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[4110-03] 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, Pack-Ing, or Holding
AGENCY: Food and Drug Administration. ACTION: Final rule. SUMMARY: This document amendsthe FDA regulations that set forthcurrent good manufacturing practice(CGMP) for human and veterinarydrug products. The amendmentsupdate present regulations in light ofcurrent technology for drug manufacturing and delineate requirementsmore specifically than do the presentregulations. Although some of the provisions in these amendments representrequirements not specifically includedin the existing CGMP regulations, inmany instances the revisions are practices that have been considered implicit in the regulations or are at leastconsidered by most manufacturers tobe desirable- requirements for theirown operations.
Under the Federal Food. Drug, andCosmetic Act, a drug is deemed to beadulterated unless the methods used in its manufacture, processing. packing. and holding, and the facilities andcontrols used therefor, conform to current good manufacturing practice sothat the drug meets the safety requirements of the act and has the identity and strength and meets thequality and purity characteristics thatit is represented to have. The regulations are being updated and mademore explicit, and therefore less subject to varylng interpretations, to assure that all members of the drugindustry are made aware of the levelof performance expected of them to bein compliance with the act. EFFECTIVE DATE: March 28.1979. FOR FURTHER INFORMATIONCONTACT:
Clifford G. Broker (HFD-323) (301443-5307). or Robert J. Rice, Jr.,(HFD-30) (301-443-5220), Bureau of Drugs, Food and Drug Administration, Department of Health, Education, and Welfare, 5600 FishersLane. Rockville, Md. 20857.
RULES AND REGULATIONS
SUPPLEMENTARY INFORMATION:In the FEDERAL REGISTER of February13. 1976 (41 FR 6878). the Commissioner of Food and Drugs proposed torevise the CGMP regulations, Parts210 and 211 (21 CFR Parts 210 and211). issued under section 501(a)(2)(B)of the Federal Food, Drug, and C o s metic Act (21 U.S.C. 351(a)(2)(B)). toupdate them in light of current technology and to adopt more specific requirements to assure the quality offinished drug products. Because of thenature and extent of the proposed revisions, the Commissioner alloweduntil June 14, 1976, for interested persons to submit comments.
The Commissioner received comments from 168 respondents totalingapproximately 2,000 pages. These comments represent many interests - individual consumers; nonprofit institutions or associations: health-care departments of hospitals, colleges, anduniversities: State and foreign health-care organizations; domestic and foreign drug manufacturers, repackers.and distributors; consultants to thedrug industry; drug equipment manufacturers; and numerous trade andprofessional associations representingmanufacturers, repackers, distributors,consulting engineers, and professionals in the health-care system.
In general, the comments supportedthe Commissioner’s concern for the availability of uniformly high qualitydrug products. Consumers, in particular, expressed strong support for theproposed 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 mostof the proposal.
The Commissioner is pleased to notethat where differences existed, manyinterested persons furnished alternative wording and justification in sup-Port of such ‘alternatives. The Commissioner has carefully consideredevery comment and all suggested alternatives. The final regulation, setforth below, adopts a number of therecommendations submitted. Certainother recommendatlons, not adoptedat this time, may be considered in anyfuture proposed revisions.
During the past several years, theFDA has issued a number of FEDERAL REGISTER documents relating toCGMP regulations, specifically Parts210 and 211. The following summarywill help clarify the status of thesevarious documents.
1. A proposal on returned and salvaged drug products appeared in the
IX. Buildings and Facilities (paragraphsFEDERAL REGISTER of January 16, 1975127 to 164). (40 FR 2822) and was reproposed as X.Equipment (paragraphs 165 to 198).§ 211.208 (21 CFR 211.208) in the FED- XI. Control of Components and DrugERAL REGISTER of February 13, 1976 ($! Produc t Containers and Closures (para-FR 6870). Comments on both propos- graphs 199 to 262).
als were reviewed and considered in preparing the final regulations Setforth in Part 211 below.
2. A proposal on CGMP regulationsfor human and veterinary drugs appeared in the FEDERAL REGISTER ofFebruary 13, 1976 (41 FR 6878). Thatproposal is the basis for the subjectfinal 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, 1978 (41 FR 16932) amended Part 211 (CGMP reg.ulations) by eliminating reference toglass-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 filterswould be deleted from the final regulation.
4. A proposal on CGMP regulationsfor large volume parenteral drug products (LVP) for human use was published the FEDERAL REGISTER ofJune 1. 1976 (41 FR 22202). The proposal would add a new Part 212. Comments were due by September 29. 1976and 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 222193. and the time for submitting comments was extended to October 29, 1976 by notice inthe FEDERAL REGISTER of September10, 1976 (41 FR 38540). Comments arebeing reviewed, and a specific proposalmay be published in the future.
The comments and recommendations regarding the January 16. 1975and February 13, 1976 proposals, theApril 23. 1976 amendment to the latterproposal, and the Commissioner’s conclusions concerning them are set outbelow.
TABLE OF CONTENTS FOR PREAMBLE
I. General Comments (paragraphs 1 to12).
I I . Terminology and Language in these Regulations (paragraphs 13 to 18).
III. Amendments Regarding Placement ofExpiration Date on Drug Product Labels (paragraphs 19 to 27).
IV. Amendments Regarding Drug Listing and Establishment Registration Requi rements 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 (para
graphs 89 to 126).
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45015 RULES AND REGULATIONS
XII. Production and Process Controls (paragraphs 263 to 310). XIII. Packaging and Labeling Control
(paragraphs 311 to 373). XIV. Holding and Distribution (para
graphs 374 to 379). XV. Laboratory Controls (paragraphs 380
to 422). XVI. Records and Reports (paragraphs
423 to 500). XVII. Returned and Salvaged Drug Prod
ucts (paragraphs 501 to 517).XVIII. CGMP for Certain Other Drug
Products (paragraph 518).
1. GENERAL COMMENTS
1. Many comments were received regarding the need for the proposedchanges in the CGMP regulations. Anumber of comments from individualconsumers, a State consumer servicesorganization, and a national association of health-care professionalsstrongly fuvored new or revised regulations that would improve the level of assurance that marketed drug products meet hlgh quality standards,Many other comments, particularlyfrom 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 theproposed changes, maintaining thatdrug quality would not be improved bythe proposed changes and that thecosts outweigh any benefits.
The need and rationale for an overall revision and for specific changes inthe CGMP regulations are discussedat 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 bymost manufacturers since the CGMPregulations were promulgated in 1983and last updated in 1971 mean thatthe “current good manufacturingpractice” reflected in the existing regulatlons are no longer “current” inmany respects and are not suited tocurrent manufacturing techniques. Inaddition, many requirements prompted questions about interpretation, vagueness, and omissions. The proposal was intended to solve many of theseproblems. Interested persons wereurged to revlew the proposal carefully,to identify any areas that might require clarification or modlflcatton. andto submit reasoned comments withsuggested alternative language. Theperiod provided for public commentwas 120 days instead of the usual 60days because of the length of the proposal; the novel, controversial, or complex nature of some of the proposedprovisions; and the desire to give affected persons ample time for revlew
and preparation of extensive comments.
Having reviewed the preamble of theFebruary 13, 1978, proposal and theextensive comments, the Commissioner is satisfied that an updating of theCGMP regulations is necessary anddesirable. Therefore, most of the February 13, 1976, proposal has beenadopted, but wlth numerous textualchanges, many of which are basedupon alternative language suggestedin the comments. In evaluating eachcomment, the Commissioner considered whether drug product qualitywould be assured, compromised, or unaffected by the adoption or deletion ofa regulation, as well as whether it reflected a current practice in the industry and its benefits appeared tooutweigh its costs. The Commissioneris promulgating those regulations embodying contemporary practices thatwill maintain or improve the quality ofpharmaceuticals without imposing unreasonable or excessive costs or otherburdens on manufacturers. Modifications were adopted, or decisions weremade not to finalize particular aspectsof the proposal, in order to add flexibility for manufacturers, to relieve oreliminate unjustified cost burdens, orto clarify the requirements, withoutadversely affecting the best interestsof the consumer.
The agency has completed a detailedcost analysis based on informationsubmitted by interested persons whocommented on the economic impactassessment of the proposal. This issueis discussed in a revised economicimpact assessment available at theofflce of the Hearing Clerk, Food andDrug Administration. For the reasonsset forth in the agency’s economicimpact assessment, in is believed thatthis final regulation will not causemajor economic impact, as defined byExecutive Order 11821 (as amended byExecutive Order 11949), and OMBCircular A-107.
2. A number of comments said the proposed CGMP regulations wouldimpose rigid and inflexible standardsthat would curtail progress and discourage technological innovations.Others said the proposed regulations were so detailed that sound judgmentby the manufacturers and by inspecting FDA investigators could not beused.
The Commissioner is keenly awarethat the general CGMP regulationsmust apply to a wide variety of drugproducts. Therefore, the CGMP regulations in Part 211 are intended to begeneral enough to be suitable for essentially all drug products. flexlbleenough to allow the use of sound Judgment and permit innovation, and explicit enough to provide a clear understanding of what is required. Theagency has received numerous inquir
ies requesting clarification of certainprovisions, and it sought to removeambiguities by this revislon. In finalizlng these revisions, the Commissionerhas considered past. experience, thepurposes of the CGMP regulations,the need to balance specificity and clarity with flexibility in attainingthese purposes, and the comments received in response to the proposal. Anumber of changes have been made inthese final regulations to reflect thebroad applicability of, to allow flexibility in, and to encourage innovationwithin the CGMP regulations. Theagency does intend to issue more specific CGMP regulations for uniqueclasses of products as one means ofclarifying these regulations. The Commissioner welcomes suggestions andpetitions from interested persons whofind deficiencies. excessive burdens, orinflexibility in these regulations andwho identify innovative and more efficient ways to achieve the goals ofthese regulations.
3. A number of comments addressedthe so-called “how to” versus the “what” argument; that is, the proposed CGMP regulations describe“how” a particular requirementshould be achieved rather than specifying “what” it is that is to beachieved. Many comments recommended that the regulations establishonly objectives or specifications andallow each manufacturer to determinethe best method of attaining the objective or meeting the specification.For example, one comment proposedthat FDA require positive identification of a person rather than specifyingthat a signature be used-this wouldallow use of other means of identifying a person, such as an identifyingnumber or initials.
The Commissioner believes that.with relatively few exceptions, theCGMP regulations do describe “what”is to be -accomplished and providegreat latitude in “how” the requirement is achieved. For example, writtenrecords and procedures are required,but FDA will recognize as satisfactoryany reasonable format that achievesthe desired results. Because of theneed for uniformity in certain areas of the CGMP regulations that have presented problems in the past, however,there are some Instances where it isdesirable to specify the manner inwhich requirements are to be accomplished. In promulgating these regulations, the Commissioner carefully reconsidered the need for such specificity where it appears and adopted onlythose specific requirements that arefully justified.
4. One comment, flled by an FDAemployee, recommended that self-inspection and performance auditing programs within the industry be a requirement under the CGMP regula-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
A
45016 tions to assure the reliability of drugproducts and to prevent release of defective products.
The Commissioner finds that theconcept of self-inspection and performance auditing has considerablemerit. The’ pharmaceutical industryhas made great efforts to develop self-evaluation programs, frequently usinga team of inspectors composed, at leastin part, of people from outside the area or firm being audited. The scope,elements, and intensity of such programs, however, vary from elaboratedetailed audits to rather superficial inspections conducted perhaps once ayear. The agency has considered suchprograms in the past, but has concluded that the essential elements of abeneficial program have not yet beensufficiently defined or tested. Moreover, because of the significant impactthat a requirement for self-inspectionwould have on the industry and because only one comment regardingself-inspection was received, the Commissioner concludes that furtherpublic discussion is desirable before aspecific proposal or regulation isissued.
5. One comment suggested that aproduct defect surveillance and reporting system requirement similar to thesystem developed and operated by theUnited States Pharmacopeia (U.S.P.)be a part of the CGMP regulations.The suggestion would require full participation by manufacturers, ratherthan voluntary participation, in asystem of identifying defective products, removing them from the market,and investigating the cause of thedefect.
The Commissioner notes that the Drug Product Defect ReportingSystem maintained by U.S.P. is designed to identify drug product complaints from various sources otherthan the manufacturer, such as pharmacies and hospitals, and to facilitatetransmission of this information tothe manufacturer and to FDA. Thevalue of such a reporting system is inits broad source of information. TheCGMP regulations in part 211. however, apply- only to manufacturers ofdrug products. Section 211.198 (21 CFR 211.1981 addresses the handlingof reports to the manufacturer aboutdrug product defects and requires thatmanufacturers investigate complaintsthat may have a bearing on drug product quality. Such information is subject to review by FDA.
6. Comments regarding the effect ofthese 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
RULES AN D REGULATIONS
work mandated by some of the Proposed requirements. The commentsalso expressed concern about theavailability of qualified personnel inthe health-care system and the abilityof the industry to attract such qualifled persons for relatively unimaginative duties. They suggested that theuse of a different instrument in thechecking procedure would, in some instances. offer a better chance of detecting an error than would a systemthat relies upon independent verifications by different persons using thesame instrument.
The Commissioner recognizes thatemployee interests and motivation play a major role in assuring drugproduct quality, as described in thepreamble discussion for the proposed§ 211.25, relating to employee training,for example. Good employee moraleand work motivation are highly desirable in any work situation. Because ofpotential employee resentment of anintensive “check system,” the Commissioner has considered alternatives andthe consequences of no independentverification. The requirement for verification applies to functions that involve human judgment and consequently are susceptible to humanerror. The results of such errors, if undetected and uncorrected, can include,for example, improper formulationsand improper release of drug Productsbecause of incorrect laboratory calculations. Independent verification isgenerally considered a “current” practice, not only in the drug industry butelsewhere, as a way to reduce the riskof human error. The intent of such acheck is to verify that the procedureor work was performed. It is a necessary function in the manufacture ofdrug products and is already requiredin the existing CGMP regulations.The Commissioner believes that, whileemployees may not always welcome independent verification, most accept itas a condition of their particular assignments. Given the possible seriousconsequences of errors, the “checksystem” requirement does not seem tobe 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 secondperson, is a procedure that has merit.The Commissioner encourages the useof such a procedure, but has concludedthat a separate instrument for independent measurements would be acostly and unnecessary requirement inthe CGMP renulations. These regulations separately mandate an equipment calibration and maintenance program to assure proper performanceand safeguard equipment accuracy.
7. Several comments indicated a general interest in bioavailability and
bioequivalence requirements for drugproducts. Because of the importanceof bioavailability and bioequivalenccto safe and effective use of drug Products, these comments encouraged FDA to issue regulations establishing necessary requirements to assure this typeof 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 ofJune 20. 1916 (40 FR 26157 and 26164) and made final in the FEDERAL REGISTER of January 7.1977 (42 FR 16241.
8. Several comments were received regarding written procedures to describe specific manufacturing and control operations. In general the comments agreed that written procedureswere suitable in many instances, butwere not required for every operationinvolved in the production and controlof drug products. Specific examples were cited as requiring excessive andunnecessary written procedures. Themost common example cited was§211.67(b), which proposed, in part,that there be written procedures assigning responsibility for cleaning andmaintenance and describing in detailthe maintenance and cleaning schedules, the methods, equipment, and materials to be used, and the methods ofdisassembling and reassembling allequipment used in the manufacture,processing, packing, or holding of adrug product. The objection to the requirement of this instance appears tobe in reference to "all" equipment.
The requirement for written procedures is intended to provide additional assurance of effective communication of appropriate information from firmmanagement to line personnel and ofregular performance of a firm’s established programs and procedures. It. isnot enough that employees “know their jobs.” Key personnel may beabsent without warning; personnelsubstitutions involving less experienced employees may be necessary;and new or revised instructions to employees must be adequately conveyedto those who need to know. These situations are not usual, but may occurfrequently. The most appropriatemethod for reliably relating policiesand procedures to those who mustknow them is to have them set downin 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 samecleaning schedule could be consideredtogether for convenience and would be
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in compliance with requirements of§ 211.67(b).
9. One comment suggested that written procedures are changed frequentlyand the regulations make no Provisions for dating the written proceduresand retaining outdated written procedures. The comment pointed out thatthe outdated procedures may be ofsome value in following up problemsthat may have occurred during theperiod that the written procedureswere in effect.
The Commissioner has carefullyconsidered the merits of this suggestion and concludes that specific provisions for the dating and retention forall written procedures are not neededat this time. The regulations alreadycontain this type of requirement forcertain records such as master andbatch production control records. Forother procedures. it is preferable foreach manufacturer to develop hisscheme for dating, replacing. and retaining written procedures.
10. One comment recommended thatFDA provide a complete set of correctmodel forms for use by individualfirms in their own recordkeeping. Thecomment suggested that the modelforms could be a part of the CGMPregulations, or FDA could furnishsuch information separately.
The Commissioner does not find sufficient need at this time to warrant development of such model forms. TheCGMP 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 ofmanufacturers subject to the CGMP regulations, the Commissioner is notconvinced that model forms would beso adaptable as to be useful for a majority of firms. If, however, future experience with these CGMP regulationsindicates that model forms issued asguidelines would be helpful, the Commissioner will reconsider the matter.
11. A respondent suggested promulgating the regulations under section701(e) of the Federal Food, Drug, andCosmetic Act (21 U.S.C. 371(e)) to giveopportunities for hearings on, and Judicial review of. these regulationsbefore they take final effect.
The authority to promulgate theregulations for the enforcement of thecurrent good manufacturing practiceprovisions of the act rests specificallyin section 701(a) of the act. As notedin paragraph 35. Congress voted in1962 not to require that CGMP regulations be issued under the proceduresset forth in section 701(e) of the act.The Commissioner could elect tofollow a procedure similar to that insection 701(e) of the act and hold alegislative type of hearing on Specificaspects of this proposal under 21 CFR
RULES AND REGULATIONS
Part 15. After an extensive review ofthe numerous comments, however, hehas decided that there are no particular portions of this regulation whichneed a further presentation of information or arguments. Any interestedperson may submit a petition under 21CFR 10.30 to the Commissioner requesting such a hearing and shouldidentify with specificity and supporting explanations the issues that mightbe heard. No such petition will, however. automatically delay the effectivedate of these regulations, as would be the situation under section 701(e) ofthe act; the Commissioner will grant adelay only if clearly justified.
12. In reference to the proposed requirement in §211.184(a), that theprime manufacturer, if known, belisted, one comment recommendedthat the CGMP regulations requirethat the name and lot number of theoriginal manufacturer of the finaldrug product be part of the labeling.
The Commissioner recognizes that anumber of interested persons have, atvarious times, recommended that thelabeling of drugs (whether bulk or indosage form) bear the name of themanufacturer in addition to the distributor or repacker or relabeler.Changes such as this, however, wouldhave such broad effect and would belikely to generate such enormouspublic and industry interest that theCommissioner does not believe thatthese final regulations are the properplace to consider them. Moreover.there are questions concerning the legality of such a requirement beingadopted under section 501(a)(2)(B) ofthe act (21 U.S.C. 351(a)(2)(B)). Therefore, the Commissioner declines to acton this comment at this time.
II. TERMINOLOGY AND LANGUAGE THESE REGULTIONS
13. Numerous comments were received suggesting changes in language.grammar. terminology, punctuation,sentence structure, and other editorial changes to clarify or improve upon therequirements as stated in the regulations or to elimlnate redundancies orinconsistencies. Those proposals thatraised significant policy questions, suggested changes in the substance of theregulation, or otherwise required, inthe Commissioner’s opinion, a specificresponse, are discussed individuallybelow. Many of the suggested changes.however, were more editorial and stylistic and do not warrant a detaileddiscussion that would double thelength of this preamble.
The Commissioner reviewed each ofthese numerous editorial and languagechanges to determine whether it offered an lmprovement in clarity ordefinition, eliminated an obvious erroror redundancy, promoted consistencywith other portions of the regulations,
45017 or otherwise ldentified textual problems that were not previously notedby FDA. Where the proposed alternative language or other-changes suggested by them were superior to theproposal, they were adopted in substance or verbatim. Where they didnot 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 thatconfusion can result from using“drug” and “drug product” interchangeably because, in the technicalliterature, the term “drug” usuallyrefers to the bulk drug and the term“drug product” to the finished dosageform. The comment also pointed outthat the words “phase,” “step,” and “stage” are used interchangeably andmay. in fact, describe different aspectsof a production operation.
The Commissioner finds that Parts210 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 drugsand drug products. With regard to thewords “phase.” “step,” and “stage,” hefinds that it is unnecessary to describevarious aspects of a production operation by using different words thatcan have essentially the same meaningin common usage. Therefore, for clarification, the CGMP regulations are revised to use the word “phase” consistently when describing certain aspectsof the manufacturing operations.
15. A number of comments concerned use of the phrase “to prevent”throughout the proposed CGMP regulations. The phrase appears in theseregulations to indicate that a requiredprocedure must be accomplished, oraccomplished in a manner, to precludea resultant deleterious effect, e.g.,“containers shall be opened, sampled,and resealed in a manner to preventcontamination.” In several instances,the comments objected to the phraseas being “too absolute,” stating thatthe 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. Thephrase “designed to prevent” was suggested as an alternative. A number ofcomments objected to the phrase “to prevent” when used in conjunctionwith written procedures on the basisthat written procedures in themselvesdo not prevent anything; they must beimplemented to accomplish the desired objective. The phrase “designedto prevent” was again suggested as analternative phrase.
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The Commissioner believes that it is facturing practice to assure that such (2) FDA received approximatelynot acceptable to. allow deviations drug meets the requirements of the 1,000 full new drug applications (infrom practices that could result in ad- act as to safety and has the identity cluding original submissions, resubmisverse effects upon the quality of the and strength, and meets the quality sions. and amendments). 1.500 abbrevi
6,900ated new drug applications, and The and purity characteristics which it.oc casi ondrug product. even on new animal drug applications. EachCommissioner, however, does agree purports or is represented to possess.
with the comments’ contention that The Congress intended that thewritten procedures must be imple
application contains information pertaining to the manufacturing Process-phrase itself have a unique meaning
mented to prevent anything and has and that the good manufacturingadopted the phrase “designed to pre- practice regulations represent sound
es to be used in producing the drugsubject to the application. In addition,
vent” in the applicable portions of the current methods. facilities, and con-final regulations.
about 10.000 supplements to approvedapplications, many relating to manufacturing processes. were submitted.
trols for the production of drugs to16. Several comments objected to assure safety, identity, strength, qual
adethe use of terminology such as “ ity, and purity of. the product. Thequate,” “appropriate.” “significant,” agency determines what constitutes“major” equipment and “long” peri- “current good manufacturing prac-
FDA must review and approve theseprocesses before an application may beapproved. The contents of approved
ods. The objection is that these terms tice" based upon its experience withlack the specificity needed and will the manufacture of drugs through in-result in confusion to the manufacturer.
The Commissioner has carefullyconsidered the use of these words andother words and phrases that implyabsolute requirements in judgmentalmatters. Except for the changes notedin responding to the comments by specific sections, he concludes that theterminology is appropriate as set forthin the regulations. Words such as“adequate” and “appropriate” dopermit reasonable, albeit variable, interpretation by reasonable people. butare necessary and desirable for regulations to have both broad applicabilityand flexibility. An overwhelming majority of those commenting on theproposal were greatly concerned thatthe regulations accommodate the widevariability of manufacturing and control systems, In fact, a number of comments recommended additional use ofmodifying words such as “appropriate” and “adequate” to carry a senseof flexibility in the CGMP regulations.
17. Several comments objected tothe use of the word “current” in thetitle and text of the regulations. Othercomments indicated that some of theproposed requirements, such as separation of penicillin operation8 in theproduction of veterinary drug products and the proposed statistical testing requirements. are not “current”good manufacturing practice for theindustry. Another comment requestedthat the term “current” be defined.One comment recommended that theword “current” be deleted since it isobvious that the latest regulations tobe published are current, and therefore the use of the word “current” issuperfluous.
Several of these comments reflect,the Commissioner believes, a misunderstanding rega rdingthe use of theword “current.” The a c t itself, in sec
spectional and compliance activities;upon knowledge gained from reviewing new drug applications. antibioticforms, biological product and establishment licenses. and other submissions to FDA; and upon considerationof comments from interested persons received in response to proposals toamend CGMP regulations. Althoughthe practices must be “current” in theindustry. they need not be widelyprevalent. Congress did not requirethat a majority or any other percentage of manufacturers already be following the proposed mandated practices, as long as it was a current goodmanufacturing practice in the industry, i.e., that it had been shown to beboth feasible and valuable in assuringdrug quality.
The accumulated knowledge and experience of FDA in the area of currentgood manufacturing practice is reflected in a body of information, whichwith the exception of trade secretsand information relating to pendingenforcement actions has long beenavailable to the public. This body ofinformation, which is the basis for agency expertise with respect to current good manufacturing practice, isso voluminous that formal inclusioninto the administrative record of this proceeding is not practical. Nevertheless. the Commissioner relies on thisbody of information in promulgatingthis regulation. The following list describes the information coming toFDA since active preparation of theproposal to revise the CGMP regulations began (in late 1974):
(1) FDA investigator8 conducted approximately 20.006 inspections of establishments in which drugs forhuman use are processed. and another6,000 inspection8 of veterinary drug establishments. After each inspection.
new drug applications, except thoseportions that constitute trade secrets, are available for public inspection. (21 CFR 314.14, 431.71, 514.11, and601.51.)
(3) FDA monitored more than 1,200recalls of drug8 for human use and 275recalls of veterinary products. In eachrecall resulting from a product defect.FDA investigate8 to determine themanufacturing control problems thatled to the defect. These investigations,generally embodied in establishmentinspection reports, are also publiclyavailable upon completion of regulatory activities.
(4) FDA brought over 500 legal pro-ceedings-criminal proceedings, seizures, a n d injunctions-involvingdrugs for human use and veterinaryproducts. Again, in those proceedingsarising 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, andcourt papers are publicly available.
Furthermore, FDA representativeshave participated in numerous activities-meetings. seminars, and workshops (regarding CGMP's, industrypractices. and agency policies) - withorganizations such as Parenteral DrugAssociation, the Proprietary Association, the National Association ofPharmaceutical Manufacturers, Pharmaceutical Manufacturers Association,the Packaging Institute, University ofWisconsin Industrial Pharmacy Management Conference, and the American Society for Quality Control. Theseactivities further contribute to the knowledge and experience of FDA.Many of the organizations sponsoringthese activities publish publicly available proceedings of these meetings, e.g.,Journal of the Parented Drug Association and Proprietary AssociationManufacturing Controls Seminar Pre-an FDA investigator filed an establish
s ment inspection report with the sentations.that a drug, 501(a )(2 )( B) tion spe cifie is deemed adulterated if the methods agency. With rare exceptions (for For ndditionnl information summa-used in. or the facilities or controls cases subject to active law enforce- rizing FDA’s activities for the past sevused for it smanufacture, processing. ment investigation), these reports are eral years. see 1975-1977 Annual Repacking, or holding do not conform to promptly available as public informa- ports and fiscal year 1979 Justificationor are not operated or administered in tion under FDA’s Freedom of Infor- of Appropriation Estimates for Comconformity with “current” good manu- mation regulations (21 CFR Part 20). mittee on Appropriations. (Copies
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have been placed on file with theofflce of the Hearing Clerk, FDA.1
16. Several comments asserted that CGMP regulations- must reflect the“current” practices of manufacturers of a particular type of drugs. Othersobjected to the absence of findingsspecifically supporting the conclusionthat a particular practice was a “current” practice of the manufacturers of a particular type of drug product.Among the drug products cited as theappropriate measure for current goodmanufacturing practice were veterinary drugs, medical gases, radio- pharmaceuticals, and cosmetic-type drugproducts.
The Commissioner recognizes thatdifferent types of drug products mayrequire specialized manufacturing andcontrol procedures or may not be appropriate to the application of certainprocedures that are othenvlse generally applicable to drug products. Forthis reason, he has announced his intention to issue specialized currentgood manufacturing practice regulations for particular types of drug products and, in fact, has already issued one such proposal regarding largevolume yarenteral drug products. Theregulations set forth in Part 211 (21 C F R Part 211) are designed to be applicable to all drug products in finished dosage form. They are based onpractices widely used throughout theindustry for manufacture of many finished drug products. The Commissioner rejects the idea that FDA must establish that each CGMP requirementis a current practice of the manufacturers in each subset of drug productscovered by the general requirementsof Part 211. As noted elsewhere in this preamble, the commissioner has evaluated whether thi s requirement is appropriate for particular types of drugproducts in response to specific comments. Where he has found it to be inappropriate, he has exempted theproducts from the requirement; otherwise the commissioner has concluded that all manufacturers of finished drug products should be subject to therequirements of Part 211. The Commissioner believes this is the only feasible way to approach such generalcurrent good manufacturing practiceregulations. There is no consensus onthe various subgroups of finished drugproducts, and therefore a requirementthat the currency of practice must bedocumented for each subgroup wouldultimately amount to establishing thatit was a current practice by each manufacturer of each drug product, aburden which would be impossible toestablish and unnecessary for purposes of regulation. Therefore, theCommissioner rejects these comments.
RULES AND REGULATIONS
III. AMENDMENTS REGARDING PLACEMENT OF EXPIRATION DATE ON DRUG PRODUCT LABELS
19. A substantial number of comments objected to the proposed reaulrement in § 201.17 that the expiration date appear on the shippingcarton. The majority objected on thegrounds that it is common practice forshipping containers to contain different drug products or similar drugproducts with different expirationdates. Some persons recommendedthat the expiration date be requiredon the shipping carton only when thecarton is for one drug product.
The Commissioner recognizes thatthere are valid reasons for cominglingvarious drug products, or different lotsof the same drug product, within asingle shipping carton. In such instances it may not always be practicable for each different expiration dateto appear on the shipping carton. Because of significant differences in theuse and labeling of shipping cartons,the Commissioner concludes that a requirement for the expiration date toappear on the shipping carton whensuch shipping carton is not the immediate container should not be a part ofthe regulations at this time, and thisrequirement is deleted from § 201.17.Manufacturers are encouraged, however, to provide approprlate informationto the extent possible on all shippingcartons to facilitate handling, reducethe possibility of mixups, and alloweasy identification of lots that arebeing recalled or withdrawn from themarketplace.
20. Several comments were receivedregarding expiration dating of shipping cartons containing radio- pharmaceuticals. Generally, the commentswere that such drugs usually have several separate component parts eachwith a different expiration date. Onecomment requested an exemptionfrom the entire section, while anothercomment asked for an exemption forthe shipping carton.
The Commissioner believes that§ 201.1’7, as revised, will accommodatethe special problems encountered inthe handling of radiopharmaceuticals.
21. Several comments suggested thatthe heading of this section be revisedby changing the title word fromdrugs” to “drug product” to conformto the drug product definition in§ 210.3(b)(4).
The Commissioner finds that theword "drugs" in the heading of$201.17 is more consistent with theterminology used in Part 201. Theterm “drug product,” as defined in§210.3(b)(4). is intended specificallyfor use in Part 211 to convey a meaning more limited than the generalterm “drug” as defined in section201(g) of the act. However, to clarifythat § 201.17 applies to drug products
under Parts 210 and 211, the final regulatlon in §201.17 is revised to refer to both drugs and drug products.
22. A number of comments recommended that the expiration date notbe required on outer retail package labeling, such as display cartons, if theexpiration date appearing on the immediate container is visible.
The Commissioner agrees that it washis intention to require that the expiration date be visible under usual andcustomary conditions of packaging. Henotes that section 201(k) of the actprovides for label information that iseasily 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 proposedsection does not clearly cover a situation where the producer does notpackage the material in a retail package, but markets drug products in bulkcontainers.
Although the Commissioner believesthat the situation described is coveredby the proposed regulations, the finalregulation as rewritten clearly specifies that when the expiration date of adrug, including drug products, is required, it shall appear on the immediate container. There is no exemptionfor 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 isgenerally understood that protectivewrappers for individual dosage formsthat are further packaged in immediate containers are not required to bearan expiration date. Because only onecomment about protective wrappers was received requesting a statement inthe regulations and no informationwas submitted that the issue raisedhas actually been a problem, the Commissioner concludes that further clarification of this section is not now warranted.
25. Several comments asked aboutthe acceptability of placing the expiration date on the crimp of the drugproduct tube.
Because of the wide variety of available methods and techniques of applying and presenting expiration datinginformation on the immediate container, the Commissioner has not attempted to specifically evaluate and list individual methods. In general, he findsthat the expiration date should bereadily seen under usual and customary circumstances. The tube crimp hasbeen 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. Noknown problems have been associatedwith such information appearing on
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45020 the crimp of the dispensing tube and,therefore, thia method is an acceptable way to comply with § 201.17.
26. Several comments objectedto the provisions in§ 201.17 that when single-dose containers are packed inindividual cartons. the expiration datemay properly appearon the carton only. Several respondents noted thatampules are sometimes removed fromthe outer carton, particularly in hospitals. and that valuable information that is not a part of the immediatecontainer labeling is lost.
The provision in this section regarding single-dose containers has been ineffect for a number of years and wasbased on information that such an allowance was necessary for single-dose containers, primarily glass ampules, because of technical problems inlabeling glass ampules on a batch-bybatch 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 recommend s this activity, it was not hisintent to propose revocation of the exemptions for single-dose containers aspar t of this revision of FDA regulations. Based on the few comments received which recommended additional revisions in this section, th e Commissioner will not revoke these exemptions at this time, but will consider therecommendation s for revisions for a future proposal.
27. Several comments recommended that for drugs which a als o cosmetics (see also paragraph 42(h)) expiration dates should only be placed onthe shipping carton and outer retailpackage because such products aretypicall y purchased by the user withthe outer retail package intact and theproduct is consumed in a relativelyshort 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 theexpiration dating requirements. Butthe so-called “drug-cosmetic ” type ofproducts are not free from stabilityproblems; 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 thatthe word “human ” be inserted between the words “licensed ” and "biologicals" in § 207.3(b) because veterinarybiologicals are regulated by the U.S.Department of Agriculture.
RULES AND REGULATIONS
The Commissioner agrees with these erwise costs to consumers might be in-comments and is amending the para- creased. Individual firms are in a graph accordingly. better position to determine the finan
29. One comment recommended that cial feasibility of a salvaging operthe definition of “establishment ” ation. The costs of registration, bothunder §207.3(b) he broadened to in- to the Government (and the taxpayer)clude additional categories such as and to the registrant, are quite insigbulk sales by practitioners, antique nificant and probably less than theshops, anddealers and trustees han- added costs that would result from the dling estate salesand/or bankruptcies. needless destruction of salvageable
The Commissioner agrees that thesedrug products. are all examples of establishments V. LEGAL STATUS OF CGMP that could engage in drug-salvaging REGULATIONS operations. but believes that the proposed definition of “establishment ” is 33. Several comments requested de-preferred in order to provide coverage letion of the word “drugs ” in the title for any type of establishment that en- and insertion of the words “drug prod-gages in drug, product salvaging oper- ucts ” in order to be consistentwith ations, including those identified in the title of Part 211 and the definition the comment. of § 210.3(b)(4) and § 210.1(a).
30. Two comments suggested dele- Part 210 applies to all parts betweention of the word “may” in the phrase Parts 211 and 229. Part 211 deals with “may have been subjected to" improp- finished dosage forms, but other partser storage conditions in the proposed may not. Therefore, the Commissioner§ 207.3(k) because the statement is too finds that the more general termgeneral and the requirement should “drugs ” applies better to the various only apply when the drug product has types of drugs that are likely beactually been exposed to adverse con- covered in Parts 211 to 229.ditions. 34. A number of comments objected,
The Commissionerrejects this sug- on diverse grounds, to use of the wordgestion because it may not be possible “minimum ” to describe the require-in every instanceto establish clearly ments in these regulations. Several re-the exact nature of the adverse cir- spondents believed that current goodcumstance to which a drug product manufacturing practice cannot be con-has been exposed. Therefore, in some sidered in terms of a"minimum" be-instances. the salvager may o n l y have cause that implies that firms adheringsketchy information aboutimproper to the regulations are then merely at astorage conditions. such as unusual threshold level of compliance. Other temperatures, and must assume that respondents suggested that “mini-such conditions may have occurred in mum" means that normal practices order to handle the salvaging oper- represent a higher standard and thatations properly. there is an implication that the stand
31. Three comments concerned the ards of these regulations fall below anproposed exemption of drug product acceptable level. Some comments rec-salvagers from drug listing in § 207.20. ommended that “minimum ” not be Two of the comments recommended used because no such reference to that drug productlists be submitted CGMP regulations is in the act. prior to salvaging and one respondent The Comissioner does not agreerecommended that a drug product list with these comments. Thelegislativeneed not he submitted, but should be history of the Drug Amendments ofmalntained by the salvager. 1962 shows that section 501(a)(2)(B) of
The Commissioner agrees that an in- the act was includedto raise the ventory of drugs subjected tosalvag- standards of drugs manufacturing byi n g operations should be maintained, all manufacturers to the level of the but does not agree that salvagers current good manufacturing practiceshould submita drug list under Part in the industry. Congresswas quite207 (21 CFR Part 207). To clarify that concerned about the uneven and some an inventory of drugs involved in Sal- times unacceptable quality of drugvaging operations shall be maintained. products from some portions of theprovisions are added in 9211.208 for pharmaceutical industry. The purposemaintenance of records for drug prod- of section 501(a)(2)(B) of the act is toucts subjected to salvaging operations. provide assurance that drug product
32. One comment considered the reg- quality would not fall below thatistration requirement for a drug sal- which was feasible and available under vaging firm to be a waste of taxpayers ’ contemporary technology. There is nomoney and recommended that the re- implication that the standards reprecycling of any and all drugs and phar- sented by these regulations are lessmaceuticals be prohibited. than acceptable or below the indus-
The Commissioner disagrees with try’s norm. On the other hand, therethis opinion.He does not agree that is no prohibition in the regulationsdrug product salvaging should be pro- against the manufacturing of drughibited where the integrity of the products using better, more efficient,drug product is not compromised. Oth- and innovative methods. In fact, the
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY SEPTEMBER 29, 1978
45021 Commissioner encourages use of suchmethods 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 theCGMP regulations because of theirbinding legal nature (discussed inparagraph 35); that is, failure to meetthe minimum standards of the regulation results in the product’s beingadulterated.
35. Several comments argued that §210.1 should be deleted because it is based on the erroneous propositionthat CGMP regulations can be substantive. The comments urged thatregulations 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 comment stated the following:
Sectlon 501(a)(2)(B) was enacted as partof the Drug Amendments of 1082. and, asreported by House Commlttee. thoseamendments would have included a provislon empowering the FDA to Issue GMP regulations under it formal section 701(e) rulemaking authodty. (H.R. 11581. 87th Congress. Second Session The House Com mittee Report explained: "The promulgation of these regulations would be subject toopportunity for hearing and judicial revlew. Thus, legal action could be brought against firms failing to abide by these standardsand against the products they ship.” (H.R.Rep. No. 2464, 87th Congress, Second Sesslon, 2(1962).) The present form of section 501(a)(2)(B) was first e n a c t e d b y t h e Senate. The Senate Committee Reportmade clear that the provision was Intended to authorize the F D A to Issue "interpretatlve” regulations that would constitute onlyprima facie evidence o f adulteration. (S.Rep. 1744. 87th Congress, Second Session,9(1962).) In floor action on September 27,1062. the House amended H . R . 11581 to be consistent with the Senate bill. (108 Congressional Record 10018 (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
upon notlce and in accordance with the pro-decisions cited in the preamble to the’ cedures set forth in sectlon 4 of the Admin-February 13, 1978. proposal in fact didnot support that nuthority. One comment reviewed the history of all fourproceedings and concluded:
All of the cases cited by the Commlssloner * * * recognize that the court cannot reach a conclusion contrary to Congressional intent. In those cases, there was no clear Congressional Intent and thecourts allowed the F D A to issue substantlve regulations under section 701(a) of the Act.The legislative history with respect to theproposed CGMP regulations is crystal clearand does not permit the Commlssloner to issue substantive regulations.
RULES AND REGULATIONS
Because of the fervor reflected bythese objections and because the Commissioner foresees identical objectionsbeing made to proposals to issue findlng CGMP regulations for specificclasses of drug products in the future,the Commissioner has decided that alengthy exposition of the basis for hisconcluding that FDA has legal authority to promulgate such regulations iswarranted. The Commissioner intendsthat this statement will be definitive,and he does not contemplate reconsiderina the Issue of FDA’s legal authority to issue substantive CGMP regulations in the future unless new materials. not discussed below, are broughtto his attention. The question ofwhether a particular regulation shouldbe issued as binding or interpretive, ofcourse. may always be raised, and comments on the wisdom of making theseCGMP regulations binding are discussed in paragraph 36 below in thispreamble.
With regard to the legislative history of the Drug Amendments of 1962.the Commissioner finds that none ofthe comments provided a complete oraccurate picture of the enactment ofthe current section 501(a)(2)(B) of theact. Because of the emphasis placed bythe persons objecting to “substantive” CGMP regulations on Congressionalintent, the Commissioner believes adetailed review is necessary.
On July 19. 1962. the Senate Judiciary Committee reported out S. 1552,the Senate version of what ultimatelybecame the Drug Amendments of1962. Section 5 of the July 19 billwould 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, o r 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 practicee to assure thnt such drug meets the requirements of thisAct 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 i s authorized to issue interpretative regulations,
istrative Procedure Act (5 U.3.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 page9, emphasizing that the “Secretary would be authorized to issue interpretative regulations as to whatconstitutes current good manufacturing Practice, and these regulationswould be Prima facie evidence in any
proceeding under this section of theFood, Drug, and Cosmetic Act.”
On August 3, 1962, President Kennedy submitted a series of amendmentsto the Senate Judiciary Committee. Inresponse to this and to the public controversy then erupting over thalidomide, the Committee reconsidered S.1552 and, on August 21, 1962, reportedout a revised version of the bill. One change was to reword section 5 of thebill so that section 501(a)(2) would beamended to read as follows:
(2)(A) if it has been prepared, packed, orheld under insanitary condltlons whereby Itmay have been contaminated wlth filth, or whereby It may have been rendered injurious to health; or (B) If It Is a drug and themethods used in, or the facnltles or controls used for, its manufacture. processing, packing, or holding do not conform to or are notoperated 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 theIdentity and strength, and meets the quality and purity characteristics, which It purports or is represented to possess.
The Judiciary Committee issued asecond report to explain its proposedchanges in S. 1552 (S. Rep. No. 1744.Pt. 2, 87th Cong.. 2d Sess. (Aug. 21.1962)). On pages 3 and 4, it discussedthe revision of section 5 as follows:
The President, in the recommendations submitted for the consideration of the committee with hls letter of August 3. 1082. proposed a revlsed version which Included the following principal amendments to the reported bill:
(1) It proposed to replace the provlslons on regulations with prlma facie evidentiary effect with a provision that the adequacy ofthe quallity controls be determined "in accordance wlth regulations promulgated bythe 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, wlth respectto such regulations.
� . . . .
The explanatlon accompanying the recommendatlons of the President expressedconcern lest the language as tq interpretatlve regulatlons with prima facie evidentiary effect invite endless de novo litigation on the question of what constitutes a goodmanufacturing practice each time there is enforcement action under the new qualitycontrol 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 lnsertlng provlslonsfor 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 thls Act.” Thls permitsthe Department to issue such regulations as it deslres and their scope and effect will bethe same as that of other regulations issued under such general authorlty. Numerousregulatlons have been issued under section
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45022
701(a) and have been the subject of consideratlon and appllcatlon in the courts in actions arising under the varlous provisions ofthe act not now subject to formal rulemaking procedures.
During the floor debate on S. 1552 on August 23. S e n a t o r Eastland, Chairman of the Judiciary Committee,elaborated on the meaning of section 501(a)(2) as It would be amended bythe bill:
Section 5. a s It would read under the August 20 amendments, is designed to assure that drugs are manufactured according to good manufacturing practice. Itwould deem a drug to be adulterated andthus subject to seizure If made under faclllties, 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 faclllties. methods. or controls were not operatedor administered in conformity with goodmanufacturing practice.
Since the competitive position of responsible manufacturers depends in large part onthe confidence of the medical professtonand the public, It will be In their own inter-eat to maintain high standarda of current good manufacturing practice which w i l l provide a readily determination basis for enforcement proceedings against any substandard operator. The Secretary could use his general rulemaking authorlty under section 701(a) of the act to announce what he, inthe administration of the act, consldered tobe good manufacturing practice insofar as methods, facllltles. controls, and their operatlon and administration are concerned. As in the case of other regulations, the court in the final analysis will pass upon the scopeand effect of such regulations. (108 Cong.Rec. 16303-4 (Aug. 23. 1962).)
Senator Kefauver concurred in thls change, stating, “This provision has been strengthened considerably incomparison to the bill which was reported Jn July.” (Id.. at 16306-7).
The Commissioner thus concludes that when It unanimously approved S.1652 on August 23, 1962, the Senate obviously believed that the problemidentified by the President--“endlessde novo litigation* * * each time there is enforcement action” had been resolved. The Senate must, therefore, have intended that regulatlonsJssued under sectlon 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
RULES AND REGULATIONS
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, orheld under unsanitary conditions whereby Itmay have been contaminated wlth filth. orwhereby it may have been rendered injurious to health; or (b) if It is a drug and themethods used in, or the facilities or controls used for i t s manufacture, processing. packing, or holding do not conform to or are not operated or administered in conformitywith current good manufacturing practice(as determined in accordance with regulations promulgated by the Secretary) toassure that such drug meets the requlrements of this Act as to safety and has the identity and strength, and meets the qualityand purlty characterlstlcs, which It purports or is represented to possess.
In addition. paragraph (b) of section 101 would have amended sectlon 701(e) of the act to provide that regulations under section 501(a) would be issued by formal rulemaking procedures (rather than the Jnformal procedures under sectlon 701(a) of the act).
The Committee Report accompanying H.R. 11681 explained this provision as follows (H. Rep. 2464, 87thCong., 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 Cosmetla Act to deem a drug to be adulterated If the methods. faclllties or controls used in its manufacture,processing. packaging. or holding fail to conform to, or are not operated or administered in conformity wlth, good manufacturingpractices as determined in accordance wlth regulations to be issued by the Secretary ofHealth, Education. and Welfare which are designed to assure that the drug is safe and has the identity and strength and meets thequality and purity characteristics which It purports or la represented to possess * * *
The promulgatlon of these regulatIonawould be subjectto opportunity for hearingand judicialreview. Thus, legal action couldbe brought against firms falling to abide bythese standards and against the productst h e y ship.
The House of Representatives debated H.R. 11581 on September 27,1962. Congressman Schenck offeredseveral amendments that day, one ofwhich 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 sectlon 101 of the bill, .which was approved by the commltteepro-
some particular drug product may be made. Manufacturers whose methods, facllltles,and controls exceed the minimum standards w i l l not be required to lower their own standards, so long as they can show thattheir own practices meet or exceed these minimum requirements.
The principal purposeof the provision is to assure that the same high manufacturingstandards are followed in making so-calledold drugs that the law now requires inthe making of so-callednew drugs. Before anymanufacturer la permitted to make a newdrug he must file complete details of hismanufacturing process wlth the Food andDrug Administration. It is not intended that the regulatlons issued under willsection101 apply to the manufacturer of new drugs insofar as the methods, facllltles, or controlsused in making these new drugs but thatthe Food and DrugAdministration will require that such drugs meet the requlrementof 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 amendmentwhich would make the formal rulemakingprocedures of sectlon 701(e) of the Federal Food, Drug, and Cosmetic Act applicable to regulations referred to whichmay be madepumuant 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 undersection 701(e) of the Federal Food, Drug,and Cosmetic Act in order to issue regulations as to what constitutes ‘current goodmanufacturing practice.' I favor the approach adopted by the Senate under which this determination i s made pursuant to sectlon 701(a) of the act. This procedure permits the Secretary to issue such regulations as he desires and thelr scope and effect will be the same as that of other regulationsissued under such general authority. This procedure is more flexible. Numerous regulations have been issued under this sectlon and they have been the subject of consideratlon and appllcatlon in the courts in actions arising under the various provlslons ofthe 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 Commfttee, who observed that the amendment "is taken, in part, fromthe Senate bill, S. 1552 * * * The gentleman from Ohio [Mr. Schenckl has advised me of the need not to tie this provision in with section 701(e) * * *" 108 Cong. Rec. 19016 (Sept. 27, 1962).The amendment was agreed to and, as approved by the House of Representatives. the legislation would amend sec
force as any other regulation lssued vldes simply that the drug will deem[ s i c : beunder section 701(a) of the act. H e deemed1 to be adulterated and subject toalso finds that the statement relied seizure If the methods. facllltles. or controlsupon by most comments as proof that used in the manufacture of the drug do notonly interpretlve regulations could be conform with current good manufacturingissued appeared in the first Senate
tlon 501(a)(2) to read: (2)(A) If it has been prepared, packed, or
held under unsanltary conditions whereby Itpractice, as determlned In accordance wlth Report and was explicitly reversed in regulations promulgated by the Secretary.
