SEQ CHAPTER \h \r 1 DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 111

[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.

SUMMARY:  The Food and Drug Administration (FDA, we) 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 [insert date 60 days after date of
publication in the Federal Register].

Compliance Dates: The compliance date is [insert date 12 months after
date of publication in the Federal Register]; except that for businesses
employing fewer than 500, but 20 or more full-time equivalent employees,
the compliance date is [insert date 24 months after date of publication
in the Federal Register]; and except that for businesses that employ
fewer than 20 full-time equivalent employees, the compliance date is
[insert date 36 months after date of publication in the Federal
Register].

FOR FURTHER INFORMATION CONTACT:

     Vasiliosf Frankos

     Center for Food Safety and Applied Nutrition (HFS-xxx),

     Food and Drug Administration,

     5100 Paint Branch Pkwy.,

     College Park, MD 20740,

<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

SUPPLEMENTARY INFORMATION:

Table of Contents

Background & Related Information -- What Led Us to Issue This Rule?

How is the Final Rule Organized?

What Does the Final Rule Do?

Overview of CGMP

Highlights of the Final Rule

What General Comments Did We Receive?

What Comments Did We Receive on the Structure and Organization of the
Rule?

What Comments Did We Receive on the Need for Dietary Supplement CGMP
Requirements?

What Comments Did We Receive on Written Procedures?

Overview

Written Procedures that Are Required by This Final Rule.

Written procedures for personnel (final subpart B).

Written procedures for cleaning the physical plant, including pest
control (final subpart C).

Written procedures for calibrating instruments and controls and for
calibrating, inspecting, and checking automated, mechanical, or
electronic equipment (final subpart D).

Written procedures for maintaining, cleaning, and sanitizing equipment
and utensils (final subpart D).

	Written procedures for quality control operations, including written
procedures for conducting a material review and making a disposition
decision and written procedures for approving reprocessing (final
subpart F).

Written procedure for components, packaging, labels, and product that is
received for packaging and labeling as a dietary supplement (final
subpart G).

Written procedures for laboratory operations (final subpart J).

Written procedures for manufacturing operations (final subpart K).

Written procedures for packaging and labeling operations (final subpart
L).

Written procedures for holding and distributing operations (final
subpart M).

Written procedures for returned dietary supplements (final subpart N).

Written procedures for product complaints (final subpart O).

Written Procedures That are Not Required by This Final Rule

Written procedures for final subpart E (Requirement to Establish a
Production and Process Control System).

Written procedures for preparing the master manufacturing record (final
subpart H) and for preparing the batch record (final subpart I).

Written procedures for Records and Recordkeeping (final subpart P).

Written procedures for product recalls.

Other Comments on Written Procedures

What Other General Comments Did We Receive?

What Legal Authority Comments Did We Receive?

Modeled After CGMP for Food

Records Authority

Public Health Service Act Authority

The communicable disease risk posed by dietary supplements.

Activities for which we are asserting legal authority under the PHS Act.

The interstate commerce nexus for the final rule.

The PHS Act.

The act.

Commerce Clause.

Fifth Amendment.

Miscellaneous.

What Comments Did We Receive on the General Provisions?

(Subpart A)

Organization of Final Subpart A

Who Is Subject to These Regulations? (Final § 111.1)

What Definitions Apply to This Part? (Final § 111.3)

Actual Yield

Batch

Batch Number, Lot Number, or Control Number

Component

Contact Surface

Ingredient

In process Material

Lot

Microorganisms

	10. Must

	11. Pest

	12. Physical Plant

	13. Product Complaint

	14. Quality

	15. Quality Control

	16. Quality Control UnitPersonnel

	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?

Identity.

Purity.

Strength.

Composition.

Other terms.

	26. What Definitions Did the Comments Want

             Us to Delete?

D. Do Other Statutory Provisions and Regulations Apply?

(Final § 111.5)

	E. What Sections Did We Remove From the Rule, and Why?

 	1.  “What Are These Regulations Intended to

	Accomplish?”

2. “Exclusions” (Proposed § 111.6)

	 		VII.  Comments on Personnel

(Final Subpart B)

Organization of Final Subpart B

Highlights of Changes to the Proposed Requirements for Personnel

Revisions

Changes After Considering Comments

General Comments on Proposed Subpart B

What Are the Requirements Under This Subpart for Written Procedures?
(Final § 111.8)

What Requirements Apply for Preventing Microbial Contamination From Sick
or Infected Personnel and for Hygienic Practices?(Final § 111.10)

Final § 111.10(a)

Final § 111.10(b)

What Personnel Qualification Requirements Apply? (Final § 111.12)

What Supervisor Requirements Apply?(Final § 111.13)

