Title 21--Food and Drugs

CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH, EDUCATION, AND 
WELFARE

              SUBCHAPTER C--DRUGS: GENERAL

                 [Docket No. 75N-0339]
                           
               HUMAN AND VETERINARY DRUGS
                           
Current Good Manufacturing Practice in Manufacture, Processing, Packing, or 
Holding

AGENCY:  Food and Drug Administration.

ACTION:  Final rule.

SUMMARY:  This document amends the FDA regulations that set forth current good 
manufacturing practice (CGMP) for human and veterinary drug products.  The 
amendments update present regulations in light of current technology for drug 
manufacturing and delineate requirements more specifically than do the present 
regulations.  Although some of the provisions in these amendments represent 
requirements not specifically included in the existing CGMP regulations, in many 
instances the revisions are practices that have been considered implicit in the 
regulations or are at least considered by most manufacturers to be desirable 
requirements for their own operations.
     Under the Federal Food, Drug, and Cosmetic Act, a drug is deemed to be 
adulterated unless the methods used in its manufacture, processing, packing, and 
holding, and the facilities and controls used therefor, conform to current good 
manufacturing practice so that the drug meets the safety requirements of the act 
and has the identity and strength and meets the quality and purity 
characteristics that it is represented to have.  The regulations are being 
updated and made more explicit, and therefore less subject to varying 
interpretations, to assure that all members of the drug industry are made aware 
of the level of performance expected of them to be in compliance with the act.

EFFECTIVE DATE:  March 28, 1979.

FOR FURTHER INFORMATION CONTACT:

     Clifford G. Broker (HFD-323) (301-443-5307), or Robert J. Rice, Jr., (HFD-
30) (301-443-5220), Bureau of Drugs, Food and Drug Administration, Department of 
Health, Education, and Welfare, 5600 Fishers Lane, Rockville, Md. 20857.

SUPPLEMENTARY INFORMATION:  In the FEDERAL REGISTER of February 13, 1976 (41 FR 
6878), the Commissioner of Food and Drugs proposed to revise the CGMP 
regulations, Parts 210 and 211 (21 CFR Parts 210 and 211), issued under section 
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
351(a)(2)(B)), to update them in light of current technology and to adopt more 
specific requirements to assure the quality of finished drug products.  Because 
of the nature and extent of the proposed revisions, the Commissioner allowed 
until June 14, 1976, for interested persons to submit comments.
     The Commissioner received comments from 168 respondents totaling 
approximately 2,000 pages.  These comments represent many interests--individual 
consumers; nonprofit institutions or associations; health-care departments of 
hospitals, colleges, and universities; State and foreign health-care 
organizations; domestic and foreign drug manufacturers, repackers, and 
distributors; consultants to the drug industry; drug equipment manufacturers; 
and numerous trade and professional associations representing manufacturers, 
repackers, distributors, consulting engineers, and professionals in the health-
care system.
     In general, the comments supported the Commissioner's concern for the 
availability of uniformly high quality drug products.  Consumers, in particular, 
expressed strong support for the proposed revisions, especially the provisions 
for expiration dating of pharmaceuticals.  A majority of drug manufacturers 
agreed with many of the proposed revisions, but objected to others.  A few 
manufacturers objected to most of the proposal.
     The Commissioner is pleased to note that where differences existed, many 
interested persons furnished alternative wording and justification in support of 
such alternatives.  The Commissioner has carefully considered every comment and 
all suggested alternatives.  The final regulation, set forth below, adopts a 
number of the recommendations submitted.  Certain other recommendations, not 
adopted at this time, may be considered in any future proposed revisions.
     During the past several years, the FDA has issued a number of FEDERAL 
REGISTER documents relating to CGMP regulations, specifically Parts 210 and 211.  
The following summary will help clarify the status of these various documents.
     1.  A proposal on returned and salvaged drug products appeared in the 
FEDERAL REGISTER of January 16, 1975 (40 FR 2822) and was reproposed as 211.208 
(21 CFR 211.208) in the FEDERAL REGISTER of February 13, 1976 (41 FR 6870).  
Comments on both proposals were reviewed and considered in preparing the final 
regulations set forth in Part 211 below.
     2.  A proposal on CGMP regulations for human and veterinary drugs appeared 
in the FEDERAL REGISTER of February 13, 1976 (41 FR 6878).  That proposal is the 
basis for the subject final regulations and included proposed revisions in 
201.17, 207.3, 207.20, and Parts 210 and 211, and revocation of 229.25.
     3.  A final regulation in the FEDERAL REGISTER of April 23, 1976 (41 FR 
16932) amended Part 211 (CGMP regulations) by eliminating reference to glass-
fiber filters.  It, therefore, eliminated the need for further comments on the 
February 13, 1976, proposal regarding such filters because all references to 
glass fiber-containing filters would be deleted from the final regulation.
     4.  A proposal on CGMP regulations for large volume parenteral drug 
products (LVP) for human use was published in the FEDERAL REGISTER of June 1, 
1976 (41 FR 22202).  The proposal would add a new Part 212.  Comments were due 
by September 29, 1976 and are under review.
     5.  A request for comments and information regarding small volume 
parenteral drug products (SVP) was published in the FEDERAL REGISTER of June 1, 
1976(41 FR 22219), and the time for submitting comments was extended to October 
29, 1976 by notice in the FEDERAL REGISTER of September 10, 1976 (41 FR 38540).  
Comments are being reviewed, and a specific proposal may be published in the 
future.
     The comments and recommendations regarding the January 16, 1975 and 
February 13, 1976 proposals, the April 23, 1976 amendment to the latter 
proposal, and the Commissioner's conclusions concerning them are set out below.

             TABLE OF CONTENTS FOR PREAMBLE

     I.  General Comments (paragraphs 1 to 12).
     II.  Terminology and Language in these Regulations (paragraphs 13 to 18).
     III.  Amendments Regarding Placement of Expiration Date on Drug Product 
Labels (paragraphs 19 to 27).
     IV.  Amendments Regarding Drug Listing and Establishment Registration 
Requirements for Drug Product Salvaging Operations (paragraphs 28 to 32).
     V.  Legal Status of CGMP Regulations (paragraphs 33 to 41).
     VI.  Applicability of CGMP Regulations; Exemptions (paragraphs 42 to 49).
     VII.  Definitions (paragraphs 50 to 88).
     VIII.  Organization and Personnel (paragraphs 89 to 126).
     IX.  Buildings and Facilities (paragraphs 127 to 164).
     X.  Equipment (paragraphs 165 to 198).
     XI.  Control of Components and Drug Product Containers and Closures 
(paragraphs 199 to 262).
     XII.  Production and Process Controls (paragraphs 263 to 310).
     XIII.  Packaging and Labeling Control (paragraphs 311 to 373).
     XIV.  Holding and Distribution (paragraphs 374 to 379).
     XV.  Laboratory Controls (paragraphs 380 to 422).
     XVI.  Records and Reports (paragraphs 423 to 500).
     XVII.  Returned and Salvaged Drug Products (paragraphs 501 to 517).
     XVIII.  CGMP for Certain Other Drug Products (paragraph 518).

                  I.  GENERAL COMMENTS

     1.  Many comments were received regarding the need for the proposed changes 
in the CGMP regulations.  A number of comments from individual consumers, a 
State consumer services organization, and a national association of health-care 
professionals strongly favored new or revised regulations that would improve the 
level of assurance that marketed drug products meet high quality standards.  
Many other comments, particularly from manufacturers and trade associations, 
generally supported the desirability of CGMP regulations, but objected to 
specific provisions of the proposal and questioned whether a favorable cost-
benefit ratio justified implementing some of the proposed provisions.  But some 
manufacturers, particularly smaller firms, objected to the proposed changes, 
maintaining that drug quality would not be improved by the proposed changes and 
that the costs outweigh any benefits. 
     The need and rationale for an overall revision and for specific changes in 
the CGMP regulations are discussed at length in the preamble to the February 13, 
1976 proposal.  Briefly summarizing this discussion, the technological advances 
and the general upgrading of drug quality assurance by most manufacturers since 
the CGMP regulations were promulgated in 1963 and last updated in 1971 mean that 
the "current good manufacturing practice" reflected in the existing regulations 
are no longer "current" in many respects and are not suited to current 
manufacturing techniques.  In addition, many requirements prompted questions 
about interpretation, vagueness, and omissions.  The proposal was intended to 
solve many of these problems.  Interested persons were urged to review the 
proposal carefully, to identify any areas that might require clarification or 
modification, and to submit reasoned comments with suggested alternative 
language.  The period provided for public comment was 120 days instead of the 
usual 60 days because of the length of the proposal; the novel, controversial, 
or complex nature of some of the proposed provisions; and the desire to give 
affected persons ample time for review and preparation of extensive comments.
     Having reviewed the preamble of the February 13, 1976, proposal and the 
extensive comments, the Commissioner is satisfied that an updating of the CGMP 
regulations is necessary and desirable.  Therefore, most of the February 13, 
1976, proposal has been adopted, but with numerous textual changes, many of 
which are based upon alternative language suggested in the comments.  In 
evaluating each comment, the Commissioner considered whether drug product 
quality would be assured, compromised, or unaffected by the adoption or deletion 
of a regulation, as well as whether it reflected a current practice in the 
industry and its benefits appeared to outweigh its costs.  The Commissioner is 
promulgating those regulations embodying contemporary practices that will 
maintain or improve the quality of pharmaceuticals without imposing unreasonable 
or excessive costs or other burdens on manufacturers.  Modifications were 
adopted, or decisions were made not to finalize particular aspects of the 
proposal, in order to add flexibility for manufacturers, to relieve or eliminate 
unjustified cost burdens, or to clarify the requirements, without adversely 
affecting the best interests of the consumer.
     The agency has completed a detailed cost analysis based on information 
submitted by interested persons who commented on the economic impact assessment 
of the proposal.  This issue is discussed in a revised economic impact 
assessment available at the office of the Hearing Clerk, Food and Drug 
Administration.  For the reasons set forth in the agency's economic impact 
assessment, it is believed that this final regulation will not cause major 
economic impact, as defined by Executive Order 11821 (as amended by Executive 
Order 11949), and OMB Circular A-107.
     2.  A number of comments said the proposed CGMP regulations would impose 
rigid and inflexible standards that would curtail progress and discourage 
technological innovations.  Others said the proposed regulations were so 
detailed that sound judgment by the manufacturers and by inspecting FDA 
investigators could not be used.
     The Commissioner is keenly aware that the general CGMP regulations must 
apply to a wide variety of drug products.  Therefore, the CGMP regulations in 
Part 211 are intended to be general enough to be suitable for essentially all 
drug products, flexible enough to allow the use of sound judgment and permit 
innovation, and explicit enough to provide a clear understanding of what is 
required.  The agency has received numerous inquiries requesting clarification 
of certain provisions, and it sought to remove ambiguities by this revision.  In 
finalizing these revisions, the Commissioner has considered past experience, the 
purposes of the CGMP regulations, the need to balance specificity and clarity 
with flexibility in attaining these purposes, and the comments received in 
response to the proposal.  A number of changes have been made in these final 
regulations to reflect the broad applicability of, to allow flexibility in, and 
to encourage innovation within the CGMP regulations.  The agency does intend to 
issue more specific CGMP regulations for unique classes of products as one means 
of clarifying these regulations.  The Commissioner welcomes suggestions and 
petitions from interested persons who find deficiencies, excessive burdens, or 
inflexibility in these regulations and who identify innovative and more 
efficient ways to achieve the goals of these regulations.
     3.  A number of comments addressed the so-called "how to" versus the "what" 
argument; that is, the proposed CGMP regulations describe "how" a particular 
requirement should be achieved rather than specifying "what" it is that is to be 
achieved.  Many comments recommended that the regulations establish only 
objectives or specifications and allow each manufacturer to determine the best 
method of attaining the objective or meeting the specification.  For example, 
one comment proposed that FDA require positive identification of a person rather 
than specifying that a signature be used--this would allow use of other means of 
identifying a person, such as an identifying number or initials.
     The Commissioner believes that, with relatively few exceptions, the CGMP 
regulations do describe "what" is to be accomplished and provide great latitude 
in "how" the requirement is achieved.  For example, written records and 
procedures are required, but FDA will recognize as satisfactory any reasonable 
format that achieves the desired results.  Because of the need for uniformity in 
certain areas of the CGMP regulations that have presented problems in the past, 
however, there are some instances where it is desirable to specify the manner in 
which requirements are to be accomplished.  In promulgating these regulations, 
the Commissioner carefully reconsidered the need for such specificity where it 
appears and adopted only those specific requirements that are fully justified.
     4.  One comment, filed by an FDA employee, recommended that self-inspection 
and performance auditing programs within the industry be a requirement under the 
CGMP regulations to assure the reliability of drug products and to prevent 
release of defective products.
     The Commissioner finds that the concept of self-inspection and performance 
auditing has considerable merit.  The pharmaceutical industry has made great 
efforts to develop self-evaluation programs, frequently using a team of 
inspectors composed, at least in part, of people from outside the area or firm 
being audited.  The scope, elements, and intensity of such programs, however, 
vary from elaborate detailed audits to rather superficial inspections conducted 
perhaps once a year.  The agency has considered such programs in the past, but 
has concluded that the essential elements of a beneficial program have not yet 
been sufficiently defined or tested.  Moreover, because of the significant 
impact that a requirement for self-inspection would have on the industry and 
because only one comment regarding self-inspection was received, the 
Commissioner concludes that further public discussion is desirable before a 
specific proposal or regulation is issued.
     5.  One comment suggested that a product defect surveillance and reporting 
system requirement similar to the system developed and operated by the Unites 
States Pharmacopeia (U.S.P.) be a part of the CGMP regulations.  The suggestion 
would require full participation by manufactures, rather than voluntary 
participation, in a system of identifying defective products, removing them from 
the market, and investigating the cause of the defect.
     The Commissioner notes that the Drug Product Defect Reporting System 
maintained by U.S.P. is designed to identify drug product complaints from 
various sources other than the manufacturer, such as pharmacies and hospitals, 
and to facilitate transmission of this information to the manufacturer and to 
FDA.  The value of such a reporting system is in its broad source of 
information.  The CGMP regulations in part 211, however, apply only to 
manufacturers of drug products.  Section 211.198 (21 CFR 211.198) addresses the 
handling of reports to the manufacturer about drug product defects and requires 
that manufacturers investigate complaints that may have a bearing on drug 
product quality.  Such information is subject to review by FDA.
     6.  Comments regarding the effect of these regulations on employee 
motivation were received from several interested persons.  While generally 
approving the technical aspects of the proposal, these comments expressed 
concern that employee morale may be stifled because of the "close supervision" 
or "independent verification" of their work mandated by some of the proposed 
requirements.  The comments also expressed concern about the availability of 
qualified personnel in the health-care system and the ability of the industry to 
attract such qualified persons for relatively unimaginative duties.  They 
suggested that the use of a different instrument in the checking procedure 
would, in some instances, offer a better chance of detecting an error than would 
a system that relies upon independent verifications by different persons using 
the same instrument.
     The Commissioner recognizes that employee interests and motivation play a 
major role in assuring drug product quality, as described in the preamble 
discussion for the proposed 211.25, relating to employee training, for example.  
Good employee morale and work motivation are highly desirable in any work 
situation.  Because of potential employee resentment of an intensive "check 
system," the Commissioner has considered alternatives and the consequences of no 
independent verification.  The requirement for verification applies to functions 
that involve human judgment and consequently are susceptible to human error.  
The results of such errors, if undetected and uncorrected, can include, for 
example, improper formulations and improper release of drug products because of 
incorrect laboratory calculations.  Independent verification is generally 
considered a "current" practice, not only in the drug industry but elsewhere, as 
a way to reduce the risk of human error.  The intent of such a check is to 
verify that the procedure or work was performed.  It is a necessary function in 
the manufacture of drug products and is already required in the existing CGMP 
regulations.  The Commissioner believes that, while employees may not always 
welcome independent verification, most accept it as a condition of their 
particular assignments.  Given the possible serious consequences of errors, the 
"check system" requirement does not seem to be an unjustified burden and, if 
properly explained, should not be perceived by employees negatively.
     The use of separate instruments, where practicable, as an adjunct to 
independent verification by a second person, is a procedure that has merit.  The 
Commissioner encourages the use of such a procedure, but has concluded that a 
separate instrument for independent measurements would be a costly and 
unnecessary requirement in the CGMP regulations.  These regulations separately 
mandate an equipment calibration and maintenance program to assure proper 
performance and safeguard equipment accuracy.
     7.  Several comments indicated a general interest in bioavailability and 
bioequivalence requirements for drug products.  Because of the importance of 
bioavailability and bioequivalence to safe and effective use of drug products, 
these comments encouraged FDA to issue regulations establishing necessary 
requirements to assure this type of product quality as soon as possible.
     The Commissioner advises that bioavailability and bioequivalence 
requirements for drug products were addressed in separate proposals published in 
the FEDERAL REGISTER of June 20, 1975 (40 FR 26157 and 26164) and made final in 
the FEDERAL REGISTER of January 7, 1977 (42 FR 1624).
     8.  Several comments were received regarding written procedures to describe 
specific manufacturing and control operations.  In general the comments agreed 
that written procedures were suitable in many instances, but were not required 
for every operation involved in the production and control of drug products.  
Specific examples were cited as requiring excessive and unnecessary written 
procedures.  The most common example cited was 211.67(b), which proposed, in 
part, that there be written procedures assigning responsibility for cleaning and 
maintenance and describing in detail the maintenance and cleaning schedules, the 
methods, equipment, and materials to be used, and the methods of disassembling 
and reassembling all equipment used in the manufacture, processing, packing, or 
holding of a drug product.  The objection to the requirement of this instance 
appears to be in reference to "all" equipment.
     The requirement for written procedures is intended to provide additional 
assurance of effective communication of appropriate information from firm 
management to line personnel and of regular performance of a firm's established 
programs and procedures.  It is not enough that employees "know their jobs."  
Key personnel may be absent without warning; personnel substitutions involving 
less experienced employees may be necessary; and new or revised instructions to 
employees must be adequately conveyed to those who need to know.  These 
situations are not usual, but may occur frequently.  The most appropriate method 
for reliably relating policies and procedures to those who must know them is to 
have them set down in writing, readily available, and presented in a manner 
easily understood.  The Commissioner does not believe this is a burdensome 
requirement.  The regulations do not require that a separate procedure be 
written for each and every individual piece of equipment.  Thus, for example, 
similar pieces of equipment that would have the same cleaning schedule could be 
considered together for convenience and would be in compliance with requirements 
of 211.67(b).
     9.  One comment suggested that written procedures are changed frequently 
and the regulations make no provisions for dating the written procedures and 
retaining outdated written procedures.  The comment pointed out that the 
outdated procedures may be of some value in following up problems that may have 
occurred during the period that the written procedures were in effect.
     The Commissioner has carefully considered the merits of this suggestion and 
concludes that specific provisions for the dating and retention for all written 
procedures are not needed at this time.  The regulations already contain this 
type of requirement for certain records such as master and batch production 
control records.  For other procedures, it is preferable for each manufacturer 
to develop his scheme for dating, replacing, and retaining written procedures.
     10.  One comment recommended that FDA provide a complete set of correct 
model forms for use by individual firms in their own recordkeeping.  The comment 
suggested that the model forms could be a part of the CGMP regulations, or FDA 
could furnish such information separately.
     The Commissioner does not find sufficient need at this time to warrant 
development of such model forms.  The CGMP regulations, as amended, provide 
sufficient detail for manufacturers to understand readily what is required for 
compliance with these regulations.  Because of the broad nature of the 
regulations and the wide variety of manufacturers subject to the CGMP 
regulations, the Commissioner is not convinced that model forms would be so 
adaptable as to be useful for a majority of firms.  If, however, future 
experience with these CGMP regulations indicates that model forms issued as 
guidelines would be helpful, the Commissioner will reconsider the matter.
     11.  A respondent suggested promulgating the regulations under section 
701(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 371(e)) to give 
opportunities for hearings on, and judicial review of, these regulations before 
they take final effect.
     The authority to promulgate the regulations for the enforcement of the 
current good manufacturing practice provisions of the act rests specifically in 
section 701(a) of the act.  As noted in paragraph 35, Congress voted in 1962 not 
to require that CGMP regulations be issued under the procedures set forth in 
section 701(e) of the act.  The Commissioner could elect to follow a procedure 
similar to that in section 701(e) of the act and hold a legislative type of 
hearing on specific aspects of this proposal under 21 CFR Part 15.  After an 
extensive review of the numerous comments, however, he has decided that there 
are no particular portions of this regulation which need a further presentation 
of information or arguments.  Any interested person may submit a petition under 
21 CFR 10.30 to the Commissioner requesting such a hearing and should identify 
with specificity and supporting explanations the issues that might be heard.  No 
such petition will, however, automatically delay the effective date of these 
regulations, as would be the situation under section 701(e) of the act; the 
Commissioner will grant a delay only if clearly justified.
     12.  In reference to the proposed requirement in 211.184(a), that the prime 
manufacturer, if known, be listed, one comment recommended that the CGMP 
regulations require that the name and lot number of the original manufacturer of 
the final drug product be part of the labeling.
     The Commissioner recognizes that a number of interested persons have, at 
various times, recommended that the labeling of drugs (whether bulk or in dosage 
form) bear the name of the manufacturer in addition to the distributor or 
repacker or relabeler.  Changes such as this, however, would have such broad 
effect and would be likely to generate such enormous public and industry 
interest that the Commissioner does not believe that these final regulations are 
the proper place to consider them.  Moreover, there are questions concerning the 
legality of such a requirement being adopted under section 501(a)(2)(B) of the 
act (21 U.S.C. 351(a)(2)(B)).  Therefore, the Commissioner declines to act on 
this comment at this time.

   II.  TERMINOLOGY AND LANGUAGE IN THESE REGULATIONS

     13.  Numerous comments were received suggesting changes in language, 
grammar, terminology, punctuation, sentence structure, and other editorial 
changes to clarify or improve upon the requirements as stated in the regulations 
or to eliminate redundancies or inconsistencies.  Those proposals that raised 
significant policy questions, suggested changes in the substance of the 
regulation, or otherwise required, in the Commissioner's opinion, a specific 
response, are discussed individually below.  Many of the suggested changes, 
however, were more editorial and stylistic and do not warrant a detailed 
discussion that would double the length of this preamble.
     The Commissioner reviewed each of these numerous editorial and language 
changes to determine whether it offered an improvement in clarity or definition, 
eliminated an obvious error or redundancy, promoted consistency with other 
portions of the regulations, or otherwise identified textual problems that were 
not previously noted by FDA.  Where the proposed alternative language or other 
changes suggested by them were superior to the proposal, they were adopted in 
substance or verbatim.  Where they did not offer any improvement, the 
Commissioner declined to accept them.
     14.  One comment recommended consistent usage of the words "drug," "drug 
product," "phase," "step," and "stage."  The comment suggested that confusion 
can result from using "drug" and "drug product" interchangeably because, in the 
technical literature, the term "drug" usually refers to the bulk drug and the 
term "drug product" to the finished dosage form.  The comment also pointed out 
that the words "phase," "step," and "stage" are used interchangeably and may, in 
fact, describe different aspects of a production operation.
     The Commissioner finds that Parts 210 and 211, as amended by this order, 
use "drug" and "drug product" consistently with the definitions in section 
201(g) of the act and 210.3(b)(4) of the regulations (21 CFR 210.3(b)(4)); that 
is, "drug products" refers to only finished dosage forms, while "drug" includes 
both bulk drugs and drug products.  With regard to the words "phase," "step," 
and "stage," he finds that it is unnecessary to describe various aspects of a 
production operation by using different words that can have essentially the same 
meaning in common usage.  Therefore, for clarification, the CGMP regulations are 
revised to use the word "phase" consistently when describing certain aspects of 
the manufacturing operations.
     15.  A number of comments concerned use of the phrase "to prevent" 
throughout the proposed CGMP regulations.  The phrase appears in these 
regulations to indicate that a required procedure must be accomplished, or 
accomplished in a manner, to preclude a resultant deleterious effect, e.g., 
"containers shall be opened, sampled, and resealed in a manner to prevent 
contamination."  In several instances, the comments objected to the phrase as 
being "too absolute," stating that the regulations should allow for variation 
from the desired objective on occasion because no firm should be expected to 
prevent undesirable occurrences 100 percent of the time.  The phrase "designed 
to prevent" was suggested as an alternative.  A number of comments objected to 
the phrase "to prevent" when used in conjunction with written procedures on the 
basis that written procedures in themselves do not prevent anything; they must 
be implemented to accomplish the desired objective.  The phrase "designed to 
prevent" was again suggested as an alternative phrase.
     The Commissioner believes that it is not acceptable to allow deviations 
from practices that could result in adverse effects upon the quality of the drug 
product, even on occasion.  The Commissioner, however, does agree with the 
comments' contention that written procedures must be implemented to prevent 
anything and has adopted the phrase "designed to prevent" in the applicable 
portions of the final regulations.
     16.  Several comments objected to the use of terminology such as 
"adequate," "appropriate," "significant," "major" equipment and "long" periods.  
The objection is that these terms lack the specificity needed and will result in 
confusion to the manufacturer.
     The Commissioner has carefully considered the use of these words and other 
words and phrases that imply absolute requirements in judgmental matters.  
Except for the changes noted in responding to the comments by specific sections, 
he concludes that the terminology is appropriate as set forth in the 
regulations.  Words such as "adequate" and "appropriate" do permit reasonable, 
albeit variable, interpretation by reasonable people, but are necessary and 
desirable for regulations to have both broad applicability and flexibility.  An 
overwhelming majority of those commenting on the proposal were greatly concerned 
that the regulations accommodate the wide variability of manufacturing and 
control systems.  In fact, a number of comments recommended additional use of 
modifying words such as "appropriate" and "adequate" to carry a sense of 
flexibility in the CGMP regulations.
     17.  Several comments objected to the use of the word "current" in the 
title and text of the regulations.  Other comments indicated that some of the 
proposed requirements, such as separation of penicillin operations in the 
production of veterinary drug products and the proposed statistical testing 
requirements, are not "current" good manufacturing practice for the industry.  
Another comment requested that the term "current" be defined.  One comment 
recommended that the word "current" be deleted since it is obvious that the 
latest regulations to be published are current, and therefore the use of the 
word "current" is superfluous.
     Several of these comments reflect, the Commissioner believes, a 
misunderstanding regarding the use of the word "current."  The act itself, in 
section 501(a)(2)(B), specifies that a drug is deemed adulterated if the methods 
used in, or the facilities or controls used for its manufacture, processing, 
packing, or holding do not conform to or are not operated or administered in 
conformity with "current" good manufacturing practice to assure that such drug 
meets the requirements of the act as to safety and has the identity and 
strength, and meets the quality and purity characteristics which it purports or 
is represented to possess.  The Congress intended that the phrase itself have a 
unique meaning and that the good manufacturing practice regulations represent 
sound current methods, facilities, and controls for the production of drugs to 
assure safety, identity, strength, quality, and purity of the product.  The 
agency determines what constitutes "current good manufacturing practice" based 
upon its experience with the manufacture of drugs through inspectional and 
compliance activities; upon knowledge gained from reviewing new drug 
applications, antibiotic forms, biological product and establishment licenses, 
and other submissions to FDA; and upon consideration of comments from interested 
persons received in response to proposals to amend CGMP regulations.  Although 
the practices must be "current" in the industry, they need not be widely 
prevalent.  Congress did not require that a majority or any other percentage of 
manufacturers already be following the proposed mandated practices, as long as 
it was a current good manufacturing practice in the industry, i.e., that it had 
been shown to be both feasible and valuable in assuring drug quality.
     The accumulated knowledge and experience of FDA in the area of current good 
manufacturing practice is reflected in a body of information, which with the 
exception of trade secrets and information relating to pending enforcement 
actions has long been available to the public.  This body of information, which 
is the basis for agency expertise with respect to current good manufacturing 
practice, is so voluminous that formal inclusion into the administrative record 
of this proceeding is not practical.  Nevertheless, the Commissioner relies on 
this body of information in promulgating this regulation.  The following list 
describes the information coming to FDA since active preparation of the proposal 
to revise the CGMP regulations began (in late 1974):
     (1)  FDA investigators conducted approximately 20,000 inspections of 
establishments in which drugs for human use are processed, and another 6,000 
inspections of veterinary drug establishments.  After each inspection, an FDA 
investigator filed an establishment inspection report with the agency.  With 
rare exceptions (for cases subject to active law enforcement investigation), 
these reports are promptly available as public information under FDA's Freedom 
of Information regulations (21 CFR Part 20).
     (2)  FDA received approximately 1,000 full new drug applications (including 
original submissions, resubmissions, and amendments), 1,500 abbreviated new drug 
applications, and 6,900 new animal drug applications.  Each application contains 
information pertaining to the manufacturing processes to be used in producing 
the drug subject to the application.  In addition, about 10,000 supplements to 
approved applications, many relating to manufacturing processes, were submitted.  
FDA must review and approve these processes before an application may be 
approved.  The contents of approved new drug applications, except those portions 
that constitute trade secrets, are available for public inspection.  (21 CFR 
314.14, 431.71, 514.11, and 601.51.)
     (3)  FDA monitored more than 1,200 recalls of drugs for human use and 275 
recalls of veterinary products.  In each recall resulting from a product defect, 
FDA investigates to determine the manufacturing control problems that led to the 
defect.  These investigations, generally embodied in establishment inspection 
reports, are also publicly available upon completion of regulatory activities.
     (4)  FDA brought over 500 legal proceedings--criminal proceedings, 
seizures, and injunctions--involving drugs for human use and veterinary 
products.  Again, in those proceedings arising from product defects, a full 
investigation has been conducted to support the agency's case.  In addition to 
the establishment inspection reports, testimony, documented evidence, and court 
papers are publicly available.
     Furthermore, FDA representatives have participated in numerous activities--
meetings, seminars, and workshops (regarding CGMP's, industry practices, and 
agency policies)--with organizations such as Parenteral Drug Association, the 
Proprietary Association, the National Association of Pharmaceutical 
Manufacturers, Pharmaceutical Manufacturers Association, the Packaging 
Institute, University of Wisconsin Industrial Pharmacy Management Conference, 
and the American Society for Quality Control.  These activities further 
contribute to the knowledge and experience of FDA.  Many of the organizations 
sponsoring these activities publish publicly available proceedings of these 
meetings, e.g., Journal of the Parenteral Drug Association and Proprietary 
Association Manufacturing Controls Seminar Presentations.
     For additional information summarizing FDA's activities for the past 
several years, see 1975-1977 Annual Reports and fiscal year 1979 Justification 
of Appropriation Estimates for Committee on Appropriations.  (Copies have been 
placed on file with the office of the Hearing Clerk, FDA.)
     18.  Several comments asserted that CGMP regulations must reflect the 
"current" practices of manufacturers of a particular type of drugs.  Others 
objected to the absence of findings specifically supporting the conclusion that 
a particular practice was a "current" practice of the manufacturers of a 
particular type of drug product.  Among the drug products cited as the 
appropriate measure for current good manufacturing practice were veterinary 
drugs, medical gases, radio-pharmaceuticals, and cosmetic-type drug products.
     The Commissioner recognizes that different types of drug products may 
require specialized manufacturing and control procedures or may not be 
appropriate to the application of certain procedures that are otherwise 
generally applicable to drug products.  For this reason, he has announced his 
intention to issue specialized current good manufacturing practice regulations 
for particular types of drug products and, in fact, has already issued one such 
proposal regarding large volume parenteral drug products.  The regulations set 
forth in Part 211 (21 CFR Part 211) are designed to be applicable to all drug 
products in finished dosage form.  They are based on practices widely used 
throughout the industry for manufacture of many finished drug products.  The 
Commissioner rejects the idea that FDA must establish that each CGMP requirement 
is a current practice of the manufacturers in each subset of drug products 
covered by the general requirements of Part 211.  As noted elsewhere in this 
preamble, the Commissioner has evaluated whether this requirement is appropriate 
for particular types of drug products in response to specific comments.  Where 
he has found it to be inappropriate, he has exempted the products from the 
requirement; otherwise the Commissioner has concluded that all manufacturers of 
finished drug products should be subject to the requirements of Part 211.  The 
Commissioner believes this is the only feasible way to approach such general 
current good manufacturing practice regulations.  There is no consensus on the 
various subgroups of finished drug products, and therefore a requirement that 
the currency of practice must be documented for each subgroup would ultimately 
amount to establishing that it was a current practice by each manufacturer of 
each drug product, a burden which would be impossible to establish and 
unnecessary for purposes of regulation.  Therefore, the Commissioner rejects 
these comments.

III.  AMENDMENTS REGARDING PLACEMENT OF EXPIRATION DATE ON DRUG PRODUCT LABELS

     19.  A substantial number of comments objected to the proposed requirement 
in 201.17 that the expiration date appear on the shipping carton.  The majority 
objected on the grounds that it is common practice for shipping containers to 
contain different drug products or similar drug products with different 
expiration dates.  Some persons recommended that the expiration date be required 
on the shipping carton only when the carton is for one drug product.
     The Commissioner recognizes that there are valid reasons for comingling 
various drug products, or different lots of the same drug product, within a 
single shipping carton.  In such instances it may not always be practical for 
each different expiration date to appear on the shipping carton.  Because of 
significant differences in the use and labeling of shipping cartons, the 
Commissioner concludes that a requirement for the expiration date to appear on 
the shipping carton when such shipping carton is not the immediate container 
should not be a part of the regulations at this time, and this requirement is 
deleted from 201.17.  Manufacturers are encouraged, however, to provide 
appropriate information to the extent possible on all shipping cartons to 
facilitate handling, reduce the possibility of mixups, and allow easy 
identification of lots that are being recalled or withdrawn from the 
marketplace.
     20.  Several comments were received regarding expiration dating of shipping 
cartons containing radio-pharmaceuticals.  Generally, the comments were that 
such drugs usually have several separate component parts each with a different 
expiration date.  One comment requested an exemption from the entire section, 
while another comment asked for an exemption for the shipping carton.
     The Commissioner believes that 201.17, as revised, will accommodate the 
special problems encountered in the handling of radiopharmaceuticals.
     21.  Several comments suggested that the heading of this section be revised 
by changing the title word from "drugs" to "drug product" to conform to the drug 
product definition in 210.3(b)(4).
     The Commissioner finds that the word "drugs" in the heading of 201.17 is 
more consistent with the terminology used in Part 201.  The term "drug product," 
as defined in 210.3(b)(4), is intended specifically for use in Part 211 to 
convey a meaning more limited than the general term "drug" as defined in section 
201(g) of the act.  However, to clarify that 201.17 applies to drug products 
under Parts 210 and 211, the final regulation in 201.17 is revised to refer to 
both drugs and drug products.
     22.  A number of comments recommended that the expiration date not be 
required on outer retail package labeling, such as display cartons, if the 
expiration date appearing on the immediate container is visible.
     The Commissioner agrees that it was his intention to require that the 
expiration date be visible under usual and customary conditions of packaging.  
He notes that section 201(k) of the act provides for label information that is 
easily legible through the outside container or wrapper.  Section 201.17 is 
revised to allow such alternative placement of the expiration date.
     23.  One comment said the proposed section does not clearly cover a 
situation where the producer does not package the material in a retail package, 
but markets drug products in bulk containers.
     Although the Commissioner believes that the situation described is covered 
by the proposed regulations, the final regulation as rewritten clearly specifies 
that when the expiration date of a drug, including drug products, is required, 
it shall appear on the immediate container.  There is no exemption for drug 
products in bulk containers.
     24.  One comment recommended that 201.17 specifically exclude "wrappers" 
for individual tablets, lozenges, and suppositories from the requirement of 
bearing an expiration date.
     The Commissioner finds that it is generally understood that protective 
wrappers for individual dosage forms that are further packaged in immediate 
containers are not required to bear an expiration date.  Because only one 
comment about protective wrappers was received requesting a statement in the 
regulations and no information was submitted that the issue raised has actually 
been a problem, the Commissioner concludes that further clarification of this 
section is not now warranted.
     25.  Several comments asked about the acceptability of placing the 
expiration date on the crimp of the drug product tube.
     Because of the wide variety of available methods and techniques of applying 
and presenting expiration dating information on the immediate container, the 
Commissioner has not attempted to specifically evaluate and list individual 
methods.  In general, he finds that the expiration date should be readily seen 
under usual and customary circumstances.  The tube crimp has been used for 
placing the lot or control number (as provided for under 201.100(b)(6)) and for 
placing the expiration date for some products.  No known problems have been 
associated with such information appearing on the crimp of the dispensing tube 
and, therefore, this method is an acceptable way to comply with 201.17.
     26.  Several comments objected to the provisions in 201.17 that when 
single-dose containers are packed in individual cartons, the expiration date may 
properly appear on the carton only.  Several respondents noted that ampules are 
sometimes removed from the outer carton, particularly in hospitals, and that 
valuable information that is not a part of the immediate container labeling is 
lost.
     The provision in this section regarding single-dose containers has been in 
effect for a number of years and was based on information that such an allowance 
was necessary for single-dose containers, primarily glass ampules, because of 
technical problems in labeling glass ampules on a batch-by-batch basis.  Some 
manufacturers are now placing expiration dates on single-dose containers; 
however, no information has been presented that expiration dating for all 
single-dose containers, particularly glass ampules, is feasible.  Although the 
Commissioner recommends this activity, it was not his intent to propose 
revocation of the exemptions for single-dose containers as part of this revision 
of FDA regulations.  Based on the few comments received which recommended 
additional revisions in this section, the Commissioner will not revoke these 
exemptions at this time, but will consider the recommendations for revisions for 
a future proposal.
     27.  Several comments recommended that for drugs which are also cosmetics 
(see also paragraph 42(h)) expiration dates should only be placed on the 
shipping carton and outer retail package because such products are typically 
purchased by the user with the outer retail package intact and the product is 
consumed in a relatively short period of time.
     The Commissioner advises that under the interim provisions of 211.137(f), 
most of these types of products will be exempted from the expiration dating 
requirements.  But the so-called "drug-cosmetic" type of products are not free 
from stability problems; therefore, unless such products are stable for at least 
3 years, expiration dating is required (see also paragraph 353 of this 
preamble).

IV.  AMENDMENTS REGARDING DRUG LISTING AND ESTABLISHMENT REGISTRATION 
REQUIREMENTS FOR DRUG PRODUCT SALVAGING OPERATIONS

     28.  Several comments suggested that the word "human" be inserted between 
the words "licensed" and "biologicals" in 207.3(b) because veterinary 
biologicals are regulated by the U.S. Department of Agriculture.
     The Commissioner agrees with these comments and is amending the paragraph 
accordingly.
     29.  One comment recommended that the definition of "establishment" under 
207.3(b) be broadened to include additional categories such as bulk sales by 
practitioners, antique shops, and dealers and trustees handling estate sales 
and/or bankruptcies.
     The Commissioner agrees that these are all examples of establishments that 
could engage in drug-salvaging operations, but believes that the proposed 
definition of "establishment" is preferred in order to provide coverage for any 
type of establishment that engages in drug product salvaging operations, 
including those identified in the comment.
     30.  Two comments suggested deletion of the word "may" in the phrase "may 
have been subjected to" improper storage conditions in the proposed 207.3(k) 
because the statement is too general and the requirement should only apply when 
the drug product has actually been exposed to adverse conditions.
     The Commissioner rejects this suggestion because it may not be possible in 
every instance to establish clearly the exact nature of the adverse circumstance 
to which a drug product has been exposed.  Therefore, in some instances, the 
salvager may only have sketchy information about improper storage conditions, 
such as unusual temperatures, and must assume that such conditions may have 
occurred in order to handle the salvaging operations properly.
     31.  Three comments concerned the proposed exemption of drug product 
salvagers from drug listing in 207.20.  Two of the comments recommended that 
drug product lists be submitted prior to salvaging and one respondent 
recommended that a drug product list need not be submitted, but should be 
maintained by the salvager.
     The Commissioner agrees that an inventory of drugs subjected to salvaging 
operations should be maintained, but does not agree that salvagers should submit 
a drug list under Part 207 (21 CFR Part 207).  To clarify that an inventory of 
drugs involved in salvaging operations shall be maintained, provisions are added 
in 211.208 for maintenance of records for drug products subjected to salvaging 
operations.
     32.  One comment considered the registration requirement for a drug 
salvaging firm to be a waste of taxpayers' money and recommended that the 
recycling of any and all drugs and pharmaceuticals be prohibited. 
     The Commissioner disagrees with this opinion.  He does not agree that drug 
product salvaging should be prohibited where the integrity of the drug product 
is not compromised.  Otherwise costs to consumers might be increased.  
Individual firms are in a better position to determine the financial feasibility 
of a salvaging operation.  The costs of registration, both to the Government 
(and the taxpayer) and to the registrant, are quite insignificant and probably 
less than the added costs that would result from the needless destruction of 
salvageable drug products.

          V.  LEGAL STATUS OF CGMP REGULATIONS

     33.  Several comments requested deletion of the word "drugs" in the title 
and insertion of the words "drug products" in order to be consistent with the 
title of Part 211 and the definition of 210.3(b)(4) and 210.1(a).
     Part 210 applies to all parts between Parts 211 and 229.  Part 211 deals 
with finished dosage forms, but other parts may not.  Therefore, the 
Commissioner finds that the more general term "drugs" applies better to the 
various types of drugs that are likely to be covered in Parts 211 to 229.
     34.  A number of comments objected, on diverse grounds, to use of the word 
"minimum" to describe the requirements in these regulations.  Several 
respondents believed that current good manufacturing practice cannot be 
considered in terms of a "minimum" because that implies that firms adhering to 
the regulations are then merely at a threshold level of compliance.  Other 
respondents suggested that "minimum" means that normal practices represent a 
higher standard and that there is an implication that the standards of these 
regulations fall below an acceptable level.  Some comments recommended that 
"minimum" not be used because no such reference to CGMP regulations is in the 
act.
     The Commissioner does not agree with these comments.  The legislative 
history of the Drug Amendments of 1962 shows that section 501(a)(2)(B) of the 
act was included to raise the standards of drugs manufacturing by all 
manufacturers to the level of the current good manufacturing practice in the 
industry.  Congress was quite concerned about the uneven and sometimes 
unacceptable quality of drug products from some portions of the pharmaceutical 
industry.  The purpose of section 501(a)(2)(B) of the act is to provide 
assurance that drug product quality would not fall below that which was feasible 
and available under contemporary technology.  There is no implication that the 
standards represented by these regulations are less than acceptable or below the 
industry's norm.  On the other hand, there is no prohibition in the regulations 
against the manufacturing of drug products using better, more efficient, and 
innovative methods.  In fact, the Commissioner encourages use of such methods 
because it benefits the consumer.  Although the word "minimum" does not appear 
in section 501(a)(2)(B) of the act, its use is necessary in the CGMP regulations 
because of their binding legal nature (discussed in paragraph 35); that is, 
failure to meet the minimum standards of the regulation results in the product's 
being adulterated.

             BINDING DRUG CGMP REGULATIONS

     35.  Several comments argued that 210.1 should be deleted because it is 
based on the erroneous proposition that CGMP regulations can be substantive.  
The comments urged that regulations issued under section 501(a)(2)(B) of the act 
are only interpretive.  In support of their argument, many referred to the 
legislative history of the Drug Amendments of 1962.  One commented stated the 
following:

     Section 501(a)(2)(B) was enacted as part of the Drug Amendments of 1962, 
and, as reported by House Committee, those amendments would have included a 
provision empowering the FDA to issue GMP regulations under it formal section 
701(e) rulemaking authority.  (H.R. 11581, 87th Congress, Second Session.)  The 
House Committee Report explained:  "The promulgation of these regulations would 
be subject to opportunity for hearing and judicial review.  Thus, legal action 
could be brought against firms failing to abide by these standards and against 
the products they ship."  (H.R. Rep. No. 2464, 87th Congress, Second Session, 
2(1962).)  The present form of section 501(a)(2)(B) was first enacted by the 
Senate.  The Senate Committee Report made clear that the provision was intended 
to authorize the FDA to issue "interpretative" regulations that would constitute 
only prima facie evidence of adulteration.  (S. Rep. 1744, 87th Congress, Second 
Session, 9(1962).)  In floor action on September 27, 1962, the House amended 
H.R. 11581 to be consistent with the Senate bill.  (108 Congressional Record 
19916 (daily edition 1962).)

Most of those relying on the legislative history argument quoted from the same 
Senate Committee Report.
     Other comments objecting to FDA's authority to issue binding CGMP 
regulations asserted that the four judicial decisions cited in the preamble to 
the February 13, 1976, proposal in fact did not support that authority.  One 
comment reviewed the history of all four proceedings and concluded:

     All of the cases cited by the Commissioner * * * recognize that the court 
cannot reach a conclusion contrary to Congressional intent.  In those cases, 
there was no clear Congressional intent and the courts allowed the FDA to issue 
substantive regulations under section 701(a) of the Act.  The legislative 
history with respect to the proposed CGMP regulations is crystal clear and does 
not permit the Commissioner to issue substantive regulations.

     Because of the fervor reflected by these objections and because the 
Commissioner foresees identical objections being made to proposals to issue 
binding CGMP regulations for specific classes of drug products in the future, 
the Commissioner has decided that a lengthy exposition of the basis for his 
concluding that FDA has legal authority to promulgate such regulations is 
warranted.  The Commissioner intends that this statement will be definitive, and 
he does not contemplate reconsidering the issue of FDA's legal authority to 
issue substantive CGMP regulations in the future unless new materials, not 
discussed below, are brought to his attention.  The question of whether a 
particular regulation should be issued as binding or interpretive, of course, 
may always be raised, and comments on the wisdom of making these CGMP 
regulations binding are discussed in paragraph 36 below in this preamble.
     With regard to the legislative history of the Drug Amendments of 1962, the 
Commissioner finds that none of the comments provided a complete or accurate 
picture of the enactment of the current section 501(a)(2)(B) of the act.  
Because of the emphasis placed by the persons objecting to "substantive" CGMP 
regulations on Congressional intent, the Commissioner believes a detailed review 
is necessary.
     On July 19, 1962, the Senate Judiciary Committee reported out S. 1552, the 
Senate version of what ultimately became the Drug Amendments of 1962.  Section 5 
of the July 19 bill would have amended section 501(a)(2) of the act to read as 
follows:

     (2)(A) if it has been prepared, packed, or held under insanitary conditions 
whereby it may have been contaminated with filth, or whereby it may have been 
rendered injurious to health; or (B) if it is a drug and the methods used in, or 
the facilities or controls used for, its manufacture, processing, packaging, or 
holding do not conform to current good manufacturing practice to assure that 
such drug meets the requirements of this Act as to safety and has the identity 
and strength, and meets the quality and purity characteristics, which it 
purports or is represented to possess.  The Secretary is authorized to issue 
interpretative regulations, upon notice and in accordance with the procedures 
set forth in section 4 of the Administrative Procedure Act (5 U.S.C. 1003), 
which shall, in any proceeding involving this paragraph, be prima facie evidence 
of what constitutes current good manufacturing practice.

