perform with respect to packaging and labeling
operations.
1. Final Sec. 111.127(a) and (b)
Final Sec. 111.127(a) and (b) set forth requirements for product
you receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier).
Final Sec. 111.127(a) and (b) apply to product that has left the
control of the person who manufactured the batch; for example, the
purchase of dietary supplements in bulk for packaging or labeling by a
person who will distribute the packaged and labeled dietary supplements
under a private label. If you are a packager or labeler who operates
under contract to the manufacturer, and you will return the dietary
supplement to the manufacturer, we would not consider that you are
``receiving'' product within the meaning of final Sec. 111.127(a) and
(b). We would consider you to be no different than an operating unit of
the manufacturer. In section VI of this document (subpart A), we
discuss in detail the scope of this final rule and its applicability to
contractors.
a. Final Sec. 111.127(a). Final Sec. 111.127(a) requires that
quality control operations for packaging and labeling operations
include reviewing the results of any visual examination and
documentation to ensure that specifications established under final
Sec. 111.70(f) are met for product you receive for packaging or
labeling as a dietary supplement (and for distribution rather than for
return to the supplier). Final Sec. 111.127(a) derives from the
following proposed provisions:
Proposed Sec. 111.40(a)(2) which would require you to
visually examine the supplier's invoice, guarantee, or certification to
ensure that dietary supplements you receive are consistent with your
purchase order and perform testing, as needed, to determine whether
specifications are met and
Proposed Sec. 111.40(a)(3) which would, in part, require
you to quarantine dietary supplements you receive until your quality
control unit reviews the supplier's invoice, guarantee, or
certification and performs testing, as needed, of a representative
sample to determine that specifications are met.
Final Sec. 111.127(a) includes revisions associated with final
Sec. Sec. 111.70(f) and 111.75(e) which set forth requirements for all
products you receive from a supplier for packaging or labeling as
dietary supplements (and for distribution rather than for return to the
supplier). As discussed in section X of this document, under final
Sec. 111.70(f) if you receive such product, you must establish
specifications to provide sufficient assurance that the product you
receive is adequately identified and is consistent with your purchase
order. In addition, under final Sec. 111.75(e) before you package or
label such products, you must visually examine the products and have
documentation to determine whether the specifications that you
established under final Sec. 111.70(f) are met. The documentation you
have to satisfy the requirements of final Sec. 111.75(e) is not
limited to a supplier's invoice, guarantee, or certification and, thus,
final Sec. 111.127(a) incorporates the standard set by final Sec.
111.75(e) (i.e., documentation) rather than the proposed standard of
the supplier's invoice, guarantee, or certification. In addition,
consistent with final Sec. 111.75(e), final Sec. 111.127(a) requires
quality control personnel to review the results of the visual
examination but not otherwise review the results of tests or
examinations.
[[Page 34872]]
We did not receive comments specific to quality control operations
under proposed Sec. 111.40(a)(2) or (a)(3).
b. Final Sec. 111.127(b). Final Sec. 111.127(b) requires that
quality control operations for packaging and labeling operations
include approving, and releasing from quarantine, all products you
receive for packaging and labeling as a dietary supplement (and for
distribution rather than for return to the supplier) before the
products are used for packaging and labeling. Final Sec. 111.127(b)
derives from proposed Sec. 111.40(a)(3) which, in part, would require
you to quarantine dietary supplements that you receive until your
quality control unit reviews the supplier's invoice, guarantee, or
certification and performs testing, as needed, of a representative
sample to determine that specifications are met, and approves and
releases the dietary supplements from quarantine before you use them.
As with final Sec. 111.127(a), final Sec. 111.127(b) includes
revisions associated with changes made in final Sec. Sec. 111.70(f)
and 111.75(e).
We did not receive comments specific to quality control operations
under proposed Sec. 111.40(a)(3).
2. Final Sec. 111.127(c)
Final Sec. 111.127(c) requires that quality control operations for
packaging and labeling operations include reviewing and approving all
records for packaging and label operations. Final Sec. 111.127(c)
derives from proposed Sec. 111.37(b)(10) which, in part, would require
the quality control unit to review and approve all packaging and label
records.
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(10).
3. Final Sec. 111.127(d)
Final Sec. 111.127(d) requires that quality control operations for
packaging and labeling operations include determining whether the
finished packaged and labeled dietary supplement conforms to
specifications established in accordance with final Sec. 111.70(g).
Final Sec. 111.127(d) derives from the following proposed provisions:
Proposed Sec. 111.37(b)(2) which, in part, would require
the quality control unit to determine whether all dietary supplements
conform to specifications and
Proposed Sec. 111.37(b)(11)(iv) which, in part, would
require the quality control unit to collect representative samples of
each batch of packaged and labeled dietary supplements to determine
that you used the packaging specified in the master manufacturing
record and applied the label specified in the master manufacturing
record.
For clarity, final Sec. 111.127(d) identifies the specifications
as those established in final Sec. 111.70(g).
We did not receive comments specific to quality control operations
under proposed Sec. 111.37(b)(2) or (b)(11)(iv).
4. Final Sec. 111.127(e)
Final Sec. 111.127(e) requires that quality control operations for
packaging and labeling operations include conducting any required
material review and making any required disposition decision. Final
Sec. 111.127(e) derives from the following proposed provisions:
Proposed Sec. 111.70(c) which would require you to
conduct a material review and make a disposition decision of any
packaged and labeled dietary supplement that does not meet
specifications and
Proposed Sec. 111.40(a)(3) which, in part, would require
you, if specifications are not met for a received dietary supplement,
to conduct a material review and make a disposition decision.
Final Sec. 111.127(e) includes revisions associated with final
Sec. 111.87 which requires quality control personnel to conduct any
required material review and make any required disposition decision.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.70(c) or 111.40(a)(3).
5. Final Sec. 111.127(f) and (g)
Final Sec. 111.127(f) requires that quality control operations for
packaging and labeling operations include approving or rejecting any
repackaging of a packaged dietary supplement. Final Sec. 111.127(g)
requires that quality control operations for returned dietary
supplements include approving or rejecting any relabeling of a packaged
and labeled dietary supplement. Final Sec. 111.127(f) and (g) derive
from the following proposed provisions:
Proposed Sec. 111.37(b)(10) which, in part, would require
the quality control unit to approve any repackaging and relabeling and
Proposed Sec. 111.70(d) which would require the quality
control unit to approve and document any repackaging or relabeling of a
dietary supplement.
For consistency with other provisions in this final rule (such as
final Sec. 111.90), final Sec. 111.127(f) and (g) provide that
quality control personnel must clearly choose between approving--or
rejecting--any repackaged or relabeled dietary supplements.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.37(b)(10) or 111.70(d).
6. Final Sec. 111.127(h)
Final Sec. 111.127(h) requires that quality control operations for
packaging and labeling operations include approving for release, or
rejecting, any packaged and labeled dietary supplement (including a
repackaged or relabeled dietary supplement) for distribution. Final
Sec. 111.127(h) derives from the following proposed provisions:
Proposed Sec. 111.37(b)(10) which, in part, would require
the quality control unit to approve the release of packaged and labeled
dietary supplements for distribution; and
Proposed Sec. 111.70(e) which, in part, would require the
quality control unit to approve or reject the release of any repackaged
or relabeled dietary supplement.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.37(b)(10) or 111.70(e).
L. What Quality Control Operations Are Required for Returned Dietary
Supplements? (Final Sec. 111.130)
Final Sec. 111.130 sets forth the minimum required operations
quality control personnel must perform with respect to returned dietary
supplements.