The purposeof this provlslon is to enable may have been contaminated with filth, or whereby It may have been rendered injurithe second Senate Report.
the Secretary to requlre all companiespro-One month later, the House Inter ducing drugs to observe the highstandardsstate and Foreign Commerce Commit- that are now followed by the better manu-tee reported out H.R. 11581, the House
ous to health; or (B) If It is a drug and themethods used in. or the facilities or controls used for, its manufacture, processing. pack
facturers. It is intended that the Secretary’s regulatlons will define standards minimum of good manufacturing practice, rather than setting forth an exclusivemethod by which
ing, or holding do not conform to or are not operated or administered in conformitybill that preceded the Drug Amend
ments of 1962. (H.R. Rep. No. 2464, with current good manufacturing practiceto assure that such drug meets the requlre87th Cong.. 2d Sess. (1962)). Section
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me nts of this act as to safety and has the identity and strength, and meets the qualityand purity characte ristics ,which It purportsor is represented to possess.
The Commissioner finds from thishistory thnt the House of Representatives believed that CGMP regulationswould have the same legal status asother FDA regulations, and moved torevise language to conform to S. 1652,as passed, solely to eliminate the requirement that CGMP regulntions beissued pursuant to the formal rule-making procedures of section 701(e) ofthe 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, itwas not a subject of the ConferenceReport (H. Reo. No. 2526. 87th Conn.2d Sess. (Oct. 3. 1962)), nor was itmodified or debated further by eitherthe Senate or the House when eachvoted to approve the Drug Amendments of 1962 (on October 3 and 4.1562, respectively).
Based on this complete review of thelegislative history of section 501(a)(2)(B) of the act, the Commissioner concludes that there is no support for the proposition that CongressIntended that CGMP regulationsshould be merely interpretive. At theleast, Congress wanted CGMP regulations to have the same force and effectas other regulations issued under section 701(a) of the act,. (See the secondSenate Report and Rep. Schenck’s description of his amendment, above).To the extent that a stronger Congressional mandate can be gleaned fromthe various reports. amendments, anddebates, it appears that binding standards were to be issued by FDA andissued through the less cumbersomenot ice and commentrule making procedures of section 701(a) of the actrather than the more complex section701(e) mechanism. Therefore, theCommissioner rejects the argumentthat § 210.1 exceeds the authority conferred by Congress under sections501(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 decisionshanded down since February 13. 1976are directly relevant to, and furthersupport, his conclusion that CGMPregulations can be issued as binding standards.
In 1973, the Supreme Court reviewed the legality of two interrelatedFDA regulations. One, now codified in21 CFR 314.111(a)(5). set forth indetail the scientific principles that theCommissioner believed are part of therequirement in section 505(d) of theact that the effectiveness of a drug bedemonstrated by "substantial evidence
RULES AND REGULATIONS
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 hearingon the denial or withdrawal of approval of a new drug application (NDA)presented a genuine and substantialissue of fact. At stake in the case of Weinberger v. Hynson, Westcott and Dunning, Inc., 412 U.S. 609 (1973). waswhether an applicant was entitled to afull evidentiary hearing on the approvability of its product, and at such ahearing could offer whatever evidenceit felt met the statutory standards ofeffectiveness, or whether FDA couldsummarily deny or withdraw approvalof the NDA because the agency foundthat the applicant’s evidence hid notmeet the standards in the regulationsfor evidence of effectiveness. Manufacturers contended that FDA’s regulations could not serve as the basis fordenying them a full evidentiary hearing under section 505 of the act. Theagency believed that the regulationswere a reasonable method of screeningout unnecessary hearings and therebymanaging an otherwise overwhelmingworkload. The Supreme Court concluded that both of the regulationswere within the authority of the Commissioner under section 701(a) of theact and therefore FDA could act onNDA's without a full hearing whereevidence failed to satisfy the FDA regulations. It said (id. at 622):
The standard of ‘well-controlled inves tiga tionsparticularized by the Regulations is a protecti vemeasure deslgned to ferret outthose drugs for which there Is no affirm ative, reliable evidence of effectiveness The.drug manufacturers have full and precisenotlce of the evidence they must present to sustain their NDA's and under these circumstsnces we find the FDA hearing regulations unexceptionable on any statutory orconstitutional ground.
The Supreme Court, in this and related cases, discussed FDA’s authorityto determine whether a drug was a“new drug” under section 201(p) ofthe act (and thus subject to the requirements of section 505 of the act).It described favorably the revlew ofover-the-counter (OTC) drugs underthe procedures set forth in 21 CFR330.10. by which OTC drugs are beingclassified as “new” or “generally recognized as safe and effective and notmisbranded,” the latter not subject tothe new drug provisions of the act.These procedures were also promulgated under the authority of section701(a) of the act. The Court stated, inWeinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645.653 (1973) that:
We thi nk that it is implicit in the regulatory scheme, not spelled out in haec ver bs , that FDA has jurisdicti onto decide with admlnlstratlve fina lity, subject to the types ofjudic ialrevlew provlded. the ‘new drug’ status of individual drugs or classes of
45023
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 theinterests of the public that Congress was anxious to protect by the 1062 amendments. as well as OTC drugs and drugs covered bythe 1072 [Drug Listing] Act. We are told that FDA is incapable of handling a case-load of more than perhaps 10 or 15 de novojudicial proceedings In a year. Clearly. IfFDA were required to litigate, on a case-bycase basis, the ‘new drug’ status of each drug now marketed, the regulatory scheme of the act would be severely undermined, ifnot totally destroyed. Moreover, a case-bycase approach is Inherently unfair because It requires compliance by one manufacturerw h l l e his competitors marketing similar drugs rernaln free to vlolate the Act l l l .
In a third case deciatthet the same time , Ciba Corp. v. Weinberger, 412U.S. 640 (1973). the Court said (id. at643-4) that “the definition of newdrug as used in sec201(p)(1 involves a determination of technicaland scientific questions by experts.The agency is therefore appropriatelythe arm of Government to make the threshold determination of the issueof coverage* * *”
The Commissioner notes that evenprior to these rulings, most majormanufacturers of OTC drugs had recognized the reasonableness as well aslegal propriety of the OTC review as amechanism within the authority ofsection 701(a) of the act to classifydrugs as “new” or “not new.” Indeed,for over 5 years now, these firms havebeen participating in this review, andthe Commissioner expresses his gratitude for this cooperation.
Subsequent to these rulings by thehighest Federal court, another casearose over the issue of whether FDA could promulgate regulations undersection 701(a) of the act that represented binding rules relating to prescription drugs under sec503(b) ofthe act. The specific is was whether FDA could, by regulation, declareproducts containing more tcertainamounts of vitamin A or D to be prescription drugs. The opponents of theregulation, in an interesting parallel tothe comments on the CGMP regulations, argued that only regulation issuable under sect701(eof the actprocedures could be binding and thatthe legislative history of sect503(b)of the act demonstrates that FDAcould issue only interpretive regulations. The United States Court of Appeals for the Second Circuit rejectedthese contentions in National Nutritional Foods Ass'n v. Weinberger, 512F.2d 688 (1975). It stated:
We have come recogniz that, If the administrative process is to be practicablyeffectlve , specificregulations p romulga t ed pursuant to general statutory delegation of authority must be treated as authoritative, whether labeled "substantive" "interpreor
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45024
tive," especially in areas where the agencypossesses experti se n o t s h a r e d b y t h ecourts. In the event its views are unlik ely to be distributed by the court In an enforcement proceeding l l l . Whatever doubts might have been entertai nwdregardi ng the FDA's power under §701(a) to promulgate bin ding regulations were dispelled by the
decisio ns in Weins recent’Supreme Court
RULES AND REGULATIONS
of these regulations, more regulatory proceedings are probable.
In Ciba, the Court noted the technical and scientific expertise appropriatefor at least the threshold determination of “new drug” status. The Commissioner believes that determinationof what is the “current good manufac
(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 lo coding on finished prod-t uct packages and shipping containersand to distribution records of lots,issued under sections 502(a)(4) and701(a) of the act, upheld); Federation
berger v. Hynson, Westcott, & Dunning * l l turing practice” in the drug industryand its companion cases l *l , (Id. at.696). also requires technical and scientific
of Homemakers v. Schmidt, 385 F. expertise, as well as a unique ability toobserve t he entire industry. TheseCGMP regulations were developed
* * * * * Supp. 362 (D.D.C 1974), aff ’d 539 F.2d .740 (D.C. Cir. June 10. 1976)(regula-Surely an agencywhich possess the power
to determi n administ ratively what prod- with the participation of pharmaceutical chemists employed by FDA, indi
tion establishing requirements for“imitation” foods, issued under sections 403(c) and 701(a) of the act,
e ucts are “new drugs” has the authority to
"pre scriptio n viduals qualified by formal training aswell as by valuable experience in re-
decid e w h a t p r o d u c t s a r edrugs”. (Id. at 699). upheld ): Almay, Inc. v. Weinberger,
417 F. Supp. 768 (D.D.C. June 30.1976), rev'd o n the grounds, NO. 76
viewing the good (and bad) current(and past) production and controlThe decisions in the National Nutri
tional Foods, Hynson, Bentex, and Ciba were cited by the Commissioner because he believes that they conclusively rule that regulations issued
1718 (D.C. Cir Dec. 21. 1977 authority to issue regulation regarding labelsing and supporting evidence of cosmet
techniques set forth in original NDA'sand abbreviated NDA's supplementalapplications. antibiotic certificationforms, biological establishment andunder section 701(a) of the act are
binding and that the justifications forissuing substantive regulations inother areas are directly applicable toCGMP regulations. Similar to theCourt';’s observations in Hynson quotedabove, the statutory standard of “current good manufacturing regulations”can and should be particularized as aprotective measure to identify thosemanufacturing practices which. are at a minimum necessary to assure drugquality. The drug manufacturers havefull and precise notice of the CGMPrequirements they mus fulfill to susttain the acceptability of their productsunder section 501(a)(2)(B) of the act,as the Commissioner noted in the February 13. 1976. preamble. Substantiveregulations also provide greater certainty about the agency’s expectationsbecause, in promulgating such regulations, the agency must carefully distinguish standards it seriously intendsto enforce from those it find desirable sbut not essential. Th Commissionerealso stated in the 1976 proposal thatbinding CGMP regulations wouldassist courts and expedite enforcementproceeding 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 inthe public interest, nor would it beequitable to competing manufacturerswho where not involved in such litigation. President Kennedy and thesecond Senate Report made the samearguments in deleting the reference tointerpretive regulations from S. 1552.The agency ha avoided this problemsover the last several years becauseagency priorities have been concentrated in areas other than drug CGMPenforcement; it is not anticipated thatthis allocation of resources will continue indefinitely and, with the issuance
product licenses, new animal drug applications, and proposed and finalcompcndial standards. In addition.FDA investigators who conduct and/orreview inspections of manufacturersunder the act also participated in preparing this document. Although, asone comment noted, FDA does notmanufacture drugs, it does not followthat FDA cannot determine currentgood manufacturing practice fordrugs. On the contrary, FDA may beuniquely able to do so, because it andit alone has had access to the facilitiesand records of every manufacturer ofpharmaceutical in this country.sGiven the fact that many productionand control processes are consideredby individual firms to be trade secrets,it is unlikely that competitors or independent private third parties such ascompendia1 authorities have the sameability as FDA to discover what non-public practices other than their ownare current and which of these are good.
Subsequent to the February 1976proposal, other courts have consideredand affirmed FDA’s authority to promulgate binding of substantive regulations pursuant to section 701(a) of theact. See, e.g., Cosmetic, Toiletry andFragrance Association v. Schmidt, 409F. Supp. 57 (D.D.C.. Feb. 3, 1966). appeal docketed No. 76-1242 (D.C.Cir., Feb. 5. 1976) (regulation requiringwarning labels on aerosollzed 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 Ameri. . can Frozen Food Institute v. Califano,555 F.2d 1059 (D.C. Cir. May 12. 1977)(regulations establishing common andusual names for nonstandardizedfoods, issued under sections 403(i) and701(a) of the act, upheld); National Confectioners As s'n v. Mathews, CCH Food. Drug & Cos. L. Rep. 38.062
ics claiming to be "hypoallergenic," under section 301(b),602 (a) and (b)and 701(a) of the act upheld); United
s
States v. Nova Scotia Food Prod.Corp., 417 F. Supp. 1364 (E.D.N.Y., Aug. 17. 1 97 6) , rev’d on the grounds,No. 76-6169 ( d Cir. Dec. 15, 1977)(CGMP regulations regarding briningand heating of fish in the Productionof smoked fish may be promulgatedunder sections 402(a)(4) and 701(a)ofthe act). The Commissioner notes thattwo of the cases dealt specifically withthe validity of CGMP regulationsissued under the statutory standardsrelatingto adulterated foods, which donot explicitly refer to “current goodmanufacturing practice.” It wouldindeed be anomalous that those regulations could be issued as legally binding if regulations amplifying section501(a)(2)(B)could not be.
The Commissioner interpretsmuchof the concern over FDA’s authorityto issue binding regulations as reflecting a belief that the CGMP regulations can be arbitrary, need not bebased upon actual current practice,and may exceed what is necessarily“good” for drug quality. There alsoseems to be a belief that binding regulations cannot be changed and arebeyond review by the courts. Theseperceptions are in error.
The Administrative Procedure Act clearly provides that regulationsswhich are arbitrary or capricious maybe overturned by a reviewing court. 5U.S.C. 706. The legislative history ofsection 501(a)(2)(B) of the act andcases involving enforcement of CGMPregulations, e.g., United States v. An Article oj Drug l l l “White Quadrisect”, 484 F.2d 748 (7th Cir. 1973)) established that the regulations must bebased 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
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
relied upon the knowledge and expertise of FDA staff developed from thereview of NDA's and ANDA's antibiotic certification forms, biological licenses, and compendial standards submitted to the agency, and from establishment inspections made during thelast half decade. A “good” practice wasincluded in these regulations only if itis feasible for manufacturers to implement the practice, if the practice contributes to assuring the safety. quality.and purity of the drug product, and ifthe value of the contribution or addedassurance exceeds the cost. in terms ofdollars and/or other burdens. of implementing or continuing the practice,The Commissioner does not believe itis legally required that, in addition toreliance upon agency expertise, hemust include in the record specific examples of each practice mentioned inthese regulations.
Regarding judicial review of regulations, the Commissioner notes thatsuch review is assured by the Administrative Procedure Act whether the regulations are deemed interpretive orsubstantivee. Judicial review is available in any enforcement proceedingbrought against a particular manufacturer or product. Pre-enrorcementreview is also available. Abbott Laboratories v. Gardner, 387 U.S. 136 (1978).
Thus, the Commissloner believesthat the fears that substantive, binding CGMP regulations somehow deprive individuals of legal protectionsare unfounded.
As noted at the outset of this discussion, the Commissioner does notintend in the future to reconsider the legal authority of FDA to promulgatebinding CGMP regulations under section 701(a) of the act, unless new material, not discussed above, is presented lo him that raises substantial doubtas to the correctness of the analysesand conclusions he set forth above.For reasons discussed in this paragraph and in paragraph 36 below, theCommissioner has also decided thatthese CGMP regulations shall beissued as binding. The Commissioneradvises that any person who still questions FDA’s authority to do this is welcome to seek prompt pre-enforcementjudicial review of this authority.
36. A number of comments suggested. in effect, that whether or not FDAcould lawfully issue “binding” CGMPregulations, it would be unwise for theagency to do no. These individualscited the complexity and variability ofmanufacturing control processes, emphasizing the variety of options available and the need for freedom of choiceamong these options by various manufacturers depending on cost and technological factors. They further complained that FDA lacked the expertiseto determine which practices were bestand that, by "freezing-in" techniques,
RULES AND REGULATIONS
FDA would discourageinnovation anddevelopment of new procedures whichmight increase the assurance of product quality. The comments objected tothe presumption that would followfrom a technical violation of the CGMP regulations that the productwas therefore adulterated and that in
dividuals. under the legal doctrine ofstrict criminal liability under the Federal Food, Drug, and Cosmetic Act,were criminals responsible for theseviolations. Binding regulations would.in their opinion, provide the agency noflexibility for discretion in enforcement of the act. Finally, the comments objected that there was no needfor binding regulations because therewere only a few large pharmaceuticalmanufacturers involved in productionof most drugs; because these were subject to frequent inspections by FDA;and because in the past, these firmshad been subject to few problems, fewrecalls, and rare legal proceedings.This history suggested that most firmswere in substantial compliance withthe regulations regardless of whetherthey were classified as substantive orinterpretive.
The Commissioner has evaluatedthese objections and found that, although some have merit, none is so serious as to outweigh the benefits frommaking CGMP regulations binding.Recognizing the diversity of manufacturing and control procedures, theCommissioner has endeavored wherever possible to state CGMP regulationsin the terms of objectives to be attained, rather than methods of attaining such objectives. Procedures havebeen specifiedonly where essential toassure product quality under the act.Thus, these regulations provide flexibility to manufacturers to select themethods and processes that will bemost suitable to the products and operations of the individualfirms. T h i sflexibility should also permit the development of novel approaches to atta ining the same objectives. In thosefew cases where precise procedures areset forth in these regulations. individuals who believe that alternativemechanisms may also be acceptableare invited to petition the Commissioner to amend the specific regulationto permit such alternatives.
As discussed in paragraph 35 of thispreamble, the Commissioner does notbelieve that FDA lacks sufficient expertise to develop and promulgateCGMP regulations and advises thatthe public procedures for commentingon these proposed CGMP regulations,together with the opportunity to petition the agency for changes in the regulations. provide individual manufacturers withan opportunity to correctany errors in FDA’s information.Thus, the Commissioner does not believe the agency lacks sufficient infor
45025
mation to justify making CGMPregulations binding rather than interpretive.
With regard to the alleged lack offlexibility in the enforcement of "bining" CGMP regulations. theCommissioner believes that the comments have confused the question ofwhether a violation exists with thequestion of whether FDA will takeaction upon the violation. In numerous areas, FDA has established tolerances for actionable offenses and iscurrently in the process of establishing regulations setting forth agencypolicy with regard to prosecutions forviolations of the act. It should benoted, however, that even in the absence of any CGMP regulations,whether binding or not, the doing ofor failure to doany particular actwhich is inconsistent with currentgood manufacturing practice results inthe product being legally adulterated,even if no legal action is brought. Thatis to say, the existence of CGMP regulations does not create violations ofthe law where they did not previouslyoccur. The question rather is whetherthe violator will be prosecuted or enjoined and/or the product seized, anissue beyond the scope of this rulemaking.
Finally, with regard to the objectionthat there is no need to make theseregulations binding since most majorpharmaceutical manufacturers are insubstantial compliance with the current regulations, the Commissioner believes that this is simply not relevantto the question of whether CGMP regulations should be binding or interpretive. The most significant justificationfor having the regulations bindingisto minimize the burden on the government and on the courts in a casewhere a violation does occur. Whenthe regulations are merely interpretive, the agency must provide experttestimony in each trial to demonstratewhat the current good manufacturingpractice in the industry is, notwithstanding the regulation. The cost oflocating and preparing such expertwitnesses and bringing them to thetrial, as well as the judicial time takenin hearing these witnesses, would beeliminated by having binding regulations. In the event that a challenge israised about the validity of the regulation. FDA can present to the court theadministrative record underlying theregulation in lieu of any expert testimony. Thus, it is not the proportion ofmanufacturers who are in compliancewith the regulations but the numberwho are out of compliance and whosenoncompliance justifies regulatoryaction that necessitates making theseregulations binding. For these reasonsthe Commissioner has concluded thatinsofar as he has discretion to issueCGMP regulations as either binding or
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
. .
e
l
l
s
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l
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d
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45026 interpretive. He elects to make them binding.
37. Several comments suggested thewords “where applicable" be insertedin the first sentence of § 210.1(a). Thecomments argued that, as proposed,the CGMP regulations would requireconformance to every requirement regardless of the need to do so.
The Commissioner concludes thatthere 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 agiven manufacturer’s operation do notapply. In addition, a new paragraph(b) is established in §210.2 to clarifythat the requirements apply only tothose operations subject to the CGMPregulations in which the manufactureris engaged.
38. Two comments recommendedthat the references in this section beParts 210 through 226 instead of Parts210 through 229, since §229.25 wasbeing revoked.
Since the Commissioner has reserved all parts between 210 and 229for current good manufacturing practice regulations, the reference is appropriate. Even though §229.25 hasbeen revoked. Part 229 may be used inthe future.
39. One comment suggested insertion of the phrase “and testing andquality control thereof” after thewords “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 definedin §210.3(b)(12) to includetesting and quality control of drugproducts, the Commissioner rejectsthis comment.
40. A large number of comments recommended that the personal liabilitystatement in §210.1(b) be eliminated.Some comments suggested that an individual should be held responsibleonly 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 bythe section and that it was not usefulin clarifying the requirements of theact. Another asked about the definition of “responsible.”
The Commissioner notes that actualcontamination of a drug does not haveto occur for the article to be deemedadulterated under section 501(a)(2)(B)of the act. Further, the act does notrequire a showing of intent for aperson to be held accountable underthe act. United States v. Dotterweich, 320 U.S. 277. (1943); United States v. Park. 421 U.S. 658 (1975). It would becontrary to public policy and congres-
RULES AND REGULATIONS
sional intent. as well as beyond theCommissioner’s authority, to requirethe showing of actual contamination or intent. Congress purposely did notdo so in order to provide. the maximum protection of the public health.
With regard to clarifying “person,”the Commissioner advises that theword “person ”is defined in section201(e) of the act to include corporations and partnerships as well as individuals. Under section 301(d) of theact, the adulteration of any drug is aprohibited act, and under section303(a) “any person who violates a provision of section 301” is subject tocriminal penalties. Thus, the referenceto “the person” in § 210.1(b) merelyparallels the statutory language. Thereference to the word “responsible” isin accord with interpretations of theact by the Supreme Court of theUnited States. See United States v. Park, 421 U.S. 658 (1975). Thus, theCommissioner does not believe thatthis 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 tofailure to comply with the CGMP regulations. For this reason. the languageis retained in the final order.
41. One comment said the CGMPregulations, as proposed. set up FDAas 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 Justiceserves as prosecutor, Federal judgespreside. and in criminal cases there isa right to trial by jury. The role of’FDA is twofold:First, it establishesstandards amplifying the statutorylanguage (through issuance of CGMPregulations after public comment);and second, it investigates to determine whether these standards havebeen violated. Affected persons havefull legal rights, including the rlght tochallenge the regulations as beingbeyond the authority of the act. TheCommissioner finds no rationale tosuggest these CGMP regulations compromise any person’s right to due process.
VI. APPLICABILITY OF CGMP REGULATIONS ; EXEMPT IONS
42. Many comments said thereshould be exemptions or waivers fromthe CGMP regulations for certainclasses of drugs or specialized kinds ofmanufacturing activities. These comments came from manufacturers ofbulk drugs, veterinary drug products.radiopharmaceutical drug products,
biological drug products, so-called“drug-cosmetic” products, and wholesalers and retail dispensers of drugproducts. These comments, exceptone, asserted that the CGMP regulations were inappropriate, unnecessary.excessive, or not part of current industry practice when applied to the typeof product identified; the exception(discussed in paragraph g. below). together with one comment regarding aparticular product line, questionedFDA’s legal authority to apply CGMPregulations to certain types of businesses or products.
As discussed in the preamble to theFebruary 13, 1976 proposal, the Commissioner intends to propose at futuretimes CGMP regulations for specificclasses of drug products such assmallvolume parenterals, compressed medical gases, and radlopharmaceuticals.(See. e.g., the proposal regaring LVP's published in the FEDERAL REGISTER of June 1. 19 ’76 (41 FR 22202).) Inaddition, regulations for certain kindsof manufacturingactivities such asmanufacturing of bulk drug components, repacking. or relabeling will beproposed. Generally, these future regulations will supplement, and in somesituations supersede, the more generalCGMP regulations. As these proposalsare issued, the need for waivers fromor modificationsin the general CGMPregulations should be diminished.
After considering these plans andthe comments regarding exemptionsfor specialized drug products or manufacturing activities, the Commissionerhas reached the following conclusions:
a. Bulk drugs. It is first necessary todistinguish between (1) “drug products” (i.e., finished dosage forms) thatmay 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 requirementssetforth in Part 211 are intended to applyto the preparation of a finished dosageform, whether or not inpackaged form. Thisis clearly set forth in theregulations (§§ 210.3(b)(4) and211.1(a)). Although these CGMP regulations are not applied to the manufacture of bulk drugcomponents,there are numerous instances wheregood manufacturing practices for bulkdrug components would parallel therequirements set forth in Part 211. Forthis reason. FDA will utilize the standards of Part 211 as guidelines duringinspections of manufacturers of bulkdrug components under the jurisdiction of the act.
b. Veterinary drug products. Veterinary drug products- shall continue tobe subject to the neneral CGMP regulations for all drug products, with certain specific exceptions, namely§§ 211.42(d), 211.46(d), and 211.72.Comments regarding the appropriate-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45027
ness of individual provisions of theseregulations 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 toveterinary drug products, exemptionsfor such products are stated in thatsection.
c. Radiopharmaceutical drug products. The general CGMP regulationsare suitable requirements for the preparation of radiopharmaceutical drugproducts. When the Commissioner wasaware of situations where the requirements are not appropriate, exemptionswere made from these final regulations. Supplemental requirements specific for radiopharmaceuticals will beproposed in the future.
T h e .Biological drug productsd. Commissioner notes that section
RULES AND REGULATIONS
changes to assure that the CGMP requirements would not increase manufacturing costs without a commensurate increase in safety, purity, potency, or efficacy. However, no specificexamples were submitted to FDA inresponse to the proposal that can beconsidered as areas for exempting biological drug products. The Commissioner invites interested persons tosubmit petitions under § 10.30 to amend particular provisions of theCGMP regulations to account for thespecial technologies or incompatabilities of biologics.
e. Compressed medical gases. T h e agency will propose specific CGMPregulations for compressed medicalgases. Until such regulations can beproposed for public comment, comments received and evaluated, and afinal regulation published, however,the Commissioner concludes that the
ble provisions of the CGMP regulations to insure that drug products arehandled and stored in a manner that will not contribute to loss of identity,strength, quality and purity. In addition, they are responsible for beingable to identify the distribution ofdrug products that are subject torecall or market withdrawals. Recall strategy will frequently involve wholesalers as consignees and intermediatedistributors when recalls are to the retail or consumer levels. In the FEDERAL REGISTER of June 16. 1978 (43 FR 262021. FDA published regulations toprovide guidance to manufacturersand distributors in this area. It is especially important for wholesalers tomaintain adequate records to assureeffective recall or market withdrawal. If future experience indicates to FDAthat recalls and market withdrawals are being adversely affected by inadequate recordkeeping on the part of
902(c) of the act parallels section351(g) of the Public Health Service requirements in the more general
CGMP regulations, with certain stated the wholesalers, the CommissionerAct (42 U.S.C. 262(g)), which providesthat section 351 does not affect, exceptions, are applicable. It would
not be in the public interest to delay awill give further consideration to theneed for specific CGMP regulationsfor wholesalers.
modify, repeal, or supersede the Federal Food, Drug, and Cosmetic Act. final regulation based on the February
13, 1976 proposal until FDA can pro-The agency has consistently interpreted these provisions to be additive; that
h. Drugs that are also cosmetics.A number of comments, including a petimulgate specific CGMP regulations
for compressed medical gases. tlon to the Commissioner, were re-is, although they preclude duplicativeor inconsistent regulation under the f. Repackaging and relabeling. Only
certain portions of the general CGMPceived regarding the applicability ofthe proposed general CGMP regulations to a class of products identified
two acts, where one statute speaks to amatter regarding biological productsand the other statute is silent, the ex-
regulations apply to repackaging andrelabeling operations. For example, as “cosmetic-drug products” and de
scribed as those which: (1) Meet thepress statutory provisions govern, regardless of the statute in which they
the requirements pertaining to labeling control apply to repackers and re definitions of both “drug” and “cos-
appear. Thus, for example, the provisions of section 505(i) of the act re
labelers; while the requirements for metic” under section 201 of the act; (2)represent a minimal health or safetyrisk; and (3) are marketed over-the
compounding a drug product do notapply since repackers/relabelers dogarding investigational use of new
drugs have been consistently held to not compound drug products. TheCGMP regulations apply to repackaging and relabeling operations at loca
counter for regular and frequent consumer use without dosage limitations.apply to biological products because
no part of section 351 of the PublicHealth Service Act addresses investi-
Examples of these products were described as medicated skin creams, antitions that are different from the place
of manufacture. Supplemental CGMPgalional use of biologics (21 C F R 312.1(g)). Because section 351 of the
bacterial soap, antiperspirants, andtopical sunburn prevention products.regulations regarding this unique type
of drug processing will be proposed inPublic Health Service Act does not Specifically, the comments requestedrefer to current good manufacturingpractice and because biological prod-
the future. separate CGMP regulations for this al-g. Wholesalers. Section 501(a)(2)(B) leged class of drugs, and one comment
submitted a proposed new part 213 foructs are considered to be drugs subjectto section 501(a)(2)(B) of the Federal
of the act provides that a. drug shall bedeemed to be adulterated if “the drug-cosmetic products, drafted in the
style and format of other CGMP regu-Food, Drug, and Cosmetic Act, the methods used in, or the facilities or Commissioner believes it is consistent controls used for, its manufacture, lations for drugs. Another comment
recommended that, because the drug-with both laws to apply current goodmanufacturing practices to biological
processing, packing, or holding do notconform to current good manufactur cosmetic products were so similar to
drug products. ing practice � � *." This section,Biological products are now manu- through the operation of section
related cosmetic products, CGMP regulations for those two classes of products be proposed and adopted togethfactured according to current good 301(k) of the act, applies to wholesal
manufacturing practice and regulated ers, retailers, pharmacies, and hospiunder parts 600 through 680 (21 CFR tals, as well as to manufacturers. How
er, separate from those relating todrug products generally.
The Commissioner has concludedparts 600 through 680), in particular ever, the CGMP regulations set forth the establishment license and product in part 211 apply only to establish-license provisions. Sections 219.2 and
that these regulations, except expiraments engaged in the preparation of a tion dating for certain human OTC
211.1 clearly provide that the more drug product. Therefore, these regula- drug products described in paragraphspecific biologic regulations prescribed tions do not apply to the wholesalers, 353 of this preamble, must apply to allin 21 CFR Parts 600 through 680 will retailers, pharmacies, and hospitals products meeting the definition ofsupplement or supersede, where ap- engaged in activities that are tradi- drug products, whether the drug prodpropriate, the more general drug tional to those establishments. The ucts are highly potent prescriptionCGMP regulations. The Commissioner wholesaler, however, is a particularly drugs or are OTC drugs of the type de-believes it possible that provisions In important link in the distribution scribed as “cosmetic-type.” Past expethe general CGMP regulations may be chain between manufacturer, retailer, rience of the agency has demonstratedinappropriate for certain biological and consumer. The Commissioner en- that the public has been put in a hazproducts and would make appropriate courages wholesalers to adopt applica- ardous situation because of manufac-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45028 turing errors in OTC products, such asby the substitution of spirits of camphor for castor oil. Further, the Commissioner notes that there are veryfew clearly innocuous drug products orcomponents in the OTC area. Severalexamples can be given: If appropriatestability study requirements and manufacturing controls required by CGMPregulations are not met for fluoridetoothpaste, there could be a questionof effectiveness of the products because of the unavailability of fluoridein a toothpaste. In the case of aerosolized products, control of the particlesize and identity and purity of components are important for the safety ofthe user. In the case of topical cosmetic-type drugs, the incidence of allergicreactions may be lessened by the assurance of uniform quality of theseproducts. That many- of the generalCGMP regulations are applicable toand reasonable for cosmetic-type drugproducts is evidenced by the fact thata majority of the specific suggestionssubmitted by the petitioner and othersas applicable for cosmetic-type drugproducts duplicated in substance, anumber of comments submitted byother OTC manufacturers and manufacturers of prescription drug productsand the proposed text of part 211.
Although he declines to provide abroad exemption for cosmetic-typedrugs products, the Commissionerpoints out that a number of changesproposed by the comments are adopted in the final regulations. These suggested changes were nppropriate forapplication to the manufacture of alldrugs products, however, and notmerely cosmetic-type drug products.In many instances the suggestedchanges that were adopted do notalter the original intent of the regulations, but clarify it or provide flexibility in complying. In a few cases, theproposed requirements were deleted orchanged 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 productsthat are also human foods from Part211. the Commissioner has tentativelyconcluded thnt there may be a fewsuch products that would more appropriately be regulated under the goodmanufacturing practice regulations forfood. He believes that the type of OTCdrug products that could be exemptedfrom Part 211 are those that are ordinarily marketed and consumed ashuman foods which may also fallwithin the legal definition of drugs byvirtue of their intended use. Therefore, elsewhere in this issue of theFEDERAL REGISTER, the Commissioneris proposing to exempt such productsif the products and all their ingredi-
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ents are ordinarily consumed ashuman foods. Examples of productsthat the Commissioner foresees beingcovered 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 asan antacid but ordinarily use as an ingredient of human foods under themore common “baking soda” label. Inproposing this exemption for certainOTC drug products, the Commissionerhas considered, first, the inadvisabilityof applying drug CGMP regulationsthat are not necessary to ensure appropriate quality characteristics inview of the intended use of a productand, second, the reasonableness of applying food GMP regulations to aproduct manufactured, handled, andordinarily consumed as a human food.
Therefore, the Commissioner hasstated under §211.1(c) that, pendingconsidered of the proposal, the requirements of Part 211 will not be enforced for OTC drugs that meet theproposed definition. During the interim and until further notice, regulations under Part 110 (21 CFR Part110) and, where applicable, Paris 113to 129 (21 CFR Parts 113 to 129) shallbe applied in determining whetherthese products are manufactured, processed, packed, or held under currentgood manufacturing practice.
43. One comment from a universityschool of pharmacy asked whetherfuture proposed CGMP regulationswould specifically state their applicability to such situations as (1) personnel at hospital "A" strip-packagingdrug products for its own use as well as for use in hospitals "B" and "C" (2)personnel at the warehouse of a chainof pharmacies who repackage and relabel quantities of drug products frommanufacturers’ original commercialcontainers for different units in thedrug store chain; and (3) similar repackaging and relabeling by individualpharmacists as members of informalbuying groups.
As noted in paragraph 42(g) above,section 501(a)(2)(B) of the act appliesto retail establishments, pharmacies,and hospitals, but the specific regulations in Part 211 do not. When CGMPregulations for repackers and relabelers are proposed. some of thesequestions posed in the comment willbe addressed. Regarding pharmaciesand hospitals in particular, however, itis the policy of FDA not to inspectroutinely for compliance with section501(a)(2)(B) of the act establishmentsthat operate within State or local lawsgoverning the practice of pharmacy.Nor has FDA ever sought to issue specific CGMP regulations for pharmacies engaged in traditional activities ofdispensing 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 insection 704(a) of the act. When a hospital or pharmacy is engaged in drugrepacking or relabeling operationsthat are beyond the usual conduct ofdispensing or selling drugs at retail,however, the exemptions in the actcease to apply; the establishment is required to register and is subject to regular inspections under section 704 ofthe act. Furthermore. appropriate current good manufacturing practicemust be complied with.
44. Several comments expressed concern about the applicability of CGMPregulations to foreign drug manufacturers. One comment said foreign drugmanufacturers may not uniformly besubject to the stringent controls ofUnited States manufacturers and thatsampling of foreign drug products atthe point of importation is not sufficient to assure the quality of thosedrugs. Two foreign drug manufacturers indicated that CGMP regulationshad a significant impact on their operations. Another foreign manufacturersaid 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, ofcourse, apply to manufacturing ofdrugs in other nations if the drugs arenot brought into the United States.Many foreign countries, however, haveadopted requirements similar toCGMP regulations, and foreign manufacturers may be subjected to inspection by their own governments. International organizations such as theWorld Health Organization and theEuropean Free Trade Association provide manufacturing standards and reciprocal agreements between participating countries. Overseas pharmaceutical manufacturers who export to theUnited States are inspected by FDA orunder reciprocal inspection agreements as part of the new drug application approval process and antibioticdrug certification, and individunl drugproducts are subject to intensive examination, including testing, beforebeing 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 authorityto deny entry of the article unless factory inspection is permitted or insepctional information is available about those firms covered under reciprocalinspection agreements. The UnitedStates currently has reciprocal inspection agreements under which govern-
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45029 ments will exchange inspection information about domestic firms in lieu of conducting overseas inspections. Theseagreements are with Sweden, Switzerland, and Canada. Therefore, theCommissioner finds that there is adequate coverage of imported drugs toassure compliance with CGMP regulations.
45. Several comments referred to provisions in the Medical DeviceAmendments of 1976 and requestedthat FDA consider providing for exemptions from or variances to theCGMP regulations and special advisory assistance as Congress specificallymandated regarding FDA regulationof 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 thecomments was that the proposedchanges would seriously affect the initial and continuing costs of a “small” drug manufacturer but probably havelittle economic impact on, or couldmore easily be absorbed by, a “large”pharmaceutical manufacturer. Severalcomments expressed concern that generic drug manufacturers might beeliminated because they could not meet all the requirements of the proposed CGMP regulations and stillcompete in the marketplace. Arguments were presented that, becausesmall manufacturers very often are involved with the manufacture of a small number of products (frequentlyless potent over-the-counter preparations) and almost by definition havesmall physical facilities, limited equipment, and few personnel, extensive formal quality control procedures areunnecessary to assure high quality ofthe drugs manufactured. One comment, apparently from a small manufacturer, agreed in principal with theproposed CGMP regulations, felt thatsize had very little to do with achieving good manufacturing practice, andoffered comments on specific sectionsof the proposed CGMP regulations.
The Commissioner rejects the contention that quality control procedures are unnecessary in the case ofsmall firms; FDA’s experience is thatquality control procedures fallingbelow those described in these regulations, in firms of great or small size,are often responsible for lack of drugproduct quality. The Commissioneralso rejects the argument that lesscontrol need be exerted over so-called “less potent over-the-counter preparations,” which respondents stated areoften manufactured by small firms,for the reasons explained in paragraph 42(h) above.
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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 sectionsstrongly suggested that the intent ofthe proposed regulations had beenmisunderstood. The language has beenclarified in the final regulations. Inother instances the requirements werereworded to provide for more flexibility for the varieties of procedures andcontrols that may be utilized by various manufacturers.
The Commissioner does not believe a specific provision within the CGMPregulations for variances to these regulations is necessary for small manufacturers. A mechanism already exists, however, in 21 C F R 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 conductedand participated in numerous seminars and workshops designed to assistdrug firms in interpreting and carrying out the requirements of CGMPregulations. Additionally, the agencyhas 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 effortsespecially designed to assist small businesses.
46. Several comments noted that the current good manufacturing practiceregulations do not pertain to veterinary biological products. One respondent suggested that the section specifically state that these regulationsapply only to human biological products.
The Commissioner believes that the section as proposed clearly establishesapplicability to pertinent biologicaldrug regulations, but for consistencywith 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 requestedclarification 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 hisintent. Certainly, in the case of conflicting or contradictory regulations, itwill be impossible to comply with allregulations and the regulation that is specifically applicable to the drugproduct in question would apply.
48. A comment suggested that ifmedicated premixes are meant to beexcluded from Part 210, then Part 226should 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 ln Parts211 through 229.
49. One person proposed that the term “drug product” be replaced withthe words “commercial dosage form”to exempt drugs undergoing development from the requirements of theseregulations.
The Commissioner finds that, asstated in §211.1, these CGMP regulations apply to the preparation of anydrug product for administration tohumans or animals, including thosestill in investigational stages. It is appropriate that the process by which adrug product is manufactured in thedevelopment phase be well documented and controlled in order to assure the reproducibility of the product forfurther testing and for ultimate commercial production. The Commissioneris considering proposing additionalCGMP regulations specifically designed to cover drugs in research stages.
VII. DEFINITIONS The Commissioner received hun
dreds of comments regarding definitions. General comments are listed immediately below; comments regardingspecific 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 whichare 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 arewell known or already defined in theact. Other terms the meanlng ofwhich may not be as readily recognized, or may vary in other regulationsbecause of context and needs, are defined in part 210 as a standard reference.
51. One comment suggested that allterms 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 advantagesover the more usual manner of printing. For example, some persons mightinterpret highlighting as adding emphasis that is not intended to a particular word or phrase. This suggestioncannot be adopted.
52. One respondent suggested rulesfor selecting words to be defined,namely: (1) Words which will be usedin a sense differing from that given inthe currently accepted dictionariesand words whose meaning will belimited by the regulation.
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45030 The Commissioner believes the
above criteria have been generallyused for selecting terms to be defined.He does not wish. however, to limitstrictly the criteria for determiningthe terms to be drfined in this part.53. Several comments asked tha t
commonly used terms such as “drugproduct containers,” “labeling,” and“production area” be defined.
The Commissioner finds that either the terms have already been definedelsewhere (e.g., “labeling.” which is defined in section 201(m) of the act) orthey are generally well understoodand need no further definition (e.g.,“drug product container”). He concludes that no further definitions needto be added at this time.
54. One comment suggested that“cycle of manufacture” be defined in§ 210.33(b)(2) as “any period of time inwhich the batch is not adversely altered.”
The Commissioner has consideredthis comment, but does not find thatthe suggested wording offers any advantage. The definition. as it appearedin the proposal. has been in theCGMP regulations for a number ofyears. The Comtnissioner is confidentthat this definition is well understood.
55. Several comments suggestedmodification of the term “batch” in§210.3(b)(2) by addltion of the words"is intended to have” before “uniformcharacter.” Another modification suggested was a new` phrase at the end ofthe sentence “Which is accepted andoffered for sale or distribution."
In defining a “batch.” the Commissioner has adopted the phrase “intended to have unifortn character and quality.”Using the. phrase “intendedto have” in the definition allows the use of the term“batch”withouthaving to distinguish between acceptable and unacceptable batches. If amanufactured batch does not haveuniform character and quality withinspecified limits, then the batch becomes an unacceptable or a rejectedbatch. The Commissioner rejects thephrase “which is accepted and offeredfor sale or distribution.” Thosebatches which are manufactured but,never intended for sale or distributionmay 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 “ingrcdicnt.” statingthat the former tcrtn has been used inthe drug irtdustry for “packaging supplies.”
The Commissioner recognizes thatthe term “component” is broadly usedin the English language and may havea variety of meanings However. thedefinition of this term in the proposalhas been in rffcct for a number ofyears and the Commissioner believes itis generally well understood. Because
RULES AND REGULATIONS
only three comments were received regarding this particular issue, the Commissioner concludes that the drug industry generally does not flnd the term misleading. Therefore, the recommendation is not adopted.
57. A suggestion was made that thedefinition for the word “component”in § 210.3(b)(3) should include gasesand filters, because these items needadditional control when used in the manufacture of injectable products.
The Commissioner notes that “component” includes gases that are usedas ingredients. He believes filters aremore appropriately classified as equipment. The Commissioner believes that control of gases and filtersis adequately set out in the regulations.
58. One comment suggested that thedefinition for “component” be expanded to include the phrase “raw material. chemica l compound, drug substance orpharmaceutic ingredient.”
The Commissioner agrees that theabove items when used as ingredientsare properly classed as components. Itis not necessary or desirable, however,to list each type of material that maybecome a component under the regulations, because items other than thoseidentified in the comment may also be“components.” Therefore, the suggestion is not accepted.
59. A suggestion was received to include the following phrase after theword “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” isdefined in paragraph (b)(4) of §210.3as “a finished dosage form” and restatement of the definition is inappropriate.
60. Several comments requestedclarification of the relationship amongthe definitions in § 210.3(b) (3), (7), and (8) of “component.” “active ingredient,” and “inactive ingredient.”Comments expressed concern thatproposed deflnitions of the types of ingredients do not include all materialscontemplated under the definition of“component.”
The Commissioner finds that the definition for “inactive lngredicnt” in§210.3(b)(8) should be modified so that it clearly includes “any component. other than an active ingredient.”He believes thh change wlll eliminateany misunderstanding of these definitions.
61. One comment suggested that theterm “drug product,” as proposed in§ 210.3(b)(4). could be interpreted tomean only the finished packaged unit.
T h e Commissioner finds that the term is defined as meaning “finisheddosage form” regardless of whether itis in package form.
62. A comment was received statingthat the term “drug product” as defined in 8 210.3(b)(4) excludes Placebosbecause the definition includes the phrase “active drug ingredient.”
The intended use of placebos inmedical treatment is to bring about. atherapeutic effect, without apharmacologlcally active agent, because of thepsychic effect in some patients thatmay produce symptomatic relief. Inaddition, it i s often used as a control in clinical trials for new drugs. Eventhough the chemicals from whichthe placebos aremade are not intended to cause a direct pharmacologic response,the maintenanceof their quality is important because of their use in patients, particularly in controlleddrugstudies. By its use, a placebo meetsthe definition of a “drug” contained insection 201(g) of the act. Therefore, toeliminate any doubt whether theseregulations apply to placebos,the Commissioner has revised the definition to include them specifically.
63. A number of commentsquestioned the definition of “fiber” in proposed § 210.3(b)(5) The commentswere that “fiber” had been defined arbitrarily and without scientific basis;that the definition was too gencrnland could include, for example. crystal, metal and splintered wood; andthat the definition shouldinclude dimentional parameters for the fibersize. Commentsrecommended that the definition include morphological descriptions such asthreadlike filamentous, amorphous or noncrystalline,cellular, foreign, and hairlike.Severalcomments recommended thatthe American Society for Testing and Materials definition be used. Others suggested that a length of atleast 100 microns and a length/width ratio of 10 to1 be adopted. One comment called foradopting a minimum length of 10microns and a diameter one-tenth the length.
The Commissioner finds thatthe term “fiber” has not been defined arbitrarily and without scientificbasis The basis for the fiber definition was discussed in the final regulations forasbestos-form particles in drugs forparenteral injection,which appeared In the FEDERAL REGISTER of March 14,1975 (40 FR 11865). (Those final regulations reference the definition of “fiber” appearing in " O c c u p a t i o n a lExposure to Asbestos.”criteria document, U.S. Public Health Service,National I n s t i t u t e f o r OccupationalSafety andHealth Chapter VIII, p. 6, 1972.) The Commissioner believesthat the definition should bea s broad a s possible and that the suggestedmorphological descriptions and dimensional parameters are unnecessary and inmany instances are not infortnativr.Dimensional parameters were intentionally left out because current,
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knowledge is limited as to what sizefiber does not constitute a hazard.Furthermore, the suggested fiberlength of at least 100 microns is unacceptable because most asbestos fibersreleased from asbestos-cellulose filtersare less than 70 microns in length.
The American Society for Testingand Materials“ specifications (ASTMManual F24-65, Standard Methods forMeasuring and Counting ParticulateContamination on Surfaces) for defining “fiber” are not pertinent to thesubject at-hand. They were developedspecifically for particles on surfaces ofmechanical objects as related to abrasion of such objects.
To eliminate any concern that thedefinition of fiber would include particles intentionally present, as in drugsuspensions, the final regulation ismodified by adopting the concept ofparticle contamination. Therefore,fiber means any particulate contaminant having a length at least threetimes its width.
64. Comment was received regarding§210.3(b)(8) 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 meetthe definition.
The Commissioner advises that thefinal 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 tocomments in that document, the Commissioner concluded the definitionshould include the concept that afterappropriate pretreatment such aswashing or flushing, the filter will notcontinue to release fibers into thedrug that is being filtered. The designconcept is therefore taken into account because of the distinction madebetween filters which release fibers bymedia migration, i.e., continuous release due to the nature of the filter,and filters which contain fibers fromstructural supports and contamination.
With regard to the comment thatthe requirement for nonrelease offibers is unrealistically absolute, theCommissioner finds that the definition clearly describes types of fibersthat are relied upon in the industry as“non-fiber releasing.” The Commissioner concedes that any filter may release an occasional particle, some ofwhich may meet the deflnition of“fiber” under § 210.3(b)(5). The purpose of the definition for “non-fiberreleasing filter,” which has been applied for over 2 years without apparent misunderstanding, is to provide areasonable and practical description of
RULES AND REGULATIONS
a filter that may be fabricated from anumber of different materials and will not, in the ordinary sense, introducefibers 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 releasingfilter”, FDA is studying several issuesinvoving fiber contamination and theeffects on humans to fiber exposure.Until such time as the Commissionerhas obtained sufficient information toalter has position on fiber contamination in parenteral drug products without adversely affecting the publichealth, he concludes that the definition for “non-fiber releasing filter”continues to be appropriate for theseregulations.
65. Comment was received that thedefinition of “non-fiber-releasingfilter” as written in § 210.3(a)(6) woulddiscourage the development of asbestos filters that might not be fiber releasing.