Under This Subpart, What Records Must You Make and Keep?(Final
§ 111.14)

  SEQ CHAPTER \h \r 1 VIII.  Comments on Physical Plant and Grounds

(Final Subpart C)

Organization of Final Subpart C

Highlights of Changes to the Proposed Requirements for Physical Plant
and Grounds

Revisions

Changes After Considering Comments

General Comments on Proposed Subpart C

What Sanitation Requirements Apply to Your Physical Plant?  (Final §
111.15)

Final § 111.15(a)

Final § 111.15(b)(1)

Final § 111.15(c) (Proposed § 111.15(b))

Final § 111.15(d)

Final § 111.15(e)

Final § 111.15(f)

Final § 111.15(g)

Final § 111.15(h)

Final § 111.15(i)

Final § 111.15(j)

Final § 111.15(k)

E. What Are the Requirements Under This Subpart for Written

   Procedures?(Final § 111.16)

F. What Design and Construction Requirements Apply to Your

   	   Physical Plant?(Final § 111.20)

1.  Final § 111.20(a) and (b)

2.  Final § 111.20(c)

3.  Final § 111.20(d)

	 	4.  Final § 111.20(e)

5.  Final § 111.20(f)

6.  Final § 111.20(g)

7.  Final § 111.20(h)

G. Under This Subpart, What Records Do You Make and Keep?

  	(Final § 111.23)

IX.  Comments on Requirements Related to

Equipment and Utensils

(Subpart D)

Organization of Final Subpart D

Highlights of Changes to the Proposed Requirements for Equipment and
Utensils

1. Revisions

2. Revisions Associated With the Reorganization.

3. Changes After Considering Comments

General Comments on Proposed Subpart D.

What Are the Requirements Under This Subpart for Written
Procedures?(Final § 111.25)

Final § 111.25

What Requirements Apply to the Equipment and Utensils?(Final § 111.27)

Final 111.27(a)

Final § 111.27(a).

Final § 111.27(a)(2).

Final § 111.27(a)(3).

Final § 111.27(a)(4).

Final § 111.27(a)(5).

Final § 111.27(a)(6).

Final § 111.27(a)(7).

Final § 111.27(b)

Final § 111.27(c)

Final § 111.27(d)

Final § 111.27(d)(1)

Final § 111.27(d)(2)

Final § 111.27(d)(3)

Final § 111.27(d)(4)

Final § 111.27(d)(5)

Final § 111.27(d)(6)

Final § 111.27(d)(7)

Reorganization of Certain Paragraphs in Proposed § 111.25.

What Requirements Apply to Automated, Mechanical, or Electronic
Equipment?(Final § 111.30)

Comments on the Organization and Framework of Proposed § 111.30

Comments Specific to Proposed § 111.30

Final § 111.30(a) and (b)

Final § 111.30(c)

Final § 111.30(d)

Final § 111.30(e)

3. Reorganization of Certain Paragraphs in Proposed §

   	111.30

H.  Under this Subpart, What Records Must You Make and

    Keep? (Final § 111.35)

Final § 111.35(a)

Final § 111.35(b)(1) and (b)(2)

Final § 111.35(b)(3)

Final § 111.35(b)(4)

Final § 111.35(b)(5)

Final § 111.35(b)(6)

X.   Comments on Requirement to Establish a Production and Process
Control System

(Final Subpart E)

Reorganization of Proposed § 111.35 into Final Subpart E

General Comments on Proposed § 111.35

Final Subpart E and Highlights of Changes to the Proposed Regulations

Revisions

What Are the Requirements to Implement a Production and Process Control
System? (Final § 111.55)

What Are the Design Requirements for Your Production and Process Control
System? (Final § 111.60)

What Are the Requirements For to Use a Quality Control UnitOperations?
(Final § 111.65)

What Specifications Must You Establish? (Final § 111.70)

Final § 111.70(a)

Final § 111.70(b)

Final § 111.70(c)

Final § 111.70(d)

Final § 111.70(e)

Final § 111.70(f)

Final § 111.70(g)

What is Your Responsibility for Determining Whether Established
Specifications are Met? (Final § 111.73)

What Must You do to Determine Whether Specifications are Met? (Final
§ 111.75)

Final § 111.75(a)

Final § 111.75(b)

Final § 111.75(c) and (d)

Final § 111.75(e)

Final § 111.75(f)

Final § 111.75(g)

Final § 111.75(h)

Final § 111.75(i)

J. What Must You do if Established Specifications are Not

   Met? (Final § 111.77)

	1. Final § 111.77

	2. Final § 111.77 (a)

	3. Final § 111.77 (b)

	4. Final § 111.77 (c)

K. Comments on Shelf-Life

L. What Representative Samples Must You Collect?

   (Final § 111.80)