     The accompanying bill report (S. Rep. No. 1744, 87th Cong., 2d Sess. (July 
19, 1962)), described this section at page 9, emphasizing that the "Secretary 
would be authorized to issue interpretative regulations as to what constitutes 
current good manufacturing practice, and these regulations would be prima facie 
evidence in any proceeding under this section of the Food, Drug, and Cosmetic 
Act."
     On August 3, 1962, President Kennedy submitted a series of amendments to 
the Senate Judiciary Committee.  In response to this and to the public 
controversy then erupting over thalidomide, the Committee reconsidered S. 1552 
and, on August 21, 1962, reported out a revised version of the bill.  One change 
was to reword section 5 of the bill so that section 501(a)(2) would be amended 
to read as follows:

     (2)(A) if it has been prepared, packed, or held under insanitary conditions 
whereby it may have been contaminated with filth, or whereby it may have been 
rendered injurious to health; or (B) if it is a drug and the methods used in, or 
the facilities or controls used for, its manufacture, processing, packing, or 
holding do not conform to or are not operated or administered in conformity with 
current good manufacturing practice to assure that such drug meets the 
requirements of this Act as to safety and has the identity and strength, and 
meets the quality and purity characteristics, which it purports or is 
represented to possess.

     The Judiciary Committee issued a second report to explain its proposed 
changes in S. 1552 (S. Rep. No. 1744, Pt. 2, 87th Cong., 2d Sess. (Aug. 21, 
1962)).  On pages 3 and 4, it discussed the revision of section 5 as follows:

     The President, in the recommendations submitted for the consideration of 
the committee with his letter of August 3, 1962, proposed a revised version 
which included the following principal amendments to the reported bill:
     (1) It proposed to replace the provisions on regulations with prima facie 
evidentiary effect with a provision that the adequacy of the quality controls be 
determined "in accordance with regulations promulgated by the Secretary on the 
basis of good manufacturing practice" after formal rulemaking procedures, i.e., 
after affording an opportunity for hearing, and for judicial review on the basis 
of the hearing record, with respect to such regulations.

                    *   *   *   *   *

     The explanation accompanying the recommendations of the President expressed 
concern lest the language as to interpretative regulations with prima facie 
evidentiary effect invite endless de novo litigation on the question of what 
constitutes a good manufacturing practice each time there is enforcement action 
under the new quality control provisions.  The committee acceded to the 
President's request for elimination of the "prima facie" regulatory authority in 
the bill.  It felt, however, on balance, that there was no need for inserting 
provisions for regulations through formal rulemaking on the subject of what is 
good manufacturing practice.  Section 701(a) (21 U.S.C. 371(a)) now vests in the 
Secretary "authority to promulgate regulations for the efficient enforcement of 
this Act."  This permits the Department to issue such regulations as it desires 
and their scope and effect will be the same as that of other regulations issued 
under such general authority.  Numerous regulations have been issued under 
section 701(a) and have been the subject of consideration and application in the 
courts in actions arising under the various provisions of the act not now 
subject to formal rulemaking procedures.
     During the floor debate on S. 1552 on August 23, Senator Eastland, Chairman 
of the Judiciary Committee, elaborated on the meaning of section 501(a)(2) as it 
would be amended by the bill:

     Section 5, as it would read under the August 20 amendments, is designed to 
assure that drugs are manufactured according to good manufacturing practice.  It 
would deem a drug to be adulterated and thus subject to seizure if made under 
facilities, methods, or controls that are inadequate to assure that the drug 
meets the specifications of a quality product.  Adulteration could also be found 
if such facilities, methods, or controls were not operated or administered in 
conformity with good manufacturing practice.
     Since the competitive position of responsible manufacturers depends in 
large part on the confidence of the medical profession and the public, it will 
be in their own interest to maintain high standards of current good 
manufacturing practice which will provide a readily determinable basis for 
enforcement proceedings against any substandard operator.  The Secretary could 
use his general rulemaking authority under section 701(a) of the act to announce 
what he, in the administration of the act, considers to be good manufacturing 
practice insofar as methods, facilities, controls, and their operation and 
administration are concerned.  As in the case of other regulations, the court in 
the final analysis will pass upon the scope and effect of such regulations.  
(108 Cong. Rec. 16303-4 (Aug. 23, 1962).)

     Senator Kefauver concurred in this change, stating, "This provision has 
been strengthened considerably in comparison to the bill which was reported in 
July." (Id., at 16306-7).
     The Commissioner thus concludes that when it unanimously approved S. 1552 
on August 23, 1962, the Senate obviously believed that the problem identified by 
the President--"endless de novo litigation * * * each time there is enforcement 
action"--had been resolved.  The Senate must, therefore, have intended that 
regulations issued under section 501(a)(2)(B) of the act be more than merely 
prima facie evidence of what constitutes current good manufacturing practice, 
i.e., that they be given at least the same force as any other regulation issued 
under section 701(a) of the act.  He also finds that the statement relied upon 
by most comments as proof that only interpretive regulations could be issued 
appeared in the first Senate Report and was explicitly reversed in the second 
Senate Report.
     One month later, the House Interstate and Foreign Commerce Committee 
reported out H.R. 11581, the House bill that preceded the Drug Amendments of 
1962.  (H.R. Rep. No. 2464, 87th Cong., 2d Sess. (1962)).  Section 101(a) of 
this bill proposed to amend section 501(a)(2) of the act to read as follows:

     (2)(A) if it has been prepared, packed, or held under unsanitary conditions 
whereby it may have been contaminated with filth, or whereby it may have been 
rendered injurious to health; or (B) if it is a drug and the methods used in, or 
the facilities or controls used for its manufacture, processing, packing, or 
holding do not conform to or are not operated or administered in conformity with 
current good manufacturing practice (as determined in accordance with 
regulations promulgated by the Secretary) to assure that such drug meets the 
requirements of this Act as to safety and has the identity and strength, and 
meets the quality and purity characteristics, which it purports or is 
represented to possess.

     In addition, paragraph (b) of section 101 would have amended section 701(e) 
of the act to provide that regulations under section 501(a) would be issued by 
formal rulemaking procedures (rather than the informal procedures under section 
701(a) of the act).
     The Committee Report accompanying H.R. 11581 explained this provision as 
follows (H. Rep. 2464, 87th Cong., 2d Sess. 2 (Sept. 22, 1962)):

     Section 101 of the reported bill would amend section 501(a)(1) [sic] of the 
Federal Food, Drug, and Cosmetic Act to deem a drug to be adulterated if the 
methods, facilities, or controls used in its manufacture, processing, packaging, 
or holding fail to conform to, or are not operated or administered in conformity 
with, good manufacturing practices as determined in accordance with regulations 
to be issued by the Secretary of Health, Education, and Welfare which are 
designed to assure that the drug is safe and has the identity and strength and 
meets the quality and purity characteristics which it purports or is represented 
to possess * * *
     The promulgation of these regulations would be subject to opportunity for 
hearing and judicial review.  Thus, legal action could be brought against firms 
failing to abide by these standards and against the products they ship.

     The House of Representatives debated H.R. 11581 on September 27, 1962.  
Congressman Schenck offered several amendments that day, one of which would 
delete the parenthetical element in section 101(a), and all of section 101(b), 
from the bill.  He explained this amendment as follows:

     My amendment to section 101 of the bill, which was approved by the 
committee, provides simply that the drug will deem[sic: be deemed] to be 
adulterated and subject to seizure if the methods, facilities, or controls used 
in the manufacture of the drug do not conform with current good manufacturing 
practice, as determined in accordance with regulations promulgated by the 
Secretary.
     The purpose of this provision is to enable the Secretary to require all 
companies producing drugs to observe the high standards that are now followed by 
the better manufacturers.  It is intended that the Secretary's regulations will 
define minimum standards of good manufacturing practice, rather than setting 
forth an exclusive method by which some particular drug product may be made.  
Manufacturers whose methods, facilities, and controls exceed the minimum 
standards will not be required to lower their own standards, so long as they can 
show that their own practices meet or exceed these minimum requirements.
     The principal purpose of the provision is to assure that the same high 
manufacturing standards are followed in making so-called old drugs that the law 
now requires in the making of so-called new drugs.  Before any manufacturer is 
permitted to make a new drug he must file complete details of his manufacturing 
process with the Food and Drug Administration.  It is not intended that the 
regulations issued under section 101 will apply to the manufacturer of new drugs 
insofar as the methods, facilities, or controls used in making these new drugs 
but that the Food and Drug Administration will require that such drugs meet the 
requirement of this act as to safety, and has the identity and meets the quality 
and purity characteristics which it purports or is represented to possess.
     The committee adopted an amendment which would make the formal rulemaking 
procedures of section 701(e) of the Federal Food, Drug, and Cosmetic Act 
applicable to regulations referred to which may be made pursuant to the above 
amendment.
     I am opposed to the amendment in section 101(b) of the bill which would 
require the Secretary to hold a formal hearing under section 701(e) of the 
Federal Food, Drug, and Cosmetic Act in order to issue regulations as to what 
constitutes 'current good manufacturing practice.'  I favor the approach adopted 
by the Senate under which this determination is made pursuant to section 701(a) 
of the act.  This procedure permits the Secretary to issue such regulations as 
he desires and their scope and effect will be the same as that of other 
regulations, issued under such general authority.  This procedure is more 
flexible.  Numerous regulations have been issued under this section and they 
have been the subject of consideration and application in the courts in actions 
arising under the various provisions of the act not now subject to formal 
rulemaking procedures.  (108 Cong. Rec. 19895-6 (Sept. 27, 1962).)

     The Schenck amendment was concurred in by Congressman Harris, Chairman of 
the House Commerce Committee, who observed that the amendment "is taken, in 
part, from the Senate bill, S. 1552 * * * The gentleman from Ohio [Mr. Schenck] 
has advised me of the need not to tie this provision in with section 701(e) * * 
*" 108 Cong. Rec. 19916 (Sept. 27, 1962).  The amendment was agreed to and, as 
approved by the House of Representatives, the legislation would amend section 
501(a)(2) to read:

     (2)(A) if it has been prepared, packed, or held under unsanitary conditions 
whereby it may have been contaminated with filth, or whereby it may have been 
rendered injurious to health; or (B) if it is a drug and the methods used in, or 
the facilities or controls used for, its manufacture, processing, packing, or 
holding do not conform to or are not operated or administered in conformity with 
current good manufacturing practice to assure that such drug meets the 
requirements of this act as to safety and has the identity and strength, and 
meets the quality and purity characteristics, which it purports or is 
represented to possess.

     The Commissioner finds from this history that the House of Representatives 
believed that CGMP regulations would have the same legal status as other FDA 
regulations, and moved to revise language to conform to S. 1552, as passed, 
solely to eliminate the requirement that CGMP regulations be issued pursuant to 
the formal rulemaking procedures of section 701(e) of the act.
     Because there was no difference between the House and Senate bills insofar 
as the amendment of section 501(a)(2) of the act was concerned, it was not a 
subject of the Conference Report (H. Rep. No. 2526, 87th Cong. 2d Sess. (Oct. 3, 
1962)), nor was it modified or debated further by either the Senate or the House 
when each voted to approve the Drug Amendments of 1962 (on October 3 and 4, 
1962, respectively).
     Based on this complete review of the legislative history of section 
501(a)(2)(B) of the act, the Commissioner concludes that there is no support for 
the proposition that Congress intended that CGMP regulations should be merely 
interpretive.  At the least, Congress wanted CGMP regulations to have the same 
force and effect as other regulations issued under section 701(a) of the act.  
(See the second Senate Report and Rep. Schenck's description of his amendment, 
above).  To the extent that a stronger Congressional mandate can be gleaned from 
the various reports, amendments, and debates, it appears that binding standards 
were to be issued by FDA and issued through the less cumbersome notice-and-
comment rule making procedures of section 701(a) of the act rather than the more 
complex section 701(e) mechanism.  Therefore, the Commissioner rejects the 
argument that 210.1 exceeds the authority conferred by Congress under sections 
501(a)(2)(B) and 701(a) of the act.
     With respect to judicial interpretations of FDA's authority to issue 
substantive rules, the Commissioner believes that the cases cited in the 
February 13, 1976 preamble and decisions handed down since February 13, 1976 are 
directly relevant to, and further support, his conclusion that CGMP regulations 
can be issued as binding standards.
     In 1973, the Supreme Court reviewed the legality of two interrelated FDA 
regulations.  One, now codified in 21 CFR 314.111(a)(5), set forth in detail the 
scientific principles that the Commissioner believed are part of the requirement 
in section 505(d) of the act that the effectiveness of a drug be demonstrated by 
"substantial evidence consisting of adequate and well-controlled studies."  The 
second regulation, now codified in 21 CFR 314.200, contained standards for FDA 
to determine whether a request for a hearing on the denial or withdrawal of 
approval of a new drug application (NDA) presented a genuine and substantial 
issue of fact.  At stake in the case of Weinberger v. Hynson, Westcott and 
Dunning, Inc., 412 U.S. 609(1973), was whether an applicant was entitled to a 
full evidentiary hearing on the approvability of its product, and at such a 
hearing could offer whatever evidence it felt met the statutory standards of 
effectiveness, or whether FDA could summarily deny or withdraw approval of the 
NDA because the agency found that the applicant's evidence did not meet the 
standards in the regulations for evidence of effectiveness.  Manufacturers 
contended that FDA's regulations could not serve as the basis for denying them a 
full evidentiary hearing under section 505 of the act.  The agency believed that 
the regulations were a reasonable method of screening out unnecessary hearings 
and thereby managing an otherwise overwhelming workload.  The Supreme Court 
concluded that both of the regulations were within the authority of the 
Commissioner under section 701(a) of the act and therefore FDA could act on 
NDA's without a full hearing where evidence failed to satisfy the FDA 
regulations.  It said (id. at 622):

     The standard of 'well-controlled investigations' particularized by the 
Regulations is a protective measure designed to ferret out those drugs for which 
there is no affirmative, reliable evidence of effectiveness.  The drug 
manufacturers have full and precise notice of the evidence they must present to 
sustain their NDA's, and under these circumstances we find the FDA hearing 
regulations unexceptionable on any statutory or constitutional ground.

     The Supreme Court, in this and related cases, discussed FDA's authority to 
determine whether a drug was a "new drug" under section 201(p) of the act (and 
thus subject to the requirements of section 505 of the act).  It described 
favorably the review of over-the-counter (OTC) drugs under the procedures set 
forth in 21 CFR 330.10, by which OTC drugs are being classified as "new" or 
"generally recognized as safe and effective and not misbranded," the latter not 
subject to the new drug provisions of the act.  These procedures were also 
promulgated under the authority of section 701(a) of the act.  The Court stated, 
in Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973) that:

     We think that it is implicit in the regulatory scheme, not spelled out in 
haec verba, that FDA has jurisdiction to decide with administrative finality, 
subject to the types of judicial review provided, the 'new drug' status of 
individual drugs or classes of drugs.  The deluge of litigation that would 
follow if 'me-too' drugs and OTC drugs had to receive de novo hearings in the 
courts would inure to the interests of manufacturers and merchants in drugs, but 
not to the interests of the public that Congress was anxious to protect by the 
1962 amendments, as well as OTC drugs and drugs covered by the 1972 (Drug 
Listing) Act.  We are told that FDA is incapable of handling a caseload of more 
than perhaps 10 or 15 de novo judicial proceedings in a year.  Clearly, if FDA 
were required to litigate, on a case-by-case basis, the 'new drug' status of 
each drug now marketed, the regulatory scheme of the act would be severely 
undermined, if not totally destroyed.  Moreover, a case-by-case approach is 
inherently unfair because it requires compliance by one manufacturer while his 
competitors marketing similar drugs remain free to violate the Act * * *.

     In a third case decided at the same time, Ciba Corp. v. Weinberger, 412 
U.S. 640 (1973), the Court said (id. at 643-4) that "the definition of new drug 
as used in section 201(p)(1) involves a determination of technical and 
scientific questions by experts.  The agency is therefore appropriately the arm 
of Government to make the threshold determination of the issue of coverage * * 
*."
     The Commissioner notes that even prior to these rulings, most major 
manufacturers of OTC drugs had recognized the reasonableness as well as legal 
propriety of the OTC review as a mechanism within the authority of section 
701(a) of the act to classify drugs as "new" or "not new."  Indeed, for over 5 
years now, these firms have been participating in this review, and the 
Commissioner expresses his gratitude for this cooperation.
     Subsequent to these rulings by the highest Federal court, another case 
arose over the issue of whether FDA could promulgate regulations under section 
701(a) of the act that represented binding rules relating to prescription drugs 
under section 503(b) of the act.  The specific issue was whether FDA could, by 
regulation, declare products containing more than certain amounts of vitamin A 
or D to be prescription drugs.  The opponents of the regulation, in an 
interesting parallel to the comments on the CGMP regulations, argued that only 
regulations issuable under section 701(e) of the act procedures could be binding 
and that the legislative history of section 503(b) of the act demonstrates that 
FDA could issue only interpretive regulations.  The United States Court of 
Appeals for the Second Circuit rejected these contentions in National 
Nutritional Foods Ass'n. v. Weinberger, 512 F.2d 688 (1975).  It stated:

     We have come to recognize that, if the administrative process is to be 
practicably effective, specific regulations promulgated pursuant to general 
statutory delegation of authority must be treated as authoritative, whether 
labeled "substantive" or "interpretive," especially in areas where the agency 
possesses expertise not shared by the courts.  In the event its views are 
unlikely to be distributed by the court in an enforcement proceeding * * *.  
Whatever doubts might have been entertained regarding the FDA's power under 
701(a) to promulgate binding regulations were dispelled by the Supreme Court's 
recent decision in Weinberger v. Hynson, Westcott, & Dunning * * * and its 
companion cases * * *. (id. at 696).

                   *   *   *   *   *

     Surely an agency which possess the power to determine administratively what 
products are "new drugs" has the authority to decide what products are 
"prescription drugs". (id. at 699).

     The decisions in the National Nutritional Foods, Hynson, Bentex, and Ciba 
were cited by the Commissioner because he believes that they conclusively rule 
that regulations issued under section 701(a) of the act are binding and that the 
justifications for issuing substantive regulations in other areas are directly 
applicable to CGMP regulations.  Similar to the Court's observations in Hynson 
quoted above, the statutory standard of "current good manufacturing regulations" 
can and should be particularized as a protective measure to identify those 
manufacturing practices which are at a minimum necessary to assure drug quality.  
The drug manufacturers have full and precise notice of the CGMP requirements 
they must fulfill to sustain the acceptability of their products under section 
501(a)(2)(B) of the act, as the Commissioner noted in the February 13, 1976, 
preamble.  Substantive regulations also provide greater certainty about the 
agency's expectations because, in promulgating such regulations, the agency must 
carefully distinguish standards it seriously intends to enforce from those it 
finds desirable but not essential.  The Commissioner also stated in the 1976 
proposal that binding CGMP regulations would assist courts and expedite 
enforcement proceeding under the act.
     As with "new drug" determinations discussed in Bentex, if each CGMP 
requirement has to receive a de novo hearing in each and every enforcement 
proceeding, the burden of litigation that would result would not be in the 
public interest, nor would it be equitable to competing manufacturers who where 
not involved in such litigation.  President Kennedy and the second Senate Report 
made the same arguments in deleting the reference to interpretive regulations 
from S. 1552.  The agency has avoided this problem over the last several years 
because agency priorities have been concentrated in areas other than drug CGMP 
enforcement; it is not anticipated that this allocation of resources will 
continue indefinitely and, with the issuance of these regulations, more 
regulatory proceedings are probable.
     In Ciba, the Court noted the technical and scientific expertise appropriate 
for at least the threshold determination of "new drug" status.  The Commissioner 
believes that determination of what is the "current good manufacturing practice" 
in the drug industry also requires technical and scientific expertise, as well 
as a unique ability to observe the entire industry.  These CGMP regulations were 
developed with the participation of pharmaceutical chemists employed by FDA, 
individuals qualified by formal training as well as by valuable experience in 
reviewing the good (and bad) current (and past) production and control 
techniques set forth in original NDA's and abbreviated NDA's, supplemental 
applications, antibiotic certification forms, biological establishment and 
product licenses, new animal drug applications, and proposed and final 
compendial standards.  In addition, FDA investigators who conduct and/or review 
inspections of manufacturers under the act also participated in preparing this 
document.  Although, as one comment noted, FDA does not manufacture drugs, it 
does not follow that FDA cannot determine current good manufacturing practice 
for drugs.  On the contrary, FDA may be uniquely able to do so, because it and 
it alone has had access to the facilities and records of every manufacturer of 
pharmaceuticals in this country.  Given the fact that many production and 
control processes are considered by individual firms to be trade secrets, it is 
unlikely that competitors or independent private third parties such as 
compendial authorities have the same ability as FDA to discover what non-public 
practices other than their own are current and which of these are good.
     Subsequent to the February 1976 proposal, other courts have considered and 
affirmed FDA's authority to promulgate binding of substantive regulations 
pursuant to section 701(a) of the act.  See, e.g., Cosmetic, Toiletry and 
Fragrance Association v. Schmidt, 409 F. Supp. 57 (D.D.C., Feb. 3, 1966), appeal 
docketed No. 76-1242 (D.C. Cir., Feb. 5, 1976)(regulation requiring warning 
labels on aerosolized products, issued under sections 201(n), 602(a), and 701(a) 
of the act, upheld; American Frozen Food Institute v. Mathews, 413 F. Supp. 548 
(D.D.C. March 30, 1976), aff'd sub nom. American Frozen Food Institute v. 
Califano, 555 F.2d 1059 (D.C. Cir. May 12, 1977)(regulations establishing common 
and usual names for nonstandardized foods, issued under sections 403(i) and 
701(a) of the act, upheld); National Confectioners Ass'n. v. Mathews, CCH Food, 
Drug & Cos. L. Rep. 38,062 (D.D.C. April 14, 1976), aff'd sub nom. National 
Confectioners Ass'n v. Califano, Docket No. 76-1617 (D.C. Cir. Jan. 20, 
1978)(CGMP regulations for cocoa products and confectionery relating to lot 
coding on finished product packages and shipping containers and to distribution 
records of lots, issued under sections 502(a)(4) and 701(a) of the act, upheld); 
Federation of Homemakers v. Schmidt, 385 F. Supp. 362(D.D.C. 1974), aff'd 539 
F.2d 740 (D.C. Cir. June 10, 1976)(regulation establishing requirements for 
"imitation" foods, issued under sections 403(c) and 701(a) of the act, upheld); 
Almay, Inc. v. Weinberger, 417 F. Supp. 758 (D.D.C. June 30, 1976), rev'd on the 
grounds, No. 76-1718 (D.C. Cir. Dec. 21, 1977) authority to issue regulations 
regarding labeling and supporting evidence of cosmetics claiming to be 
"hypoallergenic," under sections 301(b), 602(a) and (b) and 701(a) of the act 
upheld); United States v. Nova Scotia Food Prod. Corp., 417 F. Supp. 1364 
(E.D.N.Y., Aug. 17, 1976), rev'd on the grounds, No. 76-6169 (2d Cir. Dec. 15, 
1977)(CGMP regulations regarding brining and heating of fish in the production 
of smoked fish may be promulgated under sections 402(a)(4) and 701(a) of the 
act).  The Commissioner notes that two of the cases dealt specifically with the 
validity of CGMP regulations issued under the statutory standards relating to 
adulterated foods, which do not explicitly refer to "current good manufacturing 
practice."  It would indeed be anomalous that those regulations could be issued 
as legally binding if regulations amplifying section 501(a)(2)(B) could not be.
     The Commissioner interprets much of the concern over FDA's authority to 
issue binding regulations as reflecting a belief that the CGMP regulations can 
be arbitrary, need not be based upon actual current practice, and may exceed 
what is necessarily "good" for drug quality.  There also seems to be a belief 
that binding regulations cannot be changed and are beyond review by the courts.  
These perceptions are in error.
     The Administrative Procedure Act clearly provides that regulations which 
are arbitrary or capricious may be overturned by a reviewing court.  5 U.S.C. 
706.  The legislative history of section 501(a)(2)(B) of the act and cases 
involving enforcement of CGMP regulations, e.g., United States v. An Article of 
Drug * * * "White Quadrisect", 484 F.2d 748 (7th Cir. 1973)) established that 
the regulations must be based on current industry practice, although not 
necessarily on the predominant practice in the industry.  The agency is directed 
to consider the current "good" practices.  In determining current practice, the 
agency has relied upon the knowledge and expertise of FDA staff developed from 
the review of NDA's and ANDA's, antibiotic certification forms, biological 
licenses, and compendial standards submitted to the agency, and from 
establishment inspections made during the last half decade.  A "good" practice 
was included in these regulations only if it is feasible for manufacturers to 
implement the practice, if the practice contributes to assuring the safety, 
quality, and purity of the drug product, and if the value of the contribution or 
added assurance exceeds the cost, in terms of dollars and/or other burdens, of 
implementing or continuing the practice.  The Commissioner does not believe it 
is legally required that, in addition to reliance upon agency expertise, he must 
include in the record specific examples of each practice mentioned in these 
regulations.
     Regarding judicial review of regulations, the Commissioner notes that such 
review is assured by the Administrative Procedure Act whether the regulations 
are deemed interpretive or substantive.  Judicial review is available in any 
enforcement proceeding brought against a particular manufacturer or product.  
Pre-enforcement review is also available.  Abbott Laboratories v. Gardner, 387 
U.S. 136 (1976).
     Thus, the Commissioner believes that the fears that substantive, binding 
CGMP regulations somehow deprive individuals of legal protections are unfounded.
     As noted at the outset of this discussion, the Commissioner does not intend 
in the future to reconsider the legal authority of FDA to promulgate binding 
CGMP regulations under section 701(a) of the act, unless new material, not 
discussed above, is presented to him that raises substantial doubt as to the 
correctness of the analyses and conclusions he set forth above.  For reasons 
discussed in this paragraph and in paragraph 36 below, the Commissioner has also 
decided that these CGMP regulations shall be issued as binding.  The 
Commissioner advises that any person who still questions FDA's authority to do 
this is welcome to seek prompt pre-enforcement judicial review of this 
authority.
     36.  A number of comments suggested, in effect, that whether or not FDA 
could lawfully issue "binding" CGMP regulations, it would be unwise for the 
agency to do so.  These individuals cited the complexity and variability of 
manufacturing control processes, emphasizing the variety of options available 
and the need for freedom of choice among these options by various manufacturers 
depending on cost and technological factors.  They further complained that FDA 
lacked the expertise to determine which practices were best and that, by 
"freezing-in" techniques, FDA would discourage innovation and development of new 
procedures which might increase the assurance of product quality.  The comments 
objected to the presumption that would follow from a technical violation of the 
CGMP regulations that the product was therefore adulterated and that 
individuals, under the legal doctrine of strict criminal liability under the 
Federal Food, Drug, and Cosmetic Act, were criminally responsible for these 
violations.  Binding regulations would, in their opinion, provide the agency no 
flexibility for discretion in enforcement of the act.  Finally, the comments 
objected that there was no need for binding regulations because there were only 
a few large pharmaceutical manufacturers involved in production of most drugs; 
because these were subject to frequent inspections by FDA; and because in the 
past, these firms had been subject to few problems, few recalls, and rare legal 
proceedings.  This history suggested that most firms were in substantial 
compliance with the regulations regardless of whether they were classified as 
substantive or interpretive.
     The Commissioner has evaluated these objections and found that, although 
some have merit, none is so serious as to outweigh the benefits from making CGMP 
regulations binding.  Recognizing the diversity of manufacturing and control 
procedures, the Commissioner has endeavored wherever possible to state CGMP 
regulations in the terms of objectives to be attained, rather than methods of 
attaining such objectives.  Procedures have been specified only where essential 
to assure product quality under the act.  Thus, these regulations provide 
flexibility to manufacturers to select the methods and processes that will be 
most suitable to the products and operations of the individual firms.  This 
flexibility should also permit the development of novel approaches to attaining 
the same objectives.  In those few cases where precise procedures are set forth 
in these regulations, individuals who believe that alternative mechanisms may 
also be acceptable are invited to petition the Commissioner to amend the 
specific regulation to permit such alternatives.
     As discussed in paragraph 35 of this preamble, the Commissioner does not 
believe that FDA lacks sufficient expertise to develop and promulgate CGMP 
regulations and advises that the public procedures for commenting on these 
proposed CGMP regulations, together with the opportunity to petition the agency 
for changes in the regulations, provide individual manufacturers with an 
opportunity to correct any errors in FDA's information.  Thus, the Commissioner 
does not believe the agency lacks sufficient information to justify making CGMP 
regulations binding rather than interpretive.
     With regard to the alleged lack of flexibility in the enforcement of 
"binding" CGMP regulations, the Commissioner believes that the comments have 
confused the question of whether a violation exists with the question of whether 
FDA will take action upon the violation.  In numerous areas, FDA has established 
tolerances for actionable offenses and is currently in the process of 
establishing regulations setting forth agency policy with regard to prosecutions 
for violations of the act.  It should be noted, however, that even in the 
absence of any CGMP regulations, whether binding or not, the doing of or failure 
to do any particular act which is inconsistent with current good manufacturing 
practice results in the product being legally adulterated, even if no legal 
action is brought.  That is to say, the existence of CGMP regulations does not 
create violations of the law where they did not previously occur.  The question 
rather is whether the violator will be prosecuted or enjoined and/or the product 
seized, an issue beyond the scope of this rule making.
     Finally, with regard to the objection that there is no need to make these 
regulations binding since most major pharmaceutical manufacturers are in 
substantial compliance with the current regulations, the Commissioner believes 
that this is simply not relevant to the question of whether CGMP regulations 
should be binding or interpretive.  The most significant justification for 
having the regulations binding is to minimize the burden on the government and 
on the courts in a case where a violation does occur.  When the regulations are 
merely interpretive, the agency must provide expert testimony in each trial to 
demonstrate what the current good manufacturing practice in the industry is, 
notwithstanding the regulation.  The cost of locating and preparing such expert 
witnesses and bringing them to the trial, as well as the judicial time taken in 
hearing these witnesses, would be eliminated by having binding regulations.  In 
the event that a challenge is raised about the validity of the regulation, FDA 
can present to the court the administrative record underlying the regulation in 
lieu of any expert testimony.  Thus, it is not the proportion of manufacturers 
who are in compliance with the regulations but the number who are out of 
compliance and whose noncompliance justifies regulatory action that necessitates 
making these regulations binding.  For these reasons the Commissioner has 
concluded that insofar as he has discretion to issue CGMP regulations as either 
binding or interpretive, he elects to make them binding.
     37.  Several comments suggested the words "where applicable" be inserted in 
the first sentence of 210.1(a).  The comments argued that, as proposed, 
conformance to every requirement regardless of the need to do so.  
     The Commissioner concludes that there are numerous examples of flexibility 
built into the CGMP regulations.  Words like "appropriate" and "as necessary" 
are used in the regulations to make it clear that requirements which are not 
relevant to a given manufacturer's operation do not apply.  In addition, a new 
paragraph (b) is established in 210.2 to clarify that the requirements apply 
only to those operations subject to the CGMP regulations in which the 
manufacturer is engaged.
     38.  Two comments recommended that the references in this section be Parts 
210 through 226 instead of Parts 210 through 229, since 229.25 was being 
revoked.
     Since the Commissioner has reserved all parts between 210 and 229 for 
current good manufacturing practice regulations, the reference is appropriate.  
Even though 229.25 has been revoked, Part 229 may be used in the future.
     39.  One comment suggested insertion of the phrase "and testing and quality 
control thereof" after the words "the manufacture, processing, packing, or 
holding of a drug product" in 210.1(d).
     Because "manufacture, processing, packing, or holding of a drug product" is 
defined in 210.3(b)(12) to include testing and quality control of drug products, 
the Commissioner rejects this comment.
     40.  A large number of comments recommended that the personal liability 
statement in 210.1(b) be eliminated.  Some comments suggested that an individual 
should be held responsible only if actual contamination has occurred.  Others 
recommended modifying the liability statement by requiring willful and knowing 
intent to violate the law.  One comment said this was unclear as to who was 
covered by the section and that it was not useful in clarifying the requirements 
of the act.  Another asked about the definition of "responsible."
     The Commissioner notes that actual contamination of a drug does not have to 
occur for the article to be deemed adulterated under section 501 (a)(2)(B) of 
the act.  Further, the act does not require a showing of intent for a person to 
be held accountable under the act.  United States v. Dotterweich, 320 U.S. 277, 
(1943); United States v. Park, 421 U.S. 658 (1975).  It would be contrary to 
public policy and congressional intent, as well as beyond the Commissioner's 
authority, to require the showing of actual contamination or intent.  Congress 
purposely did not do so in order to provide the maximum protection of the public 
health.
     With regard to clarifying "person," the Commissioner advises that the word 
"person" is defined in section 201(e) of the act to include corporations and 
partnerships as well as individuals.  Under section 301(d) of the act, the 
adulteration of any drug is a prohibited act, and under section 303(a) "any 
person who violates a provision of section 301" is subject to criminal 
penalties.  Thus, the reference to "the person" in 210.1(b) merely parallels the 
statutory language.  The reference to the word "responsible" is in accord with 
interpretations of the act by the Supreme Court of the United States.  See 
United States v. Park, 421 U.S. 658 (1975).  Thus, the Commissioner does not 
believe that this language is unclear or misleading.  He also believes that, 
although 210.1(b) is not essential to the regulations and merely reflects the 
legal position of the agency, it is a useful exposition of FDA policy with 
regard to failure to comply with the CGMP regulations.  For this reason, the 
language is retained in the final order.
     41.  One comment said the CGMP regulations, as proposed, set up FDA as both 
prosecutor and judge and deprive persons of due process.
     The Commissioner finds that penalties for violation of these regulations 
(i.e., seizure of violative products, injunctive sanctions, and criminal 
prosecution) are imposed by judicial proceedings in United States courts, where 
the U.S. Department of Justice serves as prosecutor, Federal judges preside, and 
in criminal cases there is a right to trial by jury.  The role of FDA is 
twofold:  First, it establishes standards amplifying the statutory language 
(through issuance of CGMP regulations after public comment); and second, it 
investigates to determine whether these standards have been violated.  Affected 
persons have full legal rights, including the right to challenge the regulations 
as being beyond the authority of the act.  The Commissioner finds no rationale 
to suggest these CGMP regulations compromise any person's right to due process.

               VI. APPLICABILITY OF CGMP
                REGULATIONS; EXEMPTIONS

     42.  Many comments said there should be exemptions or waivers from the CGMP 
regulations for certain classes of drugs or specialized kinds of manufacturing 
activities.  These comments came from manufacturers of bulk drugs, veterinary 
drug products, radiopharmaceutical drug products, biological drug products, so-
called "drug-cosmetic" products, and wholesalers and retail dispensers of drug 
products.  These comments, except one, asserted that the CGMP regulations were 
inappropriate, unnecessary, excessive, or not part of current industry practice 
when applied to the type of product identified; the exception (discussed in 
paragraph g. below), together with one comment regarding a particular product 
line, questioned FDA's legal authority to apply CGMP regulations to certain 
types of businesses or products.
     As discussed in the preamble to the February 13, 1976 proposal, the 
Commissioner intends to propose at future times  CGMP regulations for specific 
classes of drug products such as small volume parenterals, compressed medical 
gases, and radiopharmaceuticals.  (See, e.g., the proposal regarding LVP's 
published in the FEDERAL REGISTER of June 1, 1976 (41 FR 22202).)  In addition, 
regulations for certain kinds of manufacturing activities such as manufacturing 
of bulk drug components, repacking, or relabeling will be proposed.  Generally, 
these future regulations will supplement, and in some situations supersede, the 
more general CGMP regulations.  As these proposals are issued, the need for 
waivers from or modifications in the general CGMP regulations should be 
diminished.
     After considering these plans and the comments regarding exemptions for 
specialized drug products or manufacturing activities, the Commissioner has 
reached the following conclusions:
     a.  Bulk drugs.  It is first necessary to distinguish between (1) "drug 
products" (i.e., finished dosage forms) that may be held in bulk containers, and 
(2) bulk drug "components" (i.e., ingredients intended for use in the 
manufacture or processing of a drug product).  The CGMP requirements set forth 
in Part 211 are intended to apply to the preparation of a finished dosage form, 
whether or not in packaged form.  This is clearly set forth in the regulations 
(210.3(b)(4) and 211.1(a)).  Although these CGMP regulations are not applied to 
the manufacture of bulk drug components, there are numerous instances where good 
manufacturing practices for bulk drug components would parallel the requirements 
set forth in Part 211.  For this reason.  FDA will utilize the standards of Part 
211 as guidelines during inspections of manufacturers of bulk drug components 
under the jurisdiction of the act.
     b.  Veterinary drug products.  Veterinary drug products shall continue to 
be subject to the general CGMP regulations for all drug products, with certain 
specific exceptions, namely 211.42(d), 211.46 (d), and 211.72.  Comments 
regarding the appropriateness of individual provisions of these regulations to 
veterinary drug products have been considered and responded to under the 
sections involved.  When the provisions of a section in the regulations do not 
apply to veterinary drug products, exemptions for such products are stated in 
that section.
     c.  Radiopharmaceutical drug products.  The general CGMP regulations are 
suitable requirements for the preparation of radiopharmaceutical drug products.  
When the Commissioner was aware of situations where the requirements are not 
appropriate, exemptions were made from these final regulations.  Supplemental 
requirements specific for radiopharmaceuticals will be proposed in the future.
     d.  Biological drug products.  The Commissioner notes that section 902(c) 
of the act parallels section 351(g) of the Public Health Service Act (42 U.S.C. 
262(g)), which provides that section 351 does not affect, modify, repeal, or 
supersede the Federal Food, Drug, and Cosmetic Act.  The agency has consistently 
interpreted these provisions to be additive; that is, although they preclude 
duplicative or inconsistent regulation under the two acts, where one statute 
speaks to a matter regarding biological products and the other statute is 
silent, the express statutory provisions govern, regardless of the statute in 
which they appear.  Thus, for example, the provisions of section 505(i) of the 
act regarding investigational use of new drugs have been consistently held to 
apply to biological products because no part of section 351 of the Public Health 
Service Act addresses investigational use of biologics (21 CFR 312.1(g)).  
Because section 351 of the Public Health Service Act does not refer to current 
good manufacturing practice and because biological products are considered to be 
drugs subject to section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic 
Act, the Commissioner believes it is consistent with both laws to apply current 
good manufacturing practices to biological drug products.
     Biological products are now manufactured according to current good 
manufacturing practice and regulated under parts 600 through 680 (21 CFR parts 
600 through 680), in particular the establishment license and product license 
provisions.  Sections 210.2 and 211.1 clearly provide that the more specific 
biologic regulations prescribed in 21 CFR Parts 600 through 680 will supplement 
or supersede, where appropriate, the more general drug CGMP regulations.  The 
Commissioner believes it possible that provisions in the general CGMP 
regulations may be inappropriate for certain biological products and would make 
appropriate changes to assure that the CGMP requirements would not increase 
manufacturing costs without a commensurate increase in safety, purity, potency, 
or efficacy.  However, no specific examples were submitted to FDA in response to 
the proposal that can be considered as areas for exempting biological drug 
products.  The Commissioner invites interested persons to submit petitions under 
10.30 to amend particular provisions of the CGMP regulations to account for the 
special technologies or incompatabilities of biologics.
     e.  Compressed medical gases.  The agency will propose specific CGMP 
regulations for compressed medical gases.  Until such regulations can be 
proposed for public comment, comments received and evaluated, and a final 
regulation published, however, the Commissioner concludes that the requirements 
in the more general CGMP regulations, with certain stated exceptions, are 
applicable.  It would not be in the public interest to delay a final regulation 
based on the February 13, 1976 proposal until FDA can promulgate specific CGMP 
regulations for compressed medical gases.
     f.  Repackaging and relabeling.  Only certain portions of the general CGMP 
regulations apply to repackaging and relabeling operations.  For example, the 
requirements pertaining to labeling control apply to repackers and relabelers, 
while the requirements for compounding a drug product do not apply since 
repackers/relabelers do not compound drug products.  The CGMP regulations apply 
to repackaging and relabeling operations at locations that are different from 
the place of manufacture.  Supplemental CGMP regulations regarding this unique 
type of drug processing will be proposed in the future.
     g.  Wholesalers.  Section 501(a)(2)(B) of the act provides that a drug 
shall be deemed to be adulterated if "the methods used in, or the facilities or 
controls used for, its manufacture, processing, packing, or holding do not 
conform to current good manufacturing practice * * *."  This section, through 
the operation of section 301(k) of the act, applies to wholesalers, retailers, 
pharmacies, and hospitals, as well as to manufacturers.  However, the CGMP 
regulations set forth in part 211 apply only to establishments engaged in the 
preparation of a drug product.  Therefore, these regulations do not apply to the 
wholesalers, retailers, pharmacies, and hospitals engaged in activities that are 
traditional to those establishments.  The wholesaler, however, is a particularly 
important link in the distribution chain between manufacturer, retailer, and 
consumer.  The Commissioner encourages wholesalers to adopt applicable 
provisions of the CGMP regulations to insure that drug products are handled and 
stored in a manner that will not contribute to loss of identity, strength, 
quality and purity.  In addition, they are responsible for being able to 
identify the distribution of drug products that are subject to recall or market 
withdrawals.  Recall strategy will frequently involve wholesalers as consignees 
and intermediate distributors when recalls are to the retail or consumer levels.  
In the FEDERAL REGISTER of June 16, 1978 (43 FR 26202), FDA published 
regulations to provide guidance to manufacturers and distributors in this area.  
It is especially important for wholesalers to maintain adequate records to 
assure effective recall or market withdrawal.  If future experience indicates to 
FDA that recalls and market withdrawals are being adversely affected by 
inadequate recordkeeping on the part of the wholesalers, the Commissioner will 
give further consideration to the need for specific CGMP regulations for 
wholesalers.
     h.  Drugs that are also cosmetics.  A number of comments, including a 
petition to the Commissioner, were received regarding the applicability of the 
proposed general CGMP regulations to a class of products identified as 
"cosmetic-drug products" and described as those which: (1) Meet the definitions 
of both "drug" and "cosmetic" under section 201 of the act; (2) represent a 
minimal health or safety risk; and (3) are marketed over-the-counter for regular 
and frequent consumer use without dosage limitations.  Examples of these 
products were described as medicated skin creams, anti-bacterial soap, 
antiperspirants, and topical sunburn prevention products.  Specifically, the 
comments requested separate CGMP regulations for this alleged class of drugs, 
and one comment submitted a proposed new part 213 for drug-cosmetic products, 
drafted in the style and format of other CGMP regulations for drugs.  Another 
comment recommended that, because the drug-cosmetic products were so similar to 
related cosmetic products, CGMP regulations for those two classes of products be 
proposed and adopted together, separate from those relating to drug products 
generally.
     The Commissioner has concluded that these regulations, except expiration 
dating for certain human OTC drug products described in paragraph 353 of this 
preamble, must apply to all products meeting the definition of drug products, 
whether the drug products are highly potent prescription drugs or are OTC drugs 
of the type described as "cosmetic-type."  Past experience of the agency has 
demonstrated that the public has been put in a hazardous situation because of 
manufacturing errors in OTC products, such as by the substitution of spirits of 
camphor for castor oil.  Further, the Commissioner notes that there are very few 
clearly innocuous drug products or components in the OTC area.  Several examples 
can be given:  If appropriate stability study requirements and manufacturing 
controls required by CGMP regulations are not met for fluoride toothpaste, there 
could be a question of effectiveness of the products because of the 
unavailability of fluoride in a toothpaste.  In the case of aerosolized 
products, control of the particle size and identity and purity of components are 
important for the safety of the user.  In the case of topical cosmetic-type 
drugs, the incidence of allergic reactions may be lessened by the assurance of 
uniform quality of these products.  That many of the general CGMP regulations 
are applicable to and reasonable for cosmetic-type drug products is evidenced by 
the fact that a majority of the specific suggestions submitted by the petitioner 
and others as applicable for cosmetic-type drug products duplicated in 
substance, a number of comments submitted by other OTC manufacturers and 
manufacturers of prescription drug products and the proposed text of part 211.
     Although he declines to provide a broad exemption for cosmetic-type drugs 
products, the Commissioner points out that a number of changes proposed by the 
comments are adopted in the final regulations.  These suggested changes were 
appropriate for application to the manufacture of all drugs products, however, 
and not merely cosmetic-type drug products.  In many instances the suggested 
changes that were adopted do not alter the original intent of the regulations, 
but clarify it or provide flexibility in complying.  In a few cases, the 
proposed requirements were deleted or changed where the Commissioner concluded 
that they were not necessary to assure the quality of drug products, cosmetic-
type or otherwise.
     i.  Drug products that are also foods.  Although no specific requests were 
received to exempt OTC drug products that are also human foods from Part 211, 
the Commissioner has tentatively concluded that there may be a few such products 
that would more appropriately be regulated under the good manufacturing practice 
regulations for food.  He believes that the type of OTC drug products that could 
be exempted from Part 211 are those that are ordinarily marketed and consumed as 
human foods which may also fall within the legal definition of drugs by virtue 
of their intended use.  Therefore, elsewhere in this issue of the FEDERAL 
REGISTER, the Commissioner is proposing to exempt such products if the products 
and all their ingredients are ordinarily consumed as human foods.  Examples of 
products that the Commissioner foresees being covered by the proposed exemption 
are (1) Some candy cough drops formulated entirely of ingredients ordinarily 
consumed as human foods or ingredients of human foods; and (2) sodium 
bicarbonate labeled for use as an antacid but ordinarily use as an ingredient of 
human foods under the more common "baking soda" label.  In proposing this 
exemption for certain OTC drug products, the Commissioner has considered, first, 
the inadvisability of applying drug CGMP regulations that are not necessary to 
ensure appropriate quality characteristics in view of the intended use of a 
product and, second, the reasonableness of applying food GMP regulations to a 
product manufactured, handled, and ordinarily consumed as a human food.
     Therefore, the Commissioner has stated under 211.1(c) that, pending 
considered of the proposal, the requirements of Part 211 will not be enforced 
for OTC drugs that meet the proposed definition.  During the interim and until 
further notice, regulations under Part 110 (21 CFR Part 110) and, where 
applicable, Parts 113 to 129 (21 CFR Parts 113 to 129) shall be applied in 
determining whether these products are manufactured, processed, packed, or held 
under current good manufacturing practice.
     43.  One comment from a university school of pharmacy asked whether future 
proposed CGMP regulations would specifically state their applicability to such 
situations as (1) personnel at hospital "A" strip-packaging drug products for 
its own use as well as for use in hospitals "B" and "C"; (2) personnel at the 
warehouse of a chain of pharmacies who repackage and relabel quantities of drug 
products from manufacturers' original commercial containers for different units 
in the drug store chain; and (3) similar repackaging and relabeling by 
individual pharmacists as members of informal buying groups.
     As noted in paragraph 42(g) above, section 501(a)(2)(B) of the act applies 
to retail establishments, pharmacies, and hospitals, but the specific 
regulations in Part 211 do not.  When CGMP regulations for repackers and 
relabelers are proposed, some of these questions posed in the comment will be 
addressed.  Regarding pharmacies and hospitals in particular, however, it is the 
policy of FDA not to inspect routinely for compliance with section 501(a)(2)(B) 
of the act establishments that operate within State or local laws governing the 
practice of pharmacy.  Nor has FDA ever sought to issue specific CGMP 
regulations for pharmacies engaged in traditional activities of dispensing or 
selling drugs at retail.  This policy is consistent with statutory exemptions 
provided for pharmacies regarding establishment registration in section 510(g) 
of the act and regarding establishment inspection in section 704(a) of the act.  
When a hospital or pharmacy is engaged in drug repacking or relabeling 
operations that are beyond the usual conduct of dispensing or selling drugs at 
retail, however, the exemptions in the act cease to apply; the establishment is 
required to register and is subject to regular inspections under section 704 of 
the act.  Furthermore, appropriate current good manufacturing practice must be 
complied with.
     44. Several comments expressed concern about the applicability of CGMP 
regulations to foreign drug manufacturers.  One comment said foreign drug 
manufacturers may not uniformly be subject to the stringent controls of United 
States manufacturers and that sampling of foreign drug products at the point of 
importation is not sufficient to assure the quality of those drugs.  Two foreign 
drug manufacturers indicated that CGMP regulations had a significant impact on 
their operations.  Another foreign manufacturer said their facilities were 
inspected annually by FDA with respect to antibiotic certification and new drug 
approvals.
     The act applies to drugs introduced into interstate commerce in the United 
States, including drugs imported from other countries.  It does not, of course, 
apply to manufacturing  of drugs in other nations if the drugs are not brought 
into the United States.  Many foreign countries, however, have adopted 
requirements similar to CGMP regulations, and foreign manufacturers may be 
subjected to inspection by their own governments.  International organizations 
such as the World Health Organization and the European Free Trade Association 
provide manufacturing standards and reciprocal agreements between participating 
countries.  Overseas pharmaceutical manufacturers who export to the United 
States are inspected by FDA or under reciprocal inspection agreements as part of 
the new drug application approval process and antibiotic drug certification, and 
individual drug products are subject to intensive examination, including 
testing, before being allowed into the United States.  If, for example, there is 
a question regarding the safety, identity, strength, quality, or purity of a 
drug product offered for import, FDA has authority to deny entry of the article 
unless factory inspection is permitted or inspectional information is available 
about those firms covered under reciprocal inspection agreements.  The United 
State currently has reciprocal inspection agreements under which governments 
will exchange inspection information about domestic firms in lieu of conducting 
overseas inspections.  These agreements are with Sweden, Switzerland, and 
Canada.  Therefore, the Commissioner finds that there is adequate coverage of 
imported drugs to assure compliance with CGMP regulations.
     45.  Several comments referred to provisions in the Medical Device 
Amendments of 1976 and requested that FDA consider providing for exemptions from 
or variances to the CGMP regulations and special advisory assistance as Congress 
specifically mandated regarding FDA regulation of small manufacturers of medical 
devices.  Along the same lines, a substantial number of comments were received 
from "small" drug manufacturers or organizations representing "small" drug 
manufacturers who strenuously oppose most of the proposed changes in the CGMP 
regulations.  The tenor of the majority of the comments was that the proposed 
changes would seriously affect the initial and continuing costs of a "small" 
drug manufacturer but probably have little economic impact on, or could more 
easily be absorbed by, a "large" pharmaceutical manufacturer.  Several comments 
expressed concern that generic drug manufacturers might be eliminated because 
they could not meet all the requirements of the proposed CGMP regulations and 
still compete in the marketplace.  Arguments were presented that, because small 
manufacturers very often are involved with the manufacture of a small number of 
products (frequently less potent over-the-counter preparations) and almost by 
definition have small physical facilities, limited equipment, and few personnel, 
extensive formal quality control procedures are unnecessary to assure high 
quality of the drugs manufactured.  One comment, apparently from a small 
manufacturer, agreed in principal with the proposed CGMP regulations, felt that 
size had very little to do with achieving good manufacturing practice, and 
offered comments on specific sections of the proposed CGMP regulations.
     The Commissioner rejects the contention that quality control procedures are 
unnecessary in the case of small firms; FDA's experience is that quality control 
procedures falling below those described in these regulations, in firms of great 
or small size, are often responsible for lack of drug product quality.  The 
Commissioner also rejects the argument that less control need be exerted over 
so-called "less potent over-the-counter preparations," which respondents stated 
are often manufactured by small firms, for the reasons explained in paragraph 
42(h) above. 
     The Commissioner believes that the final regulations will be no more 
burdensome for small manufacturers than for others.  Many interpretations 
offered in comments on specific sections strongly suggested that the intent of 
the proposed regulations had been misunderstood.  The language has been 
clarified in the final regulations.  In other instances the requirements were 
reworded to provide for more flexibility for the varieties of procedures and 
controls that may be utilized by various manufacturers.
     The Commissioner does not believe a specific provision within the CGMP 
regulations for variances to these regulations is necessary for small 
manufacturers.  A mechanism already exists, however, in 21 CFR 10.30 for firms 
to petition for variances to or amendments in any regulation when the 
requirements are not reasonably attainable.
     For many years FDA has conducted and participated in numerous seminars and 
workshops designed to assist drug firms in interpreting and carrying out the 
requirements of CGMP regulations.  Additionally, the agency has made films and 
publications available that are also designed to assist drug firms in their 
efforts to comply.  The agency is committed to continuing these voluntary 
compliance efforts especially designed to assist small businesses.
     46.  Several comments noted that the current good manufacturing practice 
regulations do not pertain to veterinary biological products.  One respondent 
suggested that the section specifically state that these regulations apply only 
to human biological products.
     The Commissioner believes that the section as proposed clearly establishes 
applicability to pertinent biological drug regulations, but for consistency with 
references elsewhere in the CGMP regulations to human biological drug products, 
he is revising 210.2 to specifically include reference to biological drug 
products for human use.
     47.  Several comments requested clarification of the last sentence of 210.2 
to show that conflicting or contradictory regulations would be superseded by the 
one specifically applicable to the drug product.
     The Commissioner finds that the proposed wording clearly states his intent.  
Certainly, in the case of conflicting or contradictory regulations, it will be 
impossible to comply with all regulations and the regulation that is 
specifically applicable to the drug product in question would apply.
     48.  A comment suggested that if medicated premixes are meant to be 
excluded from Part 210, then Part 226 should be specifically excluded.
     The meaning of this comment, as it relates to 210.2 is not clear.  The 
Commissioner advises that Part 210 applies to all the regulations in Parts 211 
through 229.
     49.  One person proposed that the term "drug product" be replaced with the 
words "commercial dosage form" to exempt drugs undergoing development from the 
requirements of these regulations.
     The Commissioner finds that, as stated in 211.1, these CGMP regulations 
apply to the preparation of any drug product for administration to humans or 
animals, including those still in investigational stages.  It is appropriate 
that the process by which a drug product is manufactured in the development 
phase be well documented and controlled in order to assure the reproducibility 
of the product for further testing and for ultimate commercial production.  The 
Commissioner is considering proposing additional CGMP regulations specifically 
designed to cover drugs in research stages.