The Commissioner advises that it isnot the intention of FDA to discourage the development of asbestos filters. In this regard, the preamble tothe final order in the FEDERAL REGISTER of March 14, 1975 (40 FR 11885)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 anasbestos filter for filtration of in-process materials. This use of asbestos filters is unacceptable, except under theprovision of p 211.72(b), and would defeat the purpose of the regulation.
67. A comment suggested that afterthe word “component” in § 210.3(b)(7) the phrase “other than veterinary biological immunizing or diagnosticagent” 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 theseregulations. It is not desirable or feasible to identify in these regulationsevery specific class of articles that arenot subject to CGMP regulations. Veterinnry biologicals have, however,been excluded by changes in §210.2.When an interested person has a question regarding the status of anotherindividual product or class of products(for example, the status of an articlethat may be either a drug or a device),that person may obtain a formal opinion from FDA pursuant to 21 CFR10.85.
68. Several comments asked thatlimits 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 theterm “in-process materials” is intended to apply to materials being Processed by establishments engaged inthe preparation of a drug product. Hebelieves this intent is clear when theterm is considered in the scope ofthese regulations and that no changeis needed.
69. Several comments requestedclarification whether the term "inprocess 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” includelabel printing. The regulations do notsuggest that such labeling would constitute in-process materials. References to labeling materials are clearlystated in these regulations when appropriate.
70 . One comment suggested that theword “materials” in § 210.3(b)(9) bechanged to “ingredients.”
The Commissioner concludes thatthe term “in-process materials” is incurrent usage and sees no advantageto introducing the suggested term "inprocess ingredients.”
70a. One comment stated that§210.3(b)9), and especially the word“fabricated.” is unclear and should befurther defined to eliminate any possible confusion.
The Commissioner does not agreethat the word “fabricated” is unclearwhen used in this definition. This suggestion is rejected because a broadterm such as “fabricated” is appropriate here.
71. Several comment said, in the caseof biologics, a “lot” may consist ofmore than one batch and suggestedthat this be included in the definitionof “lot” in § 210.3(b)(10).
Because the term “lot” has alreadybeen deflned specifically for biologicalproducts in 21 CFR 600.3(x) the Commissioner does not believe that anymodification of the definition in thispart is appropriate. As previously indicated, the more specific regulationsfor biological drug products take precedent over the more general.
72. Two comments said the term“lot” was used elsewhere in the CGMPregulations (e.g., § 211.84(a)) to referto containers and closures, which areneither drugs nor drug products. Theysaid either the definition in§ 210.3(b)(10) or the reference was incorrect.
The Commissioner notes that thedefinition in § 210.3(b)(10) refers tothe term “drug product,” but does notlimit to drug products the applicationsof the definition for “lot.” However,the proposed definition for “batch” islimited to drugs. Because a lot is defined as a batch or portion of a batch,
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Similarly, the definition f o r “l o t number” i s expanded to include othermaterials.
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, andthe definition is modified accordingly.
74. One comment suggested deletionof the word "complete" from§210.3(b)( 1) as superfluous and ‘subject to interpretation.
The Commissioner finds that use of the phrase “complete history” emphasizes that pertinent identifying informatlon is included.
75. Two comments suggested thatthe words "testing, and quality control of drug products” be deleted from thedefinition in §210.3(b)(12). One said these functions do not belong in thisdefinition because they introduce ambigultles elsewhere in the proposedregulations. Examples given are: (1) §211.103, which requires yield determination at the end of each distinct p h a s e o f manufacturing; and (2) §211.67(b), which requlres that procedures describe a cleaning schedule for all equipment used in manufacturing processing, packaging, or holding of a drug product. The respondent saidyield calculations and cleaning schedules do not apply to laboratory testingand equipment. Another respondentsaid the words "testing and qualitycontrol 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 drugproducts” In this paragraph. Indeed, comments were received on numerous sect ions o f the regulations (e.g., §§ 211.2 (recodified § 211.603) and 211.251 to add the phrase after referencea to "manufacture, processing,packing, and holding.” In all cases. theCommissioner has declined to make the addition. The purposes of thisdefinition are to make it clear that the phrase "manufacture, processing, packing, or holding of a drug product”includes operations that are commonlyknown 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 ofthese regulations. Section 211.103 is modified to provide that yield determinations are not required for qualitycontrol activltles. The Commissioner believes. however, that the requirements of §211.67(b) are appropriatefor quality control operations.
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The Commissioner believes that the functions of quality control and manufacturing can be included in the total concept of producing drug productsand still be independent. The com ment did not describe how the deflnition would actually cause a loss of independence of the quality controlfunction.
70. One comment suggested that theterm “warehousing” was more suitablethan 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 repented fromsection 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 producthas the identity. strength, quality andpurity which it purports to or is represented to possess."
The Commissioner does not agree that the definition is vague. T h e intent is to identify several key operations that might not be perceived as an integral part of the production of pharmaceuticals. but for purposes ofC G M P regulations must be included.It is not necessary, however, to describe every operation that is included unde the act.e responsibilities ofthe quality control unit are specifiedin § 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 duplicatefunctions such as engineering, whichare better handled by other professionals such as engineers. They also sa id the term “unit” generated confusion vis-ais the“quality control department” and “quality assurance department.” Another comment said theword “perform” shouldbe replacedw i t h “be responsible for.”
Functions that are properly those ofthe engineering department or otherspecialized units because of their unique training and experience shouldnot be duplicated or usurped by thequality control unit. Where expertiseis in other units, the responsibility of the quality control unit is to assure that such expertise has been utilized. In Order taoclear that qty
control functions may be performedby persona assigned to units outside the quality control unit. The Commissioner is replacing “perform” with “beresponsible for.” The quality control unit will still have the duty to assure that appropriate actre 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 withthe responsibility of quality control.The Commissioner is not concerned about the name given by a firmto its own unit that is responsible for quality control functions.
79. Several comments suggested useof the term “expected yield” insteadof “theoretical yield” in § 210.3(b)(17) and in § 211.192. They also suggestedthat the definition include a provisionfor normal and expected losses.
The terminology and concept of“theoretical d” appr to be understood and generad in the phar
maceutical industry. The Commissioner notes that the regulations(e.g..§§211.186(b)and 211.192) allow fornormal and excted losses before investigati or corrective actions are required. The concept of theoreticalyield is important a basis u p o n which actual or expected yields can becompared to the. theoretical yield toaid in determining acceptance.
80. One comment said the deflnltlon of “theoretical yield” is nonspecthe wording “quantity of components to be used.” A suggested alternativewording was “quantity of component specified by master production records for that operation.”
The Commissioner sees no need for the suggested revision in the definitlon section. The requirement for compounding in accordance with masterproduction records i s 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 anystage of manufacture. Another comment saidestablishing theoretical yield is not always possible for certain processes involving chemical actionsand production of biologicals.
The Commissioner believes that theoretical yield can be established forall processes. The theoretical yield for a chemical reaction for example. would be maximum yield obtainable under optimal reconditions. The Commissioner agrees that the word "stage" may not adequatelydefine the pha of manufacture atwhich the theoretical yield be determined. Therefore, he is adoptingthe phrase “appropriate phase" in paragraphs (b) (17), (18)and (19) of § 210.3.
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82. A number of comments havebeen received regarding proposedparagraphs (b)(21), (22), (23), and (24)of 0210.3. As discussed elsewhere inthis preamble, the Commissioner isnot including in these regulations, atthis time, specific requirements regarding “acceptable quality level andunacceptable quality level”; therefore,definitions for these two terms are deleted from the final regulation. Proposed paragraph (b) (21) and (24) isbeing 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 validreason exists for establishing revisedacceptance criteria following an appropriate documented quality assuranceconference.”
The Commissioner notes that theproposed 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 theproposed 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 agreewith this suggestion. The term"reject" does not denote the ultimatedisposition of the product, only that itis not acceptable for use as is.
85. One comment suggested that “sampling plans,” referred to in proposed §210.3(b)(21), are not the onlytechnique used to form a basis for acceptance and rejection.
The Commissioner has used theterm “sampling plan” in a broad context here. The term can mean both aplan for collection of physical unitsfor testing, or it can mean a scheduleby which an examination of some sortis done.
86. Numerous comments said the term “at random” should be deletedfrom proposed § 210.3(b)(24). Amongthe reasons given were that “random”has a limited meaning in statistics,that some samples are best taken on astratified basis, such as right aftereach start-up of a run, and that somesamples are taken on a timed basis.
The Commissioner is persuaded thatthe term “at random” without additional clarification may be too limitingfor this definition and modifies thefinal regulation accordingly.
87. In reviewing the proposed regulations, the Commissioner concludesthat §§ 211.2 and 211.68 should be combined-into a new §211.68. Proposed§ 211.2 is deleted, and the substance ofthe requirements is included in the
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new §211.68. The comments relating to §211.2 are discussed with those for § 211.68.
88. Three comments were receivedregarding proposed § 211.3 on definitions for Part 211. Two comments saidthe section is duplicative and shouldbe deleted. The other comment notedthat some of the words defined in referenced § 210.3 are not used in Part211.
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 adefinition section in each part of theCGMP regulations to accommodateterms specific to that individual partbut not others. This scheme has already been used in the proposedCGMP regulations for Part 212 relating to large volume parentera (LVP) ldrug products, published in the FEDERAL REGISTER of June 1. 1976 (41 FR222021. The Commissioner sees no inconsistency in that terms defined in0210.3 may not be used in Part 211,because they may be used in otherparts (e.g., Parts 225 and 226). Thedefinitions apply only where the term is used. VIII. ORGANIZATION AND PERSONNEL
89. One comment argued that, aswritten, the regulations (§§ 211.22211.34) permit the subordination ofthe 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 aconflict of interest.
The Commissioner do not agree. TheCGMP regulations do not subordinatethe quality control unit’s authorityand responsibility to any other unit.At the same time, the regulations regarding the quality control unit doesnot encroach upon the expertise or responsibility of other units in a firmand do not dictate the organizationalstructure of a firm. They simply require that the quality control unithave final responsibility for certain actions in the manufacturing process.
90. One comment suggested thatCGMP regulations assign individualcertification responsibility to personswithin the organization. This wouldinclude responsibility for review ofproduct specifications and control procedures to assure their adequacy andreliability.
The Commissioner notes that suchcontrol responsibilities are already assigned in these regulations to the quality control unit. “Certification” is notspecifically required as somethingmore than approval by the qualitycontrol unit. Assignment of individualresponsibilities within a firm shouldbe left to the discretion of management.
45033 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 itdeems flt. In addition, it was pointedout that quality control responsibilities are often performed by units ofthe firm other than the quality control unit; examples cited were formulation designed, development of themanufacturing process, and processcontrol design by research and development scientists, engineers, andother manufacturing specialists. Theduties outlined in the proposal for thequality control unit were described asduplicative of functions performedwith more expertise in other segmentsof a firm.
The Commissioner intends to makethe quality control unit responsiblefor ensuring that controls are implemented during manufacturing operations which assure drug product quality, not that the quality control unitactually perform each one of theduties. The Commissioner believesthat. even under § 211.22. managementhas the prerogative to organize its internal structure and assign responsibilities as it deems appropriate, as long assome identifiable person or unit has atleast those responsibilities assigned bythe regulations to the quality controlunit. To clarify that the quality control unit could not and should not perform duties duplicative of other partsof the organization, the Commissionerhas modified the definition of “qualitycontrol unit” in § 210.3(b)(15). Theword “perform” has been deleted andthe phrase “be responsible for” substituted. Additional clarification of theCommissioner’s position regardingthese comments may be found i n thepreamble discussion under paragraph78 of this preamble.
92. One comment asked that the responsibilities of the manufacturingunits be defined.
As long as provision is made in theseregulations for the assignment of certain quality control activities to aquality control unit, the Commissionerbelieves that other assignments shouldbe at the discretion of individualfirms’ management.
93. A comment made a distinctionbetween a quality control departmentand a quality control unit and questioned what duties would be assignedto each. Several other comments suggested that this section dealing withquality control units was primarily designed for large pharmaceutical firmsand did not take into considerationthat small firms could not comply.
The distinction made between “department” and “unit” is not requiredby the regulation, which does notspecify a name for the quality control
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_
45034 unit, but merely describes several responsibilities that a designated unitmust have. The organizational structure of the unit is left up to each individual firm’s needs.
A small firm may choose a differentmeans of structuring its organization.The term “quality control unit” is defined in § 210.3(b)(15) as any person ororganizational element. This meansthat in very small operations a singleindividual can function as the qualitycontrol unit, But that person still hasthe responsibility for implementing allthe controls and reviewing the resultsof manufacturing to assure that drugproduct quality standards have beenmet. As discussed above in paragraph45. the Commissioner rejects the ideathat quality control is not needed in asmall business.
94. A comment was made that thissection precludes the use of outsideconsulting laboratories for qualitycontrol work.
The Commissioner disagrees. Thereis no such prohibition in the regulations. A manufacturer does have a responsibility, however, to see that theoutside laboratory used is qualified todo the work and that the work is performed satisfactorily.
95. With respect to the quality control unit’s authority and responsibilityunder §211.22(a) for approval and/orrejection of raw materials, in-processmaterials, and finished products, oneperson asked that other alternativesbe permitted when materials may besuitable for other purposes and usesthan those originally intended.
Use of the word “reject” does notnecessarily 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 materialshows that it is not sultable for a particular use, It may not be used for thatpurpose and, therefore, is rejected. Itmay, however, be suitable for otheruses requiring a material with differing specifications.
96. Several comments proposed that§211.22(a) be modified so that thequality control unit would not have tohave the responsibility to review all labeling unless it is connected with themanufactured dosage form. The reasoning was that some promotional literature, not physically associated withthe drug product, had been defined as labeling in court suits where F D A charged misbranding of a product withpromotional literature, but that suchmaterial was not labeling in the sensein which these regulations referred tolabeling.
The Commissioner notes that the scope of the CGMP regulations is toset forth the facilities. methods, andcontrols to be used for the manufacture, processing, packing, or holding of
RULES AND REGULATIONS
a drug product. It is not the purposeof the CGMP regulations to control labeling such as promotional literaturethat is not associated with the drugproduct during its preparation underCGMP regulations.
97. Comments asked for modification in the last sentence of § 211.22(a)relating to production of drugs undercontract by another company. Theysuggested that the contractor could release drugs for distribution on his ownresponsibility if a certificate of analysis showed compliance with appropriate specifications. Others suggestedthat the responsibility for approvingor rejecting drug products producedby contractors appeared in this paragraph to rest with the contractor.
This paragraph clearly says that thequality control unit of a contractingfirm must approve or reject drug products produced by contractors. TheCommissioner believes this is properbecause, in the circumstances described, the contractor does not ownthe goods, but merely performs a service for the contracting firm. The responsibility to approve release of adrug product for distribution mustrest with the owner of the drug product.
98. A number of persons respondingto the proposal objected to the example of bioequivalence testing as one ofthe tests which must be performed ina quality control unit’s laboratory.Some said this type of testing was normally done outside the quality controlunit, such as by a medical unit. Otherscomplained that bioequivalence standards are in a state of flux and have notas yet been established.
Bioequivalence tests may includetests such as dissolution tests, whichare generally done in the quality control unit’s laboratory. They also mayinclude in vivo tests done by medicalunits within or outside the firm. TheCommissioner agrees, therefore, thatthis example is not necessarily onewhich generally represents the workdone in the quality control laboratory.Although he is deleting the bioequivalence testing example, in vitro dissolution tests for bioequivalence are infact an example of the type of workthat could and should be done in thequality control laboratory.
99. Two comments suggested eitherdeleting the reference in § 211.22(b) to“packaging materials” as one of thearticles tested in the quality controllaboratory, or changing it to “packingmaterials,” on the basis that the examination for suitability of such materials is more properly a function of theshipping department and relates solelyto protective qualities to prevent mutilation or breakage of drug productcontainers.
Breakage of containers can causeproduct adulteratlon and mutilation of
containers, which may result in product misbranding, The protection ofdrug products from such mechanicaldamage is just as much a function ofthe maintenance of drug product quality as placing light-sensitive productsin light-resistant containers or labeling a product with its proper nameand an accurate statement of its potency. The Commissioner notes thatprimary responsibility for selectingspecifications for packaging materialsmay be assigned to the shipping department of a firm. Under § 211.22, thequality control unit is only responsiblefor testing and approving (or rejecting) packaging materials in accordancewith these specifications. Therefore,no change is needed in the section.
100. Several comments proposedeliminating from § 211.22(b) the statement regardlng approval for rejection)of materials used in manufacturingand suggested use of words like “evaluation” or “disposition.” It was alsosuggested by others that “or” be placed between “and” and “approval”to allow for instances described as notrequiring testing for approval.
Several discussions appear in thispreamble relating to the use of thewords “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 toother acceptable uses, returning to thesupplier, or destruction are all actionsthat may occur after a decision toreject and are in no way precluded bythe rejection decision unless specifically stated by the manufacturer.
101. Clarification of the option ofusing an outside testing laboratorywas asked by respondents who wanted an explicit statement in § 211.22(b) ofthe acceptability of this means of product examination.
The thrust of § 211.22(b) is that adequate laboratory facilities shall beavailable to the quality control unitfrom whatever source. The paragraphdoes not require those facilities to beowned and operated by the drug product manufacturer, nor does it prohibitthe manufacturer from using a contract testing facility. The Commissioner does not feel clarification is neededin § 211.22(b).
102. Four comments recommendeddeletion of § 211.22(c) entirely, becauseeither (1) the requirements are adequately covered in §211.22(a), or (2)units of a firm other than the qualitycontrol unit have greater expertise inspecific areas.
The provisions of paragraph§211.22(a) differ from those of paragraph (c) in that paragraph (a) relatesto the actual production of a product,while paragraph (c) covers eventswhich occur before production. TheCommissioner realizes that not all ex-
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45035 pertise rests with the quality controlunit, and he does not believe that thequality control unit should be solelyresponsible 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 thepersons or units it believes most qualified. The Commissioner’s intent is that the quality control unit be responsible for making sure that theprocedures and specifications developed are appropriate and followed.
103. One comment indicated that the proposed § 21122(c) does not allowminor equipment changes that do notbear on drug quality, unless suchchanges are first approved by thequality control unit.
Section 211.22(c) is limited to thoseprocedures and specifications thatimpact on drug quality. Moreover. theparagraph does not prevent the production personnel from making minorequipment adjustments that mayaffect drug quality without the qualitycontrol unit’s approval of the specificchange. It does require that the procedures regarding such equipment adjustment be reviewed in advance bythe quality control unit.
104. A comment suggested that§211.22(c) be expanded to provide forspecification committees, formulacommittees, and others instead ofmaking the quality control unit totallyresponsible.
As already explained, input intospecifications and procedures maycome from any appropriate source. Ifa firm chooses to utilize specificationand/or formula committees, it is notprohibited 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 wassuggested that the paragraph as proposed is too broad and that responsibilities for the quality control unit aredescribed elsewhere.
Section 211.22(d) does not define the responsibilities of the quality controlunit, but it does require that all its responsibilities, including those requiredin § 211.22, be in writing. For consistency with other sections in the CGMPregulations, the phrase “such writtenprocedures shall be followed” is beingadded to § 211.22(d).
PERSONNEL QUALIFICATIONS
106. One comment said § 211.25 is replete with vague terminology, whichsets the stage for arbltrary and capricious actions by FDA. thereby Placingindividuals and companies in a position of unnecessary risk. Two comments stated that this section is one in
RULES AND REGULATIONS
which FDA attempts to replace management’s judgment with regulations.
The Commissioner believes that thissection must be of a general and flexible nature to allow management to exercise its prerogatives in llght of thevarious types and sizes of firms, theproducts made. the differing personnelqualifications needed. the trainingprograms which may be instituted,and other factors. Although such generality will require more judgment tobe exercised by FDA investigators whomake plant inspections, it does notpermit any arbitrary or capriciousaction by the agency. In addition tothe fact that all sanctions authorizedby the act may only be enforcedthrough judicial process, FDA is further defining its policy and standardsfor regulatory action in a series of regulations set forth in 21 CFR Part 7.The Commissioner believes this isample protection against unreasonableactions by agency personnel.
107. Many comments questioned thefrequency of the "continuing training” required- in § 211.25(a), asked for adefinition of the word “continuing,”and questioned who should receivewhat type of training.
The requirement that training be ona continuing basis is intended to mean,for example, that a single trainingcourse at the time an employee ishired, with no subsequent training activities, is not sufficient. Subsequenttraining should be sufficiently frequent to assure that employees remainfamiliar with CGMP requirements.The Commissioner does not believe itwould be prudent to specify time intervals for training in view of thebroad nature of the drug indutry andthe wide range of employee functionscovered by these regulations. TheCommissioner believes this section issufficiently clear in identifying “whoshould receive what training” in stating that each person engaged in themanufacture, processing, packing orholding of a drug product must havetraining 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 pointedout 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 combinationthereof” following the phrase “education, training, and experience.” Mostargued that §211.25(a) should alsocontain this phrase.
The intent of the requirement isthat a person have a sufficient mix oftraining, education, and experience toperform his or her job adequately.What is adequate in regard to each of
the criteria depends on the lob. It maybe that a person can adequately perform a particular job with very littleor no previous experience, or limitededucation, or with minimal training,depending on the demands of the joband the qualifications of the person.Because the intent of this section hasbeen misinterpreted, §211.25(a) is revised to include the phrase “or anycombination thereof” and be consistent with paragraph (b).
109. One comment questioned howmuch education, training, experience,or combination thereof qualifies aperson to be a supervisor under§ 211.25(b).
The Commissioner believes it shouldbe understood that broad regulationssuch as these could not reasonablyquantify the degree of education,training, and experience necessary. Itis left to management’s reasonablejudgment as to what constitutes sufficient background in these criteria sothat supervisors can perform their assigned functions in a manner to provide assurance for the quality of drugproducts within their purview.
110. One comment on §211.25 (a) and (b) said it would mean little forsome individuals to be instructed inthe legal and technical language ofthe regulations. The respondent indicated that it is more important thatpersonnel be instructed in the principles of good manufacturing practicerelevant to their particular tasks.
Section 211.25 requires training incurrent good manufacturing practiceas it relates to an employee’s function.The Commissioner intends that training be meaningful to the employee,not a formalistic but useless exerciseto satisfy a regulation. The requirement is written to provide reasonablelatitude to a firm as to the extent towhich technical and legal instructionwill be given.
111. A number of comments said therequirement in § 211.25(c) for “an adequate number of personnel” does notbelong in the section on personnelqualifications.
The Commissioner notes that theintent of this paragraph in relation tothe number of employees is that therebe an adequate number of qualifiedpersonnel. The Commissioner is revising this paragraph in the final regulation by inserting the word “qualified.” PERSONNEL RESPONSIBILITIES
112. One comment said all personswho enter the manufacturing, processing, packing, and holding areas shouldcomply with the requirements of§ 211.28 and the section should reflectthis.
The Commissioner agrees that allpersons, whether employees or not,who engage in the activities coveredby this section should comply with the
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45036 RULES AND REGULATIONS
requirements of the section. Therefore, the Commissioner is replacingthe word “employees” with the word “personnel” in § 211.28 (b) and (d ) .The Commissioner recognizes that notall persons who enter manufacturingareas are engaged in activities coveredby CGMP regulations (e.g., equipmentmanufacturer service representativesand FDA investigators). and their activities would not be limited by5211.28. Drug manufacturers are responslble, however, for monitoringsuch activities to prevent contamination of drug products. For example, allpersonnel entering a sterile area wouldbe required to wear appropriate protective apparel.
113. One comment said § 211.28 is anadditional example of the agency’s attempt to legislate and enforce regulations which must be left to the discretion of corporate management in orderto preserve our free enterprise system.
The Commissioner does not perceivehow these regulations present a threatto the free enterprise system. Theseregulations were promulgated underthe authority of section 501(a)(2)(B)of the act, which was passed by theCongress in 1962 in order to assurethat no drug product available to consumers was adulterated. The requirements of the regulations are a reasonable and necessary step toward thatgoal. They do not inhibit competition,but rather enhance it by assuring thatno manufacturer can reduce costs byeliminating those steps integral to thePrevention of adulterated products.Thus, the consumer is assured that allmarketed drugs meet the essentialstandards 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 onfalr principles of competition and freeenterprise.
114. One comment suggested that inorder to make it clear that facial haircoverings 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 thatclarification of § 211.28(a) is desirableand is therefore revising it to requirethat protective apparel, such as head,face, hand, and arm coverings, shall beworn as necessary to protect drugproducts from contamination.
115. One comment argued that themeaning of § 211.28(a) is directed tohuman drug products and should beclarified to limit its scope accordingly.
The Commissioner rejects this comment. These regulations are broad andconsider the fact that certain drugproducts, regardless of whether they
are for human or veterinary use, requlre the same amount of care in manufacturing. processing, packing, orholding in order to assure their safetyand effectiveness. The wording of thissection requires precautions to betaken as necessary to protect the particular drug products from adulteration or contamination. The degree ortypes of precautions will depend onthe particular drug product being considered.
116. One comment suggested rewording § 211.28(a) by inserting the underlined statement: “Arms and handsshall be covered or other appropriate ery. Appropriate alternatives can bemeasures taken when microbial con-used in such instances so that neithertamination is a concern when neces- personnel safety nor drug productsary to protect the drug product beinghandled”; and that the “appropriatemeasure” could mean the cleaning ofthe arms and hands with an antisepticsoap or solution as an alternative.
The Commissioner rejects this alternative wording since it would alter theintent of this paragraph. The possibility of microbial contamination is notthe only reason for wearing protectiveapparel: prevention of particulate contamination, for example, may be ofequal importance. Further, the Commissioner does not believe the phrase“as appropriate” would clarify thissection since, as written in the finalregulation, it clearly states that protective apparel shall be worn as necessary to prevent contamination of the drug product. This paragraph does notpreclude other measures such as cleaning which might be used in place of orin conjunction with protective apparel.If alternate methods were at least aseffective as protective apparel, thenprotective apparel would not be necessary.
117. One firm commented on §211.28(a) that because of its type ofoperation it does not require, nor doesit think it is necessary to have, uniforms if clothing is kept clean.
The Commissioner notes that thisparagraph does not necessarily requirethe wearing of uniforms. The requirement is that clothing be clean enoughto be appropriate for the type of dutyor operation being performed. For certain types of operations, uniforms maybe appropriate, while for other typesof operations uniforms may not be necessary.
118. Several comments noted that§211.28(a) states in part that “theyshall wear appropriate head coverings as necessary, Including facial head coverings, as necessary � � � .” And thecomments argued that this statementis “too broad as written since facialhair includes eyelashes, eyebrows,etc.”
The Commissioner intended thatthis paragraph be broad enough to srequire the covering of eyebrows andeyelashes if necessary to prevent drug
product contamination. Although herecognizes that this type of protectionwould not be usual for most operations, he would not wish to precludethe use of such measures.
119. Several comments argued that,with regard to arm coverings, thereare certain kinds of machinery andequipment which present a Personalhazard to workers using arm and handcoverings.
The Commissioner recognizes thatthe use of arm and hand coveringscould constitute a significant hazard ifused around certain types of machin
quality is compromised.120. A comment noted that the term
“authorized” in reference to Personnelwho may enter limited access areas is not defined in § 211.28(c).
The Commissioner believes that drug firms can reasonably determineon an individual basis which personnelshould be permitted to enter whatareas. The intent of this paragraph isto prevent the type of situation, forexample. where persons not trained inaseptic techniques enter aseptic processing areas for reasons not associated with aseptic processing of the drugproduct. To clarify that the authorization derives from the manufacturer,not FDA, the language of §211.28(c) is modified slightly.
121. One comment suggested thatthe word “may” in §211.28(d) be replaced by the words “is likely to” inorder to identify realistically thethreat of illness or lesions.
The Commissioner rejects this alternative wording because the phrase “is likely to” is not strong enough to statethe intent of this paragraph. Further,the alternative phrase would introduce the element of prediagnosis bythe employee’s supervisor. While supervisory personnel can reasonably beexpected to recognize health conditions that may affect the drug product, they probably would not be nbleto recognize conditions that are likelyto affect the drug product. This mayrequire more sophisticated evaluationby medical personnel. Of course, ifmedical personnel determine that theemployee’s health condition will not affect the drug product, the employeemay resume his or her routine activities.
122. One comment argued that the words “they consider” be deleted fromthe last sentence of § 211.28(d) becausethe reporting of conditions should notbe limited to conditions which an employee thinks may affect the product.Another comment said the word“health” should be inserted betweenthe words “any” and “conditions” in this sentence.
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45037 The Commissloner agrees that the
intent of this paragraph is betterserved without the phrase “they consider" and with the addition of the word “health” and has revised thefinal regulation accordingly.
123. Several comments said § 211.28(d) should not be construed to imply that supervisors are medicallyqualified to judge health conditions ofemployees.
The Commissioner does not believe the paragraph implies this. Within theframework of industrial management,the supervisor is the liaison betweenthe operating employee and higherechelons 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 conditionsnoted initially by the supervisor mayrequire evaluation by qualified medical personnel. Such medical evaluationis acknowledged in the final regulation. This section could perhaps setout more detailed procedures for dealing with employee health problems.But in the absence of significant difficulties in the area, the methods fordealing with health problems, beyondthe initial phase of removing suspectemployees from direct contact withdrug products and their components,are left to the reasonable judgment ofindividual firms.
CONSULTANTS
124. Several comments were receivedrequesting deletion of § 211.34 becausethe ultimate liability for actions takenbased on the advice of consultants still rests with the responsible officials ofthe drug product manufacturer. Theargument is that a firm’s choice ofconsultants should be a matter of itsown judgment and not one of Government review or regulation. The comments also state that FDA lacks authority under the act to prescribequalifications for consultants.
The Commissioner considers that consultants, while they are retainedby the firm, are persons engaged inthe manufacture, processing. packing,or holding of a drug product, and maylawfully be subjected to appropriatestandards of qualification to the same extent as full-time employees of thefirm. Therefore, consultants musthave education, training, and experience, or any combination thereof, sufficient to perform their assigned functions. Minor editorial amendmentshave been adopted in the final regulation to clarify this requirement.
125. Several comments requestedthat § 211.34 state that the requirements are applicable only to consultants who are retained for activitiesthat relate to the scope of the CGMPregulations.
RULES AND REGULATIONS
The Commissioner acknowledgesthat activities that are not under thescope of the CGMP regulations shouldnot 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 haveto document the qualifications of outside counsel.
Under these regulations. a consultant is a person from outside the firmwho is called on to render advice oropinion 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 needto define “consultant” in these regulations. Any person, including attorneys.employed or retained to advise on themanufacture, processing, packing orholding of drug products would beconsidered a consultant under theseregulations. However, an attorney employed or retained for legal advice-forexample, an interpretation of CGMPregulations-would not be considered aconsultant under these regulations. Inresponse to the second part of thecomment, the section requires thatrecords be maintained stating thename, address, and qualifications ofany 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 contendthat the phrase “particularly movement back through areas in whichthese materials had previously beenprocessed or held” be deleted as superfluous.
The Commissioner is revising thisparagraph to clarify the intended requirement that the flow of materialsshall be designed to prevent contamination.
128. One comment proposed thatunder §211.42(c) the paragraph be divided into those operations whichmust be in defined areas and thosewhich must be in separate areas. Anumber 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 separationbe employed as is necessary to preventcontamination or mixups. The degreeof separation will depend on the typeof operation and its proximity to otheroperations within the plant. Thephrase “separate or defined” is not in
tended necessarily to mean a separateroom or partitioned area, if other controls are adequate to prevent mixupsand contamination. In the case ofquarantined areas. for example, an effective means of identifying the quarantined goods and a paper control orother system may be used in lieu of complete physical separation. Thus,the regulations do not requrie thatspace be reserved for quarantine storage. The Commissioner believes, however, that some degree of separation,even though only spatial, would benecessary in most cases, even withelaborate supplemental control.
129. One comment maintained thatthe quarantine of containers and closures involves a great deal of spacewhich most small manufacturers donot have. The comment further contended that these items “can be examined at the packaging line just beforeuse” or “can be examined at the distributor’s facilities before shipment.”
If suitable specifications for containers and closures are simple enough topermit a quick visual examination todetermine the product’s acceptability,such an examination could be performed at the time of receipt withoutbeing in conflict with the quarantinerequirements of these regulations. Acertificate of testing received from asupplier would not preclude the necessity for examining containers and closures to determine that they are thesame articles as are represented by thecertificate. Any manufacturer whodoes not have such evidence of an article’s acceptability or does not alternatively quarantine the article until suchevidence is obtained is assuming anunacceptable risk that the article willbe used and subsequently be found unsuitable.
130. A number of comments indicated that the requirement in §211.42(c) that “operations shall be performed inspecifically defined areas of adequatesize” was unnecessarily restrictive onthe flexibility of plant space use.
The requirement relates to severaldifferent types of operations whichare enumerated in the proposal; however, the comments seemed to relatemainly to storage areas. It is the Commissioner’s belief that a significanttype of control over products is aphysical one which precludes mixupsby physically placing an article in anarea clearly identified as to status.The extent of the physical separationimposed in a particular situation canvary from locked, walled-off areas tosimple designation of an area for asingle purpose by means of a sign. Thedegree of physical control will vary depending on the other controls in useby a firm. If a firm has effective controls, whatever they may be, thatwould increase their confidence thatmixups will not occur, then the degree
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45038 of physical control may be less than inanother firm where no other controls exist.
131. One comment contended that § 211.42(c)(2) would require availability of a large separate holding area inthe warehouse for relocation of rejected supplies.
The Commissioner concludes thatpreventing the Intermingling of rejected supplies with released supplies isvery important to’ drug quality. Theregulation does not require separatefacilities as long as there is a definedarea for rejected materials. The Commissioner is not aware of any problemsin the past with regard to large numbers of rejected supplies and theirstorage. He therefore rejects the proposal.
132. One comment objects to the requirement in §211.42(c)(4) for separate storage for “in-process” materialsand suggests adding to this paragraphthe words “if storage or isolation isnecessary.”
The use of the word "storage" inthis paragraph implies holding for extended periods of time. It does notrefer to the holding of containers inproduction areas while processing isongoing. Therefore, if such storage isnot necessary, the regulation as currently written is inapplicable. On theother hand, if such storage is necessary. it is the Commissioner’s opinionthat isolation in a separate or definedarea is essential to prevent errors.Therefore, the comment’s proposal isnot accepted.
133. One comment, referring to § 211.42(c)(5) said “on-line testlng does not have to be done in a separate testing area � � *."
The requirement is for separate ordefined areas. The Commissioner belleves that the area in which testingoccurs, including on-line testing, mustbe defined or separated i n order toprevent contamination of on-line products with testing materials and improper use of products that have beentainted by the testing process.
134. One comment requested that§211.42(c)(5) be deleted since it is toobroad to be helpful.
The Commissioner disagrees wlththis comment. The intent of this paragraph is to avoid mixups by using defined areas for the entire manufactur-Ing operation. phase-by-phase. The detailed procedures are purposely notspelled out so that pharmaceuticalmanufacturers can design their operations according to their individualneeds.
135. Two comments argued that theword “quarantine” in § 211.42(c)(7) is not defined, the word means dlfferentthings to different people, and itshould be deleted.
The word “quarantine” has hadwidespread use in the pharmaceutical
RULES AND REGULATIONS
industry, and its meaning is well understood. These regulations do, however, have the effect of defining theword within the context of the pharmaceutlcal operations by indicatingthat It constitutes a control system toprevent unauthorized usage of unreleased material. The Commissionerdoes not believe further definition is necessary.
136. One comment argued that § 211.42(c)(7) “increases warehouse requirements. This is not belleved to becurrent practice in industry.”
Based on experience gained fromFDA inspections of drug manufacturers, the Commissioner believes thatmost firms now separate released andunreleased drug products. In view ofthe intent of the phrase “separate ordefined” as explained elsewhere inthis 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 productor process. One comment suggestedthat the term “aseptic processing” in § 211.42(c)(10) requires further clarificatlon to indicate that such processingis intended for products or components which are not terminally sterilized. The respondents suggested inserting a phrase which would make itclear that not all controls are necessarily required.
It is not the intent of § 211.42(c)(10) to require "aseptic processing” whensuch operations would not be necessary for the firm’s usual activities.Some firms choose to use aseptic processing for drug products not intendedto be marketed as "sterile" as a meansof controlling microbial contamination. The Commissioner agrees thatmodification is deslrable and is revising § 211.42(c)(10) to include the words“as appropriate."
138. One comment suggested that § 211.42(c)(10) should be redesignatedas 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 Commissionerconcludes that such requirements areappropriately codified.
139. Several comments objected tothe requirement under§ 211.42(c)(10)(i) that floors. walls, andceilings have smooth, hard surfaces.
The Commlssioner rejects thesecomments. It is widely acknowledgedthat smooth, hard surfaces are easierto clean and sanitize.
140. A number of comments objected t o applying t h e requirements o f §§ 121.42(d), 211.46(e), and 211.176 to
the manufacture of penicillin and non-penicillin veterinary products. Theyclaim that no evidence has been offered to demonstrate penicillin sensitivity in animals. It was proposed thatthe word “human” be inserted before the words “drug products.”
Hypersensitivity reactions to penicillin do occur in animals. Although theCommissioner acknowledges that atpresent there is less information onthe extent of the problem in animalsthan in humans, he advises that FDAhas received numerous reports of reactions in animals throughout the years.Therefore, the Commissioner believesthe requirement as proposed in§211.176 is warranted and has retained it in the final regulation. However, the Commissioner believes thatthe prohibition against the use of common facilities and air-handlingsystems in the production of veterinary drug products is not necessary atthis time. Therefore, §§211.42(d) and 211.46(e) (now 211.46(d)) are revisedaccordingly in the final regulation.
141. A number of comments suggested that § 211.42(d) can be too broadlyconstrued. It was suggested that someprocessing steps for penicillin and non-penicillin products could be performedon the same equlpment without risk ofcross-contamination.
The Commissioner believes thatthere is a possibility of trace amountsof penicillin being released duringproduct handling even under well-controlled conditions, and he thereforecannot accept this suggestlon.
142. Another comment requestedclarification of the meanlng of theword “separate” in § 211.42(d).
The Commissioner’s intent in this paragraph is to require the isolation ofpenicillin production operations fromoperations 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 theplacement of these operations in separate buildings. Effective means canalmost certainly be developed to separate such activities from one anotherto prevent cross-contamination problems within a single building. An example of the means of separation canbe found in the discussion of air-handling systems in this preamble underparagraph 172.
LIGHTING
143. Two comments said § 211.44 isvague and may lead to misinterpretation.
It is not the intent of this section tospell out precisely what is required inthe way of lighting for each type ofoperation, but rather to require thatindividual firms follow lighting stand
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45039
ards that are generally considered adequate for each of their various operations. For example, inspection of parenteral solutions for particulatematter requires a different type of illumination than a component storagearea. The Commissioner, therefore,has retained the proposed wording inthe final regulation. VENTILATION, AIR FILTRATION, AIR
HEATING, AND COOLING
144. One comment suggested thatthe word "microorganisms" i n §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 thenumber or types of microorganismsthat would be undesirable must be controlled. Therefore, the Commissioner has retained the wording asproposed in the final regulation.
145. A number of comments requested that expressions such as “when necessary,” “where applicable,” or “where appropriate” be used in thefirst sentence of § 211.46(c) to broadenthe scope of the requirement for airfiltration systems. Comments took exception to the requirement for exhausting to the outside of the building, stating that there are a number ofalternatives such as completely closedsystems properly filtered, ionizationand electrostatic precipitation, enclosed hoods, and scrubbers. Finally,two comments contended that there is no reason for air filtration systems inproduction areas where the product is already in the final sealed containerand in nonsterile processing areas.
The Commissioner believes that forthe great majority of drug productionoperations the proposed requirementis desirable and necessary to assurethe quality of drug products. While itis doubtful that such air systems arenot generally applicable to the production of nonsterile products, there maybe situations where the requirementwould not be necessary to assure thequality of drug products and wouldtherefore 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 necessarilyexhaust outside the building.
146. Several comments objected toproposed §211.46(d) on the groundsthat effective exhaust systems neednot always be “adjacent” to the equipment in dusty operations.
The Commissioner concludes thatproposed §211.46(d) is unnecessary inview of §211.46(c) as written in the final regulation. Therefore, proposed§ 211.46(d) is deleted in its entirety.
RULES AND REGULATIONS
147. One comment said proposed§ 211.46(e) (now § 211.46(d)) is too general because there would be no dangerfrom cross-contamination during penicillin fermentation (prior to processingthe dru state) and after the sealing of the product.
The Commissioner cannot agreewith this comment since the operations specified are not clearly defined. He believes the fermentationprocess could result in cross-contamination problems. For example, removal of the cake from penicillin fermentation equipment could result in airborne contamination from partly dryor dry cake. With regard to the respondent’s second example, the Commissioner is revising this requirementto make it apply only to productionoperations and not to storage, such aswarehousing of the penicillin productin sealed containers.
146. Comments were made that proposed §211.46(e) was superfluous because § 211.42(d) already required separate facilities for penicillin and non-penicillin products.
The Commissioner believes it is important to make clear in these regulations that completely separate air-handling facilities for penicillin andnonpenicillin production are required.Section 211.42(d) is written to allowpenicillin production in the samebuildings as nonpenicillin productionif the penicillin production areas canbe completely separated from allothers. However, because it is possiblefor air-handling systems between penicillin and nonpenicillin productionareas to be interconnected, the Commissioner finds it necessary to statethat any such interconnection wouldbe unacceptable.
149. One comment said proposed§211.46(e) should specify whether theair-handling system is intended foroutgoing or incoming air.
There is no single answer to thispoint since the specific requirementsfor a particular installation willdepend on individual circumstances.The purpose of the requirement isthat 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 ofoutgoing air or both.
PLUMBING
150. A number of comments on§211.48(a) said water received frommunicipal sources and certified asmeeting the requirements of SubpartJ of 42 CFR Part 72 should not haveto be tested as if it were another component.
It was not the Commissioner’s intentthat 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 potablewater coming into the plant systemshould not be adversely affected bythe in-plant plumbing.
151. A number of comments indicated that it is not necessary and is veryexpensive to require that all water in aplant be potable water. They pointedout that some systems such as sprinklers for fire control, cooling equipment, and boiler feed do not requirepotable water.
In light of these comments, theCommissioner is revising § 211.48(a) to eliminate the prohibition against non-potable water within a plant.
152. One comment said potable water should be analyzed for polychlorinated biphenyls and chloroform,and tolerances should be set becauseof the potential danger to health represented by these contaminants.
The Commissioner recognizes thatpotable water may contain amounts ofenvironmental chemical contaminantsat levels that have not been clearly established as having significant adverseeffects when ingested. Governmentagencies are investigating more meaningful specifications for testing potable water for potentially harmful impurities not already included in thestandards. Therefore, FDA has not included such requirements for testingand acceptance of potable water inthese regulations.
152. Several comments objected tothe designation of traps to preventback-siohonage in § 211.48(b). Thecomments said it is -general opinionthat traps do not prevent back-siphonage, but check valves or air break arrangements would do so.
The Commissioner agrees with thesecomments, and §211.48(b) is revised to reflect the suggested change.
154. One comment objected to equipping drains with traps because of theinflationary impact and requestedthat this paragraph be deleted.
The Commissioner notes that this paragraph is revised to eliminate thereference to traps. It now requires theuse of air breaks or other mechanical device which may increase or decreasethe cost to this person, depending onhis present method of preventingback-siphonage. However, the Commissioner considers that the necessityof preventing back-siphonage outweighs the cost factor.
WASHING AND TOILET FACILITIES
155. Several comments on §211.52argued that it is not current industrypractice to provide “hot” water, but rather to provide “tempered” water,
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45040 RULES AND REGULATIONS
thus conserving energy whiletaining adequate sanitation facilities.
The Commissioner has been unabledetermine that there is a consensus asto what is meant by “tempered water.”Therefore, he is concerned that theword “tempered” might allow the useof water that is of insufficient temperature for adequate cleaning.
156. A comment suggested that theword “easily” be deleted from § 211.52because location of washing facilitiesmay be hindered or prohibited by localplumbing codes. Further commentsaid the word “easily” is most subjective and capable of differing interpretation.
The Commissioner is not convincedthat plumbing codes would prohibiteasily accessible washing facilities inestablishments that are properly designed. Further, the Commissioner believes that the word "easily" is conciseenough to adequately describe theintent of the section. Therefore, thewording as proposed is retained in thefinal regulation.
ANIMAL FACILITIES
157. Several comments contendedthat proposed § 211.54 should be deleted since it substance is covered bythe Animal Welfare Act of 1970 (Pub.L. 91-579. 7 U.S.C. 2131). Other comments said this section implies thathousing for laboratory animals is required whether or not a firm maintains laboratory animals.
The Commissioner does not believeit is improper to make the substanceof another regulation a requirement inth CGMP regulations. It should be obvious that If a firm is not engaged in atype of operatlon covered by these regulations, then any requirement thatpertains to that type of operation doesnot apply to that firm. In reviewingthis proposed section, however, theCommissioner has concluded that itsintent is adequately covered in§ 211.173. Therefore, § 211.54 is deletedin the final regulation.
SANITATION
158. Several comments on § 211.56(a)said it is impossible to maintain allbuildings completely free from rodents, birds, insects, vermin, trash, andorganic decaying matter. In mostbuildings there is an accumulation oftrash dally in various waste basketsand in trash accumulation areas forpapers and empty cartons.
The Commissioner agrees that theintent of this sectlon could be moreclearly stated, and the text is revisedaccordingly.
159. Several comments requested thedeletion of the phrase “in detail” from§211.56(b) because, according to thelanguage In this paragraph, manufacturers would be required to documentall minute details.
The Commissioner believes that in clarify that the procedures apply tosome cases, detailed descriptions of individuals who are assigned to sanitacleaning procedures may be necessary tion work.to assure complete and proper clean- The Commissioner believes that theing. In others, that level of detail may paragraph clearly indicates that goodnot be necessary or appropriate. The sanitation procedures apply to all em-Commissioner believes that there ployees who perform sanitation work.should be a reasonable standard in de- Therefore, he rejects this comment. scribing the details of these proce- MAINTENANCE dures. Therefore, this paragraph is revised to require “sufficient” detail. 164. Several comments said the
160. Several comments requested the phrase “good state of repair” indeletion of the phrase “such written § 211.58 is vague and is subject to vary-procedures shall be followed“ from ing interpretation.§211.56(b) because, if current good The Commissioner does not agreemanufacturing practice involves writ- that the phrase “good state of repair”ing down certain procedures, it also in-is vague. It means that bulldingsvolves following them.
The Commissioner does not agreewlth this comment. Procedures may bewritten with obvious good intentionsbut never implemented, as the agencyhas discovered in some flrms. Writtenprocedures must be followed to assurethe quality of finished drug product,and the regulations should be explicitin 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 materialswill not contaminate equipment, components, or in-process materials. theuse of the word “person” according tothe comments seems to have a morepersonal use here than the general useit has in other sections. It was alsosuggested that the word “evidence”implied a need for proof of lack of anyresidue from pesticide or cleaningagent use, and that the standardshould be a lack of adverse effect instead. Several comments suggestedthat as written. this paragraph wouldrequire residue checks to be run on allbatches in an area after a visit by anexterminator.
The Commissioner finds that the objections have merit, and therefore theopening of this paragraph is rewordedto clarify the intent. It is not theintent of the Commissioner to burdenmanufacturers with testing everybatch of drug product in a partbulararea for contamination from chemicalsused to kill pests and insects.
162. Several comments requested thedeletlon of the last sentence of § 211.56(c). which allows the use ofonly those rodenticides. insecticides.and fungicides that have been registered in accordance with the FederalInsectlclde. Fungicide and RodenticideAct (7 U.S.C. 135).
The Commissioner believes it contrary to public policy to permit the useof unregistered rodenticides, insecticides, or fungicides. The comment isrejected.
163. One comment requested insertion of the phrase “employed to perform sanitation work” following theword“employees” in § 211.56(d) to
should not be in a bad state of repairso that drug products processed withinthem are adversely affected.
X. EQUIPMENT
EQUIPMENT DESIGN SIZE AND LOCATION
165. A comment suggested the deletion of the phrase in §211.63 “for itsintended use as well as for its” on thegrounds that it is redundant andtherefore unnecessary.
The Commissioner does not agreethat this phrase is redundant. Theregulatlon imposes two requirements:that equipment be such as to facilitateits operations for its intended use andthat equipment be such as to facilitateits cleaning and maintenance. Thephrase is revised in the final regulations for clarity.
166. One comment on § 211.63 notedthat medical gas manufacturers usededicated piping systems, manifoldvalve outlets, and pin index systemsfor processing medical gases. Cleaning,except at the time of initial installation and subsequent maintenance, isnot done internally.
The Commissioner notes that thissection does not dictate the frequencyof cleaning and/or maintenance. Ifcleaning and maintenance after initialinstallation are not needed, as statedin the comment, then there is no requirement in § 211.63 for such practice.