Final Sec. 111.130 modifies proposed Sec. 111.85 which set forth
requirements for returned dietary ingredients and dietary supplements,
including requirements for quality control operations for returned
dietary supplements. We did not explicitly include quality control
operations with respect to returned dietary supplements under proposed
Sec. 111.37 but did include quality control operations in proposed
Sec. 111.85 for returned dietary supplements. The provisions of the
final rule that pertain to returned dietary supplements are set forth
in final subpart N. However, we are duplicating these requirements in
subpart F to make clear that once returned products are back within
your control, quality control personnel must perform appropriate
operations before the products are redistributed, if they are approved
for redistribution. Any returned dietary supplements that are
reprocessed must be returned to your production and process control
system, and, therefore, must be properly reviewed by quality control
personnel.
1. Final Sec. 111.130(a)
Final Sec. 111.130(a) requires that quality control operations for
returned dietary supplements include conducting any required material
review and
[[Page 34873]]
making any required disposition decision. Final Sec. 111.130(a)
differs slightly from proposed Sec. 111.85(a) which, in part, would
require the quality control unit to conduct a material review and make
a disposition decision for any returned dietary supplement.
(Comment 232-233) Some comments support the proposed requirement to
specify that it is the quality control unit that conducts the material
review and makes the disposition decision regarding returned dietary
supplement products.
(Response) These comments are consistent with proposed Sec.
111.85(a) which is being incorporated into final Sec. 111.130(a).
2. Final Sec. 111.130(a)(1) and (a)(2)
Final Sec. 111.130(a)(1) requires that quality control operations
for returned dietary supplements include determining whether tests or
examination are necessary to determine compliance with product
specifications established in accordance with final Sec. 111.70(e).
Final Sec. 111.130(a)(2) requires that the review and disposition
decision for returned dietary supplements include review of the results
of any tests or examinations that are conducted to determine compliance
with product specifications established in accordance with final Sec.
111.70(e).
3. Final Sec. 111.130(b)
Final Sec. 111.130(b) requires that quality control operations for
returned dietary supplements include approving or rejecting any salvage
and redistribution of any returned dietary supplement. Final Sec.
111.130(b) derives from proposed Sec. 111.37(b)(15) which, in part,
would require the quality control unit to approve the distribution of
returned dietary supplements. As discussed in the preamble to the 2003
CGMP Proposal, ``salvage'' means to return to distribution without
reprocessing (68 FR 12157 at 12215).
For consistency with other regulations in this final rule (such as
final Sec. 111.90), final Sec. 111.130(e) provides that quality
control personnel must clearly choose between approving--or rejecting--
any salvage and redistribution.
(Comment 234) Some comments support the proposed requirement to
specify that it is the quality control unit who approves, or rejects, a
returned dietary supplement for redistribution.
(Response) These comments are consistent with proposed Sec.
111.37(b)(15) which is being incorporated into final Sec. 111.130(b).
4. Final Sec. 111.130(c)
Final Sec. 111.130(c) requires that quality control operations for
returned dietary supplements include approving or rejecting any
reprocessing of any returned dietary supplement. Final Sec. 111.130(c)
derives from proposed Sec. 111.37(b)(15) which, in part, would require
the quality control unit to approve the reprocessing of returned
dietary supplements. For consistency with other provisions of this
final rule (such as final Sec. 111.90), final Sec. 111.130(c)
provides that quality control personnel must clearly choose between
approving--or rejecting--any reprocessing.
(Comment 235) One comment argues that the responsibility to decide
whether a returned dietary supplement is reprocessed belongs with
qualified persons in manufacturing operations, and the only
responsibility of the quality control unit is to approve the
reprocessed product for distribution.
(Response) We disagree with the comment. An underlying principle of
these CGMP requirements is that quality control personnel oversee the
design and conduct of manufacturing, packaging, labeling, and holding
operations. A decision about when reprocessing is, or is not,
appropriate requires oversight.
5. Final Sec. 111.130(d)
Final Sec. 111.130(d) requires that quality control operations for
returned dietary supplements include determining whether the
reprocessed dietary supplement meets product specifications and either
approving for release, or rejecting, any returned dietary supplement
that is reprocessed. Final Sec. 111.130(d) derives from the following
proposed provisions:
Proposed Sec. 111.37(b)(2) which, in part, would require
the quality control unit to determine whether all dietary supplements
conform to specifications; and
Proposed Sec. 111.65(d) which, in part, would require
you, if a material review and disposition decision allows you to
reprocess a dietary supplement, to ensure it meets specifications and
is approved by the quality control unit.
For consistency with other regulations in this final rule (such as
final Sec. 111.90), final Sec. 111.130(d) provides that quality
control personnel must clearly choose between approving--or rejecting--
a reprocessed dietary supplement.
We did not receive comments specific to quality control operations
under proposed Sec. Sec. 111.37(b)(2) or 111.65(d).
M. What Quality Control Operations Are Required for Product Complaints?
(Final Sec. 111.135)
Final Sec. 111.135 requires that quality control operations for
product complaints include reviewing and approving decisions about
whether to investigate a product complaint and reviewing and approving
the findings and followup action of any investigation performed.
Final Sec. 111.135 derives from proposed Sec. 111.95 which would
set forth requirements for consumer complaints (now ``product
complaints''), including requirements for quality control operations
for consumer complaints. We did not explicitly include quality control
operations with respect to consumer complaints under proposed Sec.
111.37 but did include quality control operations in proposed Sec.
111.95 for review and investigation of consumer complaints. The final
rule's product complaint requirements are now set forth in final
subpart O. However, we have duplicated the requirements for quality
control operations for product complaints in subpart F to make clear
that your investigation of the product complaint has the potential to
uncover a problem with your production and process control system and,
therefore, quality control personnel must exercise appropriate
oversight of your investigation of any product complaint.
N. What Records Must You Make and Keep? (Final Sec. 111.140)
Final Sec. 111.140 sets forth the requirements for records that
quality control personnel must make and keep.
1. Final Sec. 111.140(a)
Final Sec. 111.140(a) requires quality control personnel to make
and keep records required under subpart F in accordance with subpart P.
Final Sec. 111.140(a) derives from proposed Sec. 111.37(d) with
editorial revisions associated with the reorganization.
Other than comments that generally opposed the requirements to make
and keep records, and to have records available for inspection and
copying by FDA when requested (see the discussion in section V of this
document), we did not receive comments specific to proposed Sec.
111.37(d).
2. Final Sec. 111.140(b)(1)
The final rule (final Sec. 111.103) requires you to establish and
follow written procedures for the responsibilities of the quality
control operations, including written procedures for conducting a
material review and making a disposition decision and for approving or
rejecting
[[Page 34874]]
reprocessing. The written procedures are records. Therefore, final
Sec. 111.140(b)(1) requires you to make and keep a record of the
written procedures for the responsibilities of the quality control
operations.
3. Final Sec. 111.140(b)(2)
Final Sec. 111.140(b)(2) requires written documentation, at the
time of performance, that quality control personnel performed the
review, approval, or rejection requirements under subpart F. Final
Sec. 111.140(b)(2)(i) requires quality control personnel to record the
date that the review, approval, or rejection was performed. Final Sec.
111.140(b)(2)(ii) requires quality control personnel to record the
signature of the person performing the review, approval, or rejection.
Final Sec. 111.140(b)(2) derives from proposed Sec. 111.37(c) with
revisions associated with the reorganization.
We did not receive comments specific to proposed Sec. 111.37(c).
4. Final Sec. 111.140(b)(3)
Final Sec. 111.140(b)(3) requires quality control personnel to
document any material review and disposition decision and followup and
include the documentation in the batch record. Final Sec.
111.140(b)(3) derives from proposed Sec. 111.35(j) with revisions
associated with the reorganization and a revision, associated with
final Sec. 111.87 which requires quality control personnel to conduct
the material review and make the disposition decision.