                   VII.  DEFINITIONS

     The Commissioner received hundreds of comments regarding definitions.  
General comments are listed immediately below; comments regarding specific 
definitions follow in numerical order.
     50. One respondent said this section is inconsistent because certain terms 
such as "drug" and "establishment" which are defined in the act are not defined 
here, while other terms which are defined elsewhere are also defined here.
     The Commissioner believes that the length of part 210 would be 
unnecessarily increased by including in this part the definitions of terms that 
are well known or already defined in the act.  Other terms the meaning of which 
may not be as readily recognized, or may vary in other regulations because of 
context and needs, are defined in part 210 as a standard reference.
     51. One comment suggested that all terms defined in part 210 be highlighted 
in the running text.
     The Commissioner is not convinced that highlighting defined words in the 
running text offers any advantages over the more usual manner of printing.  For 
example, some persons might interpret highlighting as adding emphasis that is 
not intended to a particular word or phrase.  This suggestion cannot be adopted.
     52. One respondent suggested rules for selecting words to be defined, 
namely: (1) Words which will be used in a sense differing from that given in the 
currently accepted dictionaries and (2) words whose meaning will be limited by 
the regulation.
     The Commissioner believes the above criteria have been generally used for 
selecting terms to be defined.  He does not wish, however, to limit strictly the 
criteria for determining the terms to be defined in this part.
     53. Several comments asked that commonly used terms such as "drug product 
containers," "labeling," and "production area" be defined.
     The Commissioner finds that either the terms have already been defined 
elsewhere (e.g., "labeling," which is defined in section 201(m) of the act) or 
they are generally well understood and need no further definition (e.g., "drug 
product container").  He concludes that no further definitions need to be added 
at this time.
     54. One comment suggested that "cycle of manufacture" be defined in 
210.3(b)(2) as "any period of time in which the batch is not adversely altered."
     The Commissioner has considered this comment, but does not find that the 
suggested wording offers any advantage.  The definition, as it appeared in the 
proposal, has been in the CGMP regulations for a number of years.  The 
Commissioner is confident that this definition is well understood.
     55. Several comments suggested modification of the term "batch" in 
210.3(b)(2) by addition of the words "is intended to have" before "uniform 
character."  Another modification suggested was a new phrase at the end of the 
sentence: "Which is accepted and offered for sale or distribution."
     In defining a "batch," the Commissioner has adopted the phrase "intended to 
have uniform character and quality."  Using the phrase "intended to have" in the 
definition allows the use of the term "batch" without having to distinguish 
between acceptable and unacceptable batches.  If a manufactured batch does not 
have uniform character and quality within specified limits, then the batch 
becomes an unacceptable or a rejected batch.  The Commissioner rejects the 
phrase "which is accepted and offered for sale or distribution."  Those batches 
which are manufactured but never intended for sale or distribution may be 
designated as trial or experimental batches by the manufacturer.
     56. Three comments on 210.3(b)(3) requested that the term "component" be 
changed to "ingredient," stating that the former term has been used in the drug 
industry for "packaging supplies."
     The Commissioner recognizes that the term "component" is broadly used in 
the English language and may have a variety of meanings.  However, the 
definition of this term in the proposal has been in effect for a number of years 
and the Commissioner believes it is generally well understood.  Because only 
three comments were received regarding this particular issue, the Commissioner 
concludes that the drug industry generally does not find the term misleading.  
Therefore, the recommendation is not adopted.
     57. A suggestion was made that the definition for the word "component" in 
210.3(b)(3) should include gases and filters, because these items need 
additional control when used in the manufacture of injectable products.
     The Commissioner notes that "component" includes gases that are used as 
ingredients.  He believes filters are more appropriately classified as 
equipment.  The Commissioner believes that control of gases and filters is 
adequately set out in the regulations.
     58. One comment suggested that the definition for "component" be expanded 
to include the phrase "raw material, chemical compound, drug substance or 
pharmaceutic ingredient."
     The Commissioner agrees that the above items when used as ingredients are 
properly classed as components.  It is not necessary or desirable, however, to 
list each type of material that may become a component under the regulations, 
because items other than those identified in the comment may also be 
"components." Therefore, the suggestion is not accepted.
     59. A suggestion was received to include the following phrase after the 
word "manufacture" in the second sentence of 210.3(b)(3): "of finished dosage 
form, e.g. tablets, capsules, solutions, etc."
     The Commissioner rejects this suggestion.  The term "drug product" is 
defined in paragraph (b)(4) of 210.3 as "a finished dosage form" and restatement 
of the definition is inappropriate.
     60. Several comments requested clarification of the relationship among the 
definitions in 210.3(b) (3), (7), and (8) of "component," "active ingredient," 
and "inactive ingredient." Comments expressed concern that proposed definitions 
of the types of ingredients do not include all materials contemplated under the 
definition of "component."
     The Commissioner finds that the definition for "inactive ingredient" in 
210.3(b)(8) should be modified so that it clearly includes "any component other 
than an active ingredient."  He believes this change will eliminate any 
misunderstanding of these definitions.
     61. One comment suggested that the term "drug product," as proposed in 
210.3(b)(4), could be interpreted to mean only the finished packaged unit.
     The Commissioner finds that the term is defined as meaning "finished dosage 
form" regardless of whether it is in package form.
     62. A comment was received stating that the term "drug product" as defined 
in 210.3(b)(4) excludes placebos because the definition includes the phrase 
"active drug ingredient."
     The intended use of placebos in medical treatment is to bring about a 
therapeutic effect, without a pharmacologically active agent, because of the 
psychic effect in some patients that may produce symptomatic relief.  In 
addition, it is often used as a control in clinical trials for new drugs.  Even 
though the chemicals from which the placebos are made are not intended to cause 
a direct pharmacologic response, the maintenance of their quality is important 
because of their use in patients, particularly in controlled drug studies.  By 
its use, a placebo meets the definition of a "drug" contained in section 201(g) 
of the act. Therefore, to eliminate any doubt whether these regulations apply to 
placebos, the Commissioner has revised the definition to include them 
specifically.
     63.  A number of comments questioned the definition of "fiber" in proposed 
210.3(b)(5).  The comments were that "fiber" had been defined arbitrarily and 
without scientific basis; that the definition was too general and could include, 
for example, crystal, metal and splintered wood; and that the definition should 
include dimensional parameters for the fiber size.  Comments recommended that 
the definition include morphological descriptions such as threadlike, 
filamentous, amorphous or noncrystalline, cellular, foreign, and hairlike.  
Several comments recommended that the American Society for Testing and Materials 
definition be used. Others suggested that a length of at least 100 microns and a 
length/width ratio of 10 to 1 be adopted.  One comment called for adopting a 
minimum length of 10 microns and a diameter one-tenth the length.
     The Commissioner finds that the term "fiber" has not been defined 
arbitrarily and without scientific basis.  The basis for the fiber definition 
was discussed in the final regulations for asbestos-form particles in drugs for 
parenteral injection, which appeared in the FEDERAL REGISTER of March 14, 1975 
(40 FR 11865). (Those final regulations reference the definition of "fiber" 
appearing in "Occupational Exposure to Asbestos," criteria document, U.S. Public 
Health Service, National Institute for Occupational Safety and Health, Chapter 
VIII, p. 6, 1972).  The Commissioner believes that the definition should be as 
broad as possible and that the suggested morphological descriptions and 
dimensional parameters are unnecessary and in many instances are not 
informative.  Dimensional parameters were intentionally left out because current 
knowledge is limited as to what size fiber does not constitute a hazard.  
Furthermore, the suggested fiber length of at least 100 microns is unacceptable 
because most asbestos fibers released from asbestos-cellulose filters are less 
than 70 microns in length.
     The American Society for Testing and Materials' specifications (ASTM Manual 
F24-65, Standard Methods for Measuring and Counting Particulate Contamination on 
Surfaces) for defining "fiber" are not pertinent to the subject at hand.  They 
were developed specifically for particles on surfaces of mechanical objects as 
related to abrasion of such objects.
     To eliminate any concern that the definition of fiber would include 
particles intentionally present, as in drug suspensions, the final regulation is 
modified by adopting the concept of particle contamination.  Therefore, fiber 
means any particulate contaminate having a length at least three times its 
width.
     64. Comment was received regarding 210.3(b)(6) that the definition for 
"non-fiber-releasing filter" should include the concept of a filter "being 
designed" not to release fibers after appropriate pretreatment.  Another comment 
said a requirement for non-release of fibers is unrealistically absolute, i.e., 
no known filter could meet the definition.
     The Commissioner advises that the final regulation adopting the definition 
for "non-fiber-releasing filter," published in the FEDERAL REGISTER of March 14, 
1975 (40 FR 11865), addressed similar issues.  In responding to comments in that 
document, the Commissioner concluded the definition should include the concept 
that after appropriate pretreatment such as washing or flushing, the filter will 
not continue to release fibers into the drug that is being filtered.  The design 
concept is therefore taken into account because of the distinction made between 
filters which release fibers by media migration, i.e., continuous release due to 
the nature of the filter, and filters which contain fibers from structural 
supports and contamination.
     With regard to the comment that the requirement for nonrelease of fibers is 
unrealistically absolute, the Commissioner finds that the definition clearly 
describes types of fibers that are relied upon in the industry as "non-fiber 
releasing."  The Commissioner concedes that any filter may release an occasional 
particle, some of which may meet the definition of "fiber" under 210.3(b)(5).  
The purpose of the definition for "non-fiber releasing filter," which has been 
applied for over 2 years without apparent misunderstanding, is to provide a 
reasonable and practical description of a filter that may be fabricated from a 
number of different materials and will not, in the ordinary sense, introduce 
fibers into the drug product during filtration.
     As discussed in detail in the preamble to the March 14, 1975 final 
regulation adopting the definitions for "fiber" and "non-fiber releasing 
filter", FDA is studying several issues involving fiber contamination and the 
effects on humans to fiber exposure. Until such time as the Commissioner has 
obtained sufficient information to alter his position on fiber contamination in 
parenteral drug products without adversely affecting the public health, he 
concludes that the definition for "non-fiber releasing filter" continues to be 
appropriate for these regulations.
     65.  Comment was received that the definition of "non-fiber-releasing 
filter" as written in 210.3(a)(6) would discourage the development of asbestos 
filters that might not be fiber releasing.
     The Commissioner advises that it is not the intention of FDA to discourage 
the development of asbestos filters.  In this regard, the preamble to the final 
order in the FEDERAL REGISTER of March 14, 1975 (40 FR 11865) addresses this 
issue in detail.
     66. One comment suggested that "non-fiber-releasing filter" be redefined to 
apply only to the final filtration of components and drug products.
     The Commissioner concludes that the suggestion would allow use of an 
asbestos filter for filtration of in-process materials.  This use of asbestos 
filters is unacceptable, except under the provision of 211.72(b), and would 
defeat the purpose of the regulation.
     67. A comment suggested that after the word "component" in 210.3(b)(7) the 
phrase "other than veterinary biological immunizing or diagnostic agent" should 
be added.
     The Commissioner finds that articles that are not deemed drug products or 
that are not under the jurisdiction of the act are not subject to these 
regulations.  It is not desirable or feasible to identify in these regulations 
every specific class of articles that are not subject to CGMP regulations.  
Veterinary biologicals have, however, been excluded by changes in 210.2.  When 
an interested person has a question regarding the status of another individual 
product or class of products (for example, the status of an article that may be 
either a drug or a device), that person may obtain a formal opinion from FDA 
pursuant to 21 CFR 10.85.
     68. Several comments asked that limits be placed on the term "in-process 
materials" defined in 210.3(b)(9) in order to restrict it to those materials 
generated "in-plant" as opposed to those materials acquired from an outside 
source.
     The Commissioner agrees that the term "in-process materials" is intended to 
apply to materials being processed by establishments engaged in the preparation 
of a drug product.  He believes this intent is clear when the term is considered 
in the scope of these regulations and that no change is needed.
     69. Several comments requested clarification whether the term "in-process 
materials" in 210.3(b)(9) includes labels printed "in-house" and other 
"nonchemical" items.
     It was not the Commissioner's intent that "in-process materials" include 
label printing.  The regulations do not suggest that such labeling would 
constitute in-process materials. References to labeling materials are clearly 
stated in these regulations when appropriate.
     70. One comment suggested that the word "materials" in 210.3(b)(9) be 
changed to "ingredients."
     The Commissioner concludes that the term "in-process materials" is in 
current usage and sees no advantage to introducing the suggested term "in-
process" ingredients."
     70a. One comment stated that 210.3(b)(9), and especially the word 
"fabricated" is unclear and should be further defined to eliminate any possible 
confusion.
     The Commissioner does not agree that the word "fabricated" is unclear when 
used in this definition.  This suggestion is rejected because a broad term such 
as "fabricated" is appropriate here.
     71. Several comments said, in the case of biologics, a "lot" may consist of 
more than one batch and suggested that this be included in the definition of 
"lot" in 210.3(b)(10).
     Because the term "lot" has already been defined specifically for biological 
products in 21 CFR 600.3(x), the Commissioner does not believe that any 
modification of the definition in this part is appropriate.  As previously 
indicated, the more specific regulations for biological drug products take 
precedent over the more general.
     72. Two comments said the term "lot" was used elsewhere in the CGMP 
regulations (e.g., 211.84(a)) to refer to containers and closures, which are 
neither drugs nor drug products.  They said either the definition in 
210.3(b)(10) or the reference was incorrect.
     The Commissioner notes that the definition in 210.3(b)(10) refers to the 
term "drug product," but does not limit to drug products the applications of the 
definition for "lot."  However, the proposed definition for "batch" is limited 
to drugs.  Because a lot is defined as a batch or portion of a batch, the 
definition for "batch" is expanded to include materials other than drugs. 
Similarly, the definition for "lot number" is expanded to include other 
materials.
     73. One comment said the definition for "lot number" in 210.3(b)(11) 
unnecessarily ruled out the use of symbols.
     It was not the Commissioner's intent to preclude the use of symbols, and 
the definition is modified accordingly.
     74. One comment suggested deletion of the word "complete" from 210.3(b)(11) 
as superfluous and subject to interpretation.
     The Commissioner finds that use of the phrase "complete history" emphasizes 
that pertinent identifying information is included.
     75. Two comments suggested that the words "testing, and quality control of 
drug products" be deleted from the definition in 210.3(b)(12).  One said these 
functions do not belong in this definition because they introduce ambiguities 
elsewhere in the proposed regulations.  Examples given are: (1) 211.103, which 
requires yield determination at the end of each distinct phase of manufacturing; 
and (2) 211.67(b), which requires that procedures describe a cleaning schedule 
for all equipment used in manufacturing, processing, packaging, or holding of a 
drug product. The respondent said yield calculations and cleaning schedules do 
not apply to laboratory testing and equipment.  Another respondent said the 
words "testing and quality control of drug products" should be deleted because 
they conflict with the concept of independent responsibility for quality control 
and manufacturing functions.
     The Commissioner sees no ambiguities arising from the inclusion of "testing 
and quality control of drug products" in this paragraph.  Indeed, comments were 
received on numerous sections of the regulations (e.g., 211.2 (recodified 
211.68) and 211.25) to add the phrase after references to "manufacture, 
processing, packing and holding."  In all cases, the Commissioner has declined 
to make the addition.  The purposes of this definition are to make it clear that 
the phrase "manufacture, processing, packing, or holding of a drug product" 
includes operations that are commonly known by other terms such as "packaging," 
"labeling," or "quality control," and to eliminate the need for inserting 
references to testing and quality control throughout the text of these 
regulations.  Section 211.103 is modified to provide that yield determinations 
are not required for quality control activities.  The Commissioner believes, 
however, that the requirements of 211.67(b) are appropriate for quality control 
operations.
     The Commissioner believes that the functions of quality control and 
manufacturing can be included in the total concept of producing drug products 
and still be independent.  The comment did not describe how the definition would 
actually cause a loss of independence of the quality control function.
     76. One comment suggested that the term "warehousing" was more suitable 
than the term "holding" in 210.3(b)(12).
     The Commissioner finds that, although the term "warehousing" describes the 
meaning intended some of the time, the more general term "holding" is more 
suitable.  The Commissioner also notes that the entire phrase "manufacture, 
processing, packing, or holding" is repeated from section 501(a)(2)(B) of the 
act.
     77. One comment said the term "quality control" is too vague in 
210.3(b)(12) because it does not cover the responsibilities of other than the 
quality control department.  The comment suggested the following wording: 
"Manufacturing, processing, packaging or holding of a drug product includes 
packaging and labeling operations, testing and other measures taken to insure 
that the drug product has the identity, strength, quality and purity which it 
purports to or is represented to possess."
     The Commissioner does not agree that the definition is vague. The intent is 
to identify several key operations that might not be perceived as an integral 
part of the production of pharmaceuticals, but for purposes of CGMP regulations 
must be included.  It is not necessary, however, to describe every operation 
that is included under the act.  The responsibilities of the quality control 
unit are specified in 211.22 and are not affected by this definition.
     78. Several comments said the definition in 210.3(b)(15) of a "quality 
control unit," taken together with its responsibilities, would mean that the 
quality control unit would duplicate functions such as engineering, which are 
better handled by other professionals such as engineers.  They also said the 
term "unit" generated confusion vis-a-vis the "quality control department" and 
"quality assurance department."  Another comment said the word "perform" should 
be replaced with "be responsible for."
     Functions that are properly those of the engineering department or other 
specialized units because of their unique training and expertise should not be 
duplicated or usurped by the quality control unit.  Where expertise is in other 
units, the responsibility of the quality control unit is to assure that such 
expertise has been utilized.  In order to make clear that quality control 
functions may be performed by persons assigned to units outside the quality 
control unit, the Commissioner is replacing "perform" with "be responsible for."  
The quality control unit will still have the duty to assure that appropriate 
actions were implemented and completed satisfactorily.  The Commissioner used 
the word "unit" because it is a term broadly applicable to any group within a 
manufacturing establishment charged with the responsibility of quality control.  
The Commissioner is not concerned about the name given by a firm to its own unit 
that is responsible for quality control functions.
     79. Several comments suggested use of the term "expected yield" instead of 
"theoretical yield" in 210.3(b)(17) and in 211.192.  They also suggested that 
the definition include a provision for normal and expected losses.
     The terminology and concept of "theoretical yield" appear to be understood 
and generally used in the pharmaceutical industry. The Commissioner notes that 
the regulations (e.g., 211.186(b)(7) and 211.192) allow for normal and expected 
losses before investigations or corrective actions are required.  The concept of 
theoretical yield is important as a basis upon which actual or expected yields 
can be compared to the theoretical yield to aid determining acceptance.
     80. One comment said the definition of "theoretical yield" is nonspecific 
in the wording "quantity of components to be used."  A suggested alternative 
wording was "quantity of component specified by master production records for 
that operation."
     The Commissioner sees no need for the suggested revision in the definition 
section.  The requirement for compounding in accordance with master production 
records is covered elsewhere in these regulations.
     81. One comment suggested insertion of the word "distinct" before the word 
"stage" in paragraphs (b) (17), (18), and (19) of 210.3 because yields cannot 
always be determined at any stage of manufacture.  Another comment said 
establishing theoretical yield is not always possible for certain processes 
involving chemical reactions and production of biologicals.
     The Commissioner believes that a theoretical yield can be established for 
all processes.  The theoretical yield for a chemical reaction, for example, 
would be maximum yield obtainable under optimal reaction conditions.  The 
Commissioner agrees that the word "stage" may not adequately define the phase of 
manufacture at which the theoretical yield should be determined.  Therefore, he 
is adopting the phrase "appropriate phase" in paragraphs (b) (17), (18), and 
(19) of 210.3.
     82.  A number of comments have been received regarding proposed paragraphs 
(b) (21), (22), (23), and (24) of 210.3.  As discussed elsewhere in this 
preamble, the Commissioner is not including in these regulations, at this time, 
specific requirements regarding "acceptable quality level and unacceptable 
quality level"; therefore, definitions for these two terms are deleted from the 
final regulation.  Proposed paragraph (b) (21) and (24) is being retained, 
however, with modifications, as 210.3(b) (20) and (21).
     83. One comment suggested including in the proposed definition of 
"acceptance criteria" (proposed 210.3(b)(21)) the sentence: "Such acceptance 
criteria may be altered if evidence demonstrates that a valid reason exists for 
establishing revised acceptance criteria following an appropriate documented 
quality assurance conference."
     The Commissioner notes that the proposed definition, now 210.3(b)(20), 
would not preclude a change in product specifications or acceptance criteria if 
such change is appropriate.  There is no need to incorporate the proposed 
language.
     84. One comment suggested elimination of the word "reject" from proposed 
210.3(b)(21), stating that material which is not accepted may be reworked or 
returned to the supplier.
     The Commissioner does not agree with this suggestion.  The term "reject" 
does not denote the ultimate disposition of the product, only that it is not 
acceptable for use as is.
     85. One comment suggested that "sampling plans," referred to in proposed 
210.3(b)(21), are not the only technique used to form a basis for acceptance and 
rejection.
     The Commissioner has used the term "sampling plan" in a broad context here.  
The term can mean both a plan for collection of physical units for testing, or 
it can mean a schedule by which an examination of some sort is done.
     86. Numerous comments said the term "at random" should be deleted from 
proposed 210.3(b)(24).  Among the reasons given were that "random" has a limited 
meaning in statistics, that some samples are best taken on a stratified basis, 
such as right after each start-up of a run, and that some samples are taken on a 
timed basis.
     The Commissioner is persuaded that the term "at random" without additional 
clarification may be too limiting for this definition and modifies the final 
regulation accordingly.
     87. In reviewing the proposed regulations, the Commissioner concludes that 
211.2 and 211.68 should be combined into a new 211.68.  Proposed 211.2 is 
deleted, and the substance of the requirements is included in the new 211.68.  
The comments relating to 211.2 are discussed with those for 211.68.
     88. Three comments were received regarding proposed 211.3 on definitions 
for Part 211.  Two comments said the section is duplicative and should be 
deleted.  The other comment noted that some of the words defined in referenced 
210.3 are not used in Part 211.
     The Commissioner finds that the reference to 210.3 that appears in 211.3 is 
valuable as a cross reference.  In addition, he anticipates a need for a 
definition section in each part of the CGMP regulations to accommodate terms 
specific to that individual part but not others.  This scheme has already been 
used in the proposed CGMP regulations for Part 212 relating to large volume 
parenteral (LVP) drug products, published in the FEDERAL REGISTER of June 1, 
1976 (41 FR 22202).  The Commissioner sees no inconsistency in that terms 
defined in 210.3 may not be used in Part 211, because they may be used in other 
parts (e.g., Parts 225 and 226).  The definitions apply only where the term is 
used.

           VIII.  ORGANIZATION AND PERSONNEL

     89. One comment argued that as written, the regulations (211.22-211.34) 
permit the subordination of the quality control unit's function to any other 
unit designated by management, including the production unit.  Such a 
subordination of quality control to production was described as a conflict of 
interest.
     The Commissioner does not agree.  The CGMP regulations do not subordinate 
the quality control unit's authority and responsibility to any other unit.  At 
the same time, the regulations regarding the quality control unit does not 
encroach upon the expertise or responsibility of other units in a firm and do 
not dictate the organizational structure of a firm.  They simply require that 
the quality control unit have final responsibility for certain actions in the 
manufacturing process.
     90. One comment suggested that CGMP regulations assign individual 
certification responsibility to persons within the organization.  This would 
include responsibility for review of product specifications and control 
procedures to assure their adequacy and reliability.
     The Commissioner notes that such control responsibilities are already 
assigned in these regulations to the quality control unit. "Certification" is 
not specifically required as something more than approval by the quality control 
unit.  Assignment of individual responsibilities within a firm should be left to 
the discretion of management.

        RESPONSIBILITIES OF QUALITY CONTROL UNIT

     91. Comments contended that 211.22, as proposed, would unreasonably 
interfere with management's right to structure its organization as it deems fit.  
In addition, it was pointed out that quality control responsibilities are often 
performed by units of the firm other than the quality control unit; examples 
cited were formulation designed, development of the manufacturing process, and 
process control design by research and development scientists, engineers, and 
other manufacturing specialists.  The duties outlined in the proposal for the 
quality control unit were described as duplicative of functions performed with 
more expertise in other segments of a firm.
     The Commissioner intends to make the quality control unit responsible for 
ensuring that controls are implemented during manufacturing operations which 
assure drug product quality, not that the quality control unit actually perform 
each one of the duties.  The Commissioner believes that, even under 211.22, 
management has the prerogative to organize its internal structure and assign 
responsibilities as it deems appropriate, as long as some identifiable person or 
unit has at least those responsibilities assigned by the regulations to the 
quality control unit.  To clarify that the quality control unit could not and 
should not perform duties duplicative of other parts of the organization, the 
Commissioner has modified the definition of "quality control unit" in 
210.3(b)(15).  The word "perform" has been deleted and the phrase "be 
responsible for" substituted. Additional clarification of the Commissioner's 
position regarding these comments may be found in the preamble discussion under 
paragraph 78 of this preamble.
     92. One comment asked that the responsibilities of the manufacturing units 
be defined.
     As long as provision is made in these regulations for the assignment of 
certain quality control activities to a quality control unit, the Commissioner 
believes that other assignments should be at the discretion of individual firms 
management.
     93. A comment made a distinction between a quality control department and a 
quality control unit and questioned what duties would be assigned to each.  
Several other comments suggested that this section dealing with quality control 
units was primarily designed for large pharmaceutical firms and did not take 
into consideration that small firms could not comply.
     The distinction made between "department" and "unit" is not required by the 
regulation, which does not specify a name for the quality control unit, but 
merely describes several responsibilities that a designated unit must have.  The 
organizational structure of the unit is left up to each individual firm's needs.
     A small firm may choose a different means of structuring its organization.  
The term "quality control unit" is defined in 210.3(b)(15) as any person or 
organizational element.  This means that in very small operations a single 
individual can function as the quality control unit.  But that person still has 
the responsibility for implementing all the controls and reviewing the results 
of manufacturing to assure that drug product quality standards have been met.  
As discussed above in paragraph 45, the Commissioner rejects the idea that 
quality control is not needed in a small business.
     94. A comment was made that this section precludes the use of outside 
consulting laboratories for quality control work.
     The Commissioner disagrees.  There is no such prohibition in the 
regulations.  A manufacturer does have a responsibility, however, to see that 
the outside laboratory used is qualified to do the work and that the work is 
performed satisfactorily.
     95. With respect to the quality control unit's authority and responsibility 
under 211.22(a) for approval and/or rejection of raw materials, in-process 
materials, and finished products, one person asked that other alternatives be 
permitted when materials may be suitable for other purposes and uses than those 
originally intended.
     Use of the word "reject" does not necessarily mean that the rejected 
material must be destroyed.  When materials are ordered by a manufacturer, they 
are ordered with a particular purpose in mind. If testing of a material shows 
that it is not suitable for a particular use, it may be used for that purpose 
and, therefore, is rejected.  It may, however, be suitable for other uses 
requiring a material with differing specifications.
     96. Several comments proposed that 211.22(a) be modified so that the 
quality control unit would not have to have the responsibility to review all 
labeling unless it is connected with the manufactured dosage form.  The 
reasoning was that some promotional literature, not physically associated with 
the drug product, had been defined as labeling in court suits where FDA charged 
misbranding of a product with promotional literature, but that such material was 
not labeling in the sense in which these regulations referred to labeling.
     The Commissioner notes that the scope of the CGMP regulations is to set 
forth the facilities, methods, and controls to be used for the manufacture, 
processing, packing, or holding of a drug product.  It is not the purpose of the 
CGMP regulations to control labeling such as promotional literature that is not 
associated with the drug product during its preparation under CGMP regulations.
     97. Comments asked for modification in the last sentence of 211.22(a) 
relating to production of drugs under contract by another company.  They 
suggested that the contractor could release drugs for distribution on his own 
responsibility if a certificate of analysis showed compliance with appropriate 
specifications.  Others suggested that the responsibility for approving or 
rejecting drug products produced by contractors appeared in this paragraph to 
rest with the contractor.
     This paragraph clearly says that the quality control unit of a contracting 
firm must approve or reject drug products produced by contractors.  The 
Commissioner believes this is proper because, in the circumstances described, 
the contractor does not own the goods, but merely performs a service for the 
contracting firm.  The responsibility to approve release of a drug product for 
distribution must rest with the owner of the drug product.
     98. A number of persons responding to the proposal objected to the example 
of bioequivalence testing as one of the tests which must be performed in a 
quality control unit's laboratory.  Some said this type of testing was normally 
done outside the quality control unit, such as by a medical unit.  Others 
complained that bioequivalence standards are in a state of flux and have not as 
yet been established.
     Bioequivalence tests may include tests such as dissolution tests, which are 
generally done in the quality control unit's laboratory.  They also may include 
in vivo tests done by medical units within or outside the firm.  The 
Commissioner agrees, therefore, that this example is not necessarily one which 
generally represents the work done in the quality control laboratory. Although 
he is deleting the bioequivalence testing example, in vitro dissolution tests 
for bioequivalence are in fact an example of the type of work that could and 
should be done in the quality control laboratory.
     99. Two comments suggested either deleting the reference in 211.22(b) to 
"packaging materials" as one of the articles tested in the quality control 
laboratory, or changing it to "packing materials," on the basis that the 
examination for suitability of such materials is more properly a function of the 
shipping department and relates solely to protective qualities to prevent 
mutilation or breakage of drug product containers.
     Breakage of containers can cause product adulteration and mutilation of 
containers, which may result in product misbranding. The protection of drug 
products from such mechanical damage is just as much a function of the 
maintenance of drug product quality as placing light-sensitive products in 
light-resistent containers or labeling a product with its proper name and an 
accurate statement of its potency.  The Commissioner notes that primary 
responsibility for selecting specifications for packaging materials may be 
assigned to the shipping department of a firm.  Under 211.22, the quality 
control unit is only responsible for testing and approving (or rejecting) 
packaging materials in accordance with these specifications.  Therefore, no 
change is needed in the section.
     100. Several comments proposed eliminating from 211.22(b) the statement 
regarding approval (or rejection) of materials used in manufacturing and 
suggested use of words like "evaluation" or "disposition."  It was also 
suggested by others that "or" be placed between "and" and "approval" to allow 
for instances described as not requiring testing for approval.
     Several discussions appear in this preamble relating to the use of the 
words "approval" and "rejection."  These words mean either that an article may 
or may not be used for production of a drug product.  Reprocessing, reworking, 
refining, diversion to other acceptable uses, returning to the supplier, or 
destruction are all actions that may occur after a decision to reject and are in 
no way precluded by the rejection decision unless specifically stated by the 
manufacturer.
     101. Clarification of the option of using an outside testing laboratory was 
asked by respondents who wanted an explicit statement in 211.22(b) of the 
acceptability of this means of product examination.
     The thrust of 211.22(b) is that adequate laboratory facilities shall be 
available to the quality control unit from whatever source.  The paragraph does 
not require those facilities to be owned and operated by the drug product 
manufacturer, nor does it prohibit the manufacturer from using a contract 
testing facility. The Commissioner does not feel clarification is needed in 
211.22(b).
     102. Four comments recommended deletion of 211.22(c) entirely, because 
either (1) the requirements are adequately covered in 211.22(a), or (2) units of 
a firm other than the quality control unit have greater expertise in specific 
areas.
     The provisions of paragraph 211.22(a) differ from those of paragraph (c) in 
that paragraph (a) relates to the actual production of a product, while 
paragraph (c) covers events which occur before production.  The Commissioner 
realizes that not all expertise rests with the quality control unit, and he does 
not believe that the quality control unit should be solely responsible for 
developing and implementing all procedures and specifications impacting on drug 
product quality.  A manufacturer may assign primary and initial responsibility 
for selecting procedures or specifications to the persons or units it believes 
most qualified. The Commissioner's intent is that the quality control unit be 
responsible for making sure that the procedures and specifications developed are 
appropriate and followed.
     103. One comment indicated that the proposed 211.22(c) does not allow minor 
equipment changes that do not bear on drug quality, unless such changes are 
first approved by the quality control unit.
     Section 211.22(c) is limited to those procedures and specifications that 
impact on drug quality.  Moreover, the paragraph does not prevent the production 
personnel from making minor equipment adjustments that may affect drug quality 
without the quality control unit's approval of the specific change.  It does 
require that the procedures regarding such equipment adjustment be reviewed in 
advance by the quality control unit.
     104. A comment suggested that 211.22(c) be expanded to provide for 
specification committees, formula committees, and others instead of making the 
quality control unit totally responsible.
     As already explained, input into specifications and procedures may come 
from any appropriate source.  If a firm chooses to utilize specification and/or 
formula committees, it is not prohibited from doing so by these regulations.
     105. One firm suggested rewording of 211.22(d) to eliminate the word 
"responsibilities" and to add the word "routine" before "procedures."  It was 
suggested that the paragraph as proposed is too broad and that responsibilities 
for the quality control unit are described elsewhere.
     Section 211.22(d) does not define the responsibilities of the quality 
control unit, but it does require that all its responsibilities, including those 
required in 211.22, be in writing.  For consistency with other sections in the 
CGMP regulations, the phrase "such written procedures shall be followed" is 
being added to 211.22(d).

                PERSONNEL QUALIFICATIONS

     106. One comment said 211.25 is replete with vague terminology, which sets 
the stage for arbitrary and capricious actions by FDA, thereby placing 
individuals and companies in a position of unnecessary risk.  Two comments 
stated that this section is one in which FDA attempts to replace management's 
judgment with regulations.
     The Commissioner believes that this section must be of a general and 
flexible nature to allow management to exercise its prerogatives in light of the 
various types and sizes of firms, the products made, the differing personnel 
qualifications needed, the training programs which may be instituted, and other 
factors. Although such generality will require more judgment to be exercised by 
FDA investigators who make plant inspections, it does not permit any arbitrary 
or capricious action by the agency.  In addition to the fact that all sanctions 
authorized by the act may only be enforced through judicial process, FDA is 
further defining its policy and standards for regulatory action in a series of 
regulations set forth in 21 CFR Part 7.  The Commissioner believes this is ample 
protection against unreasonable actions by agency personnel.
     107. Many comments questioned the frequency of the "continuing training" 
required in 211.25(a), asked for a definition of the word "continuing," and 
questioned who should receive what type of training.
     The requirement that training be on a continuing basis is intended to mean, 
for example, that a single training course at the time an employee is hired, 
with no subsequent training activities, is not sufficient.  Subsequent training 
should be sufficiently frequent to assure that employees remain familiar with 
CGMP requirements.  The Commissioner does not believe it would be prudent to 
specify time intervals for training in view of the broad nature of the drug 
industry and the wide range of employee functions covered by these regulations.  
The Commissioner believes this section is sufficiently clear in identifying "who 
should receive what training" in stating that each person engaged in the 
manufacture, processing, packing or holding of a drug product must have training 
in current good manufacturing practice that relates to that person's functions 
in the firm.  The requirements of 211.25(a) apply to supervisors as well as 
other employees; 211.25(b) contains an additional requirement for supervisory 
personnel.
     108. Numerous comments pointed out that paragraphs (a) and (b) of 211.25 
are not consistent in that 211.25(b), but not paragraph (a), contains the phrase 
"or any combination thereof" following the phrase "education, training, and 
experience."  Most argued that 211.25(a) should also contain this phrase.
     The intent of the requirement is that a person have a sufficient mix of 
training, education, and experience to perform his or her job adequately.  What 
is adequate in regard to each of the criteria depends on the job.  It may be 
that a person can adequately perform a particular job with very little or no 
previous experience, or limited education, or with minimal training, depending 
on the demands of the job and the qualifications of the person.  Because the 
intent of this section has been misinterpreted, 211.25(a) is revised to include 
the phrase "or any combination thereof" and be consistent with paragraph (b).
     109. One comment questioned how much education, training, experience, or 
combination thereof qualifies a person to be a supervisor under 211.25(b).
     The Commissioner believes it should be understood that broad regulations 
such as these could not reasonably quantify the degree of education, training, 
and experience necessary.  It is left to management's reasonable judgment as to 
what constitutes sufficient background in these criteria so that supervisors can 
perform their assigned functions in a manner to provide assurance for the 
quality of drug products within their purview.
     110. One comment on 211.25 (a) and (b) said it would mean little for some 
individuals to be instructed in the legal and technical language of the 
regulations.  The respondent indicated that it is more important that personnel 
be instructed in the principles of good manufacturing practice relevant to their 
particular tasks.
     Section 211.25 requires training in current good manufacturing practice as 
it relates to an employee's function.  The Commissioner intends that training be 
meaningful to the employee, not a formalistic but useless exercise to satisfy a 
regulation.  The requirement is written to provide reasonable latitude to a firm 
as to the extent to which technical and legal instruction will be given.
     111. A number of comments said the requirement in 211.25(c) for "an 
adequate number of personnel" does not belong in the section on personnel 
qualifications.
     The Commissioner notes that the intent of this paragraph in relation to the 
number of employees is that there be an adequate number of qualified personnel.  
The Commissioner is revising this paragraph in the final regulation by inserting 
the word "qualified."