EQUIPMENT CONSTRUCTION
167. A number of comments arguedthat §211.65(a) literally requires thatall product contact surfaces be totallyinert. The respondents maintainedthat this requirement is practically impossible to achieve and that the following wording should be added:
"* * *so as to alter the safety, identity, strength, quallty or purity of thedrug beyond the official or other established requirements.”
The Commissioner recognizes thatdrug product contact surfaces may bereactive to some minute extent, andthe paragraph is revised in the finalregulation in accordance with suggested alternative wording.
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168. A number of comment suggest- 172. One comment said the list ofed adding the phrase beyond the offi- procedural requirements for equipcial or other established require- ment cleaning should be deleted fromments" to the end of §211.65(b) to §211.112(a) since it is unnecessarilydefine better the standards to be used specific and unduly restrictive.for evaluating any possible changes The Commissioner does not agreecaused by product contacts. that the list of required procedures is
The Commissioner agrees with the either too restrictive or too specific.substance of these comments. The pro- He believes that all the items areposed phrase is added at the end of common-sense procedures that mostthe sentence in §211.65(b) for the firms would incorporate. but somesame reason as explained in reference would not in the absence of CGMPto §211.65(a). A similar change is regulations.made in § 211.67(a). 174. One comment on proposed
§211.112 argued that the word “shall”EQUIPMENT CLEANING AND MAINTENANCE in the sentence regarding establish169. In reviewing the proposed regu- ment of procedures should be replaced
lations the Commissioner concludes by the word “may” because the judgthat §§211.67 and 211.112 should be ment of the manufacturing personnelcombined into a new § 211.6‘7. Section should determine proper sanitary pro211.112 is deleted from the final regu- cedures.lation, and the substance of the re- The Commissioner rejects this sugquirements in proposed §211.112 are gestion. The purpose of these regula-included in the new § 211.67. The com- tions is to assure that each firm estabments below include those relating to lish appropriate written procedures re-both proposed §§ 211.67 and 211.122. garding sanitation. Precise procedures
170. Several comments said written are left to the reasonable judgment ofprocedures and documentation re- manufacturing personnel, as long asquired by § 211.61 should apply only to the objectives of the requirement aremajor equipment, not to items such as met.ladles, buckets, and spatulas. 176. One comment said that § 211.67
The Commissioner does not neces- as written requires the cleaning andsarily intend to require detailed proce- maintenance of all equipment used indures for cleaning each type of utensil. the manufacture, processing, packing,For example. such equipment may be and holding of a drug product, whichgrouped when convenient. However, would include laboratory equipment,the Commissioner believes that at fork lifts, and truck fleets.least general written procedures Any equipment used in associationshould be instituted for cleaning uten- with drug manufacturing that couldsils. Although not “major” pieces of have an adverse effect on drug prod-equipment, utensils can be just as uct quality if improperly maintained ismuch a source of contamination. De- covered by this section. Ordinarily, of pending on the type of operation, it course, fork lifts and fleet trucks may be necessary, for example, to would not be considered, but it is notsanitize or use procedures other than inconceivable, for example, that thesimple washing. failure of a refrigeration unit in a
171. One comment said §211.67 truck could have a serious deleteriousshould be strengthened by requiring effect on drug products that must bethat cleaning and identification be kept cool. Laboratory equipment,performed by a competent individual when used for the quality control ofspecifically trained for these oper- drug products, is an integral part ofations. the manufacture, processing, packing,
The Commissioner rejects the com- or holding of drug products and therement because it would be repetitive of fore clearly is included in the scope ofthe requirements in §211.26 on per- § 211.67.sonnel qualifications. 176. Several comments on §211.67
172. One comment on §211.67(a) said argued that requiring written procethat when equipment is dedicated toa dures for the method used in the dis-single component or product, the use assembling and reassembling of all of water solution or gas purging would equipment is overly burdensome andserve only to introduce material which not necessary. It was recommendedshould not be in the final product. that the paragraph be deleted or rew-
This paragraph does not prescribe ritten to requlre such measures for sigwhat compounds must be used for nlflcant pieces of equipment only. Itcleaning, the manner, or the exact fre- was also recommended that parts quency of cleaning. To do so would be which come into contact with drug impossible, given the variety of prod- products be dissassembled, cleaned anducts, equipment, manufacturing oper- reassembled. but not necessarily theations, and cleaning techniques. Selec-entlre piece of equlpment.tion is best left to each manufacturer, The Commissioner concludes thatwho also retains responslblllty for as- the extent to which equipment mustsuring that their cleaningoperations be disassembled depends on the typedo not contaminate the drug product. of equipment and other variable fac
45041 tors. The equipment must be disassembled to the extent necessary to prevent subsequent contamination and/ormalfunction. 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 equlpment and objected that the word“maintenance” is too general a term.One comment recommended that theparagraph be revised to read, “Thereshall be written procedures assigningresponsibility for and describing preventive maintenance programs andcleaning schedules.”
The Commissioner does not agreethat rewording the paragraph, as suggested,is necessary. Maintenancemeans keeping a building, machinery,or other facilities in a good state ofrepair: and the term is understoodthroughout the industry.
176. One comment said §211.67(b) isnot relevant to good manufacturingpractice for most products. The comment further said the description ofthe methods of disassembling, cleaning,and sterilizing is applicable only toparenteral drugs.
The Commissioner does not agreewith this comment. Other types ofequipment, for example, automatictableting machines, also require disassembllng, cleaning, and reassembling.
179. Several. comments requestedthat the phrase “such written procedures shall be followed” be deletedfrom § 211.67(b).
The Commissioner does not agreewith this comment. The requirementfor written procedures is only part ofthe requirement for the use of currentgood manufacturing practice in theproduction of drugs. An equally critical part of the requirement is that the written procedures be followed.
180. One comment objected to therequirement In §211.67(c) for makingthe maintenance and cleaning recordsa 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 i s that cleaning andmaintenance records be readily identifiable with equipment usage in theevent of a problem where drug products must be investigated. Where the same equipment is used for a numberof dlfferent drug products. for example, cleaning and maintenance recordsmay not be easily retrleved. Section211.182 in the final ‘regulations provides, however, that individual equlpment logs are not required whereequipment is dedicated to the manufacture of one product and thebatches are manufactured in numerical sequence.
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45042 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 tothe record retention period.
The Commissioner disagrees withthese comments. Section 211.182 provides the specific information and
clean-,form in which equipment usageing, and maintenance records must be
RULES AND REGULATIONS
that FDA does not have the authorityto prohibit the use of equipment isacademic, however, because there is noprohibition stated or implied. Testingand quality control are an inherentpart of the manufacture, processing,packaging. and holding of drug products as defined in
er.” The comment also suggested deletion of the phrase“data from the computer.”
The Commissioner agrees that input to the computer must be checked foraccuracy and is revising the paragraphaccordingly in § 211.68(b). He does not
§210.3(b)(12). agree that “data from the computer” Therefore, such equipment may also need not be checked for accuracy andbe used for testing and quality control. therefore rejects that portion of the
kept and is appropriate so that firmssubject to these regulations are madeaware of their responsibilities.
Further, improper cleaning and sanitizing could contribute as significantlyto adulteration of products as couldother problems in the manufacturingprocess and, in the event of contaminated products, the firm should be able to identify the cause of the contamination. The retention of theserecords under § 211.180 thereforeshould be consistent with other recordkeeping requirements throughoutthe CGMP regulations.
EQUIPMENT CALIBRATION
182. The Commissioner is combiningthe substantive requirements of pro
185. Numerous comments suggestedthat the requirement in proposed§211.2(b) for a backup file of hardcopy data be amended to provide forother types of backup data, such asduplicate tapes or microfilm.
The Commissioner is convinced thatIt would be proper to allow for backupsystems other than hard copy, andthis paragraph is revised accordingly as § 211.68(b). Measures must be taken,however, to assure that backup dataare exact and complete and that theyare secure from alteration, inadvertenterasure, and loss.
186. Several comments objected tothe requirement in proposed § 211.2(b) for checking computer reproductionsof formulas and other records or data
comment. In considering the comments on the section and as a result ofdiscussions with FDA staff knowledgeable in the computer field, the Commissioner has become aware that useof 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 equipmentrecorders should be calibrated.
The Commissioner believes that recorders are an integral part of precision equipment systems. A faulty recorder may give unreliable results that
posed §§211..2 and 211.68 to form new each time they are used, on the may affect the quality of finishedare rou-Comments on proposed grounds that it should be sufficient to drug products. Recorders that .211.68§
§§211.2 and 211.68 will be discussed verify only the accuracy of the first tinely calibrated, inspected, andhere. reproduction. checked reduce the margin for error
183. One comment requested thatproposed §211.2(a) be modified topermit the use of equipment otherthan the types listed. One commentargued that the use of computersshould be allowed. Several commentssuggested deletion of the word “precision” since it i s superfluous and redundant.
The intent of this paragraph is toallow the use of any equipment thatwill perform a function satisfactorilyin accordance with the requirementsin Part 211. The Commissioner istherefore revising this paragraph inthe final regulation (now §211.68(a))to permit the use of any automatic,mechanical, electronic, or other types
computers orincuding ,of equipment-related systems, that will achieve this
The intent of this requirement is toensure that each reproduction is thesame 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 productionerror and the distribution of an adulterated product. The Commissionertherefore does not agree that only thefirst reproduction need be checked foraccuracy. If a computer system hasthe capability, however, to verify itsoutput, such as with audit trials, thiscould be considered as a check for accuracy.
18’7. One comment suggested dele-
and assure the quality of drug products.
191. A comment said the intent of§211.68(a) is not clear as to the useand type of equipment that is applicable. The comment further said precision equipment that has no effect onthe drug product quality should beexempted from the written programrequirements.
The paragraph refers to equipmentwhich is used in the manufacture. processing, packing, and holding of drugsand may therefore have an effect ondrug product quality. No examples ofequipment which did not have aneffect on drug product quality were offered.tion from proposed §211.2(b) of the
listing of items requiring backup data. 192. A comment requested that theThe Commissioner now believes that term “precision automatic equipment"
be defined. The respondent said itgoal. Use of modifying word "preci- the listing of data to be included assion" is not necessary because the hard copy data is not necessary. The
intent of this paragraph is thatcould, for example, include tabletcounters and liquid fillers which areparagraph requires that any equip
ment perform a function satisfactori backup data be kept of any informa- checked on a routine in-processbasistion that is computerized. not that cer- where there is no need for routine calily.
184. One comment suggested that the word "permit" in § 211.2(a) be replaced by the word“recognize.” which
tain information be computerized. bration or inspection.The Commissioner believes thnt188. One comment suggested dele
tion of the word "appropriate" in the tablet counters and liquid fillers aresecond sentence of proposed § 211.2(b), examples of automaticwould better expressthe Intent of the
paragraph. Several comments precision
equipment. When routing in-processchecks are made, regardless of the
charging it to be superfluous.ques-The Commissioner rejects this sug
gestion. Controls required by this time interval, such checks should bemust be adequate to
tioned the statutory authority of FDA to permit or prohibit the use of specific types or classes of equipment. paragraph performed according to prescribed pro-
achieve their purpose, but are not re- cedures and records kept in accordquired to exceed this level. ance with the requirements of this
The revision of proposed § 211.2(a) (now §211.68(a)) eliminates the word“permit.” The authority to promul 189. One comment suggested that paragraph.
the third sentence of proposedgate CGMP regulations includes theauthority to regulate the use of equip
193. Several comments on § 211.68(b)§211.2(b) be modified by deleting the said the mandatory time interval of 6word “reproductions” and replacing it months for calibration checks onment that could have a bearing on
drug product quality. The argument with the phrase“input to the comput- scales and balances is arbitrary.
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45043 The Commissioner agrees that time
intervals longer than 6 months may beappropriate in some cases. Because§ 211.68(a) requires that automatic,mechanical, and electronic equipment,including scales and balances, be calibrated routinely to assure the qualityof 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 onlyto weight scales.
The deletion of §211.68(b), as proposed, removes the reference to“weight”; however, the Commissionerfinds that any scale or balance usedfor testing of production operations isrequired to be accurate and must becalibrated and checked routinely as required in § 211.68(a).
194. A comment requested an additional paragraph covering the standardization of tablet punch and diesets.
Although the Commissioner believesthat the comment has merit, he doesnot believe that it is generally appropriate in a general set of regulations toidentify specific equipment used o n l y in the manufacturing of one dosageform. Such requirements are more appropriate in regulations for specificdosage forms.
FILTERS
195. A number of comments on § 211.72 requested clarification whether this section is intended to apply toboth air filters and solution filters.Other comments requested clarification that the proposed paragraphs (b) and (c) refer only to injectable drugproducts intended for human use.
The Commissioner finds that theintent of this section is to eliminatethe use of fiber-releasing filters inliquid filtration systems during production of injectable drug products forhuman use. Revisions appearing in thefinal regulation clarify this intent. Additional background information regarding this requirement can be foundin the FEDERAL REGISTER of March 14.1975 (40 FR 11865), which establishedthe basic requirements for this section.
196. Several comments suggestedthat this section be deleted because itpertains only to injectable drug products and therefore should be placed inthe specific regulations for this typeof drug product.
The Commissioner agrees that thissection and a portion of § 211.94 applyonly to injectable drug products forhuman use and that such requirements will be suitable for the morespecific regulations for large and smallvolume parenterals for human usewhen such regulations are in effect.
RULES AND REGULATIONS
The Commissioner previously concluded in the final regulation published inthe FEDERAL REGISTER of March 14,1975 (40 FR 11865) that the use offiber-releasing filters in the production of human injectables requiredcodification in the general CGMP regulations until final LVP and SVPCGMP regulations are codified. Theseprovisions-will be incorporated in themore specific regulations regardinghuman parenteral drug products whenthey are published as final regulations. Again, the Commissioner reminds interested persons that this section has been in effect since April 14,1975 (40 F R 118651.
197. One comment noted that by thetime the final regulation becomes effective, proposed § 211.72(c) will be inoperative, since it requires substitutionon or before September 14, 1976.
The Commissioner agrees with thiscomment and is therefore deletingparagraph (c) of § 211.72.
198. One comment objected to beingforced to use filters in drug production.
Section 211.72 does not require theuse of filters in the manufacture, processing, or packing of injectable drugproducts. However, if filters are used,§ 211.72 specifies types of filters thatcannot 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 refilteredthrough a nonfiber-releasing filter. XI. CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES
GENERAL REQUIREMENTS
199. Several comments suggestedthat the requirements for containersand closures in proposed §§211.80(a) and 211.89 be separated from those forcomponents and in-process materialsbecause the testing controls, systems,and criteria differ.
The Commissioner finds that thecontrol of in-process materials is moreappropriate in Subpart F-ProductionProcess Controls; therefore, all references in Subpart E to In-process materials are deleted. Proposed § 211.88 andcertain requirements proposed in§211.89 are now in § 211.110(c) and (d).It is appropriate to consider control ofcomponents, drug product containers,and closures together, however, because the separation of requirementsfor control of containers and closuresfrom components in the CGMP regulations would necessitate the unwarranted duplication of numerous sections of text. The variations in handling, examining, or testing can beadequately addressed by each manufacturer in the written procedures required by the various sections.
200. One comment argued that theseproposed requirements in Subpart E
would place an additional burden onsmall manufacturers and that such requirements are unnecessary, particularly with OTC pharmaceuticals.
Drug product containers and closures play a critical role in assuringthat the patient is provided a drugproduct of essentially the samestrength, quality, and purity as whenit was produced by the manufacturer.The Commissioner cannot agree thatOTC drug products should not receivethe same degree of protection as Prescription drug products. It has been FDA's experience that “small” manufacturers can attain the same degreeof quality of their drug products aslarge manufacturers. There cannot bedifferent standards of quality of drugproducts for large and small manufacturers, nor can there be differentstandards of quality for OTC and prescription drug products.
201. One comment on §211.80(a)raised several issues relative to thehandling of bulk components beingheld in storage tanks or silos. including the commingling of a new shipment with the remainder from previous shipments and how such lotsshould be identified.
Combining a new bulk shipment of acomponent in a bulk storage tank withthe remainder of a previously received,tested, and approved component lotcauses the cornpositing of the material. The result is that the previouslyapproved material becomes in integralpart of an unapnroved new lot andcannot be used until such lot is approved for use. However, a manufacturer may choose not to commingleapproved lots with unapproved lots ofcomponents in bulk storage. In someinstances a manufacturer may be ableto test components appropriatelybefore introduction to bulk storaae asfor 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 “indetail” because it would require thedocumentation of minutiae and voluminous written procedures.
The Commissioner agrees that thephrase “in detail” could be construedto include description of insignificantprotions of the procedure, which is notthe intent. Therefore, he is insertingthe word “sufficient” before the word “detail.”
203. Comments were received on § 211.80(a) recommending replacementof the phrase "approval or rejection" with the word "disposition."
The Commissioner disagrees withthis suggestion. Written proceduresmust spell out the criteria for approvalor rejection in view of such material’s intended use.
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45044 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 thatwritten procedures are appropriate regardless of the size or complexity ofthe operation. Written procedures provide a basis for the uniform performance of a function.
205. One comment suggested addingto § 211.80(b) the phrase “so as to alterthe safety or efficacy of the drugproduct.”
The Commissioner finds that it isreasonable to conclude that contamination would affect drug quality.Therefore, the suggested phrase is unnecessary and is not included in thefinal regulations.
206. Numerous comments stronglyobjected to the requirement in§ 211.80(c) that components. drugproduct containers, or closures bestored at least 2 feet away from walls,maintaining that it would severelyreduce the available storage area andthereby necessitate additional space tostore the same amount of materialwith an attendant inordinate and unnecessary inflationary impact. Some ofthese comments suggested that this sanitation-oriented requirement beplaced in § 211.58 or combined with§211.80(b). Additionally, some comments offered alternate wording suchas: to permit cleaning and inspection.to allow for appropriate sanitation operations, and to allow for effectivesanitation practice. Some commentsquestioned whether this requirementonly refers to outside walls or includesall walls, such as mesh screened walls,vault walls, partitions. and refrigerator and freezer walls. Some commentsquestioned whether free-standingshelves also had to be “at least 2 feetaway from walls,” since shelving issometimes attached to the wall forsafety reasons.
The Commissioner has carefullyevaluated this paragraph in light ofhis intention to provide suitable spacing in storage a r e a s for cleaning andinspection and concludes that a specific requirement for at least a 2-foot space between the wall and such material can be deleted, but a requirementto store materials in a way that allowsfor cleaning and inspection will be retained. He is also deleting the words“on pallets or free standing shelves” toallow for other suitable methods ofstorage. The Commissioner believes itpreferable to codify this requirementin this section rather than in § 211.56.
207. Numerous comments on §211.80(d) objected to the proposedrequirement to identify each containerin a lot being received since manyitems, such a s containers. closures. andexcipients are palletized. This require-
RULES AND REGULATIONS
ment. as proposed, would mandatethat each pallet load be broken downso that each unit on the pallet could be identified, then repalletized. thereby increasing the potential for damageand mixups. This procedure is allegedto have an unnecessary inflationaryimpact.
The Commissioner recognizes thatthere are situations where it would beinappropriate to identify each containerer of component, drug product container, or closure such as mentioned inthe proposed regulation. He agreesthat some provision should be madefor these situations. He is thereforeamending this paragraph by addingthe words “or grouping of containers.”Any individual unit separated from agrouping must be identified with theappropriate information required bythis paragraph.
208. Some comments requested aclarification of the word “disposition”in §211.80(d) that would distinguishbetween a simple transfer of the material and use of the material for a particular purpose.
The Commissioner believes that theword “disposition” appropriate1 ycovers any use or change in controlstatus of the lot, including both ofthose cited in the comments.
209. Some comments questioned theintent of the last phrase of § 211.80(d).The respondents stated that if theintent is to identify those containersthat have been opened, then a periodshould be placed after the parenthesesand a suggested new sentence added toclarify the intent.
The Commissioner agrees that thisphrase could be interpreted to requirethat, only the lot be marked to indicatewhether and when it had been openedand sampled. The reauirement for thesampling of lots is contained in§ 211.84. Therefore. he concludes Chatthe requirement in §211.80(d) regarding identifying sampled containers is more appropriate1y placed in §211.84(c), which will clarify theintent to identify containers whichhave been sampled.
210. One comment on §211.80(d)suggested that when a shipment ofcomponents contains more than onemanufacturer’s lot number. the recipient be allowed the option of assigninga single code number for this shipment.
The Commissioner rejects this suggestion inasmuch as it would eithercomplicate or negate tracing a component back to a particular manufacturer’s lot or the subsequent tracing of aparticular lot of component used to alot of drug products.
211. One comment objected to therequirement in §211.80(d) that containers of drug product containersbear an identifiable lot number, on thegrounds that this is not standard prac
tice in the industry. The comment suggested that the recipient provide atinctive code for such containers.
The requirement is that each lot ofeach shipment be identified with atinctive code. If a lot number furnished by the supplier is distinctivefor each lot in each shipment, thenthe recipient, i.e., the drug productmanufacturer, can use the lot numberas the distinctive code. If, however,there is no lot number or the lotnumber is not distinctive for each lotin each shipment, then the recipient isresponsible for designating his owndistinctive 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 closuresaratel y.
The identification of articles received, camparison with materials ordered, and examination of the overallcondition of the material received Iscarried out in much the same way regardless of the character of the articlereceived. The Commissioner sees noadvantage to promulgating two separate regulations on receiving andage of materials, one for components,and the other for containers and sures. To do so would simply be redundant.
213. A number of comments on§ 211.82(a) said individual containersof components. containers, andsures need not be visually examinedbefore acceptance as long as theychecked before use. The rationale for the comments is that a visual check ofeach container is impractical and unrealistic for large shipments of bagged materials that are palletized as aand/or shrink-wrapped. The respondents suggested that tearing apart materials packaged in that manner wouldbe costly and could be better donebefore use rather than in a receiving area.
It was the Commissioner’s intent in this paragraph to provide for a simplecheck at the time of receipt to detectobvious problems such as the wrongarticle, damaged containers, or visible contamination which would precludeany further handling of the materials.He recognizes. however, that individual container examination of large lotsof bagged or boxed materials is impractical when they are received. Therefore, this requirement is revisedto prpvide for examination of eachcontainer or grouping of containers.
214. A number of comments pressed concern over the possibility of contamination if containers of components and other materials are opened for examination in the receiving areasof factories. To avoid cross-contamina
29, 1978
45045
tion 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 sealsmust be broken for purposes of examination. It is the intent of this paragraph that a visual examination beperformed. In most cases it would beadequate to limit the examination toshipping containers. If the firm feelsan inspection should be made indepth, proper precautions must betaken to prevent cross-contamination.
215. Several comments in regard to§211.82(b) objected to the concept ofsetting a special area aside for quarantined materials. They felt that reserving space for this purpose and movingstock into and out of this special quarantine area would be costly because ofthe 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 ofthis preamble that describes the variety and degree of physical quarantineprocedures which, when combined with other controls, provide the assurance necessary to prevent untestedand unreleased materials from beingused in drug manufacturing operations.
216. Several comments on §§ 211.82(b) and 211.84(a) proposed that components should be “tested” w h e r e a s 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 agreethat appropriate testing of containersand closures can be limited i n 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 usethe word “examination” along with‘testing” to suggest a lesser type oftesting, if appropriate, however; andthe Commissioner is therefore addingthe phrase “or examined. as appropriate” to prevent any misinterpretationof §§ 211.82(b) and 211.84(a). TESTING AND APPROVAL OR REJECTION OF COMPONENTS, DRUG PRODUCT CONTAIN
ERS. AND CLOSURES
217. Citing various reasons, comments suggested that § 211.84(a) be re-’ vised to permit use of components,drug product containers, and closures,simultaneously with testing and with precautions to prevent release of thedrug product until the tests indicatecompliance with specifications.
As a genernl principle, such procedures would violate the precepts ofgood quality control because untested
RULES AND REGULATIONS
and possibly noncomplying materialswould be used in drug product processing. Although initially it would appearthat the manufacturer merely assumes the risk of having to recondition or destroy a processed lot thatwas found to contain unsatisfactorycomponents, containers, or closures,the Commissioner is concerned that processing while testing substantiallyincreases the risk to the consumer that an unsatisfactory lot might erroneously be released. The Commissioner cannot accept such risks or thesesuggestions.
218. Two comments on § 211.84 suggested that the only practical test ofproduct 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 whichthe suitability of a container-closuresystem can be determined before itsuse. Manufacturers do develop specifications for product acceptance whenmaking their purchases. Such purchases are made with definite knowledge of what is needed. The regulationsimply requires that checks be madeto assure that what has been received is what has been ordered.
219. One comment suggested that aprotocol or certificate from the container manufacturer that the container meets the U.S.P. requirements beacceptable 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 verificationof the supplier’s test results. Therefore, he would have no reservationabout accepting a certificate or reportof analysis with each shipment of drugproduct containers-as long as the lotof containers is appropriately identified, the supplier’s results are periodically verified, and their certificate provides all appropriate testing. A newparagraph, §211.184(d)(3), is added to clarify this provision.
220. One comment interpreted§ 211.84(a) to require that each lot ofcomponents, drug product containers,and closures be tested before each use in processing.
This paragraph does not requiresuch a practice, nor is that Intended.
221. Several comments questionedthe meaning of container identification in § 211.84(a) and its relationshipto a similar requirement in § 211.80.
The Commissioner is deleting the requirement regarding container identification from § 211.84(a) because suchrequirement more appropriately appears in § 211.80.
222. Several veterinary drug manufacturers responded that the testingrequirements for drug product containers and closures in §211.84(a)
should not apply to veterinary drugsor that a very simple visual examination of such items would be all that is necessary for animal products. Onecomment said the requirements forcontainers and closures in Subpart Eare not current good manufacturingpractice for the veterinary drug industry.
The Commissioner does not acceptthe stated premise that the veterinarydrug industry does not exercise suchcontrol over these containers and closures to ensure the protection of theirdrug products from external influences such as light, moisture, and microbes. The agency’s experience in inspecting veterinary drug manufacturers and in reviewing new animal drugapplications indicates that this is notso. The requirements of Subpart E canand should apply to both human andveterinary drug products.
223. A number of comments on §211.84(b) objected to a requirementfor the use of statistical criteria to determine the sample sizes for testing.Many of the comments recommendedthat the requirement be made optional or that it be applied only when necessary or appropriate. Some suggestedthat few people in the pharmaceuticalindustry understand statistical methods and that even experts differ on interpretation and application. One comment suggested that representativesamples are impossible for all materials and suggested that random sampling be permitted.
The Commissioner believes that statistical methods provide a rationalbasis for determining sample sizes,provide assurance that an adequatesample has been obtained, and increase the user’s confidence that the results from testing of the sample arerepresentative of the true condition ofthe product sampled. The Commissioner recognizes, however, that othersampling plans, derived by othermeans, may also be adequate, and thissection is revised to allow the use of alternative types of sampling plans. Thiswill allow for use of random samplingmethods if appropriate.
224. A few comments requested thatcontainers and closures not be included in the representative sample requirement of § 211.184(b). No rationale was included to explain the request.
If the comments meant that other sampling methods such as randomsampling are more appropriate, thenthe change made in this paragraphwill be responsive to these comments.If the comments meant that containers and closures should not be sampledat all, the Commissioner rejects thecomments because he believes that examinations must be made on productcontainers and closures to assure their suitability for use in drug productpackaging.
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45046 RULES AND REGULATIONS
225. One comment requested explanation of an acceptable “past qualityhistory of a supplier,” as suggested by§ 211.84(b).
The Commissioner did not use theword “acceptable” in his proposal, but did permit the past quality history tobe used in determining sampling plansfor articles received from various suppliers. The object of considering thepast quality history is that the fewerthe problems encountered with materials from a particular supplier andthe more often that supplier’s products meet specifications, the less extensive the sampling schedule mayneed to be for that material. Conversely, the more problems encounteredwith articles from a particular supplier, the more extensive the samplingschedules for the articles need to be.
226. One comment suggested thatthe word “incoming” be insertedbefore the word “shipment” so thatthe sentence is clear that no referenceis being made to outgoing shipments.
The Commissioner believes the
to provide manufacturers ) 211.84(c)(1 §with more latitude in this operation.The Commissioner does not agree,however, tha t control s used in sampling are uniform throughout thepharmaceutical 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 thissection as follows: provisions for handling sterile materials; a requirementthat each container that is sampled bemarked; and identification of the location within a container from which asample was taken.
The Commissioner believes that theproposed requirements, with one exception, provide sufficient control ofsampling procedures. The language ofthis section is general to allow for awide variety of methods of. handlingproducts with a wide variety of characteristics. It is not the Commissioner’sintent to design a specific control pro
ments objected to the proposed samplecontainer identification as being tooburdensome because the information 29, available in other documents. Onecomment suggested that an in-housecode to identify samples is adequate.Another said that the proposedsample container identification is nota current good manufacturing practice.’
It is not the Commissione r’s intent that all the listed lnformation appearon the sample container. Section211.84(c)(5) is reworded to requireonly a means whereby sample containers can be related to the required identification information.
233. One respondent expressed concern that the requirement for openingcontainers for sampling in a suitable area would lead to separate areas foreach 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
dealing with cross-con-) 211.84(c)(2meaning of the section is clear and cedure which a manufacturer must §that the sentence refers to materials follow, or to preclude flexibility in
tion problems could occur with theidentity test requirement for activeand inactive ingredients in
tamination because the requirementreceived for use in drug production. meeting this objective, I t is sufficient should relate to the contamination ofTherefore, no change is made in the here to state the control desired and components and not containers.final regulation. leave the specifics to the reasonable The Commissioner agrees that the227. One comment suggested dele- judgment of the manufacturer. The protection from contamination, as retion of the reserve requirement in Commissioner believes that the sug should relate, §211.84(c)(2) quired in § 211.84(b) because such a requirement gestion for identifying the locationsappears i n§ 211.170(a ) and is appropri- within a container where samples haveate only for components.
To clarify his intent here, the Commissioner is adding the words “whererequired b y § 211.170.”
228. Two comments recommendedthat the requirement in § 211.84(b) fortesting each shipment of each lot isunnecessary when a previous shipment of the same lot had been re-
been taken is inherent i n § 211.84. Toclarify that containers from whichsamples are taken must be marked inorder to produce an appropriaterecord, the Commissioner is adding a new § 211.84(c)(6).
231. A number of comments were re-relating to ) §211.84(c)(4ceived o n
to the content sof sampled containers.The final regulation is clarified in thisregard.
235. Twenty-eight comments on§211.84(d)(1) stated in essence thatthe word “specific” should be deletedwith reference to identity test s because there may not be specific identity tests for each component. Thewords “appropriat e” and “if available"component subsampling and composit
ceived, tested, and approved. ing of subsamples. The majority of were suggested for use instead.The Commissioner feels that exami- those commenting recommended that The Commissioner recognizes that
nation of each lot of each shipment re- the regulations allow for cornpositing. the accuracy and precision of testingceived is necessary even though a por- procedures vary. The purpose of
to assure that someis) §211.84(d)(1identification procedure is used for
Some respondents stated that samtion of the same lot has previously pling at multiple levels is not alwaysbeen received. tested, and approved.Subsequent shipments may have beensubjected to different conditionswhich may have caused changes inmaterials so that, although one shipment of a particular lot has met specifications, another may not.
229. Fifteen comments oncontainers stated tha t ) 211.84(c)(1 §
from which samples are being collect-
necessary. Others suggested that theinstances be spelled out where sampling at multiple levels is necessary.One comment indicated that compositing is a satisfactory procedure if thecontainer contents are all going to beused in a single drug product lot.
The intent of this proposed sectionis to prohibit the compositing of samples taken from different portions of acontainer when there is a possibility
each component and that it is as specific as possible. Otherwise, the testhas little value for purposes of identifying a material. This paragraph isreworded in recognition that specificidentify tests do not exist for all materials.
236. One comment said interpreta
ed do not always need to be wiped orvacuumed. In addition, two other com that the composition of the material
being sampled may vary within the § 211.84(d) ( 1) in multiple-ingredientcomponents. The suggestion was made
ments requested deletion of all theparagraphs as unnecessary because allmanufacturers know what they needto do.
container. There is no general prohibition in the regulations on cornpositingsamples where such compositingwould not mask subdivisions of the
that the wording be changed so thatan identity test for each component
The Commissioner agrees that acontainer of components may not
had to be performed whether i twa s an active or inactive ingredient.sample that do not meet specifica
tions.always need cleaning before samplingand that, where cleaning is needed,
The Commissioner is clarifying232. A number of comments suggest
ed changes in the requirements pro-for identifying) 211.84(c)(5 §posed i n
the sample containers. Thre e com
§ 211.84(d)(1 )in the final regulation bvrequiring at least one tes t to verify the identity of each component of the
wiping or vacuuming may not necessarily be the most effective means ofcleaning. Therefore. he is revising drug product.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
237 . F ive comments sai d there should be no requirement in§211.84(d)(1) for an identity test forinactive components.
The Commissioner believes it is important to identify inactive components to avoid erroneously using unsuitable components to manufacture adrug product.
238. The use of organic chemical reactions as indications of product identity in bulk chemical processingwas recommended by one respondent as anacceptable identity test under § 211.84(d)(1 ).
The Commissioner advises that the final regulation does not preclude organic chemical reactions as indicatorsof component identity, if appropriate.
239. A number of comments relatingto validation of a supplier’s testresults recommended that that portion of§ 211.84(d)(2 ) be deleted. The argument wa s that the validation requirement would preclude the use of procedures other than those used by thesupplier. One change in the wordingwas suggested: that the word “monitors” be used in place of “establishes.”
The Commissioner believes that alternative procedures may be an acceptable means of validating methodsused in the testing of materials by asupplier. The regulations do not preclude the use of alternative methods.
About the word “monitors” in placeof “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 ofanalysis, the manufacturer must firstestablish that those reports are reliable. That relia bility is established bythe manufacturer’s own testing which,when compared to the supplier’s data,shows agreement within specifiedlimits over a period of time. Once thatreliability isestablished, then the levelof the manufacturer’s validation testing may be reduced and reliance onthe supplier's report may increase.Continuing checks should be made onthe supplier’s reports because somekind of periodic monitoring must occur to assure the continued reliability of the supplier's test results.
240. One comment suggested thatthe word “complete” should be deletedfrom § 211.84(d)(2) as a descriptiveterm for the supplier’s report of ananalysis.
The Commissioner ’s intent inthis paragraph is to allow for alternative routine testing where reiliable reportsof analysis are available for components. He finds that the criteria for accepting reports of analysis adequatelyprovide for their proper applicationand that the modifying term “complete” is not necessary. Thefinal regulation is revised accordingly.
RULES AND REGULATIONS
241. One comment said suppliers’ reports of analysis are not always reliable and suggested that severaladd it ional guarantees be requiredin § 211 .84 (d)(2 ). They included, in addition to the report of analysis, a guarantee of the type described in section303(c) of the act, a certification thatthe testing reported was done within 7days of the report, and a guaranteethat at the time of shipment/receiptthat the component will still conformto protocol specifications.
Suppliers’ reports of analysis mustbe validated to establish thereliab ilityof the suppliers’ analysis. Additionalspecified requirements relating to supplier’s test results do not now appearto be necessary for these regulations.
242. One comment expressed concern that the validation requirementin § 211.84 (d)(2) would lock a manufacturer into a single supplier, presumably because of the investmentln validation procedures.
The Commissioner advises thatreliance on a supplier’s report of analysisis not mandatory-it is optionalin lieu of testing by the manufacturer. Although an investment in validati on might persuade a manufacturer torem ain wi th a single supplier , t h i s does not constitute sufficientrea son,in the Commissioner's opinion, to preclude the use of this approach by manufacturers. Competition among suppliers should not be adversely affected bythis option.
243. One respondent proposedde leting the word “all” with reference to the phrase in §211.84(d)(2) that testing be done in accordance “with all appropriate specifications,” apparentlyto allow for less stringent testing ifdeemed appropriate by the manufacturer.
The Commissioner believes thesuggested change would alter the meaning of § 211.84(d)(2). The intent Is thatappropriate specifications beestablished. Once appropriate specificationshave been set. it is not acceptable totest for less stringent specifications.
244. A comment suggested deletionfrom proposed § 211.84(d)(3) (now§211.84(d)(4)) of the reference tomicroscoplc examination, stating that itdoes not seem to relate to any of theother provisions in this section.
The Commissioner recognizes that§ 211.84(d) could list various othertypes of examinations, but he does notbelieve it inappropriate to specify aparticular requlrement for microscopicexamination when appropriate, whilenot listing others. For certain classesof drugs, particulate contamination isof increasing concern. Identification and classification of particulate mattermay properly require microscopic examinatlon. Therefore, the Commissioner believes reference tomicroscop
45047 ic examination is worthy of emphasisin the regulations.
245. Eleven comments on proposed § 211.84(d)(4) and (5) (now § 211.84(d) (5) and (6), respectively) -indicatedthat requiring materials to be eitherapproved or rejected after testing doesnot take into account other categoriesof material status into which materials could fall if they do not meet specifications. For example, comments saidthat materials could be reprocessed orapproved 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 ofdisposing of materials which do not meet acceptance criteria. If materialsare being tested for their acceptabilityfor manufacturing a particular drugproduct and they do not meet thosecriteria, however, they must be rejected for that use.This requirement hasbeen set forth in §211.84(e) n o w, rather than in(d)(5) and (d)(6). There is no prohibition against the use ofsuch materials after appropriatereprocessing, or for other uses for whichthe acceptance criteria can be met.
246. One comment suggested thatexamination of material under proposed §211.84(d)(5) be limited to visible contamination.
Other types of examination may benecessary to identify contamination,because contamination that is notvisible may adulterate a material as significantly as visible matter. Therefore,the suggestion is rejected.
247. One comment suggested a newrequirement 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 testingof representative samples. There appears to be no need to repeat itin § 211.84(d).
248. One comment said with regardto proposed § 211.84(d)(5) that it is themanufacturer’s responsibility to determine the need for testing for microbialcontamination.
The Commissioner agrees that it isthe manufacturer’s responsibility todetermine what materials are liable to microbial contamination, but havingmade that determination, the manufacturer must proceed to test thosematerials for such contamination.
249. The requirement in proposed § 211.84(d)(5) for microbiological t e s t ing of materials liable to bacterial contamination was interpreted by onecomment as requiring sterility tests for containers and closures used i n aseptic filling operations.
The Commissioner agrees that anevaluation of a final production of
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45048 aseptically produced sterile productswould include the testing of containersand closures. Once a procedure is validated, periodic testing and controlmonitoring are necessary to assurethat the processing controls continueto work. USE OF APPROVED COMPONENTS, DRUG PRODUCT CONTAINERS, AND CLOSURES
250. A substantial number of comments objected to the requirementthat, without exception, approvedcomponents, containers, and closuresmust 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 newsupplier, or equipment, or processes inrelation to a new container; or that onoccasion the oldest stock might bephysically inaccessible for a shortperiod of time. Several commentsdeemed the regulation unnecessary because some containers are inert.
The Commissioner believes that the concept of using the oldest approvedstock of components, containers, andclosures is fundamentally sound. Eveninert containers may be subject to increased breakage, cracking, or otherdefects after prolonged storage. Theremay, however, be legitimate reasonsfor varying from this requirement insome instances. Therefore, this sectionis revised to provide for exceptionsfrom the first-in, first-out requirementby adding a provision that deviationfrom this requirement is permitted ifsuch deviation is temporary and appropriate. RETESTING OF APPROVED COMPONENTS, DRUG PRODUCT CONTAINERS, AND CLO
SURES
251. Several comments on $211.87 did not agree that components. drugproduct containers. and closures should all be retested in accordance with established requirements. Theymaintained that components requirespecific retestlng procedures to assurecontinued identification, strength,quality, and purity, whereas the likelihood of deviation of containers and closures from specifications because ofdeterioration is considerably less andshould not require the same degree ofretesting as components. They contended that stating requirements forretesting components and containerswithin the same section by the use ofqualifying statements like “appropriately” or “as necessary” would weakenthe former to accomodate the latter. They therefore proposed that this section be divided into two subsections,one for retesting components and asecond 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 nec-
RULES AND REGULATIONS
essary.” The Commissioner recognizesthat all the objectives of retestinglisted in this section-to reestablish identity, strength, quality and purity-are not necessarily applicable to allcontainers and closures because. all containers and closures are not necessarily tested originally for all these attributes. He also recognizes that theperiod for appropriate retesting variesnot only according to conditions ofstorage, but also according to the typeof component and the type of container and closure. The Commissioner retains the wording of the proposal inthe final regulation.
252. One comment suggested thatthe 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 appropriatetest for the attribute being considered.Therefore, this section is modified inaccordance 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 requirementapplies to all rejected components,drug product containers, and closureswhether they be lots, batches, portions of lots or batches, or otherwiseidentified.
254. Several comments suggestedthat this section be expanded to dealwith the subsequent. disposition of rejected materials.
The Commissioner notes that the criteria for reprocessing rejected materials are adequately covered in othersections of this part. It is not necessary to deal with other methods of disposition because they are varied, arewithin the manufacturer’s discretion,and may include destruction, return tothe supplier, or use in other productswhere specifications are met. TheCommiussioner believes the major concerns of FDA are that rejected materials are not inadvertently used in aproduct for which they are not acceptable and that any such materials thatare reprocessed and found suitable forreuse 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 toshipping cartons and containers forholding of in-process materials.
As recognized by the majority ofcomments received about this paragraph, the section heading introducesrequirements regarding drug productcontainers and closures. The Commissioner finds that minor editorial changes in the text will clarify thatthis section is intended to apply to drug product containers. Requirements elsewhere in the regulationsdeal with appropriate handling ofcomponents 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 thissection. Another comment said that once the suitability of a container-closure system had been established, itshould not be necessary to test eachlot in minute detail.
The Commissioner finds that specific detailed requirements for testing ofthe container-closure system are notnecessary for this section. Usually,manufacturers already have the benefit of experience with containers fabricated from materials with well-known properties. Further, the requirementof § 211.166, particularly paragraphs(a)(4) and (b), will provide substantialinformation relative to the suitabilityof a container-closure system. Wherethe 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 notspecify detailed testing of each andevery lot of containers. Manufacturersare responsible for the extent andmanner of sampling and testing ofdrug product containers and closures.Adequate sampling and testing of containers will depend on a number offactors. The duty of the manufactureris 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.
256. All of the numerous comments on § 211.94(b) requested that the requirement that container-closure systems “provide adequate protection” bemodified to the limits of “normal” storage and use of the product or tolimits of use and storage set forth onthe label.
The Commissioner agrees that t.hcproposed regulation requires a level ofprotection that may not be possible toachieve in unforeseen’ circumstances. Therefore, the final regulations are revised to include the concept of foresee-
FEDERAL REGISTER, VOL 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
able conditions. The Commissioner believes, however, that the acceptabilityof container-closure systems under arelatively narrow range of conditionsthat might be considered “normal” isnot 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 intransit can be reasonably foreseen bymanufacturers and should be taken into account when considering thesuitability 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 responsibilityto see that these items are clean, manufacturers may not always have toperform a separate cleaning operation.Examples of items which may notalways need cleaning were cited, such as: caps, liners, blisters, neutralizers,and films.
In proposing this requirement, theCommissioner intended that containers and closures be clean before use. In some instances this will require the
manufacturer to perform separate,and sometimes extensive, cleaningcycles. In other instances it may notbe necessary for the manufacturer toundertake a specific cleaning operation. In any event, containers shouldnot be released by the quality controlunit, as specified in § 211.84(a), untilprocedures, standards, or specifications, established under § 211.94(d)have been met. To clarify the intent ofthis sectlon the word- “cleaned” is changed to “clean.”
260. The majority of the commentsregarding § 211.94(c) were directed atthe requirement, currently in effect.that containers and closures be cleansed with water that has been filtered through a nonfiber-releasingfilter of specified pore size. Commentsstrongly objected to this requirementfor 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 thatsolvents other than water are used for cleansing; others objected to the poresize requirements because of highvolume demands of cleaning cycles. Inaddition, arguments were presentedthat by requiring filtration of cleaningwater for injectable containers, newproblems of microbial and pyrogencontamination are possible.
In particular, the United StatesPharmacopeia submitted comments bythe Subcommittee on Particulate and
RULES AND REGULATIONS
Chemical Contamination, National Coordinating Committee on LargeVolume Parenterals (NCCLVP), whose committee membership includes representatives from major health care organizations, industry. and government.The NCCLVP expressed concern thatthe requirement for filtered cleaningwater presents disadvantages and potential hazards that far outweigh thebenefits. The specific reasons for theirconcern are as follows:
1. Water lines for transferring cleaningwater for injectable containers are designed.constructed, and maintained to deliver large quantities of high quality water under highpressures. In order to maintain the integrityof these llnes and the quality of the water.disruptions must be minimized . The need to routinely install , test. and replace bacteriaretentiv e filters of the type required will und o u b t e d l y com promis e theintegrity designed into these lines. Furthermore, thepressure 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 microorgani s m s and particulates, significant accumulation of such contamination can occur on the filter surface. Proliferation of bacteria on the intact filter can lead to the generationof pyrogens or the growth of certain bacteria through the f i l t e r pores if a 0.45-micron filter i s used. Since high flow rates and pressures are required. the chance for mechanical failure and breakage of the f i l t e r i s increased. thereby increasing the r isk for the passage of a bolus of bacteria
3. Because of the microbial Jeopardy described above, these filters will require scrupulous maintenance. Such efforts w i l l result i n significant penalties to the process inboth mater ia l and labor costs.
It is the opinion of the Subcommittee on Particulate and Chemical Contaminants that if a fiber-releasingfilter is not employed in the processand a final rinse is performed withhlgh-quality. microbiologically c on trolled 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 F R 11865). At that time the Commissionerhad concluded that it was prudent torequire that containers and closuresfor human injectable drugs becleansed with water that has been filtered through a nonfiber-releasingfilter of a specified pore size. In view of comments received, the Commissioner is concerned that the requirement for filtered cleaning water mayintroduce new problems that outweighrisks 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,
45049 published in the FEDERAL REGISTER of June 1.1978 (41 FR 22202).
Because of the comments received,the Commissioner finds that there is substantial good reason to suspend, atleast temporarily, the requirementthat injectable containers and closures be cleansed with filtered water to remove fibers. T h e Commissioner wishes, however, to serve notice thatthe issue of fiber removal from parenteral drugs, including where suchfibers may be introduced through thecleaning cycle of containers. continuesto be an important problem underreview by FDA. Until FDA has additional information on the fiber content of cleaning water and the significance of such fibers, however, thefinal regulations are revised to deletethe requirement for filtered cleansingwater. But this action in no way affects the agency’s position on fiber-releasing filters in the manufacture ofinjectable drug products for humanuse (see § 211.72).
261. Almost all the comments on § 211.94(e) said it was a restatement of the other parts of this section andtherefore should be eliminated. One comment said the phrase "the holdingof” was redundant since, by definition,containers are used “for the holding" of a product.
The Cmmissioner finds that the requirement of the proposed paragraphis not necessary in this section becausea similar requirement appears in§211.165(g). Therefore, he is deletingthe proposed paragraph (e) from thissection.
DOCUMENTATION OF CONTROLS
262. A number of comments suggested that §211.96 be deleted on thegrounds that it duplicates provisionsof § 211.84.
The Commissioner agrees that bothsections deal with documentation of the receipt, testing, or examinationand disposition of components, drugproduct containers, and closures. Therefore, § 211.96 is deleted.
XII. PRODUCTION AND PROCESS CONTROLS
WRITTEN PROCEDURES; DEVIATIONS
263. One comment on §211.100 saidwrltten procedures for manufacturingand quality control should be revlewedand approved by “the appropriate organizational units” instead of by thequality control unit because the quality control unit does not necessarilypossess an expertise greater than thatin other units. Another comment said the quality control unit does not havea sufficiently wlde expertise to reviewand approve all areas of drug productmanufacturing, including such areasas production. engineering. research,safety, and regulatory affairs. A third
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45050 comment said the requirement for approval of written procedures for manufacturing and quality control by appropriate organizational units otherthan the quality control unit shouldbe deleted.
The Commissioner rejects thesecomments, He has not proposed thatquality control have complete expertise in all of these areas. The requirement for review and approval of manufacturing and control procedures isclearly a requirement that the qualitycontrol unit review these proceduresin light of what may affect the product in terms of safety and quality. TOremove from the quality control unitthe responsibility for approving written procedures would diminish the authority and responsibility that shouldbe vested in the quality control function. Further, based on the agency’sexperience with the industry, theCommissioner believes that the concept of quality control review and approval for procedures that have abearing on the quality and safety of adrug product is current practice. Thissection also properly requires reviewand approval by other appropriate organizational units. Therefore, thequality control unit’s function doesnot replace the expertise that wouldbe vested in other units.
264. Another comment on § 211.100said requiring review and approval bythe quality control uni is infringingtunreasonably on individual manufacturers in determining their own organizational structures.
The Commissioner does not believethat this requirement unduly dictatesorganizational structure. For example,it does not designate to whom thequality control unit or othe organizartional units must report.