Final Sec. 111.140(b)(3) details the type of information that must
be included as part of this documentation. Five paragraphs derive from
proposed Sec. 111.35(j)(1) through (j)(5), with editorial changes
associated with the reorganization. One paragraph is associated with
final Sec. 111.90(b) which requires that you not reprocess any
component or dietary supplement that is rejected or treat a component
or make an in-process adjustment to make it suitable for use in the
manufacture of a dietary supplement, unless quality control personnel
conduct a material review and make a disposition decision that is based
on a scientifically valid reason and approve the reprocessing,
treatment, or in-process adjustment. Another paragraph derives, in
part, from proposed Sec. 111.37(c)(2) which would require the
signature of the quality control unit person performing the
requirement.
The documentation that must be included under final Sec.
111.140(b)(3) is as follows:
Section 111.140(b)(3)(i)--Identification of the specific
deviation or the unanticipated occurrence;
Section 111.140(b)(3)(ii)--A description of your
investigation into the cause of the deviation from the specification or
the unanticipated occurrence;
Section 111.140(b)(3)(iii)--An evaluation of whether the
deviation or unanticipated occurrence has resulted in or could lead to
a failure to ensure the quality of the dietary supplement or a failure
to package and label the dietary supplement as specified in the master
manufacturing record;
Section 111.140(b)(3)(iv)--Identification of the action(s)
taken to correct, and prevent a recurrence of, the deviation or the
unanticipated occurrence;
Section 111.140(b)(3)(v)--An explanation of what you did
with the component, dietary supplement, packaging, or label;
Section 111.140(b)(3)(vi)--A scientifically valid reason
for any reprocessing of a dietary supplement that is rejected, or the
treatment or in-process adjustment of a component that is rejected; and
Section 111.140(b)(3)(vii)--The signature of the
individual(s) designated to perform the quality control operation, who
conducted the material review and made the disposition decision, and of
each qualified individual who provided information relevant to that
material review and disposition decision.
We did not receive comments specific to proposed Sec. 111.35(j).
XII. Comments on the Production and Process Control System:
Requirements for Components, Packaging, and Labels, and for Product
that You Receive for Packaging or Labeling as a Dietary Supplement
(Final Subpart G)
A. Organization of Final Subpart G
In the 2003 CGMP Proposal, the requirements for production and
process controls related to components, packaging, dietary ingredients,
labels, and dietary supplements that you receive were set forth in
proposed Sec. 111.40. As shown in table 8 of this document, we are
reorganizing the requirements related to components, packaging, labels,
and product that you receive for packaging and labeling as a dietary
supplement, into a distinct subpart (final Subpart G--Production and
Process Control System: Requirements for Components, Packaging, and
Labels, and for Product that You Receive for Packaging or Labeling as a
Dietary Supplement). Table 8 lists the sections in final subpart G and
identifies the sections in the 2003 CGMP Proposal that form the basis
of the final rule.
Table 8.--Derivation of Sections in Final Subpart G
------------------------------------------------------------------------
Final Rule 2003 CGMP Proposal
------------------------------------------------------------------------
Sec. 111.153 What Are the requirements N/A
under this subpart G for written
procedures?
------------------------------------------------------------------------
Sec. 111.155 What requirements apply to Sec. 111.40(a)(1) through
components of dietary supplements? (a)(5)
Sec. 111.35(d)(1) throug
(d)(5)
------------------------------------------------------------------------
Sec. 111.160 What requirements apply to Sec. 111.35(e)(4)
packaging and labels received? Sec. 111.40(a)(2) and (b)
------------------------------------------------------------------------
Sec. 111.165 What requirements apply to Sec. 111.40(a)
a product received for packaging or
labeling as a dietary supplement (and
for distribution rather than for return
to the supplier)?
------------------------------------------------------------------------
Sec. 111.170 What requirements apply to Sec. 111.74
rejected components, packaging, and
labels, and to rejected products that
are received for packaging or labeling
as a dietary supplement?
------------------------------------------------------------------------
Sec. 111.180 Under this subpart G, what Sec. 111.40(c)(1)(i)
records must you make and keep? through (c)(1)(iv) and
(c)(2)
Sec. 111.35(d)(4)
------------------------------------------------------------------------
B. Highlights of Changes to the Proposed Requirements for Components,
Packaging, and Labels, and Product That You Receive for Packaging or
Labeling as a Dietary Supplement
1. Revisions
The final rule:
Applies to persons who manufacture, package, label, or
hold a dietary supplement unless subject to an exclusion in Sec.
111.1.
Includes requirements that apply to components, including
components that are dietary ingredients, regardless of whether you
receive the components or manufacture them yourself (final Sec. Sec.
111.70(b) and 111.75(a)).
Separates the requirements for product you receive from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather
[[Page 34875]]
than for return to the supplier) (final Sec. 111.165) from the
requirements for components (final Sec. 111.155).
2. Changes After Considering Comments
The final rule incorporates a new requirement to establish and
follow written procedures for fulfilling the requirements for
components, packaging, labels, and product you receive from a supplier
for packaging or labeling as a dietary supplement for distribution
rather than for return to the supplier.
C. General Comments on Proposed Sec. 111.40 (Final Subpart G)
(Comment 236) One comment states that many companies use an
electronic material resource planning system to control the status of
inventory, and assert this type of system provides suitable controls to
ensure only materials that are approved by the quality control unit are
used. The comment notes only the quality control unit has the authority
to release any material in quarantine and asks whether such a system
would comply with the requirements of the proposed regulation.
(Response) Based on the limited information provided by the
comment, it appears the electronic inventory system that the comment
describes would comply with the requirements of final Sec.
111.155(c)(3) to quarantine components until quality control personnel
release them for use in manufacture, provided that appropriate controls
are established and used to ensure the system functions in accordance
with its intended use as required by final Sec. 111.30(e). We are
making no changes based on this comment.
D. What Are the Requirements Under This Subpart for Written Procedures?
(Final Sec. 111.153)
We received many comments that recommended written procedures for
various provisions. We address the need for written procedures
generally in section IV of this document. We also respond to individual
comments on specific provisions in the same section.
Final Sec. 111.153 requires you to establish and follow written
procedures for fulfilling the requirements of subpart G. Under final
Sec. 111.180(b)(1), as a conforming requirement, we require you to
make and keep records of such written procedures. Such records would be
available to us under the requirements in Subpart P--Records and
Recordkeeping.
E. What Requirements Apply to Components of Dietary Supplements? (Final
Sec. 111.155)
The final rule applies only to persons who manufacture, package,
label, or hold dietary supplements unless subject to an exclusion under
final Sec. 111.1. The effect of this revision is that the requirements
that derive from proposed Sec. 111.40(a) for components you receive
now apply to all components, whether you receive them or manufacture
them yourself.
The final rule separates the requirements for product you receive
from a supplier for packaging or labeling as a dietary supplement (and
for distribution rather than for return to the supplier) (final Sec.
111.165) from the analogous requirements for components, packaging, and
labels (final Sec. 111.155).
1. Proposed Sec. 111.35(d)
In proposed Sec. 111.35(d), we would require that any substance,
other than a ``dietary ingredient'' within the meaning of section
201(ff) of the act, that is subject to section 409 of the act, be: (1)
Authorized for use as a food additive under section 409 of the act; or
(2) authorized by a prior sanction consistent with Sec. 170.3(l) (21
CFR 170.3(l)); or (3) if used as a color additive, subject to a listing
that, by the terms of that listing (including a listing for use in
coloring foods generally), includes the use in a dietary supplement; or
(4) GRAS for use in a dietary supplement. We also proposed that any
claim that a substance is GRAS must be supported by a citation to the
agency's regulations or by an explanation for why there is general
recognition of safety of the use of the substance in a dietary
supplement. Further, under Sec. 111.35(d)(5), we proposed to require
that you comply with all other applicable statutory and regulatory
requirements under the act.