Final § 111.80(a)

Final § 111.80(b)

Final § 111.80(c)

Final § 111.80(d)

Final § 111.80(e)

M. What Are the Requirements for Reserve Samples?

   (Final § 111.83)

Final § 111.83(a)

Final § 111.83(b)(1)

Final § 111.83(b)(2)

Final § 111.83(b)(3)

Final § 111.83(b)(4)

	N. Who Conducts a Material Review and Makes a Disposition

   	Decision? (Final § 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 § 111.70 is not
Met? (Final § 111.90)

Final § 111.90

Final § 111.90(a)

Final § 111.90(b)

Final § 111.90(c)

	P. Under this Subpart, What Records Must You Make and Keep?

     (Final § 111.95)

§ 111.95(a)

§ 111.95(b)

XI.  Comments on Requirements for Quality Control

(Final Subpart F)

Organization of Final Subpart F

Highlights of Changes to the Proposed Requirements for

        Quality Control Operations

Revisions

Changes associated With the Reorganization

Changes After Considering Comments

  	C. General Comments on Proposed § 111.37 (Final Subpart F)

  	D. What Are the Requirements Under This Subpart for Written

        Procedures? (Final § 111.103)

  	E. What must the Quality Control Unit Personnel Do? (Final §
111.105)

Final § 111.105(a)

Final § 111.105(b), (c), d), and (e)

Final § 111.105(f)

Final § 111.105(g)

Final § 111.105(h)

Final § 111.105(i)

	F. What Quality Control Operations Are Required for

        Laboratory Operations Associated With the Production and

        Process Control System? (Final § 111.110)

Final § 111.110(a)

Final § 111.110(b)

Final § 111.110(c)

	G. What Quality Control Operations Are Required for

        a Material Review and Disposition Decision?

       (Final § 111.113)

Final § 111.113(a)

Final § 111.113(b)

Final § 111.113(c)

What Quality Control Operations Are Required for

   Equipment, Instruments, and Controls? (Final § 111.117)

Final § 111.117(a) through (c)

Final § 111.117(d)

What Quality Control Operations Are Required for

   Components, Packaging, and Labels Before Use in the

   Manufacture of a Dietary Supplement? (Final § 111.120)

Final § 111.120(a)

Final § 111.120(b)

Final § 111.120(c)

Final § 111.120(d)

Final § 111.120(e)

What Quality Control Operations Are Required for the

        Master Manufacturing Record, the Batch Production

        Record, and Manufacturing Operations? (Final § 111.123)

Final § 111.123(a)(1)

Final § 111.123(a)(2)

Final § 111.123(a)(3)

Final § 111.123(a)(4)

Final § 111.123(a)(5)

Final § 111.123(a)(6)

Final § 111.123(a)(7)

Final § 111.123(a)(8)

Final § 111.123(b)

	K. What Quality Control Operations Are Required for

        Packaging and Labeling Operations? (Final § 111.127)

Final § 111.127(a) and (b)

Final § 111.127(a)

Final § 111.127(b)

Final § 111.127(c)

Final § 111.127(d)

Final § 111.127(e)

Final § 111.127(f) and (g)

Final § 111.127(h)

L. What Quality Control Operations Are Required for

   Returned Dietary Supplements? (Final § 111.130)

Final § 111.130(a)

Final § 111.130(a)(1) and (2)

Final § 111.130(b)

Final § 111.130(c)

Final § 111.130(d)

	M. What Quality Control Operations Are Required for

        Product Complaints? (Final § 111.135)

N. What Records Must the Quality

   Control Unit Personnel Make and Keep? (Final § 111.140)

Final § 111.140(a)

Final § 111.140(b)(1)

Final § 111.140(b)(2)

Final § 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)

Organization of Final Subpart G

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

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.40 (Final Subpart G)

What Are the Requirements Under This Subpart for Written Procedures?
(Final § 111.153)

What Requirements Apply to Components of Dietary Supplements? (Final §
111.155)

Proposed § 111.35(d)

Final § 111.155(a)

Final § 111.155(b)

Final § 111.155(c)

Final § 111.155(d)

Final § 111.155(e)

What Requirements Apply to Packaging and Labels

   Received? (Final § 111.160)

Final § 111.160(a)

Final § 111.160(b)

Final § 111.160(c)

Final § 111.160(d)

Final § 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 § 111.165)

Final § 111.165(a)

Final § 111.165(b)

Final § 111.165(c)

Final § 111.165(d)

Final § 111.165(e)

H. What Requirements Apply to Rejected Components,

   Packaging, Labels, and to Rejected Products That are

   Received for Packaging or Labeling as a Dietary

   Supplement? (Final § 111.170)

I. Under this Subpart, What Records Must You Make and Keep

   (Final § 111.180)