265. One comment on §211.100(a)said appropriate units should be required to review, as wel as draft andlapprove, manufacturing and controlprocedures.
The Commissioner agrees and is inserting the word “reviewed.”
266. One comment suggested thatthe word “justified” in the last sentence of §211.100(b) be replaced bythe word “explained.” Another comment proposed substitution of theword “approved.”
The Commissioner believes that theword “justified” properly reflects theintent. 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. Theremust be a valid reason for a deviation.
267. One comment on§211.100(b) said only significan deviations shouldtbe recorded and justified.
Section 211.100(b) requires that written procedures shall include all requirements as specified in subpart F of
RULES AND REGULATIONS
the CGMP regulations. This subpartdoes not require written proceduresfor every conceivable or minute detailof production and control. When suchprocedures are essential, th Commise sioner maintains that any deviationfrom them is significant and should berecorded and justified. To modify theregulation as proposed would imply,however, that only some deviationsare significant.
268. A comment proposed deletingfrom § 211.100(b) the phras “e and shall be documented at the time ofperformance.”
Documentation of performance, inthe Commissioner’s opinion, certifiesthat the written procedures have beenfollowed. 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 ofcomponents” is an unfamiliar phraseand is not defined.
The Commissioner recognizes thatnot all firms use the same terminologyto define similar phenomena. He believes the heading is clear when considered in light of the context of thesection and that no change or definition Is needed.
270. One comment said §211.10 is1addressed to dosage form productionand cannot profitably be applied tochemical manufacture.
These CGMP regulations apply tofinished dosage form drugs (under§§210.3(b)(4) and 211.1) and are notbinding requirements for chemicalmanufacturing. The Commissioner maintains that these regulations canserve as useful guidelines in the manufacture of chemicals. The agency plansto develop specific CGMP regulationson production of bulk drugs.
271. One comment said it would bedifficult to follow the requirements of§ 211.101 when producingradlopharmaceuticals because the exact quantity of the radionuclideavailable before the production cyclebegins is not known, and the components measurement must be performed aseptically.
The Commissioner is rewordlng§ 211.101 to allow for its application toradiopharmaceuticals Further, this.comment will be considered when specific CGMP regulations are proposedfor radiopharmaceutical drug products.
272. One comment said the operation supervisor may or may not bethe same person as the one checkingthe operation and suggested adding anew paragraph (e) to § 211.101 to havethe appropriate entries made on thebatch record.
The Commissioner believes that§ 21 1.188(b)(11) adequately covers 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 publishedmonographs permitting 85 or 90 percent of labeled claim as a basis for certification.
The Commissioner notes that thisparagraph does not prohibit the release of batches of drug products ifthe percentage of active ingredients iswithin acceptable limits. Th Commise sioner recognizes that acceptablelimits 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 expressedconcern that every active ingredientamount would have to be recalculatedto provlde 100 percent and that a newmaster production record would haveto be prepared for each new lot ofactive ingredient because every lot ofactive ingredient may not have thesame potency value.
The Commissioner believes that useof the word “intent” should be emphasized. Drug products must be formulated to provide 100 percent of labeledpotency based on the usual assay ofactive ingredients. Active ingredientsthat are slightly above or below theusual value, but are within appropriate established specifications, may beused without reformulation providedthat the resultant drug product willprovide a percentage of active ingredient that is within acceptable limits.The criteria for acceptance of components should be such that proper usewill result ln an acceptable drug product.
275. One comment said i is extreme-tly difficult to formulate a biologicalproduct to fulfill the requirement of§ 211.101(a) because the potency valueis assigned after the manufacturingprocess has been completed.
The Commissioner again emphasizedthe use of the word “intent.” The example given ln the comment does notshow that there is intent to formulatesuch products at less than 100 percentof labeled claims; rather, it virtuallyprecludes such an intent by the natureof that process.
276. One comment wanted to substitute the words “the amount of activeingredient specified in the master production and control record of the drugproduct ” for the words "100 percent ofthe labeled amount of active ingredient” since over-the-counter drugs arcnot required by law to note the quantities of active ingredients in th labele ing.
The Commissioner agrees with theobject of the comment, but believesthe suggested wording i inadequate s
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.
because it would not prohibit themaster record from containing a formulation intended to provide less than100 percent of labeled potency. Instead, the Commissioner is revisingthe final regulation by adding thephrase “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 measuredprecisely; (2) clarification of this section is needed to -allow for the use of bulk components without previoussubdivision, weighing, or measuring:(3) clarification is needed to allow for direct weighing of components into abatch.
The Commissioner finds that § 211.101(a) as written is not flexibleenough to permit procedures such asare given as examples in the comments. Therefore, the first sentence ofthis paragraph is revised to read asfollows in the final regulation: “Components for drug product manufacturing shall be weighed, measured. orsubdivided, as appropriate.”
278. Numerous comments requestedclarification of § 211.101(b) regardingthe necessary identification of component containers. The comments pointed out that in some instances components are dispersed, but that the manufacturing department would makethat decision for specific batch usage.Several comments said the identification information was available through alternate control systems.
The Commissioner believes that, aswritten, the final regulation takes intoconsideration the physical dispersal ofcomponents. Comments that the required identification information isavailable through alternative controlsystems gave no examples; therefore,no change is made in the regulation.
279. Several comments objected tothe word “strength” in § 211.101(b)(4) and wanted it deleted.
The Commissioner rejects thesecomments. If a component containerdoes not adequately identify the batchin which the component isto be used,there is a potential for mixups. The term “ s t r e n g t h ” is defined in § 210.3(b)( 16), so there can be no ambiguity in its meaning.
280. Two comments suggested thatuse of component lot numbers andproduct lot numbers on the same container presents a possibility of mixupsince the wrong numbers may be written on the batch record.
The Commissioner finds that it is necessary to have this information fora complete drug product history. As apractical matter the requirement willprobably not pose a problem becausemost firms already have number iden-
RULES AND REGULATIONS
tification systems that readily distinguish component lot numbers fromdrug product batch or lot numbers.
281. Several comments objected tothe requirement in §211.101(c) thateach container of component dispensed to manufacturing be examinedby a second person.
The Commissioner believes the requirement is necessary and does notbelieve it will be a burden to the industry. The Commissioner also notes thatthe substance of the requirement is no different from that s t a t e d i n §211.40(a) of the CGMP regulationscurrently in force, and it reflects current industry practice.
282. Several comments said that in some cases, such as with bulk component systems, there are automatedmethods for checking that could replace a second manual check.
The Commissioner wishes to pointout that the use of automated systemsis permitted under § 211.68. The requirement of this section would be met if the second individual verifies that the automated system is workingproperly.
MANUFACTURING INSTRUCTIONS
283. Some comments suggested deleting §211.102 because the subjectand intent are adequately covered by§ 211.100.
The Commissioner agrees with thesecomments, and this section is deleted in the final regulation.
CALCULATION OF YIELD
284. Several comments on 5211.103 said the requirement for determination of yields at each distinct phase ofmanufacturing, processing, packing, orholding is ambiguous and subject tovaried interpretations in view of the agency’s use of the terminology “eachdistinct phase.” Others said some typeof drug products do not lend themselves to a determination of yield ateach distinct phase of manufacturing,such as certain biological products andthose operations using continuous runs.
The Commissioner agrees becausewhat is “distinct” is subject to different interpretation and not applicablein other cases. Therefore, he is revising the section to require yield determination at each “appropriate” phaseof production.
285. Several comments said the requirement in § 211.103 for Independentverification by a second person is unnecessary.
The Commissioner finds that independent verification is a current practice and has been, in substance, aCGMP requirement since 1963. Independent verification has been found tobe a valid means of uncovering errorswhich might. if left undetected, ad
45051 versely affect drug product quality.Therefore he rejects these comments.
286. Several comments said, in substance, that calculating the percentageof theoretical yield is not the onlymethod of comparison.
The Commissioner does not believe that the wording as proposed wouldpreclude the use of, for example, astandard range of acceptable yield. Ultimately, however, acceptance must bebased on a ratio of actual yield totheoretical yield.
EQUIPMENT IDENTIFICATION
287. Several comments on §211.105pointed out that there are cases whereseveral pieces of equipment aregrouped together to perform a function and that in such situations, collective identification of the equipmentshould be sufficient rather than identification on individual components ofthe grouping.
The Commissioner feels that such a procedure is acceptable only if theequipment is permanently installedand used only for one purpose andonly one batch of a drug product canbe processed on it at one time. Thisprocedure would eliminate the need toidentify equipment when there couldbe no misunderstanding as to whatdrug product is being processed. Insuch cases of equipment dedication.identification of the grouping can beconsidered as meeting the requirements of this section. The language ofthe final regulation more clearly provides for this situation.
288. One comment requested clarification of the terms “production” and“major equipment” as u s e d i n §211.105. The comment questionedwhether 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 printingand insert folding are not generallyperformed as a function of the production of a particular batch of drugproduct. 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 asspatulas, ladles, and scoops, for whicha requirement for identification maybe unreasonable. Because it would be impractical to categorize every knownpiece of drug manufacturing equipment, a determination as to what equipment should be identified mustbe based by the manufacturer on appropriate criteria.
289. A number of comments on § 211.105(a) questioned the meaning ofthe term “processing lines” and requested a definition.
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:
prod-
45052 The term “processing lines” is used
in a broad sense to include the varietyof equipment that may be used in adrug manufacturing plant. For example, it may include a liquid filling“line” or a packaging “line” or anyother kind of “line” used to convey aproduct through an operation, or toand from an operation, such as a pipeused to carry liquid from a bulk tankto another part of the plant.
290. Several comments on§ 211.105(b) suggested that where amanufacturer has only one of a particular type of equipment, it is unnecessary to use a distinctive code ornumber to identify it in the batch records. It was recommended that the equipment could simply be named.
Since the intent of the code ornumber is to provide identification ofthe specific equipment used to processa drug product, the Commissioner hasno objection to identifying the equipment by name under conditions specified in the comment. Wording of thisparagraph 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 testsidentified in the proposal were not appropriate to all dosage forms.
It was not the Commissioner’s intentto require that the particular testslisted apply to all dosage forms. Thetests identified were meant to be examples of the types of tests thatshould be run on various dosageforms, but were not necessarily appropriate to all. Therefore, to make hisintent clear. this paragraph is revisedto 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 changingthe wording because minor manufacturing problems may cause majormanufacturing defects.
293. One comment recommendedthat the first part of the opening sentence in §211.110(a) be deleted because procedures do not assure batchuniformity and integrity of drug products.
The Commissioner agrees that thewritten procedures do not in themselves assure drug product quality the procedures must be administeredto have an effect. The Commissionernotes, however. that the requirementincludes that established proceduresbe followed. Therefore, the commentis rejected.
RULES AND REGULATIONS
294. Several comments suggested deleting or revising the references in§ 211.110(b) to statistical methods fordetermining in-process specifications.Some comments said statistical procedures for this purpose were not wellunderstood either by industry or byFDA. Others said other means of determining in-process specificationsshould be allowed in addition to statistical means. One comment said manufacturers with tight limits and littlebatch variability would be penalizedby this requirement. Another comment was that, because finished product specifications are arbitrarily de-rived,use of statistical techniquesduring in-process phases would be inappropriate. Several comments indicated that, in the case of new productsor new manufacturers, there is nomanufacturing history so other meansof developing in-process specificationsshould be permitted.
The Commissioner is persuaded thatthere are other valid means of developing in-process specifications as alternatives to statistical methods. Therefore, the final regulation is revised toprovide for the application of statistical procedures, when appropriate. TheCommissioner emphasizes, however,that in-process specifications must bemeaningful in terms of achieving thedesired finished product characteristics. Further. after product historiesare developed, the Commissioner encourages manufacturers to performstatistical analyses on their productsand processes with a view to controlling batch-to-batch variability to themaximum 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 anoptional sense.
The Commissioner recognizes thatthere are instances where the effect ofvariability during drug manufacturingphases cannot be predicted in relationto the drug product. Further, theremay be instances where there are nosuitable points, during in-processphases, to sample and test. The finalregulations are reworded to clarifythis.
296. One comment suggested thatallowance be made in §211.110(b) forthe use of in-process tests for adjustment purposes.
The Commissioner finds that specific references to in-process tests for adjustment purposes are unneccessaryThe regulations provide flexibility tothe manufacturer for establishing procedures for any appropriate in-processtest and determining the significanceof testing results.
297. As noted above in paragraph199. the Commissioner concurred withrecommendations to transfer requirements for in-process materials in pro
posed §§211.88 and 211.89 from Subpart E to Subpart F in new § 211.110(c)and (d) comments on the proposedsections 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 itwould require complete testing of in-process materials at each significantstep in production. It was suggested,too, that in-process testing doneduring production to determine theneed for equipment adjustment or tomonitor equipment adjustment neednot be reviewed by the quality controlunit.
The Commissioner concludes that the intent of this section, as modifiedin the final regulation, is clear. Thereis no requirement that the quality control unit approve or reject in-processmaterials at the completion of eachand every individual test or examination. Approved written proceduresmay provide for minor equipment adjustments. checking, and monitoringof in-process material production.However, at the completion of a significant phase, for example, the quality control unit must approve or rejectthe 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 necessaryfor these regulations, the Commissioner finds that it would not be practicalto define either of these terms becausethey can cover many types of situations and products. They should beread within the context of the handling of specific products and thecharacteristics of those products. Along period for holding an unstableproduct is obviously going to be quitedifferent from a long period for holding a very stable product. In the sameway, significant phases in the processing of drug products can vary greatlydepending on the methods used andnature of the individual products. Thedetermination of what is a “significantphase” and a “long period” musttherefore be the responsibility of thedrug processor. TIME LIMITATIONS ON PRODUCTION
300. Several comments on §211.111said there may be situations, such asmechanical failures or when materialin bulk form has to be remixed, wherethe processing time would of necessitybe extended beyond previously established limits.
The Commissioner is revising thissection to provide that deviation fromestablished time limits may be acceptable if such deviation does not compromise the quality of the drug
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45053RULES AND REGULATIONS
uct. Such deviation must also be justified and documented.
301. One comment suggested thatthe words “when appropriate” be deleted from §211.111, placing theburden of time limits on the manufacturer in all instances.
The Commissioner rejects thi s suggestion in view of the general natureof these regulations. There may b e instances where establishin g time limits for production would serve no practical purpose in assuring drug productquality.
CONTROL OF MICROBIOLOGICAL CONTAMINATION
302. A respondent said that the requirements o f §211.113(a ) are redundant for “chemical processing” operations.
The Commissione r is not sure what the comment meant by “chemical processing,” but believes the comment may refer to in-process materials. Ifthat is the case. the Commissioner does not agree. The possibility of microbiological contaminatio nis an important concern in drug products,both nonsterile and sterile, and requires emphasi s in the regulations toassure that special precautions aretaken, over and above other precautions to assure product acceptability,and to assure that no microbiologicalcontamination occurs durin gprocessing which could have an adverse effect on the drug product.
303. One comment sai d§211.113should 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 compressedmedical gases. If microbiological contamination is not a problem with suchdrug products, then appropriate procedures may be less extensive than thoseneeded for more susceptible drugproducts.
304. Several comments requestedclarification of the term "objectiona b l e microorganisms " a s used in § 211.113(a ) or suggested alternativedescriptions of objectionable microorganisms suc h a s harmful or pathogenic nnd fecal indicato rmicroorganisms
The Commissioner deliberatelychose the word “objectionable” " as the appropriate modifier for the term “microorganism " in this paragraph to this suggestion is rejected.cover a number of circumstances. Mi- 309. One comment suggested alter
native wording in order to clarify that
tion to the unique circumstances of aparticular formulation, a particular ingredient, a particular method of manufacture, or the conditions found at aparticular firm. The Commissioner believes that the use of the word “objectionable” in a very broad sense is amore practical means of expressingthe kind of control he intends.
305. One comment recommended that § 211.113(b ) be separated into twoparts: Paragraph (b ) would then applyto products manufactured by a sterilefill operation, and a new paragraph (c)would apply to a terminal sterilization process.
The Commissioner believe s this paragraph, as written, can apply toboth sterile fill process and terminalsterilization process. In both instancesthere must be validation of the process used to show that it produces asterile product.
306. One comment suggested that§211.113(b) would require the manufacture of nonsterile products underthe same conditions required for sterile products. The comment furthersaid that in some cases smaller numbers of microorganisms could be tolerated if kept under certain levels thatcould be established.
The Commissione r emphasize sthat it is not his intent to require nonsterile products to beproducedunder sterile conditions. He has previously explained under paragraph 304. hisintent in using the word "objectionable.” Section 211.113(b) clearly statesthat it applies only to drug productspurporting to be sterile.
REPROCESSING
307. Two comments suggested thatthe word “appropriate” be inserted before the phrase “established standards” in § 211.115(a)
The Commissione r finds that the suggested alternative wording offersno improvement over the proposedwordlng. Reprocessed batches mustmeet all established standards, specifications, and characteristics.
308. One comment suggested thatthe word “all” be deleted from § 211.115(a ) after the phrase “conform with.”
The Commissioner believes that the paragraph, as proposed, clearly statesthe intent regarding conformance with
specifica-, all established standards tions, and characteristics. Therefore,
batches that are not reprocessed areadequately stated in other sectionsunder Part 211.
310. A number of respondents objected to the direct authority glven tothe quality control unit under §211.115(b) in approving the reprocessing o f nonconformin g batches. They believe that such rejectedbatches should be either reviewed and approved subject to all normal tests byquality control or’should be allowed to be reprocessed when the written procedures approved by quality controlauthorize and set forth the criteria for such reprocessing.
The Commissioner rejects thesecomments because they would not beconsistent with accepted quality control practices. Reprocessing of drugproducts suggests that a problem occurred during production of a particular batch. The Commissioner does not believe i t is reasonable to expect thatpreexisting reprocessing procedurescan be written to cover every reprocessing situation. Therefore, it is appropriate that individual reprocessingprocedures be reviewed and approvedby the quality control unit. XII. PACKAGING AND LABELING CONTROL
311. Many comments suggestedchanging the title of this subpart to‘Printed Packaeinn and Labeling Control.” Some comments suggested inserting the word “printed” before “labeling and packaging materials.”
The Commissioner disagrees withthe suggestions to change the titlesince thls subpart includes controls forpackaging materials that are not labeling. Insertion of the word “printed” to precede the word “labeling” would beconfusing because, under section201(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 1211.122 is too broad in that it would include such item s as corrugated dividers, pads, and blister-packing liners.
The Commissioner advises that the term “packaging materials” as used inthis subpart refers to packaging materials other than containers and closures covered under Subpart E. Typically, unlabeled packing materials donot have to be examined as thoroughly a s labeling materials. The Commissloner intends that §211.122. as written, allow for different treatment ofcroorganisms could be objectionable
by virture of their total numbers or §211.115(a) applies only to batches unlabeled packaging materials and la-their detrimental effect on the product or by their potential for causing
that are reprocessed. beling materials.The Commissioner agrees with the 313. There were several comments
substance of this comment and isillness in the persons ingesting them.A definition of the term is not practi
regardin g § § 211.122. 211.186(b)(8 )and adopting In part the alternativ e word-Ing by revising the first three lines of
211.188(b)(8) stating that the word“labeling” is too broad because it could be construe d
cal in the regulations, however, because the objectionable nature of a microorganism may develop only in rela
§211.115(a). The Commissioner notes that the requirements for handling
as including advertising and promotional material and
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.
45054 therefore is beyond the purview of theproposed CGMP regulations.
As previously discussed in paragraph96. the regulations in this part setforth the facilities. methods, and controls to be used for the manufacture processing, packing, or holding of adrug product. Therefore, these regulations do not apply to labelin g or advertising that is not associated with thedrug product during its preparationunder CGMP regulations.
314. One comment said $211.122 does not represent current practice.and no need for the proposed languagehas been demonstrated.
The Commissioner notes that this section, as finalized, does not differsubstantially from existing requirements. He believes this section represents current good manufacturingpractice and is a significant aspect ofany firm’s quality control program. Healso believes that drug product recallsinitiated because of packaging and labeling errors indicate that the controlsdescribed in this sectio n are needed.
315. One comment suggested thatthe last sentence in §211.122(a), pertaining to release of packaging and labeling materials after approval by thequality control unit. be replaced. Therespondent believes that the use of unreleased lots of labeling and packagingmaterials should be permitted a s longas approval is obtained before marketing.
As discussed earlier in this preamble,in paragraph 217 regarding use of unreleased components, drug productcontainers and closures. the Commissioner cannot accept this suggestion.It is not acceptable quality controlpractice to use unreleased materials inany phase of production. The Commissioner believes that use of released components, in-process materials. containers and closures, labeling, andpackaging materials is generally regarded by manufacturers as necessary to quality control.
316. Several comments recommended deletion from § 211.122(a) of the word s “in detail.” and one comment said that, as written. the paragraphwould require documentation of allminute details.
The Commissioner recognizes thatdifferent materials such as unlabeled packaging material.as opposed to labeling, will require written proceduresof different degrees of complexity regarding their receipt. identification.storage. handling, andexamination and/or testing. Therefore. theCommissionrr 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.
RULES AND REGULATIONS
The Commissioner advises that the degree of sampling will depend on thematerial to be examine d or tested. The intent of this paragraph is to requireat least a representative sampling ofall labeling and packaging materials.The final regulation is clarified in thisregard.
318. One comment recommended deletion of the first sentence from §211.122(b) a s it is redundant based on the requirements cited in § 211.122(a).
The Commissioner believes that § 211.122(b) as proposed clearly spellsout the basis for approval or rejectionand clearly states that rejected materials shall not be used in operations forwhich they are unsuitable. Therefore,he does not believe paragraph (b) tobe redundant.
319. Two comments said 5 211.122(b)is overly restrictive in that it requireslabeling or packaging materials notmeeting specifications to be rejectedeven though the rejection may not bebased on a serious defect., and thus thematerial could be used.
The Commissioner asserts that it is up to the firm to establish appropriatespecifications. These specificationsshould 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 thatcould not affect the safety or qualityof the drug product.
320. One comment interpreted§211.122(b) to tacitly allow use of aprovisional release concept. for materials that are found to be out of specifications for their original use butwould 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 provisionalrelease. Materials rejected for one use must be completely tested and/or examined to determine their suitabilityfor any alternative use prior to suchalternative use.
321. A comment said labeling andpackaging materials approved for useshould be rotated so that the oldest approved stock is used first.
The Commissioner agrees that useof the oldest stock first is a desirable practice for most materials. The attributes of these types of materials thatare related to age, however. do notnormally have an effect on the drugproduct. as would be the case withcomponents. containers. and closures.Therefore. the Commissioner has decided that a mandatory requirementfor 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 outweighbenefits, and consequently the paragraph should be deleted.
The Commissioner agrees that theproposed requirement for disposition,including dates and personnel involved, is unnecessary for packagingmaterials and believes that it was those proposed requirements thatwere for the most. part being objectedto. Further. $211.125 establishes the more specific control requirement forlabeling. Therefore, § 211.122(c) is modified to require only that recordsbe maintained for labeling and packaging material indicating receipt, examination, or testing, and whether accepted or rejected. Many firms alreadyrecord this information. The burden on firms not recording such information should not be too great because arecord of this information is currentlyrequired for components; therefore,the firms need only incorporate packaging and labeling materials into thesystem already employed for components.
323. Several comments on §211.122(d) wanted the exclusion of packagingmaterials other than labeling and aless restrictive wording than “separatecompartments ” for labeling.
The Commissioner is convinced that It is not necessary in most instances toseparate unlabeled packaging materials in the same manner as labels and other labeling. Therefore. § 211.122(d) is revised in the final regulation toapply to labels and other labelingonly. The Commissioner is also replacing the phras e “separate compartments” with the word “separately ” because it may not be feasible to placeInto compartments bulky packagingmaterials 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 differentquantity-of-contents statements is infact 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 avoidrepeating requirements of § 211.122 (a) and (b). The final regulation refersonly to obsolete and outdated labels. labeling, and packaging materials. Obsolete and outdated labels, labeling.and packaging materials must be destroyed to eliminate mixups betweencurrently used labels, for example, and obsolete labels. Such mixups can leadto serious mislabeling incidents.
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45055 RULES AND REGULATIONS
326. Five comments on §211.122(f) serted in §211.125(b) after the word contended that gang printing is not a“master” because the master record good manufacturing practice and does not contain the information re-should be forbidden. garding the lot number or the expira-
Although the Commissioner wishes tion date to be placed on the label.to discourage gang printing, he does The Commissioner notes that therecognize that, under stringent con- intent of this paragraph is to ensuretrols, gang printing can be safely used. that the proper labeling is issued to
327. Two comments dealt with moni- the batch. He agrees that, as this comtoring 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 secondperson at the beginning of the run toassure * * *” and the other suggested " * * *shall be monitored by the QC unit to assure * * * . "
The word “monitor” is being usedhere to describe an in-process production check on a piece of equipment toassure that it is working properly. Insuch a case, the “monitoring” can appropriately be done by someone on theproduction line. The Commissionernotes 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” mustapply only to items associated withthe unit package. It further said thereis nothing to be gained by accountingfor any advertising that is includedwith 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 therespondent is advertising under theact, then the CGMP regulations donot apply. However, as hasbeen discussed previously, where labeling associated with a drug product during itspreparation under CGMP regulationsis involved, then the regulations Inthis section apply.
329. One comment questioned themeaning of “strict control” in §211.125(a) and recommended thatthis paragraph be expanded to includecertain specific features of strict control, such as requiring locked labeling transport containers.
The Commissioner believes that it would be impractical to list specificfeatures of strict control that would relate to all firms. Numerous comments were received that objected tospecifying a “how to” approach instead of an “objective” approach. Thisis an instance of the regulations stating an objective that is sought andleaving the method of attaining thatobjective to the reasonable discretionand ingenuity of the firm. The Commissioner, therefore, rejects this recommendation.
330. One comment recommended that the words ‘and/or batch” be in
ment points out, it is the batch record that usually contains the lot or control number and the expiration dateand is therefore amending the paragraph to provide for this situation byincluding the words “or batch” after the word “master.”
331. Some comments on §211.125(c)asserted that labeling reconciliationdoes not detect vendor mixups or errors.
The Commissioner agrees with thisstatement and notes that labeling isrequired to be examlned or tested forthese deficiencies by §211.122 before being issued for use.
332. Several comments suggestedsubstituting the word “significant” for “any” in §211.125(c) because the proposed wording would require an evaluation if there was a discrepancy ofonly one label.
The Commissioner believes that these objections are suitably resolvedby 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 controlprocedures, labeling reconciliation isunnecessarily expensive and time consuming and does not preclude misbranding.
The Commissioner believes that label reconciliation is important because labeling mixups are one of themajor reasons for recalls. Regardlessof the sophistication of the labelingsystem used, lack of labeling reconciliation would be a weak link in the total control of labels from their receipt totheir use.
334. One comment on §211.125(c)argued that the institution of elaborate control procedures for a half-dozen individually typed labels is morean 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 agreewith this statement. Misapplication oflabeled cartons can cause a recipientto wonder which is correct-the carton label or the contalner label. Furthermore, the Commissioner believes thatsuch reconciliation is not overly burd
densome or costly and is a currentpractice in the industry.
336. Several comments on § 211.125(d) suggested that recoding ofexcess labeling be permitted in lieu ofdestruction.
The Commissioner rejects these suggestions. The possibility of erroroutweighs any benefit that would bederived from salvaging labeling withobsolete lot numbers. The agency’s experience indicates that the majority ofdrug firms destroy excess labeling thatbears lot or control numbers.
337. Some comments suggestedadding wording to §211.125(d) to denote when destruction of labelingshould take place.
The Commissioner believes that excess labeling bearing lot or controlnumbers should be destroyed as soonas possible after labeling of the batchand before labeling of any subsequentbatches. In view of the requirementsin §211.130(d), however, the Commissioner does not consider it necessary toset forth exactly when destructionmust take place.
338. One comment on §211.125(e)argued that cut labels and labelingshould not be returned to stock because of the inherent danger ofmixup. but rather should be countedand destroyed.
The Commissioner finds that this suggestion would be too restrictive forthose manufacturers who use cut labels. He believes that with propercontrol, cut labels can be used withoutthe 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 thesecomments 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. Onecomment said a standard of reasonableness should be employed for theintended 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 unnecessarilyrepititious of § 211.125(c).
The Commissioner does not agreethat this paragraph is redundant. Section 211.125(c) requires the employment of certain procedures, whereasparagraph (f) requires those procedures to be in writing and to be followed.
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45056 PACKAGING AND LABELING OPERATIONS
342. Comments on §211.130(a) suggested that mixups and contaminationcan be prevented by spatial separation as well as by physical separation as required in § 211.130(a).
In using the word “physical,” theCommissioner intended that spatialseparation be considered as a type ofphysical separation. To preclude misinterpretation, he is revising this paragraph to clarify that spatial separation can be an acceptable method ofseparation.
343. One comment suggested insertion of the phrase “the probability of”be tween “o f” and “mixups” in§ 211.130(a).
The Commissioner rejects this suggestion because he believes it wouldmake the paragraph confusing.
344. One comment suggested thatthe 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 regulationsto specify all appropriate labeling,containers, or shipping cartons thatshould be required to bear a lot or control number. It is sufficient for these regulations to require that the manufacturing history of the drug productcan 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 maybe kept according to production runs,which may include a n u m b e r o f batches.
The Commissioner rejects a substitution for the word “batch.” it is the intent of the Commissioner that the batch production and control recordsbe complete. Because the examinationof labeling and packaging materialsbefore use is a function of the production of a batch, the batch recordwould not be complete without this information.
346. One comment said certain packaging materials, such as corrugatedpaper, 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 somekind must be performed to assure thatthe material is suitable for its intended use. Packaging materials often provide product protection, and the characteristics of packaging materials mustbe taken into account.
347. Some comments in §211.130(d)said it is not necessary to clear a lineof packaging materials such a s bottles.cotton, caps, circulars. or other general packaging materials if that packaging material is to be used on subsequent batches of the identical drug
RULES AND REGULATIONS
product to be packaged in the identical package unit. Several comments regardlng proposed § 211.130(e) arguedthat packaging and labeling materialcommon to the succeeding productionrun not be removed from the finishingarea after the completion of operations and prior to the next run.
The Commissioner does not intend to require that packaging materialscommon to consecutive batches of a drug product be removed betweensuch batches. Revision of §211.130(d)has clarified the requirements for removal of previously used packagingand labeling materials. Further, theCommissioner finds that the requirements of paragraph (e) are adequatelycovered in paragraph (d), and therefore proposed § 211.130(e) is deleted in the final regulation.
DRUG PRODUCT INSPECTION
348. Several comments on §211.134argued that the requirement for assuring that every container and packagehas the correct label would require 100percent examination of the drug product during or after finishing operations.
It is not the intent of the Commissioner to require loo-percent inspection of the drug product either duringor after finishing operations. To clarify this section the Commlssloner 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 regulationrequires a high level of confidence, butdoes not necessarily require loo-percent inspection. The Commissioner encourages 100-percent inspection byeither visual or automatic methods because drug product labeling mixupshave been a major cause of recalls, Although loo-percent inspection mightnot provide absolute assurance, itwould provide a higher lever of confidence that every container and package in a lot has the correct label.
349. A comment said the parenthetical phrase “tvlsually. mechanically orelectronically)” 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 precisionautomatic, mechanical, or electronicequipment in all phases of drug product manufacture, processing, packing,and holding. Therefore, there is no reason to repeat this statement ineach section where such equipmentmight be used.
350. A comment argued that thewording of §211.134(b) implies thatthe “representative sample” should betaken from sealed and palletized shipping cases.
If shipping containers are labeled tocontain a particular drug product,
then it is the Commissioner’s intentlon that individual shipping containers be examined to assure that the correct drug product is in the appropriatecontainers. A lot or batch does not necessarily have to be sampled after ithas been palletlzed because, generallyspeaking. palletizing is not considered as part of the finishing operation referred to in §211.1347(b).
351. One comment on §211.134(b)recommended that, in addition tovisual examination, an identity test berequired on the drug product if thefirm packs physically similar drug products.
The Commissioner does not agreewith the suggestion that this paragraph contain provisions for identitytesting if the firm packs drug productsthat are physically similar. Section211.120 (d) and (e) provides for theclearance of packaging and labelingareas before use. Section 211.165 Provides for physically testing the drugproduct after packaging. The purposeof this paragraph Is to provide assurance that the correct labeling hasbeen applied.
352. One comment said the results of the examination need not be recorded on the batch production or controlrecords if they are recorded elsewhere.
The Commissioner rejects thls comment. It is important that the batchproduction and control records becomplete regarding the history of thebatch, including the results of examination of the drug product after packaging and labeling. It is not essential. however, that all informatlon that belongs in the batch production or control record necessarily be on o n e pieceof paper.
EXPIRATION DATING
353. Many commented on proposed § 211.13’7. which would require expiration dating for all drug products. Anumber of comments agreed that expiration dating was appropriate for certain drug products, for example, thosesubject to fairly short-term deterioration, but objected strongly to requiring expiration dating for all drug products and concluded that a requirementfor expiration dating of all drug products would not benefit the consumer. A few comments objected specificallyto expiration dating for over-thecounter drug products or drug products whose active ingredient is knownto be extremely stable and that have,for all practical purposes, an unlimitedshelf life. Examples given of suchstable products include naturally occurring chemical compounds that aremined from the earth, refined, packaged. and sold for medical purposes. Anumber of comments from consumers were very strongly in favor of expiration dating for all drug products.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
The Commissioner notes a trendtoward voluntary dating of many perishable consumer products, particularly food and drug products. He believesthat this trend has been generated inlarge part by consumers and consumerorganizations who have expressedgreat interest in expiration dating ofsuch products and by manufacturersresponding to this interest.
The pharmaceutical industry hasbeen aware for a number of years thatFDA believes it is in the public interest for manufacturers to provide information regarding the stability of itsdrug products. In the preamble toamendments to CGMP regulationspublished in the FEDERAL REGISTER of January 15, 1971 (36 FR 601). theCommissioner announced his conclusion that the interests of consumersmust be served by the establishmentof valid expiration dates for drugproducts. At the time, the Commissioner expanded basic requirements inthe CGMP regulations for stabilitytesting to allow time for manufacturers to accumulate data to support explration dating.
In the preamble to the February 13,1976 proposal, the background regarding expiration dating was discussed atlength. The Commissioner pointed outthat a number of drug manufacturerswere already voluntarily providing expiration dates for thelr products;many products such as antibiotics, biologics and drugs liable to deterioration were already required to bear expiration dates; and the latest editionsof the United States Pharmacopeta(U.S.P.) and National Formular y(N.F.) require expiration dating for allproducts subject to compendial requirements.
The Commissioner does not believethat expiration dating of drug products places an undue burden on drugmanufacturers. Those who have beencomplying with the 1971 CGMP requirement for stability testing formost drug products, already have dataavailable on which to base a suitableexpiration date. When new productsare 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 severalfactors, including accelerated studies.
Although no sound arguments werepresented to the Commissioner thatexpiration dating of most drug products would not benefit the consumer,the Commissioner has tentatively concluded that it may not be advantageous to consumers, in considerationof cost vs. benefit, to require expiration dating for human OTC drug products if their labeling does not beardosage limitations and they are stablefor at least 3 years, as supported byappropriate stability data. Therefore,
RULES AND REGULATIONS
the Commissioner has elected to delayimplementation of the requirementfor expiration dating for these products and is proposing elsewhere in thisissue of the FEDERAL REGISTER toexempt these products from expiration dating. The Commissioner expects that types of products thatwould be affected by this exemptionwould include a number of medicatedshampoos, topical lotions, creams andointments, medicated toothpaste. andrubbing alcohol. The Commissioneradvises that until comments submittedin response to this proposal for exemption can be carefully evaluated and adecision made as to the suitability ofsuch an exemption, the Food andDrug Administration will not enforcethe expiration dating requirements ofthis section for the type of productsthat he is proposing to exempt. TheCommissioner believes it is significantthat the types of products he proposesto exempt from expiration dating areacceptable for frequent and often prolonged use without dosage limitation,and typically the contents of the retailpackage are used in a relatively shortperiod of time. The Commissioner alsonotes that few of these products currently bear expiration dating, and heis not yet persuaded in considerationof the comments that thecosts involved in requiring expiration datingfor these products can be justified onthe basis of the information availableto him at this time.
354. After reviewing the commentsfrom indlvidual consumers, the Commissioner believes that some privatecitizens misunderstood the applicability of expiration dating for all drugproducts and believed that the requirement for expiration dating willextend to drugs dispensed by a pharmacist on the written order or prescription of a physician. Section 503 ofthe act specifies the kind of information that must be supplied by thepharmacist to the consumer regardingthe prescription drug. While the Commissioner has found that a number ofpharmacists voluntarily indicate anexpiration date on the prescriptiondrug container given to the patient,such transfer of information is not required by law and, until the subjectregulations are in effect, such expiration information will not be availableto pharmacists for all prescriptiondrug products. The Congress is nowconsidering bills to amend the act toprovide for expiration dating on allprescription drugs dispensed to consumers. The agency supports such legislative proposals.
355. Several comments opposed theinclusion of expiration dating i nCGMP regulations on the ground thatthe misbranding section of the act,section 502 and, in particular paragraph (h) of that section, provides for
45057
expiration dating to tlne exclusion ofthe adulteration section, section 501.especially paragraph (a)(2)(B) relatingto CGMP regulations. Further comment was that regulations issued under section 502(h) of the. act aresubject to the administrative provisions of section 701(e) of the act,which includes provisions for a publichearing if requested.
The Commissioner rejects these arguments. No paragraph of section 502of the act expressly refers to expiration dating. Paragraph (h) of section502 describes products liable to deterioration and the packaging and labeling that may be necessary to minimizesuch deterioration. Although expiration dating might be considered implicit in this paragraph. the Commissioner does not find any basis for concluding that only labeling referred toin paragraph (h) of section 502 of theact can be required to carry dated labeling, or that the only statutory authority for FDA to enforce expirationdating is under this paragraph. Henotes. for example, that where expiration dating is required by an officialcompendium 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 theact clearly provides to FDA broad authority to assure the quality, purity,identity, and strength of drug products at least through the time ofdispensing to patients or sale to consumers. The determination of stability of adrug product and the reporting of thisinformation through an appropriateexpiration date are an integral part ofthe assurance of drug quality.
356. A number of comments opposedexpiration dating specifically for overthe-counter drug products. The arguments were primarily that: (1) ManyOTC drugs are extremely stable andthat expiration dating is of little valuefor products whose stability can bemeasured in terms of many years; and(2) that any required expiration datingfor OTC drug products should coincide with final regulations developedunder the current OTC drug reviewprocess. In the latter case, commentsexpressed concern that labelingchanges required by expiration datingand probable labeling changes and formulation changes required at a laterdate under final OTC drug review regulations would be an unfair burden onmanufacturers.
The Commissioner notes that he hasalready discussed in paragraph 353.the interim enforcement policy regarding human OTC drug products thatare stable and marketed withoutdosage limitations. But he sees novalid reason for separating requirements for drug expiration dating forprescription drug products and mostOTC drug products. The Commission-
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stability period, and the regulationspermit 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 20or 30 years, without expiration datingit is unlikely that the user of the drugproduct is going to know this information. The Commissioner believes thatexpiration dating will be more thanmarginally beneficial to consumerseven for drugs that are unusuallystable. First, it will reinforce pharmacist and consumer confidence in theproduct, and thus will avoid unnecessary disposal and replacement of oldbut not outdated drug products.Second, it will prevent confusion fordrug dispensers and probably consumers that would naturally occur in asystem where some, but not all, products carried expiration dating.
The Commissioner sees no undueburden on manufacturers in requiringexpiration dating of over-thecounterdrug products prior to final OTC drugmonographs. The Commissioner notesthat a wide variety of methods for expiration dating of drug products areavailable and that many of thesemethods do not require changes or reprinting of labels. If formulationchanges are required as a result of afinal OTC drug monograph, the regulations in §211 .166 provide for development of tentative expiration dates.Since the expert OTC advisor yreview panels will not be considering the expiration dating of OTC drugs as a routine matter in their deliberations, theCommissioner sees no valid reason forfurther delaying expiration dating formost OTC drug products.
357. Comment was received from theAmerican Homeopathic Medical Association, representing the views of various aspectsof homeopathic medicine,including manufacturers of homeo
re-specifically ,pathic drug products
RULES AND REGULATIONS
er recognizes that firms should ordi- homeopathic drugs from the Over-the- problem (see 21 CFR 2 0 1 . 1 0 0 ( bnarily be freeto select any expiration Counter Drug Review (see the FEDERAL Currently, a substantial number of
FR(3 7 2 197 , 11of Ma y EGISTER Rdate that falls within the documented9464)). Further, homeopathic drugswere excluded from review under the NAS/NRC Drug Efficacy StudyReview (DESI) and distributors of homeopathic drugs have not been required to list such drugs under theDrug Listing provision of the act.(Manufacturers. however, are requiredto register as drug establishments.)
Because of the unique nature of homeopathic drugs, the Commissionerhas reconsidered the value of stabilitytesting and expiration dating for thissmall class of drug products and concludes the need for expiration datingand complete stability testing, as proposed, are unnecessary in this group.The imprecise nature of determiningextremely low levels of active ingredients for each of a large number of attenuations (dilutions) that may be prepared for each drug substance, andthe fact that factors such as potency,absorption, bioavailability and othermeasures of effectiveness do notappear to be applicable to homeopathic drugs, have convinced the Commissioner that requiring an expirationdate for such products would be a burdensome requirement that would notresult in any added assurance of drugquality to the user.
Certain provisions of the proposedstability testing requirements, especially those relating to determining anexpiration date, are als inapproprioate. On the other hand, some stabilityinformation. such as the compatibilityof 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 expressedconcern whether small labels of somedrug products could accommodate an
drug products are packaged in a widevariety of containers, with a substantial range of label sizes, yet theseoften are marked with an expirationdate. For example, a number of drugproducts for use in hospitals are beingpackaged in “ ” containersunit dosagethat bear all the required informationas well as an expiration date. TheCommissioner believes that technology and the availability of differentmethods of placing the expiration dateon the immediate container are now at a state where it is reasonable to expectthat any drug product package can accommodate an expiration date. Therewill still be individual situations whrreit will be necessary to determinewhether a particular packaging constitutes a protective or convenience wrap and therefore is not required to bearfull labeling, or constitutes the immediate container, and therefore shouldbear all required labeling includingexpiration date. If a packager of drugshas any question regardingmatter. FDA will render an opinionupon request from the packager. Therequest should be sent to AdvisoryOpinions Branch (HFD-35), Bureau ofDrugs. Food and Drug Administration,5600 Fishers Lane. Rockville, Md.20857. and should include full information regarding the packagingas well as examples of the packaging materials and labeling.
359. One comment expressed concern that the presence of an expiration date on small containers mayserve only to detract from the conspicuousness of other information including warnings and dosage recommendations.
The Commissioner rejects this argument. The practicality and advisabilityof requiring specific items o iformaf tion on the immediate container mustalways be evaluated in light of whether it might compromise o obliterater
questing an exemption from the proposed requirement of expirationdating and related stability testing fortheir products. The basis for the request is that homeopathic drugs characteristically contain such extremelysmall quantities of active ingredientsthat the finished product cannot betested by usual analytical methods.Further, because of the theory behindhomeopathic medicine, regard for determining the specific level of activeingredient and the normal measures ofstability are inappropriate.
The Commissioner notes that h omeopathic medicine and drugs usedfor homeotherapeutics are unique anddiffer substantially from other formsof pharmaceutical products. Previously, the Commissioner has exempted
to their own specific small-sized products. In one instance, a manufacturerindicated that it would be required topurchase new equipment in order toapply the expiration date to the crimpof the tube for a medicated cream. Inanother instance a manufacturer indicated that its products were individually packaged in a way that the unitsstay with an outer packaging until allthe individual units are used; it inquired whether each individuallywrapped unit was required to bear anexpiration date.
The problem of certain labels beingtoo small to accommodate statementsrequired by FDA has been raisedmany times in the past. A specific regulation has been issued to address this
expiration date. Several other com- the value of entire labeling of the imments raised questions regarding the mediate container. The Commissionerapplicability of the expiration dating finds that a uniformly short statement
of an expiration date will not interferewith the conspicuousness of other required information. Further, ‘the Commissioner finds that there is no practical alternative to convey expirationdating information other than to placeit on the immediate container.
360. Several comments were receivedregarding the need for expirationdating of cylinders of compressedmedical gases. One comment notedthat expiration dating of these drugproducts would not benefit the patient.
The value of imparting stabilityformation to consumers or to thosewho dispense drug products ha beensdiscussed previously. As stated earlier,the Commissioner cannot agree that
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45059 expiration dating of most drug products would not benefit the user,whether or not the patient is personally aware of the expiration date. TheCommissioner sees no justification atthis time. for exempting compressedmedical gases from the requirement ofexpiration dating.
361. One comment objected to expiration dating of OTC drug productssuch as absorbent cotton, gauze bandages, eye pads, triangular bandages,cotton bails, and surgical gauze. Thecomment was that these products lastindefinitely and that some of theseproducts, dating back from World WarI, are being sold and are perfectly satisfactory. Another comment expressedan opinion that, with regard to expiration dating, all attention seems to befocused on the stability of the drugformulation. The comment concluded that other factors, such as packagingand storage conditions, must contribute to the determination of an appropriate expiration date.
The Commissioner notes that these comments, apparently from oppositepoints of view, illustrate his concernthat all persons should understandthat there are other factors to be considered besides the stability of a specific active ingredient in determining asuitable expiration date; these includethe stability of the inactive ingredients, the interaction of active and inactive ingredients, the manufacturingprocess, the dosage form, the container closure system, the conditionsunder which the drug product isshipped, stored, and handled bywholesalers and retailers, and thelength of time between initial manufacture and final use. For example,the period of time in which the sterility of a drug product can be assuredmay be substantially less than the inherent stability of the active ingredient. Thus, the expiration date for asterile drug product may have a different basis than that for a nonsterile drug product of the same active ingredient. Container closure systems ortablet coatings, for example, may increase or decrease the shelf life of the drug product. Therefore, as mentionedearlier, a number of factors must betaken into account in considering a drug product’s stability. The Commissioner also notes that articles such as cotton, gauze. bandages, and eye padsare 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 certainkinds of medical devices is now under consideration by FDA.
362. Several comments recommended that FDA consider requiring thatexpiration dates fall within the same 1or 2 tnonths of every calendar year.For example, It w a s suggested that all
RULES AND REGULATIONS
drug products bear an expiration datethat would end in January (or January and July) of the calendar year forwhich the manufacture has established a date of expiration. The comments indicated that such a procedurewould not interfere with establishingdating periods in multiples of 6months or 1 year and would allow persons who need to make inventories of drug product stocks to easily surveysuch stocks for outdated drug products.
While the Commissioner sees merit in a provision that would allow all outdated products to be readily identifiedand removed only once or twice annually, he believes that such a requirement would not be justified at thistime. Manufacturers may use an expiration dating scheme that will providean appropriate uniform expirationcutoff date to facilitate inventory control over outdated drug products inthe channels of distribution. The Commissioner will further consider the utility and currency of such apractice and whether future regulations would be appropriate.
363. Several comments spoke to theissue of a maximum expiration date,such as 5 years, about which the Commissioner had requested informationand data that would establish whether any fixed maximum arbitrary date isin 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 stabilityformulations and packaging. Anothercomment, which supposed that a 5year dating period is generally acceptable to the pharmaceutical industry,recommended that such maximum expiration dating period be adopted withprovisions that the time period couldbe extended on the basis of adequatedata. This same comment suggestedthat an advantage of a maximum expiration date would be to limit the length of time the drug product is notunder 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 tothe February 13. 1976. proposal, for information and data showing that theestablishment of an arbitrary date (5years or any other time period) is inthe interest of the consumer, resultedin generally unfavorable commentsand no information or data to supportpublic interest in a maximum expiration date, either by consumers or Industry. Therefore, the Commissionerconcludes that he has insufficient information at this time to find that set
ting a specific maximum expirationdating period is suitable or desirablefor drug products.
364. A number of comments objectedto the word “statistically” or the phrase “statistically validated” used in § 211.137(a) in reference to the use of a“statistically validated expiration datedetermined by appropriate stabilitytest.” The arguments were that for some drua products the expirationperiod is established based on characteristics or attributes (e.g., color of tablets) which are subjective and notamenable to statistical analysis. Fornew drug products, stability data maybe quite limited and there are insufficient data for meaningful statisticalanalysis. In such cases, a manufacturer stated, expiration dates are conservatively assigned. Another commentindicated that statistical validation is duplicative and open to dispute in interoretation. Several comments indicated that they were unsure as towhat was required for statistical validation. Another comment explainedthat expiration dates are currently derived from actual stabllity tests involving the use of accelerated stabilitytests. The comments said that such accelerated stability tests do not need to be statistically validated as long as there is adeauate justification for useof the conversion factors that relate the conditions of the study to labeledconditions. Another comment said the use of statistics to derive an expirationdate is only one of many ways that avalid expiration date can be obtained.Most comments on this paragraph suggested deletion of the word “statistically” or the phrase “statistically validated.” Several comments suggestedrevised wording to incorporate thephrases “appropriate expiration date” or “statistically or mathematicallyvalidated date.”