We received several comments objecting to one or more of the
provisions of proposed Sec. 111.35(d) and to our statement in the
preamble to the 2003 CGMP Proposal regarding how we would apply the
provisions of proposed Sec. 111.35(d)(4). After considering these
comments, we have deleted the requirements in Sec. 111.35(d) in this
final rule.
(Comment 237) Several comments recommend proposed Sec. 111.35(d)
be deleted because the statute already requires that ingredients, other
than ``dietary ingredients,'' be approved as a food additive or a color
additive, or be GRAS. Some comments assert that proposed Sec.
111.35(d) and proposed Sec. 111.5 already require compliance with all
other applicable statutory and regulatory requirements under the act,
and therefore, there is no need to refer to food additive, color
additive, and GRAS requirements. Some comments assert that proposed
Sec. 111.35(d) is unnecessary because there is no such requirement in
the food CGMPs. Other comments assert this proposed requirement should
be deleted because it is only tangentially related to the manufacturing
process, and CGMP should be focused on setting minimum standards for
manufacturing systems and steps in the production and distribution of
dietary supplements that are required to produce safe and accurately
labeled products. Other comments assert that because the drug CGMPs do
not have such a requirement, dietary supplement CGMPs should not have
such a requirement.
Other comments did not object to the principle underlying proposed
Sec. 111.35(d), i.e., that we need to ensure GRAS substances used in
dietary supplements are GRAS under the manufacturer's specified use.
However many comments disagreed, for various reasons, with the proposed
requirement in Sec. 111.35(d)(4) that a claim that a substance is GRAS
must be supported by a citation to our regulations or by an explanation
for why there is general recognition of safety of the use of the
substance in a dietary supplement.
(Response) We agree that proposed Sec. 111.35(d) is unnecessary
because there are already existing statutory and regulatory
requirements related to the lawful use of ingredients used in dietary
supplements. We do not have to repeat those requirements in this final
rule. Ensuring the ingredients you use to manufacture a dietary
supplement are lawful under the applicable statutory and regulatory
requirements is the responsibility of the dietary supplement
manufacturer.
For the reasons set forth in the previous paragraphs, we are
deleting proposed Sec. 111.35(d)(4) from the final rule. Because we
are deleting this provision, it is unnecessary to respond to the
various comments related to the documentation that proposed Sec.
111.35(d)(4) would have required, or whether we could not have included
such requirements in the dietary supplement CGMP final rule because the
requirements are not in food or drug CGMP regulations.
We also agree that proposed Sec. 111.35(d)(5) is redundant to
proposed Sec. 111.5 and final Sec. 111.5 and are therefore not
repeating proposed Sec. 111.35(d)(5) in final Sec. 111.35.
Although we are deleting Sec. 111.35(d) from the final rule, there
were several
[[Page 34876]]
comments that we received, and respond to in the following paragraphs,
that seemed to question whether existing statutory and regulatory
requirements apply to the use of ingredients in a dietary supplement.
(Comment 238) One comment suggests components not found in finished
goods in a material amount should not be subject to the same GRAS
requirements as those found in a material amount. Another comment
states dietary supplements are excluded from the food additive
definition in section 201(s) of the act, and that components that
constitute the dietary supplement are also excluded from the food
additive definition. The comment suggests that, under proposed Sec.
111.35(d), we are erroneously trying to maintain food additive
authority for dietary supplements.
(Response) The assertion that dietary supplements and all of their
components are not subject to the food additive provisions of the act's
definition is incorrect. We do maintain authority over the use of
certain substances, as color additives, food additives,\10\ or GRAS
substances that may be used in manufacturing dietary supplements.
---------------------------------------------------------------------------
\10\Although we refer to the term ``food additive'' in the
preamble, the reader should also consider color additives and
substances prior-sanctioned for such use as being relevant to the
discussion.
---------------------------------------------------------------------------
The food additive definition in section 201(s) of the act excludes
``an ingredient described in paragraph (ff) in, or intended for use in,
a dietary supplement.'' Thus, a ``dietary ingredient'' described in
section 201(ff)(1) of the act is not a ``food additive.'' Nor can the
use of a dietary ingredient be considered to be GRAS, since the GRAS
status itself is an exception to the definition of a food additive.
However, ingredients that may be used in a dietary supplement, other
than those excepted in section 201(s), are subject to our regulatory
authority as a food additive, unless their use is GRAS or authorized by
a prior sanction. Thus, it is incorrect to say, as the comment asserts,
that dietary supplements and all of their components are not subject to
the food additive definition.
We also disagree that components not found in finished goods in a
material amount should not be subject to the same GRAS requirements as
those found in a material amount. It is not clear what the comment
meant by ``material amount.'' A food additive means ``any substance the
intended use of which results or may reasonably be expected to result,
directly or indirectly, in its becoming a component or otherwise
affecting the characteristics of any food'' if the use of such
substance is not GRAS (section 201(s) of the act).\11\ We have
discretion to determine whether an ingredient is one where the agency
would find the presence to be ``de minimis'' (Monsanto v. Kennedy, 613
F.2d 947, 956 (D.C. Cir. 1979)). However, whether the agency would find
it appropriate to exercise such discretion with respect to the use of a
particular ingredient is beyond the scope of this final rule.
---------------------------------------------------------------------------
\11\It is important to note that it is the use of the substance,
not the substance itself, that must be GRAS. The amount of a
substance in the food is a critical factor in determining whether
the use would be GRAS.
---------------------------------------------------------------------------
(Comment 239) Several comments questioned whether certain
ingredients would be considered GRAS. One comment stated excipients
regularly used in pharmaceuticals for many years and safely used in
dietary supplements may not be considered GRAS for use in foods,
approved for use as a food additive, or considered a dietary
ingredient. An example provided was ``croscarmellose sodium'' used for
disintegration. The comment asks permission to use any recognized
excipient, an excipient that is monographed in a recognized compendium,
used in drug products, or shown to be in use prior to the
implementation of the final rule. Other comments stated proposed Sec.
111.35(d) would be overly burdensome since many ingredients are GRAS
for broad food use, have been used in dietary supplements without
specific recognition as a GRAS use, and should be permitted. Other
comments state substances listed in the USP National Formulary, Food
Chemical Codex, the American Pharmaceutical Associations Handbook of
Pharmaceutical Excipients, and FDA's inactive ingredient guide are
considered GRAS based on a history of common use even though there is
no listing of these substances as GRAS.
(Response) The GRAS status of specific uses of excipients cannot be
treated as a general class and is beyond the scope of this final rule.
It is possible that the data needed to support safe uses as an
excipient in a drug may be widely known among experts and form a basis
for a consensus that use in a dietary supplement is safe. However, use
of drugs containing the excipient may be short term or may be
intermittent, leading to far less exposure than routine use in some
dietary supplements. As human exposure increases, not only does the
safety profile of the intended excipient become more important, but the
purity specifications also become more critical. We advise persons who
need more information about the basis for concluding that a use of a
substance is GRAS to consult Sec. 170.30 and our GRAS Proposal to
establish a notification program for the use of GRAS substances (62 FR
18938, April 17, 1997).
(Comment 240) Some comments assert it is not feasible to require
that starting materials used by bulk ingredient manufacturers be GRAS
or approved food additives. The comments state many ingredients are not
food grade substances or approved for use in food until after
processing. One comment states raw materials may become dietary
ingredients after processing, but the materials from which the dietary
ingredient is derived are not considered to be a GRAS ingredient, a
dietary ingredient, or a dietary supplement. The comment gives examples
of Ginkgo biloba leaves or Saw palmetto or cartilage. The comment asks
us to consider natural products (from animal, mineral, or vegetable
origin) to be included in the rule as potential raw materials for
nutritional supplements. Another comment expresses concern that a soy
isolate, from which natural vitamin E is derived, would not be
considered a GRAS substance.