Final § 111.180(a)

Final § 111.180(b)(1)

Final § 111.180(b)(2)

Final § 111.180(b)(3)

  SEQ CHAPTER \h \r 1 XIII.  Comments on the Production and Process
Control System:

Requirements for the Master Manufacturing Record

(Final Subpart H)

Organization of Final Subpart H

Highlights of Changes to the Proposed Requirements for the Master
Manufacturing Record

Revisions

Changes Associated With the Reorganization

Changes After Considering Comments

General Comments on Proposed § 111.45 (Final Subpart H)

Comments on Written Procedures

Comments That Support Proposed § 111.45

What is the Requirement to Establish a Master Manufacturing Record?
(Final § 111.205)

Final § 111.205(a)

Final § 111.205(b)(1)

Final § 111.205(b)(2)

Final § 111.205(c)

What Must the Master Manufacturing Record Include? (Final

     § 111.210)

Final § 111.210(a)

Final § 111.210(b)

Final § 111.210(c)

Final § 111.210(d)

Final § 111.210(e)

Final § 111.210(f)

Final § 111.210(g)

Final § 111.210(h)(1)

Final § 111.210(h)(2)

Final § 111.210(h)(3)

Final § 111.210(h)(4)

Final § 111.210(h)(5)

Quality Control Responsibility (Proposed § 111.45(c))

XIV.  Comments on the Production and Process Control System:

Requirements for the Batch Production Record

(Final Subpart I)

Organization of Final Subpart I

Highlights of Changes to the Proposed Requirements for the Batch
Production Record

Revisions

Changes Associated With the Reorganization

Changes After Considering Comments

What is the Requirement to Establish a Batch Production Record? (Final
§ 111.255)

What Must the Batch Record Include? (Final § 111.260)

Final § 111.260(a)

Final § 111.260(b)

Final § 111.260(c)

Final § 111.260(d)

Final § 111.260(e) and (f)

Final § 111.260(g)

Final § 111.260(h)

Final § 111.260(i)

Final § 111.260(j)

Final § 111.260(j)(1)

Final § 111.260(j)(2)

Final § 111.260(j)(2)(i) through (j)(2)(iv)

     	10. Final § 111.260(k)

General comments on proposed § 111.70(g)

Final § 111.260(k)(1)

Final § 111.260(k)(2)

Final § 111.260(k)(3)

     	11. Final § 111.260(l)

Final § 111.260(l)(1)

Final § 111.260(l)(1)(i)

Final § 111.260(l)(1)(ii)

Final § 111.260(l)(2)

Final § 111.260(l)(3)

Final § 111.260(l)(4)

12. Final § 111.260(m)

    		13. Final § 111.260(n)

 	E. Review of Batch Production Record Deviations (Proposed

        § 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)

Organization of Final Subpart J

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 § 111.303)

   	D. What Are the Requirements for the Laboratory Facilities?

        (Final § 111.310)

   	E. What Are the Requirements for Laboratory Control

        Processes? (Final § 111.315)

1. Final § 111.315(a)

2. Final § 111.315(b)

3. Final § 111.315(c)

4. Final § 111.315(d)

5. Final § 111.315(e)

F. What Requirements Apply to Laboratory Methods for

   Testing and Examination? (Final § 111.320)

   		1. Final § 111.320(a)

   		2. Final § 111.320(b)

G. Appropriate Test Method Validation

   (Proposed § 111.60(b)(1)(v))

H. Under This Subpart, What Records must You Make and Keep?

        (Final § 111.325)

  		1. Final § 111.325(a)

  		2. Final § 111.325(b)(1)

  		3. Final § 111.325(b)(2)

XVI.  Comments on the Production and Process Control System:

Requirements for Manufacturing Operations

(Final Subpart K)

Organization of Final Subpart K

Highlights of Changes to the Proposed Requirements for Manufacturing
Operations

Revisions

Changes Made After Considering Comments

Revisions Associated With the Reorganization

General Comments on Manufacturing Operations

What Are the Requirements Under This Subpart for Written Procedures?
(Final § 111.353)

What Are the Design Requirements for Manufacturing Operations? (Final §
111.355)

What Are the Requirements for Sanitation? (Final § 111.360)

What Precautions Must You Take to Prevent Contamination? (Final §
111.365)

     	1. Final § 111.365(a)

2. Final § 111.365(b)

3. Final § 111.365(c)

4. Final § 111.365(d)

5. Final § 111.365(e)

6. Final § 111.365(f)

7. Final § 111.365(g)

8. Final § 111.365(h)

9.  Final § 111.365(i)

10. Final § 111.365(j)

11. Final § 111.365(k)

H. What Requirements Apply to Rejected Dietary Supplements?

        (Final § 111.370)

I. Under This Subpart, What Records Must You Make and Keep?

        (Final § 111.375)

 XVII. Comments on Requirements for

Packaging and Labeling Operations

(Final Subpart L)

Organization of Final Subpart L

Highlights of Changes to the Proposed Requirements for Packaging and
Labeling Operations

Revisions

Changes Associated With the Reorganization

Changes After Considering Comments

General Comments on Proposed Requirements for Packaging and Labeling
Operations

General Comments on Requirements for What Must Be on the

     Product Label Rather than for Labeling Operations

What are the Requirements under this Subpart for Written

     Procedures? (Final § 111.403)

What Requirements Apply to Packaging and Labels?

  (Final § 111.410)

Final § 111.410(a)

Final § 111.410(b)

Final § 111.410(c)

Final § 111.410(d)

G. What Requirements Apply to Filling, Assembling,

   Packaging, Labeling, and Related Operations?

   (Final § 111.415)

H. What Requirements Apply to Repackaging and Relabeling?

        (Final § 111.420)

1. Final § 111.420(a)

2. Final § 111.420 (b) and (c)

  	I. What Requirements Apply to a Packaged and Labeled

        Dietary Supplement That is Rejected for Distribution?

        (Final § 111.425)

Under this Subpart L, What Records Must You Make and

   Keep? (Final § 111.430)

1. Final § 111.430(a)

2. Final § 111.430(b)

XVIII.  Comments on Holding and Distributing

(Final Subpart M)

Organization of Final Subpart M

Highlights of Changes to the Proposed Requirements for Holding and
Distributing

Revisions

Changes Associated With the Reorganization

Changes After Considering Comments

General Comments on Proposed §§ 11.80, 111.82, 111.83, and 111.85

What are the Requirements Under This Subpart for Written Procedures?
(Final § 111.453)

What Requirements Apply to Holding Components, Dietary Supplements,
Packaging, and Labels? (Final § 111.455)

1. Final § 111.455(a)

2. Final § 111.455(b)

3. Final § 111.455(c)

What Requirements Apply to Holding In-process Material?   (Final
§ 111.460)

1. Final § 111.460(a)

2. Final § 111.460(b)

Proposed Requirement for Holding Reserve Samples of Components (Proposed
§ 111.83(a))

What Requirements Apply to Holding Reserve Samples of Dietary
Supplements? (Final § 111.465)

1. Final § 111.465(a)

     	2. Final § 111.465(b)

What Requirements Apply to Distributing Dietary Supplements?  (Final
§ 111.470)

Under this Subpart, What Records Must You Make and Keep? (Final
§ 111.475)

XIX.  Comments on Returned Dietary Supplements

  (Final Subpart N)

Organization of Final Subpart N

Highlights of Changes to the Proposed Requirements for Returned Dietary
Supplements

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.85

What are the Requirements under This Subpart for Written Procedures?
(Final § 111.503)

What Requirements Apply When a Returned Dietary Supplement is Received?
(Final § 111.510)

When Must a Returned Dietary Supplement be Destroyed, or Otherwise
Suitably Disposed of? (Final § 111.515)

When May a Returned Dietary Supplement Be Salvaged? (Final § 111.520)

What Requirements Apply to a Returned Dietary Supplement That the
Quality Control Unit Personnel Approves for Reprocessing?  (Final
§ 111.525)

When Must an Investigation of Manufacturing Be Conducted of Your
Manufacturing Processes and Other Batches? (Final § 111.530)

Under This Subpart, What Records Must You Make and Keep? (Final
§ 111.535)

Final § 111.535(a)

Final § 111.535(b)(1)

Final § 111.535(b)(2)

Final § 111.535(b)(3)

Final § 111.535(b)(4)

XX.  Comments on Product Complaints (Final Subpart O)

Organization of Final Subpart O

Highlights of Changes to the Proposed Requirements for Product
Complaints

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.95(Final Subpart O)

What Are the Requirements Under This Subpart for Written Procedures?
(Final § 111.553)

What Requirements Apply to the Review and Investigation of a Product
Complaint? (Final § 111.560)

Final § 111.560(a)(1)

Final § 111.560(a)(2), (b), and (c)

Under This Subpart, What Records Must You Make and Keep?  (Final
§ 111.570)

Final § 111.570(a)

Final § 111.570(b)(1)

Final § 111.570(b)(2)

Final § 111.570(b)(2)(i)

Final § 111.570(b)(2)(ii)

  SEQ CHAPTER \h \r 1 XXI.  Comments on Records and Recordkeeping

(Final Subpart P)

Organization of Final Subpart P

Highlights of Changes to the Proposed Requirements for Records and
Recordkeeping

Revisions

Changes After Considering Comments

General Comments on Proposed § 111.125

What Requirements Apply to the Record That You Mmake and Keep? (Final §
111.605)

Final § 111.605(a)

Final § 111.605(b)

Final § 111.605(c)

What Records Must Be Made Available to FDA?