The Commissioner finds that § 211.166 on stability testing, whichhas been modified in the final regulation. contains the requirements thatare the basis for establishing an expiration date. An appropriate expirationdate, determined in conformance withthe provision of §211.166. will meetthe 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 suggestedthat the 6-month delayed effectivedate proposed bv the Commissioner was insufficient to allow accumulation of the necessary data to determine appropriate expiration dates. Severalfirms suggested a 3-year delayed effective date for this requirement; anothersuggested a 2-year delayed effectivedate. Another firm indicated that it was common industry practice to allow a 3- to 5-percent seasonal return and
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45060 redistribution of OTC products. Thisfirm requested provisions in the regulations to allow for such redistribution from inventory of drug products thatdo not bear expiration dates.
The Commissioner believes that the industry has been on notice concerning expiration dating for a number ofyears and should have data developedunder the basic stability requirementsthat have been in effect since 1963.Because of such general widespreadknowledge and the “state of the art”regarding expiration dating, a 6-monthdelayed effective date in adopting thisrequirement should be an adequatetransitional period in which to establish expiration dating procedures. Toallow distribution (or redistribution)of labeled stocks, however, the expiratlon dating required by these regulations shall not apply to stocks of drugproducts that have been labeled priorto 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 tentativeexpiration dates based on acceleratedstudies combined with basic stabilityinformation.
In revising § 211.137 in response toother comments, the Commissionerhas included a specific reference in§211.137(a) to § 211.166. As codified.§211.137 clearly refers to the use ofappropriate stability tests and stability studies described in §211.166.Thus, the Commissioner now sees nopossible contradiction in these two sections.
367. Several comments objected tothe introductory phrase “to assure” in § 211.137(a). The comments were thatthe phrase is an impossible restraintand that an expiration date cannot“assure” that a drug meets Identity.strength, quality, and purity standards.
The Commissioner cannot agreewith these comments. In commonusage, the word “assure” implies aconfidence that can reasonably be expected. The purpose of expirationdating is to inform users of the drugproduct that they can reliably expectthat the product meets the professedstandards 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 newdrug applications (NDA's) would constitute compliance with this section.
The Commissioner believes that it isunnecessary for the regulations tospecify that adherence to dating periods in approved NDA’s would constitute compliance with § 211.137(a).Dating periods for products covered byapproved NDA’s are based on stabilitydata submitted as part of the NDA’s.
RULES AND REGULATIONS
These stability data have generallycome from testing programs that fulfill the reauirements of § 211.166. If SO,then such-data also fulfill the requirements of § 211.137(a). If not, the NDAprobably was approved many yearsago and new testing, using more sophisticated techniques, is appropriate.For such products, the new CGMP requirements should not be and are notmet by the approved NDA, and testingcomplying with § 211.166 is required.
369. Several comments recommended that §211.137(a) be revised to include a statement to the effect that adrug product would not be required tobear an expiration date if it is determined on the basis of appropriate stability tests and on distribution andconsumer usage patterns that theproduct will be consumed before significant deterioration occurs.
The Commissioner notes that he hasconsidered stability and consumerusage patterns in establishing the interim enforcement policy discussed inparagraph 353 of this preamble. Buthe does not agree that-the suggestedrevision would be suitable for all drugproducts, namely, prescription drugproducts and OTC drug products withdosage limitations. Such Provisionwould ignore a basic principle of expiration dating-that the manufacturerfurnish information to reduce thechances of outdated drug productsbeing consumed. The Commissionerdoes not think it is realistic to assumethat every unit of a drug product willbe consumed within a specific periodof time, notwithstanding the considerable experience many manufacturershave regarding distribution and consumer use patterns. Information regarding distribution and consumer usepatterns, however. will serve to assistmanufacturers to estimate the quantity and duration of stability information that would be worth developing;that is, if a supplier is confident thatmore than 90 percent of a product isout of the distribution chain in 3years, the supplier may not wish toIncur the expense of establishing a 5year stability for the product and labeling it with a 5-year expiration date.
370. Some comments said proposed § 2111.137(b) was somewhat redundantwhen viewed in light of paragraphs(a), (c) and (e) of this section. Thecomments also recommended that ifparagraph (b) were retained, the references to appropriate statistical analysis should be deleted. One commentrecommended that paragraph (b) berevised to include mathematical use aswell as statistical analysis. Anothercomment stated that the phrase“readily available data” should be further defined.
The Commissioner finds that withminor editorial differences the essential provisions of this paragraph also
appear elsewhere in 9211.137. 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). specificallysuggesting that drug products suitablefor storage at room temperature notbe 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 concludethat the expected normal handlingconditions of the drug product do notrequire specific labeling instructions,or the manufacturer may elect to include any special handling or storageinstructions to preserve the product’s stability. An editorial change in thefinal regulation clarifies that storageinstructions are not required in everyinstance.
372. One comment suggested thatwhen proposed §211.137 (d) and (e)are read in conjunction with $201.17,it is obvious that expiration dates arerequired only for labeling described in§201.17 and therefore package insertsare excluded. The comments suggestedthat the language in the section be revised to specifically exclude packageinserts from a requirement to bear expiration dates.
The Commissioner sees no reasonthat the regulations exclude, by name,package inserts from a requirement tobear an expiration date. The regulations in 9201.17 and, by reference, in§ 211.137. clearly specify which labeling is required to bear expiration information. To designate, by name, thelabeling not required to bear such information is impractical because it includes more than the package insertand it is unnecessary and potentiallyconfusing.
373. One comment recommendedadding a new paragraph in §211.137.which would provide that in the case of licensed biological drug products. anexpiration date, if applicable, eithershall be determined by regulationsspecific for the product involved, orshall constitute part of the product license.
The Commissioner cannot adopt thissuggestion. A biological drug productshould bear an expiration date even if one has not been specifically established for that product either in regulations for the drug product involvedor as part of the product license.
X I I I . HOLDING AND DISTRIBUTION
WAREHOUSING PROCEDURES
374. A comment said § 211.142 shouldnot require rigid physical separation
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
suffi-
8
45061
of quarantined drug products beforerelease by the quality control unit.
The Commissioner did not intend,nor does this section state, that rigidphysical separation of quarantineddrug products is necessarily requiredbefore release by the quality controlunit. The degree of separation necessary would be dependent on othersteps taken to assure that quarantineddrug products are not used prematurely. For example, proper paper controlor computer systems could offset theneed for physical separation.
375. One comment recommended that the words “of temperature, humidity, and light” be deleted from proposed § 211.142(b) because humidityand light are not controllable in a normally operated warehouse.
The Commissioner disagrees thathumidity and light cannot be controlled in a warehouse. However, henotes the regulation does not requirethese factors to be controlled unless the identity, strength, quality, andpurity of the drug products would beaffected. The Commissioner believes that the regulation as written clearlyrequires that all drug products bestored under conditions that are consistent with maintaining the stabilityof the product. The conditions of storage will vary according to the particular product; hence the use of the word“appropriate” in this paragraph. Atthe very least, storage conditions should always be such that there areno 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 unnecessarywhen applied to the great majority ofdrug 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 othersto be recalled. Therefore, the Commisstoner 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 certaininformation_ Section 211.150(b) requires that distribution recordkeepingsystems include the capability of identifying the distribution of any specific
RULES AND REGULATIONS
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 practicewithin the pharmaceutical industry tohave 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 Commissionerhas legal authority under section501(a)(2)(B) of the act to require themfor all drug suppliers. The question ofFDA-requested recalls is subject toseparate regulations published in the FEDERAL REGISTER of June 18, 1978 (43 F R 26202).
378. One comment said the distribution records maintained by compressedmedical gas suppliers are adequate toaccomplish §211.150(b), but the reauirement of §211.198 calling for thelot number on distribution records is unnecessary. Further comment saidcompressed medical gas lots are distributed in a very small geographicalarea and to a very llmited number ofaccounts, and recall is a much simplerproblem for medical gases than for thewidely distributed multiple-unit lot drugs.
The Commissioner fails to understand how the intent of §211.150(b) can be accompllshed without meetingthe requirements of §211.196, and no such information was provided in thecomment. The intent of § 211.150(b) isthat a firm be able to determine how much of a given lot. if any. wasshipped to each consignee and onwhat date. The Commissioner does not believe that compressed medical gasesshould be exempt from this requirement, because they are potent drugs.and distribution accountability is of asmuch importance in case of recall ofthem as for any other drug.
379. One comment said the phrase“and appropriate” should be insertedafter the word “possible” at the end ofthe proposed § 211.150(a).
The Commissioner agrees with thiscomment. In addition, the wording inthe final regulation for this sectionhas 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 thefirst-in, first-out requirement is permitted if such deviation is temporaryand appropriate.
XIV. LABORATORY CONTROLS GENERAL REQUIREMENTS
380. One comment recommended that the word “justified” in the lastsentence of proposed §211.160(a) be changed to “explained.”
It is not enough, in the Commissioner’s view, that a deviation from stand
ards beexplained. The deviation mustbe 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 asseparate 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, bea part of the same document. Theword is used here in a general senserather than as a reference to a singledocument.
382. One comment said §211.160(a) is ambiguous because it does not definerequirements. The comment askedwhether documentation is needed showing completion of requirements.
The Commissioner advises that §211.160(a) is intended to refer to requirements that appear throughoutSubpart I-Laboratory Controls. Awording change in the final regulationclarifies this intent. With regard tothe respondent’s question concerningdocumentation, the Commissoner alsoadvises 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 proceduresand merely requiring documentationof what was done. The reasons for proposing this deletion were not madeclear.
The Commissioner believes that adequate controls include not only standards and specifications but also thesampling plans and testing proceduresto determine acceptability. Theseplans and procedures must be determined in advance of implementation-otherwise no systematic or comprehensive evaluation of the acceptabilityof materials and finished products canbe assured.
384. A comment suggested insertingthe phrase “or a reference to” after the word “description” in the sentencereferring to descriptions of samplingplans and testing procedures in specifications.
The Commissioner interprets thecomment’s concern to relate to the extent of the description required forthe sampling and testing proceduresused when these are set forth in detail in other documenti. The descriptiondepends on a number of factors, butcertainly could include references toauthoritative procedures such as theofficial compendia. The Commissionerdoes not believe the language need bemodified, however, because he believesthe word “description” provides
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45062 cient latltude for the use of references,where appropriate.
385. A comment said the requlrement in §211.160(b)(4), provldlng forremedial actlon in the event equipment calibration checks showed problems, is impractical because a course ofaction for each possible event couldnot be wrltten. Instead, it suggestedthe paragraph read "* * * provisionsfor investigations to determine thenecessary actlon.”
The Commissioner believes thatbroad instructions can be developedfor remedlal action. The regulations inthls section do not specify the detail inwhich such provisions must be developed. In some cases, these instructionscould provlde principally for an investigatlon to detennlne the cause of aproblem. In other instances, for example, where a problem can be expectedto occur regularly, detailed instructions may be practical.
388. 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 areonly required as appropriate t is notthe Commissioner’s intent to requireinappropriate standards and testing.The substance, extent, and complexityof controls will vary with components.containers, closures, and labellng, butsuitable specifications, standards, sampllng plans, and test procedures arenecessary for each. TESTING AND RELEASE FOR DISTRIBUTION
387. Comments on § 211.165(a) pointed out that potency assays are oftentests for identlty, and therefore thereference to identity tests should be removed.
The Commissioner does not believethat every potency assay would alsoserve as an identity test. In those caseswhere one test can suffice for bothpurposes, the wording of this paragraph would accept a single test.
388. One comment asked for an exemption from the prerelease sterilityand pyrogen testing requirements of§ 211.165(a) of shortlived radioactivematerials.
The Commissioner recognizes thatfor shourt-lived radiopharmaceutlcals itis not possible to obtain results ofthese tests before the active materialdegrades below a useful level. Therefore, the f inal regulatlons in § 211.165(a) permit release of thosespecific batches that are undergoingsterility and/or pyrogen testing. priorto completion of those tests, providedsuch testing is completed as soon as possible.
389. Several comments requestedclarification of §211.165(a) to determine whether it means that potencyassays have to be done at both the
RULES AND REGULATIONS
bulk and packaged drug productphases, or only at the bulk phase.
The Commissioner purposely wordedthis paragraph so that manufacturerscould choose to do potency assays ateither phase, but certainly before release for marketing. There is nointent, once the product is in its finished dosage form, to require potencytesting of more than one phase by themanufacturer. The Commissioner believes the paragraph is clear in thisregard.
390. Two comments maintained that identification and potency testing ofeach active ingredient in a combination product or in small batches ofOTC products constitutes a highly inflationary procedure.
The Commissioner believes that testing to assure that a product is what itpurports to be is basic to a quality control program for any drug product.Further, he notes that the substanceof this requirement, has been in the CGMP regulations since 1963 and isgenerally a current industry practice.Therefore. he finds that such a basicprocedure- should not have a significant inflationary impact or that thlscost 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 deletingreferences to testing, on the groundsthat §211.160 adequately covers therequirements for written testing plans.
The Commissioner notes that § 211.160 has general objectives regarding sampling and testing of drug products. Requirements for release of drugproducts are more specifically described In §211.166. Therefore, theCommissioner declines to accept thiscomment.
392. Several comments objected to orredefined the concepts of acceptablequality level (AQL) and unacceptablequality level (UQL) used in establishing acceptance criteria and statisticalquality control criteria as proposed in§ 211.165(d). The comments pointedout that the concepts of AQL andUQL are not uniformly Interpreted.and their use in establishing acceptance criteria and statistical qualitycontrol criteria is not uniformly applied. Comments expressed concernthat the concepts of AQL and UQL asacceptance criteria are premature andnot currently a part of good manufacturlng practice. One comment suggested that these proposed CGMP regulations would require extensive changesIn testing procedures, facilities, anduse of manpower. Several objectionswere raised relative to the “usually 95percent” level of hlgh probability ofacceptance. Respondents polnted outthat thls figure might be applicable for some pharmaceutical dosage
forms, but would be too high forothers.
As anticipated by the Commissioner,the concepts of AQL and UQL in establishing acceptance and statisticquality proved quite controversialFrom an analysis of the comments,the Commissloner believes that It Is impractical at this time to establish auniform system of AQL and UQL asproposed in the regulations. Section 211.166 is therefore modified to allow greater latitude in establishing acceptance criteria, while retaining the basicrequirements that acceptance criteriafor sampling and testing, and for acceptance levels, be based on appropriate statistlcal quality control criteria.The Commissioner is convinced that sound statistical methodology shouldbe applied to the procedures for testing of attributes or variables thatimpact on the quality of drug productsand the evaluation of the results of such testing to determine acceptanceor rejection of the lot. The uses of AQL and UQL are examples of statistically derived levels for acceptance orrejection. The Commlssloner believesthat more study must be glven to thlsaspect of manufacturing practice andadvises that In the future FDA willinvite additional industry comment regarding revision of this section.
393. Several comments asked, wlthregard to §211.165(e), whether officialcompendia test methods or methodsfrom recognized sources have to bevalidated. The comments also recommended that guidelines be providedfor documentation.
It is not the Commlssloner’s intentto require the validation of authoritative test methodology. Section211.194(a)(2) of these regulations indicates that reference to official sourceswill suffice as documentation of a validated method. The intent of this section is that assurance of accuracy andreliability be provided for all testmethods 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 someother unofficial source, validation of the method must be provlded. 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 laboratoryreference standards received from official sources and/or wlth a protocolneed not be tested. In addition, respondents recommended that secondary in-house standards should betested against reference standards. Insertion of “standard solutions” wasalso suggested in this section. One respondent suggested inclusion of a requirement for an expiration date onstandards.
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”
”
45063 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 ndopted as proposed.The Commissioner recognizes that laboratory reference standards can be interpreted to mean either standard reference materials prepared by a firmown laboratories, or standards received from outside sources, e.g., official U.S.P. reference standards or FDA reference standards. Further, theCommissioner recognizes that complete testing by the user of many reference standards is not practicable although, generally, a specific identitytest should be performed to verifysuch standard. The Commissionerfinds that the requirements in § 211.160 provide the manufacturerthe necessary flexibility to establishappropriate laboratory controls overthe receipt or preparation of referencestandards 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 toin""statisticalthe use of the word
RULES AND REGULATIONS
The Commissioner believes that it isclear in the context of this sectionthat the standards and specificationsreferred to are those for acceptance orrejection. As stated elsewhere in this preamble, the standards for acceptance or rejection must be realisticwhile at the same time appropriate toassure the quality of the drug product.
’sAny deviation from such standards isnot acceptable. On the other hand,there is no requirement that a firm establish specifications or standardsthat do not relate to the quality of thedrug product.
STABILITY TESTING
399. One comment on §211.166(a)questioned the need to prepare a written testing program to assess stabilitycharacteristics of products such asborax and boric acid because methodsof assay and analytical procedures forthese materials are well documented.
The Commissioner notes that thewritten testing program includes morethan just a description of the methodby which a drug product is tested. Itincludes all the requirements listed inthis section. If the test method used isan official compendial method or
403. A comment on § 211.166 requested that the importance of stabilitytesting of bulk active ingredients beemphasized 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 finisheddosage forms. Therefore, it would notbe appropriate to include a requirement for bulk drugs in these regulations. The Commissioner believes thatappropriate stability testing for activeingredients is a requirement under section 501(a)(2)(B) of the act because alldrugs, including bulk drug ingredients,must be produced in conformance withcurrent good manufacturing practice.Stability testing of bulk drug ingredients is a current good manufacturingpractice, and the Commissioner willpropose to include It in the projectedCGMP 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 re-other authoritative method, then it quest for the exemption. The stabilitywould be sufficient to refer to the of an active ingredient 1s not the only
characteristic that should be exam-proposed § 211.165(g) (redesignated source of the method to satisfy that§211.165(f) in the final regulations), part of the requirement for written ined in a stability testing program. Astating that statistical criteria are not procedures for the testing program. product may leach compounds fromalways relevant. 400. Several comments requested its packaging materials or be affectedThe Commissioner is deleting the that the word “statistically” be re- by heat or moisture in ways whichin the final regula-""statistical word tion because the phrase “ moved as a modifer of “valid estimates could be detrimental to product qual
ity without affectlng its strength.and anyother relevant quality control criteriais sufficient to include statistical criteria where appropriate.
396. One comment requested deletion of the entire proposed paragraph(g) of § 211.165, because it is repetltive of § 211.84(e).
The Commissioner agrees that thereis repetition between § 211.84(e) andproposed § 211.165(g) (now§211.165(f)); however. he notes thatthe 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 tothe wording of the second sentence ofproposed § 211.165(g). They contendedit is not possible to determine beforehand whether reprocessed materialwill meet appropriate standards andspecifications.
The Commissioner accepts thesesuggestions and is rewording the provision, now § 211.165(f), so that it moreclearly permits reprocessing of rejected materials.
398. Several comments argued thatproposed § 211.165(g) should beworded to allow use of materials thatdeviate from standards and specifications that have no bearing on thequality of the drug product.
of stability” in § 211.166(a)(1).” The Commissioner is modifying thefinal regulation to clarify that the statistical criteria apply solely to samplesize and test intervals to provide assurance that every batch of drug productproduced 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 t h e phrase “where feasible” would suggestserious gaps in analytical methodologyin drug manufacturing operations thatin 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 theuse of container closure systems for astability testing program that are“similar” to the marketed container/closure system rather than the“same.”
The Commissioner concludes thatthe container-closure system should bethe same as the one used for marketing the drug product with regard to attributes that could possibly affect stability.
405. A comment asked whether thereference samples in §211.166 can betaken from regular production batchesfor stability testing programs.
The Commissioner notes that § 211.166(b) clearly states that reference samples must be taken from regular production batches for stabilitytesting 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 thisparagraph 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 productsthat purport to be sterile and/or pyrogen free.
407. One comment sald an apparentconflict existed between § 211.167(a) and proposed § 211.165(d)(2), whichwould require destructive testing ofthe batch for the characteristics ofsterility and/or pyrogenicity.
The Commissioner notes that proposed § 211.165(d)(2) specifically acknowledged that it would not be appropriate to destructively test the
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45064 entire batch. Section §211.165(d) is reworded in thefinal regulation, withparagraph (d)(2) deleted, and theCommissioner 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 abrasivesubstances. Alternative wording wassuggested that would provide for suchspecifications 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 Commissloner recognizes thattests for particles other than metal a r egenerally not as precise as those testsfor metal particles. The United StatesPharmacopeia and FDA regulationsfor antibiotic ophthalmic ointments (21 CFR- 436.206) contain reauirementa for testing for metal particles and limits for such particles. The majority of firms manufacturing ophthalmic ointments perform tests for otherparticle matter in addition to theU.S.P. or FDA required tests for metalparticles. The Commissioner considersit a current industry practice for manufacturers to reduce or control theharshness and/or abrasiveness of ophthalmic ointment drug products thatmay 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 o t h e rthan those for metal particles. Somefirms employ a subjective test forabrasiveness, such as rubbing a sampleof the drug product between the fingers; the Commlssloner does not consider this type of test adequate, however, unless the individual is qualifiedto conduct this organoleptic test.
409. One comment called attentionto situations in which the coating oftablets in different coating pansduring the manufacturing process mayaffect the release pattern and suggested that each pan he sampled, tested,and accepted or rejected on an individual basis.
The Commissioner recognizes thesignificance of proper coating in relation to its effect on the release patternof active ingredients. Section 211.110requires in-process controls to validatethe performance of processes thatmay cause variability in the in-processmaterial and the drug product. Sections 211.165 and 211.167 also requiresatisfactory conformance to finisheddrug product specifications. While hebelieves this to be adequate at this
RULES AND REGULATIONS
time, the Commissioner will considerthe need for more specific reauirements, either in the general CGMPregulations or in specific CGMP regulations for sustained release drugproducts or drug product tablets, because of unique problems that may bepresented by tablet coatings, especially if active ingredients are in such coatings.
RESERVE SAMPLES
410. Numerous comments on §211.170(a) said reserve samples ofcomponents need not be kept for 2years beyond the expiration date ofthe products containing them. There were numerous alternatives suggested,ranging from 2 years after use of thecomponent to 1 year after the expiration date of the last drug product containing the component.
The Commissioner has concluded that the requirement for retention ofsamples for 2 years beyond the expiration date i s not necessary. The 2-year requirement had been proposed tomake the period consistent with thepresent alternative requirement of 2years after distribution of the lastdrug product incorporating the component, If longer than a period of 1 yearafter the expiration date. The Commissioner is revising the final regulation in §211.170 to require retentionfor 1 year after the expiration date ofthe last lot of drug product containingthe component. Where no expirationdate la required, such as for humanOTC drug products meeting the criteria for exemption under § 211.137. theretention period is 3 years after distribution of the last drug product lotcontaining the active ingredient. The J-year retention period also applies tothe reserve sample of the drug productunder §211.170(b) and to retentlon of records and reports in §211.180. Appropriate revisions are made in thefinal regulations.
411. Several comments recommend-cd that hazardous and unstable materials be exempt from the reserve sample requlrement in § 2111.170(a).Other comments suggested that inactive Ingredients also be exempted.
The Commissioner has concluded that storage of some types of materials may constitute an unnecessaryburden or a safety problem. The section, as revised, will eliminate retention of inactive ingredients. He believes that deletion of retention requirements for inactive ingredientswill eliminate most of the objectionsregarding hazardous and unstable materials; most of those materials citedby respondents are used as inactive ingredients. For those active ingredientsthat may be hazardous, though, theCommissloner concludes that the need for retaining samples of such active in
gredients outweighs potential problems of storage.
412. A comment suggested that theword “appropriate” be inserted beforethe word “tests” in §211.170(a) because some tests require extremelylarge quantities of component.
The Commissioner understands this comment to object to maintaining reserve samples when the amount of material needed to conduct the requiredtests is large. The Commissioner hasconcluded that the advantages ofkeeping 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 ofmultiple shipments of the same lotnumber of components.
The Commissioner rejects this comment. Conditions of transit and storage can vary from shipment to shipment; such variable conditions canproduce variations i n the lots of different shipments.
414. Several comments on §211.170(b) said the requirement forinspecting reserve samples of drugproducts annually is unnecessary inconsideration of the requirement forstability studies and, further, that deterioration normally cannot be detected by inspection. Other comments saidFDA should clarify its intent whetheror not inspection was meant to requirecomplete testing and whether suchtesting would be required if suchwould affect the integrity of thesample.
The Commissioner has concludedthat the requirement for annual inspection is sound. Stability studieswould not, in the usual sense, provide an opportunity for evaluating stabilityon a batch-by-batch basis. The intentof the regulation is not to require complete testing on each batch of reservesample on an annual basis, but ratherto require examination, such as wouldbe done visually, and § 211.170(b) is revised to so state. The Commissionerrecognizes that such examinationwould not provide the type of assurance that could be obtained by complete analysis, but the burden thatcomplete testing would place on theindustry would be unreasonable andunnecessary considering the requirements for establishing stability. TheCommissioner is -also revising§211.170(b) to require annual Inspection only if it c a n be done without affecting the integrity of the sample.
415. One comment said the amount of paperwork could be reduced if onlysamples that were found defectiveduring 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 re-
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45065
quired by this paragraph in the individual batch record for the product, ifthat is what the comment suggested. Arecord of samples must be kept so thattest results can be correlated with each batch and the test results keptwith other stability data.
416. Several comments said the requirement for retention of reservesamples in the same container-closuresystems in which they are marketed isimpractical in the case of very large orbulk containers.
The Commissioner has concluded that there are instances, for examplethose involving very large or bulk containers, where it would be impracticalto store reserve samples in the samesize container as is used for the marketed product. Although the Commissioner finds that the same immediate container-closure system is preferredfor storage of the reserve sample, he isrevising the final regulation to allowthe use of an immediate container-closure system having essentlally thesame characteristics as the marketed container. This means, for example,that one size container may representseveral sizes from the same batch, provided all ‘containers were essentiallythe same except for size. The storagerequirements for reserve samplesdiffer slightly from the storage requirements for stability study samplesin § 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 anduse 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 bythe use of animals that may have beenexposed to adverse environmental conditions. The identification and maintenance of adequate records on animalsare likewise intended to assure the validity of the test results. The intent ofthe 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 arequite detailed, but do not expresslydeal with the two items of most immediate concern for drug quality purposes. The user of such animals fordrug testing would, therefore, be required to comply with both the CGMPrequirements of the act and the re-
RULES AND REGULATIONS
quirements of the Animal WelfareAct.
418. A comment said because not all manufacturers have animal facilities,the regulation should make it clearthat §211.173 applies only when animals are maintained for test purposes.
The Commissioner believes that it is clear that if animals are not used, thesection does not apply. The intent ofthe section is not to require the use ofanimals, but rather to set standardsapplicable when animals are used.Therefore, the Commissioner sees noneed to accept this comment.
419. One comment argued that therequirement for physical separation ofanimal maintenance facilities would be an undue hardship because it does notallow for flexible use of space by themanufacturer.
The Commissioner notes that §211.173 does not speak of physicalseparation. The degree of separationin 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 drugproduct or the manufacturing facilities.
420. A comment said identification and recordkeeping for use of individual animals is unnecessary if the animalis used only once.
The Commissioner rejects this comment. Identification of each animal and adequate recordkeeping are abasic part of any biological test inorder to assure accurate results. Even rodent species used only once shouldbe accounted for on an individual basis to prevent inadvertent reuse, whichmay result in inaccurate test results.The Commissioner has dealt at some length with problems uncovered in reviewing drug testing in animals (seeproposed regulations for good laboratory practice published in the Federal REGISTER of November 19. 1976 (41 F R 51206)).
PENICILLIN CONTAMINATION 421. A comment on §211.176 said
that because zero penicillin levels arerequired, raw material suppliersshould certify that their products arepenicillin free.
The Commissioner believes that, although drug manufacturers can attheir own initiative request such certification from suppliers, FDA shouldnot require suppliers of raw materialsto test every lot of raw materials forpenicillin, even when no reasonablepossibility exists that they have beencontaminated with penicillin. Thiswould place an unnecessary burden onsuppliers.
422. A comment said FDA is not qualified to test for penicillin contamination because FDA receives multiplesamples 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 thatare individually placed in sealed plastic or paper bags. Analyses for penicillin cross-contamination are conducted in a laboratory facility separate fromthat used for penicillin certificationanalyses. Positive and negative controls are run, and the analyses are conducted in laminar flow hoods under positive pressure. Thus, FDA is quitecapable of determining the presenceor 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 2years after the expiration date of thebatch. They mentioned the increasedcost of record storage and noted thatadverse reactions, complaints, recalls,and other phenomena justifyingrecord storage generally occur shortlyafter beginning distribution. Varioustime periods were recommended as alternatives. Several comments suggested a retention period of 2 years afterthe batch was approved for marketing.
The Commissioner finds that these records must be available for review for a reasonable time period beyondthe expiration date of the productscovered in the records to provide anopportunity for appropriate followupof any complaints or other adverse reports received during the entire marketing period. In reconsidering theextent of such retention period inlight of the comments, however, theCommissioner has determined that a l-year period following the expirationdate will generally be adequate toassure that the records will be available for review if necessary. In the caseof certain OTC drug products notbeing required to bear an expirationdate because they meet the criteria forexemption under §211.137. the recordretention period is 3 years after distribution of the batch. This 3-year periodis considered appropriate because theexemption is based on an assumptionthat such products will be used within3 years after manufacture. Therefore,record retention for 3 years after distribution should be adequate to coverthe time period during which recordsare most likely to be needed. TheCommissioner recognizes that thesefinal regulations will require retentionof records beyond that currently required in the CGMP regulations. TheCGMP regulations require the retention of certain records, e.g., batch production and control records, for timeperiods that are based on the distribu-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
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45066 RULES AND REGULATIONS
tion of the lot or, where applicable,the expiration date of the batch. Thecurrent regulations do not clearlyspecify the record retention period forother records. For some firms, the retention period for records will notchange as a result of this regulation,as their practice is being incorporated
i n these regulations. In other cases,however, these regulations will requireretention of records for a period oftime longer than the minimum retention period specified in previousCGMP regulations. With specificregard 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 suitabletrue copies in other forms such as microfilm is permitted. The Commissioner believes that, in keeping withmodem business practices, there aremany record retention systems thatwould 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
ment of articles in interstate commerce and does not mention the retention of records as described in §211.180.
The Commissioner disagrees withthis comment. Section 703 of the act permits FDA access to records of interstate shipment in the possession ofcarriers (i.e..transportation companies) or other persons receiving orholding food, drugs, devices, or cosmetics in interstate commerce. The provisions of section 703 do not applyto the manufacturers of drug productsinsofar as records of production areconcerned.
425. One comment suggested that retention of records for components thathave an indefinite stability or components that are used only occasionallyto produce batches of drug productsbe excluded from §211.180(b).
The Commissioner rejects this suggestion. The retention period is related to the expiration dates of thebatches of drug products containingthat batch of the component in orderto assure that the records would be available for review during the marketing of the drug products and for areasonable period thereafter.TheCommissioner seriously questionswhether any drug product can be considered indefinitely stable or would infact carry an expiration date thatwould require record retention for anextraordinarily long time. Finally, theCommissioner notes that because the manufacturer has discretion to establish an expiration date that is lessthan the actual stability of the drug
product, the manufacturer also hasreasonable control over the periodsduring which he must retain records.
426. One comment said §211.180(b)is overly inclusive and should bereworded 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 thiscomment. The definition of “component” appearing in the CGMP regulations would only include ingredientsintended for use inthe 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 tocomponents “that come into actual limit the scope of inspection grantedcontact with the drug product as re- " as re-to FDA.
of certain records that show the move-items are not subject to deterioration.
quested in this comment. Therefore,the Commissioner cannot agree thatthe requirement as proposed is too extensive, and he sees no justificationfor revisions in the language in this paragraph.
427. Some comments suggested thatreference to drug product containersand closures be deleted because these
One comment suggested that the requirement be retained for parenteralsonly.
The Commissioner does not agreethat reference to container/closurerecord retention should be deleted because they are not subject to deterioration. The Commissioner is aware that some container/closure systemsare subject to deterioration and thereare 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 arisewith either the product, the contain-er/closure system, or both. Completerecords would also make possible a determination of whether or not other batches or other drug products are orcould be involved with the same problem. The failure to have these records available for any investigation couldprevent the resolution of an undesirable condition. Therefore, the Commissioner is retaining this requirement toinclude all drug product containersand closures.
428. A comment on § 211.180(b) wassubmitted regarding the retention ofrecords for compressed medical gases.The comment, which assumed that expiration dating would not be requiredfor compressed medical gases, requested a retention period to be some logical and meaningful period.
The Commissioner finds that there is no justification for excluding reten
tion of records required for compressed medical gases under this paragraph. The Commissioner has also decided to require expiration dating formedical gases.
428a. Several comments objected toreference to recordkeeping and recordinspection requirements in proposed§211.180 (c) and (d) insofar as theyapply to over-the-counter (OTC) drugsand to “not new” drugs. These comments pointed out that section 704(a)of the act authorizes inspection of records regarding prescription drugs onlyand 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 actindicating a congressional intent to
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
L. 87-781 which extendedthe Drug Amend19621f 1962 )Pub.
(1961)),FDA's authority to review records forprescription drugs under the mandat o ry inspection authority of section704 of the act. He finds that Congressdid not include in the scope of the inspection authority under section 704of the act (and its concomitant enforcement section under section 301(f)of the act) authority to inspect recordsregarding the manufacture of OTCdrug products or research data on prescription drugs that are not “newdrugs" as defined in section 201(p) ofthe act. The Commissioner also finds,however, that section 704 of the act does not exhaust the varieties of inspections that FDA may be authorizedto make regarding such drug products.
Manufacture of any drug productwithout compliance with current goodmanufacturing practices renders theproduct adulterated, a prohibited actunder section 301(b) of the act and a Federal crime under section 303 of the act. Thus, if FDA had reliable infordicating that an OTC or old mation in
drug product was being manufacturedin violation of current good manufacturing practice, the agency couldobtain a search warrant that would authorize FDA to inspect manufacturing records regarding the drug productto seek evidence regarding the allegedcriminal offense.
A second type of FDA inspectioninto OTC drug production recordswould be in conjunction with inspections under Government-wide DrugQuality Assurance Programs. Manufacturers contracting to provide OTCdrug products to the Department ofDefense, the Veterans Administration,or the Public Health Service must, asa condition under those contracts.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
permit FDA to inspect the plant, facilities, and records’ regarding theproduct to determine compliance withthe Federal Food, Drug, and CosmeticAct. If the manufacturer withdraws his consent for FDA to inspect, FDAwill decline to accept the product onbehalf of the purchasing Governmentagency, 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 prohibitedact under section 301(e) of the act. Itis conceivable that an NDA for an OTC drug would be subject to record-keeping requirements regarding manufacturing activities, and if so. FDAcould inspect these records, notwithstanding section ‘704 of the act.
This does not necessarily identify allcircumstances in which FDA may beauthorized to make an inspection ofrecords regarding the manufacture ofan OTC drug product or research dataon “not new” drugs. See, generally,Horton, “Warrantless InspectionUnder the Food, Drug, and CosmeticAct,” 42 G.W. Law Rev. 1089 (1974).
The purpose of §211.180(c) is toassure that all appropriate recordswere properly collected, indexed, andheld at the site where an inspectionwould occur so that, in the event of anauthorized inspection by FDA, theserecords would be readily reviewable bythe 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 amanufacturer to submit to an inspection that was not legally authorized.To clarify this, the Commissioner isinserting the word “authorized” before the word “inspection” in§ 211.180(c)
429. Several comments objected tothe requirement that records be readily available at the establishmentwhere such recorded activities take place on the grounds that most firmswith multiple facilities maintain central record storage facilities and thatcompliance with § 211.180(c) would require needless and unnecessary duplication of the records and storage facilities. These comments suggestedthat provision be made for centralrecord storage sites, provided that therequested records be made available ina reasonable period of time.
The Commissioner does not agreewith the contention that keepingthese records or copies of them at theestablishment where the activities took place would be unnecessary andwould require needless and unneces-
RULES AND REGULATIONS
sary duplication of the records and facilities. He is of the opinion that mostfirms today keep the records or copiesof them at the site where they weregenerated. These critical records mustbe available to both plant personneland FDA for review. To require thatplant personnel and FDA investigatorsplace orders for specific records to another facility and then wait for delivery would not be prudent. There is thedistinct probability that operatingunder these circumstances would greatly extend the time needed to conduct an investigation of a problem orto conduct the required inspections.
The Commissioner does believe,however, that records that can be immediately retrieved from another location by computer or other electronicmeans meet the requirement of beingreadily available at the establishment.The final regulation includes this provision. As the Commissioner stated in reply to other comments regardingrecord storage, these regulations donot preclude the use of other recordstorage systems, such as microfilm ormicrofiche. Where other systems areemployed there must be associated capability for viewing and copying. Thefinal regulations include a new§ 211.180(d) to clarify these provisions.
430. One comment suggested thatthe regulation provide guarantees thatthe FDA investigator will not copythese records or if they are copied,that they will not be released under the Freedom of Information Act.
The Commissioner cannot agreewith the first suggestion. There aremany instances where the investigatorwho makes the inspection does nothave 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 completereview of the records at the plant site.The Commissioner believes that true reproduction of records, comparedwith handwritten copies, assures theirauthenticity and decreases inspectional time. While the copying of appropriate records has always been implicit in CGMP regulations, there havebeen instances where investigatorswere restricted by manufacturers tohandwritten copying of the records.Therefore, § 211.180(c) is being amended in the final regulation to clarify that records are subject to copyingduring the course of an inspection.
The Commissioner also rejects therespondent’s suggestion that documents not be released under the F r e e dom of Information Act. The Commissioner is required by law to releasedocuments in his possession unlessthey contain information or are ofsuch a nature that a request for release could be denied. In this regard,
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the Commissioner specifically refers tothe FDA regulations describing publicdisclosure of “trade secret” information in FDA files (21 CFR Part 20. particulary § 20.61).
431. Numerous comments objected to § 211180(e) (proposed as
to §211. on the grounds that the requirement for the generation of awritten summary is not current practice and would have an unnecessaryinflationary impact without any noticeable effect on improving the quality of drug products in general. Someof these comments argued that theproposal did not specify what datawere to be summarized. Other respondents questioned the authority of theFDA 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 carefullyconsidered the extensive comments regarding the proposed requirements forwritten summaries and concludes that revisions in this paragraph are justified. The purpose is to provide reliableprocedures for a manufacturer toreview the quality standards for eachdrug product. The Commissioner agrees that mechanisms other thanwritten summaries may be appropriatefor such evaluation. Therefore, thefinal regulation is amended to requirethat manufacturers establish their own written procedures for annualevaluation of the quality standards foreach drug product. While not specifying what review mechanism must beused, the Commissioner encouragesthe use of written summaries as one practical means of drug productreview. The Commissioner believes that some manufacturers are currently using such written summaries togood advantage in establishing drugproduct 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 thisrequirement would not affect the integrity of the drug product. Some ofthese comments suggested an exclusion for small businesses because the corporate officials would be writingthemselves 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 hasbeen the agency’s experience that corporate officials have not been advised of potential or real adverse conditionsbrought to light either by the firm's own quality control system or by FDAAs a result, corrective actions have not
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45068 been instituted where they might havebeen, had company officials beenaware of such conditions. Correspondence from FDA to firms regarding inspectional findings and recalls is directed to top officials as a matter ofpolicy, but not all conditions specifiedin §211.180(f) are the subject of inspections or recalls, and even in thecase of inspection and recalls theremay be a period of time before FDA correspondence which deals with thesubject is issued. The Commissionerdoes not believe that the requirementsof §211.180(f) are burdensome and is confident that the concept of keepingofficials 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 thisparagraph are an unwarranted intrusion into corporate duties. They willprovide added assurance that effortsare being directed toward the prevention and/or correction of conditionsthat could affect the quality of thedrug product. Moreover, responsible
officials already have very rigid legalduties to be aware of, and t o take action upon, conditions contributingto drug adulteration (United States v.Park, 421 U.S. 658,1975; United States v. Dotterweich 320 U.S. 277, 19431.
In view of the comments, however,the Commissioner is deleting the proposed requirement regarding routinequarterly written reports in order toallow manufacturers flexibility in establishing procedures to keep appropriate management fully informed asto important matters involving possible quality control problems. In addition, the final regulation provides anexception for officials, whether inlarge 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 211.166 recommended that the requirement for signatures be deleted ormodified to provide for initials. orother specific employee identification,e.g. an employee number.
The Commissioner is persuaded thatthe requirement for a full signaturemay not be warranted in view of thespace that would be required in therecords and the burden of continuallywriting a full signature on recordsthat arc repetitive. For less repetitivetype of records. such as master recordsreferred to in §211.186, the Commissioner has decided to retain the requirement for a full signature. TheCommissioner rejects the suggestionthat a distinctive employee number beallowed because it would detract from the concept of personal involvement.
RULES AND REGULATIONS
Numbers, in the Commissioner’s opinion, may be easily recorded by personsother than those who actually perform the function.
434. Some comments suggested thatthe word “strength” be deleted from§211.182 as superfluous because thisinformation is readily derived throughthe lot or batch number.
The Commissioner agrees that theword “strength” can be deleted. Theremaining required information is sufficient to identify the batch.
435. Several comments objected tothe 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 logsfor stirrers, scoops, and ladles.
The Commissioner agrees that thisrequirement, as proposed, could beconstrued to include such items as ladles, stirrers, scoops, spoons, andspatulas, 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 properlyand adequately cleaned before re-use,but only documentation of such activities.
436. One comment on §211.182doubted the need for routinely double-checking cleaning and maintenance. itargued that this would require thecheckup person to be present duringthe operation. A second comment saidthe requirement for checking routinemaintenance would be overly burdensome.
The Commissioner notes that the purpose of this requirement is that asecond person determine that appropriate cleaning and maintenance wasperformed. He does not believe thatthis necessitates that the person doingthe checking be present during theentlre operation. Changes in the finalregulation clarify this intent and alsoexclude from the required checkingroutine maintenance activities such as lubrication and adjustments.
437. Several comments on §211.182objected to keeping logs inasmuch asthe information is readily available in other records, such as the batchrecord.
The Commissioner rejects this viewbecause in most instances batches are not processed consecutively on anyone piece of equipment. If the practicewere not followed and one attemptedto determine the chronological use ofa particular piece of major equipmentto ascertain, e.g.. whether severalbatches 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 necessarywhen equipment is dedicated to a single product.
The Commissioner agrees that ifequipment is dedicated to the manufacture of one product, the requirement for individual equipment logswould not be necessary, provided thatlots or batches of such products followin numerical order and are manufactured in numerical sequence. In suchcases where the use of dedicated equipment is employed, the records ofcleaning, maintenance, and use shallbe 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 thedrug product’s final testing.
The Commissioner is aware that dirty or poorly maintained equipmentcan introduce characteristics to a drugproduct that may not be detected byfinal examinations. Moreover, it is in the manufacturer’s interest as well as the public’s to prevent quality assurance problems, rather than simplydetect them. Therefore, the Commissioner rejects this comment.
440. Comments objected to the requirement for one log for each piece ofequipment containing the informationregarding cleaning and maintenancewhen a portion of the cleaning ormaintenance may be performed eitherat another location or by a differentdepartment.
The Commissioner notes that it is not the intent of this section to limit the number of logs for each piece ofequipment to one. The intent is thatthere be one or more logs for eachmajor piece of equipment which, intheir entirety, contain the informationrequired by this section. The Commissioner does not believe the section implies otherwise. COMPONENT, DRUG PRODUCT CONTAINER.
CLOSURE, AND LABELING RECORDS
441. Several comments requested anexemption of veterinary drug productsfrom the requirements in § 211.184 (a) and (c). For drug product containersand closures, it was also suggestedthat the section be modified to indicate that the requirements regardingproduct containers and closures should apply only to the drug products intended for human use.
The Commissioner rejects thesecomments. 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 tothe proposed r e q u i r e m e n t s in § 211.184(a) for the lot history of durgproduct containers and closures. Comments were that existing controlsproduct containers and closures aresufficient and in some instances the supplier’s lot number and the location of the manufacturer are not known.
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Another comment expressed concernthat reporting of the name and location of the prime manufacturer “if known” was not sufficient and such reporting should be mandatory.
The Commissioner cannot agreethat the information relating to thelot history of drug product containersand 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 mostmanufacturers, but may not have beenpreviously organized in such a manneras to facilitate identification of drugproduct containers and closures. TheCommissioner acknowledges that, occasionally, information such as the supplier’s lot number or location of the manufacturer is not known. The proposed regulation already providedfor 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 alwaysbe available. This modification, however, does not diminish the control oversuch drug product containers and closures by the drug manufacturer. Thereeeiving code, specified in § 211.80,will serve to identify the received lotto the drug manufacturer. The Commissioner encourages all suppliers toadopt batch or lot identification to aidin locating components, drug productcontainers, and closures in the event it becomes necessary to do so to protectthe public health.
About the comment for mandatoryrecording of the prime manufacturerin all cases, the Commissioner concludes that such a requirement is notnecessary. Because such information isusually readily available, however, andmay be useful to the manufacturer inconsidering the suitability of suppliersor allow for tracing the complete history of the component, container, orclosure, it should be recorded whenavailable.
443. One comment on §211.184(b)recommended substituting the phrase“subsequent disposition assigned tothe material” for the phrase “conclusions derived therefrom” in the last line of this paragraph because underthe sections cited in the proposedparagraph, the only possible decisionsare release, restrict, reprocess, orreject.
The Commissioner cannot agreewith this comment and believes the comment may have misinterpreted theproposed requirement. Results of testsor examinations required under thesections cited in this paragraph areclearly to be included, but all tests andexaminations must be considered. There are a wide range of conclusionsthat may be drawn from results of
RULES AND REGULATIONS
tests or examinations. For example, atest failure resulting from impropertesting procedure would be recorded,but the lot would not necessarily berejected based on that one improperlyperformed test. The Commissionerfinds that this paragraph should be finalized as proposed.
444. Many comments addressed§211.184(c). Most agreed that an inventory record and reconciliation fordrug product components was appropriate, but objected to inventory records and reconciliation for drug product containers and closures. Others contended that inventory records, butnot reconciliation, were also appropriate for drug product containers andclosures. Arguments were primarilythat recordkeeping to this extent was unnecessary, burdensome, and not current practice. Some comments wereconcerned that extensive records and reconciliation would be required forpackaging materials such as cottonfiller material used in packaging tablets and capsules. Several commentsrecommended changes in the proposedlanguage that would clearly requirethat the inventory record be sufficientto establish the batch or lot of drugproduct in which component, drugproduct container, and closure areused.
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 theuse of components, drug product containers, and closures. To clarify theintent that such inventory records areintended to allow for determination as to the batch or lot of drug product associated with the recorded inventory,the Commissioner is modifying theproposed wording in this section(§ 211.184(c) and in § 211.188(g)).
The Commissioner agrees with thecomments that reconciliation of the use of each lot of drug product container and closure should not be required. Although there are instanceswhere such reconciliation could be valuable to the drug manufacturer, itshould not be mandatory for all drugproducts 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 productcomponent must be inventoried and itsuse reconciled in order to provideadded assurance of product integrity.
The Commissioner emphasizes thatthis section does not pertain to allpackaging materials, but only drugproduct containers and closures. Thus,individual inventory records for pack
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aging materials such as cotton fillerand package liners are not requiredunder this section, although recordsregarding the receipt, examination ortesting, and disposition for packagingmaterials generally are required in§ 211.122, particularly in paragraph(c) .
445. One comment objected to§211.184(d) on the grounds that itcould be interpreted to require eachperson on the manufacturing line whomakes an inspection to record that inspection as it is made. The commentrecommended deleting the word “all” from the paragraph.
The Commissioner finds that this paragraph is intended to provide forthe documentation of the examination of labeling as required elsewhere inthe CGMP regulations. To eliminatethe possibility of misinterpretation,§ 211.184(d) is revised by substitutingthe 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 thatrecords 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 controlrecords” as used in §211.186(a) was not limited to “appropriate masterproduction 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 recordthat is appropriate for the particularbatch for the drug product. The Commissioner believes both paragraphs aswritten are clear in this regard.
447. Several comments argued thatthe “full signature, hand written” isnot necessary and that the paragraphshould be changed to allow for othermeans of identifying the persons whoprepare 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 whomthe initials were intended to represent.Further. the Commissioner does not believe this requirement to be burdensome because master production andcontrol records in most cases would be infrequently established or changed.
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45070 440. One comment proposed accept
ance of other validating techniques inthe first sentence of §211.186(a) on the grounds that verification can beaccomplished by machine.
The Commissioner is not aware of how master production and controlrecords can be totally prepared andverified by machine. Although calculators or computers might assist in preparation and verification by aiding thepersons involved, the initial information would have to be fed into the calculator or computer by a responsible person, and a second responsibleperson would have to verify that thehard data fed into the machine were valid. Where appropriate. the use ofautomated equipment and computersis allowed under § 211.68 providedhard data are kept of certain recordssuch as master production and controlrecords.
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 producton the master production and controlrecords.
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 usedto a great extent in the drug manufacturing industry, a requirement for conversion to the metric system as thesole method of measure could be an unnecessary burden upon industry atthis time. Such a requirement may beimposed in the future by the Commissioner, in keeping with national lawson conversion to the metric systemand good manufacturing practice.
451. One comment said the requirement, in 8211.186(b)(4) for using the same weight or measure system shouldbe deleted or revised to allow firms to change the master formulas graduallyover a period of years or as the drugproduct is reformulated.
The Commissioner believes that the large majority of drug firms alreadycomply with this requirement,. TheCommissioner notes that the effective date of this final regulation allows sufficient time for the remaining firms tocomply with this section and thereforerejects the suggestion that firms be allowed to change their systems over a period of years.
452. One respondent recommendedthat the requirement for “using the same weight system” in § 211.186(b)(4)should not be applied to veterinarydrugs because these are often produced in large volumes or masses.
The Commissioner finds no justification for exempting veterinary drugs
RULES AND REGULATIONS
from this requirement. The fact thatlarge volumes or masses are involved is not a convincing argument that the requirements for use of a consistentmeasurement system should not apply to the manufacture of veterinarypharmaceuticals. 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 nothingto the integrity of the product.
The Commissioner rejects this comment. The regulation does not require“repetitious” calculation of theoreticalyield; instead, one calculation must bemade part of the master productionand control records, together with appropriate tolerances from this calculation beyond which an investigation formanufacturing errors would be required.
454. One comment said the theoretical yield percentage, which if exceededwould require an investigation under§211.192, should not be included inthe record as required in § 211.186(b)(7) because t h e investigation is the responsibility of the qualitycontrol unit.
The Commissioner does not understand the reasoning behind this comment. The fact that this information appears in master or batch recordsdoes not displace responsibility of thequality control unit.
455. One comment said the requirement. in § 211.186(b)(7) for a statementof theoretical yield does not take intoaccount that there is sometimes a shortage In the actual yield because amanufacturer may discard a portion ofa batch due to a problem with the“pharmaceutical elegance” of theproduct.
The Commissioner sees no reason to accept this comment. The purpose ofthe theoretical yield requirement is to serve as an indicator of a possibleerror when compared to the actualyield. If the manufacturer can accountfor the shortage in the actual yield ofthe product by documenting that adefinite portion of the lot was discarded because of its inelegance, the regulations have been followed.
456. One comment argued that thelabel should be required to be maintained on file and not physically attached to the master production orcontrol record.
The requirement does not state thatthe label has to be glued or stapled tothe master record, for example, if thisis what the respondent means by“physically attached.” Since 1963. theCGMP regulations have required thata specimen or copy of each label be included in the master production andcontrol record. This requirement isneeded in order to make the master production and control record com
plete with respect to all aspects of processing. and should not be changed.
4 5 7 . Several comments regarding§§ 211.186(b)(8) and 211.188(b)(8) saidlithographed 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 willfulfill the intent of these sections.
BATCH PRODUCTION AND CONTROL RECORDS
458. One comment on §211.188 saidbatch production and control recordsshould be permitted to be extensivelysimplified because lots are repetitiveand are usually processed on identicalequipment in an identical manner formonths or years.
The Commissioner notes that this comment fails to specify what simplifications are proposed. The purpose ofthese regulations is to provide for awritten system which, when followed,results in a reproducible high-qualitydrug product. The Commissioner believes that “simplifying” the batchand record controls by reducing thetypes of information required would have an adverse effect upon the quality of the drug product and would notreflect current industry practice. Onthe other hand, use of forms to easethe recording of information (withoutomitting 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 1211.188. ifit is a photocopy-reproduction of themaster production and control record.Further comment recommended that the words “where necessary” be inserted after the word “accuracy” in thethird line of §211.188(a).
The purpose of this requirement isfirst of all to make sure that the correct master production or controlrecord has been copied. Also whilephotocopying may be the most accurate and preferred means of producinga batch production and control record, no system is infallible. For example. aspot or mark on the plate glass surfaceof 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 abatch production and control record isalways necessary to assure that such records are correct.
460. A comment said § 211.188 should explicitly allow the use of ba t ch production or control records produced by a computer.The Commissioner notes that. § 211.68 clearly permits the use of com-
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puters in the manufacture, processing,packing or storage of drug products.Section 211.188 does not limit the means by which a batch production orcontrol record may be produced. TheCommissioner does not believe that repetitiously providing for the use ofcomputers 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 “manufacturingticket” that does not contain all the information in the master productionor control record.
Although the Commissioner is notsure of the intended meaning of “manufacturing ticket,” he notes that theword "appropriate" i n § 211.188(a)refers to the master production andcontrol 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 andcontrol record. As stated in this paragraph, the batch production and control record shall be “An accurate reproduction of the appropriate masterproduction or control record, checkedfor accuracy, dated, and signed.” If aportion of the batch production recordwere sent to a particular departmentthat is involved only in the operationcovered by that portion of the batchrecord, the Commissioner would consider that practice to be consistentwith the requirements of this section.
462. A comment said provisionsshould be made in §211.188 for batchproduction and control records only tothe extent that each operation is performed by each establishment, because some operations such as packaging are often performed by anotherfirm.
The Commissioner advises that a new §210.2(b) is added to these final regulations to clarify the applicabilityof CGMP regulations to persons engaged in only some of the operationssubject to these regulations.
463. Several comments said the words “and after” should be deleted from §211.188(b)(6) as requiring unnecessary and burdensome duplicativeinspections.
The Commissioner rejects this comment. To prevent mixups and to reconcile the label count after packaging, it is necessary to inspect the premisesafter each packaging operation. It isalso necessary to inspect before thenext packaging operation because foreign materials other than those from aprevious packaging operation could beintroduced into packaging operations.
RULES AND REGULATIONS
For those packaging operations that are “back-to-back” with essentially notime interval, a single inspection will meet the requirement of 0 211.188(b)(6).
464. Comment on § 211.188(b)(7) saidthe statement of percentage of theoretical yield should be ascertainedonly at the completion of compounding and packaging because some drugmanufacturing processes are not complicated operations.
The Commissioner concludes that this section will have to be applied inconsideration of the complexity of theprocessing needed for each drug product. The calculation of the percentageof theoretical yield only after completion of compounding and packagingmay be appropriate in some caseswhere, for example, drug productmanufacturing is not complicated. Therevised final regulation should clarifythat this flexibility is intended.
465. A comment said radio- pharmaceuticals should be exempt from therequirement in §211.188(b)(7) for developing theoretical yield data becauseits determination would involve re-assay of the unused bulk radioactivematerial.
The Commissioner believes that this section as revised in the final regulation responds to this comment in that the requlrement applies at “appropriate stages” of processing. The Commissioner also notes that this section does not specify the tolerance levelsfor acceptance of actual yields. Suchlevels will vary depending on the drugproduct being produced.
466. Several comments said the words “or if impractical, a label revislon number,” should be inserted after“specimen” in § 211.188(b)(8).
The Commissioner rejects this comment. This requirement provides aready means for production personnelto verify visually the processing recordagainst what is actually being processed and provides a more completerecord than a label revision number might furnish.
PRODUCTION RECORD REVIEW
467. One comment on §211.192 indicated that accountability is of moreconcern than actual versus theoretical yields.
The concept of accountability is implicit in the use of theoretical yieldsand particularly in the comparisonmade between actual and theoretical yields. The material produced, considering accountable losses, is the actualyield. Comparison of the actual yieldwith the theoretical yield, i.e., whatshould have been produced, requires adetermination of acceptability. Theactual yield is acceptable if losses havebeen satisfactorily accounted for.
4507 1
467a. One comment proposed replacing the word “all” at the beginning of § 211.192 with “batch.”
The Commissioner agrees that theintent of this section is to requirereview of those records that directlyrelate to batch production and control.Therefore, the comment is adopted inthe final regulation.
468. A comment described the quality control unit review of productionand control records in §211.192 as anexcessive requirement because itwould 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 bereviewed by the quality control unitfor release purposes. The regulation is revised to clarify this.
469. One comment proposed that asingle individual should certify thatthe review for quality control considerations required in § 211.192 has been made.
The Commissioner finds that because of the wide variety of activitiesand operations which the quality control unit is responsible for approvingor rejecting, a number of differentmethods of expressing or indicatingapproval or rejection may be appropriate. For example, in some firms the“Director of Quality Control’* maypersonally sign all approvals or rejections. In other firms, however, the"Director of Quality Control” may delegate this responsibility to subordinates. However, the Commissionerdoes not believe it is appropriate forhim to dictate that specific persons besolely authorized to perform thesefunctions.
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 andshould not be part of the records.
The intent of this section is that lab oratory records Include data derivedfrom tests that are necessary to assure compliance with established specifications and standards. The final regulatlon is revised accordingly.
471. Several comments suggestedthat the word “quantity” be deleted from § 211.194(a)(1) because this information is contained in other records,and the requirement is excessive andof no value.
The Commissioner rejects these suggestions because it would be pertinent,upon review. to determine whetherthe size of sample drawn is representative. A record of the size of the sampledrawn also allows for a reconciliation
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45072 of the amounts used for each test with the amount of total sample. Thiscould provide important informationfor any investigation that may be instituted following marketing of thebatch or lot. The Commissioner doesnot believe that recording the size ofthe sample is burdensome.
472. A comment questioned the needfor recording in the laboratory recordsthe date of receipt of a sample by thelaboratory, as required by §211.194(a)(1). The comment suggested use ofthe date of sampling instead.
The Commissioner does not agreethat recording the date of receipt of asample 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 agranulation, may be influenced by theelapsed time between sampling andassay. It therefore becomes necessaryto know both when the sample wasdrawn and when it was received by thelaboratory. The final regulations arerevised to clarify that both the date ofsampling and the date of receipt foranalysis 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 toprovlde enough of adescription toidentify the sample properly, sucashthe name of the drug product and theform of the sample, e.g.. granulation,raw material, or powder. The Commissioner concludes that this is reasonable information to require and, thatth e requirement reflects current practice.
474. One comment said the meaningof 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 thecontext of §211.194(a)(1) could be interpreted to mean only the number ofsample containers with no reference tothe amount of sample in each container. The size of sample containers couldrange, for example, from a liter container to a container that holds only afew grams. Further, the Commissionerdoes not believe this requirement to beeither unreasonable or burdensome.
The Commissioner also concludesthat the meanlng of the word “source” in § 211.194(a)(1) needs clarification. “Source” of the sample is intended tomean the location, e.g., a specific drumnumber and storage area or in-processphase. The final regulation is revisedin this regard.
RULES AND REGULATIONS
475. Several comments suggestedthat 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 agreewith these comments. The last sentence of §211.194(a)(2) requires thattesting methods, whether such methods have been developed by the manufacturer or are from official compendia, be verified under actual conditionsof use. The Commissioner does not believe that the requirement in this lastsentence is explicitly stated previously.
470. One comment argued that therequirement in § 211.194(a)(2) that laboratory records contain a statement ofeach analytical method used in theanalysis of a sample should be limited to assays and should not extend toother tests such as physical tests.
The Commissioner does not agreethat the requirement should be limited to assays of components of drugproducts. Tests or examinations otherthan assays are an integral part of thehistory of a drug product. especially insituations where a physical test mightbe as critical as an assay-for example.in determining particle size, dissolution rate, or tablet hardness. Recognizing, however, that this section asworded ln the proposal is somewhatambiguous in this regard, the Commissioner is rewording the final regulation to reflect that the requirementapplies to all tests, including examinations and assays.
477. Several comments suggestedthat the words “where appropriate," “where meaningful,” or “where required "at be added point, the end of§211.194(a)(3). One comment reasonedthat the size of the sample is not pertinent for many laboratory tests, e.g..melting point, infrared Identification.qualitative colorimetrlc spot tests, andPH.
The Commissioner accepts thep H . of these suggestions and is revising § 211.194(a)(3) accordingly byadding the phrase “where appropriate” ln order to provide for test procedures where a nonspecific weight or measure is used.
478. Several comments requested deletlon 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 wouldcreate additlonal files.
The Commissioner believes that allgraphs. charts, and spectra used toshow a product’s acceptability must beretained for future reference. Theserecords would be needed to carry out any investigation required under theseregulations.
479. Several comments requested deletion o f the requirement in
§ 211.194(a)(4) that laboratory recordsinclude 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-processmaterials, or drug products and therefore rejects the request for deletion.
480. Several comments requested§211.194(a) (4) and (5) be revised totake into account calculations and data derived from automatic testingequipment, such as computers.
The Commissioner notes that § 211.68 already provides for calculations and data derived from automated equipment and that such provisionsneed not be restated in every sectionwhere they would apply.
481. In considering comments relating to proposed §211.194(a)(6), theCommissioner concludes that those requirements are more appropriatelycodified as §211.194(b). Specific comments are responded to beginning withparagraph 488 below.
482. Some comments on proposed § 211.194(a)(7)(now § 211.194(a)(6))recommended that the phrase “drugproduct contalner. closure” be alteredto apply only to human drug productcontainers and closures.
The Commissioner finds that record-keeping should apply to pertinenin-tformatlon regardless of the intendeduse of the drug product.
483. Several comments on proposed§ 211.194(a)(7)objected to requiringthe laboratory to make a comparisonof the test result against an established standard, especially wherae standard is not known to the laboratory personnel. Some of these comments suggested alternative wordingto clarify this. One comment objectedto requiring this statement if the reported result was close to the specification.
The Commissioner believes there must be established standards that alltest results are compared against,whether they be precise standards, anacceptable range of values withinmaximum and minimum values, or theabsence or presence of certain attributes. The Commissioner does not understand how respondents wouldevaluate thesignificance of test results if no standards for comparisonexist. Therefore this requirement asproposed is retained in the final regulation.
484. Several comments on proposed § 211.194(a)(8)(now § 211.194(a)(7))suggested the use of alternatlve systems of identification instead of a full signature of the person who performseach assay or test. Suggested alternatives were employee numbers or initials.
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The Commissioner agrees that a fullsignature is not needed in this instance and therefore is amending§211.194(a)(7) to allow the use of initials.
485. Several comments suggestedthat § 21 1.194(a)(8) ( p r o p o s e d a s§211.194(a)(9)) be deleted on a varietyof grounds-it would be a waste oftechnical manpower; it would be inflationary; and it is not current practicefor the veterinary industry. Othercomments suggested provision for arandom 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 verificationof the laboratory work to insure that the proper procedures were used andfollowed, that the calculations are correct, and that, the record is complete.A review of laboratory records is necessary to insure that the correct testwas performed, that the calculationsare correct, and that the record iscomplete. This is not wasteful of resources or unjustifiably costly.
The Commissioner finds it difficult to accept the stated premise that theveterinary drug industry does notreview laboratory records to determinewhether the proper tests, assays, orexaminations have been performedand that the results are valid. It is the Commissioner’s belief that drugs forveterinary use, like drugs for humanuse, must be produced under appropriate control.
The Commissioner rejects the suggested revisions that limit the reviewto 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 procedurewas used, the calculations are correct,and the laboratory record is complete.
486. Some comments suggested thatthe records reviewed need not alwaysbe “original.”
The Commissioner notes that “original” is used to convey the intent thatthe records reviewed be those which contain the data used in conductingtests. 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 revlewed.
487. One comment suggested thatthe word “signature” be substitutedfor the word “endorsement” in § 211.194(a)(8).
To clarify § 211.194(a)(8). It is revisedto state that the records shall consist of initials or signature.
486. One comment on proposed § 211.194(a)(6) (now § 211.194(b)) suggested inclusion of the phrase “or suit-
RULES AND REGULATIONS
able reference to” after the phrase “afull description of.”
The Commissioner agrees that it isnot necessary to describe fully a modification of an established method each time the method is used. The Commissioner has appropriately reworded thisrequirement in the final regulation toclarify 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 whenconsidered in the context of this section, now codified as § 211.194(b). Theterm is used broadly to denote any materials, for example components, in-process materials, drug products, containers. or closures, which are testedin consideration of the quality of thedrug product.
490. One comment on proposed § 211.194(a)(6)` (now §211.194(b)) suggested that the word “significant” beinserted before “modification” to preclude the necessity of validating aminor change, such as glassware.
The Commissioner rejects this suggestion. If a method, when developed,published, and adopted, describes aprocedure to be followed and types ofmaterials to be used in its application,then any deviation from the prescribed procedures or materials mayinvalidate the results.
491. Comments on §§ 211.194( c ) and (d) ( p r o p o s e d as §§211.194(b) a n d 211.194(c), respectively) recommendedsubstituting the word “adequate” for“complete” or deleting the word “complete” because these sections do notdetail the criteria for the content of the records.
The Commissioner rejects these recommendations because the word “complete” is intended to require that therecords contain all the generated dataof all of the tests performed to assurethat the laboratory reference standards, reagents, and standard solutionsare suitable for use and ’that periodiccalibration of pertinent equipment was accomplished. The Commissioner believes that it is not feasible to list in detail all the tests or procedures to beperformed.
492. Several comments suggested deletion of the phrase “apparatus,gauges, and recording devices,” andothers recommended deletion of the word “apparatus,” in both §§ 211.160(b) and211.194(d). One comment said this requirement, as stated,could be Interpreted by FDA investigators as including beakers, hot plates,and plpette washers.
The Commissioner notes that §211.194(d) cites §211.160(b)(4), which requires the calibration of instruments, apparatus, gauges, and record
45073 ing devices at suitable intervals. In thecase of pipettes, for example, it wouldnot be suitable to calibrate at intervals since under normal conditions of use their capacity does not fluctuate. TheCommissioner also recognizes thatsome equipment and apparatus cannotbe 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 testingof drug products, not components orin-process materials; therefore, therecord retention provisions of§211.194(e) should apply only to sta
bility testing of drug products.The Commissioner agrees that the
recordkeeping requirement of § 211.194(e) is intended to apply to stability testing performed in accordancewith § 211.166, and the final regulationis revised accordingly. The Commissioner advises, however, that wherestability 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 stabilitytesting are appropriately includedunder § 211.194(e).
DISTRIBUTION RECORDS
494. Several comments suggestedthat § 211.196 be revised to providethat 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 inthis 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 recallis sound. Under such a system recallscould 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 whonever received the product could becontacted, thus taxing the resources ofthe firm and FDA. A blanket recall mlght also cause unneeded patientanxiety and even drug shortages. Additionally, the Commissioner does notbelieve that the same accountabilityfor each lot is inherent in a systemthat relies on contacting every customer. The amount of a recalled productthat each customer received may benecessary information if the danger tohealth is severe enough to requirethat each unit of a recalled drug product be accounted for.
496. One comment on § 211.196 questioned the necessity for a lot numberon distribution records being main-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
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45074
tained by suppliers of compressedmedical gas.
The Commissioner strongly believesthat the requirements of this sectionshould apply to compressed medicalgas fillers. Compressed medical gasesare potent drug products and, for example, a mixup in labeling of cylinderscould constitute a most serious healthproblem. It could be imperative thatevery cylinder of a particular lot be accounted for. The Commissioner realizes that usually, compressed medicalgases are distributed within a relatively small geographical area and to alimited number of customers, but this is not a sufficient reason to exemptsuppliers from the requirements ofthis section. The requirements of§ 211.196 should not constitute a majorburden on this industry in view of thelimited number of customers that aretypically serviced by one establishment.
497. One comment on § 211.190 questioned the appropriateness of a customer code number on the distributionrecord in place of the customer’s nameand address if there is a breakdown ofthe code.
The Commissioner would deem theuse of this type of system to be incompliance with the requirements ofthis section as long as adequate controls are employed to insure the accuracy of the code and legibility on thedistribution record.
COMPLAINT FILES
498. Many comments addressed § 211.198(a). The comments mostly objected to designation of the qualitycontrol unit for reviewing all complaints.
The Commissioner has consideredthe extensive objections and concludesthat revisions are necessary to clarifythe intended requirements regardingcomplaint files. As indicated in thepreamble to the February 13. 1976.Proposal, the object is to specify moreclearly how complaints regarding drugproducts are to be handled. It is notFDA’s intention to restrict or limitreview of such complaints to any oneunit in the firm's organization, but toassure that the quality control unit isproperly involved. Where there is acomplaint involving the possible failure of a drug product to meet any of’its specifications, the quality controlunit is probably the most appropriateunit to determine whether an lnvestigation under the procedures describedin § 211.192 is required.
To provide manufacturers with asmuch latitude as possible for efficientreview of drug product complaints, thefinal regulations provide that writtenprocedures for handling complaints include review by the quality controlunit where there is a possible failure
RULES AND REGULATIONS
of a drug product to meet its specifications.
The final regulations also providethat in such instances the quality control unit shall make a determinationas to the need for an investigation inaccordance with §211.192. This provision allows judgment in determiningthe extent of the investigation. Tosafeguard against perfunctory reviewof complaints, §211.198(b) requires astatement of the rationale for determining that no investigation is necessary and the identity of the personmaking that determination.
499. The comments regarding the recordkeeping provisions of § 211.198(b)objected primarily to the proposed requirement that companies that havemore than one establishment maintaina copy of each complaint record at theestablishment where the drug productinvolved was manufactured, processed,or packed (but not necessarily at everyestablishment where held only). Anumber of firms indicated that reportsof complaints are currently centralizedat one location, which often is theheadquarters office. The commentswere that duplicate records requiredat 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 locationsto store and retrieve data and records.
The Commissioner finds that somerevisions in the proposed requirements are Justified. He recognizes that manyfirms with multifacility operationsdepend 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 locationprovided that the written records areavailable for inspection. Where an investigation under §211.192 is actuallyconducted, § 211.180(c) requires thatrecords or copies of records of the investigation be readily available at theestablishment where the activities described in the records occurred. Thismeans that a record of an investigatlon conducted under §211.192 mustbe maintained at the establishmentwhere conducted, but that other records (e.g., of a medical investigatlonlregarding the drug product complaintmay be maintained at a central location. The Commissioner believes that the provisions of § 211.198 will providesufficient information regarding complaints about drug products that canbe 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 writ
ten complaint record include thereason that no investigation is necessary and the name of the responsibleperson 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, theCommissioner finds that the writtenrecord or a copy of it may be maintained at the place of manufacture, ifknown, or alternatively at a facilitywhere it would be readily available for inspection.
500. Many comments objected to thel-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 drugproduct must either be destroyed orreprocessed; an argument was madethat reshipment of goods "as is"should not be excluded as a possibility.
The Commissioner does not believethat the section as worded excludesthe possibility of reshipment “as is.”As it applies to destruction or reprocessing, § 211.204 concerns returneddrug products that have been held,stored, or shipped. before or duringtheir return, under conditions thatcast doubt on their Integrity. This section does not prohibit reshipmentwithout reprocessing of a drug productif its integrity was never in doubt, or ifinitially in doubt, subsequent lnvestigations prove the drug product satisfactory. To preclude the possibility ofmisinterpretation, however, the Commissioner is revising this section in thefinal regulation.
502. One comment recommendedthat reshipment of returned drugproducts to charitable organizationsshould be exempt from the requirement in § 211.204 for recording quantities or lot numbers.
The Commissioner does not believethat shipments of drug products tocharitable organizations should be anyless controlled than drug productsshipped to other categories of consumers.
503. Several comments said bioavailability is merely one facet of drugquality, and there is no need to mention it separately in § 211.204. Anothercomment said mentioning bioavailabllity is inappropriate for CGMP regulations.
The Commissioner finds that bioavailabillty is only one facet of drugquality and finds that it is unnecessary to mention only one of manyfacets that could be listed.
504. One comment on §211.204 saidthe only true measure of bioavailablllty is in vivo testing and that in vlvo
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45075 testing of returned goods is neithercurrent practice nor realistic.
The Commissioner notes that bioavailability testing is not necessarily arequirement for releasing returned goods. If conditions were such thatdoubt was cast on a drug product’s bioavailability then suitable bioavailability testing would be required beforethe returned product could be releasedfor distribution. Tests for bioavailability other than in vivo testing are recognized by FDA as valid in appropriate cases.
505. Several comments argued thatthe recordkeeping provisions of§ 211.204 are unnecessary, redundant,and unduly costly for many operations.
The Commissioner does not agreewith this position. He does not believesuch recordkeeping to be unduly burdensome. This section does not requireseparate records for returned goodscontaining all the information required by this section, but rather requires firms to be able to identifywhich, if any, drug products have beenreturned and for what reason, and tobe able to determine their disposition.The section would not prevent, for example, the disposition portion of therecords on returned goods from beinga part of normal distribution records ifthe lot involved were reshipped.
The Commissioner does not agreethat the requirements for returnedgoods are unnecessary. For example, aportion of a lot of drug product maybe returned because of unusual shipping conditions and the rest of the lotremain in normal trade channels. If the returned portion of the lot weredestroyed and no record were made,there would be an incomplete recordof distribution for the lot. In the case of recall, for example, a part of the lotcould 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 goodsthat 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 fromthis requirement.
50’7. One comment on § 211.204 recommended that time limits be established for destruction or reworking areturned drug product-a maximum30-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 arbitrarytime limits. That processing must notgo beyond appropriate limits is adequately covered elsewhere in theseregulations.
RULES AND 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, thesection is revised accordingly in thefinal 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 alsoto in-process materials unless furtherspecified. 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 toin-process materials. The section clearly refers to drug products, and thatterm is defined in § 210.3. The control of in-process materials, also defined in§ 210.3(b), is covered elsewhere in Part211.
510. One comment argued that§211.208 is contradictory in that itprohibits salvaging and return of drugproducts to the marketplace, and thenpermits such procedures.
The Commissioner disagrees withthis comment. The section prohibitsthe salvaging of drug products and/orreturn to the marketplace when thedrug products have been exposed toimproper storage conditions. The purpose of this section is to provide for anappropriate procedure for determiningthe suitability of salvaging drug products that may have been exposed tosuch conditions. The Commissioner believes that this section is adequately,worded to convey its meaning.
511. Another comment recommended that the wording of §211.208 bechanged to allow manufacturers to determine what testing accurately reflects the condition of the product.
The Commissioner rejects this comment. The requirements of this sectionare the minimum procedures necessary to assure the safety and qualityof drug products that may have been exposed to improper storage conditions.
512. A comment said it is unclear when § 211.206 applies and when§ 211.204. “Returned Drug Products”is applicable.
The applicability of these sectionsdepends on the history of the drugproduct. Section 211.204 is revised torequire that the reason for return beincluded in the records pertaining to
the returned drug. If the drug productis being returned because of possibleexposure to improper conditions, thedrug product salvaging requirementsof § 211.208 must also be applied. TheCommissioner believes that both sections clearly state their intent.
513. One comment said the phrase“evidence that the product meets allapplicable standards of identity,strength, quality, and purity” shouldbe deleted throughout §211.208 because it is unnecessarily detailed andrestrictive.
The Commissioner does not understand how the requirement that adrug product meets all applicablestandards of identity, strength, quality, and purity could reasonably beconsidered either too detailed or tod restrictive. Anything less would notassure the quality and safety of thedrug product or that the product wssnot 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 nothave absolute control over a drug onceit leaves their premises, and withoutevidence of proper control, drugs couldnot be returned under the proposedregulations. even in the normal courseof a firm’s business. They cited examples such as returning overstockeditems, drugs which were ordered ordistributed in error, seasonal items, recertified antibiotics. or drugs requiringrelabeling.
The Commissioner finds that the CGMP regulations do not prohibitdrug products; being returned. Theregulations clearly allow redistributionof returned drug products that meetapplicable standards of safety, identity, strength, quality, and purity. Ifthere is no question whether the drugproducts have been properly storedafter 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 maximumis preferred by FDA and could be abasis for defining “prolonged storage.”
The Commissioner finds that, inview of the requirements regarding expiration dating of drug products, theproposed reference to prolonged storage in § 211.208 is unnecessary. TheCommissioner concludes that this section should be further revised for simplicity, by referring to “improper storage conditions” rather than “improperstorage or abnormal environmentalconditions.”
516. One comment on $211.208 recommended that organoleptic examina-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45076 tions be considered acceptable as evidence, provided such a determinationis made by a pharmacist or chemisthaving 1 year’s experience in the field.
Organoleptlc examinations alonewould never be enough to insure thata drug has maintained its strength,purity, and quality after it has been ina 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 reclaimingof active ingredients from drug products that have been salvaged.
The Commhsloner finds that drugproducts that have been subjected toimproper storage conditions shouldnot be salvaged because of the result-Ing questionable integrity of the drugproduct. Therefore, such drug products are clearly not suitable for reprocessing, including reclaiming of activeingredients. However, where salvagingis permissible under the provisions of$211.208, any appropriate reprocessingis allowed. The Commissioner believesthe regulations are clear in thlsregard. XVII. CGMP FOR CERTAIN OTHER
DRUG PRODUCTS 518. No comments or objections ad
dressed proposed revocation of§ 229.25. Section 229.25 is the only section contained in Part 229 (21 CFR Part 229). and the Commissioner seesno immediate need for retaining thatpart as currently used. Therefore, theentire Part 229 is revoked in thesefinal regulations and reserved forfuture use.
The Commissioner has carefullyconsidered the environmental effectsof the proposed regulation and. because the proposed action will not significantly affect the quality of thehuman environment. has concludedthat an environmental impact statement is not required. A copy of the envlronmental impact assessment is onfile with the Hearing Clerk, Food andDrug 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 asamended, 59 Stat. 463 as amended, 76Stat. 794 as amended. 82 Stat. 343-351 (21 U.S.C. 351. 352. 355. 356. 357. 360,360b, 371)) and the Drug Llstlng Actof 1972 (Pub. L. 92-387; 86 Stat. 559562) and under authority delegated tothe Commlsstoner (21 CFR 5.1). Chapter I of Title 21 of the Code of FederalRegulations is amended as follows:
PART 201 - LABELING 1. By revising § 201.17 to read as fol
lows:
RULES AND REGULATIONS
§ 201.17 Drugs; location of expirationdate.
When an expiration date of a drug lsrequired, e.g., expiration datlng of drug products required by §211.137 ofthis chapter, it shall appear on the immediate container and also the outer package, if any, unless it is easily legible through such outer package. However, when single-dose containers arepacked in individual cartons, the expiration date may properly appear onthe individual carton instead of the immediate product container.
PART 207-REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION
2. By revising paragraph (b) andadding new paragraph (k) in § 207.3 to read as follows: § 207.3 Definitions.
. . . . . (b) "Establishment" means a place
of business under one management atone general physical location. Theterm includes. among others, independent laboratories that engage lncontrol activities for registered drugestablishments (e.g., "consulting" laboratories), manufacturers of medicated feeds and of vltamln products thatare “drugs” within the meaning of section 201(g) of the act, human blooddonor centers, animal facilities usedfor the production or control testlngof licensed human biologlcals, and establishments engaged ln drug productsalvaglng.
. . . . . (k) “Drug product salvaging ” is the
act of segregating drug products thatmay have been subjected to improperstorage conditions such as extremes in temperature, humidity, smoke, fumes,pressure, age, or radiation for the purpose of returning some or all of the products to the marketplace. § 207.20 [Amended]
3. By amending §207.20 Who must register and submit a drug list in Subpart B of Part 207 b adding a commayand the phrase “nor is drug listing required for establlshments engaged indrug product salvaging” before theperlod at the end of paragraph (a).
PART 210 - CURRENT GOOD MANUFACTURING PRACTICES IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS: GENERAL
4. By revising Part 210 to read as follows: Sec. 210.1 Status of current goodmanufactur
ing practice regulations.210.2 Applicability of current good manu
facturing practice regulations. 210.3 Definitions.
AUTHORITY: Secs. 501. 701, 52 Stat. 10491050 as amended. 1055-1056 as amended (21 U.S.C. 351,371).
§ 210.1 Status of current good manufacturing practice regulations.
(a) The regulations set forth ln thispart and ln Parts 211 through 229 ofthis chapter contain the minimum current good manufacturing practice formethods to be used in, and the facilities or controls to be used for, themanufacture, processing, packing, orholding of a drug to assure that suchdrug meets the requirements of theact as to safety, and has the identityand strength and meets the qualityand purity characteristics that it purports or is represented to possess.
(b) The faflure to comply with anyregulation set forth ln this part and inParts 211 through 229 of this chapterln the manufacture, processing, packing. or holdlng of a drug shall rendersuch drug to be adulterated under section 501(a)(2)(B) of the act and suchdrug, as well a s the person who is responsible for the failure to comply,shall be subject to regulatory action. § 210.2 Applicability of current good man
ufacturing practice regulations. (a) The regulations ln this part and
in Parts 211 through 229 of this chapter a s they may pertain to a drug andin Parts 600 through 680 of this chapter as they may pertain to a biologicalproduct for human use, shall be considered to supplement, not supersede,each other, unless the regulations explicitly provide otherwise. In the eventthat it is impossible to comply with allapplicable regulations ln these parts,the regulations specifically applicableto the drug in question shall supersedethe more general.
(b) If a person engages in only someoperations subject to the regulationsin this part and in Parts 211 through229 and Parts 600 through 680 of this chapter, and not in others, that personneed only comply with those regulations applicable to the operations inwhich he or she is engaged. § 210.3 Definitions.
(a) The definitions and interpretatlons contained in section 201 of the
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
s
, . r
t
.
t g
.
llters.
t
n
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n
act shall be applicable to such termswhen used in this part and in Parts 211 through 229 of this chapter.
(b) The following definitions ofterms apply to this part and to Parts 211 through 229 of this chapter.
(1) “Act” means the Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.).
(2) “Batch” means a specific quantity of a drug or other material that isintended to have uniform character and quality, within specified limits,and is produced according to a singlemanufacturing order during the samecycle of manufacture.
(3) “Component” means any ingredient intended for use in the manufacture of a drug product, including thosethat may not appear in such drugproduct.
(4) “Drug product” means a finisheddosage form, for example, tablet, capsule, solution, etc., that contains anactive drug ingredient generally, butnot necessarily, in association with inactive ingredients. The term also includes a finished dosage form thatdoes not contain an active ingredientbut is intended to be used as a placebo.
(5) “Fiber” means any particulatecontaminant with a length at leastthree times greater than its width.
(6) “Non-fiber-releasing filter”means any filter, which after any appropriate pretreatment such as washing or flushing, will not release fibers
RULES AND REGULATIONS
(11) “Lot number, control number,or batch number” means any sidtinctive combination of letters, numbers,or symbols, or any combination ofthem, from which the complete history of the manufacture, processing,packing, holding. and distribution of abatch or lot of drug product or other material can be determined.
(12) “Manufacture. processing, packing, or holding of a drug product” includes packaging and labeling operations, testing. and quality control ofdrug products.
(13) “Medicated feed” means any “complete feed,” “feed supplement,” or “feed concentrate” as defined in§558.3 of this chapter and is a feedthat contains one or more drugs as defined in section 201(g) of the act.Medicated feeds are subject to Part225 of this chapter.
(14) “Medicated premix” means asubstance that meets the definition inp558.3 of this chapter for a “feedpremix,” except that it contains one or more drugs as defined in section 201(g)of the act and is intended for manufacturing use in the production of amedicated feed. Medicated premixesare subject to Part 226 of this chapter.
(15) “Quality control unit” meansany person or organizational elementdesignated by the firm to be responsible for the duties relating to qualitycontrol.
(16) “Strength” means:
45077
plan, that are necessary for making adecision to accept or reject a lot orbatch (or any other convenient subgroups of manufactured units).
(21) “Representative sample” means a sample that consists of a number ofunits that are drawn based on rational criteria such as random sampling andintended to-assure that the sample accurately portrays the material beingsampled.
PART 221 - CURRENTGOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS
5. By revising Part 211 to read as follows:
Subpart A - General Provisions
Sec.211.1 Scope.211.3 Definitions
Subpart B - Organization ond personnel 211.22 Responsibilities of quality control
unit. 211.25 Personnel qualifications. 211.28 Personnel responsibilities.211.34 Consultants.
Subpart C - Buildings and Facilities 211.42 Design and construction features.211.44 Lighting.211.46 Ventilation, air filtration air heat
ing and cooling.2 1 1 . 4 8 P l u m b i n g .
0211.6Sewage and refuse.2Washing and
6211.5Sanitation. 211.5 toilet facilities.
into the component or drug product (i) The concentration of the drugthat is being filtered. All filters com- substance (for example, weight/posed of asbestos are deemed to be weight, weight/volume, or unit dose/fiber-releasing filters. volume basis), and/or
(7) “Active ingredient” means anycomponent that is intended to furnishpharmacological activity o r o t h e r direct effect in the diagnosis, cure,mitigation. treatment, or prevention ofdisease, or to affect the structure ofany function of the body of man orother animals. The term includesthose components that may undergochemical change in the manufacture
(ii) The potency, that is, the therapeutic activity of the drug product a sindicated by appropriate laboratorytests or by adequately developed andcontrolled clinical data (expressed. forexample, in terms of units by reference to a standard).
(17) “Theoretical yield” means thequantity that would be produced atany appropriate phase of manufac-
Maintenance.6211.5
Subpart D-Equipment SCC.211.63 Equipment design, size and loca. .non. 211.65 Equipment construction. 2 1 1 . 6 7 Equipment cleaning and mainte
nance. 211.68 Automatic, mechanical, and elec
tronlc equipment. 211.72 ltFis.erof the drug product and be present in
the drug product in a modified formintended to furnish the specified activity or effect.
(8) “Inactive ingredient” means anycomponent other than an “active ingredient.”
(9) “In-process material” means anymaterial fabricated, compounded,blended , or derived by chemical reaction that is produced for, and used in,
ture, processing, or packing of a particular drug product, based upon thequantity of components to be used, inthe absence of any loss or error inactual production.
(18) “Actual yield” means the quantity that is actually produced at anyappropriate phase of manufacture,processing, or packing of a particulardrug product.
(19) “Percentage of theoreticalyield” means the ratio of the actual
Subpart E-Control of Components ond Drug Product Containers and Closures
211.60 General requirements.211.62 Receipt and storage of untested
components, drug product containers.and closures.
211.64 Testing and approval or rejection of components. drug product containers.and closures.
211.66 Use of approved components. drugproduc t containers, and closures.
Retesting 7’211.6 of approved components.drug product containers, and closures.cifi c eidentified portion of a batch, manufacture, processing, or packing of 211.80 Rejected components. drug producthaving uniform character and quality a particular drug product) to the theo containers. and closures.w ithin specified limits; or, in the case retical yield (at the same phase), 211.94 Drug product containers and clo
of a drug product produced con- stated as a percentage. sures.t in ous process, it is a speci identi- (20) “Acceptance criteria” means thef iedamount produced in a unit of time product specifications and acceptance/ Subpart F-Production and Process Controls or quantity in a manner that assures rejection criteria, such as acceptable 211.100 Written procedures; d e v i a t i o n s its having uniform character and qual- quality level and unacceptable quality 211.101 Charge-in of components.i ty within specified limits. level, with an associated sampling 211.103 Calculation of yleld.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
t he preparaion of the drug product. ( 10) “1 ot" means a batch, or a spe- yield (at any appropriate phase of
L
45078
211.105 Equipment identification. 211.110 Sampling and te sti ng of in-process
materials and drug products.211.111 Time limitations on production.211.113 Control of microbiological con
tamination. 211.115 Re pr oce ssi ng
Subpart G-Packaging and Labeling Control 211.122 Materials examination and usage
criteria. 211.125 Labeling issuance.211.130 Packaging and labeling operations.211.134 Drug product inspection.211.137 Expiration dating.
Subpart H-Holding and Distribution 211.142 Warehousing procedures.211.150 Distribution procedures
Subpart I - Laboratory Controls 211.160 General requirements.211.165 Te st ing and release for distribu
tion. 211.166 Stability testing.211.167 Special testing requirements.211.170 Reserve samples.211.173 Laboratory animals. 211.176 Penicillin contamination.
Subpart J - Records and Reports 211.180 General re qui re men ts .211.182 Equipment cleaning and use log.
RULES AND REGULATIONS
question shall supersede the regulation in this part.
(c) Pending consideration of a Proposed exemption, published in theFEDERAL REGISTER of November 29. 1978. the requirements in this Partshall not be enforced for OTC drugproducts if the products and all theiringredients are ordinarily marketedand consumed as human foods, andwhich products may also fall withinthe legal definition of drugs by virtueof their intended use. Therefore, untilfurther notice, regulations under Part110 of this chapter, and where applicable, Parts 113 to 129 of this chapter,shall be applied in determining whether these OTC drug products that arealso foods are manufactured, processed, packed, or held under currentgood manufacturing practice.
§ 211.3 Definitions. The definitions set forth in § 210.3 of
this chapter apply in this part. Subpart B-Organization and
Personnel § 211.22 Responsibilities of quality control
unit. (a) There shall be a quality control211.184 Component, drug product co nt ain
e r , closure. and labeling records. unit that shall have the responsibility211.186 Master production and control re c - and authority to approve or reject all
ords. 211.188 Batch production and control rec
ords. 211.192 Production record review. 211.194 Laboratory records.211.196 Distribution records. 211.198 Complaint files.
211.204 Returned drug products.211.208 Drug product slavaging.
AUTHORITY : Secs. 501. 701. 52 Stat. 10491050 as amended, 1055-1056 as amended (21 U.S.C. 351. 371).
components, drug product containers.closures, in-process materials, packaging material, labeling. and drug products, and the authority to review production records to assure that no errors have occurred or, if errors haveoccurred. that they have been fully investigated. The quality control unitshall be responsible for approving orrejecting drug products manufactured,processed, packed, or held under contract by another company.
(b) Adequate laboratory facilities forthe testing and approval (or rejection)of components. drug product contain
in-,ers, closures, packaging materials
performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and writtenprocedures required by these regulations) as they relate to the employee’s functions. Training in current goodmanufacturing practice shall be conducted by qualified individuals on acontinuing basis and with sufficientfrequency to assure that employeesremain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture, processing,packing, or holding of a drug productshall have the education, training, andexperience, or any combination thereof, to perform assigned functions insuch a manner as to provide assurancethat the drug product has the safety,identity, strength, quality. and puritythat it purports or is represented to possess.
(c) There shall be an adequatenumber of qualified personnel to perform and supervise the manufacture,processing, packing, or holding of eachdrug product.
§ 211.28 Personnel responsibilities. (a) Personnel engaged in the manu
facture, processing, packing, or holding of a drug product shall wear cleanclothing appropriate for the dutlesthey perform. Protective apparel, suchas head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.
(b) Personnel shall practice goodsanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter thoseareas of the buildings and facilitiesdesignated as limited-access areas.
(d) Any person shown at any time(either by medical examination or supervisory observation) to have an apparent illness or open lesions that may
facturing practice for preparation ofdrug products for administration tohumans or animals.
(b) The current good manufacturing practice regulations in this chapter, asthey pertain to drug products. and inParts 600 through 680 of this chapter.as they pertain to biological productsfor human use, shall be considered tosupplement. not supersede. the regulations in this part unless the regula
tions explicitly provide otherwise. Inthe event it is impossible to complywith applicable regulations both inthis part and in other parts of thischapter or in Parts 600 through 680 ofthis chapter, the regulation specifically applicable to the drug product in
Subpart A - General Provisions process materials, and drug products adversely affect the safety or quality§ 211.1 Scope. shall be available to the quality con- of drug products shall be excluded
(a) The regulations in this part con- trol unit. from direct contact with components.in-,drug product containers, closurestain the minimum current good manu (c) The quality control unit shall
have the responsibility for approvingor rejecting all procedures or specifications impacting on the identity,strength, quality. and purity of thedrug product.
(d) The responsibilities and procedures applicable to the quality controlunit shall be in writing; such writtenprocedures shall be followed.
§211.25 Personnel qualifications (a) Each person engaged in the man
ufacture, processing, packing, or holding of a drug product shall have education, training, and experience, orany combination thereof, to enablethat person to perform the assignedfunctions. Training shall be in the particular operations that the employee
process materials. and drug productsuntil the condition is corrected or determined by competent medical personnel not to jeopardize the safety orquality of drug products. All personnelshall be instructed to report to supervisory personnel any health conditionsthat may have an adverse effect on drug products. § 211.34 Consultants.
Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, toadvise on the subject for which theyare retained. Records shall be maintained stating the name, address, and
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RULES AND REGULATIONS 45079 qualifications of any consultants andthe type of service they provide.
Subpart C-Buildings and Facilities § 211.42 Design and construction features.
(a) Any building or buildings used inthe manufacture, processing, packing,or holding of a drug product shall beof suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
(b) Any such building shall haveadequate space for the orderly placement of equipment and materials toprevent mixups between differentcomponents, drug product containers,closures, labeling, in-process materials.or drug products, and to prevent contamination. The flow of components.drug product containers, closures, labeling, in-process materials, and drugproducts through the building orbuildings shall be designed to preventcontamination.
(c) Operations shall be performed’ withln specifically defined areas ofadequate-size. Thdre shall be separateor defined areas for the firm’s operations to prevent contamination ormixups as follows:
(1) Receipt, identification storage,and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sampling. testing, or examination by the quality control unit beforerelease for manufacturing or packaging.
(2) Holding rejected components,drug product containers, closures, andlabeling before disposition;
(3) Storage of released components.drug product containers. closures. andlabeling:
(4) Storage of in-process materials;(5) Manufacturing and processing
operations;(6) Packaging and labeling oper
ations;(7) Quarantine storage before re
lease of drug products;(8) Storage of drug products after re
lease;(9) Control and laboratory oper
ations;(10) Aseptic processing. which in
cludes as appropriate:( i ) Floors. walls. and ceilings of
smooth, hard surfaces that are easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered throughhigh-efficiency particulate air filtersunder positive pressure, regardless ofwhether flow is laminar or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment toproduce aseptic conditions;
(vi) A system for maintaining any § 211.56 Senitation.equipment used to control the aseptic (a) Any building used in the manu-conditions. facture, processing, packing, or hold(d) Operations relating to the manu- ing of a drug product shall be main-facture, processing. and packing oftained in a clean and sanitary condipenicillin shall be performed in facili- tion, Any such building shall be free ofties separate from those used for other infestation b y rodents. birds, insects,drug products for human use. and other vermin (other than labora
tory animals). Trash and organic§ 211.44 Lighting. waste matter shall be held and dis-Adequate lighting shall be provided posed of in a timely and sanitary
in all areas. manner.(b) There shall be written proce§211.46 Ventilation, air filtration. air dures assigning responsibility for saniheating and cooling. tation and describing in sufficient
(a) Adequate ventilation shall bedetail the cleaning schedules, methprovided. ods, equipment, and materials to be
(b) Equipment for adequate control used in cleaning the buildings and fa-over air pressure. micro-organisms, cilities; such written procedures shalldust, humidity, and temperature shall be followed. be provided when appropriate for the (c) There shall be written procemanufacture, processing, packing, ordures for use of suitable rodenticides,holding of a drug product.
(c) Air filtration systems. includingprefilters and particulate matter alrfilters, shall be used when appropriateon air supplies to production areas. Ifalr is recirculated to production areas,measures shall be taken to contro relcirculation of dust from production. In areas, where air contamination occursduring production, there shall be adequate exhaust systems or other systems adequate to control contaminants.
(d) Air-handling systems for themanufacture. processing, and packingof penicillin shall be completely separate from those for other drug products for human use. § 211.48 Plumbing.
(a) Potable water shall be suppliedunder continuous positive pressure ina plumbing system free of defects thatcould contribute contamination to anydrug product. Potable water shallmeet the standards prescribed in thePublic Health Service Drinking WaterStandards set forth in Subpart J of 42CFR Part 72. Water not meeting such standards shall not be permitted inthe potable water system.
(b) Drains shall be of adequate sizeand, where connected directly to asewer, shall be provided with an airbreak or other mechanical device toprevent back-siphonage. § 211.50 Sewage and refuse.
Sewage, trash. and other refuse inand from the building and immediate premises shall be disposed of in a safeand sanitary manner. § 211.52 Washing and toilet facilities.
Adequate washing facilities shall beprovided, including hot and coldwater. soap or detergent, air driers orsingle-service towels, and clean toiletfacilities easily accesible to working areas.
insecticides, fungicides. fumigatingagents. and cleaning and sanitizingagents. Such written procedures shallbe designed to prevent the contamination of equipment, components, drugproduct containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shallnot be used unless registered and usedin accordance with the Federal Insecticide. Fungicide, and Rodenticide Act(7 U.S.C. 135).
(d) Sanitatlon procedures shalla p p l y to work performed by contract& or temporary employees a s well a swork performed by full-time employees during the ordinary course of operations. § 211.58 Maintenance.
Any building used in the manufacture, processing. packing, or holding ofa drug product shall be maintained ina good state of repair.