               PERSONNEL RESPONSIBILITIES

     112. One comment said all persons who enter the manufacturing, processing, 
packing, and holding areas should comply with the requirements of 211.28 and the 
section should reflect this.
     The Commissioner agrees that all persons, whether employees or not, who 
engage in the activities covered by this section should comply with the 
requirements of the section.  Therefore, the Commissioner is replacing the word 
"employees" with the word "personnel" in 211.28 (b) and (d).  The Commissioner 
recognizes that not all persons who enter manufacturing areas are engaged in 
activities covered by CGMP regulations (e.g., equipment manufacturer service 
representatives and FDA investigators), and their activities would not be 
limited by 211.28.  Drug manufacturers are responsible, however, for monitoring 
such activities to prevent contamination of drug products.  For example, all 
personnel entering a sterile area would be required to wear appropriate 
protective apparel.
     113. One comment said 211.28 is an additional example of the agency's 
attempt to legislate and enforce regulations which must be left to the 
discretion of corporate management in order to preserve our free enterprise 
system.
     The Commissioner does not perceive how these regulations present a threat 
to the free enterprise system.  These regulations were promulgated under the 
authority of section 501(a)(2)(B) of the act, which was passed by the Congress 
in 1962 in order to assure that no drug product available to consumers was 
adulterated.  The requirements of the regulations are a reasonable and necessary 
step toward that goal.  They do not inhibit competition, but rather enhance it 
by assuring that no manufacturer can reduce costs by eliminating those steps 
integral to the prevention of adulterated products.  Thus, the consumer is 
assured that all marketed drugs meet the essential standards of identity, 
strength, quality, and purity; and consequently, selection of drugs by the 
consumer (directly or with the advice of a physician of pharmacist) will be 
based on fair principles of competition and free enterprise.
     114. One comment suggested that in order to make it clear that facial hair 
coverings should be worn only if necessary, the second sentence of 211.28(a) 
should be reworded to read as follows:  "They shall wear appropriate head 
coverings, including facial hair coverings, as necessary to prevent 
contamination of drug products."
     The Commissioner recognizes that clarification of 211.28(a) is desirable 
and is therefore revising it to require that protective apparel, such as head, 
face, hand, and arm coverings, shall be worn as necessary to protect drug 
products from contamination.
     115.  One comment argued that the meaning of 211.28(a) is directed to human 
drug products and should be clarified to limit its scope accordingly.
     The Commissioner rejects this comment.  These regulations are broad and 
consider the fact that certain drug products, regardless of whether they are for 
human or veterinary use, require the same amount of care in manufacturing, 
processing, packing, or holding in order to assure their safety and 
effectiveness.  The wording of this section requires precautions to be taken as 
necessary to protect the particular drug products from adulteration or 
contamination.  The degree or types of precautions will depend on the particular 
drug product being considered.
     116. One comment suggested rewording 211.28(a) by inserting the underlined 
statement: "Arms and hands shall be covered or other appropriate measures taken 
when microbial contamination is a concern when necessary to protect the drug 
product being handled"; and that this "appropriate measure" could mean the 
cleaning of the arms and hands with an antiseptic soap or solution as an 
alternative.
     The Commissioner rejects this alternative wording since it would alter the 
intent of this paragraph.  The possibility of microbial contamination is not the 
only reason for wearing protective apparel; prevention of particulate 
contamination, for example, may be of equal importance.  Further, the 
Commissioner does not believe the phrase "as appropriate" would clarify this 
section since, as written in the final regulation, it clearly states that 
protective apparel shall be worn as necessary to prevent contamination of the 
drug product.  This paragraph does not preclude other measures such as cleaning 
which might be used in place of or in conjunction with protective apparel.  If 
alternate methods were at least as effective as protective apparel, then 
protective apparel would not be necessary.
     117. One firm commented on 211.28(a) that because of its type of operation 
it does not require, nor does it think it is necessary to have, uniforms if 
clothing is kept clean.
     The Commissioner notes that this paragraph does not necessarily require the 
wearing of uniforms.  The requirement is that clothing be clean enough to be 
appropriate for the type of duty or operation being performed.  For certain 
types of operations, uniforms may be appropriate, while for other types of 
operations uniforms may not be necessary.
     118. Several comments noted that 211.28(a) states in part that "they shall 
wear appropriate head coverings as necessary, including facial head coverings as 
necessary ***."  And the comments argued that this statement is "too broad as 
written since facial hair includes eyelashes, eyebrows, etc."
     The Commissioner intended that this paragraph be broad enough to require 
the covering of eyebrows and eyelashes if necessary to prevent drug product 
contamination.  Although he recognizes that this type of protection would not be 
usual for most operations, he would not wish to preclude the use of such 
measures.
     119. Several comments argued that, with regard to arm coverings, there are 
certain kinds of machinery and equipment which present a personal hazard to 
workers using arm and hand coverings.
     The Commissioner recognizes that the use of arm and hand coverings could 
constitute a significant hazard if used around certain types of machinery.  
Appropriate alternatives can be used in such instances so that neither personnel 
safety nor drug product quality is compromised.
     120. A comment noted that the term "authorized" in reference to personnel 
who may enter limited access areas is not defined in 211.28(c).
     The Commissioner believes that drug firms can reasonably determine on an 
individual basis which personnel should be permitted to enter what areas.  The 
intent of this paragraph is to prevent the type of situation, for example, where 
persons not trained in aseptic techniques enter aseptic processing areas for 
reasons not associated with aseptic processing of the drug product. To clarify 
that the authorization derives from the manufacturer, not FDA, the language of 
211.28(c) is modified slightly.
     121. One comment suggested that the word "may" in 211.28(d) be replaced by 
the words "is likely to" in order to identify realistically the threat of 
illness or lesions.
     The Commissioner rejects this alternative wording because the phrase "is 
likely to" is not strong enough to state the intent of this paragraph.  Further, 
the alternative phrase would introduce the element of prediagnosis by the 
employee's supervisor.  While supervisory personnel can reasonably be expected 
to recognize health conditions that may affect the drug product, they probably 
would not be able to recognize conditions that are likely to affect the drug 
product.  This may require more sophisticated evaluation by medical personnel.  
Of course, if medical personnel determine that the employee's health condition 
will not affect the drug product, the employee may resume his or her routine 
activities.
     122. One comment argued that the words "they consider" be deleted from the 
last sentence of 211.28(d) because the reporting of conditions should not be 
limited to conditions which an employee thinks may affect the product.  Another 
comment said the word "health" should be inserted between the words "any" and 
"conditions" in this sentence.
     The Commissioner agrees that the intent of this paragraph is better served 
without the phrase "they consider" and with the addition of the word "health" 
and has revised the final regulation accordingly.
     123. Several comments said 211.28(d) should not be construed to imply that 
supervisors are medically qualified to judge health conditions of employees.
     The Commissioner does not believe the paragraph implies this.  Within the 
framework of industrial management, the supervisor is the liaison between the 
operating employee and higher echelons of the company.  It is the supervisor who 
is most likely, on a day-to-day basis, to notice health conditions that may 
affect the drug product.  Of course any such conditions noted initially by the 
supervisor may require evaluation by qualified medical personnel. Such medical 
evaluation is acknowledged in the final regulation. This section could perhaps 
set out more detailed procedures for dealing with employee health problems.  But 
in the absence of significant difficulties in the area, the methods for dealing 
with health problems, beyond the initial phase of removing suspect employees 
from direct contact with drug products and their components, are left to the 
reasonable judgment of individual firms.

                      CONSULTANTS

     124. Several comments were received requesting deletion of 211.34 because 
the ultimate liability for actions taken based on the advice of consultants 
still rests with the responsible officials of the drug product manufacturer.  
The argument is that a firm's choice of consultants should be a matter of its 
own judgment and not one of Government review or regulation.  The comments also 
state that FDA lacks authority under the act to prescribe qualifications for 
consultants.
     The Commissioner considers that consultants, while they are retained by the 
firm, are persons engaged in the manufacture, processing, packing, or holding of 
a drug product, and may lawfully be subjected to appropriate standards of 
qualification to the same extent as full-time employees of the firm.  Therefore, 
consultants must have education, training, and experience, or any combination 
thereof, sufficient to perform their assigned functions.  Minor editorial 
amendments have been adopted in the final regulation to clarify this 
requirement.
     125. Several comments requested that 211.34 state that the requirements are 
applicable only to consultants who are retained for activities that relate to 
the scope of the CGMP regulations.
     The Commissioner acknowledges that activities that are not under the scope 
of the CGMP regulations should not be subject to such requirements.  The final 
regulations are clear in this regard.
     126. One comment asked that the term "consultant" be better defined in 
211.34 to clarify, for example, whether the term "consultant" includes 
attorneys.  It also asked if firms will have to document the qualifications of 
outside counsel.
     Under these regulations, a consultant is a person from outside the firm who 
is called on to render advice or opinion on current good manufacturing practice 
as it relates to the facilities or controls to be used in the manufacture, 
processing, packing, or holding of drug products.  The Commissioner believes 
this is generally well understood in the industry and sees no need to define 
"consultant" in these regulations.  Any person, including attorneys, employed or 
retained to advise on the manufacture, processing, packing or holding of drug 
products would be considered a consultant under these regulations.  However, an 
attorney employed or retained for legal advice--for example, an interpretation 
of CGMP regulations--would not be considered a consultant under these 
regulations.  In response to the second part of the comment, the section 
requires that records be maintained stating the name, address, and 
qualifications of any consultant used.

             IX.  BUILDINGS AND FACILITIES

            DESIGN AND CONSTRUCTION FEATURES

     127. A number of comments suggested that the last sentence of 211.42(b), 
which deals with unnecessary traffic, is ambiguous.  Two comments contend that 
the phrase "particularly movement back through areas in which these materials 
had previously been processed or held" be deleted as superfluous.
     The Commissioner is revising this paragraph to clarify the intended 
requirement that the flow of materials shall be designed to prevent 
contamination.
     128. One comment proposed that under 211.42(c) the paragraph be divided 
into those operations which must be in defined areas and those which must be in 
separate areas.  A number of comments regarding this section and 211.89 objected 
to a requirement that areas be set aside exclusively for quarantine storage.
     The intent of this paragraph is to require that enough physical separation 
be employed as is necessary to prevent contamination or mixups.  The degree of 
separation will depend on the type of operation and its proximity to other 
operations within the plant.  The phrase "separate or defined" is not intended 
necessarily to mean a separate room or partitioned area, if other controls are 
adequate to prevent mixups and contamination.  In the case of quarantined areas, 
for example, an effective means of identifying the quarantined goods and a paper 
control or other system may be used in lieu of complete physical separation.  
Thus, the regulations do not require that space be reserved for quarantine 
storage.  The Commissioner believes, however, that some degree of separation, 
even though only spatial, would be necessary in most cases, even with elaborate 
supplemental control.
     129. One comment maintained that the quarantine of containers and closures 
involves a great deal of space which most small manufacturers do not have.  The 
comment further contended that these items "can be examined at the packaging 
line just before use" or "can be examined at the distributor's facilities before 
shipment."
     If suitable specifications for containers and closures are simple enough to 
permit a quick visual examination to determine the product's acceptability, such 
an examination could be performed at the time of receipt without being in 
conflict with the quarantine requirements of these regulations.  A certificate 
of testing received from a supplier would not preclude the necessity for 
examining containers and closures to determine that they are the same articles 
as are represented by the certificate.  Any manufacturer who does not have such 
evidence of an article's acceptability or does not alternatively quarantine the 
article until such evidence is obtained is assuming an unacceptable risk that 
the article will be used and subsequently be found unsuitable.
     130. A number of comments indicated that the requirement in 211.42(c) that 
"operations shall be performed in specifically defined areas of adequate size" 
was unnecessarily restrictive on the flexibility of plant space use.
     The requirement relates to several different types of operations which are 
enumerated in the proposal; however, the comments seemed to relate mainly to 
storage areas.  It is the Commissioner's belief that a significant type of 
control over products is a physical one which precludes mixups by physically 
placing an article in an area clearly identified as to status.  The extent of 
the physical separation imposed in a particular situation can vary from locked, 
walled-off areas to simple designation of an area for a single purpose by means 
of a sign.  The degree of physical control will vary depending on the other 
controls in use by a firm.  If a firm has effective controls, whatever they may 
be, that would increase their confidence that mixups will not occur, then the 
degree of physical control may be less than in another firm where no other 
controls exist.
     131. One comment contended that 211.42(c)(2) would require availability of 
a large separate holding area in the warehouse for relocation of rejected 
supplies.
     The Commissioner concludes that preventing the intermingling of rejected 
supplies with released supplies is very important to drug quality.  The 
regulation does not require separate facilities as long as there is a defined 
area for rejected materials.  The Commissioner is not aware of any problems in 
the past with regard to large numbers of rejected supplies and their storage.  
He therefore rejects the proposal.
     132. One comment objects to the requirement in 211.42(c)(4) for separate 
storage for "in-process" materials and suggests adding to this paragraph the 
words "if storage or isolation is necessary."
     The use of the word "storage" in this paragraph implies holding for 
extended periods of time.  It does not refer to the holding of containers in 
production areas while processing is ongoing.  Therefore, if such storage is not 
necessary, the regulation as currently written is applicable.  On the other 
hand, if such storage is necessary, it is the Commissioner's opinion that 
isolation in a separate or defined area is essential to prevent errors.  
Therefore, the comment's proposal is not accepted.
     133. One comment, referring to 211.42(c)(5) said "on-line testing does not 
have to be done in a separate testing area ***."
     The requirement is for separate or defined areas.  The Commissioner 
believes that the area in which testing occurs, including on-line testing, must 
be defined or separated in order to prevent contamination of on-line products 
with testing materials and improper use of products that have been tainted by 
the testing process.
     134. One comment requested that 211.42(c)(5) be deleted since it is too 
broad to be helpful.
     The Commissioner disagrees with this comment.  The intent of this paragraph 
is to avoid mixups by using defined areas for the entire manufacturing 
operation, phase-by-phase.  The detailed procedures are purposely not spelled 
out so that pharmaceutical manufacturers can design their operations according 
to their individual needs.
     135. Two comments argued that the word "quarantine" in 211.42(c)(7) is not 
defined, the word means different things to different people, and it should be 
deleted.
     The word "quarantine" has had widespread use in the pharmaceutical 
industry, and its meaning is well understood.  These regulations do, however, 
have the effect of defining the word within the context of the pharmaceutical 
operations by indicating that it constitutes a control system to prevent 
unauthorized usage of unreleased material.  The Commissioner does not believe 
further definition is necessary.
     136. One comment argued that 211.42(c)(7) "increases warehouse 
requirements.  This is not believed to be current practice in industry."
     Based on experience gained from FDA inspections of drug manufacturers, the 
Commissioner believes that most firms now separate released and unreleased drug 
products.  In view of the intent of the phrase "separate or defined" as 
explained elsewhere in this preamble, the Commissioner concludes that 
211.42(c)(7) and, similarly, 211.42(c)(8) reflect current industry practice and 
will not increase warehouse requirements.
     137. A number of comments indicated that all the controls listed under 
211.42(c)(10) are not needed in aseptic processing areas for every product or 
process.  One comment suggested that the term "aseptic processing" in 
211.42(c)(10) requires further clarification to indicate that such processing is 
intended for products or components which are not terminally sterilized.  The 
respondents suggested inserting a phrase which would make it clear that not all 
controls are necessarily required.
     It is not the intent of 211.42(c)(10) to require "aseptic processing" when 
such operations would not be necessary for the firm's usual activities.  Some 
firms choose to use aseptic processing for drug products not intended to be 
marketed as "sterile" as a means of controlling microbial contamination.  The 
Commissioner agrees that modification is desirable and is revising 211.42(c)(10) 
to include the words "as appropriate."
     138. One comment suggested that 211.42(c)(10) should be redesignated as 
paragraph (d) because it is unrelated to paragraph (c).
     These requirements relate to separate or defined areas for certain 
operations to prevent product contamination or mixups.  The Commissioner 
concludes that such requirements are appropriately codified.
     139. Several comments objected to the requirement under 211.42(c)(10)(i) 
that floors, walls, and ceilings have smooth, hard surfaces.
     The Commissioner rejects these comments.  It is widely acknowledged that 
smooth, hard surfaces are easier to clean and sanitize.
     140. A number of comments objected to applying the requirements of 
121.42(d), 211.46(e), and 211.176 to the manufacturer of penicillin and 
nonpenicillin veterinary products. They claim that no evidence has been offered 
to demonstrate penicillin sensitivity in animals.  It was proposed that the word 
"human" be inserted before the words "drug products."
     Hypersensitivity reactions to penicillin do occur in animals. Although the 
Commissioner acknowledges that at present there is less information on the 
extent of the problem in animals than in humans, he advises that FDA has 
received numerous reports of reactions in animals throughout the years.  
Therefore, the Commissioner believes the requirement as proposed in 211.176 is 
warranted and has retained it in the final regulation.  However, the 
Commissioner believes that the prohibition against the use of common facilities 
and air-handling systems in the production of veterinary drug products is not 
necessary at this time.  Therefore, 211.42(d) and 211.46(e) (now 211.46(d)) are 
revised accordingly in the final regulation.
     141. A number of comments suggested that 211.42(d) can be too broadly 
construed.  It was suggested that some processing steps for penicillin and 
nonpenicillin products could be performed on the same equipment without risk of 
cross-contamination.
     The Commissioner believes that there is a possibility of trace amounts of 
penicillin being released during product handling even under well-controlled 
conditions, and he therefore cannot accept this suggestion.
     142. Another comment requested clarification of the meaning of the word 
"separate" in 211.42(d).
     The Commissioner's intent in this paragraph is to require the isolation of 
penicillin production operations from operations for nonpenicillin products.  
Separation can be achieved in a facility, building, or plant by effectively 
isolating and sealing off from one another these two types of operations.  This 
does not necessarily mean separation by geographical distance or the placement 
of these operations in separate buildings.  Effective means can almost certainly 
be developed to separate such activities from one another to prevent cross-
contamination problems within a single building.  An example of the means of 
separation can be found in the discussion of air-handling systems in this 
preamble under paragraph 172.

                        LIGHTING

143. Two comments said 211.44 is vague and may lead to misinterpretation.
     It is not the intent of this section to spell out precisely what is 
required in the way of lighting for each type of operation, but rather to 
require that individual firms follow lighting standards that are generally 
considered adequate for each of their various operations.  For example, 
inspection of parenteral solutions for particulate matter requires a different 
type of illumination than a component storage area.  The Commissioner, 
therefore, has retained the proposed wording in the final regulation.

            VENTILATION, AIR FILTRATION, AIR
                  HEATING, AND COOLING

     144. One comment suggested that the word "microorganisms" in 211.46(b) be 
modified by the term "objectionable."
     The Commissioner finds that this paragraph, by use of the phrases "adequate 
control" and "when appropriate," adequately states that the number or types of 
microorganisms that would be undesirable must be controlled.  Therefore, the 
Commissioner has retained the wording as proposed in the final regulation.
     145. A number of comments requested that expressions such as "when 
necessary," "where applicable," or "where appropriate" be used in the first 
sentence of 211.46(c) to broaden the scope of the requirement for air filtration 
systems.  Comments took exception to the requirement for exhausting to the 
outside of the building, stating that there are a number of alternatives such as 
completely closed systems properly filtered, ionization and electrostatic 
precipitation, enclosed hoods, and scrubbers.  Finally, two comments contended 
that there is no reason for air filtration systems in production areas where the 
product is already in the final sealed container and in nonsterile processing 
areas.
     The Commissioner believes that for the great majority of drug production 
operations the proposed requirement is desirable and necessary to assure the 
quality of drug products.  While it is doubtful that such air systems are not 
generally applicable to the production of nonsterile products, there may be 
situations where the requirement would not be necessary to assure the quality of 
drug products and would therefore be unreasonable.  Therefore, 211.46(c) is 
revised in the final regulation to require such filtration systems where 
appropriate.  This paragraph as rewritten also allows alternative systems which 
do not necessarily exhaust outside the building.
     146. Several comments objected to proposed 211.46(d) on the grounds that 
effective exhaust systems need not always be "adjacent" to the equipment in 
dusty operations.
     The Commissioner concludes that proposed 211.46(d) is unnecessary in view 
of 211.46(c) as written in the final regulation. Therefore, proposed 211.46(d) 
is deleted in its entirety.
     147. One comment said proposed 211.46(e) (now 211.46(d)) is too general 
because there would be no danger from cross-contamination during penicillin 
fermentation (prior to processing the dry state) and after the sealing of the 
product.
     The Commissioner cannot agree with this comment since the operations 
specified are not clearly defined.  He believes the fermentation process could 
result in cross-contamination problems. For example, removal of the cake from 
penicillin fermentation equipment could result in airborne contamination from 
partly dry or dry cake.  With regard to the respondent's second example, the 
Commissioner is revising this requirement to make it apply only to production 
operations and not to storage, such as warehousing of the penicillin product in 
sealed containers.
     148. Comments were made that proposed 211.46(e) was superfluous because 
211.42(d) already required separate facilities for penicillin and nonpenicillin 
products.
     The Commissioner believes it is important to make clear in these 
regulations that completely separate air handling facilities for penicillin and 
nonpenicillin production are required.  Section 211.42(d) is written to allow 
penicillin production in the same buildings as nonpenicillin production if the 
penicillin production areas can be completely separated from all others.  
However, because it is possible for air-handling systems between penicillin and 
nonpenicillin production areas to be interconnected, the Commissioner finds it 
necessary to state that any such interconnection would be unacceptable.
     149. One comment said proposed 211.46(e) should specify whether the air-
handling system is intended for outgoing or incoming air.
     There is no single answer to this point since the specific requirements for 
a particular installation will depend on individual circumstances.  The purpose 
of the requirement is that no cross-contamination occur between penicillin and 
nonpenicillin operations.  The means by which the objective is achieved may 
require filtration of incoming air of filtration of outgoing air or both.

                        PLUMBING

     150. A number of comments on 211.48(a) said water received from municipal 
sources and certified as meeting the requirements of Subpart J of 42 CFR Part 72 
should not have to be tested as if it were another component.
     It was not the Commissioner's intent that potable water received from 
municipal sources require acceptance testing by a drug manufacturer unless the 
water is obtained from sources that do not control the water quality to assure 
compliance with Public Health Service standards.  Of course, water of unknown 
quality such as a firm's own wells must be tested, and potable water coming into 
the plant system should not be adversely affected by the in-plant plumbing.
     151. A number of comments indicated that it is not necessary and is very 
expensive to require that all water in a plant be potable water.  They pointed 
out that some systems such as sprinklers for fire control, cooling equipment, 
and boiler feed do not require potable water.
     In light of these comments, the Commissioner is revising 211.48(a) to 
eliminate the prohibition against nonpotable water within a plant.
     152.  One comment said potable water should be analyzed for polychlorinated 
biphenyls and chloroform, and tolerances should be set because of the potential 
danger to health represented by these contaminants.
     The Commissioner recognizes that potable water may contain amounts of 
environmental chemical contaminants at levels that have not been clearly 
established as having significant adverse effects when ingested.  Government 
agencies are investigating more meaningful specifications for testing potable 
water for potentially harmful impurities not already included in the standards. 
Therefore, FDA has not included such requirements for testing and acceptance of 
potable water in these regulations.
     153. Several comments objected to the designation of traps to prevent back-
siphonage in 211.48(b).  The comments said it is general opinion that traps do 
not prevent back-siphonage, but check valves or air break arrangements would do 
so.
     The Commissioner agrees with these comments, and 211.48(b) is revised to 
reflect the suggested change.
     154. One comment objected to equipping drains with traps because of the 
inflationary impact and requested that this paragraph be deleted.
     The Commissioner notes that this paragraph is revised to eliminate the 
reference to traps.  It now requires the use of air breaks or other mechanical 
device which may increase or decrease the cost to this person, depending on his 
present method of preventing back-siphonage.  However, the Commissioner 
considers that the necessity of preventing back-siphonage outweighs the cost 
factor.

             WASHING AND TOILET FACILITIES

     155. Several comments on 211.52 argued that it is not current industry 
practice to provide "hot" water, but rather to provide "tempered" water, thus 
conserving energy while maintaining adequate sanitation facilities.
     The Commissioner has been unable determine that there is a consensus as to 
what is meant by "tempered water."  Therefore, he is concerned that the word 
"tempered" might allow the use of water that is of insufficient temperature for 
adequate cleaning.
     156. A comment suggested that the word "easily" be deleted from 211.52 
because location of washing facilities may be hindered or prohibited by local 
plumbing codes.  Further comment said the word "easily" is most subjective and 
capable of differing interpretation.
     The Commissioner is not convinced that plumbing codes would prohibit easily 
accessible washing facilities in establishments that are properly designed.  
Further, the Commissioner believes that the word "easily" is concise enough to 
adequately describe the intent of the section.  Therefore, the wording as 
proposed is retained in the final regulation.

                   ANIMAL FACILITIES

     157. Several comments contended that proposed 211.54 should be deleted 
since it substance is covered by the Animal Welfare Act of 1970 (Pub. L. 91-579, 
7 U.S.C. 2131).  Other comments said this section implies that housing for 
laboratory animals is required whether or not a firm maintains laboratory 
animals.
     The Commissioner does not believe it is improper to make the substance of 
another regulation a requirement in th CGMP regulations.  It should be obvious 
that if a firm is not engaged in a type of operation covered by these 
regulations, then any requirement that pertains to that type of operation does 
not apply to that firm.  In reviewing this proposed section, however, the 
Commissioner has concluded that its intent is adequately covered in 211.173.  
Therefore, 211.54 is deleted in the final regulation.

                       SANITATION

     158. Several comments on 211.56(a) said it is impossible to maintain all 
buildings completely free from rodents, birds, insects, vermin, trash, and 
organic decaying matter.  In most buildings there is an accumulation of trash 
daily in various waste baskets and in trash accumulation areas for papers and 
empty cartons.
     The Commissioner agrees that the intent of this section could be more 
clearly stated, and the text is revised accordingly.
     159. Several comments requested the deletion of the phrase "in detail" from 
211.56(b), because, according to the language in this paragraph, manufacturers 
would be required to document all minute details.
     The Commissioner believes that in some cases, detailed descriptions of 
cleaning procedures may be necessary to assure complete and proper cleaning.  In 
others, that level of detail may not be necessary or appropriate.  The 
Commissioner believes that there should be a reasonable standard in describing 
the details of these procedures.  Therefore, this paragraph is revised to 
require "sufficient" detail.
     160. Several comments requested the deletion of the phrase "such written 
procedures shall be followed" from 211.56(b) because, if current good 
manufacturing practice involves writing down certain procedures, it also 
involves following them.
     The Commissioner does not agree with this comment.  Procedures may be 
written with obvious good intentions but never implemented, as the agency has 
discovered in some firms.  Written procedures must be followed to assure the 
quality of finished drug product, and the regulations should be explicit in 
stating this point.
     161. Comments regarding 211.56(c) objected to the use of the word "person" 
and to the requirement of "evidence" that use of such materials will not 
contaminate equipment, components, or in-process materials.  The use of the word 
"person" according to the comments seems to have a more personal use here than 
the general use it has in other sections.  It was also suggested that the word 
"evidence" implied a need for proof of lack of any residue from pesticide or 
cleaning agent use, and that the standard should be a lack of adverse effect 
instead.  Several comments suggested that as written, this paragraph would 
require residue checks to be run on all batches in an area after a visit by an 
exterminator.
     The Commissioner finds that the objections have merit, and therefore the 
opening of this paragraph is reworded to clarify the intent.  It is not the 
intent of the Commissioner to burden manufacturers with testing every batch of 
drug product in a particular area for contamination from chemicals used to kill 
pests and insects.
     162. Several comments requested the deletion of the last sentence of 
211.56(c), which allows the use of only those rodenticides, insecticides, and 
fungicides that have been registered in accordance with the Federal Insecticide, 
Fungicide and Rodenticide Act (7 U.S.C. 135).
     The Commissioner believes it contrary to public policy to permit the use of 
unregistered rodenticides, insecticides, or fungicides.  The comment is 
rejected.
     163. One comment requested insertion of the phrase "employed to perform 
sanitation work" following the word "employees" in 211.56(d) to clarify that the 
procedures apply to individuals who are assigned to sanitation work.
     The Commissioner believes that the paragraph clearly indicates that good 
sanitation procedures apply to all employees who perform sanitation work.  
Therefore, he rejects this comment.

                      MAINTENANCE

     164. Several comments said the phrase "good state of repair" in 211.58 is 
vague and is subject to varying interpretation.
     The Commissioner does not agree that the phrase "good state of repair" is 
vague.  It means that buildings should not be in a bad state of repair so that 
drug products processed within them are adversely affected.

                     X.  EQUIPMENT

          EQUIPMENT DESIGN, SIZE AND LOCATION

     165.  A comment suggested the deletion of the phrase in 211.63 "for its 
intended use as well as for its" on the grounds that it is redundant and 
therefore unnecessary.
     The Commissioner does not agree that this phrase is redundant. The 
regulation imposes two requirements:  that equipment be such as to facilitate 
its operations for its intended use and that equipment be such as to facilitate 
its cleaning and maintenance. The phrase is revised in the final regulations for 
clarity.
     166. One comment on 211.63 noted that medical gas manufacturers use 
dedicated piping systems, manifold valve outlets, and pin index systems for 
processing medical gases.  Cleaning except at the time of initial installation 
and subsequent maintenance, is not done internally.
     The Commissioner notes that this section does not dictate the frequency of 
cleaning and/or maintenance.  If cleaning and maintenance after initial 
installation are not needed, as stated in the comment, then there is no 
requirement in 211.63 for such practice.

                 EQUIPMENT CONSTRUCTION

     167. A number of comments argued that 211.65(a) literally requires that all 
product contact surfaces be totally inert.  The respondents maintained that this 
requirement is practically impossible to achieve and that the following wording 
should be added: "* * * so as to alter the safety, identity, strength, quality 
or purity of the drug beyond the official or other established requirements."
     The Commissioner recognizes that drug product contact surfaces may be 
reactive to some minute extent, and the paragraph is revised in the final 
regulation in accordance with suggested alternative wording.
     168. A number of comments suggested adding the phrase "beyond the official 
or other established requirements" to the end of 211.65(b) to define better the 
standards to be used for evaluating any possible changes caused by product 
contacts.
     The Commissioner agrees with the substance of these comments. The proposed 
phrase is added at the end of the sentence in 211.65(b) for the same reason as 
explained in reference to 211.65(a).  A similar change is made in 211.67(a).

           EQUIPMENT CLEANING AND MAINTENANCE

     169. In reviewing the proposed regulations the Commissioner concludes that 
211.67 and 211.112 should be combined into a new 211.67.  Section 211.112 is 
deleted from the final regulation, and the substance of the requirements in 
proposed 211.112 are included in the new 211.67.  The comments below include 
those relating to both proposed 211.67 and 211.112.
     170. Several comments said written procedures and documentation required by 
211.67 should apply only to major equipment, not to items such as ladles, 
buckets, and spatulas.
     The Commissioner does not necessarily intend to require detailed procedures 
for cleaning each type of utensil.  For example, such equipment may be grouped 
when convenient.  However, the Commissioner believes that at least general 
written procedures should be instituted for cleaning utensils.  Although not 
"major" pieces of equipment, utensils can be just as much a source of 
contamination.  Depending on the type of operation, it may be necessary, for 
example, to sanitize or use procedures other than simple washing.
     171. One comment said 211.67 should be strengthened by requiring that 
cleaning and identification be performed by a competent individual specifically 
trained for these operations.
     The Commissioner rejects this comment because it would be repetitive of the 
requirements in 211.25 on personnel qualifications.
     172. One comment on 211.67(a) said that when equipment is dedicated to a 
single component or product, the use of water solution or gas purging would 
serve only to introduce material which should not be in the final product.
     This paragraph does not prescribe what compounds must be used for cleaning, 
the manner, or the exact frequency of cleaning.  To do so would be impossible, 
given the variety of products, equipment, manufacturing operations, and cleaning 
techniques. Selection is best left to each manufacturer, who also retains 
responsibility for assuring that their cleaning operations do not contaminate 
the drug product.
     173. One comment said the list of procedural requirements for equipment 
cleaning should be deleted from 211.112(a) since it is unnecessarily specific 
and unduly restrictive.
     The Commissioner does not agree that the list of required procedures is 
either too restrictive or too specific.  He believes that all the items are 
common sense procedures that most firms would incorporate, but some would not in 
the absence of CGMP regulations.
     174. One comment on proposed 211.112 argued that the word "shall" in the 
sentence regarding establishment of procedures should be replaced by the word 
"may" because the judgment of the manufacturing personnel should determine 
proper sanitary procedures.
     The Commissioner rejects this suggestion.  The purpose of these regulations 
is to assure that each firm establish appropriate written procedures regarding 
sanitation.  Precise procedures are left to the reasonable judgment of 
manufacturing personnel, as long as the objectives of the requirement are met.
     175. One comment said that 211.67 as written requires the cleaning and 
maintenance of all equipment used in the manufacture, processing, packing, and 
holding of a drug product, which would include laboratory equipment, fork lifts, 
and truck fleets.
     Any equipment used in association with drug manufacturing that could have 
an adverse effect on drug product quality if improperly maintained is covered by 
this section.  Ordinarily, of course, fork lifts and fleet trucks would not be 
considered, but it is not inconceivable, for example, that the failure of a 
refrigeration unit in a truck could have a serious deleterious effect on drug 
products that must be kept cool.  Laboratory equipment, when used for the 
quality control of drug products, is an integral part of the manufacture, 
processing, packing, or holding of drug products and therefore clearly is 
included in the scope of 211.67.
     176. Several comments on 211.67 argued that requiring written procedures 
for the method used in the disassembling and reassembling of all equipment is 
overly burdensome and not necessary.  It was recommended that the paragraph be 
deleted or rewritten to require such measures for significant pieces of 
equipment only.  It was also recommended that parts which come into contact with 
drug products be disassembled, cleaned and reassembled, but not necessarily the 
entire piece of equipment.
     The Commissioner concludes that the extent to which equipment must be 
disassembled depends on the type of equipment and other variable factors.  The 
equipment must be disassembled to the extent necessary to prevent subsequent 
contamination and/or malfunction. The regulations in 211.67(b)(3) are clarified 
in this regard.
     177. Several comments said 211.67(b) would require written procedures for 
"maintenance" of equipment and objected that the word "maintenance" is too 
general a term.  One comment recommended that the paragraph be revised to read, 
"There shall be written procedures assigning responsibility for and describing 
preventive maintenance programs and cleaning schedules."
     The Commissioner does not agree that rewording the paragraph, as suggested, 
is necessary.  Maintenance means keeping a building, machinery, or other 
facilities in a good state of repair; and the term is understood throughout the 
industry.
     178. One comment said 211.67(b) is not relevant to good manufacturing 
practice for most products.  The comment further said the description of the 
methods of disasembling, cleaning, and sterilizing is applicable only to 
parenteral drugs.
     The Commissioner does not agree with this comment.  Other types of 
equipment, for example, automatic tableting machines, also require 
disassembling, cleaning, and reassembling.
     179. Several comments requested that the phrase "such written procedures 
shall be followed" be deleted from 211.67(b).
     The Commissioner does not agree with this comment.  The requirement for 
written procedures is only part of the requirement for the use of current good 
manufacturing practice in the production of drugs.  An equally critical part of 
the requirement is that the written procedures be followed.
     180. One comment objected to the requirement in 211.67(c) for making the 
maintenance and cleaning records a part of the equipment use log (as required in 
211.182) because the information is readily available in batch records.
     The Commissioner rejects this comment.  The intent of the record retention 
requirement is that cleaning and maintenance records be readily identifiable 
with equipment usage in the event of a problem where drug products must be 
investigated.  Where the same equipment is used for a number of different drug 
products, for example, cleaning and maintenance records may not be easily 
retrieved.  Section 211.182 in the final regulations provides, however, that 
individual equipment logs are not required where equipment is dedicated to the 
manufacture of one product and the batches are manufactured in numerical 
sequence.
     181. Several comments requested the deletion from proposed 211.67(c) and 
211.112(a)(6) of the references to 211.180 and 211.182 with regard to the record 
retention period.
     The Commissioner disagrees with these comments.  Section 211.182 provides 
the specific information and form in which equipment usage, cleaning, and 
maintenance records must be kept and is appropriate so that firms subject to 
these regulations are made aware of their responsibilities.
     Further, improper cleaning and sanitizing could contribute as significantly 
to adulteration of products as could other problems in the manufacturing process 
and, in the event of contaminated products, the firm should be able to identify 
the cause of the contamination.  The retention of these records under 211.180 
therefore should be consistent with other recordkeeping requirements throughout 
the CGMP regulations.

                 EQUIPMENT CALIBRATION

     182. The Commissioner is combining the substantive requirements of proposed 
211.2 and 211.68 to form new 211.68. Comments on proposed 211.2 and 211.68 will 
be discussed here.
     183. One comment requested that proposed 211.2(a) be modified to permit the 
use of equipment other than the types listed.  One comment argued that the use 
of computers should be allowed. Several comments suggested deletion of the word 
"precision" since it is superfluous and redundant.
     The intent of this paragraph is to allow the use of any equipment that will 
perform a function satisfactorily in accordance with the requirements in Part 
211.  The Commissioner is therefore revising this paragraph in the final 
regulation (now 211.68(a)) to permit the use of any automatic, mechanical, 
electronic, or other types of equipment, including computers or related systems, 
that will achieve this goal.  Use of modifying word "precision" is not necessary 
because the paragraph requires that any equipment perform a function 
satisfactorily.
     184. One comment suggested that the word "permit" in 211.2(a) be replaced 
by the word "recognize," which would better express the intent of the paragraph.  
Several comments questioned the statutory authority of FDA to permit or prohibit 
the use of specific types or classes of equipment.
     The revision of proposed 211.2(a) (now 211.68(a)) eliminates the word 
"permit."  The authority to promulgate CGMP regulations includes the authority 
to regulate the use of equipment that could have a bearing on drug product 
quality.  The argument that FDA does not have the authority to prohibit the use 
of equipment is academic, however, because there is no prohibition stated or 
implied.  Testing and quality control are an inherent part of the manufacture, 
processing, packaging, and holding of drug products as defined in 210.3(b)(12).  
Therefore, such equipment may also be used for testing and quality control. 
     185. Numerous comments suggested that the requirement in proposed 211.2(b) 
for a backup file of hard copy data be amended to provide for other types of 
backup data, such as duplicate tapes or microfilm.
     The Commissioner is convinced that it would be proper to allow for backup 
systems other than hard copy, and this paragraph is revised accordingly as 
211.68(b).  Measures must be taken, however, to assure that backup data are 
exact and complete and that they are secure from alteration, inadvertent 
erasure, and loss.
     186. Several comments objected to the requirement in proposed 211.2(b) for 
checking computer reproductions of formulas and other records or data each time 
they are used, on the grounds that it should be sufficient to verify only the 
accuracy of the first reproduction.
     The intent of this requirement is to ensure that each reproduction is the 
same as the original.  Computer printouts do, on occasion, contain errors.  
Whether due to faulty input, programming, malfunction, or other reasons, they 
can result in a serious production error and the distribution of an adulterated 
product.  The Commissioner therefore does not agree that only the first 
reproduction need be checked for accuracy.  If a computer system has the 
capability, however, to verify its output, such as with audit trials, this could 
be considered as a check for accuracy.
     187. One comment suggested deletion from proposed 211.2(b) of the listing 
of items requiring backup data.
     The Commissioner now believes that the listing of data to be included as 
hard copy data is not necessary.  The intent of this paragraph is that backup 
data be kept of any information that is computerized, not that certain 
information be computerized.
     188. One comment suggested deletion of the word "appropriate" in the second 
sentence of proposed 211.2(b), charging it to be superfluous.
     The Commissioner rejects this suggestion.  Controls required by this 
paragraph must be adequate to achieve their purpose, but are not required to 
exceed this level.
     189. One comment suggested that the third sentence of proposed 211.2(b) be 
modified by deleting the word "reproductions" and replacing it with the phrase 
"input to the computer."  The comment also suggested deletion of the phrase 
"data from the computer."
     The Commissioner agrees that input to the computer must be checked for 
accuracy and is revising the paragraph accordingly in 211.68(b).  He does not 
agree that "data from the computer" need not be checked for accuracy and 
therefore rejects that portion of the comment.  In considering the comments on 
the section and as a result of discussions with FDA staff knowledgeable in the 
computer field, the Commissioner has become aware that use of the word 
"computer" may be too restrictive so as to exclude data processing systems that 
do not compute.  Therefore, the words "related systems" are added to include 
those systems that function only as data storage and retrieval.
     190. One comment on 211.68(a) asked whether electronic equipment recorders 
should be calibrated.
     The Commissioner believes that recorders are an integral part of precision 
equipment systems.  A faulty recorder may give unreliable results that may 
affect the quality of finished drug products.  Recorders that are routinely 
calibrated, inspected, and checked reduce the margin for error and assure the 
quality of drug products.
     191. A comment said the intent of 211.68(a) is not clear as to the use and 
type of equipment that is applicable.  The comment further said precision 
equipment that has no effect on the drug product quality should be exempted from 
the written program requirements.
     The paragraph refers to equipment which is used in the manufacture, 
processing, packing, and holding of drugs and may therefore have an effect on 
drug product quality.  No examples of equipment which did not have an effect on 
drug product quality were offered.
     192. A comment requested that the term "precision automatic equipment" be 
defined.  The respondent said it could, for example, include tablet counters and 
liquid fillers which are checked on a routine in-process basis where there is no 
need for routine calibration or inspection.
     The Commissioner believes that tablet counters and liquid fillers are 
examples of precision automatic equipment.  When routing in-process checks are 
made, regardless of the time interval, such checks should be performed according 
to prescribed procedures and records kept in accordance with the requirements of 
this paragraph.
     193. Several comments on 211.68(b) said the mandatory time interval of 6 
months for calibration checks on scales and balances is arbitrary.
     The Commissioner agrees that time intervals longer than 6 months may be 
appropriate in some cases.  Because 211.68(a) requires that automatic, 
mechanical, and electronic equipment, including scales and balances, be 
calibrated routinely to assure the quality of drug products, the provisions of 
211.68(b) are unnecessary and therefore are deleted.
     193a. A comment requested the insertion of the word "weight" before the 
word "scales" in 211.68(b) to clarify that this requirement applies only to 
weight scales.
     The deletion of 211.68(b), as proposed, removes the reference to "weight"; 
however, the Commissioner finds that any scale or balance used for testing of 
production operations is required to be accurate and must be calibrated and 
checked routinely as required in 211.68(a).
     194. A comment requested an additional paragraph covering the 
standardization of tablet punch and die sets.
     Although the Commissioner believes that the comment has merit, he does not 
believe that it is generally appropriate in a general set of regulations to 
identify specific equipment used only in the manufacturing of one dosage form.  
Such requirements are more appropriate in regulations for specific dosage forms.

                        FILTERS

     195. A number of comments on 211.72 requested clarification whether this 
section is intended to apply to both air filters and solution filters.  Other 
comments requested clarification that the proposed paragraphs (b) and (c) refer 
only to injectable drug products intended for human use.
     The Commissioner finds that the intent of this section is to eliminate the 
use of fiber-releasing filters in liquid filtration systems during production of 
injectable drug products for human use.  Revisions appearing in the final 
regulation clarify this intent.  Additional background information regarding 
this requirement can be found in the FEDERAL REGISTER of March 14, 1975 (40 FR 
11865), which established the basic requirements for this section.
     196. Several comments suggested that this section be deleted because it 
pertains only to injectable drug products and therefore should be placed in the 
specific regulations for this type of drug product.
     The Commissioner agrees that this section and a portion of 211.94 apply 
only to injectable drug products for human use and that such requirements will 
be suitable for the more specific regulations for large and small volume 
parenterals for human use when such regulations are in effect.  The Commissioner 
previously concluded in the final regulation published in the FEDERAL REGISTER 
of March 14, 1975 (40 FR 11865) that the use of fiber-releasing filters in the 
production of human injectables required codification in the general CGMP 
regulations until final LVP and SVP CGMP regulations are codified.  These 
provisions will be incorporated in the more specific regulations regarding human 
parenteral drug products when they are published as final regulations.  Again, 
the Commissioner reminds interested persons that this section has been in effect 
since April 14, 1975 (40 FR 11865).
     197. One comment noted that by the time the final regulation becomes 
effective, proposed 211.72(c) will be inoperative, since it requires 
substitution on or before September 14, 1976.
     The Commissioner agrees with this comment and is therefore deleting 
paragraph (c) of 211.72.
     198. One comment objected to being forced to use filters in drug 
production.
     Section 211.72 does not require the use of filters in the manufacture, 
processing, or packing of injectable drug products. However, if filters are 
used, 211.72 specifies types of filters that cannot be used unless the drug 
product cannot be manufactured, processed, or packed without their use, and also 
requires that in this eventuality the drug product be refiltered through a 
nonfiber-releasing filter.

           XI. CONTROL OF COMPONENTS AND DRUG
            PRODUCT CONTAINERS AND CLOSURES

                  GENERAL REQUIREMENTS

     199. Several comments suggested that the requirements for containers and 
closures in proposed 211.80(a) and 211.89 be separated from those for components 
and in-process materials because the testing controls, systems, and criteria 
differ.
     The Commissioner finds that the control of in-process materials is more 
appropriate in Subpart F-Production Process Controls; therefore, all references 
in Subpart E to in-process materials are deleted.  Proposed 211.88 and certain 
requirements proposed in 211.89 are now in 211.110(c) and (d).  It is 
appropriate to consider control of components, drug product containers, and 
closures together, however, because the separation of requirements for control 
of containers and closures from components in the CGMP regulations would 
necessitate the unwarranted duplication of numerous sections of text.  The 
variations in handling, examining, or testing can be adequately addressed by 
each manufacturer in the written procedures required by the various sections.
     200. One comment argued that these proposed requirements in Subpart E would 
place an additional burden on small manufacturers and that such requirements are 
unnecessary, particularly with OTC pharmaceuticals.
     Drug product containers and closures play a critical role in assuring that 
the patient is provided a drug product of essentially the same strength, 
quality, and purity as when it was produced by the manufacturer.  The 
Commissioner cannot agree that OTC drug products should not receive the same 
degree of protection as prescription drug products.  It has been FDA's 
experience that "small" manufacturers can attain the same degree of quality of 
their drug products as large manufacturers.  There cannot be different standards 
of quality of drug products for large and small manufacturers, nor can there be 
different standards of quality for OTC and prescription drug products.
     201. One comment on 211.80(a) raised several issues relative to the 
handling of bulk components being held in storage tanks or silos, including the 
commingling of a new shipment with the remainder from previous shipments and how 
such lots should be identified.
     Combining a new bulk shipment of a component in a bulk storage tank with 
the remainder of a previously received, tested, and approved component lot 
causes the compositing of the material.  The result is that the previously 
approved material becomes an integral part of an unapproved new lot and cannot 
be used until such lot is approved for use.  However, a manufacturer may choose 
not to commingle approved lots with unapproved lots of components in bulk 
storage.  In some instances a manufacturer may be able to test components 
appropriately before introduction to bulk storage as, for example, when a 
shipment of components is received with a valid certificate of analysis and 
where identification testing may be sufficient.
     202. Some comments suggested deletion from 211.80(a) of the words "in 
detail" because it would require the documentation of minutiae and voluminous 
written procedures.
     The Commissioner agrees that the phrase "in detail" could be construed to 
include description of insignificant portions of the procedure, which is not the 
intent.  Therefore, he is inserting the word "sufficient" before the word 
"detail."
     203. Comments were received on 211.80(a) recommending replacement of the 
phrase "approval or rejection" with the word "disposition."
     The Commissioner disagrees with this suggestion.  Written procedures must 
spell out the criteria for approval or rejection in view of such material's 
intended use.
     204. One comment suggested that the first sentence of 211.80(a) be preceded 
by the phrase "where appropriate" to allow for the size and complexity of the 
operation.
     The Commissioner believes that written procedures are appropriate 
regardless of the size or complexity of the operation. Written procedures 
provide a basis for the uniform performance of a function.
     205. One comment suggested adding to 211.80(b) the phrase "so as to alter 
the safety or efficacy of the drug product."
     The Commissioner finds that it is reasonable to conclude that contamination 
would affect drug quality.  Therefore, the suggested phrase is unnecessary and 
is not included in the final regulations.
     206.  Numerous comments strongly objected to the requirement in 211.80(c) 
that components, drug product containers, or closures be stored at least 2 feet 
away from walls, maintaining that it would severely reduce the available storage 
area and thereby necessitate additional space to store the amount of material 
with an attendant inordinate and unnecessary inflationary impact.  Some of these 
comments suggested that this sanitation-oriented requirement be placed in 211.56 
or combined with 211.80(b). Additionally, some comments offered alternate 
wording such as:  to permit cleaning and inspection, to allow for appropriate 
sanitation operations, and to allow for effective sanitation practice.  Some 
comments questioned whether this requirement only refers to outside walls or 
includes all walls, such as mesh screened walls, vault walls, partitions, and 
refrigerator and freezer walls.  Some comments questioned whether free-standing 
shelves also had to be "at least 2 feet away from walls," since shelving is 
sometimes attached to the wall for safety reasons.
     The Commissioner has carefully evaluated this paragraph in light of his 
intention to provide suitable spacing in storage areas for cleaning and 
inspection and concludes that a specific requirement for at least 2-foot space 
between the wall and such material can be deleted, but a requirement to store 
materials in a way that allows for cleaning and inspection will be retained.  He 
is also deleting the words "on pallets or free standing shelves" to allow for 
other suitable methods of storage.  The Commissioner believes it preferable to 
codify this requirement in this section rather than in 211.56.
     207. Numerous comments on 211.80(d) objected to the proposed requirement to 
identify each container in a lot being received since many items, such as 
containers, closures, and excipients are palletized.  This requirement, as 
proposed, would mandate that each pallet load be broken down so that each unit 
on the pallet could be identified, then repalletized, thereby increasing the 
potential for damage and mixups.  This procedure is alleged to have an 
unnecessary inflationary impact.
     The Commissioner recognizes that there are situations where it would be 
inappropriate to identify each container of component, drug product container, 
or closure such as mentioned in the proposed regulation.  He agrees that some 
provision should be made for these situations.  He is therefore amending this 
paragraph by adding the words "or grouping of containers."  Any individual unit 
separated from a grouping must be identified with the appropriate information 
required by this paragraph.
     208. Some comments requested a clarification of the word "disposition" in 
211.80(d) that would distinguish between a simple transfer of the material and 
use of the material for a particular purpose.
     The Commissioner believes that the word "disposition" appropriately covers 
any use or change in control status of the lot, including both those cited in 
the comments.
     209. Some comments questioned the intent of the last phrase of 211.80(d).  
The respondents stated that if the intent is to identify those containers that 
have been opened, then a period should be placed after the parentheses and a 
suggested new sentence added to clarify the intent.
     The Commissioner agrees that this phrase could be interpreted to require 
that only the lot be marked to indicate whether and when it had been opened and 
sampled.  The requirement for the sampling of lots is contained in 211.84.  
Therefore, he concludes that the requirement in 211.80(d) regarding identifying 
sampled containers is more appropriately placed in 211.84(c), which will clarify 
the intent to identify containers which have been sampled.
     210. One comment on 211.80(d) suggested that when a shipment of components 
contains more than one manufacturer's lot number, the recipient be allowed the 
option of assigning a single code number for this shipment.
     The Commissioner rejects this suggestion inasmuch as it would either 
complicate or negate tracing a component back to a particular manufacturer's lot 
or the subsequent tracing of a particular lot of component used to a lot of drug 
products.
     211. One comment objected to the requirement in 211.80(d) that containers 
of drug product containers bear an identifiable lot number, on the grounds that 
this is not standard practice in the industry.  The comment suggested that the 
recipient provide a distinctive code for such containers.
     The requirement is that each lot of each shipment be identified with a 
distinctive code.  If a lot number furnished by the supplier is distinctive for 
each lot in each shipment, then the recipient, i.e., the drug product 
manufacturer, can use the lot number as the distinctive code.  If, however, 
there is no lot number or the lot number is not distinctive for each lot in each 
shipment, then the recipient is responsible for designating his own distinctive 
code.