  (Final § 111.610)

1. Final § 111.610(a)

2. Final § 111.610(b)

XXII.   Other Comments and Miscellaneous

Comments on Guidance Documents To Be Used with the Final Rule

Comments on Consideration for Other CGMP Programs

Comments on Public Involvement

Public Involvement

Comments on Implementation and Enforcement

E. Removal of References to Part 112

XX  SEQ CHAPTER \h \r 1 III. Paperwork Reduction Act of 1995

XXI  SEQ CHAPTER \h \r 1 V. Analysis of Impacts

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

     		a. Consumption

b. Manufacturing

		5. Baseline Risk

 		6. Benefits

a. Reduced health costs associated with a reduced

   number of acute illnesses

   		b. Fewer products recalled

   		c. Reduced health costs associated with a reduced

             number of chronic illnesses and conditions

   		d. Benefits from known nutritional effects

   		e. Benefits form uncertain nutritional effects

   		f. Total benefits

7. Costs

   		a. Description of the costs

	   		b. Summary of general comments on costs

     	8. Summary of Benefits and Costs

     	9. Uncertainties in the Analysis

C. Initial Final Regulatory Flexibility Analysis

1. Introduction

2. Economic Effects on Small Entities

        		a. Number of small entities affected

        		b. Costs to small entities

3. Regulatory Options

        		a. Exemptions for small entities

	   		b. Longer compliance periods

4. Description of Recordkeeping and Reporting

5. Summary

D. Unfunded Mandates

XXV. 	Analysis of Environmental Impact

XXVI. 	Federalism

XXVII.  	References

	I.  Background & Related Information– What Led Us to Issue This Rule?

     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.

     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 part).

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. 1-6).  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 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 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 FEDERAL REGISTER we are also issuing an
interim final regulation 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, Subpart E), provided certain
conditions are met and also includes a requirement for retention of
records related to the FDA grant of an exception request.

	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.

The following table 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

Proposed Subpart and Title	Proposed Sections in the Subpart	Final
Subpart and Title	Final Sections in the Subpart

A – General Provisions	111.1

111.2

111.3

111.5

111.6	A – General Provisions	111.1

111.3

111.5

B – Personnel	111.10

111.12

111.13	B – Personnel	111.8 (new)

111.10

111.12

111.13

111.14 (new)

C – Physical Plant	111.15

111.20	C – Physical Plant and Grounds	111.15

111.16 (new)

111.20

111.23 (formerly proposed § 111.15(d)(3) and (e)(2))

D – Equipment and Utensils	111.25

111.30	D – Equipment and Utensils	111.25 (formerly proposed §
111.25(c)(1) and (e)(1))

111.27 (formerly proposed § 111.25 (a), (b), (d)1, and (e))

111.30

111.35 (formerly proposed §§ 111.25 (c)(1), (c)(2), (d), (f),
111.30(b)(2), (b)(5), and (c), 111.50(c)(4))

E – Production and Process Controls	111.35

111.37

111.40

111.45

111.50

111.60

111.65

111.70

111.74	E – Requirement to Establish a Production and Process Control
System	111.55 (formerly proposed § 111.35(a))

111.60 (formerly proposed § 111.35(b))

111.65 (formerly proposed § 111.35(c))

111.70 (formerly proposed § 111.35(e),(f),(g), and (k))

111.73 (formerly proposed § 111.35 (f), (g), and (h)

111.75 (formerly proposed § 111.35(e) through (i), (k), (l)), § 111.37
(b)(11(iv), and

§ 111.40(a)(2)

111.77 (new)

111.80 (formerly proposed § 111.37(b)(11))

111.83 (formerly proposed §§ 111.37(b)(12), 111.50(h), and
111.83(b)(2))

111.87 (formerly proposed §§ 111.35(i), and (n), 111.37(b)(5) and
(b)(14), 111.40(a)(3), 111.50(d)(1), 111.85(a) and (c))

111.90 (formerly proposed §§ 111.35(i)(4), 111.50(d)(1), 111.50(f) and
(g), and 111.65(d))

111.95 (formerly proposed § 111.35 and (o))

F – Production and Process Control System: Requirements for Quality
Control	111.103 (new)

111.105 (formerly proposed § 111.37(a), (b)(1), (b)(11), and (b)(12))

111.110 (formerly proposed § 111.37(b)(9) and (b)(13))

111.113 (formerly proposed §§ 111.35(i)(2),(i)(3), (i)(4)(i),
(i)(4)(ii), (j), and (n), 111.37(b)(3), (c), 111.40(a)(3) and (b)(2),
111.50(d)(1), 111.65(d), and 111.70(c))

111.117 (formerly proposed §§ 111.30(b)(4), 111.37(b)(6) through
(b)(8))

111.120 (formerly proposed §§ 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 §§ 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), 111.50(d)(1),
(d)(2), and (g))

111.127 (formerly proposed §§ 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 §§ 111.37(b)(2) and (b)(15), and 111.85(a))

111.135 (new)

111.140 (formerly proposed §§ 111.35(j), 111.37(c) and (d),

G – Production and Process Control System:  Requirements for
Components, Packaging, and Labels and for Product that You Receive for
Packaging or Labeling a Dietary Supplement	111.153 (new)

111.155 (formerly proposed §§ 111.35(d)(1)-(5) and 111.40(a)(1)-(5))

111.160 (formerly proposed §§ 111.35(e)(4), and 111.40(a)(2) and
(b)(1)-(4))

111.165 (formerly proposed § 111.40(a)(1)-(5))

111.170 (formerly proposed § 111.74)

111.180 (formerly proposed §§ 111.35(d)(4), and 111.40(c)(1)(i)-(iv)
and (c)(2))

H – Production and Process Control System: Requirements for the Master
Manufacturing Record	111.205 (formerly proposed § 111.45(a)(1), (a)(2),
and (d))

111.210 (formerly proposed § 111.45(b))

I – Production and Process Control System: Requirements for the Batch
Production Record	111.255 (formerly proposed § 111.50(a), (b) and (i))

111.260 (formerly proposed §§ 111.35(i)(2),(j), (m), and (o)(2),
111.37(b)(3),(5),(9) and 111.50(c)(1) through (c)(11), (c)(13), (c)(14),
(d)(2), and (e), (g) and 111.70 (b)(6) and (g))

J – Production and Process Control System: Requirements for Laboratory
Operations	111.303 (new)

111.310 (formerly proposed § 111.60(a))

111.315 (formerly proposed § 111.60(b)(1))

111.320 (formerly proposed § 111.60(c), and (d))

111.325 (formerly proposed § 111.60(b)(2) and (b)(3))

K – Production and Process Control System: Requirements for
Manufacturing Operations	111.353 (new)

111.355 (formerly proposed § 111.65(a))

111.360 (formerly proposed § 111.65(b))

111.365 (formerly proposed § 111.65(c))

111.370 (formerly proposed § 111.74)

111.375 (new)

L – Production and Process Control System: Requirements for Packaging
and Labeling Operations	111.403 (new)

111.410 (formerly proposed § 111.70(a), (b)(6) and (f))

111.415 (formerly proposed § 111.70(b))

111.420 (formerly proposed § 111.70(d) and (e))

111.425 (formerly proposed § 111.74)

111.430 (formerly proposed § 111.70 (g) and (h))

F – Holding and Distributing	111.80

111.82

111.83

111.85

111.90	M – Holding and Distributing	111.453 (new)

111.455 (formerly proposed § 111.80)

111.460 (formerly proposed § 111.82)

111.465 (formerly proposed § 111.83(b)(1)and (b)(2))

111.470 (formerly proposed § 111.90)

111.475 (new)

N – Returned Dietary Supplements	111.503 (new)

111.510 (formerly proposed § 111.85(a))

111.515 (formerly proposed § 111.85(b) and (c))

111.520 (formerly proposed § 111.37(b)(15))

111.525 (formerly proposed § 111.50(g))

111.530 (formerly proposed § 111.85(d))

111.535 (formerly proposed §§ 111.50(g) and 111.85(e)and (f))

G – Consumer Complaints	111.95	O – Product Complaints	111.553 (new)

111.560 (formerly proposed § 111.95(a) through (d))

111.570 (formerly proposed § 111.95(e)and(f))

H – Records and Recordkeeping	111.125	P – Records and Recordkeeping
111.605 (formerly proposed § 111.125((a) and (b))

111.610 (formerly proposed § 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, 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 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 21 CFR 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 – 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), thermally processed low-acid canned food (part 113),
acidified food (part 114), and bottled water (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. 7-8).  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
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 meets 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.  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).  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.”

	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 the
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 sections 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 sections 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 (proposed § 111.35(d)(21 CFR 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 component, in the
manufacture of a dietary supplement that would adulterate the product
under relevant provisions of the act, such as sections 402(a)(1) or
402(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
§ 111.35(e)).  Thus, the manufacturer would not have been able to
establish a specification, consistent with proposed § 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
§ 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 § 111.35(e)(1))
and for the finished batch of dietary supplement (proposed
§ 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 § 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 (proposed §§  111.45(b)((7);
111.50(c)(12); 111.70(b)(7)) so that the dietary supplement label would
accurately identify the dietary supplement.  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 (proposed § 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 generally recognized as safe (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
codified to 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, 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.
 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.