Subpart D-Equipment § 211.62 Equipment design, size, and loca
tion. Equipment used in the manufacture,
processing, packing, or holding of adrug product shall be of appropriatedesing adequate size, and suitably located to facilitate operations for its intended use and for its cleaning andmaintenance. § 211.65 Equipment construction.
(a) Equipment shall be constructedso that-surfaces that contact components, in-process materials, or drugproducts shall not be reactive, additive, or absorptive so as to alter thesafety, Identity, strength, quality, orpurity of the drug product beyond theofficial or other established requirements.
(b) Any substances required for operation, such as lubricants or coolants.shall not come into contact with com-
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ponents, drug product containers,closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality, or purity of thedrug product beyond the official orother established requirements. §211.67 Equipment cleaning and mainte
nance. (a) Equipment and utensils shall be
cleaned, maintained, and sanitized atappropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength,quality, or purity of the drug productbeyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaningand maintenance of equipment, including utensils, used in the manufacture, Processing, packing or holding ofa drug product. These proceduresshall include, but are not necessarilylimited to, the following:
(1) Assignment of responsibility forcleaning and maintaining equipment;
(2) Maintenance and cleaning schedules, including, where appropriate,sanitizing schedules:
(3 ) A description in sufficient detailof the methods, equipment, and materials used in cleaning and maintenanceoperations. and the methods of disassembling and reassembling equipment as necessary to assure proper cleaningand maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipmentfrom contamination prior to use;
(6) Inspectlon of equipment forcleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in §§211.180 and211.182. § 211.68 Automatic, mechanical, and elec
tronic equipment. (a) Automatic, mechanical, or elec
tronic equipment or other types ofequipment, including computers, or related systems that will perform a function satisfactorily, may be used in themanufacture, processing, packing, andholding of a drug product. If suchequipment is so used, it shall be routinely calibrated. inspected,or checkedaccording to a written program designed to assure proper performance.Written records of those calibrationchecks and inspections shall be maintained.
(b) Appropriate controls shall be exercised over computer or related systems to assure that changes in masterProduction and control records orother records are instituted only byauthorized personnel. Input to andoutput from the computer or relatedsystem of formula or other records ordata shall be checked for accuracy. A
RULES AND REGULATIONS
backup file of data entered into thecomputer or related system shall bemaintained except where certain data,such as calculations performed in connection with laboratory analysis, aree l i m a t e d by computerization orother automated processes. In such instances a written record of the program shall be maintained along withappropriate validation data. Hard copyor alternative systems, such as duplicates, tapes, or microfilm, designed toassure that backup data are exact andcomplete and that it is secure from alteration, inadvertent erasures, or lossshall be maintained. § 211.72 Filters.
Filters for liquid filtration used inthe manufacture, processing, or packing of injectable drug products intended for human use shall not releasefibers into such products Fiber-releas.ing filters may not be used in the manufacture, processing, or packing ofthese injectable drug products unlessit is not possible to manufacture suchdrug products without the use of suchfilters. If use of a fiber-releasing filteris necessary, an additional non-fiberreleasing filter of 0.22 micron maximum mean porosity (0.45 micron if themanufacturing conditions so dictate)shall subsequently be used to reducethe content of particles in the injectable drug product. Use of an asbestos-containing filter, with or without subsequent use of a specific non-fiber-releasing filter, is permissible only uponsubmission of proof to the appropriatebureau of the Food and Drug Administration that use of a non-fiber-releasing filter will, or is likely to, compromise the safety or effectiveness of theinjectable drug product.
Subpart E-Control of Componentsand Drug Product Containers andClosures
§ 211.80 General requirements. (a) There shall be written proce
dures describing in sufficient detailthe receipt, identification, storage,handling, sampling, testing, and approval or rejection of components anddrug product containers and closures;such written procedures shall be followed.
(b) Components and drug productcontainers and closures shall at alltimes be handled and stored in amanner to prevent contamination.
(c) Bagged or boxed components ordrug product containers, or closuresshall be stored off the floor and suitably spaced to permit cleaning and inspection.
(d) Each container or grouping ofcontainers for components or drugproduct containers, or closures shallbe identified with a distinctive code
for each lot in each shipment received.This code shall be used in recordingthe disposition of each lot. Each lotshall be appropriately identified as toits status (i.e., quarantined, approved.or rejected). § 211.82 Receipt and storage of untestedcomponents, drug product containers,and closures.
(a) Upon receipt and before acceptance, each container or grouping ofcontainers of components, drug product containers, and closures shall beexamined visually for appropriate labeling as to contents, containerdamage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be storedunder quarantine until they have beentested or examined, as appropriate,and released. Storage within the areashall conform to the requirements of§ 211.80. § 211.84 Testing and approval or rejection
of components, drug product containers, and closures.
(a) Each lot of components, drugproduct containers, and closures shallbe withheld from use until the lo hastbeen sampled, tested, or examined, asappropriate, and released for use bythe quality control unit.
(b) Representative samples of eachshipment of each lot shall be collectedfor testing or examination. Thenumber of containers to be sampled,and the amount of material to betaken from each container, shall bcbased upon appropriate criteria suchas statistical criteria for componentvariability, confidence levels, anddegree of precision desired, the pastquality history of the supplier, andthe quantity needed for analysis andreserve where required by § 211.170.
(c) Samples shall be collected in accordance with the following procedures:
(1) The containers of components selected shall be cleaned where necessary, by appropriate means.
(2) The containers shall be opened,sampled, and resealed in a manner designed to prevent contamination oftheir contents and contamination ofother components, drug product containers, or closures.
(3) Sterile equipment and asepticsampling techniques shall be usedwhen necessary.
(4) If it is necessary to sample a component from the top, middle, andbottom of its container, such samplesubdivisions shall not be cornpositedfor testing.
(5) Sample containers shall be identified so that the following information can be determined: name of thematerial sampled, the lot number, thecontainer from which the sample was
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45081
taken, the data on which the sample w a s taken, and the name of the personwho collected the sample.
(6) Containers from which sampleshave been taken shall be marked toshow that samples have been removedfrom them.
(d) Samples shall be examined andtested as follows:
(1) At least one test shall be conducted to verify the identity of eachcomponent of a drug product. Specificidentlfy tests, if they exist, shall beused.
(2) Each component shall be testedfor conformity with all appropriatewritten specifications for purity.strength, and quality. In lieu of suchtesting by the manufacturer, a reportof analysis may be accepted from thesupplier of a component, provided thatat least one specific identity test isconducted on such component by themanufacturer, and provided that themanufacturer establishes the reliability of the supplier’s analyses throughappropriate validation of the supplier’s test results at appropriate interva ls .
(3) Containers and closures shall be tested for conformance with all appropriate written Procedures. In lieu ofsuch testing by the manufacturer, acertificate of testing may be acceptedfrom the supplier, provided that atleast a visual identification is conducted on such containers/closures by themanufacturer and provided that themanufacturer establishes the reliability of the supplier’s test resultsthrough appropriate validation of thesupplier’s test results at appropriate intervals.
(4) When appropriate, componentsshall be microscopically examined.
(5) Each lot of a component. drugproduct container, or closure that isliable to contamination with filth,insect infestation, or other extraneousadultcrant shall be examined againstestablished specifications for such contamination.
(6) Each lot of a component, drugproduct container, or closure that isliable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.
(e) Any lot of components, drugproduct containers. or closures that meets the approprlate written specifications of Identity, strength, quality, and purity and related tests under paragraph (d) of this section may beapproved and released for use. Any lotof such material that does not meetsuch specifications shall be rejected.
§ 211.86 Use of approved components,drug product containers. and closures
Components, drug product containers, and closures approved for useshall be rotated so that the oldest ap-
RULES AND REGULATIONS
proved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate. §211.87 Retesting of approved compo
nents, drug product containers, andclosures.
Components, drug product containers. and closures shall be retested orreexamined, as appropriate, for identity, strength, quality, and Purity andapproved or rejected by the qualitycontrol unit in accordance with§ 211.84 as necessary, e.g., after storagefor long periods or after exposure toair, heat or other conditions thatmight adversely affect the component.drug product container, or closure. § 211.89 Rejected components, drug prod
uct containers, and closures. Rejected components, drug product
containers, and closures shall be identified and controlled under a quarantine system designed to prevent theiruse in manufacturing or processing o perations for which they are unsuitable.
§ 211.94 Drug product containers and closures
(a) Drug product containers and closures shall not be reactive, additive, orabsorptive so as to alter the safety,identity, strength, quality, or Purity ofthe drug beyond the official or established requirements.
(b) Container closure systems shallprovide adequatt protection againstforeseeable external factors in storageand use that can cause deteriorationor contamination of the drug product.
(c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that theyare suitable for their intended use.
(d) Standards or specifications,methods of testing, and, where indicated, methods of cleaning, sterilizing,and processing to remove pyrogenicproperties shall be written and followed for drug product containers andclosures.
Subpart F-Production and Process Controls
§ 211.100 Written procedures; deviations. (a) There shall be written proce
dures for production and process control designed to assure that the drugproducts have the identity, strength,quality and Purity they purport or arerepresented to possess. Such procedures shall include all requirements inthis subpart. These written procedures, including any changes, shall bedrafted, revlewed. and approved bythe appropriate organizational units
and reviewed and approved by thequality control unit.
(b) Written production and processcontrol procedures shall be followed inthe execution of the various production and process control functions andshall be documented at the time of performance. Any deviation from thewritten procedures shall be recordedand justified. § 211.101 Charge-in of components.
Written production and control procedures shall include the following,which are designed to assure that thedrug products produced have the identity, strength, quality, and purity theypurport or are represented to possess:
(a) The batch shall be formulatedwith the intent to provide not lessthan 100 percent of the labeled or established amount of active ingredient.
(b) Components for drug productmanufacturing shall be weighed, measured, or subdivided as appropriate. If acomponent is removed from the original container to another, the new container shall be identified with the following information:
(1) Component name or item code;(2) Receiving or control number;(3) Weight or measure in new con
tainer;(4) Batch for which component was
dispensed, including its product name,strength, and lot number.
(c) Weighing, measuring. or subdividing operations for components shallbe adequately supervised. Each container of component dispensed to manufacturing shall be examined by asecond person to assure that:
(1) The component was released bythe quality control unit;
(2) The weight or measure is correct a s stated in the batch production records;
(3 ) The containers are properly identified.
(d) Each component shall be addedto the batch by one person and verified by a second person. § 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be determinedat the conclusion of each appropriatephase of manufacturing, processing,packaging, or holding of the drugproduct. Such calculations shall beperformed by one person and independently verified by a second person. §§ 211.105 Equipment identification.
(a) All compounding and storagecontainers, processing lines, and majorequipment used durlng the productionof a batch of a drug product shall beproperly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.
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45082 RULES AND REGULATIONS
(b) Major equipment shall be identified by a distinctive identificationnumber or code that shall be recorded in the batch production record toshow the specific equipment used inthe manufacture of each batch of a drug product. In cases where only oneof a particular type of equipmentexists in a manufacturing facility. thename of the equipment may be used in lieu of a distinctive identificationnumber or code. § 211.110 Sampling and testing of in-proc
e s s materials and drug products. (a) To assure batch uniformity and
integrity of drug products. written procedures shall be established andfollowed that describe the in-processcontrols. and tests, or examinations tobe conducted on appropriate samplesof in-process materials of each batch.Such control procedures shall be established to monitor the output and tovalidate the performance of thosemanufacturing processes that may beresponsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include but arenot limited to, the following, whereappropriate:
(1) Tablet or capsule weight variation;
(2) Disintegration time; (3) Adequacy of mixing to assure
uniformity and homogeneity rate;; (4) Dissolution time and rate; (5) Clarity completeness. or pH of
solutions. (b) Valid in-process specifications for
such characteristics shall be consistent with drug product final specificationsand shall be derived from previous acceptable process average and processvariability estimates where possibleand determined by the application of suitable statistical procedures whereappropriate. Examination and testingof samples shall assure that the drugproduct and in-process material conform to specifications.
(c) In-process materials shall betested for identity, strength, quality,and purity as appropriate and approved or rejected by the quality control unit, during the production process, e.g.. at commencement or completion of significant phases or after storage for long periods.
(d) Rejected in-process materials shall be identified and controlled under a quarantine system designed toprevent their use in manufacturing orprocessing operations for which theyare unsuitable.
$211.11 I Time limitations on production. When appropriate, time limits for
the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may
be acceptable if such deviation does (f) Gang printing of labeling to be not compromise the quality of the used for different drug products or difdrug product. Such deviation shall be ferent strengths of the same drugjustified and documented. product (or labeling of the same size
and identical or similar format and/or§ 211.113 Control of microbiological con-color schemes) shall be mlnimlzed. Iftamination.
(a) Appropriate written procedures,designed to prevent objectlonable microorganisms in drug products not required to be sterile, shall be established and followed.
(b) Appropriate written procedures,designed to prevent microbiologicalcontamination of drug products purporting to be sterile, shall be established and followed. Such proceduresshall include validation of any sterilization process.
§ 211.115 Reprocessing. (a) Written procedures shall be es
tabllshed and followed prescribing asystem for reprocessing batches thatdo not conform to standards or specifications and the steps to be taken toinsure that the reprocessed batcheswill conform with all established standards, specifications, and characteristics.
(b) Reprocessing shall not be performed without the review and approval of the quality control unit. S u b p a r tG-Packaging andlabeling
Control §211.122 Materials examination and
usage criteria (a) There shall be written proce
dures describing in sufficient detail the receipt. identification, storage,handling, sampling, examlnatlon. and/ or testing of labeling and packagingmaterials; such written proceduresshall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate writtenspecifications may be approved and released for use. Any labeling or packaging materials that do not meet suchspecifications shall be rejected to prevent their use in operations for which they are unsuitable.
(c) Records shall be maintained for each shipment received of each different labeling and packaging materialindicating receipt, examination or testing, and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug product,strength, dosage form, or quantity ofcontents shall be stored separatelywith suitable identification. Access to the storage area shall be limited to authorized personnel.
(e) Obsolete and outdated labels, labeling, and other packaging materialsshall be destroyed.
gang printing is employed, packagingand labeling operations shall providefor special control procedures, takinginto consideration sheet layout, stacking, cutting, and handling during andafter printing.
(g) Printing devices on, or associatedwith, manufacturing lines used to imprint labeling upon the drug productunit label or case shall be monitored to assure that all imprinting conforms to the print specified in the batch production record.
§ 211.125 Labeling issuance. (a) Strict control shall be exercised
over labeling issued for use in drugproduct labeling operations.
(b) Labeling materials issued for abatch shall be carefully examined foridentity and conformity to the labeling specified in the master or batchproduction records.
(c) Procedures shall be utilized toreconcile the quantities of labelingissued, used, and returned, and shall require evaluation of discrepanclesfound between the quantity of drugproduct finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. Such dlscrepancles shall be investigated in accordance with § 211.192.
(d) All excess labeling bearing lot orcontrol numbers shall be destroyed.
(e) Returned labeling shall be maintained and stored in a manner to prevent mixups and provlde proper identification.
(f) Procedures shall be written describing in sufficient detail the control procedures employed for the issuanceof labeling; such written proceduresshall be followed. §211.130 Packaging and labeling oper
ations. There shall be written procedures
designed to assure that correct labels,labeling. and packaging materials areused for drug products; such writtenprocedures shall be followed. Theseprocedures shall incorporate the following features:
(a) Prevention of mixups and cross-contamination by physical or spatialseparation from operations on otherdrug products.
(b) Identification of the drug product with a lot or control number thatpermits determination of the historyof the manufacture and control of thebatch.
(c) Examlnatlon of packaging and labeling materials for suitability andcorrectness before packaging oper-
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45083 ations, and documentation of such examination in the batch productionrecord.
(d) Inspection of the packaging andlabeling facilities immediately before use toassure that all drug productshave been removed from previous operations. Inspection shnll also be madeto assure that packaging and labelingmaterials not suitable for subsequentoperations have been removed. Resultsof inspection shall be documented in the batch production records.
§ 211.134 Drug product inepectlon. (a) Packaged and labeled products
shall be examined during finishing operations to provide assurance that containers and packages in the lot havethe correct label.
(b) A representative sample of units shall be collected at the completion offinishing operations and shall be visually examined for correct labeling.
(c) Results of these examinations shall be recorded in the batch production or control records. § 411.137 Expiration datlng.
(a) To assure that a drug productmeets applicable standards of identity,strength, quality, and purity at thetime of use, it shall bear an expirationdate determined by appropriate stability testing described in § 211.166.
(b) Expiration dates shall be related to any storageconditions stated on the labeling, as determined by stabilitystudies described in § 211.166.
(c) If the drug product is to be reconstituted at the time of dispensingits labeling shall bear expiration information for both the reconstituted and unreconstituted drug products.
(d) Expiration dates shall appear onlabeling in accordance with the requirements of § 201.1 ’7 of this chapter.
(e) Homeopathic drug products shallbe exempt from the requirements ofquality, and purity. Laboratory con-this section.
(f) Pending consideration of a proposed exemption, published in theFEDERAL REGISTER of September 29,1978, the requirements in this section shall not be enforced for human OTC drug products if their labeling doesnot bear dosage limitations and theyare stable for at least 3 years as supported by appropriate stability data.
Subpart H-Holding and Distr ibut ion § 211.14 W a re ho us ing procedures.
Written procedures describing thewarehousing of drug products shall beestablished and followed. They shallInclude:
(a) Quarantine of drug productsbefore release by the quality controlunit.
(b) Stornge of drug products underappropriate conditions of temperature,humidity, and light so that the identi-
RULES AND REGULATIONS
ty, strength, quality, and purity of thedrug products are not affected. § 211.150 Distributio p r o c e d u r e s .n
Written procedures shall be established, and followed, describing thedistribution of drug products. Theyshall include:
(a) A procedure whereby the oldestapproved stock of a drug product isdistributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
(b) A system by which the distribution of each lot of drug product can bereadily determined to facilitate itsrecall if necessary.
Subpart I - Laboratory Controls § 211.160 General r e q u i r e m e n t s .
(a) The establishment of any specifications, standards, sampling plans,test procedures, or other laboratorycontrol mechanisms required by thissubpart. including any ge in such specificationstandards,samplingplans, test procedures, or other laboratory control mechanisms, shall bedrafted by the appropriate organizational unit and reviewed and approvedby the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures,or other laboratory control mechanisms shall be recorded and justified.
( b ) Laboratory controls shall includethe establishment of scientificallysound and appropriate specifications,standards, sampling plans, and testprocedures designed to assure thatcomponents. drug product containers,closures, in-process materials, labeling.and drug products conform to appropriate standards of identity, strength,
trols shall include: ( 1) Determination of conformance to
appropriate written specifications forthe acceptance of each lot within eachshipment of components, drug productcontainers, closures, and labeling usedin the manufacture, processing, packing, or holdlng of drug products. Thespecifications shall include a descriptlon of the sampling and testing procedures used. Samples shall be representative and adquately identified.Such procedures shall also require appropriate retesting of any component,drug product container, or closurethat is subject to deterioration.
(2) Determination of conformance towritten specifications and a description of sampling and testing procedures for In-process materials. Suchsamples shall be representative andproperly identified.
(3) Determination of conformance towritten descriptions of sampling proce
dures and appropriate specificationsfor drug products. Such samples shallbe representative and properly identified.
(4) The calibration of instruments, apparatus, gauges, an d recording devices at suitable intervals in accordance with an established written program containing specific directions,schedules, limits for accuracy and precision, and provisions for remedialaction in the event accuracy and/orprecision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting establishedspecifications shall not be used.
§ 211.166 Teetln a n drelease for distribugtion.
(a) For each batch of drug product,there shall be appropriate laboratorydetermination of satisfactory conformance to final specifications for thedrug product, including the identltyand strength of each active ingredient,Prior to release. Where sterility and/or pyrogen testing are conducted onspecific b a t c h e s o f shortlived radiopharmaceuticals, such batches may be released r to completion ofsterility and/or pyrogen testing. provided such testing is completed as soonas possible.
(b) There shall be appropriate laboratory testing, as necessary, of eachbatch of drug product required to befree of objectionable microorganisms.
(c) Any sampling and testing plansshall be described in written procedures that shall include the method of sampling and the number of units perbatch to be tested; such written procedure shall be followed.
(d) Acceptance criteria fo sampling and testing conducted by thequality control unit shall be adequateto assure that batches of drug products meet each appro specification and appropriate statistical qualitycontrol criteria as a condition for their approval and release. The statisticalquality control criteria shall includeappropriate acceptance levels and/orappropriate rejection levels.
(e) The accurancsensitivity, specificity, a n d reproducibility o f t es t methods employed by the firm shallbe established and documented. Such validation and documentation may beaccomplishei In accordance with § 211.194(a)(2).
(f) Drug products failing to meet established standards or specificand any other relevant quality controlcriteria shall be rejected. Repromay be performeprior to acceptanceand use. reprocessed materialmeet appropriate standards, spetions, and any other rele critieria. § 211.166 Stab i li ty testing.
(a) There shall be a written tgprogram designed to asses stabil-
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2
45084 ity characteristics of drug products.The results of such stability testingshall be used in determining appropriate storage conditions and expirationdates. The written program shall befollowed and shall include:
(1) Sample size and test intervalsbased on statistical criteria for eachattribute examined to assure valid estlmates of stability;
(2) Storage conditions for samplesretained for testing;
(3) Reliable, meaningful, and specific test methods;
(4) Testing of the drug product inthe same container-closure system asthat in which the drug product is marketed;
(5) Testing of drug products for reconstitution at the time of dispensing(as directed in the labeling) as well asafter they are reconstituted.
(b) An adequate number of batchesof each drug product shall be tested todetermine an appropriate expirationdate and a record of such, data shall bemaintained. Accelerated studies, combined with basic stability informationon the components, drug products,and container-closure system. may beused to support tentative expirationdates provided full shelf life studiesare not available and are being conducted. Where data from acceleratedstudies are used to project a tentativeexpiration date that is beyond a datesupported by actual shelf life studies,there must be stability studies conducted, including drug product testingat appropriate intervals, until the tentative expiration date is verified or theappropriate expiration date determined.
(c) For homeopathic drug products.the requirements of this section are asfollows:
(1) There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicatethat there is no degradation of theproduct for the normal or expectedperiod of use.
(2) Evaluation of stability shall bebased on the same container-closure system in which the drug product isbeing marketed. § 211.167 Special testing requirements.
(a) For each batch of drug productpurporting to be sterile and/or pyrogen-free. there shall be appropriatelaboratory testing to determine conformance to such requirements. Thetest procedures shall be in writing andshall be followed.
(b) For each batch of ophthalmicointment, there shall be appropriatetesting to determine conformance tospecifications regarding the presenceof foreign particles and harsh or abra-
RULES AND REGULATIONS
sive substances. The test proceduresshall be in writing and shall be followed.
(c) For each batch of controlled-release dosage form, there shall be appropriate laboratory testing to determine conformance to the specifications for the rate of release of each active ingredient. The test proceduresshall be in writing and shall be followed.
§ 211.170 Reserve samples. (a) An appropriately identified re
serve sample representative of each lotin each shipment of each active ingredient shall be retained for at least 1year after the expiration date of thelast lot of the drug product containingthe active ingredient or, in the case ofcertain OTC drug products lacking expiration dating because they meet thecriteria for exemption under § 211.137.3 years after distribution of the lastdrug product lot containing the activeingredient. It shall consist of at leasttwice the quantity necessary for alltests required to determine whetherthe active ingredient meets its established specifications, except the quantity requirement shall not apply forsterility and pyrogen samples.
(b) A properly identified reservesample representative of each lot orbatch of drug product shall be storedunder conditions consistent with product labeling and shah be retained forat least 1 year after the expirationdate of the drug product or in the caseof certain OTC drug products lackingexpiration dating because they meetthe criteria for exemption under§211.137. 3 years after distribution ofthe lot or batch of drug product. Thesample shall be stored in the same immediate container-closure system inwhich the drug product is marketed oran immediate container-closure systemhaving essentially the same characteristics. The sample shall consist of atleast twice the quantity necessary toperform all the required tests. exceptthose for sterility and pyrogens. Suchsamples shall be at least visually examined annually for evidence of deterioration unless such examinationwould affect the integrity of the samples. The results of such examinationshall be recorded and maintained withother stability data on the drug product. Samples of compressed medicalgases need not be retained. § 211.173 Laboratory animals.
Animals used in testing components,in-process materials, or drug productsfor compliance with established specifications shall be maintained and controlled in a manner that assures theirsuitability for their intended use.They shall be identified, and adequaterecords shall be maintained showingthe history of their use.
§ 211.176 Penicillin contamination. If a reasonable possibility exists that
a non-penicillin drug product has beenexposed to cross-contamination withpenicillin, the non-penicillin drugproductr shall be tested for the preence of penicillin. Such drug productshall not be marketed if detectablelevels are found when tested accordingto procedures specified in “Proceduresfor Detecting and Measuring PenicillinContamination in Drugs.” 1
Subpart J - Records and Reports § 211.180 General requirements.
(a) Any production, control, or distribution record that is required to bemaintained in compliance with this part and is specifically associated witha batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in thecase of certain OTC drug productslacking expiration dating because theymeet the criteria for exemption under§ 211.137, 3 years after distribution ofthe batch.
(b) Records shall be maintained forall components, drug product containers, closures, and labeling for at least 1year after the expiration date or, inthe case of certain OTC drug productslacking expiration dating because theymeet the criteria for exemption under§211.137, 3 years after distribution ofthe last lot of drug product incorporating the component or using the con-tamer, closure, or labeling.
(c) All records required under thispart, or copies of such records, shall bereadily available for authorized inspection during the retention period at theestablishment where the activities described in such records occurred.These records or copies thereof shallbe subject to photocopying or othermeans of reproduction as part of suchinspection. Records that can be immediately retrieved from another location by computer or other electronicmeans shall be considered as meetingthe requirements of this paragraph.
(d) Records required under this partmay be retained either as original records or a s true copies such as photocopies, microfilm. microfiche, or otheraccurate reproductions of the originalrecords. Where reduction techniques,such as microfilming, are used, suitable reader and photocopying equipment shall be readily available.
(e) Written records required by thispart shall be maintained so that datatherein can be used for evaluating,least annually, the quality standardsof each drug product to determine theneed for changes in drug productspecifications or manufacturing or
‘Copies may be obtained from: Director.NCAA (HFD-430), Food and Drug Administration, 200 C St. SW., Washington, DC.20204.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45085 control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:
(1) A review of every batch, whetherapproved or rejected, and, where applicable, records associated with thebatch.
(2) A review of complaints, recalls,returned or salvaged drug products,and investigations conducted under§ 211.192 for each drug product.
( f ) Procedures shall be established to assure that the responsible off of the firm, if they are not personally involved in or immediately aware ofsuch actions, are notified in writing ofany investigations conducted under§§ 211.198, 211.20 or 211.208 of these regulations, any recalls, reports of inspectional observations issued by theFood and Drug Administration, or anyregulatory actions relating to goodmanufacturing practices brought bythe Food and Drug Administration. § 211.182 Equipment cleaning and use. log
A written record of major equipmentcleaning, maintenance (except routinemaintenance such a s lubrication and adjustmets&, and use shall be included in individual equipment logs thatshow the date, time, product, and lotnumber of each batch processed. Ifequipment is dedicated to manufacture of one product, then individualequipment logs are not requlred, provided that lots or batches of such product follow in numerical order andare manufactured in numerical sequence. In cases where dedicated equipment is employed, the records ofcleaning. maintenance, and use shall be part of the batch record. The persons performing and double-checkingthe cleaning and maintenance shalldate and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order. §211.184 Component, drug product con
tainer, closure, and labeling recordr. These records shall include the fol
lowing:(a) The identity and quantlty of
each shipment of each lot of components. drug product containers, closures, and labeling: the name of thesuppller; the supplier’s lot number(s)if known; the receiving code as specified in 9211.80: and the date of receipt. The name and location of theprime manufacturer, if different fromthe supplier, shall be listed if known.
(b) The result s of an test o examination performed (including those performed as requlred by §211.82(a), §211.84(d), or §211.122(a)) a n d t h e conclusions derlved therefrom.
(c) An individual inventory record ofeach component, drug product container, and closure and, for each com-
RULES AND REGULATIONS
ponent, a reconciliation of the use ofeach lot of such component. The inventory record shall contain sufficientinformation to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure.
(d) Documentation of the examination and review of labels and labelingfor conformity with established specifications in accord with §§211.122(c) and 211.130(c)
(e) The disposition of rejected components, drug product containers, closure, and labeling. §211.186 Master production and control
records. (a) To assure uniformity from batch
to batch, master production and control records for each drug product, including each batch size thereof, shallbe prepared, dated, and signed (fullsignature, handwritten) by one personand independently checked, dated, andsigned by a second person. The preparation of master production and control records shall be described in a written procedure end such writtenprocedure shall be followed.
(b) Master production and controlrecords shall include:
(1) The name and strength of theproduct and a description of thedosage form;
(2) The name and weight or measureof each active Ingredient per dosageunit or per unit of weight or measureof the drug product, and a statementof the total weight or measure of anydosage unit;
(3) A complete list of componentsdesignated by names or codes sufficiently specific to indicate any specialquality characteristic;
(4) An accurate statement of the weight or measure of each component,using the same weight system (metric,avoirdupois, or apothecary1 for each component. Reasonable variations may be permitted, however, In the amount o f components necessary forthe preparation in the dosage form,provided they are justified in themaster production and control records;
(5) A statement concerning any calculated excess of component;
(6) A statement of theoretical weightor measure at appropriate phases ofprocessing:
(7) A statement of theoretical yield,including the maximum and minimum percentages of theoretical yieldbeyond which investigation according to § 2 11.192 is required;
(8) A description of the drug productcontainers, closures, and packagingmaterials, including a specimen orcopy of each label and all other labeling signed and dated by the person orpersons responsible for approval ofsuch labeling;
(9) Complete manufacturing andcontrol instructions, sampling andtesting procedures, specifications, special notations, and precautions to befollowed. §211.188 Batch production and control
recorde. Batch production and control rec
ords shall be prepared for each batchof drug product produced and shall include complete information relating tothe productlon and control of eachbatch. These records shall include:
(a) An accurate reproduction of theappropriate master productlon or control record, checked for accuracy,dated, and signed;
(b) Documentation that each significant step in the manufacture, processing, packing, or holdlng of the batchwas accomplished, including:
(1) Dates;(2) Identlty of individual major
equipment and lines used;(3) Specific identification of each
batch of component or in-process material used;
(4) Weights and measures of components used in the course of processing;
(5) In-process and laboratory controlresults;
(6) Inspection of the packaging andlabeling area before and after use;
(7) A statement of the actual yieldand a statement of the percentage oftheoretical yield at appropriate phasesof processing;
(8) Complete labeling control records, including specimens or copies ofall labeling used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;(11) Identification of the persons
performing and directly supervising orchecking each significant step in theoperatlon;
(12) Any investigation made according to § 211.192.
(13) Results of examinations made in accordance with § 211.134. § 211.192 Production record review.
All drug product production andcontrol records, including those forpackaging and labeling, shall be reviewed and approved by the qualltycontrol unit to determine compliancewith all established, approved writtenprocedures before a batch is releasedor distributed. Any unexplained discrepancy (Including a percentage oftheoretical yleld exceeding the maximum or minimum percentages established in master productlon and control records) or the failure of a batchor any of its components to meet anyof its specifications shall be thoroughly investigated, whether or not thebatch has alrady been distributed. T h e investigation shall extend to otherbatches of the same drug product and
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45086 other drug products that may havebeen associated with the specific failure or discrepancy. A written record ofthe investigation shall be made andshall include the conclusions and followup. § 211.194 Laboratory records.
(a) Laboratory records shall includecomplete data derived from all tests necessary to assure compliance withestablished specifications and standards, including examinations andassays. as follows:
(1) A description of the sample received for testing with identificationof source (that &location from wheresample was obtained). quantity, lotnumber or other distinctive code, datesample was taken, and date samplewas received for testing.
(2) A statement of each method used in the testing of the sample. The statement shall indicate the location of data that establish that the methods used in the testing of the sample meetproper standards of accuracy and reliability as applied to the producttested. (If the method employed is inthe current revision of the United States Pharmacopeia, National Formulary, Association of Official Analytical Chemists, Book of Methods.* or inother recognized standard references,or is detailed in an approved new drugapplication and the referenced methodis not modified, a statement indicatingthe method and reference will suffice).The suitability of all testing methodsused shall be verified under actual conditions of use.
(3) A statement of the weight ormeasure of sample used for each test,where appropriate.
(4) A complete record of all data secured in the course of each test, including all graphs, charts, and spectrafrom laboratory instrumentation,properly identified to show the specific component, drug product container,closure, in-process material, or drugproduct, and lot tested.
(5) A record of all calculations performed in connection with the test. including units of measure. conversionfactors, and equivalency factors.
(6) A statement of the results of tests and how the results comparewith established standards of identity,strength, quality. and purity for thecomponent, drug product container,closure, in-process material, or drugproduct tested.
(7) The initials or signature of theperson who performs each test andthe date(s) the tests were performed.
(8) The initials or signature of asecond person showing that the original records have been reviewed for ac
‘Copies may be obtained from: Associatlon of Official Analytical Chemists, P.O.Box 540, Benjamin Franklin Statlon. Washington. DC. 20204.
RULES AND REGULATIONS
curacy, completeness. and compliancewith established standards.
(b) Complete records shall be maintained of any modification of an established method employed in testing.Such records shall include the reason for the modification and data to verifythat the modification produced resultsthat are at least as accurate and reliable for the material being’tested as the established method.
(c) Complete records shall be maintained of any testing and standardization of laboratory reference standards,reagents, and standard solutions.
(d) Complete records shall be maintained of the periodic calibration oflaboratory instruments, apparatus,gauges, and recording devices requiredby §211.160(b)(4).
(e) Complete records shall be maintained of all stability testing performed in accordance with § 211.166. § 211.196 Distribution recorde.
Distribution records shall contain the name and strength of the productand a description of the dosage form.name and address of the consignee.date and quantity shipped, and lot orcontrol number of the drug product. § 211.198 Complaint files.
(a) Written procedures describingthe handling of all written and oralcomplaints regarding a drug productshall be established and followed. Such procedures shall include provisions for review by the quality controlunit, of any complaint involving thepossible failure of a drug product tomeet any of its specifications and, forsuch drug products, a determination as to the need for an investigation inaccordance with § 211.192.
(b) A written record of each complaint shall be maintained in a file designated for drug product complaints.The file regarding such drug productcomplaints shall be maintained at theestablishment where the drug productinvolved was manufactured, processed,or packed, or such file may be maintained at another facility if the written records in such files are readilyavailable for inspection at that otherfacility. Written records involving adrug product shall be maintained untilat least 1 year after the expirationdate of the drug product, or 1 yearafter the date that the complaint wasreceived, whichever is longer. In thecase of certain OTC drug productslacking expiration dating because theymeet the criteria for exemption under$211.13’7. such written records shall be maintained for 3 years after distribution of the drug product.
(1) The written record shall includethe following information, whereknown: the name and strength of thedrug product, lot number, name of
complainant, nature of complaint, andreply to complainant.
(2) Where an investigation under § 211.192 is conducted. the written record shall include the findings ofthe investigation and followup. Therecord or copy of the record of the investigation shall be maintained at theestablishment where the investigationo c c u r r e d in accordance with § 211.180(c).
(3) Where an investigation under § 211.192 is not conducted. the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination. Subpart K-Returned and Salvaged
Drug Products § 211.204 Returned drug products.
Returned drug products shall beidentified as such and held. If the Conditions under which returned drugproducts have been held, stored, orshipped before or during their return.or if the condition of the drug product, its container, carton, or labeling.as a result of storage or shipping, casts doubt on the safety, identity, strength.quality or purity of the drug product,the returned drug product shall be destroyed unless examination, testing, orother investigations prove the drugproduct meets appropriate standardsof safety, identity, strength. quality.or purity. A drug product may be reprocessed provided the subsequentdrug product meets appropriate standards, specifications, and characteristics. Records of returned drug products shall be maintained and shall include the name and label potency ofthe drug product dosage form, lotnumber (or control number or batchnumber). reason for the return, quantity returned. date of disposition, andultimate disposition of the returneddrug product. If the reason for a drugproduct being returned implicates associated batches, an appropriate investigation shall be conducted in accordance with the requirements of§ 211.192. Procedures for the holding,testing, and reprocessing of returneddrug products shall be in writing andshall be followed.
§ 211.208 Drug product salvaging. Drug products that have been sub
jected to improper storage conditionsincluding extremes in temperature,humidity. smoke, fumes, pressure, age.or radiation due to natural disasters,fires, accidents. or eauipment failuresshall not be salvaged and returned to the marketplace. Whrncvcr there is a question whether drug products havebeen subjected to such conditions, salvaging operations may be conductedonly if there is (a) evidence from labo-
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45087RULES AND REGULATIONS
ratory tests and assays (includinganimal feeding studies where applicable) that the drug products meet allapplicable standards of identity,strength. quality, and purity and (b)evidence from inspection of the Premises that the drug products and theirassociated packaging were not subjected to improper storage conditions as aresult of the disaster or accident. Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate s tandards o f identity.strength, quality, and purity. Recordsincluding name, lot number. anddis
position shall be maintained for drugproducts subject to this section.
PART 229-CURRENT GOOD MANUFACTURING PRACTICE FOR CERTAIN OTHER DRUG PRODUCTS
§ 229.25 [Revoked]6. By revoking § 229.25 and thereby
revoking Part 229. Effective date.. This regulation shall
be effective on March 1. 1979. The expiration dating requirements underthese amendments and not previouslyin effect shall apply to drug productsmanufactured after that date.
(Secs. 501, 502, 505, 506, 507, 510. 701, 52Stat. 1049-1053 as amended, 59 Stat. 463 as amended, 76 Stat. 704 as amended (21 U.S.C.351. 352, 355. 356. 357. 360. 371); Pub. L. 02381, 86 Stat. 559-562.).
Dated: September 15, 1979. SHERWIN GARDNER,
Acting Commissioner ofFood and Drugs.
NOTE - Incorporation by reference materials approved by the Director of the Officeof the Federal Register on March 11. 1078(footnote 2) end October 21. 1077 (footnote1). Copies of referenced materials are on file at the FEDERAL REGISTER library. (FR Doc. 78-27121 Filed B-22-78; 12:43 pm)
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
45088
[4110-03] DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE
Food and Drug Administration
[21 CFR Part 21 1]
[Docket No. 78N-0140]
HUMAN AND VETERINARY DRUGS; CURRENTGOOD MANUFACTURING PRACTICE FOR DRUG PRODUCTS
Exemptions for Certain OTC Drug Products AGENCY: Food and Drug Administration. ACTION: Proposed Rule. SUMMARY: Based on comments received in response to proposed changesin current good manufacturing practice regulations for drugs, the agencyis proposing two additional provisions
(1) An exemption from re-:as follows quired expiration dating for human
drug products)(OTC over-the-counter
PROPOSED RULES
adopted after careful consideration ofextensive comments from the public,including consumers, regulated industry, and health care professionals, inresponse to a proposal published inthe FEDERAL REGISTER of February 13.1976 (41 FR 68781. In light of thosecomments, the Commissioner concluded that there was sufficient reason to reconsider whether all human OTC drug products should bear an expiration date and whether OTC drug products that are ordinarily marketed andconsumed as human foods and that may also fall within the legal definition of drugs by virtue of their intended use are more appropriately inspected under good manufacturing Practiceregulations for foods rather thanthose for drugs. To fully considerthese issues, the Commissioner has delayed implementing certain require-
CFR Part(21 1ments under Part 21 211) until comments on this proposalcan be evaluated and final regulationspublished.
In considering the desirability ofexempting any class of drugs from expiration dating, the Commiss ioneris concerned that drug products that may be unstable are routinely in themarketplace and may not be fully consumed before deterioration occurs. For example, significant stability problemshave been noted with some fluoride toothpastes. Therefore, to m i n i m i z e the possibility that human OTC drugproducts with relatively short periodsof stability are permitted to be marketed without expiration dating. the Commissioner proposes that, as a condition for exemption, the drug productmust be shown to be stable for at least 3 years. The 3-year time period is proposed on the assumption that mostdrug products of this type will be usedby consumers well within the 3-yearperiod. The Commissioner notes thatone comment to the February 13, 1976CGMP proposal stated that, based on information regarding a leading medi
that are marketed without dosagelimitations and are stable for at least 3 years; and ( 2 ) an exemption providingfor OTC drug products that are ordinarily marketed and consumed ashuman foods and that may also fallwithin the legal definition of drugs byvirtue of their intended use to be inspected under good manufacturingpractice regulations for foods ratherthan such regulations for drugs. Untilfinal regulations under this proposalare published, manufacturers maysafe and are consumed so quickly thatcontinue to market without expirationdates human OTC drug products thatmeet the proposed definitions. Similarly, until final regulations are adopted, good manufacturing practice regulations for foods will be applied toOTC drug products that are ordinarilymarketed and consumed as human foods and that may also fall withinthe legal definition of drugs by virtueof their intended use. DATE: Comments by November 28,1978. ADDRESS: Written comments to the
,-(HFAHearing Clerk 305) Food and
OTC DRUG PRODUCTS WITHOUT DOSAGE L IMITATIONS
As discussed in the preamble to thefinal regulations for Part 211. a substantial number of comments were received concerning a proposed requirement that all drug products bear anexpiration date. Many comments, particularly those from certain segmentsof the human OTC drug industry, suggested that some drug products are so
expiration dating would be unnecessary for them. Respondents suggested as examples of such human OTC drugproducts medicated shampoos andtopical lotions, creams, and ointments,fluoride toothpaste. and rubbing alcohol. Many persons objected to expiration dating for these classes of humanOTC drug products on the basis thatadding such information to immediate containers and outer retail packageswas not cost-effective in relationshipto the benefit derived by the consumer.
The Commissioner recognizes that
cated shampoo, there is a 95 percentprobability that all of a batch of thepreparation is consumed within 83weeks (1.6 years). Several other comments also suggested that a specifictime period of stability (e.g. 3 or 5years) would be appropriate for determining whether to require an expiration date for certain human OTC drugproducts.
The Commissioner is limiting theproposed exemption under § 211.137 to human OTC drug products because hebelieves that it is inappropriate forveterinary drug products. The veterinary drug industry differs significantly in nature and scope from thehuman drug industry. Many of theveterinary drug products available forOTC sale contain active ingredientsthat would cause these products tobear the prescription legend if labeledfor human use. Examples of such veterinary drug products are topical sulfonamides, nitrofurans, neomycin sulfate, oxytetracycline, hydrocortisone,
many human OTC drug products are and polymyxin B. Consumers must beDrug Administration, Room 4-65. 5600 safe and suitable for frequent and assured that these drug products areFishers Lane, Rockville, MD 20857. often prolonged use. Such products of sufficient potency to achieve theirF O R F U R T H E R I N F O R M A T I O N are marketed without dosage limita- intended therapeutic effect for animalCONTACT: tions and, typically, the contents of care.
the retail package are used in a rela- T h e Commissioner bel ieves that Clifford G. Broker ( H F D (301)3 2 3 443-5307), or Robert J. Rice, Jr.,
Bureau of.(301-443-5220))30 Drugs. Departmentcation, and Welfare, 5600 Fishers
- tively short time. He believes that,given the high market volume of these
OTC veterinary drug products thatare stable for at least 3 years and thattypes of preparations, their safety, are labeled without dosage limitationsand the speed with which they are are likely to remain in distribution
(HFD-of Health, Edu-
Lane, Rockville. MD 20857. SUPPLEMENTARY INFORMATION: Elsewhere in this issue of the FEDERAL R EGISTER . the Commissioner of Food and Drugs is issuing final regulationsfor current good manufacturing prac
for human and veteri-)(CGMP tice nary drug products. They are being
usually used, the advantages of expiration dating to the consumer may notbe worth the added cost, which is ultimately borne by the consumer. Therefore, the Commissioner considers itreasonable to propose to exempthuman OTC drug products that haveno dosage limitations from the expiration dating requirements of §211.137.
channels longer than OTC humandrug products that meet the same criteria. During this distribution period,such veterinary drug products may beexposed to adverse storage conditions,such as those encountered in some feed stores, that may affect their stability.
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978
s
PROPOSED RULES 45089
OTC DRUG PRODUCTS ORDINARILY MARKETED AND CONSUMED AS HUMAN FOODS THAT MAY ALSO FALL W ITHIN THE LEGAL DEFINITION OF DRUGS BY VIRTUE OF THEIR INTENDED USE The Commissioner has tentatively
concluded that a few products ordlnarily consumed as human foods, but alsomarketed as drugs, would be more appropriately regulated under good manufacturing practice regulations forfoods, i.e., 21 CFR Part 110 and, if appropriate, 21 CFR Parts 113 through129. Therefore, he proposes to exemptfrom Part 211. OTC drug productsthat are also human foods, If they areordinarily consumed as human foodsand if all their ingredients are ordinarily consumed as human foods. Examples of products that the Commissioner believes would be covered by theproposed exemption are (1) somecandy cough drops that are formulated entirely of ingredients ordinarilyconsumed as human foods or ingredients of human food products; and (2)sodium bicarbonate labeled for use asan antacid, but ordinarily used as an ingredient of human foods under themore common "baking soda” label.
In proposing this exemption fordrugs that are also human foods. theCommissioner has considered, first,the inadvisability of applying drugCGMP regulations that are not necessary to assure appropriate qualitycharacteristics in view of the intendeduse of a product and, second, the reasonableness of applying human foodGMP regulations to a product manu-.factured, handled, and ordinarily con-sumed as a human food.
The Commissioner has consideredthe merits of applylng an exemptionfrom Part 211 to OTC drug productsthat are also animal foods, and thatotherwise would meet the criteria forexemption. He has concluded that theCGMP's for human food are not suitable for determining compliance withcurrent good manufacturing practicefor certain types of animal food. Healso notes that no existing CGPM regulations apply to animal-feed. Therefore, the Commissioner has limited the proposed exemption from Part 211
to OTC drug products ordinarily consumed and marketed as human foodand that otherwise meet the criteriafor exemption in this FEDERAL REGISTER proposal.
The Commissioner especially invitescomments on the desirability of providing these exemptions. He also requests comment on whether theclasses of drug products proposed forexemption are adequately defined,particularly on the adequacy of atleast a 3-year period of stability. He invites manufacturers to identify products that appear likely to be exemptedunder this proposal.
The Commissioner wishes to make clear that in proposing these exemptions for these types of products, hedoes not intend that the products beexempt from other provisions of theact and regulations that are applicableto drugs or drug products.
The Commissioner has determinedthat this document does not contain an agency action covered by 21 CFR25.1(b), and consideration by theagency of the need for preparing anenvironmental impact statement is not required.
Therefore. under the Federal Food.Drug, and Cosmetic Act (secs. 501, 502.505. 506. 507, 512. 701, 52 Stat. 10491053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463 as amended, 82 Stat. 343-351 (21 U.S.C. 351.352,355, 356, 357, 360b, 371)) and under authority delegated to him (21 CFR 5.11.the Commissioner proposes to amendPart 211 as follows:
1. In §211.1 by revising paragraph(c) to read as follows: § 211.1 Scope.
� * * * * (c) OTC drug products ordinarily
marketed and consumed as humanfoods that may also fall within thelegal definition of drugs by virtue oftheir intended use: Drug products thatmeet these criteria shall be subject toPart 110 of this chapter, and whereapplicable, Parts 113 through 129 ofthis chapter, in determining whethersuch products are manufactured. Pro-
cessed, packed, or held in conformance with ‘current good manufacturingpractice.
2. In § 211.137 by revising paragraph(f) to read as follows: § 211.137 Expiration datlng.
. . � . . (f) Human OTC drug products are
exempt from the requirements of thissection if their labeling does not beardosage limitation and they are stablefor at least 3 years, as supported byappropriate stability data.
Interested persons may, on or beforeNovember 28. 1978, submit to theHearing Clerk (HFA-305), Food andDrug Administration. Rm. 4-65, 5600Fishers Lane, Rockville, Md. 20857,written comments regarding this Proposal. Four copies of all commentsshall be submitted, except that individuals m a y submit single copies ofcomments, and shall be identified withthe Hearing Clerk docket numberfound in brackets in the heading ofthis document. Received commentsmay be seen in the above office between the hours of 9 a.m. and 4 P.m.,Monday through Friday.
In accordance with Executive Order12044, the economic effects of thisproposal have been carefully analyzed,and it has been determlned that theproposed rulemaking does not involvemajor economic consequences as defined by that order. Assessment of theeconomic impact has been made inconjunction with the economic impactassessment of the final regulations forcurrent good manufacturing practicefor human and veterinary drugs(Docket No. 75N-0339) appearing elsewhere in this issue of the FEDERAL REGISTER . A copy of the economicimpact assessment is on file with theHearing Clerk, Food and Drug Administration.
Dated: September 15. 1978. S H E R WI N G A R D N E R,Acting Commissioner
of Food and Drugs. (FR Doc. 78-27122 Filed 9-22-78: 12:43 p m ]
FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978