      RECEIPT AND STORAGE OF UNTESTED COMPONENTS,
         DRUG PRODUCT CONTAINERS, AND CLOSURES

     212. One comment proposed that 211.82(a) be divided to cover components, 
and containers and closures separately.
     The identification of articles received, camparison with materials ordered, 
and examination of the overall condition of the material received is carried out 
in much the same way regardless of the character of the article received.  The 
Commissioner sees no advantage to promulgating two separate regulations on 
receiving and storage of materials, one for components, and the other for 
containers and closures.  To do so would simply be redundant.
     213. A number of comments on 211.82(a) said individual containers of 
components, containers, and closures need not be visually examined before 
acceptance as long as they are checked before use.  The rationale for the 
comments is that a visual check of each container is impractical and unrealistic 
for large shipments of bagged materials that are palletized as a unit and/or 
shrink-wrapped.  The respondents suggested that tearing apart materials packaged 
in that manner would be costly and could be better done before use rather than 
in a receiving area.
     It was the Commissioner's intent in this paragraph to provide for a simple 
check at the time of receipt to detect obvious problems such as the wrong 
article, damaged containers, or visible contamination which would preclude any 
further handling of the materials.  He recognizes, however, that individual 
container examination of large lots of bagged or boxed materials is impractical 
when they are received.  Therefore, this requirement is revised to provide for 
examination of each container or grouping of containers.
     214. A number of comments expressed concern over the possibility of 
contamination if containers of components and other materials are opened for 
examination in the receiving areas of factories.  To avoid cross-contamination 
it was suggested that examinations be limited to the exterior of the containers 
or to shipping containers.
     The Commissioner notes that this paragraph does not specify that seals must 
be broken for purposes of examination.  It is the intent of this paragraph that 
a visual examination be performed. In most cases it would be adequate to limit 
the examination to shipping containers.  If the firm feels an inspection should 
be made in depth, proper precautions must be taken to prevent cross-
contamination.
     215. Several comments in regard to 211.82(b) objected to the concept of 
setting a special area aside for quarantined materials. They felt that reserving 
space for this purpose and moving stock into and out of this special quarantine 
area would be costly because of the additional space and labor required.  
Further, some felt that paperwork systems can accomplish quarantine purposes.
     The Commissioner refers to the detailed discussion in paragraph 128 of this 
preamble that describes the variety and degree of physical quarantine procedures 
which, when combined with other controls, provide the assurance necessary to 
prevent untested and unreleased materials from being used in drug manufacturing 
operations.
     216. Several comments on 211.82(b) and 211.84(a) proposed that components 
should be "tested" whereas containers and closures should be "examined 
visually," and that the word "tested" should be deleted whenever it refers to 
containers and closures.
     The Commissioner does not agree that appropriate testing of containers and 
closures can be limited in all cases to visual examination.  Even in instances 
where visual examination would suffice, however, the word "testing" is meant to 
include such examination.  Other CGMP regulations do use the word "examination" 
along with "testing" to suggest a lesser type of testing, if appropriate, 
however; and the Commissioner is therefore adding the phrase "or examined, as 
appropriate" to prevent any misinterpretation of 211.82(b) and 211.84(a).

    TESTING AND APPROVAL OR REJECTION OF COMPONENTS,
         DRUG PRODUCT CONTAINERS, AND CLOSURES

     217. Citing various reasons, comments suggested that 211.84(a) be revised 
to permit use of components, drug product containers, and closures, 
simultaneously with testing and with precautions to prevent release of the drug 
product until the tests indicate compliance with specifications.
     As a general principle, such procedures would violate the precepts of good 
quality control because untested and possibly noncomplying materials would be 
used in drug product processing. Although initially it would appear that the 
manufacturer merely assumes the risk of having to recondition or destroy a 
processed lot that was found to contain unsatisfactory components, containers, 
or closures, the Commissioner is concerned that processing while testing 
substantially increases the risk to the consumer that an unsatisfactory lot 
might erroneously be released. The Commissioner cannot accept such risks or 
these suggestions.
     218. Two comments on 211.84 suggested that the only practical test of 
product container and closure acceptability is the actual use of them.
     The Commissioner rejects the concept.  He notes that there are techniques 
available and in use by which the suitability of a container-closure system can 
be determined before its use. Manufacturers do develop specifications for 
product acceptance when making their purchases.  Such purchases are made with 
definite knowledge of what is needed.  The regulation simply requires that 
checks be made to assure that what has been received is what has been ordered.
     219. One comment suggested that a protocol or certificate from the 
container manufacturer that the container meets the U.S.P. requirements be 
acceptable in lieu of the recipient performing the tests.
     The Commissioner notes that certificates or reports of analysis are 
acceptable for components with certain provisions, such as periodical 
verification of the supplier's test results. Therefore, he would have no 
reservation about accepting a certificate or report of analysis with each 
shipment of drug product containers--as long as the lot of containers is 
appropriately identified, the supplier's results are periodically verified, and 
their certificate provides all appropriate testing.  A new paragraph, 
211.184(d)(3), is added to clarify this provision.
     220. One comment interpreted 211.84(a) to require that each lot of 
components, drug product containers, and closures be tested before each use in 
processing.
     This paragraph does not require such a practice, nor is that intended.
     221. Several comments questioned the meaning of container identification in 
211.84(a) and its relationship to a similar requirement in 211.80.
     The Commissioner is deleting the requirement regarding container 
identification from 211.84(a) because such requirement more appropriately 
appears in 211.80.
     222. Several veterinary drug manufacturers responded that the testing 
requirements for drug product containers and closures in 211.84(a) should not 
apply to veterinary drugs or that a very simple visual examination of such items 
would be all that is necessary for animal products.  One comment said the 
requirements for containers and closures in Subpart E are not current good 
manufacturing practice for the veterinary drug industry.
     The Commissioner does not accept the stated premise that the veterinary 
drug industry does not exercise such control over these containers and closures 
to ensure the protection of their drug products from external influences such as 
light, moisture, and microbes.  The agency's experience in inspecting veterinary 
drug manufacturers and in reviewing new animal drug applications indicates that 
this is not so.  The requirements of Subpart E can and should apply to both 
human and veterinary drug products.
     223. A number of comments on 211.84(b) objected to a requirement for the 
use of statistical criteria to determine the sample sizes for testing.  Many of 
the comments recommended that the requirement be made optional or that it be 
applied only when necessary or appropriate.  Some suggested that few people in 
the pharmaceutical industry understand statistical methods and that even experts 
differ on interpretation and application.  One comment suggested that 
representative samples are impossible for all materials and suggested that 
random, sampling be permitted.
     The Commissioner believes that statistical methods provide a rational basis 
for determining sample sizes, provide assurance that an adequate sample has been 
obtained, and increase the user's confidence that the results from testing of 
the sample are representative of the true conditions of the product sampled.  
The Commissioner recognizes, however, that other sampling plans, derived by 
other means, may also be adequate, and this section is revised to allow the use 
of alternative types of sampling plans. This will allow for use of random 
sampling methods if appropriate.
     224. A few comments requested that containers and closures not be included 
in the representative sample requirement of 211.84(b). No rationale was included 
to explain the request.
     If the comments meant that other sampling methods such as random sampling 
are more appropriate, then the change made in this paragraph will be responsive 
to these comments.  If the comments meant that containers and closures should 
not be sampled at all, the Commissioner rejects the comments because he believes 
that examinations must be made on product containers and closures to assure 
their suitability for use in drug product packaging.
     225. One comment requested explanation of an acceptable "past quality 
history of a supplier," as suggested by 211.84(b).
     The Commissioner did not use the word "acceptable" in his proposal, but did 
permit the past quality history to be used in determining sampling plans for 
articles received from various suppliers.  The object of considering the past 
quality history is that the fewer the problems encountered with materials from a 
particular supplier and the more often that supplier's products meet 
specifications, the less extensive the sampling schedule may need to be for that 
material.  Conversely, the more problems encountered with articles from a 
particular supplier, the more extensive the sampling schedules for the articles 
need to be.
     226.  One comment suggested that the word "incoming" be inserted before the 
word "shipment" so that the sentence is clear that no reference is being made to 
outgoing shipments.
     The Commissioner believes the meaning of the section is clear and that the 
sentence refers to materials received for use in drug production.  Therefore, no 
change is made in the final regulation.
     227. One comment suggested deletion of the reserve requirement in 211.84(b) 
because such a requirement appears in 211.170(a) and is appropriate only for 
components.
     To clarify his intent here, the Commissioner is adding the words "where 
required by 211.170."
     228. Two comments recommended that the requirement in 211.84(b) for testing 
each shipment of each lot is unnecessary when a previous shipment of the same 
lot had been received, tested, and approved.
     The Commissioner feels that examination of each lot of each shipment 
received is necessary even though a portion of the same lot has previously been 
received, tested, and approved.  Subsequent shipments may have been subjected to 
different conditions which may have caused changes in materials so that, 
although one shipment of a particular lot has met specifications, another may 
not.
     229. Fifteen comments on 211.84(c)(1) stated that containers from which 
samples are being collected do not always need to be wiped or vacuumed.  In 
addition, two other comments requested deletion of all the paragraphs as 
unnecessary because all manufacturers know what they need to do.
     The Commissioner agrees that a container of components may not always need 
cleaning before sampling and that, where cleaning is needed, wiping or vacuuming 
may not necessarily be the most effective means of cleaning.  Therefore, he is 
revising 211.84(c)(1) to provide manufacturers with more latitude in this 
operation.  The Commissioner does not agree, however, that controls used in 
sampling are uniform throughout the pharmaceutical industry.  Some manufacturers 
already have the controls required here, while others do not.  Therefore, this 
requirement is appropriate in the CGMP regulations.
     230. Several comments suggested inclusion of additional controls in this 
section as follows:  provisions for handling sterile materials; a requirement 
that each container that is sampled be marked; and identification of the 
location within a container from which a sample was taken.
     The Commissioner believes that the proposed requirements, with one 
exception, provide sufficient control of sampling procedures.  The language of 
this section is general to allow for a wide variety of methods of handling 
products with a wide variety of characteristics.  It is not the Commissioner's 
intent to design a specific control procedure which a manufacturer must follow, 
or to preclude flexibility in meeting this objective.  It is sufficient here to 
state the control desired and leave the specifics to the reasonable judgment of 
the manufacturer.  The Commissioner believes that the suggestion for identifying 
the locations within a container where samples have been taken is inherent in 
211.84.  To clarify that containers from which samples are taken must be marked 
in order to produce an appropriate record, the Commissioner is adding a new 
211.84(c)(6).
     231. A number of comments were received on 211.84(c)(4) relating to 
component subsampling and compositing of subsamples. The majority of those 
commenting recommended that the regulations allow for compositing.  Some 
respondents stated that sampling at multiple levels is not always necessary.  
Others suggested that the instances be spelled out where sampling at multiple 
levels is necessary.  One comment indicated that compositing is a satisfactory 
procedure if the container contents are all going to be used in a single drug 
product lot.
     The intent of this proposed section is to prohibit the compositing of 
samples taken from different portions of a container when there is a possibility 
that the composition of the material being sampled may vary within the 
container.  There is no general prohibition in the regulations on compositing 
samples where such compositing would not mask subdivisions of the sample that do 
not meet specifications.
     232. A number of comments suggested changes in the requirements proposed in 
211.84(c)(5) for identifying the sample containers.  Three comments objected to 
the proposed sample container identification as being too burdensome because the 
information is available in other documents.  One comment suggested that an in-
house code to identify samples is adequate.  Another said that the proposed 
sample container identification is not a current good manufacturing practice.
     It is not the Commissioner's intent that all the listed information appear 
on the sample container.  Section 211.84(c)(5) is reworded to require only a 
means whereby sample containers can be related to the required identification 
information.
     233. One respondent expressed concern that the requirement for opening 
containers for sampling in a suitable area would lead to separate areas for each 
ingredient.
     This paragraph is revised in the final regulation, and the words "suitable 
area" are deleted.
     234. One comment suggested deletion of the word "containers" in 
211.84(c)(2) dealing with cross-contamination because the requirement should 
relate to the contamination of components and no containers.
     The Commissioner agrees that the protection from contamination, as required 
in 211.84(c)(2), should relate to the contents of sampled containers.  The final 
regulation is clarified in this regard.
     235. Twenty-eight comments on 211.84(d)(1) stated in essence that the word 
"specific" should be deleted with reference to identity tests because there may 
not be specific identity tests for each component.  The words "appropriate" and 
"if available" were suggested for use instead.
     The Commissioner recognizes that the accuracy and precision of testing 
procedures vary.  The purpose of 211.84(d)(1) is to assure that some 
identification procedure is used for each component and that it is as specific 
as possible.  Otherwise, the test has little value for purposes of identifying a 
material.  This paragraph is reworded in recognition that specific identity 
tests do not exists for all materials.
     236. One comment said interpretation problems could occur with the identity 
test requirement for active and inactive ingredients in 211.84(d)(1) in 
multiple-ingredient components.  The suggestion was made that the wording be 
changed so that an identity test for each component had to be performed whether 
it was an active or inactive ingredient.
     The Commissioner is clarifying 211.84(d)(1) in the final regulation by 
requiring at least one test to verify the identity of each component of the drug 
product.
     237. Five comments said there should be no requirement in 211.84(d)(1) for 
an identity test for inactive components.
     The Commissioner believes it is important to identify inactive components 
to avoid erroneously using unsuitable components to manufacture a drug product.
     238. The use of organic chemical reactions as indications of product 
identity in bulk chemical processing was recommended by one respondent as an 
acceptable identity test under 211.84(d)(1).
     The Commissioner advises that the final regulation does not preclude 
organic chemical reactions as indicators of component identity, if appropriate.
     239. A number of comments relating to validation of a supplier's test 
results recommended that that portion of 211.84(d)(2) be deleted.  The argument 
was that the validation requirement would preclude the use of procedures other 
than those used by the supplier.  One change in the wording was suggested: that 
the word "monitors" be used in place of "establishes."
     The Commissioner believes that alternative procedures may be an acceptable 
means of validating methods used in the testing of materials by a supplier.  The 
regulations do not preclude the use of alternative methods.
     About the word "monitors" in place of "establishes," the Commissioner 
believes that the meaning of this sentence would be changed if the substitution 
were made.  If a manufacturer wishes to rely on a supplier's report of analysis, 
the manufacturer must first establish that those reports are reliable.  That 
reliability is established by the manufacturer's own testing which, when 
compared to the supplier's data, shows agreement within specified limits over a 
period of time.  Once that reliability is established, then the level of the 
manufacturer's validation testing may be reduced and reliance on the supplier's 
report may increase.  Continuing checks should be made on the supplier's reports 
because some kind of periodic monitoring must occur to assure the continued 
reliability of the supplier's test results.
     240. One comment suggested that the word "complete" should be deleted from 
211.84(d)(2) as a descriptive term for the supplier's report of an analysis.
     The Commissioner's intent in this paragraph is to allow for alternative 
routine testing where reliable reports of analysis are available for components.  
He finds that the criteria for accepting reports of analysis adequately provide 
for their proper application and that the modifying term "complete" is not 
necessary.  The final regulation is revised accordingly.
     241. One comment said suppliers' reports of analysis are not always 
reliable and suggested that several additional guarantees be required in 
211.84(d)(2).  They included, in addition to the report of analysis, a guarantee 
of the type described in section 303(c) of the act, a certification that the 
testing reported was done within 7 days of the report, and a guarantee that at 
the time of shipment/receipt that the component will still conform to protocol 
specifications.
     Suppliers' reports of analysis must be validated to establish the 
reliability of the suppliers' analysis.  Additional specified requirements 
relating to suppliers' test results do not now appear to be necessary for these 
regulations.
     242. One comment expressed concern that the validation requirement in 
211.84(d)(2) would lock a manufacturer into a single supplier, presumably 
because of the investment in validation procedures.
     The Commissioner advises that reliance on a supplier's report of analysis 
is not mandatory--it is optional in lieu of testing by the manufacturer.  
Although an investment in validation might persuade a manufacturer to remain 
with a single supplier, this does not constitute sufficient reason, in the 
Commissioner's opinion, to preclude the use of this approach by manufacturers.  
Competition among suppliers should not be adversely affected by this option.
     243. One respondent proposed deleting the word "all" with reference to the 
phrase in 211.84(d)(2) that testing be done in accordance "with all appropriate 
specifications," apparently to allow for less stringent testing if deemed 
appropriate by the manufacturer.
     The Commissioner believes the suggested change would alter the meaning of 
211.84(d)(2).  The intent is that appropriate specifications be established.  
Once appropriate specifications have been set, it is not acceptable to test for 
less stringent specifications.
     244. A comment suggested deletion from proposed 211.84(d)(3) (now 
211.84(d)(4)) of the reference to microscopic examination, stating that it does 
not seem to relate to any of the other provisions in this section.
     The Commissioner recognizes that 211.84(d) could list various other types 
of examinations, but he does not believe it inappropriate to specify a 
particular requirement for microscopic examination when appropriate, while not 
listing others.  For certain classes of drugs, particulate contamination is of 
increasing concern.  Identification and classification of particulate matter may 
properly require microscopic examination. Therefore, the Commissioner believes 
reference to microscopic examination is worthy of emphasis in the regulations.
     245. Eleven comments on proposed 211.84(d) (4) and (5) (now 211.84(d)(5) 
and (6), respectively) indicated that requiring materials to be either approved 
or rejected after testing does not take into account other categories of 
material status into which materials could fall if they do not meet 
specifications.  For example, comments said that materials could be reprocessed 
or approved for alternative uses and proposed that a revision be made to 
recognize these other possible classifications.
     The Commissioner agrees that destruction may not be the only way of 
disposing of materials which do not meet acceptance criteria.  If materials are 
being tested for their acceptability for manufacturing a particular drug product 
and they do not meet those criteria, however, they must be rejected for that 
use.  This requirement has been set forth in 211.84(e) now, rather than in 
(d)(5) and (d)(6).  There is no prohibition against the use of such materials 
after appropriate reprocessing, or for other uses for which the acceptance 
criteria can be met.
     246. One comment suggested that examination of material under proposed 
211.84(d)(5) be limited to visible contamination.
     Other types of examination may be necessary to identify contamination, 
because contamination that is not visible may adulterate a material as 
significantly as visible matter. Therefore, the suggestion is rejected.
     247. One comment suggested a new requirement be added to 211.84(d) that 
representative samples of materials be examined for filth or microbiological 
contamination.
     The Commissioner notes that other paragraphs in this section, particularly 
211.84 (a) and (b), require testing of representative samples.  There appears to 
be no need to repeat it in 211.84(d).
     248. One comment said with regard to proposed 211.84(d)(5) that it is the 
manufacturer's responsibility to determine the need for testing for microbial 
contamination.
     The Commissioner agrees that it is the manufacturer's responsibility to 
determine what materials are liable to microbial contamination, but having made 
that determination, the manufacturer must proceed to test those materials for 
such contamination.
     249. The requirement in proposed 211.84(d)(5) for microbiological testing 
of materials liable to bacterial contamination was interpreted by one comment as 
requiring sterility tests for containers and closures used in aseptic filling 
operations.
     The Commissioner agrees that an evaluation of a final production of 
aseptically produced sterile products would include the testing of containers 
and closures.  Once a procedure is validated, periodic testing and control 
monitoring are necessary to assure that the processing controls continue to 
work.

            USE OF APPROVED COMPONENTS, DRUG
            PRODUCT CONTAINERS, AND CLOSURES

     250. A substantial number of comments objected to the requirement that, 
without exception, approved components, containers, and closures must be used on 
a first-in, first-out basis.  These comments pointed out, for example, that on 
occasion a manufacturer might wish to evaluate a new supplier, or equipment, or 
processes in relation to a new container; or that on occasion the oldest stock 
might be physically inaccessible for a short period of time.  Several comments 
deemed the regulation unnecessary because some containers are inert.
     The Commissioner believes that the concept of using the oldest approved 
stock of components, containers, and closures is fundamentally sound.  Even 
inert containers may be subject to increased breakage, cracking, or other 
defects after prolonged storage.  There may, however, be legitimate reasons for 
varying from this requirement in some instances.  Therefore, this section is 
revised to provide for exceptions from the first-in, first-out requirement by 
adding a provision that deviation from this requirement is permitted if such 
deviation is temporary and appropriate.

           RETESTING OF APPROVED COMPONENTS,
         DRUG PRODUCT CONTAINERS, AND CLOSURES

     251. Several comments on 211.87 did not agree that components, drug product 
containers, and closures should all be retested in accordance with established 
requirements.  They maintained that components require specific retesting 
procedures to assure continued identification, strength, quality, and purity, 
whereas the likelihood of deviation of containers and closures from 
specifications because of deterioration is considerably less and should not 
require the same degree of retesting as components. They contended that stating 
requirements for retesting components and containers within the same section by 
the use of qualifying statements like "appropriately" or "as necessary" would 
weaken the former to accomodate the latter.  They therefore proposed that this 
section be divided into two subsections, one for retesting components and a 
second for containers and closures.
     The Commissioner believes that this section allows for different treatment 
of containers and closures versus components by use of the phrase "as 
necessary."  The Commissioner recognizes that all the objectives of retesting 
listed in this section--to reestablish identity, strength, quality and purity--
are not necessarily applicable to all containers and closures because all 
containers and closures are not necessarily tested originally for all these 
attributes.  He also recognizes that the period for appropriate retesting varies 
not only according to conditions of storage, but also according to the type of 
component and the type of container and closure.  The Commissioner retains the 
wording of the proposal in the final regulation.
     252. One comment suggested that the words "or examined" be added after the 
word "retested" in 211.87.
     The Commissioner agrees that examination is not precluded by this section 
if examination is the appropriate test for the attribute being considered.  
Therefore, this section is modified in accordance with the respondent's 
suggestion.

           REJECTED COMPONENTS, DRUG PRODUCT
                CONTAINERS AND CLOSURES

     253. One comment recommended that in 211.89 the words "lots of" be inserted 
between the words "rejected" and "components."
     The Commissioner rejects this recommendation since the requirement applies 
to all rejected components, drug product containers, and closures whether they 
be lots, batches, portions of lots or batches, or otherwise identified.
     254. Several comments suggested that this section be expanded to deal with 
the subsequent disposition of rejected materials.
     The Commissioner notes that the criteria for reprocessing rejected 
materials are adequately covered in other sections of this part.  It is not 
necessary to deal with other methods of disposition because they are varied, are 
within the manufacturer's discretion, and may include destruction, return to the 
supplier, or use in other products where specifications are met.  The 
Commissioner believes the major concerns of FDA are that rejected materials are 
not inadvertently used in a product for which they are not acceptable and that 
any such materials that are reprocessed and found suitable for reuse meet 
specifications, standards, and characteristics for the intended use.

              DRUG PRODUCT CONTAINERS AND
                        CLOSURES

     255. A number of comments asked about the meaning of the word "container" 
in 211.94(a).  For example, respondents inquired about the applicability of the 
proposed requirements to shipping cartons and containers for holding of in-
process materials.
     As recognized by the majority of comments received about this paragraph, 
the section heading introduces requirements regarding drug product containers 
and closures.  The Commissioner finds that minor editorial changes in the text 
will clarify that this section is intended to apply to drug product containers.  
Requirements elsewhere in the regulations deal with appropriate handling of 
components and in-process materials.
     256. Several comments on 211.94(a) involved testing requirements for 
container and closure systems.  One comment recommended that specific testing 
requirements be included in this section.  Another comment said that once the 
suitability of a container-closure system had been established, it should not be 
necessary to test each lot in minute detail.
     The Commissioner finds that specific detailed requirements for testing of 
the container-closure system are not necessary for this section.  Usually, 
manufacturers already have the benefit of experience with containers fabricated 
from materials with well-known properties.   Further, the requirement of 
211.166, particularly paragraphs (a)(4) and (b), will provide substantial 
information relative to the suitability of a container-closure system.  Where 
the manufacturer does not have adequate information regarding the container-
closure system, the responsibility is on such manufacturer to establish the 
suitability of the container-closure system for its drug product.  The final 
CGMP regulations do not specify detailed testing of each and every lot of 
containers. Manufacturers are responsible for the extend and manner of sampling 
and testing of drug product containers and closures.  Adequate sampling and 
testing of containers will depend on a number of factors.  The duty of the 
manufacturer is to assure that the container-closure system meets appropriate 
specifications that have been established for a particular packaged drug 
product.
     257. One comment suggested that 211.94(a) also specify that the container-
closure system "be clean."
     Revisions in 211.94(c) clearly provide for the use of clean containers and 
closures.
     258. All of the numerous comments on 211.94(b) requested that the 
requirement that container-closure systems "provide adequate protection" be 
modified to the limits of "normal" storage and use of the product or to limits 
of use and storage set forth on the label.
     The Commissioner agrees that the proposed regulation requires a level of 
protection that may not be possible to achieve in unforeseen circumstances.  
Therefore, the final regulations are revised to include the concept of 
foreseeable conditions.  The Commissioner believes, however, that the 
acceptability of container-closure systems under a relatively narrow range of 
conditions that might be considered "normal" is not sufficient.  It is 
reasonable for manufacturers to consider conditions that can be expected to 
occur occasionally; for example, extreme temperature variations that may be 
encountered during winter and summer months for drug products that are in 
transit can be reasonably foreseen by manufacturers and should be taken into 
account when considering the suitability of container-closure systems.
     259. About 50 comments were received concerning 211.94(c). Most suggested 
modification of the requirement that containers and closure systems always be 
cleaned before usage.  Many indicated that although it was the drug 
manufacturer's responsibility to see that these items are clean, manufacturers 
may not always have to perform a separate cleaning operation.  Examples of items 
which may not always need cleaning were cited, such as:  caps, liners, blisters, 
neutralizers, and films.
     In proposing this requirement, the Commissioner intended that containers 
and closures be clean before use.  In some instances this will require the 
manufacturer to perform separate, and sometimes extensive, cleaning cycles.  In 
other instances it may not be necessary for the manufacturer to undertake a 
specific cleaning operation.  In any event, containers should not be released by 
the quality control unit, as specified in 211.84(a), until procedures, 
standards, or specifications, established under 211.94(d) have been met.  To 
clarify the intent of this section the word "cleaned" is changed to "clean."
     260. The majority of the comments regarding 211.94(c) were directed at the 
requirement, currently in effect, that containers and closures be cleansed with 
water that has been filtered through a nonfiber-releasing filter of specified 
pore size.  Comments strongly objected to this requirement for a number of 
reasons.  A few read the paragraph as requiring that containers be recleansed 
with water, whether or not a cleaning cycle is necessary; several respondents 
noted that solvents other than water are used for cleansing; others objected to 
the pore size requirements because of high volume demands of cleaning cycles.  
In addition, arguments were presented that by requiring filtration of cleaning 
water for injectable containers, new problems of microbial and pyrogen 
contamination are possible.
     In particular, the United States Pharmacopeia submitted comments by the 
Subcommittee on Particulate and Chemical Contamination, National Coordinating 
Committee on Large Volume Parenterals (NCCLVP), whose committee membership 
includes representatives from major health care organizations, industry, and 
government.  The NCCLVP expressed concern that the requirement for filtered 
cleaning water presents disadvantages and potential hazards that far outweigh 
the benefits.  The specific reasons for their concern are as follows:

     1. Water lines for transferring cleaning water for injectable containers 
are designed, constructed, and maintained to deliver large quantities of high 
quality water under high pressures.  In order to maintain the integrity of these 
lines and the quality of the water, disruptions must be minimized.  The need to 
routinely install, test, and replace bacteria-retentive filters of the type 
required will undoubtedly compromise the integrity designed into these lines.  
Furthermore, the pressure drop resulting from the inclusion of such filters will 
jeopardize the quality of the wash.
     2. Cleansing and rinsing procedures require copious volumes of water.  Even 
with water containing low levels of microorganisms and particulates, significant 
accumulation of such contamination can occur on the filter surface.  
Proliferation of bacteria on the intact filter can lead to the generation of 
pyrogens or the growth of certain bacteria through the filter pores if a 0.45-
micron filter is used.  Since high flow rates and pressures are required, the 
chance for mechanical failure and breakage of the filter is increased, thereby 
increasing the risk for the passage of a bolus of bacteria.
     3. Because of the microbial jeopardy described above, these filters will 
require scrupulous maintenance.  Such efforts will result in significant 
penalties to the process in both material and labor costs.

     It is the opinion of the Subcommittee on Particulate and Chemical 
Contaminants that if a fiber-releasing filter is not employed in the process and 
a final rinse is performed with high-quality, microbiologically controlled 
water, it would appear to be unreasonable to introduce the disadvantages 
described above.
     The final regulation regarding asbestos particles in drugs for parenteral 
injection was published in the FEDERAL REGISTER  of March 14, 1975 (40 FR 
11865).  At that time the Commissioner had concluded that it was prudent to 
require that containers and closures for human injectable drugs be cleansed with 
water that has been filtered through a nonfiber-releasing filter of a specified 
pore size.  In view of comments received, the Commissioner is concerned that the 
requirement for filtered cleaning water may introduce new problems that outweigh 
risks of potential asbestos particle contamination from the container cleaning 
operations.  The Commissioner notes that he raised a similar issue in the 
preamble to the CGMP regulations for large volume parenterals, published in the 
FEDERAL REGISTER  of June 1, 1976 (41 FR 22202).
     Because of the comments received the Commissioner finds that there is 
substantial good reason to suspend, at least temporarily, the requirement that 
injectable containers and closures be cleansed with filtered water to remove 
fibers.  The Commissioner wishes, however, to serve notice that the issue of 
fiber removal from parenteral drugs, including where such fibers may be 
introduced through the cleaning cycle of containers, continues to be an 
important problem under review by FDA.  Until FDA has additional information on 
the fiber content of cleaning water and the significance of such fibers, 
however, the final regulations are revised to delete the requirement for 
filtered cleansing water. But this action in no way affects the agency's 
position on fiber-releasing filters in the manufacture of injectable drug 
products for human use (see 211.72).
     261. Almost all the comments on 211.94(e) said it was a restatement of the 
other parts of this section and therefore should be eliminated.  One comment 
said the phrase "the holding of" was redundant since, by definition, containers 
are used "for the holding" of a product.
     The Commissioner finds that the requirement of the proposed paragraph is 
not necessary in this section because a similar requirement appears in 
211.165(g).  Therefore, he is deleting the proposed paragraph (e) from this 
section.

               DOCUMENTATION OF CONTROLS

     262. A number of comments suggested that 211.96 be deleted on the grounds 
that it duplicates provisions of 211.84.
     The Commissioner agrees that both sections deal with documentation of the 
receipt, testing, or examination and disposition of components, drug product 
containers, and closures. Therefore, 211.96 is deleted.

              XII.  PRODUCTION AND PROCESS
                        CONTROLS

             WRITTEN PROCEDURES; DEVIATIONS

     263. One comment on 211.100 said written procedures for manufacturing and 
quality control should be reviewed and approved by "the appropriate 
organizational units" instead of by the quality control unit because the quality 
control unit does not necessarily possess an expertise greater than that in 
other units.  Another comment said the quality control unit does not have a 
sufficiently wide expertise to review and approve all areas of drug product 
manufacturing, including such areas as production, engineering, research, 
safety, and regulatory affairs.  A third comment said the requirement for 
approval of written procedures for manufacturing and quality control by 
appropriate organizational units other than the quality control unit should be 
deleted.
     The Commissioner rejects these comments.  He has not proposed that quality 
control have complete expertise in all of these areas. The requirement for 
review and approval of manufacturing and control procedures is clearly a 
requirement that the quality control unit review these procedures in light of 
what may affect the product in terms of safety and quality.  To remove from the 
quality control unit the responsibility for approving written procedures would 
diminish the authority and responsibility that should be vested in the quality 
control function.  Further, based on the agency's experience with the industry, 
the Commissioner believes that the concept of quality control review and 
approval for procedures that have a bearing on the quality and safety of a drug 
product is current practice.  This section also properly requires review and 
approval by other appropriate organizational units.  Therefore, the quality 
control unit's function does not replace the expertise that would be vested in 
other units.
     264. Another comment on 211.100 said requiring review and approval by the 
quality control unit is infringing unreasonably on individual manufacturers in 
determining their own organizational structures.
     The Commissioner does not believe that this requirement unduly dictates 
organizational structure.  For example, it does not designate to whom the 
quality control unit or other organizational units must report.
     265. One comment on 211.100(a) said appropriate units should be required to 
review, as well as draft and approve, manufacturing and control procedures.
     The Commissioner agrees and is inserting the word "reviewed."
     266. One comment suggested that the word "justified" in the last sentence 
of 211.100(b) be replaced by the word "explained." Another comment proposed 
substitution of the word "approved."
     The Commissioner believes that the word "justified" properly reflects the 
intent.  All production and process control procedures must be approved, whether 
initial or subsequent changes.  It is not necessarily enough to "explain" or 
"approve" a deviation.  There must be a valid reason for a deviation.
     267. One comment on 211.100(b) said only significant deviations should be 
recorded and justified.
     Section 211.100(b) requires that written procedures shall include all 
requirements as specified in subpart F of the CGMP regulations.  This subpart 
does not require written procedures for every conceivable or minute detail of 
production and control.  When such procedures are essential, the Commissioner 
maintains that any deviation from them is significant and should be recorded and 
justified.  To modify the regulation as proposed would imply, however, that only 
some deviations are significant.
     268. A comment proposed deleting from 211.100(b) the phrase "and shall be 
documented at the time of performance."
     Documentation of performance, in the Commissioner's opinion, certifies that 
the written procedures have been followed.  He concludes that it is a necessary 
part of this section.

                CHARGE-IN OF COMPONENTS

     269. One comment on 211.101 stated that the heading "charge-in of 
components" is an unfamiliar phrase and is not defined.
     The Commissioner recognizes that not all firms use the same terminology to 
define similar phenomena.  He believes the heading is clear when considered in 
light of the context of the section and that no change or definition is needed.
     270. One comment said 211.101 is addressed to dosage form production and 
cannot profitably be applied to chemical manufacture.
     These CGMP regulations apply to finished dosage form drugs (under 
210.3(b)(4) and 211.1) and are not binding requirements for chemical 
manufacturing.  The Commissioner maintains that these regulations can serve as 
useful guidelines in the manufacture of chemicals.  The agency plans to develop 
specific CGMP regulations on production of bulk drugs.
     271. One comment said it would be difficult to follow the requirements of 
211.101 when producing radiopharmaceuticals because the exact quantity of the 
radionuclide available before the production cycle begins is not known, and the 
components measurement must be performed aseptically.
     The Commissioner is rewording 211.101 to allow for its application to 
radiopharmaceuticals.  Further, this comment will be considered when specific 
CGMP regulations are proposed for radiopharmaceutical drug products.
     272. One comment said the operation supervisor may or may not be the same 
person as the one checking the operation and suggested adding a new paragraph 
(e) to 211.101 to have the appropriate entries made on the batch record.
     The Commissioner believes that 211.188(b)(11) adequately cover this.
     273. One comment said 211.101(a) is ambiguous because the word "intent" 
needs defining.  The respondent pointed out that antibiotic products are 
certified under published monographs permitting 85 or 90 percent of labeled 
claim as a basis for certification.
     The Commissioner notes that this paragraph does not prohibit the release of 
batches of drug products if the percentage of active ingredients is within 
acceptable limits.  The Commissioner recognizes that acceptable limits are in 
most cases a few percentage points above and below 100 percent of labeled 
potency. What is prohibited is the purposeful formulation of a product to yield 
less than the label declaration.
     274. Several comments expressed concern that every active ingredient amount 
would have to be recalculated to provide 100 percent and that a new master 
production record would have to be prepared for each new lot of active 
ingredient because every lot of active ingredient may not have the same potency 
value.
     The Commissioner believes that use of the word "intent" should be 
emphasized.  Drug products must be formulated to provide 100 percent of labeled 
potency based on the usual assay of active ingredients.  Active ingredients that 
are slightly above or below the usual value, but are within appropriate 
established specifications, may be used without reformulation provided that the 
resultant drug product will provide a percentage of active ingredient that is 
within acceptable limits.  The criteria for acceptance of components should be 
such that proper use will result in an acceptable drug product.
     275. One comment said it is extremely difficult to formulate a biological 
product to fulfill the requirement of 211.101(a) because the potency value is 
assigned after the manufacturing process has been completed.
     The Commissioner again emphasized the use of the word "intent."  The 
example given in the comment does not show that there is intent to formulate 
such products at less than 100 percent of labeled claims; rather, it virtually 
precludes such an intent by the nature of that process.
     276. One comment wanted to substitute the words "the amount of active 
ingredient specified in the master production and control record of the drug 
product" for the words "100 percent of the labeled amount of active ingredient" 
since over-the-counter drugs are not required by law to note the quantities of 
active ingredients in the labeling.
     The Commissioner agrees with the object of the comment, but believes the 
suggested wording is inadequate because it would not prohibit the master record 
from containing a formulation intended to provide less than 100 percent of 
labeled potency.  Instead, the Commissioner is revising the final regulation by 
adding the phrase "or established" after the word "labeled."  This would 
therefore include formulations established through new drug applications and 
over-the-counter drug monographs.
     277. Many comments on 211.101(a) said that: (1) It appears that all 
components must be weighed or measured precisely; (2) clarification of this 
section is needed to allow for the use of bulk components without previous 
subdivision, weighing, or measuring; (3) clarification is needed to allow for 
direct weighing of components into a batch.
     The Commissioner finds that 211.101(a) as written is not flexible enough to 
permit procedures such as are given as examples in the comments.  Therefore, the 
first sentence of this paragraph is revised to read as follows in the final 
regulation: "Components for drug product manufacturing shall be weighed, 
measured, or subdivided, as appropriate."
     278. Numerous comments requested clarification of 211.101(b) regarding the 
necessary identification of component containers. The comments pointed out that 
in some instances components are dispersed, but that the manufacturing 
department would make that decision for specific batch usage.  Several comments 
said the identification information was available through alternate control 
systems.
     The Commissioner believes that, as written, the final regulation takes into 
consideration the physical dispersal of components.  Comments that the required 
identification information is available through alternative control systems gave 
no examples; therefore, no change is made in the regulation.
     279. Several comments objected to the word "strength" in 211.101(b)(4) and 
wanted it deleted.
     The Commissioner rejects these comments.  If a component container does not 
adequately identify the batch in which the component is to be used, there is a 
potential for mixups.  The term "strength" is defined in 210.3(b)(16), so there 
can be no ambiguity in its meaning.
     280. Two comments suggested that use of component lot numbers and product 
lot numbers on the same container presents a possibility of mixup since the 
wrong numbers may be written on the batch record.
     The Commissioner finds that it is necessary to have this information for a 
complete drug product history.  As a practical matter the requirement will 
probably not pose a problem because most firms already have number 
identification systems that readily distinguish component lot numbers from drug 
product batch or lot numbers.
     281. Several comments objected to the requirement in 211.101(c) that each 
container of component dispensed to manufacturing be examined by a second 
person.
     The Commissioner believes the requirement is necessary and does not believe 
it will be a burden to the industry.  The Commissioner also notes that the 
substance of the requirement is no different from that stated in 211.40(a) of 
the CGMP regulations currently in force, and it reflects current industry 
practice.
     282. Several comments said that in some cases, such as with bulk component 
systems, there are automated methods for checking that could replace a second 
manual check.
     The Commissioner wishes to point out that the use of automated systems is 
permitted under 211.68.  The requirement of this section would be met if the 
second individual verifies that the automated system is working properly.

               MANUFACTURING INSTRUCTIONS

     283. Some comments suggested deleting 211.102 because the subject and 
intent are adequately covered by 211.100.
     The Commissioner agrees with these comments, and this section is deleted in 
the final regulation.

                  CALCULATION OF YIELD

     284. Several comments on 211.103 said the requirement for determination of 
yields at each distinct phase of manufacturing, processing, packing, or holding 
is ambiguous and subject to varied interpretations in view of the agency's use 
of the terminology "each distinct phase."  Others said some type of drug 
products do not lend themselves to a determination of yield at each distinct 
phase of manufacturing, such as certain biological products and those operations 
using continuous runs.
     The Commissioner agrees because what is "distinct" is subject to different 
interpretation and not applicable in other cases. Therefore, he is revising the 
section to require yield determination at each "appropriate" phase of 
production.
     285. Several comments said the requirement in 211.103 for independent 
verification by a second person is unnecessary.
     The Commissioner finds that independent verification is a current practice 
and has been, in substance, a CGMP requirement since 1963.  Independent 
verification has been found to be a valid means of uncovering errors which 
might, if left undetected, adversely affect drug product quality.  Therefore he 
rejects these comments.
     286. Several comments said, in substance, that calculating the percentage 
of theoretical yield is not the only method of comparison.
     The Commissioner does not believe that the wording as proposed would 
preclude the use of, for example, a standard range of acceptable yield.  
Ultimately, however, acceptance must be based on a ratio of actual yield to 
theoretical yield.

                EQUIPMENT IDENTIFICATION

     287. Several comments on 211.105 pointed out that there are cases where 
several pieces of equipment are grouped together to perform a function and that 
in such situations, collective identification of the equipment should be 
sufficient rather than identification on individual components of the grouping.
     The Commissioner feels that such a procedure is acceptable only if the 
equipment is permanently installed and used only for one purpose and only one 
batch of a drug product can be processed on it at one time.  This procedure 
would eliminate the need to identify equipment when there could be no 
misunderstanding as to what drug product is being processed.  In such cases of 
equipment dedication, identification of the grouping can be considered as 
meeting the requirements of this section.  The language of the final regulation 
more clearly provides for this situation.
     288. One comment requested clarification of the terms production" and 
"major equipment" as used in 211.105.  The comment questioned whether equipment 
for label printing, insert folding, or other similar operations not used in 
dosage form preparation should be identified in the batch record.
     Operations such as label printing and insert folding are not generally 
performed as a function of the production of a particular batch of drug product.  
Such operations are not suitable for consideration under 211.105, but are 
subject to the requirements of 211.122.  The phrase "major equipment" is used in 
211.105 to distinguish it from minor equipment such as spatulas, ladles, and 
scoops, for which a requirement for identification may be unreasonable.  Because 
it would be impractical to categorize every known piece of drug manufacturing 
equipment, a determination as to what equipment should be identified must be 
based by the manufacturer on appropriate criteria.
     289. A number of comments on 211.105(a) questioned the meaning of the term 
"processing lines" and requested a definition.
     The term "processing lines" is used in a broad sense to include the variety 
of equipment that may be used in a drug manufacturing plant.  For example, it 
may include a liquid filling "line" or a packaging "line" or any other kind of 
"line" used to convey a product through an operation, or to and from an 
operation, such as a pipe used to carry liquid from a bulk tank to another part 
of the plant.
     290. Several comments on 211.105(b) suggested that where a manufacturer has 
only one of a particular type of equipment, it is unnecessary to use a 
distinctive code or number to identify it in the batch records.  It was 
recommended that the equipment could simply be named.
     Since the intent of the code or number is to provide identification of the 
specific equipment used to process a drug product, the Commissioner has no 
objection to identifying the equipment by name under conditions specified in the 
comment. Wording of this paragraph in the final regulation provides for 
identification of equipment, under certain circumstances, by name.