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 sections 402(a)(1), (a)(2), (a)(3) and (a)(4) of the act.
For example, under § 110.5 (food CGMP), the criteria and definitions
apply in determining whether a food is adulterated under sections
402(a)(3) and (a)(4) of the act.  Specifically, § 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, § 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 sections 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 sections
402(a)(1), (a)(2),(a)(3), and (a)(4) of the act.  Thus, this final rule
is not designed to specifically prevent all 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 § 111.35(e)
(now final § 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 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 an 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 mix-up in your process control and you
do not put the representative label specified in the master
manufacturing record on the product.  Such a mix-up would be a violation
of dietary supplement CGMP requirements (see e.g., final
§§ 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 current good
manufacturing practice regulations 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 § 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 §
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 § 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 use implementation of a quality control unit 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 the quality control unit personnel conducts a material
review and makes a disposition decision;

●	Requires the quality control unit 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 the quality control
unitquality 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 3 2 years beyond the date of
distribution of the last batch of dietary supplements associated with
those records.

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.

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 § 111.35(e)) than to list such contaminants as
part of the testing requirements (proposed § 111.35(k)).  Other
comments say it would be more logical to list the tests that are
considered appropriate as part of proposed § 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 § 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 re-write 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
inter-related nature of the proposed rule by combining most similar
requirements.  Both proposed §§ 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 (§ 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 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, 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 sections 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, 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 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 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 nonfood-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, 10; see, also, 68 FR 12157, at 12162-63, March
13, 2003)  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 post marketing adverse event reports or
consumers’ illnesses.

	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
sections 411(c)(1)(B)(i) and (c)(1)(B)(ii) of the act, which describe
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 sections 402(f) and 402(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 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 § 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 § 111.15 (68 FR 12157 at 12187); calibrating instruments
and controls under proposed § 111.25(b), (c), and (d) (68 FR 12157 at
12191); maintaining, cleaning, and sanitizing equipment and utensils
under proposed § 111.25(e) (68 FR 12157 at 12192); calibrating,
inspecting, and checking automatic equipment under proposed § 111.30
(68 FR 12157 at 12193); the duties of the quality control unit under
proposed § 111.37 (68 FR 12157 at 12201); implementing the proposed
requirements for receipt of components, dietary supplements, packaging,
and labels under proposed § 111.40(a) and (b) (68 12157 at FR 12203);
preparing the master manufacturing record under proposed § 111.45 (68
FR 12157 at 12205); laboratory operations under proposed § 111.60 (68
FR 12157 at 12209); manufacturing operations under proposed § 111.65
(68 FR 12157 at 12211); packaging and labeling operations under proposed
§ 111.70 (68 FR 12157 at 12213); holding components, dietary
supplements, packaging, labels, and in-process materials under proposed
§§ 111.80 and 111.82 (68 FR 12157 at 12214); identifying,
quarantining, and salvaging returned dietary supplements under proposed
§ 111.85 (68 FR 12157 at 12216); and receiving, reviewing, and
investigating consumer complaints under proposed § 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 (IOS), 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 § 111.37(b)(l) 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 § 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 § 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 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 § 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 § 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 § 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 § 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 § 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 §
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 §§ 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 mix-ups 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 the quality control unit personnel to carry out its 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 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 this section immediately below, 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 with 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 §
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. 117).

	We include in final subpart B a requirement (final § 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 § 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 §
111.25(a)) and for calibrating, inspecting, and checking automated,
mechanical, and electronic equipment (final § 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 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 § 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 § 111.25(c)).  Final § 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 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 § 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 §
111.25(c) relates to proposed § 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 § 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 § 111.70(e) in section X, 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 by the quality control unit to carry out its 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 §
111.103).  We agree with the comments that there should be written
procedures for investigating failures in manufacturing operations.  In
the 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 below in section X and XI,
the final rule requires that the quality control unit 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 § 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 the quality control
unit thatpersonnel who must approve or reject any reprocessing (see
final §§ 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, the
quality control unit 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 § 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 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 § 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 § 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 § 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 mix-ups, 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, mix-ups 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 §
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 a CGMP standards, and that mix-ups 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 mix-up, 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 and distributing
operations (final § 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 the quality control unit personnel conducts a material
review and makes a disposition decision.  You must destroy, or otherwise
suitably dispose of, any returned dietary supplement that the quality
control unit personnel does 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 the quality control unit personnel conducted its 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 § 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 § 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 § 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 §§ 111.55 and 111.60); use aimplement
quality control unit operations in your operations to ensure the quality