(Response) These comments seem to be concerned about the regulatory
status of substances used as raw materials in the manufacture of a
dietary ingredient or dietary supplement. An important consideration,
however, is whether such materials become a component of the dietary
ingredient or dietary supplement.
Dietary ingredient manufacturers who manufacture dietary
ingredients for further processing by another person into a dietary
supplement are outside the scope of this final rule. However, such
manufacturers are still subject to other applicable statutory and
regulatory provisions. For example, if you are a dietary ingredient
manufacturer that uses a material in the manufacture of a dietary
ingredient, and the material becomes part of the dietary ingredient, we
would consider it to be part of the dietary ingredient and subject to
the exception to the food additive definition in section 201(s)(6) of
the act. However, because the material becomes a component of the
dietary ingredient, you are subject to the applicable statutory and
regulatory requirements that would apply to the dietary ingredient,
including the safety of the dietary ingredient.
If you use a material, other than a dietary ingredient, in the
manufacture of a dietary supplement, that becomes a
[[Page 34877]]
part of the dietary supplement, you are subject to the applicable
statutory and regulatory requirements that apply to the use of such
material, including its safety for such use. In this case, the use of
the material would be subject to regulation as a food additive (unless
it is GRAS or prior-sanctioned).
Alternatively, if you use material in the manufacture of a dietary
ingredient or a dietary supplement that does not become part of the
dietary ingredient or dietary supplement, then we would not consider
the material to be a food.
(Comment 241) Several comments state the color additive provision
would be too restrictive if it only allowed colors listed for use in a
dietary supplement, rather than colors listed for use in foods
generally. Some comments note none of the color additives currently
approved generally for ``food'' use is approved specifically for
dietary supplements within the food category. Another comment argues we
gave no rationale for requiring a categorical listing under specific
color additives for dietary supplements. The comment states color
additives are not used in any greater amount in supplements than in
foods and, if anything, are probably used less because supplements are
consumed in smaller amounts than foods and less color additive must be
used to achieve the desired effect. One comment notes it was not
familiar with any evidence to indicate that a color additive (whether
it is certified or exempt) found by us to be safe for use in foods is
not safe in dietary supplements.
(Response) We acknowledge that the combination of proposed Sec.
111.35(d)(3) and several color additive listings is confusing and could
lead to incorrect conclusions about whether specific color additives
may lawfully be used in a dietary supplement. As the comments point
out, some listings for color additives (such as for the certified
colors FD&C Blue No. 1 (21 CFR 74.101) and FD&C Red No. 40 (21 CFR
74.340)) list the color additive ``for coloring foods (including
dietary supplements) generally'' (i.e., the listings specifically
identify dietary supplements as a food category in which the color
additive may be used). In contrast, some listings for color additives
(such as for annatto extract (21 CFR 73.30) and for beta-carotene (21
CFR 73.95)) list the color additive ``for coloring foods generally''
(i.e., without specifically identifying dietary supplements as a food
category in which the color additive may be used). In general, the
terms of either of these two kinds of listings (i.e., ``for coloring
foods (including dietary supplements) generally'' and ``for coloring
foods generally'') mean we saw no need for restriction of the use of
the color additive when FDA approved the listing of that color
additive. Thus, a color additive listed for use in food generally may
be used in a dietary supplement.
Although most listings of color additives provide for the use of
the color additive in food generally, some listings for color additives
restrict the use of the color additive in terms of the food category in
which it may be used. For example, under 21 CFR 73.125 sodium copper
chlorophyllin may be safely used to color citrus-based dry beverage
mixes in an amount not exceeding 0.2 percent in the dry mix, and the
terms of this listing would not include the use in a dietary
supplement. We list a color additive with restrictions such as these
when for example, the person who submits a petition for us to approve
the listing of a color additive only requests a specific use, or when
the available data and information only support the safety of a limited
consumption of the color additive.
2. Final Sec. 111.155(a)
Final Sec. 111.155(a) (proposed Sec. 111.40(a)(1)) requires you
to visually examine each immediate container or grouping of immediate
containers in a shipment you receive for appropriate content label,
container damage, or broken seals to determine whether the container
condition may have resulted in contamination or deterioration of the
components. Final Sec. 111.155(a) is substantially similar to proposed
Sec. 111.40(a)(1) which would require you, for components you receive,
to visually examine each container or grouping of containers in a
shipment for appropriate content label, container damage, or broken
seals to determine whether the container condition has resulted in
contamination or deterioration of the components. Because you do not
receive shipments for components you make, we are revising proposed
Sec. 111.40(a) so that it applies only to shipments of components you
receive. We have added the word ``immediate'' to identify the container
as the one in contact with the dietary supplement or component. We also
have changed ``has resulted'' to ``may have resulted'' since in some
cases you may not be able to make a final determination from a visual
inspection alone whether the container condition has resulted in
contamination or deterioration of the components.
(Comment 242) One comment supports the proposed requirements of
proposed Sec. 111.40(a) as an effective guideline for the inspection
of purchased ingredients.
(Response) The provisions of final Sec. 111.155(a) are
requirements, not guidelines, as stated by the comment.
3. Final Sec. 111.155(b)
Final Sec. 111.155(b) (proposed Sec. 111.40(a)(2)) requires you
to visually examine the supplier's invoice, guarantee, or certification
in a shipment you receive to ensure that the components are consistent
with your purchase order. Final Sec. 111.155(b) is substantially
similar to proposed Sec. 111.40(a)(2) which would require you to
visually examine the supplier's invoice, guarantee, or certification to
ensure the components are consistent with your purchase order and
perform testing, as needed, to determine whether specifications are
met. As with final Sec. 111.155(a), final Sec. 111.155(b) clarifies
that the invoice, guarantee, or certification comes in the shipment you
receive.
Final Sec. 111.155(b) does not include any requirements related to
testing components. Final Sec. 111.75(a) sets forth the requirements
to test or examine components; final Sec. Sec. 111.110 and 111.120 set
forth requirements for quality control personnel to ensure that
appropriate tests or examinations are conducted, review the results of
any tests or examination, determine whether components conform to
specifications, and approve the components before they are used in the
manufacture of a dietary supplement. Given this set of requirements, it
would be redundant to set forth requirements regarding testing for
components in final subpart G.
We did not receive comments specific to the requirements of
proposed Sec. 111.40(a)(2).
4. Final Sec. 111.155(c)
Final Sec. 111.155(c) (proposed Sec. 111.40(a)(3)) requires you
to quarantine components before you use them in the manufacture of a
dietary supplement until:
You collect representative samples of each unique lot of
components (and, for components that you receive, of each unique
shipment, and of each unique lot within each unique shipment);
Quality control personnel review and approve the results
of any test or examinations conducted on components; and
Quality control personnel approve the components for use
in the manufacture of a dietary supplement, including approval of any
treatment (including in-process adjustments) of components to make them
suitable for use in the manufacture of a dietary supplement, and
release them from quarantine.
[[Page 34878]]
Final Sec. 111.155 modifies proposed Sec. 111.40(a)(3) which
would require:
You to quarantine components until your quality control
unit reviews the supplier's invoice, guarantee, or certification;
The quality control unit to perform testing, as needed, of
a representative sample to determine that specifications are met;
You to conduct a material review and make a disposition
decision if specifications are not met; and
The quality control unit to approve and release the
components from quarantine before you use them.
Final Sec. 111.155(c) includes revisions related to the following
changes to other provisions already discussed.