          SAMPLING OF IN-PROCESS MATERIALS AND
                     DRUG PRODUCTS

     291. Many comments on 211.110(a) pointed out that all in-process tests 
identified in the proposal were not appropriate to all dosage forms.
     It was not the Commissioner's intent to require that the particular tests 
listed apply to all dosage forms.  The tests identified were meant to be 
examples of the types of tests that should be run on various dosage forms, but 
were not necessarily appropriate to all.  Therefore, to make his intent clear, 
this paragraph is revised to show that these controls shall include those 
listed, where appropriate.
     292. Two comments on 211.110(a) indicated that the word "manufacturing" 
should be modified by the word "major" and that the word "variability" should be 
modified by the word "significant."
     The Commissioner is not changing the wording because minor manufacturing 
problems may cause major manufacturing defects.
     293. One comment recommended that the first part of the opening sentence in 
211.110(a) be deleted because procedures do not assure batch uniformity and 
integrity of drug products.
     The Commissioner agrees that the written procedures do not in themselves 
assure drug product quality--the procedures must be administered to have an 
effect.  The Commissioner notes, however, that the requirement includes that 
established procedures be followed.  Therefore, the comment is rejected.
     294.  Several comments suggested deleting or revising the references in 
211.110(b) to statistical methods for determining in-process specifications.  
Some comments said statistical procedures for this purpose were not well 
understood either by industry or by FDA.  Others said other means of determining 
in-process specifications should be allowed in addition to statistical means. 
One comment said manufacturers with tight limits and little batch variability 
would be penalized by this requirement.  Another comment was that, because 
finished product specifications are arbitrarily derived, use of statistical 
techniques during in-process phases would be inappropriate.  Several comments 
indicated that, in the case of new products or new manufacturers, there is no 
manufacturing history so other means of developing in-process specifications 
should be permitted.
     The Commissioner is persuaded that there are other valid means of 
developing in-process specifications as alternatives to statistical methods.  
Therefore, the final regulation is revised to provide for application of 
statistical procedures, when appropriate.  The Commissioner emphasizes, however, 
that in-process specifications must be meaningful in terms of achieving the 
desired finished product characteristics.  Further, after product histories are 
developed, the Commissioner encourages manufacturers to perform statistical 
analyses on their products and processes with a view to controlling batch-to-
batch variability to the maximum extent possible.
     295. Three comments suggested that 211.110(b) requires in-process testing, 
whether needed or not, but that paragraph (a) only requires testing in an 
optional sense.
     The Commissioner recognizes that there are instances where the effect of 
variability during drug manufacturing phases cannot be predicted in relation to 
the drug product.  Further, there may be instances where there are no suitable 
points, during in-process phases, to sample and test.  The final regulations are 
reworded to clarify this.
     296. One comment suggested that allowance be made in 211.110(b) for the use 
of in-process tests for adjustment purposes.
     The Commissioner finds that specific references to in-process tests for 
adjustment purposes are unnecessary.  The regulations provide flexibility to the 
manufacturer for establishing procedures for any appropriate in-process test and 
determining the significance of testing results.
     297. As noted above in paragraph 199, the Commissioner concurred with 
recommendations to transfer requirements for in-process materials in proposed 
211.88 and 211.89 from Subpart E to Subpart F in new 211.110(c) and (d). 
comments on the proposed sections will be addressed in this section of the 
preamble, using the new section numbers.
     298. A number of comments suggested that 211.110(c) (proposed as 211.88) is 
overly restrictive because it would require complete testing of in-process 
materials at each significant step in production.  It was suggested, too, that 
in-process testing done during production to determine the need for equipment 
adjustment or to monitor equipment adjustment need not be reviewed by the 
quality control unit.
     The Commissioner concludes that the intent of this section, as modified in 
the final regulation, is clear.  There is no requirement that the quality 
control unit approve or reject in-process materials at the completion of each 
and every individual test or examination.  Approved written procedures may 
provide for minor equipment adjustments, checking, and monitoring of in-process 
material production.  However, at the completion of a significant phase, for 
example, the quality control unit must approve or reject the in-process material 
before proceeding to the next phase.
     299. One comment suggested defining the terms "significant stages" and 
"long periods" in proposed 211.88 (now 211.110(c)).
     To maintain the flexibility necessary for these regulations, the 
Commissioner finds that it would not be practical to define either of these 
terms because they can cover many types of situations and products.  They should 
be read within the context of the handling of specific products and the 
characteristics of those products.  A long period for holding an unstable 
product is obviously going to be quite different from a long period for holding 
a very stable product.  In the same way, significant phases in the processing of 
drug products can vary greatly depending on the methods used and nature of the 
individual products.  The determination of what is a "significant phase" and a 
"long period" must therefore be the responsibility of the drug processor.

             TIME LIMITATIONS ON PRODUCTION

     300. Several comments on 211.111 said there may be situations, such as 
mechanical failures or when material in bulk form has to be remixed, where the 
processing time would of necessity be extended beyond previously established 
limits.
     The Commissioner is revising this section to provide that deviation from 
established time limits may be acceptable if such deviation does not compromise 
the quality of the drug product. Such deviation must also be justified and 
documented.
     301. One comment suggested that the words "when appropriate" be deleted 
from 211.111, placing the burden of time limits on the manufacturer in all 
instances.
     The Commissioner rejects this suggestion in view of the general nature of 
these regulations.  There may be instances where establishing time limits for 
production would serve no practical purpose in assuring drug product quality.

               CONTROL OF MICROBIOLOGICAL
                     CONTAMINATION

     302. A respondent said that the requirements of 211.113(a) are redundant 
for "chemical processing" operations.
     The Commissioner is not sure what the comment meant by "chemical 
processing," but believes the comment may refer to in-process materials.  If 
that is the case, the Commissioner does not agree.  The possibility of 
microbiological contamination is an important concern in drug products, both 
nonsterile and sterile, and requires emphasis in the regulations to assure that 
special precautions are taken, over and above other precautions to assure 
product acceptability, and to assure that no microbiological contamination 
occurs during processing which could have an adverse effect on the drug product.
     303. One comment said 211.113 should not apply to medical gases because 
microbiological contamination is not a problem with such drugs.
     The Commissioner notes that there is little information available in the 
literature on microbiological and particulate contamination of compressed 
medical gases.  If microbiological contamination is not a problem with such drug 
products, then appropriate procedures may be less extensive than those needed 
for more susceptible drug products.
     304. Several comments requested clarification of the term "objectionable 
microorganisms" as used in 211.113(a) or suggested alternative descriptions of 
objectionable microorganisms such as harmful or pathogenic and fecal indicator 
microorganisms.
     The Commissioner deliberately chose the word "objectionable" as the 
appropriate modifier for the term "microorganisms" in this paragraph to cover a 
number of circumstances.  Microorganisms could be objectionable by virtue of 
their total numbers or their detrimental effect on the product or by their 
potential for causing illness in the persons ingesting them.  A definition of 
the term is not practical in the regulations, however, because the objectionable 
nature of a microorganism may develop only in relation to the unique 
circumstances of a particular formulation, a particular ingredient, a particular 
method of manufacture, or the conditions found at a particular firm.  The 
Commissioner believes that the use of the word "objectionable" in a very broad 
sense is a more practical means of expressing the kind of control he intends.
     305.  One comment recommended that 211.113(b) be separated into two parts:  
Paragraph (b) would then apply to products manufactured by a sterile fill 
operation, and a new paragraph (c) would apply to a terminal sterilization 
process.
     The Commissioner believes this paragraph, as written, can apply to both 
sterile fill process and terminal sterilization process.  In both instances 
there must be validation of the process used to show that it produces a sterile 
product.
     306. One comment suggested that 211.113(b) would require the manufacture of 
nonsterile products under the same conditions required for sterile products.  
The comment further said that in some cases smaller numbers of microorganisms 
could be tolerated if kept under certain levels that could be established.
     The Commissioner emphasizes that it is not his intent to require nonsterile 
products to be produced under sterile conditions.  He has previously explained 
under paragraph 304, his intent in using the word "objectionable."  Section 
211.113(b) clearly states that it applies only to drug products purporting to be 
sterile.

                      REPROCESSING

     307. Two comments suggested that the word "appropriate" be inserted before 
the phrase "established standards" in 211.115(a).
     The Commissioner finds that the suggested alternative wording offers no 
improvement over the proposed wording.  Reprocessed batches must meet all 
established standards, specifications, and characteristics.
     308. One comment suggested that the word "all" be deleted from 211.115(a) 
after the phrase "conform with."
     The Commissioner believes that the paragraph, as proposed, clearly states 
the intent regarding conformance with all established standards, specifications, 
and characteristics. Therefore, this suggestion is rejected.
     309. One comment suggested alternative wording in order to clarify that 
211.115(a) applies only to batches that are reprocessed.
     The Commissioner agrees with the substance of this comment and is adopting 
in part the alternative wording by revising the first three lines of 211.115(a).  
The Commissioner notes that the requirements for handling batches that are not 
reprocessed are adequately stated in other sections under Part 211.
     310. A number of respondents objected to the direct authority given to the 
quality control unit under 211.115(b) in approving the reprocessing of 
nonconforming batches.  They believe that such rejected batches should be either 
reviewed and approved subject to all normal tests by quality control or should 
be allowed to be reprocessed when the written procedures approved by quality 
control authorize and set forth the criteria for such reprocessing.
     The Commissioner rejects these comments because they would not be 
consistent with accepted quality control practices. Reprocessing of drug 
products suggests that a problem occurred during production of a particular 
batch.  The Commissioner does not believe it is reasonable to expect that 
preexisting reprocessing procedures can be written to cover every reprocessing 
situation. Therefore, it is appropriate that individual reprocessing procedures 
be reviewed and approved by the quality control unit.

          XII.  PACKAGING AND LABELING CONTROL

     311. Many comments suggested changing the title of this subpart to "Printed 
Packaging and Labeling Control."  Some comments suggested inserting the word 
"printed" before "labeling and packaging materials."
     The Commissioner disagrees with the suggestions to change the title since 
this subpart includes controls for packaging materials that are not labeling.  
Insertion of the word "printed" to precede the word "labeling" would be 
confusing because, under section 201(m) of the act, labeling is written, printed 
or graphic material.

            MATERIALS EXAMINATION AND USAGE
                        CRITERIA

     312. Several comments stated that the term "packaging materials" in 211.122 
is too broad in that it would include such items as corrugated dividers, pads, 
and blister-packing liners.
     The Commissioner advises that the term "packaging materials" as used in 
this subpart refers to packaging materials other than containers and closures 
covered under Subpart E.  Typically, unlabeled packing materials do not have to 
be examined as thoroughly as labeling materials.  The Commissioner intends that 
211.122, as written, allow for different treatment of unlabeled packaging 
materials and labeling materials.
     313. There were several comments regarding 211.122, 211.186(b)(8) and 
211.188(b)(8), stating that the word "labeling" is too broad because it could be 
construed as including advertising and promotional material and therefore is 
beyond the purview of the proposed CGMP regulations.
     As previously discussed in paragraph 96, the regulations in this part set 
forth the facilities, methods, and controls to be used for the manufacture 
processing, packing, or holding of a drug product.  Therefore, these regulations 
do not apply to labeling or advertising that is not associated with the drug 
product during its preparation under CGMP regulations.
     314. One comment said 211.122 does not represent current practice, and no 
need for the proposed language has been demonstrated.
     The Commissioner notes that this section, as finalized, does not differ 
substantially from existing requirements.  He believes this section represents 
current good manufacturing practice and is a significant aspect of any firm's 
quality control program.  He also believes that drug product recalls initiated 
because of packaging and labeling errors indicate that the controls described in 
this section are needed.
     315. One comment suggested that the last sentence in 211.122(a), pertaining 
to release of packaging and labeling materials after approval by the quality 
control unit, be replaced. The respondent believes that the use of unreleased 
lots of labeling and packaging materials should be permitted as long as approval 
is obtained before marketing.
     As discussed earlier in this preamble, in paragraph 217 regarding use of 
unreleased components, drug product containers and closures, the Commissioner 
cannot accept this suggestion.  It is not acceptable quality control practice to 
use unreleased materials in any phase of production.  The Commissioner believes 
that use of released components, in-process materials, containers and closures, 
labeling, and packaging materials is generally regarded by manufacturers as 
necessary to quality control.
     316. Several comments recommended deletion from 211.122(a) of the words "in 
detail," and one comment said that, as written, the paragraph would require 
documentation of all minute details.
     The Commissioner recognizes that different materials such as unlabeled 
packaging materials, as opposed to labeling, will require written procedures of 
different degrees of complexity regarding their receipt, identification, 
storage, handling, and examination and/or testing.  Therefore, the Commissioner 
is revising the phrase "in detail" to "in sufficient detail."
     317. One comment understood 211.122(a) to require the quality control unit 
to examine each container of material before acceptance.  The comment 
recommended statistical sampling of materials instead.
     The Commissioner advises that the degree of sampling will depend on the 
material to be examined or tested.  The intent of this paragraph is to require 
at least a representative sampling of all labeling and packaging materials.  The 
final regulation is clarified in this regard.
     318. One comment recommended deletion of the first sentence from 
211.122(b), as it is redundant based on the requirements cited in 211.122(a).
     The Commissioner believes that 211.122(b) as proposed clearly spells out 
the basis for approval or rejection and clearly states that rejected materials 
shall not be used in operations for which they are unsuitable.  Therefore, he 
does not believe paragraph (b) to be redundant.
     319. Two comments said 211.122(b) is overly restrictive in that it requires 
labeling or packaging materials not meeting specifications to be rejected even 
though the rejection may not be based on a serious defect, and thus the material 
could be used.
     The Commissioner asserts that it is up to the firm to establish appropriate 
specifications.  The specifications should be realistic so as to assure the 
safety and quality of the drug product, but they need not be so restrictive as 
to prevent the use of materials that could not affect the safety or quality of 
the drug product.
     320. One comment interpreted 211.122(b) to tacitly allow use of a 
provisional release concept for materials that are found to be out of 
specifications for their original use but would be suitable for use in other 
operations.  Therefore, the comment said this concept should be stated 
explicitly in the regulations.
     The Commissioner does not believe that this paragraph implies the 
acceptability of any kind of provisional release.  Materials rejected for one 
use must be completely tested and/or examined to determine their suitability for 
any alternative use prior to such alternative use.
     321. A comment said labeling and packaging materials approved for use 
should be rotated so that the oldest approved stock is used first.
     The Commissioner agrees that use of the oldest stock first is a desirable 
practice for most materials.  The attributes of these types of materials that 
are related to age, however, do not normally have an effect on the drug product, 
as would be the case with components, containers, and closures.  Therefore, the 
Commissioner has decided that a mandatory requirement for using the oldest stock 
first is not necessary here.  He has required, though, in 211.122(e) that 
obsolete labeling be destroyed. 
     322. A number of comments on 211.122(c) said this is not current industry 
practice, that costs outweigh benefits, and consequently the paragraph should be 
deleted.
     The Commissioner agrees that the proposed requirement for disposition, 
including dates and personnel involved, is unnecessary for packaging materials 
and believes that it was those proposed requirements that were for the most part 
being objected to. Further, 211.125 establishes the more specific control 
requirement for labeling.  Therefore, 211.122(c) is modified to require only 
that records be maintained for labeling and packaging material indicating 
receipt, examination, or testing, and whether accepted or rejected.  Many firms 
already record this information.  The burden on firms not recording such 
information should not be too great because a record of this information is 
currently required for components; therefore, the firms need only incorporate 
packaging and labeling materials into the system already employed for 
components.
     323. Several comments on 211.122(d) wanted the exclusion of packaging 
materials other than labeling and a less restrictive wording than "separate 
compartments" for labeling.
     The Commissioner is convinced that it is not necessary in most instances to 
separate unlabeled packaging materials in the same manner as labels and other 
labeling.  Therefore, 211.122(d) is revised in the final regulation to apply to 
labels and other labeling only.  The Commissioner is also replacing the phrase 
"separate compartments" with the word "separately" because it may not be 
feasible to place into compartments bulky packaging materials that are labeled 
and therefore considered labeling.
     324. One comment requested deletion of the phrase "or quantity of contents" 
in 211.122(d).
     The Commissioner rejects this request since labeling with different 
quantity-of-contents statements is in fact different labeling.
     325. Many comments suggested deletion of 211.122(e) as redundant.  Other 
comments objected to the word "destroyed."
     The Commissioner considered the comments and is convinced that this 
paragraph should be revised to avoid repeating requirements of 211.122(a) and 
(b).  The final regulation refers only to obsolete and outdated labels, 
labeling, and packaging materials.  Obsolete and outdated labels, labeling, and 
packaging materials must be destroyed to eliminate mixups between currently used 
labels, for example, and obsolete labels.  Such mixups can lead to serious 
mislabeling incidents.
     326. Five comments on 211.122(f) contended that gang printing is not a good 
manufacturing practice and should be forbidden.
     Although the Commissioner wishes to discourage gang printing, he does 
recognize that, under stringent controls, gang printing can be safely used.
     327. Two comments dealt with monitoring of the printing procedure in 
211.122(g).  One said it should be worded "* * * shall be set up by one person 
and be inspected by a second person at the beginning of the run to assure * * *" 
and the other suggested "* * * shall be monitored by the QC unit to assure * * 
*."
     The word "monitor" is being used here to describe an in-process production 
check on a piece of equipment to assure that it is working properly.  In such a 
case, the "monitoring" can appropriately be done by someone on the production 
line.  The Commissioner notes that 211.134(a) and (b) contains a requirement for 
further examination for proper labeling.  The Commissioner sees no need to 
revise this requirement.

                   LABELING ISSUANCE

     328. One comment assumed that in 211.125 the term "labeling" must apply 
only to items associated with the unit package.  It further said there is 
nothing to be gained by accounting for any advertising that is included with OTC 
packages or shipping cartons simply because of the legal definition of labeling 
under the act.
     The Commissioner advises that if the printed material referred to by the 
respondent is advertising under the act, then the CGMP regulations do not apply.  
However, as has been discussed previously, where labeling associated with a drug 
product during its preparation under CGMP regulations is involved, then the 
regulations in this section apply.
     329. One comment questioned the meaning of "strict control" in 211.125(a) 
and recommended that this paragraph be expanded to include certain specific 
features of strict control, such as requiring locked labeling transport 
containers.
     The Commissioner believes that it would be impractical to list specific 
features of strict control that would relate to all firms. Numerous comments 
were received that objected to specifying a "how to" approach instead of an 
"objective" approach.  This is an instance of the regulations stating an 
objective that is sought and leaving the method of attaining that objective to 
the reasonable discretion and ingenuity of the firm.  The Commissioner, 
therefore, rejects this recommendation.
     330. One comment recommended that the words "and/or batch" be inserted in 
211.125(b) after the word "master" because the master record does not contain 
the information regarding the lot number or the expiration date to be placed on 
the label.
     The Commissioner notes that the intent of this paragraph is to ensure that 
the proper labeling is issued to the batch.  He agrees that, as this comment 
points out, it is the batch record that usually contains the lot or control 
number and the expiration date and is therefore amending the paragraph to 
provide for this situation by including the words "or batch" after the word 
"master."
     331. Some comments on 211.125(c) asserted that labeling reconciliation does 
not detect vendor mixups or errors.
     The Commissioner agrees with this statement and notes that labeling is 
required to be examined or tested for these deficiencies by 211.122 before being 
issued for use.
     332. Several comments suggested substituting the word "significant" for 
"any" in 211.125(c) because the proposed wording would require an evaluation if 
there was a discrepancy of only one label.
     The Commissioner believes that these objections are suitably resolved by 
revising the wording to allow deviations within narrow preset limits.
     333. Some comments on 211.125(c) said that in situations where there is 
unique labeling, unique labeling equipment, single-product packaging lines, and 
other adequate quality control procedures, labeling reconciliation is 
unnecessarily expensive and time consuming and does not preclude misbranding.
     The Commissioner believes that label reconciliation is important because 
labeling mixups are one of the major reasons for recalls.  Regardless of the 
sophistication of the labeling system used, lack of labeling reconciliation 
would be a weak link in the total control of labels from their receipt to their 
use.
     334. One comment on 211.125(c) argued that the institution of elaborate 
control procedures for a half-dozen individually typed labels is more an 
annoyance than a hardship.
     It is difficult for the Commissioner to believe that the reconciliation 
requirement, when applied to six labels, is either an annoyance or a hardship.
     335. One comment on 211.125(c) said there is little reason to reconcile 
shipping container labeling.
     The Commissioner does not agree with this statement. Misapplication of 
labeled cartons can cause a recipient to wonder which is correct--the carton 
label or the container label. Furthermore, the Commissioner believes that such 
reconciliation is not overly burdensome or costly and is a current practice in 
the industry.
     336. Several comments on 211.125(d) suggested that recoding of excess 
labeling be permitted in lieu of destruction.
     The Commissioner rejects these suggestions.  The possibility of error 
outweighs any benefit that would be derived from salvaging labeling with 
obsolete lot numbers.  The agency's experience indicates that the majority of 
drug firms destroy excess labeling that bears lot or control numbers.
     337. Some comments suggested adding wording to 211.125(d) to denote when 
destruction of labeling should take place.
     The Commissioner believes that excess labeling bearing lot or control 
numbers should be destroyed as soon as possible after labeling of the batch and 
before labeling of any subsequent batches.  In view of the requirements in 
211.130(d), however, the Commissioner does not consider it necessary to set 
forth exactly when destruction must take place.
     338. One comment on 211.125(e) argued that cut labels and labeling should 
not be returned to stock because of the inherent danger of mixup, but rather 
should be counted and destroyed.
     The Commissioner finds that this suggestion would be too restrictive for 
those manufacturers who use cut labels.  He believes that with proper control, 
cut labels can be used without the occurrence of mixups.
     339. Some comments suggested incorporating proposed 211.125(f) into 
211.125(c) where much of the intent is already covered.
     The Commissioner agrees with these comments and has revised the final 
regulations accordingly.
     340. Several comments suggested deletion of the words "in detail" from 
proposed 211.125(g) (now 211.125(f)) because they are superfluous and 
potentially misleading.  One comment said a standard of reasonableness should be 
employed for the intended purpose.
     The Commissioner notes that the words "in detail" could be construed as 
requiring inclusion of minute detail.  Therefore, the Commissioner is inserting 
the word "sufficient" before the word "detail."
     341. One comment suggested deletion of proposed 211.125(g) (now 211.125(f)) 
because it is unnecessarily repititious of 211.125(c).
     The Commissioner does not agree that this paragraph is redundant.  Section 
211.125(c) requires the employment of certain procedures, whereas paragraph (f) 
requires those procedures to be in writing and to be followed.

           PACKAGING AND LABELING OPERATIONS

     342. Comments on 211.130(a) suggested that mixups and contamination can be 
prevented by spatial separation as well as by physical separation as required in 
211.130(a).
     In using the word "physical," the Commissioner intended that spatial 
separation be considered as a type of physical separation. To preclude 
misinterpretation, he is revising this paragraph to clarify that spatial 
separation can be an acceptable method of separation.
     343. One comment suggested insertion of the phrase "the probability of" 
between "of" and "mixups" in 211.130(a).
     The Commissioner rejects this suggestion because he believes it would make 
the paragraph confusing.
     344. One comment suggested that the word "container" be inserted between 
the words "product" and "with" in 211.130(b).
     The Commissioner finds that it is not the purpose of CGMP regulations to 
specify all appropriate labeling, containers, or shipping cartons that should be 
required to bear a lot or control number.  It is sufficient for these 
regulations to require that the manufacturing history of the drug product can be 
determined from a lot or control number.
     345. One comment on 211.130(c) suggested that the word "batch" be replaced 
by the word "appropriate," because in large operations, records may be kept 
according to production runs, which may include a number of batches.
     The Commissioner rejects a substitution for the word "batch." it is the 
intent of the Commissioner that the batch production and control records be 
complete.  Because the examination of labeling and packaging materials before 
use is a function of the production of a batch, the batch record would not be 
complete without this information.
     346. One comment said certain packaging materials, such as corrugated 
paper, should not come under the requirements of 211.130(c).
     The nature and extent of the examination of packaging materials, including 
corrugated paper, will vary, but, nonetheless, an examination of some kind must 
be performed to assure that the material is suitable for its intended use.  
Packaging materials often provide product protection, and the characteristics of 
packaging materials must be taken into account.
     347. Some comments in 211.130(d) said it is not necessary to clear a line 
of packaging materials such as bottles, cotton, caps, circulars, or other 
general packaging materials if that packaging material is to be used on 
subsequent batches of the identical drug product to be packaged in the identical 
package unit.  Several comments regarding proposed 211.130(e) argued that 
packaging and labeling material common to the succeeding production run not be 
removed from the finishing area after the completion of operations and prior to 
the next run.
     The Commissioner does not intend to require that packaging materials common 
to consecutive batches of a drug product be removed between such batches.  
Revision of 211.130(d) has clarified the requirements for removal of previously 
used packaging and labeling materials.  Further, the Commissioner finds that the 
requirements of paragraph (e) are adequately covered in paragraph (d), and 
therefore proposed 211.130(e) is deleted in the final regulation.

                DRUG PRODUCT INSPECTION

     348. Several comments on 211.134 argued that the requirement for assuring 
that every container and package has the correct label would require 100 percent 
examination of the drug product during or after finishing operations.
     It is not the intent of the Commissioner to require 100-percent inspection 
of the drug product either during or after finishing operations.  To clarify 
this section the Commissioner is deleting the word "every" in 211.134(a).  He is 
also replacing the word "assure" with the phrase "provide assurance."  The 
Commissioner notes that this section as written in the final regulation requires 
a high level of confidence, but does not necessarily require 100-percent 
inspection.  The Commissioner encourages 100-percent inspection by either visual 
or automatic methods because drug product labeling mixups have been a major 
cause of recalls.  Although 100-percent inspection might not provide absolute 
assurance, it would provide a higher level of confidence that every container 
and package in a lot has the correct label.
     349. A comment said the parenthetical phrase "(visually, mechanically or 
electronically)" should be inserted after the word "examined" in line 2 of 
211.134(a).
     The Commissioner notes that 211.68(a) permits the use of precision 
automatic, mechanical, or electronic equipment in all phases of drug product 
manufacture, processing, packing, and holding.  Therefore, there is no reason to 
repeat this statement in each section where such equipment might be used.
     350. A comment argued that the wording of 211.134(b) implies that the 
"representative sample" should be taken from sealed and palletized shipping 
cases.
     If shipping containers are labeled to contain a particular drug product, 
then it is the Commissioner's intention that individual shipping containers be 
examined to assure that the correct drug product is in the appropriate 
containers.  A lot or batch does not necessarily have to be sampled after it has 
been palletized because, generally speaking, palletizing is not considered as 
part of the finishing operation referred to in 211.134(b).
     351. One comment on 211.134(b) recommended that, in addition to visual 
examination, an identity test be required on the drug product if the firm packs 
physically similar drug products.
     The Commissioner does not agree with the suggestion that this paragraph 
contain provisions for identity testing if the firm packs drug products that are 
physically similar.  Section 211.120(d) and (e) provides for the clearance of 
packaging and labeling areas before use.  Section 211.165 provides for 
physically testing the drug product after packaging.  The purpose of this 
paragraph is to provide assurance that the correct labeling has been applied.
     352. One comment said the results of the examination need not be recorded 
on the batch production or control records if they are recorded elsewhere.
     The Commissioner rejects this comment.  It is important that the batch 
production and control records be complete regarding the history of the batch, 
including the results of examination of the drug product after packaging and 
labeling.  It is not essential, however, that all information that belongs in 
the batch production or control record necessarily be on one piece of paper.

                   EXPIRATION DATING

     353. Many commented on proposed 211.137, which would require expiration 
dating for all drug products.  A number of comments agreed that expiration 
dating was appropriate for certain drug products, for example, those subject to 
fairly short-term deterioration, but objected strongly to requiring expiration 
dating for all drug products and concluded that a requirement for expiration 
dating of all drug products would not benefit the consumer.  A few comments 
objected specifically to expiration dating for over-the-counter drug products or 
drug products whose active ingredient is known to be extremely stable and that 
have, for all practical purposes, an unlimited shelf life.  Examples given of 
such stable products include naturally occurring chemical compounds that are 
mined from the earth, refined, packaged, and sold for medical purposes.  A 
number of comments from consumers were very strongly in favor of expiration 
dating for all drug products.
     The Commissioner notes a trend toward voluntary dating of many perishable 
consumer products, particularly food and drug products. He believes that this 
trend has been generated in large part by consumers and consumer organizations 
who have expressed great interest in expiration dating of such products and by 
manufacturers responding to this interest.
     The pharmaceutical industry has been aware for a number of years that FDA 
believes it is in the public interest for manufacturers to provide information 
regarding the stability of its drug products.  In the preamble to amendments to 
CGMP regulations published in the FEDERAL REGISTER January 15, 1971 (36 FR 601), 
the Commissioner announced his conclusion that the interests of consumers must 
be served by the establishment of valid expiration dates for drug products.  At 
the time, the Commissioner expanded basic requirements in the CGMP regulations 
for stability testing to allow time for manufacturers to accumulate data to 
support expiration dating.
     In the preamble to the February 13, 1976 proposal, the background regarding 
expiration dating was discussed at length. The Commissioner pointed out that a 
number of drug manufacturers were already voluntarily providing expiration dates 
for their products; many products such as antibiotics, biologics, and drugs 
liable to deterioration were already required to bear expiration dates; and the 
latest editions of the United States Pharmacopeia (U.S.P.) and National 
Formulary (N.F.) require expiration dating for all products subject to 
compendial requirements.
     The Commissioner does not believe that expiration dating of drug products 
places an undue burden on drug manufacturers.  Those who have been complying 
with the 1971 CGMP requirement for stability testing will, for most drug 
products, already have data available on which to base a suitable expiration 
date.  When new products are being manufactured or when stability data are not 
otherwise available, the new CGMP regulations in 211.166 clearly provide for a 
tentative expiration date based on several factors, including accelerated 
studies.
     Although no sound arguments were represented to the Commissioner that 
expiration dating of most drug products would not benefit the consumer, the 
Commissioner has tentatively concluded that it may not be advantageous to 
consumers, in consideration of cost vs. benefit, to require expiration dating 
for human OTC drug products if their labeling does not bear dosage limitations 
and they are stable for at least 3 years, as supported by appropriate stability 
data.  Therefore, the Commissioner has elected to delay implementation of the 
requirement for expiration dating for these products and is proposing elsewhere 
in this issue of the FEDERAL REGISTER to exempt these products from expiration 
dating.  The Commissioner expects that types of products that would be affected 
by this exemption would include a number of medicated shampoos, topical lotions, 
creams and ointments, medicated toothpaste, and rubbing alcohol.  The 
Commissioner advises that until comments submitted in response to this proposal 
for exemption can be carefully evaluated and a decision made as to the 
suitability of such an exemption, the Food and Drug Administration will not 
enforce the expiration dating requirements of this section for the type of 
products that he is proposing to exempt.  The Commissioner believes it is 
significant that the types of products he proposes to exempt from expiration 
dating are acceptable for frequent and often prolonged use without dosage 
limitation, and typically the contents of the retail package are used in a 
relatively short period of time.  The Commissioner also notes that few of these 
products currently bear expiration dating, and he is not yet persuaded in 
consideration of the comments that the costs involved in requiring expiration 
dating for these products can be justified on the basis of the information 
available to him at this time.
     354. After reviewing the comments from individual consumers, the 
Commissioner believes that some private citizens misunderstood the applicability 
of expiration dating for all drug products and believed that the requirement for 
expiration dating will extend to drugs dispensed by a pharmacist on the written 
order or prescription of a physician.  Section 503 of the act specifies the kind 
of information that must be supplied by the pharmacist to the consumer regarding 
the prescription drug.  While the Commissioner has found that a number of 
pharmacists voluntarily indicate an expiration date on the prescription drug 
container given to the patient, such transfer of information is not required by 
law and, until the subject regulations are in effect, such expiration 
information will not be available to pharmacists for all prescription drug 
products.  The Congress is now considering bills to amend the act to provide for 
expiration dating on all prescription drugs dispensed to consumers.  The agency 
supports such legislative proposals.
     355. Several comments opposed the inclusion of expiration dating in CGMP 
regulations on the ground that the misbranding section of the act, section 502 
and, in particular paragraph (h) of that section, provides for expiration dating 
to the exclusion of the adulteration section, section 501, especially paragraph 
(a)(2)(B) relating to CGMP regulations.  Further comment was that regulations 
issued under section 502(h) of the act are subject to the administrative 
provisions of section 701(e) of the act, which includes provisions for a public 
hearing if requested.
     The Commissioner rejects these arguments.  No paragraph of section 502 of 
the act expressly refers to expiration dating. Paragraph (h) of section 502 
describes products liable to deterioration and the packaging and labeling that 
may be necessary to minimize such deterioration.  Although expiration dating 
might be considered implicit in this paragraph, the Commissioner does not find 
any basis for concluding that only labeling referred to in paragraph (h) of 
section 502 of the act can be required to carry dated labeling, or that the only 
statutory authority for FDA to enforce expiration dating is under this 
paragraph.  He notes, for example, that where expiration dating is required by 
an official compendium such as U.S.P. or N.F., FDA has authority to enforce this 
requirement under paragraph (g) of section 502.  Section 502(a)(2)(B) of the act 
clearly provides to FDA broad authority to assure the quality, purity, identity, 
and strength of drug products at least through the time of dispensing to 
patients or sale to consumers.  The determination of stability of a drug product 
and the reporting of this information through an appropriate expiration date are 
an integral part of the assurance of drug quality.
     356. A number of comments opposed expiration dating specifically for over-
the-counter drug products.  The arguments were primarily that:  (1) Many OTC 
drugs are extremely stable and that expiration dating is of little value for 
products whose stability can be measured in terms of many years; and (2) that 
any required expiration dating for OTC drug products should coincide with final 
regulations developed under the current OTC drug review process.  In the latter 
case, comments expressed concern that labeling changes required by expiration 
dating and probable labeling changes and formulation changes required at a later 
date under final OTC drug review regulations would be an unfair burden on 
manufacturers.
     The Commissioner notes that he has already discussed in paragraph 353, the 
interim enforcement policy regarding human OTC drug products that are stable and 
marketed without dosage limitations.  But he sees no valid reason for separating 
requirements for drug expiration dating for prescription drug products and most 
OTC drug products.  The Commissioner recognizes that firms should ordinarily be 
free to select any expiration date that falls within the documented stability 
period, and the regulations permit manufacturers to use any expiration date that 
is supported by appropriate stability data.  Even if a manufacturer knows that 
the active ingredient of its drug product is stable for 20 or 30 years, without 
expiration dating it is unlikely that the user of the drug product is going to 
know this information.  The Commissioner believes that expiration dating will be 
more than marginally beneficial to consumers even for drugs that are unusually 
stable.  First, it will reinforce pharmacist and consumer confidence in the 
product, and thus will avoid unnecessary disposal and replacement of old but not 
outdated drug products.  Second, it will prevent confusion for drug dispensers 
and probably consumers that would naturally occur in a system where some, but 
not all, products carried expiration dating.
     The Commissioner sees no undue burden on manufacturers in requiring 
expiration dating of over-the-counter drug products prior to final OTC drug 
monographs.  The Commissioner notes that a wide variety of methods for 
expiration dating of drug products are available and that many of these methods 
do not require changes or reprinting of labels.  If formulation changes are 
required as a result of a final OTC drug monograph, the regulations in 211.166 
provide for development of tentative expiration dates.  Since the expert OTC 
advisory review panels will not be considering the expiration dating of OTC 
drugs as a routine matter in their deliberations, the Commissioner sees no valid 
reason for further delaying expiration dating for most OTC drug products.
     357. Comment was received from the American Homeopathic Medical 
Association, representing the views of various aspects of homeopathic medicine, 
including manufacturers of homeopathic drug products, specifically requesting an 
exemption from the proposed requirement of expiration dating and related 
stability testing for their products.  The basis for the request is that 
homeophatic drugs characteristically contain such extremely small quantities of 
active ingredients that the finished product cannot be tested by usual 
analytical methods.  Further, because of the theory behind homeopathic medicine, 
regard for determining the specific level of active ingredient and the normal 
measures of stability are inappropriate.
     The Commissioner notes that homeopathic medicine and drugs used for 
homeotherapeutics are unique and differ substantially from other forms of 
pharmaceutical products.  Previously, the Commissioner has exempted homeopathic 
drugs from the Over-the-Counter Drug Review (see the FEDERAL REGISTER of May 11, 
1972 (37 FR 9464)).  Further, homeopathic drugs were excluded from review under 
the NAS/NRC Drug Efficacy Study Review (DESI) and distributors of homeopathic 
drugs have not been required to list such drugs under the Drug Listing provision 
of the act. (Manufacturers, however, are required to register as drug 
establishments.)
     Because of the unique nature of homeopathic drugs, the Commissioner has 
reconsidered the value of stability testing and expiration dating for this small 
class of drug products and concludes the need for expiration dating and complete 
stability testing, as proposed, are unnecessary in this group.  The imprecise 
nature of determining extremely low levels of active ingredients for each of a 
large number of attenuations (dilutions) that may be prepared for each drug 
substance, and the fact that factors such as potency, absorption, 
bioavailability and other measures of effectiveness do not appear to be 
applicable to homeopathic drugs, have convinced the Commissioner that requiring 
an expiration date for such products would be a burdensome requirement that 
would not result in any added assurance of drug quality to the user.
     Certain provisions of the proposed stability testing requirements, 
especially those relating to determining an expiration date, are also 
inappropriate.  On the other hand, some stability information, such as the 
compatibility of ingredients based on testing or examination and marketing 
experience, is necessary for this class of drug products.  The final regulations 
are amended in 211.166 by modifying the stability testing requirements for 
homeopathic drugs.
     358. Several comments expressed concern whether small labels of some drug 
products could accommodate an expiration date. Several other comments raised 
questions regarding the applicability of the expiration dating to their own 
specific small-sized products.  In one instance, a manufacturer indicated that 
it would be required to purchase new equipment in order to apply the expiration 
date to the crimp of the tube for a medicated cream.  In another instance a 
manufacturer indicated that its products were individually packaged in a way 
that the units stay with an outer packaging until all the individual units are 
used; it inquired whether each individually wrapped unit was required to bear an 
expiration date.
     The problem of certain labels being too small to accommodate statements 
required by FDA has been raised many times in the past. A specific regulation 
has been issued to address this problem (see 21 CFR 201.100(b)(6)).  Currently, 
a substantial number of drug products are packaged in a wide variety of 
containers, with a substantial range of label sizes, yet these often are marked 
with an expiration date.  For example, a number of drug products for use in 
hospitals are being packaged in "unit dosage" containers that bear all the 
required information as well as an expiration date. The Commissioner believes 
that technology and the availability of different methods of placing the 
expiration date on the immediate container are now at a state where it is 
reasonable to expect that any drug product package can accommodate an expiration 
date.  There will still be individual situations where it will be necessary to 
determine whether a particular packaging constitutes a protective or convenience 
wrap and therefore is not required to bear full labeling, or constitutes the 
immediate container, and therefore should bear all required labeling including 
an expiration date.  If a packager of drugs has any question regarding this 
matter, FDA will render an opinion upon request from the packager.  The request 
should be sent to Advisory Opinions Branch (HFD-35), Bureau of Drugs, Food and 
Drug Administration, 5600 Fishers Lane, Rockville, Md. 20857, and should include 
full information regarding the packaging as well as examples of the packaging 
materials and labeling.
     359. One comment expressed concern that the presence of an expiration date 
on small containers may serve only to detract from the conspicuousness of other 
information, including warnings and dosage recommendations.
     The Commissioner rejects this argument.  The practicality and advisability 
of requiring specific items of information on the immediate container must 
always be evaluated in light of whether it might compromise or obliterate the 
value of entire labeling of the immediate container.  The Commissioner finds 
that a uniformly short statement of an expiration date will not interfere with 
the conspicuousness of other required information.  Further, the Commissioner 
finds that there is no practical alternative to convey expiration dating 
information other than to place it on the immediate container.
     360. Several comments were received regarding the need for expiration 
dating of cylinders of compressed medical gases.  One comment noted that 
expiration dating of these drug products would not benefit the patient.
     The value of imparting stability information to consumers or to those who 
dispense drug products has been discussed previously. As stated earlier, the 
Commissioner cannot agree that expiration dating of most drug products would not 
benefit the user, whether or not the patient is personally aware of the 
expiration date.  The Commissioner sees no justification at this time for 
exempting compressed medical gases from the requirement of expiration dating.
     361. One comment objected to expiration dating of OTC drug products such as 
absorbent cotton, gauze bandages, eye pads, triangular bandages, cotton balls, 
and surgical gauze.  The comment was that these products last indefinitely and 
that some of these products, dating back from World War I, are being sold and 
are perfectly satisfactory.  Another comment expressed an opinion that, with 
regard to expiration dating, all attention seems to be focused on the stability 
of the drug formulation.  The comment concluded that other factors, such as 
packaging and storage conditions, must contribute to the determination of an 
appropriate expiration date.
     The Commissioner notes that these comments, apparently from opposite points 
of view, illustrate his concern that all persons should understand that there 
are other factors to be considered besides the stability of a specific active 
ingredient in determining a suitable expiration date; these include the 
stability of the inactive ingredients, the interaction of active and inactive 
ingredients, the manufacturing process, the dosage form, the container closure 
system, the conditions under which the drug product is shipped, stored, and 
handled by wholesalers and retailers, and the length of time between initial 
manufacture and final use.  For example, the period of time in which the 
sterility of a drug product can be assured may be substantially less than the 
inherent stability of the active ingredient.  Thus, the expiration date for a 
sterile drug product may have a different basis than that for a nonsterile drug 
product of the same active ingredient. Container closure systems or tablet 
coatings, for example, may increase or decrease the shelf life of the drug 
product. Therefore, as mentioned earlier, a number of factors must be taken into 
account in considering a drug product's stability.  The Commissioner also notes 
that articles such as cotton, gauze, bandages, and eye pads are now considered 
devices and will be handled under the Medical Device Amendments of 1976 and are 
no longer subject to these CGMP regulations.  Expiration dating for certain 
kinds of medical devices is now under consideration by FDA.
     362. Several comments recommended that FDA consider requiring that 
expiration dates fall within the same 1 or 2 months of every calendar year.  For 
example, it was suggested that all drug products bear an expiration date that 
would end in January (or January and July) of the calendar year for which the 
manufacture has established a date of expiration.  The comments indicated that 
such a procedure would not interfere with establishing dating periods in 
multiples of 6 months or 1 year and would allow persons who need to make 
inventories of drug product stocks to easily survey such stocks for outdated 
drug products.
     While the Commissioner sees merit in a provision that would allow all 
outdated products to be readily identified and removed only once or twice 
annually, he believes that such a requirement would not be justified at this 
time.  Manufacturers may use an expiration dating scheme that will provide an 
appropriate uniform expiration cutoff date to facilitate inventory control over 
outdated drug products in the channels of distribution.  The Commissioner will 
further consider utility and currency of such a practice and whether future 
regulations would be appropriate.
     363. Several comments spoke to the issue of a maximum expiration date, such 
as 5 years, about which the Commissioner had requested information and data that 
would establish whether any fixed maximum arbitrary date is in the best interest 
of the consumer.  Most comments expressed strong opposition to a fixed maximum 
expiration date.  One such comment expressed the view that a maximum expiration 
dating period would discourage development of improved stability formulations 
and packaging.  Another comment, which supposed that a 5-year dating period is 
generally acceptable to the pharmaceutical industry, recommended that such 
maximum expiration dating period be adopted with provisions that the time period 
could be extended on the basis of adequate data.  This same comment suggested 
that an advantage of a maximum expiration date would be to limit the length of 
time the drug product is not under the control of the manufacturer.  The time 
limit would reduce the possibility of damage by environmental agents, adverse 
changes in packaging materials, and obsolete labeling.
     The Commissioner advises that his request, appearing in the preamble to the 
February 13, 1976, proposal, for information and data showing that the 
establishment of an arbitrary date (5 years or any other time period) is in the 
interest of the consumer, resulted in generally unfavorable comments and no 
information or data to support public interest in a maximum expiration date, 
either by consumers or industry.  Therefore, the Commissioner concludes that he 
has insufficient information at this time to find that setting a specific 
maximum expiration dating period is suitable or desirable for drug products.
     364. A number of comments objected to the word "statistically" or the 
phrase "statistically validated" used in 211.137(a) in reference to the use of a 
"statistically validated expiration date determined by appropriate stability 
test."  The arguments were that for some drug products the expiration period is 
established based on characteristics or attributes (e.g., color of tablets) 
which are subjective and not amenable to statistical analysis.  For new drug 
products, stability data may be quite limited and there are insufficient data 
for meaningful statistical analysis.  In such cases, a manufacturer stated, 
expiration dates are conservatively assigned.  Another comment indicated that 
statistical validation is duplicative and open to dispute in interpretation.  
Several comments indicated that they were unsure as to what was required for 
statistical validation.   Another comment explained that expiration dates are 
currently derived from actual stability tests involving the use of accelerated 
stability tests.  The comments said that such accelerated stability tests do not 
need to be statistically validated as long as there is adequate justification 
for use of the conversion factors that relate the conditions of the study to 
labeled conditions.  Another comment said the use of statistics to derive an 
expiration date is only one of many ways that a valid expiration date can be 
obtained.  Most comments on this paragraph suggested deletion of the word 
"statistically" or the phrase "statistically validated."  Several comments 
suggested revised wording to incorporate the phrases "appropriate expiration 
date" or "statistically or mathematically validated date."
     The Commissioner finds that 211.166 on stability testing, which has been 
modified in the final regulations, contains the requirements that are the basis 
for establishing an expiration date.  An appropriate expiration date, determined 
in conformance with the provision of 211.166, will meet the requirements of 
211.137; therefore, the statistical validation requirement is not necessary to 
211.137.  The final regulation has been revised to clarify this issue.
     365. Several comments suggested that the 6-month delayed effective date 
proposed by the Commissioner was insufficient to allow accumulation of the 
necessary data to determine appropriate expiration dates.  Several firms 
suggested a 3-year delayed effective date for this requirement; another 
suggested a 2-year delayed effective date.  Another firm indicated that it was 
common industry practice to allow a 3- to 5-percent seasonal return and 
redistribution of OTC products.  This firm requested provisions in the 
regulations to allow for such redistribution from inventory of drug products 
that do not bear expiration dates.
     The Commissioner believes that the industry has been on notice concerning 
expiration dating for a number of years and should have data developed under the 
basic stability requirements that have been in effect since 1963.  Because of 
such general widespread knowledge and the "state of the art" regarding 
expiration dating, a 6-month delayed effective date in adopting this requirement 
should be an adequate transitional period in which to establish expiration 
dating procedures.  To allow distribution (or redistribution) of labeled stocks, 
however, the expiration dating required by these regulations shall not apply to 
stocks of drug products that have been labeled prior to the effective date of 
these regulations.
     366. One comment said 211.137(a) and 211.166 are inconsistent in that 
211.166 permits the use of tentative expiration dates based on accelerated 
studies combined with basic stability information.
     In revising 211.137 in response to other comments, the Commissioner has 
included a specific reference in 211.137(a) to 211.166.  As codified, 211.137 
clearly refers to the use of appropriate stability tests and stability studies 
described in 211.166.  Thus, the Commissioner now sees no possible contradiction 
in these two sections.
     367. Several comments objected to the introductory phrase "to assure" in 
211.137(a).  The comments were that the phrase is an impossible restraint and 
that an expiration date cannot "assure" that a drug meets identity, strength, 
quality, and purity standards.
     The Commissioner cannot agree with these comments.  In common usage, the 
word "assure" implies a confidence that can reasonably be expected.  The purpose 
of expiration dating is to inform users of the drug product that they can 
reliably expect that the product meets the professed standards of identity, 
strength, quality, and purity at the time of actual use.
     368. One comment suggested that 211.137(a) should provide that adherence to 
dating periods in approved new drug applications (NDA's) would constitute 
compliance with this section.
     The Commissioner believes that it is unnecessary for the regulations to 
specify that adherence to dating periods in approved NDA's would constitute 
compliance with 211.137(a).  Dating periods for products covered by approved 
NDA's are based on stability data submitted as part of the NDA's.  These 
stability data have generally come from testing programs that fulfill the 
requirements of 211.166.  If so, then such data also fulfill the requirements of 
211.137(a).  If not, the NDA probably was approved many years ago and new 
testing, using more sophisticated techniques, is appropriate.  For such 
products, the new CGMP requirements should not be and are not met by the 
approved NDA, and testing complying with 211.166 is required.
     369. Several comments recommended that 211.137(a) be revised to include a 
statement to the effect that a drug product would not be required to bear an 
expiration date if it is determined on the basis of appropriate stability tests 
and on distribution and consumer usage patterns that the product will be 
consumed before significant deterioration occurs.
     The Commissioner notes that he has considered stability and consumer usage 
patterns in establishing the interim enforcement policy discussed in paragraph 
353 of this preamble.  But he does not agree that the suggested revision would 
be suitable for all drug products, namely, prescription drug products and OTC 
drug products with dosage limitations.  Such provision would ignore a basic 
principle of expiration dating--that the manufacturer furnish information to 
reduce the chances of outdated drug products being consumed.  The Commissioner 
does not think it is realistic to assume that every unit of a drug product will 
be consumed within a specific period of time, notwithstanding the considerable 
experience many manufacturers have regarding distribution and consumer use 
patterns.  Information regarding distribution and consumer use patterns, 
however, will serve to assist manufacturers to estimate the quantity and 
duration of stability information that would be worth developing; that is, if a 
supplier is confident that more than 90 percent of a product is out of the 
distribution chain in 3 years, the supplier may not wish to incur the expense of 
establishing a 5-year stability for the product and labeling it with a 5-year 
expiration date.
     370. Some comments said proposed 211.137(b) was somewhat redundant when 
viewed in light of paragraphs (a), (c), and (e) of this section.  The comments 
also recommended that if paragraph (b) were retained, the references to 
appropriate statistical analysis should be deleted.  One comment recommended 
that paragraph (b) be revised to include mathematical use as well as statistical 
analysis.  Another comment stated that the phrase "readily available data" 
should be further defined.
     The Commissioner finds that with minor editorial differences the essential 
provisions of this paragraph also appear elsewhere in 211.137.  Therefore, he 
has decided that the proposed 211.137(b) will be deleted.
     371. A number of comments objected to the provisions of proposed 211.137(c) 
(recodified as 211.137(b) in the final regulation), specifically suggesting that 
drug products suitable for storage at room temperature not be required to bear 
appropriate storage conditions on the labeling.
     The intent of proposed 211.137(c) is to relate expiration dates to any 
storage conditions determined by the manufacturer of a drug product to be 
important and thus stated in the labeling.  A manufacturer may conclude that the 
expected normal handling conditions of the drug product do not require specific 
labeling instructions, or the manufacturer may elect to include any special 
handling or storage instructions to preserve the product's stability.  An 
editorial change in the final regulation clarifies that storage instructions are 
not required in every instance.
     372. One comment suggested that when proposed 211.137 (d) and (e) are read 
in conjunction with 201.17, it is obvious that expiration dates are required 
only for labeling described in 201.17 and therefore package inserts are 
excluded.  The comments suggested that the language in the section be revised to 
specifically exclude package inserts from a requirement to bear expiration 
dates.
     The Commissioner sees no reason that the regulations exclude, by name, 
package inserts from a requirement to bear an expiration date.  The regulations 
in 201.17 and, by reference, in 211.137, clearly specify which labeling is 
required to bear expiration information.  To designate, by name, the labeling 
not required to bear such information is impractical because it includes more 
than the package insert and it is unnecessary and potentially confusing.
     373. One comment recommended adding a new paragraph in 211.137, which would 
provide that in the case of licensed biological drug products, an expiration 
date, if applicable, either shall be determined by regulations specific for the 
product involved, or shall constitute part of the product license.
     The Commissioner cannot adopt this suggestion.  A biological drug product 
should bear an expiration date even if one has not been specifically established 
for that product either in regulations for the drug product involved or as part 
of the product license.

