in

45014

[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).

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

45018 RULES AND REGULATIONS

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

45019

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

FEDERAL REGISTER, VOL 43, NO.190-FRIDAY, SEPTEMBER 29, 1978

to

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

1978

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

e

l

.

d

d

. s

”

s .

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-

RULES AND REGULATIONS

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

(the

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.

RULES AND REGULATIONS

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

s

)

:

r

,

:

)

.

.

l

l

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,

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

45031

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,

. FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

in

r

l

)

8

45032 the definition for “batch” is expandedto include materials other than drugs.

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.

RULES AND REGULATIONS

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

RULES AND REGULATIONS

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

FEDERAL REGISTER, VOL 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

_

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

.FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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,

,FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

main-

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

r .

,

,

d

RULES AND REGULATIONS

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

.

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

:

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL 43, NO. 190 - FRIDAY SEPTEMBER 29, 1978

.

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

45058

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

”

”

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

e

s

n

) s

d

s

e

s y

m

e

e

lt

ll egi sl at iv e e

)

.

y n

d

)

g

) e

e

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,

45067

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

45069

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.

1978 ,FRIDAY SEPTEMBER 29 .FEDERAL REGISTER, VOL. 43, NO 190 ­

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

y

1

1

)

1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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

D

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

, g

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

)

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

45080

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

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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.

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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-

FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978

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