Under final Sec. 111.110, quality control personnel
ensure that all appropriate tests and examinations are conducted, and
review and approve the results of tests and examinations conducted on
components, but quality control personnel are not required to conduct
the tests or examinations;
Under final Sec. 111.80(a), we establish the convention
in this final rule of referring to ``each unique lot within each unique
shipment'' rather than ``each shipment lot;''
The requirements to conduct a material review and make a
disposition decision are already set forth in final Sec. Sec. 111.87,
111.113, and 111.120 and, therefore, are not repeated in final Sec.
111.155; and
Under final Sec. 111.90(c), any batch of dietary
supplement that is reprocessed, that contains components that you have
treated, or to which you have made in-process adjustments to make them
suitable for use in the manufacture of the dietary supplement, must
meet all product specifications for the dietary supplement and be
approved by quality control personnel before being released for
distribution.
(Comment 243) Some comments address the requirement to quarantine
components before you use them and assert that it is not feasible to
quarantine incoming materials in a continuous extraction and
purification operation, such as one built adjacent to a soy crushing or
vegetable oil refinery to receive a continuous side stream flow from
that operation. One comment explains that in such operations,
quarantine and quality control approval occurs later in the process
after the material has been isolated and concentrated in a stable
matrix suitable for holding. One comment suggests proposed Sec.
111.40(a)(3) state ``quarantine components or dietary supplements as
applicable * * *''.
(Response) We decline to revise proposed Sec. 111.40(a)(3) as
suggested by the comments. The comment describes a situation where a
manufacturer of a dietary supplement is also manufacturing a dietary
ingredient or other component but only provides limited information. It
appears that, however, the procedures described for quarantine of the
isolated, stable matrix, with subsequent evaluation by quality control
personnel before release for use in the manufacture of the dietary
supplement, would satisfy the requirements of final Sec. 111.155(c),
provided quality control personnel are able to determine that all
specifications for the component are met.
(Comment 244) One comment states that plant personnel who are not
formally part of the manufacturer's quality control unit can conduct
the quality control functions required for the release of materials
from quarantine before use.
(Response) As already discussed with respect to the definition of
quality control personnel (see section VI of this document), these
comments may have misunderstood the role of the quality control unit
(now quality control personnel). To clarify that role, final Sec.
111.12(b) states you must identify a qualified person who is
responsible for your quality control operations.
(Comment 245) One comment suggests components that cannot be used
in a short time should be retested at least yearly.
(Response) We are making no changes to the provision after
considering this comment. Whether any tests or examinations must be
repeated over time, or whether the information in a certificate of
analysis remains valid over time, is a matter to be decided by the
manufacturer based on the established characteristics and shelf life of
the component.
5. Final Sec. 111.155(d)
Final Sec. 111.155(d)(1) (proposed Sec. 111.40(a)(4)) requires
you to identify each unique lot within each unique shipment of
components you receive and any lot of components that you produce in a
manner that allows you to trace the lot to the supplier, the date
received, the name of the component, the status of the component (e.g.,
quarantined, approved, or rejected), and to the dietary supplement you
manufactured and distributed. Final Sec. 111.155(d)(2) requires you to
use this unique identifier whenever you record the disposition of each
unique lot within each unique shipment of components that you receive
and any lot of components that you produce.
Final Sec. 111.155(d)(1) and (d)(2) are substantially similar to
proposed Sec. 111.40(a)(4) which would require you to identify each
lot of components in a shipment in a manner that allows you to trace
the shipment to the supplier, the date received, the name of the
component, and the status (e.g., quarantined, approved, or rejected),
and to trace the shipment lot to the dietary supplement you
manufactured and distributed. Proposed Sec. 111.40(a)(4) also would
require you to use this unique identifier whenever you record the
disposition of each shipment lot received.
Final Sec. 111.155(d)(1) and (d)(2) include revisions associated
with final Sec. 111.80(a).
We did not receive comments specific to proposed Sec.
111.40(a)(4).
6. Final Sec. 111.155(e)
Final Sec. 111.155(e) (proposed Sec. 111.40(a)(5)) requires you
to hold components under conditions that will protect against
contamination and deterioration and avoid mixups.
We did not receive comments specific to proposed Sec.
111.40(a)(5).
F. What Requirements Apply to Packaging and Labels Received? (Final
Sec. 111.160)
1. Final Sec. 111.160(a)
Final Sec. 111.160(a) (proposed Sec. 111.40(b)(1)) requires you
to visually examine each immediate container or grouping of immediate
containers in a shipment for appropriate content label, container
damage, or broken seals to determine whether the container condition
may have resulted in contamination or deterioration of the packaging
and labels. Final Sec. 111.160(a) is similar to proposed Sec.
111.40(b)(1) with the addition of the word ``immediate'' to identify
the container as the container that is in contact with the packaging or
labels and substituting ``may have'' for ``has'' before the word
``resulted'' as discussed in this section.
We did not receive comments specific to proposed Sec.
111.40(b)(1).
2. Final Sec. 111.160(b)
Final Sec. 111.160(b) requires you to visually examine the
supplier's invoice, guarantee, or certification in a shipment to ensure
the packaging or labels are consistent with your purchase order. Final
Sec. 111.160(b) is a new requirement that is analogous to proposed
Sec. 111.40(a)(2). We are requiring in final Sec. 111.160(b), that,
as part of your visual identification, you compare what was received,
based on the supplier's invoice, guarantee, or certification, with
[[Page 34879]]
your purchase order so you can ensure your specifications for packaging
and labels are met. This is consistent with what you would do with
respect to components and dietary supplements you receive. Without
final Sec. 111.160(b), the review by quality control personnel under
final Sec. 111.120(a) would be a matter of performing receiving
operations rather than performing quality control operations; as
already discussed in this section, some comments asserted the quality
control unit should focus on reviewing the work of others rather than
conducting the operations themselves. Thus, final Sec. 111.160 is
consistent with these comments.
3. Final Sec. 111.160(c)
Final Sec. 111.160(c) requires you to quarantine packaging and
labels before you use them in the manufacture of a dietary supplement
until:
You collect representative samples of each unique
shipment, and of each unique lot within each unique shipment, of
packaging and labels and, at a minimum, conduct a visual identification
of the immediate containers and closures;
Quality control personnel review and approve the results
of any tests or examinations conducted on the packaging and labels; and
Quality control personnel approve the packaging and labels
for use in the manufacture of a dietary supplement and release them
from quarantine.
Final Sec. 111.160(c) is similar to proposed Sec. 111.40(b)(2)
which would require that:
You quarantine packaging and labels until your quality
control unit tests or examines a representative sample to determine
that specifications are met;
You conduct at least a visual identification of the
containers and closures;
If specifications are not met, you conduct a material
review and make a disposition decision; and
Your quality control unit approve and release packaging
and labels from quarantine before you use them.
Final Sec. 111.160(c) includes revisions that reflect the
following change already discussed in this final rule:
Refers to ``each unique lot within each unique shipment''
rather than ``each shipment lot''.
We did not receive comments specific to proposed Sec.
111.40(b)(2).
4. Final Sec. 111.160(d)
Final Sec. 111.160(d)(1) requires you to identify each unique lot
within each unique shipment of packaging and labels in a manner that
allows you to trace the lot to the supplier, the date received, the
name of the packaging and label, the status of the packaging and label
(e.g., quarantined, approved, or rejected), and to the dietary
supplement you distributed. Final Sec. 111.160(d)(2) requires you to
use this unique identifier whenever you record the disposition of each
unique lot within each unique shipment of packaging and labels. Final
Sec. 111.160(d) derives from proposed Sec. 111.40(b)(3) which would
require you to identify each shipment lot of packaging and labels in a
manner that allows you to trace the shipment lot to the supplier, the
date received, the name of the packaging and label and the status
(e.g., quarantined, approved, or rejected) and to trace the shipment
lot to the dietary supplement manufactured and distributed. Proposed
Sec. 111.40(b)(3) also would require that you use this unique
identifier whenever you record the disposition of each shipment lot
received.
Final Sec. 111.160(d) includes revisions that reflect the
following changes already discussed in this final rule:
Reference to ``each unique lot within each unique
shipment'' rather than ``each shipment lot.''
As a clarification, final Sec. 111.160(d)(2) refers to
the ``dietary supplement that you distributed'' rather than to the
``dietary supplement manufactured and distributed'' to avoid a narrow--
and incorrect--interpretation of ``manufactured.'' Under proposed Sec.
111.40(b)(3), we used the term ``manufactured'' in a broad sense that
includes any aspect of the manufacturing process rather than a narrow
sense that applied to manufacturing operations for producing a batch of
dietary supplement. Both proposed Sec. 111.40(b)(3) and final Sec.
111.160(e) address the need to trace the packaging and labels that you
use to the product that you distribute, regardless of whether your role
in the manufacturing process includes the production of the batch or
includes only packaging a dietary supplement you receive from a
supplier.
(Comment 246) One comment believes packaging and labels are rarely
the source of quality problems. This comment suggests proposed Sec.
111.40(b)(3) allow the use of packaging approved by the quality control
unit without the need to use a specific lot identification number. The
comment explains that this type of flexibility is needed when they have
dozens of short run lots each day and use less than a carton of
packaging supplies for each run.
(Response) This comment may have misinterpreted proposed Sec.
111.40(b)(3). Under proposed Sec. 111.40(b)(3) (final Sec.
111.160(d)) you must assign the identifier to each unique lot within
each unique shipment of packaging and labels when you receive them
rather than each time that you use them. This number would stay the
same for each of the short runs described by the comment. We are making
no changes to the requirement.
5. Final Sec. 111.160(e)
Final Sec. 111.160(e) requires you to hold packaging and labels
under conditions that will protect against contamination and
deterioration, and avoid mixups. Final Sec. 111.160(e) is identical to
proposed Sec. 111.40(b)(4).
We did not receive comments specific to proposed Sec.
111.40(b)(4).
G. What Requirements Apply to a Product Received for Packaging or
Labeling as a Dietary Supplement (and for distribution rather than for
return to the supplier)? (Final Sec. 111.165)
Final Sec. 111.165 (proposed Sec. 111.40(a)) sets out actions you
must take when you receive a product for packaging and labeling and for
distribution. Final Sec. 111.165 includes editorial changes associated
with the reorganization and revisions that reflect changes we are
making to other sections of the final rule.
Final Sec. 111.165 sets forth requirements for ``product that you
receive from a supplier for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier)'' rather than for ``dietary supplements that you receive.''
The final rule separates the requirements in proposed Sec.
111.40(a) for product that you receive from a supplier for packaging or
labeling as a dietary supplement (and for distribution rather than for
return to the supplier) (final Sec. 111.165) from the analogous
requirements for components, packaging, and labels (final Sec.
111.155).
1. Final Sec. 111.165(a)
Final Sec. 111.165(a) requires you to visually examine each
immediate container or grouping of immediate containers in a shipment
of product you receive for packaging or labeling as a dietary
supplement (and for distribution rather than for return to the
supplier) for appropriate content label, container damage, or broken
seals to determine whether the container condition may have resulted in
contamination or deterioration of the received product. Final Sec.
111.165(a) is substantially similar to proposed Sec. 111.40(a)(1)
[[Page 34880]]
which, in part, would impose this requirement for dietary supplements
you receive. We have added the word ``immediate'' to identify the
container as the container that is in contact with the product you
receive for packaging or labeling as a dietary supplement and
substituted ``may have'' for ``has'' before the word ``resulted'' as
explained in this section.
2. Final Sec. 111.165(b)
Final Sec. 111.165(b) requires you to visually examine the
supplier's invoice, guarantee, or certification in a shipment of the
received product to ensure the received product is consistent with your
purchase order. Final Sec. 111.165(b) is substantially similar to
proposed Sec. 111.40(a)(2) which, in part, would establish a similar
requirement for dietary supplements that you receive.
3. Final Sec. 111.165(c)
Final Sec. 111.165(c) requires you to quarantine the received
product until:
You collect representative samples of each unique
shipment, and of each unique lot within each unique shipment, of
received product;
Quality control personnel review and approve the
documentation to determine whether the received product meets the
specifications that you established under Sec. 111.70(f); and
Quality control personnel approve the received product for
packaging or labeling as a dietary supplement and release the received
product from quarantine.
Final Sec. 111.165(c) is similar to proposed Sec. 111.40(a)(3)
which, in part, would require that:
You quarantine dietary supplements that you receive until
your quality control unit reviews the suppliers invoice, guarantee, or
certification;
The quality control unit performs testing, as needed, of a
representative sample to determine that specifications are met;
You conduct a material review and make a disposition
decision if specifications are not met; and
The quality control unit approves and releases the dietary
supplements that you receive from quarantine before you use them.
Final Sec. 111.165(c) includes revisions that reflect that under
final Sec. 111.75(e) before you package or label a product you
received for packaging or labeling as a dietary supplement, you must
visually examine the product and have documentation to determine
whether the specifications you established under Sec. 111.70(f) are
met, but not otherwise examine or conduct tests.
4. Final Sec. 111.165(d)
Final Sec. 111.165(d)(1) requires that you identify each unique
lot within each unique shipment of received product in a manner that
allows you to trace the lot to the supplier, the date received, the
name of the received product, the status of the received product (e.g.,
quarantined, approved, or rejected), and to the product you packaged or
labeled and distributed as a dietary supplement. Final Sec.
111.165(d)(2) requires you to use this unique identifier whenever you
record the disposition of each unique lot within each unique shipment
of the received product. Final Sec. 111.165(d) derives from proposed
Sec. 111.40(a)(4) which would require you, in part, to identify each
lot of dietary supplements in a shipment in a manner that allows you to
trace the shipment to the supplier, the date received, the name of the
dietary supplement, and the status (e.g., quarantined, approved, or
rejected), and to trace the shipment lot to the dietary supplement
manufactured and distributed. Proposed Sec. 111.40(a)(4) also would
require you to use this identifier whenever you record the disposition
of each shipment lot received.
Final Sec. 111.165(d) includes a revision associated with final
Sec. 111.80 referring to ``each unique lot within each unique
shipment'' rather than ``each shipment lot.''
5. Final Sec. 111.165(e)
Final Sec. 111.165(e) requires you to hold the received product
under conditions that will protect against contamination and
deterioration, and avoid mixups. Final Sec. 111.165(e) derives from
proposed Sec. 111.40(a)(5) with editorial changes associated with the
reorganization.
H. What Requirements Apply to Rejected Components, Packaging, and
Labels, and to Rejected Products That Are Received for Packaging or
Labeling as a Dietary Supplement? (Final Sec. 111.170)
Final Sec. 111.170 requires you to clearly identify, hold, and
control under a quarantine system for appropriate disposition any
component, packaging, and label, and any product you receive for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier), that is rejected and
unsuitable for use in manufacturing, packaging, or labeling operations.
Final Sec. 111.170 is substantially similar to proposed Sec. 111.74
which would require you to clearly identify, hold, and control under a
quarantine system any component, dietary supplement, packaging, and
label that is rejected and unsuitable for use in manufacturing,
packaging, or labeling operations.
We did not receive comments specific to proposed Sec. 111.74.
Final Sec. 111.170 includes revisions associated with the series of
provisions that distinguish a product you receive for packaging or
labeling as a dietary supplement (and for distribution rather than for
return to the supplier) from a dietary supplement you manufacture.
I. Under This Subpart, What Records Must You Make and Keep? (Final
Sec. 111.180)
Final Sec. 111.180 sets forth the requirements to make and keep
records associated with components, packaging, labels, and product you
receive for packaging and labeling as a dietary supplement. Final Sec.
111.180 derives from proposed Sec. 111.40(c).
1. Final Sec. 111.180(a)
Final Sec. 111.180(a) requires you to make and keep records
required under subpart G in accordance with subpart P. Final Sec.
111.180(a) derives from proposed Sec. 111.40(c)(2), with editorial
changes associated with the reorganization.
We did not receive comments specific to the requirements set forth
in final Sec. 111.180(a).
2. Final Sec. 111.180(b)(1)
Final Sec. 111.153 requires you to establish and follow written
procedures to fulfill the requirements of subpart G. These written
procedures are records. Therefore, final Sec. 111.180(b)(1) requires
you to make and keep a record of the written procedures for fulfilling
the requirements of subpart G.
3. Final Sec. 111.180(b)(2)
Final Sec. 111.180(b)(2) requires you to make and keep receiving
records (including records such as certificates of analysis, suppliers'
invoices, and suppliers' guarantees) for components, packaging, and
labels, and for products you receive for packaging or labeling as
dietary supplements (and for distribution rather than for return to the
supplier). Final Sec. 111.180(b)(2) derives from proposed Sec.
111.40(c)(2) with editorial changes associated with the reorganization.
Final Sec. 111.180(b)(2) also includes revisions associated with the
series of provisions that distinguish a product you receive for
packaging or labeling as a dietary supplement (and for distribution
rather than for return to the supplier) from a dietary supplement you
manufacture. Because the final rule provides that you may rely, under
[[Page 34881]]
certain circumstances, on a certificate of analysis to ensure that some
component specifications are met (final Sec. 111.75(a)(2)(ii)) and
that you may rely, in part, on documentation to determine whether
specifications for received products are met, we specifically identify
a certificate of analysis and common forms of documentation as being
``receiving records'' for purposes of this rule.
(Comment 247) One comment on proposed Sec. 111.40(c)(2) points out
the recordkeeping requirements of any final rule will be a costly
burden for a company that produces multiple ingredient products in
several packaging configurations and will be much greater than the
burden for a company that produces batches of single ingredient
products in one packaging configuration.
(Response) We acknowledge that companies that produce multiple
ingredient products in several packaging configurations will have more
records to keep than companies that produce single ingredient products
in one packaging configuration. However, these records are necessary to
be able to determine the source of the component, packaging, and
labels, so that if adulteration of the dietary supplement occurs, the
records will show the source of the material so that its use can be
stopped.
4. Final Sec. 111.180(b)(3)
Final Sec. 111.180(b)(3) requires you to make and keep
documentation that the requirements of subpart G were met. Under final
Sec. 111.180(b)(3)(i), the person who performs the required activity
must document, at the time of performance, that the required operation
was performed. Under final Sec. 111.180(b)(3)(ii), the documentation
must include:
The date that the components, packaging, labels, or
products you receive for packaging or labeling as a dietary supplement
were received;
The initials of the person performing the required
operation;
The results of any tests or examinations conducted on
components, packaging, or labels, and of any visual examination of
product you receive for packaging or labeling as a dietary supplement;
and
Any material review and disposition decision conducted on
components, packaging, labels, or products that you receive for
packaging or labeling as a dietary supplement.
Final Sec. 111.180(b)(3) differs from proposed Sec.
111.40(c)(1)(i) through (c)(1)(iv), by referring to ``required
operation'' rather than ``requirement.'' Additionally as a conforming
revision associated with final Sec. 111.75(a) which requires
appropriate tests and examinations, final Sec. 111.180(b)(3) requires
you to include in the documentation the results of any examinations as
well as tests. Final Sec. 111.180(b)(3) also includes revisions
associated with the series of changes that distinguish a product that
you receive for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier) from a dietary
supplement that you manufacture.
(Comment 248) A few comments note proposed Sec. 111.40(c) requires
the signature of the person performing the requirement, whereas other
sections of the 2003 CGMP Proposal, such as proposed Sec.
111.50(c)(2), only require the initials of the person performing the
requirement. One comment requests the format for the requirement to
document the person performing the step be made consistent throughout
the regulations.
(Response) We agree that the identity of the person performing a
requirement should be required throughout the final rule and that this
can be accomplished through initials except for operations that are
performed by quality control personnel. Therefore, we are revising the
requirements so that a signature (and not initials) is required for any
operation performed by quality control personnel (see final Sec.
111.140). Because Sec. 111.40(c)(1)(ii) is not a quality control
operation, we also revised proposed Sec. 111.40(c)(1)(ii) (final Sec.
111.180(b)(3)) to require the initials, rather than the signature, of
the person performing the required operation. Initials are required for
other circumstances that do not involve quality control operations,
including final Sec. 111.180(b)(3). However, whenever this final rule
requires initials, a signature is also acceptable, because a signature
would achieve the goal of identifying the person who performed the
requirement.
XIII. Comments on the Production and Process Control System:
Requirements for the Master Manufacturing Record (Final Subpart H)
A. Organization of Final Subpart H
In the 2003 CGMP Proposal, the requirements for the master
manufacturing record were set forth in proposed Sec. 111.45. As shown
in table 9 of this document, we are setting forth the requirements for
the master manufacturing record in a distinct subpart (final Subpart
H--Production and Process Control System: Requirements for the Master
Manufacturing Record). Table 9 lists the sections in final subpart H
and identifies the proposed provisions that form the basis for the
final rule.
Table 9.--Derivation of Sections in Final Subpart H
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Final Rule 2003 CGMP Proposal
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Sec. 111.205 What is the requirement to Sec. 111.45(a)(1), (a)(2),
establish a master manufacturing record? and (d)
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Sec. 111.210 What must the master Sec. 111.45(b)
manufacturing record include?
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The requirements in final subpart H are set forth from the
perspective of the manufacture of a batch of a dietary supplement. You
must comply with all requirements that pertain to your activity.
However, you must comply with the requirement to prepare and follow a
``master manufacturing record'' regardless of whether you manufacture a
batch, or whether you package or label product you receive from a
supplier for packaging or labeling as a dietary supplement (and for
distribution rather than for return to the supplier). If you are a
packager or labeler, you only need to include those parts relevant to
your process. For example, if you are a labeler, under final Sec.
111.210(c) you would not need to include an accurate statement of the
weight or measure of each component to be used because you would be
starting from packages already filled.
B. Highlights of Changes to the Proposed Requirements for the Master
Manufacturing Record
1. Revisions
The final rule:
Includes revisions that reflect that the final rule
applies to persons who manufacture, package, label, or hold dietary
supplements unless subject to an exclusion in Sec. 111.1;
Includes revisions so the requirements for the master
manufacturing record are consistent with final Sec. 111.70(a) which
requires you to establish a specification for any point, step, or stage
in the manufacturing process where control is necessary to ensure the
quality of the dietary supplement and that the dietary supplement is
packaged and labeled as specified in the master manufacturing record;
and
Includes a revision associated with final Sec. 111.75(h),
which provides for the use of either tests or examinations for
complying with the requirements of part 111.
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2. Changes Associated With the Reorganization
The proposed requirement (Sec. 111.45(c)) that the quality control
unit approve each master manufacturing record and any modifications to
a master manufacturing record is set forth as final Sec. 111.123(a) in
subpart F, rather than in final subpart H, with the changes we made to
the definition of ``quality control unit'' to ``quality control
personnel'' as explained in section VI of this document (subpart A).
3. Changes After Considering Comments
The final rule:
Retains a requirement to state any intentional overage of
a dietary ingredient but does not require an explanation for such an
overage;