            XIII.  HOLDING AND DISTRIBUTION

                 WAREHOUSING PROCEDURES

     374. A comment said 211.142 should not require rigid physical separation of 
quarantined drug products before release by the quality control unit.
     The Commissioner did not intend, nor does this section state, that rigid 
physical separation of quarantined drug products is necessarily required before 
release by the quality control unit. The degree of separation necessary would be 
dependent on other steps taken to assure that quarantined drug products are not 
used prematurely.  For example, proper paper control or computer systems could 
offset the need for physical separation.
     375. One comment recommended that the words "of temperature, humidity, and 
light" be deleted from proposed 211.142(b) because humidity and light are not 
controllable in a normally operated warehouse.
     The Commissioner disagrees that humidity and light cannot be controlled in 
a warehouse.  However, he notes the regulation does not require these factors to 
be controlled unless the identity, strength, quality, and purity of the drug 
products would be affected.  The Commissioner believes that the regulation as 
written clearly requires that all drug products be stored under conditions that 
are consistent with maintaining the stability of the product. The conditions of 
storage will vary according to the particular product; hence the use of the word 
"appropriate" in this paragraph. At the very least, storage conditions should 
always be such that there are no extremes.  If the conditions of temperature, 
humidity, and light are extreme enough, almost any drug product would be 
affected.

                DISTRIBUTION PROCEDURES

     376. A comment on 211.150(b) said a requirement of lot number traceability 
is inappropriate and unnecessary when applied to the great majority of drug 
products for which the incidence of recall is extremely low.
     The Commissioner notes that this requirement is already in the existing 
CGMP regulations and is "current practice."  He does not have information to 
support a contention that certain drugs are less likely than others to be 
recalled.  Therefore, the Commissioner cannot accept this comment.
     377. One comment said 211.150(b) should be deleted and 211.150(a) 
recodified into the introductory text of 211.150 because the act does not 
provide for recalls and because the objective of 211.150(b) is substantially 
covered under 211.196.
     The Commissioner does not believe that these two sections are redundant.  
Section 211.196 requires that distribution records be kept containing certain 
information.  Section 211.150(b) requires that distribution recordkeeping 
systems include the capability of identifying the distribution of any specific 
lot so that a recall may be facilitated.  The Commissioner also does not believe 
that 211.150 mandates recalls.  Section 211.150 recognizes that it is a current 
good manufacturing practice within the pharmaceutical industry to have 
appropriate systems to carry out the occasional recalls or withdrawals from 
distribution of drug products.  These actions are generally voluntarily 
undertaken by manufacturers. Because such mechanisms are a current and good 
practice, the Commissioner has legal authority under section 501(a)(2)(B) of the 
act to require them for all drug suppliers.  The question of FDA-requested 
recalls is subject to separate regulations published in the FEDERAL REGISTER of 
June 16, 1978 (43 FR 26202).
     378. One comment said the distribution records maintained by compressed 
medical gas suppliers are adequate to accomplish 211.150(b), but the requirement 
of 211.196 calling for the lot number on distribution records is unnecessary.  
Further comment said compressed medical gas lots are distributed in a very small 
geographical area and to a very limited number of accounts, and recall is a much 
simpler problem for medical gases than for the widely distributed multiple-unit 
lot drugs.
     The Commissioner fails to understand how the intent of 211.150(b) can be 
accomplished without meeting the requirements of 211.196, and no such 
information was provided in the comment.  The intent of 211.150(b) is that a 
firm be able to determine how much of a given lot, if any, was shipped to each 
consignee and on what date.  The Commissioner does not believe that compressed 
medical gases should be exempt from this requirement, because they are potent 
drugs, and distribution accountability is of as much importance in case of 
recall of them as for any other drug.
     379. One comment said the phrase "and appropriate" should be inserted after 
the word "possible" at the end of the proposed 211.150(a).
     The Commissioner agrees with this comment.  In addition, the wording in the 
final regulation for this section has been revised to make it consistent with 
211.86 as it pertains to the first-in, first-out concept.  The final regulation 
provides that deviation from the first-in, first-out requirement is permitted if 
such deviation is temporary and appropriate.

               XIV.  LABORATORY CONTROLS

                  GENERAL REQUIREMENTS

     380. One comment recommended that the word "justified" in the last sentence 
of proposed 211.160(a) be changed to "explained."
     It is not enough, in the Commissioner's view, that a deviation from 
standards be explained.  The deviation must be supported by sufficient reason to 
show that it is needed and has no adverse impact on the drug product.  
Therefore, the recommendation is not adopted.
     381. A comment requested a definition for "specification" in 211.160(a) so 
that it would describe a general category rather than a single document, and 
specifications could be prepared as separate documents for separate areas.
     The Commissioner does not believe that, as written, the regulation requires 
that all specifications for all areas, such as sampling and testing, be a part 
of the same document.  The word is used here in a general sense rather than as a 
reference to a single document.
     382. One comment said 211.160(a) is ambiguous because it does not define 
requirements.  The comment asked whether documentation is needed showing 
completion of requirements.
     The Commissioner advises that 211.160(a) is intended to refer to 
requirements that appear throughout Subpart I--Laboratory Controls.  A wording 
change in the final regulation clarifies this intent.  With regard to the 
respondent's question concerning documentation, the Commissioner also advises 
that 211.194(a) contains a requirement for documentation.
     383. Two comments proposed deleting the references in 211.160(b) to 
sampling plans and testing procedures and merely requiring documentation of what 
was done.  The reasons for proposing this deletion were not made clear.
     The Commissioner believes that adequate controls include not only standards 
and specifications but also the sampling plans and testing procedures to 
determine acceptability.  These plans and procedures must be determined in 
advance of implementation--otherwise no systematic or comprehensive evaluation 
of the acceptability of materials and finished products can be assured.
     384. A comment suggested inserting the phrase "or a reference to" after the 
word "description" in the sentence referring to descriptions of sampling plans 
and testing procedures in specifications.
     The Commissioner interprets the comment's concern to relate to the extent 
of the description required for the sampling and testing procedures used when 
these are set forth in detail in other documents.  The description depends on a 
number of factors, but certainly could include references to authoritative 
procedures such as the official compendia.  The Commissioner does not believe 
the language need be modified, however, because he believes the word 
"description" provides sufficient latitude for the use of references, where 
appropriate.
     385. A comment said the requirement in 211.160(b)(4), providing for 
remedial action in the event equipment calibration checks showed problems, is 
impractical because a course of action for each possible event could not be 
written.  Instead, it suggested the paragraph read "* * * provisions for 
investigations to determine the necessary action."
     The Commissioner believes that broad instructions can be developed for 
remedial action.  The regulations in this section do not specify the detail in 
which such provisions must be developed. In some cases, these instructions could 
provide principally for an investigation to determine the cause of a problem.  
In other instances, for example, where a problem can be expected to occur 
regularly, detailed instructions may be practical.
     386. Several comments felt that inclusion in 211.160(b) of components, drug 
products, and in-process materials with containers, closures, and labeling was 
irrational.
     Controls throughout this section are only required as appropriate.  It is 
not the Commissioner's intent to require inappropriate standards and testing.  
The substance, extent, and complexity of controls will vary with components, 
container, closures, and labeling, but suitable specifications, standards, 
sampling plans, and test procedures are necessary for each.

          TESTING AND RELEASE FOR DISTRIBUTION

     387. Comments on 211.165(a) pointed out that potency assays are often tests 
for identity, and therefore the reference to identity tests should be removed.
     The Commissioner does not believe that every potency assay would also serve 
as an identity test.  In those cases where one test can suffice for both 
purposes, the wording of this paragraph would accept a single test.
     388. One comment asked for an exemption from the prerelease sterility and 
pyrogen testing requirements of 211.165(a) of shortlived radioactive materials.
     The Commissioner recognizes that for short-lived radiopharmaceuticals it is 
not possible to obtain results of these tests before the active material 
degrades below a useful level. Therefore, the final regulations in 211.165(a) 
permit release of those specific batches that are undergoing sterility and/or 
pyrogen testing, prior to completion of those tests, provided such testing is 
completed as soon as possible.
     389. Several comments requested clarification of 211.165(a) to determine 
whether it means that potency assays have to be done at both the bulk and 
packaged drug product phases, or only at the bulk phase.
     The Commissioner purposely worded this paragraph so that manufacturers 
could choose to do potency assays at either phase, but certainly before release 
for marketing.  There is no intent, once the product is in its finished dosage 
form, to require potency testing of more than one phase by the manufacturer.  
The Commissioner believes the paragraph is clear in this regard.
     390. Two comments maintained that identification and potency testing of 
each active ingredient in a combination product or in small batches of OTC 
products constitutes a highly inflationary procedure.
     The Commissioner believes that testing to assure that a product is what it 
purports to be is basic to a quality control program for any drug product.  
Further, he notes that the substance of this requirement has been in the CGMP 
regulations since 1963 and is generally a current industry practice.  Therefore, 
he finds that such a basic procedure should not have a significant inflationary 
impact or that this cost is unjustified in view of the assurances the procedure 
gives the consumer.  The comments are rejected.
     391. A comment suggested limiting 211.165(c) to sampling by deleting 
references to testing, on the grounds that 211.160 adequately covers the 
requirements for written testing plans.
     The Commissioner notes that 211.160 has general objectives regarding 
sampling and testing of drug products.  Requirements for release of drug 
products are more specifically described in 211.165.  Therefore, the 
Commissioner declines to accept this comment.
     392. Several comments objected to or redefined the concepts of acceptable 
quality level (AQL) and unacceptable quality level (UQL) used in establishing 
acceptance criteria and statistical quality control criteria as proposed in 
211.165(d). The comments pointed out that the concepts of AQL and UQL are not 
uniformly interpreted, and their use in establishing acceptance criteria and 
statistical quality control criteria is not uniformly applied.  Comments 
expressed concern that the concepts of AQL and UQL as acceptance criteria are 
premature and not currently a part of good manufacturing practice.  One comment 
suggested that these proposed CGMP regulations would require extensive changes 
in testing procedures, facilities, and use of manpower.  Several objections were 
raised relative to the "usually 95 percent" level of high probability of 
acceptance.  Respondents pointed out that this figure might be applicable for 
some pharmaceutical dosage forms, but would be too high for others.
     As anticipated by the Commissioner, the concepts of AQL and UQL in 
establishing acceptance and statistical quality proved quite controversial.  
From an analysis of the comments, the Commissioner believes that it is 
impractical at this time to establish a uniform system of AQL and UQL as 
proposed in the regulations.  Section 211.165 is therefore modified to allow 
greater latitude in establishing acceptance criteria, while retaining the basic 
requirements that acceptance criteria for sampling and testing, and for 
acceptance levels, be based on appropriate statistical quality control criteria.  
The Commissioner is convinced that sound statistical methodology should be 
applied to the procedures for testing of attributes or variables that impact on 
the quality of drug products and the evaluation of the results of such testing 
to determine acceptance or rejection of the lot.  The uses of AQL and UQL are 
examples of statistically derived levels for acceptance or rejection.  The 
Commissioner believes that more study must be given to this aspect of 
manufacturing practice and advises that in the future FDA will invite additional 
industry comment regarding revision of this section.
     393. Several comments asked, with regard to 211.165(e), whether official 
compendia test methods or methods from recognized sources have to be validated.  
The comments also recommended that guidelines be provided for documentation.
     It is not the Commissioner's intent to require the validation of 
authoritative test methodology.  Section 211.194(a)(2) of these regulations 
indicates that reference to official sources will suffice as documentation of a 
validated method.  The intent of this section is that assurance of accuracy and 
reliability be provided for all test methods used.  In the case of methods from 
official sources, such as compendia, reference to the source is documentation 
enough.  For methods modified or developed by the firm or some other unofficial 
source, validation of the method must be provided.  To clarify this issue, the 
final regulation in 211.165(e) refers to 211.194(a)(2).
     394. A number of comments on 211.165(f) proposed that laboratory reference 
standards received from official sources and/or with a protocol need not be 
tested.  In addition, respondents recommended that secondary in-house standards 
should be tested against reference standards.  Insertion of "standard solutions" 
was also suggested in this section.  One respondent suggested inclusion of a 
requirement for an expiration date on standards.
     In considering the comments in light of requirements elsewhere in the 
regulations, particularly 211.160(b), the Commissioner concludes that the 
proposed requirements in 211.165(f) should not be adopted as proposed.  The 
Commissioner recognizes that laboratory reference standards can be interpreted 
to mean either standard reference materials prepared by a firm's own 
laboratories, or standards received from outside sources, e.g., official U.S.P. 
reference standards or FDA reference standards.  Further, the Commissioner 
recognizes that complete testing by the user of many reference standards is not 
practicable although, generally, a specific identity test should be performed to 
verify such standard. The Commissioner finds that the requirements in 211.160 
provide the manufacturer the necessary flexibility to establish appropriate 
laboratory controls over the receipt or preparation of reference standards and 
to verify that such reference materials are suitable for their intended use.  
Therefore, proposed 211.165(f) is deleted in the final regulation.
     395. Several comments objected to the use of the word "statistical" in 
proposed 211.165(g) (redesignated 211.165(f) in the final regulations), stating 
that statistical criteria are not always relevant.
     The Commissioner is deleting the word "statistical" in the final regulation 
because the phrase "and any other relevant quality control criteria" is 
sufficient to include statistical criteria where appropriate.
     396. One comment requested deletion of the entire proposed paragraph (g) of 
211.165, because it is repetitive of 211.84(e).
     The Commissioner agrees that there is repetition between 211.84(e) and 
proposed 211.165(g) (now 211.165(f)); however, he notes that the former does not 
cover drug products that are covered under the latter.  The final regulation is 
revised to eliminate repetitious requirements.
     397. Several comments objected to the wording of the second sentence of 
proposed 211.165(g).  They contended it is not possible to determine beforehand 
whether reprocessed material will meet appropriate standards and specifications.
     The Commissioner accepts these suggestions and is rewording the provision, 
now 211.165(f), so that it more clearly permits reprocessing of rejected 
materials.
     398. Several comments argued that proposed 211.165(g) should be worded to 
allow use of materials that deviate from standards and specifications that have 
no bearing on the quality of the drug product.
     The Commissioner believes that it is clear in the context of this section 
that the standards and specifications referred to are those for acceptance or 
rejection.  As stated elsewhere in this preamble, the standards for acceptance 
or rejection must be realistic while at the same time appropriate to assure the 
quality of the drug product.  Any deviation from such standards is not 
acceptable.  On the other hand, there is no requirement that a firm establish 
specifications or standards that do not relate to the quality of the drug 
product.

                   STABILITY TESTING

     399. One comment on 211.166(a) questioned the need to prepare a written 
testing program to assess stability characteristics of products such as borax 
and boric acid because methods of assay and analytical procedures for these 
materials are well documented.
     The Commissioner notes that the written testing program includes more than 
just a description of the method by which a drug product is tested.  It includes 
all the requirements listed in this section.  If the test method used is an 
official compendial method or other authoritative method, then it would be 
sufficient to refer to the source of the method to satisfy that part of the 
requirement for written procedures for the testing program.
     400. Several comments requested that the word "statistically" be removed as 
a modifier of "valid estimates of stability" in 211.166(a)(1).
     The Commissioner is modifying the final regulation to clarify that the 
statistical criteria apply solely to sample size and test intervals to provide 
assurance that every batch of drug product produced has essentially the same 
stability characteristics.
     401. Several comments requested insertion of the words "where feasible" 
after the words "reliable, meaningful and specific test methods" in 
211.166(a)(3).
     The Commissioner believes the phrase "where feasible" would suggest serious 
gaps in analytical methodology in drug manufacturing operations that in fact do 
not exist.  The manufacturer has a responsibility to use test methods most 
suitable to assess the stability characteristics of his drug products.
     402. Several comments requested the use of container closure systems for a 
stability testing program that are "similar" to the marketed container/closure 
system rather than the "same."
     The Commissioner concludes that the container-closure system should be the 
same as the one used for marketing the drug product with regard to attributes 
that could possibly affect stability.
     403. A comment on 211.166 requested that the importance of stability 
testing of bulk active ingredients be emphasized because many manufacturers feel 
that stability testing applies only to finished dosage forms.
     The requirement in these regulations for performing stability tests applies 
only to "drug products," which are defined in 210.3(b)(4) as finished dosage 
forms.  Therefore, it would not be appropriate to include a requirement for bulk 
drugs in these regulations.  The Commissioner believes that appropriate 
stability testing for active ingredients is a requirement under section 
501(a)(2)(B) of the act because all drugs, including bulk drug ingredients, must 
be produced in conformance with current good manufacturing practice.  Stability 
testing of bulk drug ingredients is a current good manufacturing practice, and 
the Commissioner will propose to include it in the projected CGMP regulations 
for bulk drugs.
     404. One comment requested the exemption of extremely stable compounds, 
such as calcium carbonate, from the stability testing requirements.
     The Commissioner denies the request for the exemption.  The stability of an 
active ingredient is not the only characteristic that should be examined in a 
stability testing program.  A product may leach compounds from its packaging 
materials or be affected by heat or moisture in ways which could be detrimental 
to product quality without affecting its strength.
     405. A comment asked whether the reference samples in 211.166 can be taken 
from regular production batches for stability testing programs.
     The Commissioner notes that 211.166(b) clearly states that reference 
samples must be taken from regular production batches for stability testing 
programs.

              SPECIAL TESTING REQUIREMENTS

     406. Several comments on 211.167(a) recommended that sterility and/or 
pyrogen testing for veterinary drugs be excluded as unnecessary.
     The Commissioner finds that this paragraph does not establish whether any 
class of drugs is to be sterile and/or pyrogen free. The requirements of 
211.167(a) relate to drug products that purport to be sterile and/or pyrogen 
free.
     407. One comment said an apparent conflict existed between 211.167(a) and 
proposed 211.165(d)(2), which would require destructive testing of the batch for 
the characteristics of sterility and/or pyrogenicity.
     The Commissioner notes that proposed 211.165(d)(2) specifically 
acknowledged that it would not be appropriate to destructively test the entire 
batch.  Section 211.165(d) is reworded in the final regulation, with paragraph 
(d)(2) deleted, and the Commissioner sees no conflict between it and 211.167(a).
     408. One comment on proposed 211.167(b) said collaborative laboratory 
studies have not established procedures for accurate and reliable testing for 
the presence of all types of foreign particles and harsh and abrasive 
substances.  Alternative wording was suggested that would provide for such 
specifications and testing on an individual firm basis.  Other comments 
recommended that the requirement be restricted to testing for metal particles, 
as is currently required by the compendia.
     The Commissioner recognizes that tests for particles other than metal are 
generally not as precise as those tests for metal particles.  The United States 
Pharmacopeia and FDA regulations for antibiotic ophthalmic ointments (21 CFR 
436.206) contain requirements for testing for metal particles and limits for 
such particles.  The majority of firms manufacturing ophthalmic ointments 
perform tests for other particle matter in addition to the U.S.P. or FDA 
required tests for metal particles.  The Commissioner considers it a current 
industry practice for manufacturers to reduce or control the harshness and/or 
abrasiveness of ophthalmic ointment drug products that may be caused by any 
particles, including the components themselves. Components may, for example, 
contribute to harshness and/or abrasiveness of the ophthalmic ointment because 
of crystalline size and shape.  The Commissioner is retaining provisions for 
appropriate testing other than those for metal particles.  Some firms employ a 
subjective test for abrasiveness, such as rubbing a sample of the drug product 
between the fingers; the Commissioner does not consider this type of test 
adequate, however, unless the individual is qualified to conduct this 
organoleptic test.
     409. One comment called attention to situations in which the coating of 
tablets in different coating pans during the manufacturing process may affect 
the release pattern and suggested that each pan he sampled, tested, and accepted 
or rejected on an individual basis.
     The Commissioner recognizes the significance of proper coating in relation 
to its effect on the release pattern of active ingredients.  Section 211.110 
requires in-process controls to validate the performance of processes that may 
cause variability in the in-process material and the drug product.  Sections 
211.165 and 211.167 also require satisfactory conformance to finished drug 
product specifications.  While he believes this to be adequate at this time, the 
Commissioner will consider the need for more specific requirements, either in 
the general CGMP regulations or in specific CGMP regulations for sustained 
release drug products or drug product tablets, because of unique problems that 
may be presented by tablet coatings, especially if active incredients are in 
such coatings.

                    RESERVE SAMPLES

     410. Numerous comments on 211.170(a) said reserve samples of components 
need not be kept for 2 years beyond the expiration date of the products 
containing them.  There were numerous alternatives suggested, ranging from 2 
years after use of the component to 1 year after the expiration date of the last 
drug product containing the component.
     The Commissioner has concluded that the requirement for retention of 
samples for 2 years beyond the expiration date is not necessary.  The 2-year 
requirement had been proposed to make the period consistent with the present 
alternative requirement of 2 years after distribution of the last drug product 
incorporating the component, if longer than a period of 1 year after the 
expiration date.  The Commissioner is revising the final regulation in 211.170 
to require retention for 1 year after the expiration date of the last lot of 
drug product containing the component.  Where no expiration date is required, 
such as for human OTC drug products meeting the criteria for exemption under 
211.137, the retention period is 3 years after distribution of the last drug 
product lot containing the active ingredient.  The 3-year retention period also 
applies to the reserve sample of the drug product under 211.170(b) and to 
retention of records and reports in 211.180.  Appropriate revisions are made in 
the final regulations.
     411.  Several comments recommended that hazardous and unstable materials be 
exempt from the reserve sample requirement in 211.170(a).  Other comments 
suggested that inactive ingredients also be exempted.
     The Commissioner has concluded that storage of some types of materials may 
constitute an unnecessary burden or a safety problem. The section, as revised, 
will eliminate retention of inactive ingredients.  He believes that deletion of 
retention requirements for inactive ingredients will eliminate most of the 
objections regarding hazardous and unstable materials; most of those materials 
cited by respondents are used as inactive ingredients.  For those active 
ingredients that may be hazardous, though, the Commissioner concludes that the 
need for retaining samples of such active ingredients outweighs potential 
problems of storage.
     412. A comment suggested that the word "appropriate" be inserted before the 
word "tests" in 211.170(a) because some tests require extremely large quantities 
of component.
     The Commissioner understands this comment to object to maintaining reserve 
samples when the amount of material needed to conduct the required tests is 
large.  The Commissioner has concluded that the advantages of keeping such 
amounts of active ingredients outweigh any expected burden.  He advises that 
this is an existing CGMP requirement.
     413. One comment said it is not necessary to retain reserve samples of 
multiple shipments of the same lot number of components.
     The Commissioner rejects this comment.  Conditions of transit and storage 
can vary from shipment to shipment; such variable conditions can produce 
variations in the lots of different shipments.
     414. Several comments on 211.170(b) said the requirement for inspecting 
reserve samples of drug products annually is unnecessary in consideration of the 
requirement for stability studies and, further, that deterioration normally 
cannot be detected by inspection.  Other comments said FDA should clarify its 
intent whether or not inspection was meant to require complete testing and 
whether such testing would be required if such would affect the integrity of the 
sample.
     The Commissioner has concluded that the requirement for annual inspection 
is sound.  Stability studies would not, in the usual sense, provide an 
opportunity for evaluating stability on a batch-by-batch basis.  The intent of 
the regulation is not to require complete testing on each batch of reserve 
sample on an annual basis, but rather to require examination, such as would be 
done visually, and 211.170(b) is revised to so state.  The Commissioner 
recognizes that such examination would not provide the type of assurance that 
could be obtained by complete analysis, but the burden that complete testing 
would place on the industry would be unreasonable and unnecessary considering 
the requirements for establishing stability.  The Commissioner is also revising 
211.170(b) to require annual inspection only if it can be done without affecting 
the integrity of the sample.
     415. One comment said the amount of paperwork could be reduced if only 
samples that were found defective during annual inspection were recorded on the 
individual product record.
     The Commissioner does not intend that there be a requirement for recording 
the results of examination required by this paragraph in the individual batch 
record for the product, if that is what the comment suggested.  A record of 
samples must be kept so that test results can be correlated with each batch and 
the test results kept with other stability data.
     416. Several comments said the requirement for retention of reserve samples 
in the same container-closure systems in which they are marketed is impractical 
in the case of very large or bulk containers.
     The Commissioner has concluded that there are instances, for example those 
involving very large or bulk containers, where it would be impractical to store 
reserve samples in the same size containers as is used for the marketed product.  
Although the Commissioner finds that the same immediate container-closure system 
is preferred for storage of the reserve sample, he is revising the final 
regulation to allow the use of an immediate container-closure system having 
essentially the same characteristics as the marketed container.  This means, for 
example, that one size container may represent several sizes from the same 
batch, provided all containers were essentially the same except for size.  The 
storage requirements for reserve samples differ slightly from the storage 
requirements for stability study samples in 211.166 because to obtain accurate 
stability data it is essential to duplicate the conditions that could affect 
stability.

                   LABORATORY ANIMALS

     417. A comment said this section (211.173) should be deleted because the 
Laboratory Animal Welfare Act, enforced by the Department of Agriculture, 
already regulates the care and use of laboratory animals.
     The Commissioner notes that the CGMP requirements for the maintenance and 
control of laboratory animals are intended to assure that animal test results 
are valid in that the results have not been affected by the use of animals that 
may have been exposed to adverse environmental conditions.  The identification 
and maintenance of adequate records on animals are likewise intended to assure 
the validity of the test results.  The intent of the Animal Welfare Act (7 
U.S.C. 2131-2155) is, among other things, "to insure that certain animals 
intended for use in research facilities * * * are provided human care and 
treatment."  Regulations implementing that act are quite detailed, but do not 
expressly deal with the two items of most immediate concern for drug quality 
purposes.  The user of such animals for drug testing would, therefore, be 
required to comply with both the CGMP requirements of the act and the 
requirements of the Animal Welfare Act.
     418. A comment said because not all manufacturers have animal facilities, 
the regulation should make it clear that 211.173 applies only when animals are 
maintained for test purposes.
     The Commissioner believes that it is clear that if animals are not used, 
the section does not apply.  The intent of the section is not to require the use 
of animals, but rather to set standards applicable when animals are used.  
Therefore, the Commissioner sees no need to accept this comment.
     419. One comment argued that the requirement for physical separation of 
animal maintenance facilities would be an undue hardship because it does not 
allow for flexible use of space by the manufacturer.
     The Commissioner notes that 211.173 does not speak of physical separation.  
The degree of separation in maintenance and control of animal facilities should 
be sufficient to assure that animal test results are valid in that the animal 
facilities do not contribute contamination to the drug product or the 
manufacturing facilities.
     420. A comment said identification and recordkeeping for use of individual 
animals is unnecessary if the animal is used only once.
     The Commissioner rejects this comment.  Identification of each animal and 
adequate recordkeeping are a basic part of any biological test in order to 
assure accurate results.  Even rodent species used only once should be accounted 
for on an individual basis to prevent inadvertent reuse, which may result in 
inaccurate test results.   The Commissioner has dealt at some length with 
problems uncovered in reviewing drug testing in animals (see proposed 
regulations for good laboratory practice published in the FEDERAL REGISTER of 
November 19, 1976 (41 FR 51206)).

                PENICILLIN CONTAMINATION

     421. A comment on 211.176 said that because zero penicillin levels are 
required, raw material suppliers should certify that their products are 
penicillin free.
     The Commissioner believes that, although drug manufacturers can at their 
own initiative request such certification from suppliers, FDA should not require 
suppliers of raw materials to test every lot of raw materials for penicillin, 
even when no reasonable possibility exists that they have been contaminated with 
penicillin.  This would place an unnecessary burden on suppliers.
     422. A comment said FDA is not qualified to test for penicillin 
contamination because FDA receives multiple samples in the same cartons, and 
they are kept together in the same room in the testing laboratory.     The 
Commissioner has concluded that there is no basis for this comment.  Samples for 
cross-contamination testing are received by the FDA laboratory in sealed 
containers that are individually placed in sealed plastic or paper bags. 
Analyses for penicillin cross-contamination are conducted in a laboratory 
facility separate from that used for penicillin certification analyses.  
Positive and negative controls are run, and the analyses are conducted in 
laminar flow hoods under positive pressure.  Thus, FDA is quite capable of 
determining the presence or absence of penicillin contamination.

                XV.  RECORDS AND REPORTS

                  GENERAL REQUIREMENTS

     423.  Some comments on 211.180(a) objected to maintaining production, 
control, and distribution records for 2 years after the expiration date of the 
batch.  They mentioned the increased cost of record storage and noted that 
adverse reactions, complaints, recalls, and other phenomena justifying record 
storage generally occur shortly after beginning distribution.  Various time 
periods were recommended as alternatives.  Several comments suggested a 
retention period of 2 years after the batch was approved for marketing.
     The Commissioner finds that these records must be available for review for 
a reasonable time period beyond the expiration date of the products covered in 
the records to provide an opportunity for appropriate followup of any complaints 
or other adverse reports received during the entire marketing period.  In 
reconsidering the extent of such retention period in light of the comments, 
however, the Commissioner has determined that a 1-year period following the 
expiration date will generally be adequate to assure that the records will be 
available for review if necessary.  In the case of certain OTC drug products not 
being required to bear an expiration date because they meet the criteria for 
exemption under 211.137, the record retention period is 3 years after 
distribution of the batch.  This 3-year period is considered appropriate because 
the exemption is based on an assumption that such products will be used within 3 
years after manufacture.  Therefore, record retention for 3 years after 
distribution should be adequate to cover the time period during which records 
are most likely to be needed.  The Commissioner recognizes that these final 
regulations will require retention of records beyond that currently required in 
the CGMP regulations.  The CGMP regulations require the retention of certain 
records, e.g., batch production and control records, for time periods that are 
based on the distribution of the lot or, where applicable, the expiration date 
of the batch.  The current regulations do not clearly specify the record 
retention period for other records.  For some firms, the retention period for 
records will not change as a result of this regulation, as their practice is 
being incorporated in these regulations.  In other cases, however, these 
regulations will require retention of records for a period of time longer than 
the minimum retention period specified in previous CGMP regulations.  With 
specific regard to physical space for the storage of records, the Commissioner 
advises that the regulations do not generally require retention of original 
records, and that retention of suitable true copies in other forms such as 
microfilm is permitted.  The Commissioner believes that, in keeping with modern 
business practices, there are many record retention systems that would fulfill 
the intent of the record retention provisions.  Section 211.180(d) of the final 
regulations specifically provides for this flexibility.
     424. One comment said 211.180 should be deleted because section 703 of the 
act prescribes the maintenance of certain records that show the movement of 
articles in interstate commerce and does not mention the retention of records as 
described in 211.180.
     The Commissioner disagrees with this comment.  Section 703 of the act 
permits FDA access to records of interstate shipment in the possession of 
carriers (i.e., transportation companies) or other persons receiving or holding 
food, drugs, devices, or cosmetics in interstate commerce.  The provisions of 
section 703 do not apply to the manufacturers of drug products insofar as 
records of production are concerned.
     425. One comment suggested that retention of records for components that 
have an indefinite stability or components that are used only occasionally to 
produce batches of drug products be excluded from 211.180(b).
     The Commissioner rejects this suggestion.  The retention period is related 
to the expiration dates of the batches of drug products containing that batch of 
the component in order to assure that the records would be available for review 
during the marketing of the drug products and for a reasonable period 
thereafter.  The Commissioner seriously questions whether any drug product can 
be considered indefinitely stable or would in fact carry an expiration date that 
would require record retention for an extraordinarily long time.  Finally, the 
Commissioner notes that because the manufacturer has discretion to establish an 
expiration date that is less than the actual stability of the drug product, the 
manufacturer also has reasonable control over the periods during which he must 
retain records.
     426. One comment said 211.180(b) is overly inclusive and should be reworded 
to include only those components that come in actual contact with the drug 
product.
     The Commissioner is unclear on the use of the word "component" in this 
comment.   The definition of "component" appearing in the CGMP regulations would 
only include ingredients intended for use in the manufacture of a drug product, 
including those that may not appear in the final product.  Section 211.180(b) 
limits records to components actually incorporated in the drug product.  Thus, 
it seems obvious that the regulations only apply to components "that come into 
actual contact with the drug product" as requested in this comment.  Therefore, 
the Commissioner cannot agree that the requirement as proposed is too extensive, 
and he sees no justification for revisions in the language in this paragraph.
     427. Some comments suggested that reference to drug product containers and 
closures be deleted because these items are not subject to deterioration.  One 
comment suggested that the requirement be retained for parenterals only.
     The Commissioner does not agree that reference to container/closure record 
retention should be deleted because they are not subject to deterioration.  The 
Commissioner is aware that some container/closure systems are subject to 
deterioration and there are other possible problems with containers and closures 
that may adversely affect the drug product.  The purpose and intent of 
recordkeeping requirements is to be able to trace the complete history of a 
batch and thereby enable a firm and FDA to investigate fully any problems that 
may arise with either the product, the container/closure system, or both.  
Complete records would also make possible a determination of whether or not 
other batches or other drug products are or could be involved with the same 
problem. The failure to have these records available for any investigation could 
prevent the resolution of an undesirable condition. Therefore, the Commissioner 
is retaining this requirement to include all drug product containers and 
closures.
     428. A comment on 211.180(b) was submitted regarding the retention of 
records for compressed medical gases.  The comment, which assumed that 
expiration dating would not be required for compressed medical gases, requested 
a retention period to be some logical and meaningful period.
     The Commissioner finds that there is no justification for excluding 
retention of records required for compressed medical gases under this paragraph.  
The Commissioner has also decided to require expiration dating for medical 
gases.
     428a. Several comments objected to reference to recordkeeping and record 
inspection requirements in proposed 211.180 (c) and (d) insofar as they apply to 
over-the-counter (OTC) drugs and to "not new" drugs.  These comments pointed out 
that section 704(a) of the act authorizes inspection of records regarding 
prescription drugs only and inspection of records regarding research data only 
on "new drugs" subject to section 505 of the act.  One comment cited extensively 
from the legislative history of section 704 of the act indicating a 
congressional intent to limit the scope of inspection granted to FDA.
     The Commissioner has reviewed the legislative history of the 1953 
amendments (Pub. L. 83-217), which originally enacted section 704(a) of the act, 
as well as the amendments contained in the Drug Amendments of 1962 (Pub. L. 87-
781 (1961)), which extended FDA's authority to review records for prescription 
drugs under the mandatory inspection authority of section 704 of the act.  He 
finds that Congress did not include in the scope of the inspection authority 
under section 704 of the act (and its concomitant enforcement section under 
section 301(f) of the act) authority to inspect records regarding the 
manufacture of OTC drug products or research data on prescription drugs that are 
not "new drugs" as defined in section 201(p) of the act.  The Commissioner also 
finds, however, that section 704 of the act does not exhaust the varieties of 
inspections that FDA may be authorized to make regarding such drug products.
     Manufacture of any drug product without compliance with current good 
manufacturing practices renders the product adulterated, a prohibited act under 
section 301(b) of the act and a Federal crime under section 303 of the act.  
Thus, if FDA had reliable information indicating that an OTC or old drug product 
was being manufactured in violation of current good manufacturing practice, the 
agency could obtain a search warrant that would authorize FDA to inspect 
manufacturing records regarding the drug product to seek evidence regarding the 
alleged criminal offense.
     A second type of FDA inspection into OTC drug production records would be 
in conjunction with inspections under Government-wide Drug Quality Assurance 
Programs.  Manufacturers contracting to provide OTC drug products to the 
Department of Defense, the Veterans Administration, or the Public Health Service 
must, as a condition under those contracts, permit FDA to inspect the plant, 
facilities, and records regarding the product to determine compliance with the 
Federal Food, Drug, and Cosmetic Act.  If the manufacturer withdraws his consent 
for FDA to inspect, FDA will decline to accept the product on behalf of the 
purchasing Government agency, and if that agency so decides, the contract may be 
terminated.
     A third example of an inspection authorized under the act is found in 
section 505(j)(2) of the act where a manufacturer must permit inspection of 
records regarding new drugs which are required under section 505(j)(1) of the 
act; failure to do this is a prohibited act under section 301(e) of the act.   
It is conceivable that an NDA for an OTC drug would be subject to recordkeeping 
requirements regarding manufacturing activities, and if so, FDA could inspect 
these records, notwithstanding section 704 of the act.
     This does not necessarily identify all circumstances in which FDA may be 
authorized to make an inspection of records regarding the manufacture of an OTC 
drug product or research data on "not new" drugs.  See, generally, Horton, 
"Warrantless Inspection Under the Food, Drug, and Cosmetic Act," 42 G.W. Law 
Rev. 1089 (1974).
     The purpose of 211.180(c) is to assure that all appropriate records were 
properly collected, indexed, and held at the site where an inspection would 
occur so that, in the event of an authorized inspection by FDA, these records 
would be readily reviewable by the FDA inspector.  Otherwise, an unnecessary 
delay may occur if the manufacturer had to locate and collect the appropriate 
records for an inspection.  It is not the intent of these paragraphs of the 
regulations to compel a manufacturer to submit to an inspection that was not 
legally authorized.  To clarify this, the Commissioner is inserting the word 
"authorized" before the word "inspection" in 211.180(c).
     429. Several comments objected to the requirement that records be readily 
available at the establishment where such recorded activities take place on the 
grounds that most firms with multiple facilities maintain central record storage 
facilities and that compliance with 211.180(c) would require needless and 
unnecessary duplication of the records and storage facilities.  These comments 
suggested that provision be made for central record storage sites, provided that 
the requested records be made available in a reasonable period of time.
     The Commissioner does not agree with the contention that keeping these 
records or copies of them at the establishment where the activities took place 
would be unnecessary and would require needless and unnecessary duplication of 
the records and facilities. He is of the opinion that most firms today keep the 
records or copies of them at the site where they were generated.  These critical 
records must be available to both plant personnel and FDA for review.  To 
require that plant personnel and FDA investigators place orders for specific 
records to another facility and then wait for delivery would not be prudent.  
There is the distinct probability that operating under these circumstances would 
greatly extend the time needed to conduct an investigation of a problem or to 
conduct the required inspections.
     The Commissioner does believe, however, that records that can be 
immediately retrieved from another location by computer or other electronic 
means meet the requirement of being readily available at the establishment.  The 
final regulation includes this provision. As the Commissioner stated in reply to 
other comments regarding record storage, these regulations do not preclude the 
use of other record storage systems, such as microfilm or microfiche.  Where 
other systems are employed there must be associated capability for viewing and 
copying.  The final regulations include a new 211.180(d) to clarify these 
provisions.
     430. One comment suggested that the regulation provide guarantees that the 
FDA investigator will not copy these records or if they are copied, that they 
will not be released under the Freedom of Information Act.
     The Commissioner cannot agree with the first suggestion. There are many 
instances where the investigator who makes the inspection does not have the time 
to review records at the establishment for all of the facets involved.  In 
addition, this suggested provision would result in an inordinate expenditure of 
FDA resources to provide adequate time for a complete review of the records at 
the plant site.  The Commissioner believes that true reproduction of records, 
compared with handwritten copies, assures their authenticity and decreases 
inspectional time.  While the copying of appropriate records has always been 
implicit in CGMP regulations, there have been instances where investigators were 
restricted by manufacturers to handwritten copying of the records. Therefore, 
211.180(c) is being amended in the final regulation to clarify that records are 
subject to copying during the course of an inspection.
     The Commissioner also rejects the respondent's suggestion that documents 
not be released under the Freedom of Information Act. The Commissioner is 
required by law to release documents in his possession unless they contain 
information or are of such a nature that a request for release could be denied.  
In this regard, the Commissioner specifically refers to the FDA regulations 
describing public disclosure of "trade secret" information in FDA files (21 CFR 
Part 20, particularly 20.61).
     431. Numerous comments objected to 211.180(e) (proposed as 211.180(d)) on 
the grounds that the requirement for the generation of a written summary is not 
current practice and would have an unnecessary inflationary impact without any 
noticeable effect on improving the quality of drug products in general.  Some of 
these comments argued that the proposal did not specify what data were to be 
summarized.  Other respondents questioned the authority of the FDA to require 
these summaries.  Numerous additional comments were submitted suggesting that 
these summaries be prepared "when necessary" or "when needed."  Several other 
comments objected to the required retention period.
     The Commissioner has carefully considered the extensive comments regarding 
the proposed requirements for written summaries and concludes that revisions in 
this paragraph are justified.  The purpose is to provide reliable procedures for 
a manufacturer to review the quality standards for each drug product.  The 
Commissioner agrees that mechanisms other than written summaries may be 
appropriate for such evaluation.  Therefore, the final regulation is amended to 
require that manufacturers establish their own written procedures for annual 
evaluation of the quality standards for each drug product.  While not specifying 
what review mechanism must be used, the Commissioner encourages the use of 
written summaries as one practical means of drug product review. The 
Commissioner believes that some manufacturers are currently using such written 
summaries to good advantage in establishing drug product profiles.
     432. Several comments objected to 211.180(f) (proposed as 211.180(e)) on 
the basis that it is an unwarranted intrusion into corporate duties and 
responsibilities, and adherence to this requirement would not affect the 
integrity of the drug product. Some of these comments suggested an exclusion for 
small businesses because the corporate officials would be writing themselves 
reports.  Still others suggested limiting these reports to significant findings.
     The Commissioner believes there are sound reasons for this proposed 
requirement.  From time to time it has been the agency's experience that 
corporate officials have not been advised of potential or real adverse 
conditions brought to light either by the firm's own quality control system or 
by FDA.  As a result, corrective actions have not been instituted where they 
might have been, had company officials been aware of such conditions. 
Correspondence from FDA to firms regarding inspectional findings and recalls is 
directed to top officials as a matter of policy, but not all conditions 
specified in 211.180(f) are the subject of inspections or recalls, and even in 
the case of inspection and recalls there may be a period of time before FDA 
correspondence which deals with the subject is issued.  The Commissioner does 
not believe that the requirements of 211.180(f) are burdensome and is confident 
that the concept of keeping officials informed of such situations as specified 
in 211.180(f) is, for the most part, current industry practice.
     The Commissioner rejects the argument that the requirements of this 
paragraph are an unwarranted intrusion into corporate duties. They will provide 
added assurance that efforts are being directed toward the prevention and/or 
correction of conditions that could effect the quality of the drug product.  
Moreover, responsible officials already have very rigid legal duties to be aware 
of, and to take action upon, conditions contributing to drug adulteration 
(United States v. Park, 421 U.S. 658, 1975; United States v. Dotterweich, 320 
U.S. 277, 1943).
     In view of the comments, however, the Commissioner is deleting the proposed 
requirement regarding routine quarterly written reports in order to allow 
manufacturers flexibility in establishing procedures to keep appropriate 
management fully informed as to important matters involving possible quality 
control problems.  In addition, the final regulation provides an exception for 
officials, whether in large or small firms, who are personally involved or 
immediately aware of investigations, recalls, reports of inspectional 
operations, and regulatory actions relating to CGMP regulations.

             EQUIPMENT CLEANING AND USE LOG

     433. Several comments on 211.182 and 211.186 recommended that the 
requirement for signatures be deleted or modified to provide for initials, or 
other specific employee identification, e.g. an employee number.
     The Commissioner is persuaded that the requirement for a full signature may 
not be warranted in view of the space that would be required in the records and 
the burden of continually writing a full signature on records that are 
repetitive.  For less repetitive type of records, such as master records 
referred to in 211.186, the Commissioner has decided to retain the requirement 
for a full signature.  The Commissioner rejects the suggestion that a 
distinctive employee number be allowed because it would detract from the concept 
of personal involvement.  Numbers, in the Commissioner's opinion, may be easily 
recorded by persons other than those who actually perform the function.
     434. Some comments suggested that the word "strength" be deleted from 
211.182 as superfluous because this information is readily derived through the 
lot or batch number.
     The Commissioner agrees that the word "strength" can be deleted.  The 
remaining required information is sufficient to identify the batch.
     435. Several comments objected to the requirement in 211.182 that an 
individual written record of all equipment cleaning and maintenance would have 
to be double-checked and signed.  This requirement could include logs for 
stirrers, scoops, and ladles.
     The Commissioner agrees that this requirement, as proposed, could be 
construed to include such items as ladles, stirrers, scoops, spoons, and 
spatulas.  Therefore, the word "major" is being inserted before "equipment."  
This change does not affect the responsibility of assuring that all utensils and 
other equipment are properly and adequately cleaned before re-use, but only 
documentation of such activities.
     436. One comment on 211.182 doubted the need for routinely double-checking 
cleaning and maintenance.  it argued that this would require the checkup person 
to be present during the operation.  A second comment said the requirement for 
checking routine maintenance would be overly burdensome.
     The Commissioner notes that the purpose of this requirement is that a 
second person determine that appropriate cleaning and maintenance was performed.  
He does not believe that this necessitates that the person doing the checking be 
present during the entire operation.   Changes in the final regulation clarify 
this intent and also exclude from the required checking routine maintenance 
activities such as lubrication and adjustments.
     437. Several comments on 211.182 objected to keeping logs inasmuch as the 
information is readily available in other records, such as the batch record.
     The Commissioner rejects this view because in most instances batches are 
not processed consecutively on any one piece of equipment.  If the practice were 
not followed and one attempted to determine the chronological use of a 
particular piece of major equipment to ascertain, e.g., whether several batches 
were affected by a malfunction, a burdensome review of numerous batch records 
would be necessary.
     438. Some comments said logs required in 211.182 are not necessary when 
equipment is dedicated to a single product.
     The Commissioner agrees that if equipment is dedicated to the manufacture 
of one product, the requirement for individual equipment logs would not be 
necessary, provided that lots or batches of such products follow in numerical 
order and are manufactured in numerical sequence.  In such cases where the use 
of dedicated equipment is employed, the records of cleaning, maintenance, and 
use shall be part of the batch record.  The Commissioner is revising this 
section accordingly.
     439. One comment said 211.182 is an unnecessary burden on the manufacturer 
who places reliance on the drug product's final testing.
     The Commissioner is aware that dirty or poorly maintained equipment can 
introduce characteristics to a drug product that may not be detected by final 
examinations.  Moreover, it is in the manufacturer's interest as well as the 
public's to prevent quality assurance problems, rather than simply detect them.  
Therefore, the Commissioner rejects this comment.
     440. Comments objected to the requirement for one log for each piece of 
equipment containing the information regarding cleaning and maintenance when a 
portion of the cleaning or maintenance may be performed either at another 
location or by a different department.
     The Commissioner notes that it is not the intent of this section to limit 
the number of logs for each piece of equipment to one.  The intent is that there 
be one or more logs for each major piece of equipment which, in their entirety, 
contain the information required by this section.  The Commissioner does not 
believe the section implies otherwise.

           COMPONENT, DRUG PRODUCT CONTAINER,
             CLOSURE, AND LABELING RECORDS

     441. Several comments requested an exemption of veterinary drug products 
from the requirements in 211.184 (a) and (c).  For drug product containers and 
closures, it was also suggested that the section be modified to indicate that 
the requirements regarding product containers and closures should apply only to 
the drug products intended for human use.
     The Commissioner rejects these comments.  He sees no sound arguments that 
drugs intended for veterinary use should be subjected to lesser controls than 
human drug products.
     442. Several comments objected to the proposed requirements in 211.184(a) 
for the lot history of drug product containers and closures.  Comments were that 
existing controls product containers and closures are sufficient and in some 
instances the supplier's lot number and the location of the manufacturer are not 
known. Another comment expressed concern that reporting of the name and location 
of the prime manufacturer "if known" was not sufficient and such reporting 
should be mandatory.
     The Commissioner cannot agree that the information relating to the lot 
history of drug product containers and closures is not important in providing 
prompt and accurate identification of such lots, when necessary.  Generally, the 
required information is already available and recorded by most manufacturers, 
but may not have been previously organized in such a manner as to facilitate 
identification of drug product containers and closures.  The Commissioner 
acknowledges that, occasionally, information such as the supplier's lot number 
or location of the manufacturer is not known.  The proposed regulation already 
provided for the instances where the name and location of the prime 
manufacturer, when different from those of the supplier, is not known, and the 
final regulation also takes into account that a supplier's lot number may not 
always be available.  This modification, however, does not diminish the control 
over such drug product containers and closures by the drug manufacturer.  The 
receiving code, specified in 211.80, will serve to identify the received lot to 
the drug manufacturer. The Commissioner encourages all suppliers to adopt batch 
or lot identification to aid in locating components, drug product containers, 
and closures in the event it becomes necessary to do so to protect the public 
health.
     About the comment for mandatory recording of the prime manufacturer in all 
cases, the Commissioner concludes that such a requirement is not necessary.  
Because such information is usually readily available, however, and may be 
useful to the manufacturer in considering the suitability of suppliers or allow 
for tracing the complete history of the component, container, or closure, it 
should be recorded when available.
     443. One comment on 211.184(b) recommended substituting the phrase 
"subsequent disposition assigned to the material" for the phrase "conclusions 
derived therefrom" in the last line of this paragraph because under the sections 
cited in the proposed paragraph, the only possible decisions are release, 
restrict, reprocess, or reject.
     The Commissioner cannot agree with this comment and believes the comment 
may have misinterpreted the proposed requirement. Results of tests or 
examinations required under the sections cited in this paragraph are clearly to 
be included, but all tests and examinations must be considered.  There are a 
wide range of conclusions that may be drawn from results of tests or 
examinations.  For example, a test failure resulting from improper testing 
procedure would be recorded, but the lot would not necessarily be rejected based 
on that one improperly performed test.  The Commissioner finds that this 
paragraph should be finalized as proposed.
     444. Many comments addressed 211.184(c).  Most agreed that an inventory 
record and reconciliation for drug product components was appropriate, but 
objected to inventory records and reconciliation for drug product containers and 
closures.  Others contended that inventory records, but not reconciliation, were 
also appropriate for drug product containers and closures.  Arguments were 
primarily that recordkeeping to this extent was unnecessary, burdensome, and not 
current practice.  Some comments were concerned that extensive records and 
reconciliation would be required for packaging materials such as cotton filler 
material used in packaging tablets and capsules.  Several comments recommended 
changes in the proposed language that would clearly require that the inventory 
record be sufficient to establish the batch or lot of drug product in which 
component, drug product container, and closure are used.
     The Commissioner has reconsidered the need for individual inventory records 
and reconciliation of the use for components, drug product containers, and 
closures.  He finds that individual inventory records are necessary to provide 
an adequate history regarding the use of components, drug product containers, 
and closures.  To clarify the intent that such inventory records are intended to 
allow for determination as to the batch or lot of drug product associated with 
the recorded inventory, the Commissioner is modifying the proposed wording in 
this section (211.184(c) and in 211.188(g)).
     The Commissioner agrees with the comments that reconciliation of the use of 
each lot of drug product container and closure should not be required.  Although 
there are instances where such reconciliation could be valuable to the drug 
manufacturer, it should not be mandatory for all drug products and all drug 
manufacturers.  The CGMP regulations elsewhere provide considerable control over 
the approval and use of drug product containers and closures.  Because of the 
more critical nature of the ingredients on the other hand, each drug product 
component must be inventoried and its use reconciled in order to provide added 
assurance of product integrity.
     The Commissioner emphasizes that this section does not pertain to all 
packaging materials, but only drug product containers and closures.  Thus, 
individual inventory records for packaging materials such as cotton filler and 
package liners are not required under this section, although records regarding 
the receipt, examination or testing, and disposition for packaging materials 
generally are required in 211.122, particularly in paragraph (c).
     445. One comment objected to 211.184(d) on the grounds that it could be 
interpreted to require each person on the manufacturing line who makes an 
inspection to record that inspection as it is made.  The comment recommended 
deleting the word "all" from the paragraph.
     The Commissioner finds that this paragraph is intended to provide for the 
documentation of the examination of labeling as required elsewhere in the CGMP 
regulations.  To eliminate the possibility of misinterpretation, 211.184(d) is 
revised by substituting the words "the examination" for the words "all 
inspection" to conform more closely to the language used elsewhere.
     In considering the final regulation, the Commissioner finds that a new 
211.184(e) is desirable to clarify that records regarding the disposition of 
rejected drug product containers, closures, and labeling must be maintained.

             MASTER PRODUCTION AND CONTROL
                        RECORDS

     446. One comment noted that the phrase "master production and control 
records" as used in 211.186(a) was not limited to "appropriate master production 
or control records" as in 211.188(a), and requested clarification in regard to 
use of the word "appropriate."
     The word "appropriate" in 211.188(a) is intended to denote the master 
production or control record that is appropriate for the particular batch for 
the drug product.  The Commissioner believes both paragraphs as written are 
clear in this regard.
     447. Several comments argued that the "full signature, hand written" is not 
necessary and that the paragraph should be changed to allow for other means of 
identifying the persons who prepare and check the master production or control 
cards, such as initials, registered initials and/or signature stamps.
     The Commissioner believes the requirement for a full signature is 
appropriate when applied to master records.  In the past, FDA has on occasion 
found instances where firms could not identify the person or persons whom the 
initials were intended to represent. Further, the Commissioner does not believe 
this requirement to be burdensome because master production and control records 
in most cases would be infrequently established or changed.
     448. One comment proposed acceptance of other validating techniques in the 
first sentence of 211.186(a) on the grounds that verification can be 
accomplished by machine.
     The Commissioner is not aware of how master production and control records 
can be totally prepared and verified by machine. Although calculators or 
computers might assist in preparation and verification by aiding the persons 
involved, the initial information would have to be fed into the calculator or 
computer by a responsible person, and a second responsible person would have to 
verify that the hard data fed into the machine were valid.  Where appropriate, 
the use of automated equipment and computers is allowed under 211.68 provided 
hard data are kept of certain records such as master production and control 
records.
     449. One comment said the words "where appropriate" should be inserted 
after "strength" in the first line of 211.186(b)(1).
     The Commissioner rejects this comment because it is appropriate to include 
the strength of the drug product on the master production and control records.
     450. One comment said 211.186(b)(4) should be revised to require use of the 
metric system of measurement only.
     The Commissioner rejects this comment.  While the metric system is used to 
a great extent in the drug manufacturing industry, a requirement for conversion 
to the metric system as the sole method of measure could be an unnecessary 
burden upon industry at this time.  Such a requirement may be imposed in the 
future by the Commissioner, in keeping with national laws on conversion to the 
metric system and good manufacturing practice.
     451. One comment said the requirement for 211.186(b)(4) for using the same 
weight or measure system should be deleted or revised to allow firms to change 
the master formulas gradually over a period of years or as the drug product is 
reformulated.
     The Commissioner believes that the large majority of drug firms already 
comply with this requirement.  The Commissioner notes that the effective date of 
this final regulation allows sufficient time for the remaining firms to comply 
with this section and therefore rejects the suggestion that firms be allowed to 
change their systems over a period of years.
     452. One respondent recommended that the requirement for "using the same 
weight system" in 211.186(b)(4) should not be applied to veterinary drugs 
because these are often produced in large volumes or masses.
     The Commissioner finds no justification for exempting veterinary drugs from 
this requirement.  The fact that large volumes or masses are involved is not a 
convincing argument that the requirements for use of a consistent measurement 
system should not apply to the manufacture of veterinary pharmaceuticals.  Drug 
products for human use are also often manufactured in large volumes or masses.
     453. One comment on 211.186(b)(7) said repetitious calculation of 
percentage of theoretical yield adds nothing to the integrity of the product.
     The Commissioner rejects this comment.  The regulation does not require 
"repetitious" calculation of theoretical yield; instead, one calculation must be 
made part of the master production and control records, together with 
appropriate tolerances from this calculation beyond which an investigation for 
manufacturing errors would be required.
     454. One comment said the theoretical yield percentage, which if exceeded 
would require an investigation under 211.192, should not be included in the 
record as required in 211.186(b)(7) because the investigation is the 
responsibility of the quality control unit.
     The Commissioner does not understand the reasoning behind this comment.  
The fact that this information appears in master or batch records does not 
displace responsibility of the quality control unit.
     455. One comment said the requirement in 211.186(b)(7) for a statement of 
theoretical yield does not take into account that there is sometimes a shortage 
in the actual yield because a manufacturer may discard a portion of a batch due 
to a problem with the "pharmaceutical elegance" of the product.
     The Commissioner sees no reason to accept this comment.  The purpose of the 
theoretical yield requirement is to serve as an indicator of a possible error 
when compared to the actual yield. If the manufacturer can account for the 
shortage in the actual yield of the product by documenting that a definite 
portion of the lot was discarded because of its inelegance, the regulations have 
been followed.
     456. One comment argued that the label should be required to be  maintained 
on file and not physically attached to the master production or control record.
     The requirement does not state that the label has to be glued or stapled to 
the master record, for example, if this is what the respondent means by 
"physically attached."  Since 1963, the CGMP regulations have required that a 
specimen or copy of each label be included in the master production and control 
record.  This requirement is needed in order to make the master production and 
control record complete with respect to all aspects of processing, and should 
not be changed.
     457. Several comments regarding 211.186(b)(8) and 211.188(b)(8) said 
lithographed bottles, cans, and ampules cannot be kept on file.
     The Commissioner notes that the final regulations provide that a "specimen 
or copy" be included in the master and batch production or control record.  A 
photograph, photocopy, or other accurate reproduction will fulfill the intent of 
these sections.

          BATCH PRODUCTION AND CONTROL RECORDS

     458. One comment on 211.188 said batch production and control records 
should be permitted to be extensively simplified because lots are repetitive and 
are usually processed on identical equipment in an identical manner for months 
or years.
     The Commissioner notes that this comment fails to specify what 
simplifications are proposed.  The purpose of these regulations is to provide 
for a written system which, when followed, results in a reproducible high-
quality drug product.  The Commissioner believes that "simplifying" the batch 
and record controls by reducing the types of information required would have an 
adverse effect upon the quality of the drug product and would not reflect 
current industry practice.  On the other hand, use of forms to ease the 
recording of information (without omitting any) would fulfill the provisions of 
this section.
     459. A comment said there is no need to check a batch production and 
control record, as required in 211.188, if it is a photocopy reproduction of the 
master production and control record. Further comment recommended that the words 
"where necessary" be inserted after the word "accuracy" in the third line of 
211.188(a).
     The purpose of this requirement is first of all to make sure that the 
correct master production or control record has been copied.  Also while 
photocopying may be the most accurate and preferred means of producing a batch 
production and control record, no system is infallible.  For example, a spot or 
mark on the plate glass surface of the copier could result in the obliteration 
of a letter or the addition of a period onto the photocopy reproduction, and 
this might change the formula.  The Commissioner believes that the checking, 
dating, and signing of a batch production and control record is always necessary 
to assure that such records are correct.
     460. A comment said 211.188 should explicitly allow the use of batch 
production or control records produced by a computer.
     The Commissioner notes that 211.68 clearly permits the use of computers in 
the manufacture, processing, packing or storage of drug products.  Section 
211.188 does not limit the means by which a batch production or control record 
may be produced.  The Commissioner does not believe that repetitiously providing 
for the use of computers or any other means of reproducing batch production and 
control records in each section where it is applicable is necessary.
     461. Several comments said 211.188 is unclear as to what records are 
encompassed in the requirements.  Specifically, one asked whether the term 
"appropriate" in 211.188(a) allows a manufacturer to use a "manufacturing 
ticket" that does not contain all the information in the master production or 
control record.
     Although the Commissioner is not sure of the intended meaning of 
"manufacturing ticket," he notes that the word "appropriate" in 211.188(a) 
refers to the master production and control record for the size of batch, 
strength, and dosage form that is to be manufactured.  The term "appropriate" is 
not intended to allow a manufacturer to delete any pertinent information from 
the batch production and control record.  As stated in this paragraph, the batch 
production and control record shall be "An accurate reproduction of the 
appropriate master production or control record, checked for accuracy, dated, 
and signed."  If a portion of the batch production record were sent to a 
particular department that is involved only in the operation covered by that 
portion of the batch record, the Commissioner would consider that practice to be 
consistent with the requirements of this section.
     462. A comment said provisions should be made in 211.188 for batch 
production and control records only to the extent that each operation is 
performed by each establishment, because some operations such as packaging are 
often performed by another firm.
     The Commissioner advises that a new 210.2(b) is added to these final 
regulations to clarify the applicability of CGMP regulations to persons engaged 
in only some of the operations subject to these regulations.
     463. Several comments said the words "and after" should be deleted from 
211.188(b)(6) as requiring unnecessary and burdensome duplicative inspections.
     The Commissioner rejects this comment.  To prevent mixups and to reconcile 
the label count after packaging, it is necessary to inspect the premises after 
each packaging operation.  It is also necessary to inspect before the next 
packaging operation because foreign materials other than those from a previous 
packaging operation could be introduced into packaging operations.  For those 
packaging operations that are "back-to-back" with essentially no time interval, 
a single inspection will meet the requirement of 211.188(b)(6).
     464. Comment on 211.188(b)(7) said the statement of percentage of 
theoretical yield should be ascertained only at the completion of compounding 
and packaging because some drug manufacturing processes are not complicated 
operations.
     The Commissioner concludes that this section will have to be applied in 
consideration of the complexity of the processing needed for each drug product.  
The calculation of the percentage of theoretical yield only after completion of 
compounding and packaging may be appropriate in some cases where, for example, 
drug product manufacturing is not complicated.  The revised final regulation 
should clarify that this flexibility is intended.
     465. A comment said radio-pharmaceuticals should be exempt from the 
requirement in 211.188(b)(7), for developing theoretical yield data because its 
determination would involve reassay of the unused bulk radioactive material.
     The Commissioner believes that this section as revised in the final 
regulation responds to this comment in that the requirement applies at 
"appropriate stages" of processing.  The Commissioner also notes that this 
section does not specify the tolerance levels for acceptance of actual yields.  
Such levels will vary depending on the drug product being produced.
     466. Several comments said the words "or if impractical, a label revision 
number," should be inserted after "specimen" in 211.188(b)(8).
     The Commissioner rejects this comment.  This requirement provides a ready 
means for production personnel to verify visually the processing record against 
what is actually being processed and provides a more complete record than a 
label revision number might furnish.

                PRODUCTION RECORD REVIEW

     467. One comment on 211.192 indicated that accountability is of more 
concern than actual versus theoretical yields.
     The concept of accountability is implicit in the use of theoretical yields 
and particularly in the comparison made between actual and theoretical yields.  
The material produced, considering accountable losses, is the actual yield.  
Comparison of the actual yield with the theoretical yield, i.e., what should 
have been produced, requires a determination of acceptability.  The actual yield 
is acceptable if losses have been satisfactorily accounted for.
     467a. One comment proposed replacing the word "all" at the beginning of 
211.192 with "batch."
     The Commissioner agrees that the intent of this section is to require 
review of those records that directly relate to batch production and control.  
Therefore, the comment is adopted in the final regulation.
     468. A comment described the quality control unit review of production and 
control records in 211.192 as an excessive requirement because it would include 
reviews of internal manpower or labor use records.
     The Commissioner does not intend that documents outside those which impact 
on drug product identity, strength, quality, and purity should be reviewed by 
the quality control unit for release purposes.  The regulation is revised to 
clarify this.
     469. One comment proposed that a single individual should certify that the 
review for quality control considerations required in 211.192 has been made.
     The Commissioner finds that because of the wide variety of activities and 
operations which the quality control unit is responsible for approving or 
rejecting, a number of different methods of expressing or indicating approval or 
rejection may be appropriate.  For example, in some firms the "Director of 
Quality Control" may personally sign all approvals or rejections.  In other 
firms, however, the "Director of Quality Control" may delegate this 
responsibility to subordinates.  However, the Commissioner does not believe it 
is appropriate for him to dictate that specific persons be solely authorized to 
perform these functions.

                   LABORATORY RECORDS

     470. One comment suggested revising 211.194(a) by inserting the word 
"required" before "test," because not all laboratory tests are germane in 
determining the product's acceptability.  It was stated that some tests are 
primarily for informational purposes and should not be part of the records.
     The intent of this section is that laboratory records include data derived 
from tests that are necessary to assure compliance with established 
specifications and standards.  The final regulation is revised accordingly.
     471. Several comments suggested that the word "quantity" be deleted from 
211.194(a)(1) because this information is contained in other records, and the 
requirement is excessive and of no value.
     The Commissioner rejects these suggestions because it would be pertinent, 
upon review, to determine whether the size of sample drawn is representative.  A 
record of the size of the sample drawn also allows for a reconciliation of the 
amounts used for each test with the amount of total sample.  This could provide 
important information for any investigation that may be instituted following 
marketing of the batch or lot.  The Commissioner does not believe that recording 
the size of the sample is burdensome.
     472. A comment questioned the need for recording in the laboratory records 
the date of receipt of a sample by the laboratory, as required by 211.194(a)(1).  
The comment suggested use of the date of sampling instead.
     The Commissioner does not agree that recording the date of receipt of a 
sample by the laboratory is unnecessary.  Laboratories commonly log samples 
showing the date that they are received by the laboratory.  Some analyses, such 
as moisture content of a granulation, may be influenced by the elapsed time 
between sampling and assay.  It therefore becomes necessary to know both when 
the sample was drawn and when it was received by the laboratory.  The final 
regulations are revised to clarify that both the date of sampling and the date 
of receipt for analysis and testing are required.
     473. One comment on 211.194(a)(1) questioned the necessity of describing 
the sample if the other specified information is available.
     The intent of this requirement is to provide enough of a description to 
identify the sample properly, such as the name of the drug product and the form 
of the sample, e.g., granulation, raw material, or powder.  The Commissioner 
concludes that this is reasonable information to require and, that the 
requirement reflects current practice.
     474. One comment said the meaning of the words "source" and "quantity" in 
211.194(a)(1) is not clear.  The comment further stated that "quantity" could 
mean the number of sample containers, which is a reasonable requirement, or it 
could mean the weight or measure in each sample container, which is not 
reasonable.
     The Commissioner rejects the argument that the word "quantity" in the 
context of 211.194(a)(1) could be interpreted to mean only the number of sample 
containers with no reference to the amount of sample in each container.  The 
size of sample containers could range, for example, from a liter container to a 
container that holds only a few grams.  Further, the Commissioner does not 
believe this requirement to be either unreasonable or burdensome.
     The Commissioner also concludes that the meaning of the word "source" in 
211.194(a)(1) needs clarification.  "Source" of the sample is intended to mean 
the location, e.g., a specific drum number and storage area or in-process phase.  
The final regulation is revised in this regard.
     475. Several comments suggested that the last sentence of 211.194(a)(2) be 
deleted because the requirement was stated in the second sentence in this 
paragraph.
     The Commissioner does not agree with these comments.  The last sentence of 
211.194(a)(2) requires that testing methods, whether such methods have been 
developed by the manufacturer or are from official compendia, be verified under 
actual conditions of use. The Commissioner does not believe that the requirement 
in this last sentence is explicitly stated previously.
     476. One comment argued that the requirement in 211.194(a)(2) that 
laboratory records contain a statement of each analytical method used in the 
analysis of a sample should be limited to assays and should not extend to other 
tests such as physical tests.
     The Commissioner does not agree that the requirement should be limited to 
assays of components of drug products.  Tests or examinations other than assays 
are an integral part of the history of a drug product, especially in situations 
where a physical test might be as critical as an assay--for example, in 
determining particle size, dissolution rate, or tablet hardness.  Recognizing, 
however, that this section as worded in the proposal is somewhat ambiguous in  
this regard, the Commissioner is rewording the final regulation to reflect that 
the requirement applies to all tests, including examinations and assays.
     477. Several comments suggested that the words "where appropriate," "where 
meaningful," or "where required" be added at the end of 211.194(a)(3).  One 
comment reasoned that the size of the sample is not pertinent for many 
laboratory tests, e.g., melting point, infrared identification, qualitative 
colorimetric spot tests, and pH.
     The Commissioner accepts the intent of these suggestions and is revising 
211.194(a)(3) accordingly by adding the phrase "where appropriate" in order to 
provide for test procedures where a nonspecific weight or measure is used.
     478. Several comments requested deletion of the requirement in 
211.194(a)(4) to include all "graphs, charts, and spectra from laboratory 
instrumentation" in laboratory records because they are not needed and would 
create additional files.
     The Commissioner believes that all graphs, charts, and spectra used to show 
a product's acceptability must be retained for future reference.  These records 
would be needed to carry out any investigation required under these regulations.
     479. Several comments requested deletion of the requirement in 
211.194(a)(4) that laboratory records include data on testing of drug product 
containers and closures.
     The Commissioner believes that the records generated showing the 
acceptability or nonacceptability of the containers and closures are as 
necessary as those for components, in-process materials, or drug products and 
therefore rejects the request for deletion.
     480. Several comments requested 211.194(a) (4) and (5) be revised to take 
into account calculations and data derived from automatic testing equipment, 
such as computers.
     The Commissioner notes that 211.68 already provides for calculations and 
data derived from automated equipment and that such provisions need not be 
restated in every section where they would apply.
     481. In considering comments relating to proposed 211.194(a)(6), the 
Commissioner concludes that those requirements are more appropriately codified 
as 211.194(b).  Specific comments are responded to beginning with paragraph 488 
below.
     482. Some comments on proposed 211.194(a)(7) (now 211.194(a)(6)) 
recommended that the phrase "drug product container, closure" be altered to 
apply only to human drug product containers and closures.
     The Commissioner finds that recordkeeping should apply to pertinent 
information regardless of the intended use of the drug product.
     483. Several comments on proposed 211.194(a)(7) objected to requiring the 
laboratory to make a comparison of the test result against an established 
standard, especially where a standard is not known to the laboratory personnel.  
Some of these comments suggested alternative wording to clarify this.  One 
comment objected to requiring this statement if the reported result was close to 
the specification.
     The Commissioner believes there must be established standards that all test 
results are compared against, whether they be precise standards, an acceptable 
range of values within maximum and minimum values, or the absence or presence of 
certain attributes. The Commissioner does not understand how respondents would 
evaluate the significance of test results if no standards for comparison exist.  
Therefor, this requirement as proposed is retained in the final regulation.
     484. Several comments on proposed 211.194(a)(8) (now 211.194(a)(7)) 
suggested the use of alternative systems of identification instead of a full 
signature of the person who performs each assay or test.  Suggested alternatives 
were employee numbers or initials.
     The Commissioner agrees that a full signature is not needed in this 
instance and therefore is amending 211.194(a)(7) to allow the use of initials.
     485. Several comments suggested that 211.194(a)(8) (proposed as 
211.194(a)(9)) be deleted on a variety of grounds--it would be a waste of 
technical manpower; it would be inflationary; and it is not current practice for 
the veterinary industry.  Other comments suggested provision for a random review 
or the insertion of the phrase "when such records are audited."
     The Commissioner has evaluated all these comments in light of the objective 
of having independent verification of the laboratory work to insure that the 
proper procedures were used and followed, that the calculations are correct, and 
that the record is complete. A review of laboratory records is necessary to 
insure that the correct test was performed, that the calculations are correct, 
and that the record is complete.  This is not wasteful of resources or 
unjustifiably costly.
     The Commissioner finds it difficult to accept the stated premise that the 
veterinary drug industry does not review laboratory records to determine whether 
the proper tests, assays, or examinations have been performed and that the 
results are valid. It is the Commissioner's belief that drugs for veterinary 
use, like drugs for human use, must be produced under appropriate control.
     The Commissioner rejects the suggested revisions that limit the review to a 
random basis or to periodic audits.  The analytical record for each batch must 
be reviewed in order to detect whether or not the correct procedure was used, 
the calculations are correct, and the laboratory record is complete.
     486. Some comments suggested that the records reviewed need not always be 
"original."
     The Commissioner notes that "original" is used to convey the intent that 
the records reviewed be those which contain the data used in conducting tests.  
The original records give the necessary assurance that complete information is 
being reviewed.  Further, the Commissioner believes it is feasible, and does not 
believe it is burdensome, to require that the original records be reviewed.
     487. One comment suggested that the word "signature" be substituted for the 
word "endorsement" in 211.194(a)(8).
     To clarify 211.194(a)(8), it is revised to state that the records shall 
consist of initials or signature.
     488. One comment on proposed 211.194(a)(6) (now 211.194(b)) suggested 
inclusion of the phrase "or suitable reference to" after the phrase "a full 
description of."
     The Commissioner agrees that it is not necessary to describe fully a 
modification of an established method each time the method is used.  The 
Commissioner has appropriately reworded this requirement in the final regulation 
to clarify this issue.
     489. One comment on proposed 211.194(a)(6) suggested that the word "sample" 
be substituted for the word "material" because "material" is undefined.
     The Commissioner believes that the meaning of "material" is clear when 
considered in the context of this section, now codified as 211.194(b).  The term 
is used broadly to denote any materials, for example components, in-process 
materials, drug products, containers, or closures, which are tested in 
consideration of the quality of the drug product.
     490. One comment on proposed 211.194(a)(6) (now 211.194(b)) suggested that 
the word "significant" be inserted before "modification" to preclude the 
necessity of validating a minor change, such as glassware.
     The Commissioner rejects this suggestion.  If a method, when developed, 
published, and adopted, describes a procedure to be followed and types of 
materials to be used in its application, then any deviation from the prescribed 
procedures or materials may invalidate the results.
     491. Comments on 211.194 (c) and (d) (proposed as 211.194(b) and 
211.194(c), respectively) recommended substituting the word "adequate" for 
"complete" or deleting the word "complete" because these sections do not detail 
the criteria for the content of the records.
     The Commissioner rejects these recommendations because the word "complete" 
is intended to require that the records contain all the generated data of all of 
the tests performed to assure that the laboratory reference standards, reagents, 
and standard solutions are suitable for use and that periodic calibration of 
pertinent equipment was accomplished.  The Commissioner believes that it is not 
feasible to list in detail all the tests or procedures to be performed.
     492. Several comments suggested deletion of the phrase "apparatus, gauges, 
and recording devices," and others recommended deletion of the word "apparatus," 
in both 211.160(b) and 211.194(d).  One comment said this requirement, as 
stated, could be interpreted by FDA investigators as including beakers, hot 
plates, and pipette washers.
     The Commissioner notes that 211.194(d) cites 211.160(b)(4), which requires 
the calibration of instruments, apparatus, gauges, and recording devices at 
suitable intervals.  In the case of pipettes, for example, it would not be 
suitable to calibrate at intervals since under normal conditions of use their 
capacity does not fluctuate.  The Commissioner also recognizes that some 
equipment and apparatus cannot be calibrated, in which case the requirement 
obviously does not apply.
     493. Comments on 211.194(e) (proposed as 211.194(d)) pointed out that 
211.166 only requires stability testing of drug products, not components or in-
process materials; therefore, the record retention provisions of 211.194(e) 
should apply only to stability testing of drug products.
     The Commissioner agrees that the recordkeeping requirement of 211.194(e) is 
intended to apply to stability testing performed in accordance with 211.166, and 
the final regulation is revised accordingly.  The Commissioner advises, however, 
that where stability testing of components or in-process materials is conducted, 
for example, as a part of the testing program to assess the stability 
characteristics of the drug product under 211.166, the records of such stability 
testing are appropriately included under 211.194(e).

                  DISTRIBUTION RECORDS

     494. Several comments suggested that 211.196 be revised to provide that 
information required by this section be readily retrievable.
     The Commissioner notes that this is provided for in 211.150(b).  There is 
no need to repeat such a provision in this section.
     495. One comment on 211.196 said the lot or control number is not necessary 
because recalls can be accomplished by contacting every customer.
     The Commissioner does not believe that reliance on this system of 
contacting every customer in case of recall is sound.  Under such a system 
recalls could be delayed if customers who received recalled products were not 
contacted because they were not customers at the time of initiation of the 
recall.  Conversely, customers who never received the product could be 
contacted, thus taxing the resources of the firm and FDA.  A blanket recall 
might also cause unneeded patient anxiety and even drug shortages. Additionally, 
the Commissioner does not believe that the same accountability for each lot is 
inherent in a system that relies on contacting every customer.  The amount of a 
recalled product that each customer received may be necessary information if the 
danger to health is severe enough to require that each unit of a recalled drug 
product be accounted for.
     496. One comment on 211.196 questioned the necessity for a lot number on 
distribution records being maintained by suppliers of compressed medical gas.
     The Commissioner strongly believes that the requirements of this section 
should apply to compressed medical gas fillers. Compressed medical gases are 
potent drug products and, for example, a mixup in labeling of cylinders could 
constitute a most serious health problem.  It could be imperative that every 
cylinder of a particular lot be accounted for.  The Commissioner realizes that 
usually, compressed medical gases are distributed within a relatively small 
geographical area and to a limited number of customers, but this is not a 
sufficient reason to exempt suppliers from the requirements of this section.  
The requirements of 211.196 should not constitute a major burden on this 
industry in view of the limited number of customers that are typically serviced 
by one establishment.
     497. One comment on 211.196 questioned the appropriateness of a customer 
code number on the distribution record in place of the customer's name and 
address if there is a breakdown of the code.
     The Commissioner would deem the use of this type of system to be in 
compliance with the requirements of this section as long as adequate controls 
are employed to insure the accuracy of the code and legibility on the 
distribution record.

                    COMPLAINT FILES

     498. Many comments addressed 211.198(a).  The comments mostly objected to 
designation of the quality control unit for reviewing all complaints.
     The Commissioner has considered the extensive objections and concludes that 
revisions are necessary to clarify the intended requirements regarding complaint 
files.  As indicated in the preamble to the February 13, 1976, proposal, the 
object is to specify more clearly how complaints regarding drug products are to 
be handled.  It is not FDA's intention to restrict or limit review of such 
complaints to any one unit in the firm's organization, but to assure that the 
quality control unit is properly involved. Where there is a complaint involving 
the possible failure of a drug product to meet any of its specifications, the 
quality control unit is probably the most appropriate unit to determine whether 
an investigation under the procedures described in 211.192 is required.
     To provide manufacturers with as much latitude as possible for efficient 
review of drug product complaints, the final regulations provide that written 
procedures for handling complaints include review by the quality control unit 
where there is a possible failure of a drug product to meet its specifications.
     The final regulations also provide that in such instances the quality 
control unit shall make a determination as to the need for an investigation in 
accordance with 211.192.  This provision allows judgment in determining the 
extent of the investigation.  To safeguard against perfunctory review of 
complaints, 211.198(b) requires a statement of the rationale for determining 
that no investigation is necessary and the identity of the person making that 
determination.
     499. The comments regarding the recordkeeping provisions of 211.198(b) 
objected primarily to the proposed requirement that companies that have more 
than one establishment maintain a copy of each complaint record at the 
establishment where the drug product involved was manufactured, processed, or 
packed (but not necessarily at every establishment where held only).  A number 
of firms indicated that reports of complaints are currently centralized at one 
location, which often is the headquarters office.  The comments were that 
duplicate records required at several locations would be confusing, and it would 
be difficult to be certain that every such record is complete.  The comments 
also cited increased use of electronic and/or mechanical systems at central 
locations to store and retrieve data and records.
     The Commissioner finds that some revisions in the proposed requirements are 
justified.  He recognizes that many firms with multifacility operations depend 
on centralized systems to analyze, review, and even investigate complaints 
involving drug products. Therefore, the final regulations provide that the file 
designated for written records of drug product complaints may be at a central 
location provided that the written records are available for inspection.  Where 
an investigation under 211.192 is actually conducted, 211.180(c) requires that 
records or copies of records of the investigation be readily available at the 
establishment where the activities described in the records occurred.  This 
means that a record of an investigation conducted under 211.192 must be 
maintained at the establishment where conducted, but that other records (e.g., 
of a medical investigation) regarding the drug product complaint may be 
maintained at a central location.  The Commissioner believes that the provisions 
of 211.198 will provide sufficient information regarding complaints about drug 
products that can be identified as to the point of manufacture.
     Where no investigation under 211.192 is conducted for a drug product 
complaint, the final regulations require, as was proposed, that the written 
complaint record include the reason that no investigation is necessary and the 
name of the responsible person making such a determination.  Because no 
investigation under 211.192 will have been conducted, and, in some cases, the 
point of manufacture cannot be ascertained, the Commissioner finds that the 
written record or a copy of it may be maintained at the place of manufacture, if 
known, or alternatively at a facility where it would be readily available for 
inspection.
     500. Many comments objected to the 2-year retention requirement for records 
under 211.198.
     The record retention period is revised in line with other sections.

            XVI.  RETURNED AND SALVAGED DRUG
            PRODUCTS, RETURNED DRUG PRODUCTS

     501. A number of comments said 211.204 implies that a returned drug product 
must either be destroyed or reprocessed; an argument was made that reshipment of 
goods "as is" should not be excluded as a possibility.
     The Commissioner does not believe that the section as worded excludes the 
possibility of reshipment "as is."  As it applies to destruction or 
reprocessing, 211.204 concerns returned drug products that have been held, 
stored, or shipped, before or during their return, under conditions that case 
doubt on their integrity. This section does not prohibit reshipment without 
reprocessing of a drug product if its integrity was never in doubt, or if 
initially in doubt, subsequent investigations prove the drug product 
satisfactory.  To preclude the possibility of misinterpretation, however, the 
Commissioner is revising this section in the final regulation.
     502. One comment recommended that reshipment of returned drug products to 
charitable organizations should be exempt from the requirement in 211.204 for 
recording quantities or lot numbers.
     The Commissioner does not believe that shipments of drug products to 
charitable organizations should be any less controlled than drug products 
shipped to other categories of consumers.
     503. Several comments said bioavailability is merely one facet of drug 
quality, and there is no need to mention it separately in 211.204.  Another 
comment said mentioning bioavailability is inappropriate for CGMP regulations.
     The Commissioner finds that bioavailability is only one facet of drug 
quality and finds that it is unnecessary to mention only one of many facets that 
could be listed.
     504. One comment on 211.204 said the only true measure of bioavailability 
is in vivo testing and that in vivo testing of returned goods is neither current 
practice nor realistic.
     The Commissioner notes that bioavailability testing is not necessarily a 
requirement for releasing returned goods.  If conditions were such that doubt 
was cast on a drug product's bioavailability, then suitable bioavailability 
testing would be required before the returned product could be released for 
distribution.  Tests for bioavailability other than in vivo testing are 
recognized by FDA as valid in appropriate cases.
     505. Several comments argued that the recordkeeping provisions of 211.204 
are unnecessary, redundant, and unduly costly for many operations.
     The Commissioner does not agree with this position.  He does not believe 
such recordkeeping to be unduly burdensome.  This section does not require 
separate records for returned goods containing all the information required by 
this section, but rather requires firms to be able to identify which, if any, 
drug products have been returned and for what reason, and to be able to 
determine their disposition.  The section would not prevent, for example, the 
disposition portion of the records on returned goods from being a part of normal 
distribution records if the lot involved were reshipped.
     The Commissioner does not agree that the requirements for returned goods 
are unnecessary.  For example, a portion of a lot of drug product may be 
returned because of unusual shipping conditions and the rest of the lot remain 
in normal trade channels.  If the returned portion of the lot were destroyed and 
no record were made, there would be an incomplete record of distribution for the 
lot. In the case of recall, for example, a part of the lot could not be 
accounted for.
     506. One comment on 211.204 said a record of the lot number and other 
required information need not be retained in the case of returned goods that are 
destroyed.
     The Commissioner rejects this comment.  Accountability could not be 
accomplished in determining the distribution of a lot of drug product if 
destroyed products were exempt from this requirement.
     507. One comment on 211.204 recommended that time limits be established for 
destruction or reworking a returned drug product--a maximum 30-day time limit if 
destruction is the course of action, and 60-days if it is reprocessed.
     The Commissioner finds no justification for establishing such arbitrary 
time limits.  That processing must not go beyond appropriate limits is 
adequately covered elsewhere in these regulations.
     508. One comment on 211.204 noted that the reason for the return was 
omitted from the items to be included in the records.
     The Commissioner believes that the reason for return is of primary 
importance and should be specifically included in this section.  Therefore, the 
section is revised accordingly in the final regulations.

                 DRUG PRODUCT SALVAGING

     The drug product salvaging provisions of these regulations were proposed on 
two separate occasions--in the FEDERAL REGISTER of January 16, 1975 and February 
13, 1976.  The comments discussed here include those received after both 
proposals were published.
     509. One comment said 211.208 could be interpreted as applying also to in-
process materials unless further specified.  It suggested that the title of the 
heading be changed to "Packaged Drug Product Salvaging."
     The Commissioner finds there is no suggestion that this section applies to 
in-process materials.  The section clearly refers to drug products, and that 
term is defined in 210.3.  The control of in-process materials, also defined in 
210.3(b), is covered elsewhere in Part 211.
     510. One comment argued that 211.208 is contradictory in that it prohibits 
salvaging and return of drug products to the marketplace, and then permits such 
procedures.
     The Commissioner disagrees with this comment.  The section prohibits the 
salvaging of drug products and/or return to the marketplace when the drug 
products have been exposed to improper storage conditions.  The purpose of this 
section is to provide for an appropriate procedure for determining the 
suitability of salvaging drug products that may have been exposed to such 
conditions.  The Commissioner believes that this section is adequately worded to 
convey its meaning.
     511. Another comment recommended that the wording of 211.208 be changed to 
allow manufacturers to determine what testing accurately reflects the condition 
of the product.
     The Commissioner rejects this comment.  The requirements of this section 
are the minimum procedures necessary to assure the safety and quality of drug 
products that may have been exposed to improper storage conditions.
     512. A comment said it is unclear when 211.208 applies and when 211.204, 
"Returned Drug Products" is applicable.
     The applicability of these sections depends on the history of the drug 
product.  Section 211.204 is revised to require that the reason for return be 
included in the records pertaining to the returned drug.  If the drug product is 
being returned because of possible exposure to improper conditions, the drug 
product salvaging requirements of 211.208 must also be applied.  The 
Commissioner believes that both sections clearly state their intent.
     513.  One comment said the phrase "evidence that the product meets all 
applicable standards of identity, strength, quality, and purity" should be 
deleted throughout 211.208 because it is unnecessarily detailed and restrictive.
     The Commissioner does not understand how the requirement that a drug 
product meets all applicable standards of identity, strength, quality, and 
purity could reasonably be considered either too detailed or too restrictive.  
Anything less would not assure the quality and safety of the drug product or 
that the product was not adulterated under the act.  Therefore, the comment is 
rejected.
     514. A number of comments on 211.208 expressed concern that manufacturers 
and/or distributors do not have absolute control over a drug once it leaves 
their premises, and without evidence of proper control, drugs could not be 
returned under the proposed regulations, even in the normal course of a firm's 
business.  They cited examples such as returning overstocked items, drugs which 
were ordered or distributed in error, seasonal items, recertified antibiotics, 
or drugs requiring relabeling.
     The Commissioner finds that the CGMP regulations do not prohibit drug 
products; being returned.  The regulations clearly allow redistribution of 
returned drug products that meet applicable standards of safety, identity, 
strength, quality, and purity.  If there is no question whether the drug 
products have been properly stored after leaving the manufacturer's control, the 
testing requirements of 211.208 do not apply.
     515. Three comments concerned the interpretation of "prolonged storage" in 
211.208.  One comment recommended that this term be deleted; another recommended 
that it be revised to specify a period of time.  One comment assumed that a 5-
year maximum is preferred by FDA and could be a basis for defining "prolonged 
storage."
     The Commissioner finds that, in view of the requirements regarding 
expiration dating of drug products, the proposed reference to prolonged storage 
in 211.208 is unnecessary.  The Commissioner concludes that this section should 
be further revised for simplicity, by referring to "improper storage conditions" 
rather than "improper storage or abnormal environmental conditions."
     516. One comment on 211.208 recommended that organoleptic examinations be 
considered acceptable as evidence, provided such a determination is made by a 
pharmacist or chemist having 1 year's experience in the field.
     Organoleptic examinations alone would never be enough to insure that a drug 
has maintained its strength, purity, and quality after it has been in a 
situation where it may have been exposed to improper storage conditions.  
Therefore, this comment cannot be accepted.
     517. One comment recommended that 211.208 provide for reclaiming of active 
ingredients from drug products that have been salvaged.
     The Commissioner finds that drug products that have been subjected to 
improper storage conditions should not be salvaged because of the resulting 
questionable integrity of the drug product.  Therefore, such drug products are 
clearly not suitable for reprocessing, including reclaiming of active 
ingredients. However, where salvaging is permissible under the provisions of 
211.208, any appropriate reprocessing is allowed.  The Commissioner believes the 
regulations are clear in this regard.

             XVII.  CGMP FOR CERTAIN OTHER
                     DRUG PRODUCTS

     518. No comments or objections addressed proposed revocation of 229.25.  
Section 229.25 is the only section contained in Part 229 (21 CFR Part 229), and 
the Commissioner sees no immediate need for retaining that part as currently 
used.  Therefore, the entire Part 229 is revoked in these final regulations and 
reserved for future use.
     The Commissioner has carefully considered the environmental effects of the 
proposed regulation and, because the proposed action will not significantly 
affect the quality of the human environment, has concluded that an environmental 
impact statement is not required. A copy of the environmental impact assessment 
is on file with the Hearing Clerk, Food and Drug Administration.
     Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 501, 502, 
505, 506, 507, 510, 512, 701, 52 Stat. 1049-1053 as amended, 1055-1056 as 
amended, 59 Stat. 463 as amended, 76 Stat. 794 as amended, 82 Stat. 343-351 (21 
U.S.C. 351, 352, 355, 356, 357, 360, 360b, 371)) and the Drug Listing Act of 
1972 (Pub. L. 92-387; 86 Stat. 559-562) and under authority delegated to the 
Commissioner (21 CFR 5.1), Chapter I of Title 21 of the Code of Federal 
Regulations is amended as follows: