Title 21--Food and Drugs CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE SUBCHAPTER C--DRUGS: GENERAL [Docket No. 75N-0339] HUMAN AND VETERINARY DRUGS Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding AGENCY: Food and Drug Administration. ACTION: Final rule. SUMMARY: This document amends the FDA regulations that set forth current good manufacturing practice (CGMP) for human and veterinary drug products. The amendments update present regulations in light of current technology for drug manufacturing and delineate requirements more specifically than do the present regulations. Although some of the provisions in these amendments represent requirements not specifically included in the existing CGMP regulations, in many instances the revisions are practices that have been considered implicit in the regulations or are at least considered by most manufacturers to be desirable requirements for their own operations. Under the Federal Food, Drug, and Cosmetic Act, a drug is deemed to be adulterated unless the methods used in its manufacture, processing, packing, and holding, and the facilities and controls used therefor, conform to current good manufacturing practice so that the drug meets the safety requirements of the act and has the identity and strength and meets the quality and purity characteristics that it is represented to have. The regulations are being updated and made more explicit, and therefore less subject to varying interpretations, to assure that all members of the drug industry are made aware of the level of performance expected of them to be in compliance with the act. EFFECTIVE DATE: March 28, 1979. FOR FURTHER INFORMATION CONTACT: Clifford G. Broker (HFD-323) (301-443-5307), or Robert J. Rice, Jr., (HFD- 30) (301-443-5220), Bureau of Drugs, Food and Drug Administration, Department of Health, Education, and Welfare, 5600 Fishers Lane, Rockville, Md. 20857. SUPPLEMENTARY INFORMATION: In the FEDERAL REGISTER of February 13, 1976 (41 FR 6878), the Commissioner of Food and Drugs proposed to revise the CGMP regulations, Parts 210 and 211 (21 CFR Parts 210 and 211), issued under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)), to update them in light of current technology and to adopt more specific requirements to assure the quality of finished drug products. Because of the nature and extent of the proposed revisions, the Commissioner allowed until June 14, 1976, for interested persons to submit comments. The Commissioner received comments from 168 respondents totaling approximately 2,000 pages. These comments represent many interests--individual consumers; nonprofit institutions or associations; health-care departments of hospitals, colleges, and universities; State and foreign health-care organizations; domestic and foreign drug manufacturers, repackers, and distributors; consultants to the drug industry; drug equipment manufacturers; and numerous trade and professional associations representing manufacturers, repackers, distributors, consulting engineers, and professionals in the health- care system. In general, the comments supported the Commissioner's concern for the availability of uniformly high quality drug products. Consumers, in particular, expressed strong support for the proposed revisions, especially the provisions for expiration dating of pharmaceuticals. A majority of drug manufacturers agreed with many of the proposed revisions, but objected to others. A few manufacturers objected to most of the proposal. The Commissioner is pleased to note that where differences existed, many interested persons furnished alternative wording and justification in support of such alternatives. The Commissioner has carefully considered every comment and all suggested alternatives. The final regulation, set forth below, adopts a number of the recommendations submitted. Certain other recommendations, not adopted at this time, may be considered in any future proposed revisions. During the past several years, the FDA has issued a number of FEDERAL REGISTER documents relating to CGMP regulations, specifically Parts 210 and 211. The following summary will help clarify the status of these various documents. 1. A proposal on returned and salvaged drug products appeared in the FEDERAL REGISTER of January 16, 1975 (40 FR 2822) and was reproposed as 211.208 (21 CFR 211.208) in the FEDERAL REGISTER of February 13, 1976 (41 FR 6870). Comments on both proposals were reviewed and considered in preparing the final regulations set forth in Part 211 below. 2. A proposal on CGMP regulations for human and veterinary drugs appeared in the FEDERAL REGISTER of February 13, 1976 (41 FR 6878). That proposal is the basis for the subject final regulations and included proposed revisions in 201.17, 207.3, 207.20, and Parts 210 and 211, and revocation of 229.25. 3. A final regulation in the FEDERAL REGISTER of April 23, 1976 (41 FR 16932) amended Part 211 (CGMP regulations) by eliminating reference to glass- fiber filters. It, therefore, eliminated the need for further comments on the February 13, 1976, proposal regarding such filters because all references to glass fiber-containing filters would be deleted from the final regulation. 4. A proposal on CGMP regulations for large volume parenteral drug products (LVP) for human use was published in the FEDERAL REGISTER of June 1, 1976 (41 FR 22202). The proposal would add a new Part 212. Comments were due by September 29, 1976 and are under review. 5. A request for comments and information regarding small volume parenteral drug products (SVP) was published in the FEDERAL REGISTER of June 1, 1976(41 FR 22219), and the time for submitting comments was extended to October 29, 1976 by notice in the FEDERAL REGISTER of September 10, 1976 (41 FR 38540). Comments are being reviewed, and a specific proposal may be published in the future. The comments and recommendations regarding the January 16, 1975 and February 13, 1976 proposals, the April 23, 1976 amendment to the latter proposal, and the Commissioner's conclusions concerning them are set out below. TABLE OF CONTENTS FOR PREAMBLE I. General Comments (paragraphs 1 to 12). II. Terminology and Language in these Regulations (paragraphs 13 to 18). III. Amendments Regarding Placement of Expiration Date on Drug Product Labels (paragraphs 19 to 27). IV. Amendments Regarding Drug Listing and Establishment Registration Requirements for Drug Product Salvaging Operations (paragraphs 28 to 32). V. Legal Status of CGMP Regulations (paragraphs 33 to 41). VI. Applicability of CGMP Regulations; Exemptions (paragraphs 42 to 49). VII. Definitions (paragraphs 50 to 88). VIII. Organization and Personnel (paragraphs 89 to 126). IX. Buildings and Facilities (paragraphs 127 to 164). X. Equipment (paragraphs 165 to 198). XI. Control of Components and Drug Product Containers and Closures (paragraphs 199 to 262). XII. Production and Process Controls (paragraphs 263 to 310). XIII. Packaging and Labeling Control (paragraphs 311 to 373). XIV. Holding and Distribution (paragraphs 374 to 379). XV. Laboratory Controls (paragraphs 380 to 422). XVI. Records and Reports (paragraphs 423 to 500). XVII. Returned and Salvaged Drug Products (paragraphs 501 to 517). XVIII. CGMP for Certain Other Drug Products (paragraph 518). I. GENERAL COMMENTS 1. Many comments were received regarding the need for the proposed changes in the CGMP regulations. A number of comments from individual consumers, a State consumer services organization, and a national association of health-care professionals strongly favored new or revised regulations that would improve the level of assurance that marketed drug products meet high quality standards. Many other comments, particularly from manufacturers and trade associations, generally supported the desirability of CGMP regulations, but objected to specific provisions of the proposal and questioned whether a favorable cost- benefit ratio justified implementing some of the proposed provisions. But some manufacturers, particularly smaller firms, objected to the proposed changes, maintaining that drug quality would not be improved by the proposed changes and that the costs outweigh any benefits. The need and rationale for an overall revision and for specific changes in the CGMP regulations are discussed at length in the preamble to the February 13, 1976 proposal. Briefly summarizing this discussion, the technological advances and the general upgrading of drug quality assurance by most manufacturers since the CGMP regulations were promulgated in 1963 and last updated in 1971 mean that the "current good manufacturing practice" reflected in the existing regulations are no longer "current" in many respects and are not suited to current manufacturing techniques. In addition, many requirements prompted questions about interpretation, vagueness, and omissions. The proposal was intended to solve many of these problems. Interested persons were urged to review the proposal carefully, to identify any areas that might require clarification or modification, and to submit reasoned comments with suggested alternative language. The period provided for public comment was 120 days instead of the usual 60 days because of the length of the proposal; the novel, controversial, or complex nature of some of the proposed provisions; and the desire to give affected persons ample time for review and preparation of extensive comments. Having reviewed the preamble of the February 13, 1976, proposal and the extensive comments, the Commissioner is satisfied that an updating of the CGMP regulations is necessary and desirable. Therefore, most of the February 13, 1976, proposal has been adopted, but with numerous textual changes, many of which are based upon alternative language suggested in the comments. In evaluating each comment, the Commissioner considered whether drug product quality would be assured, compromised, or unaffected by the adoption or deletion of a regulation, as well as whether it reflected a current practice in the industry and its benefits appeared to outweigh its costs. The Commissioner is promulgating those regulations embodying contemporary practices that will maintain or improve the quality of pharmaceuticals without imposing unreasonable or excessive costs or other burdens on manufacturers. Modifications were adopted, or decisions were made not to finalize particular aspects of the proposal, in order to add flexibility for manufacturers, to relieve or eliminate unjustified cost burdens, or to clarify the requirements, without adversely affecting the best interests of the consumer. The agency has completed a detailed cost analysis based on information submitted by interested persons who commented on the economic impact assessment of the proposal. This issue is discussed in a revised economic impact assessment available at the office of the Hearing Clerk, Food and Drug Administration. For the reasons set forth in the agency's economic impact assessment, it is believed that this final regulation will not cause major economic impact, as defined by Executive Order 11821 (as amended by Executive Order 11949), and OMB Circular A-107. 2. A number of comments said the proposed CGMP regulations would impose rigid and inflexible standards that would curtail progress and discourage technological innovations. Others said the proposed regulations were so detailed that sound judgment by the manufacturers and by inspecting FDA investigators could not be used. The Commissioner is keenly aware that the general CGMP regulations must apply to a wide variety of drug products. Therefore, the CGMP regulations in Part 211 are intended to be general enough to be suitable for essentially all drug products, flexible enough to allow the use of sound judgment and permit innovation, and explicit enough to provide a clear understanding of what is required. The agency has received numerous inquiries requesting clarification of certain provisions, and it sought to remove ambiguities by this revision. In finalizing these revisions, the Commissioner has considered past experience, the purposes of the CGMP regulations, the need to balance specificity and clarity with flexibility in attaining these purposes, and the comments received in response to the proposal. A number of changes have been made in these final regulations to reflect the broad applicability of, to allow flexibility in, and to encourage innovation within the CGMP regulations. The agency does intend to issue more specific CGMP regulations for unique classes of products as one means of clarifying these regulations. The Commissioner welcomes suggestions and petitions from interested persons who find deficiencies, excessive burdens, or inflexibility in these regulations and who identify innovative and more efficient ways to achieve the goals of these regulations. 3. A number of comments addressed the so-called "how to" versus the "what" argument; that is, the proposed CGMP regulations describe "how" a particular requirement should be achieved rather than specifying "what" it is that is to be achieved. Many comments recommended that the regulations establish only objectives or specifications and allow each manufacturer to determine the best method of attaining the objective or meeting the specification. For example, one comment proposed that FDA require positive identification of a person rather than specifying that a signature be used--this would allow use of other means of identifying a person, such as an identifying number or initials. The Commissioner believes that, with relatively few exceptions, the CGMP regulations do describe "what" is to be accomplished and provide great latitude in "how" the requirement is achieved. For example, written records and procedures are required, but FDA will recognize as satisfactory any reasonable format that achieves the desired results. Because of the need for uniformity in certain areas of the CGMP regulations that have presented problems in the past, however, there are some instances where it is desirable to specify the manner in which requirements are to be accomplished. In promulgating these regulations, the Commissioner carefully reconsidered the need for such specificity where it appears and adopted only those specific requirements that are fully justified. 4. One comment, filed by an FDA employee, recommended that self-inspection and performance auditing programs within the industry be a requirement under the CGMP regulations to assure the reliability of drug products and to prevent release of defective products. The Commissioner finds that the concept of self-inspection and performance auditing has considerable merit. The pharmaceutical industry has made great efforts to develop self-evaluation programs, frequently using a team of inspectors composed, at least in part, of people from outside the area or firm being audited. The scope, elements, and intensity of such programs, however, vary from elaborate detailed audits to rather superficial inspections conducted perhaps once a year. The agency has considered such programs in the past, but has concluded that the essential elements of a beneficial program have not yet been sufficiently defined or tested. Moreover, because of the significant impact that a requirement for self-inspection would have on the industry and because only one comment regarding self-inspection was received, the Commissioner concludes that further public discussion is desirable before a specific proposal or regulation is issued. 5. One comment suggested that a product defect surveillance and reporting system requirement similar to the system developed and operated by the Unites States Pharmacopeia (U.S.P.) be a part of the CGMP regulations. The suggestion would require full participation by manufactures, rather than voluntary participation, in a system of identifying defective products, removing them from the market, and investigating the cause of the defect. The Commissioner notes that the Drug Product Defect Reporting System maintained by U.S.P. is designed to identify drug product complaints from various sources other than the manufacturer, such as pharmacies and hospitals, and to facilitate transmission of this information to the manufacturer and to FDA. The value of such a reporting system is in its broad source of information. The CGMP regulations in part 211, however, apply only to manufacturers of drug products. Section 211.198 (21 CFR 211.198) addresses the handling of reports to the manufacturer about drug product defects and requires that manufacturers investigate complaints that may have a bearing on drug product quality. Such information is subject to review by FDA. 6. Comments regarding the effect of these regulations on employee motivation were received from several interested persons. While generally approving the technical aspects of the proposal, these comments expressed concern that employee morale may be stifled because of the "close supervision" or "independent verification" of their work mandated by some of the proposed requirements. The comments also expressed concern about the availability of qualified personnel in the health-care system and the ability of the industry to attract such qualified persons for relatively unimaginative duties. They suggested that the use of a different instrument in the checking procedure would, in some instances, offer a better chance of detecting an error than would a system that relies upon independent verifications by different persons using the same instrument. The Commissioner recognizes that employee interests and motivation play a major role in assuring drug product quality, as described in the preamble discussion for the proposed 211.25, relating to employee training, for example. Good employee morale and work motivation are highly desirable in any work situation. Because of potential employee resentment of an intensive "check system," the Commissioner has considered alternatives and the consequences of no independent verification. The requirement for verification applies to functions that involve human judgment and consequently are susceptible to human error. The results of such errors, if undetected and uncorrected, can include, for example, improper formulations and improper release of drug products because of incorrect laboratory calculations. Independent verification is generally considered a "current" practice, not only in the drug industry but elsewhere, as a way to reduce the risk of human error. The intent of such a check is to verify that the procedure or work was performed. It is a necessary function in the manufacture of drug products and is already required in the existing CGMP regulations. The Commissioner believes that, while employees may not always welcome independent verification, most accept it as a condition of their particular assignments. Given the possible serious consequences of errors, the "check system" requirement does not seem to be an unjustified burden and, if properly explained, should not be perceived by employees negatively. The use of separate instruments, where practicable, as an adjunct to independent verification by a second person, is a procedure that has merit. The Commissioner encourages the use of such a procedure, but has concluded that a separate instrument for independent measurements would be a costly and unnecessary requirement in the CGMP regulations. These regulations separately mandate an equipment calibration and maintenance program to assure proper performance and safeguard equipment accuracy. 7. Several comments indicated a general interest in bioavailability and bioequivalence requirements for drug products. Because of the importance of bioavailability and bioequivalence to safe and effective use of drug products, these comments encouraged FDA to issue regulations establishing necessary requirements to assure this type of product quality as soon as possible. The Commissioner advises that bioavailability and bioequivalence requirements for drug products were addressed in separate proposals published in the FEDERAL REGISTER of June 20, 1975 (40 FR 26157 and 26164) and made final in the FEDERAL REGISTER of January 7, 1977 (42 FR 1624). 8. Several comments were received regarding written procedures to describe specific manufacturing and control operations. In general the comments agreed that written procedures were suitable in many instances, but were not required for every operation involved in the production and control of drug products. Specific examples were cited as requiring excessive and unnecessary written procedures. The most common example cited was 211.67(b), which proposed, in part, that there be written procedures assigning responsibility for cleaning and maintenance and describing in detail the maintenance and cleaning schedules, the methods, equipment, and materials to be used, and the methods of disassembling and reassembling all equipment used in the manufacture, processing, packing, or holding of a drug product. The objection to the requirement of this instance appears to be in reference to "all" equipment. The requirement for written procedures is intended to provide additional assurance of effective communication of appropriate information from firm management to line personnel and of regular performance of a firm's established programs and procedures. It is not enough that employees "know their jobs." Key personnel may be absent without warning; personnel substitutions involving less experienced employees may be necessary; and new or revised instructions to employees must be adequately conveyed to those who need to know. These situations are not usual, but may occur frequently. The most appropriate method for reliably relating policies and procedures to those who must know them is to have them set down in writing, readily available, and presented in a manner easily understood. The Commissioner does not believe this is a burdensome requirement. The regulations do not require that a separate procedure be written for each and every individual piece of equipment. Thus, for example, similar pieces of equipment that would have the same cleaning schedule could be considered together for convenience and would be in compliance with requirements of 211.67(b). 9. One comment suggested that written procedures are changed frequently and the regulations make no provisions for dating the written procedures and retaining outdated written procedures. The comment pointed out that the outdated procedures may be of some value in following up problems that may have occurred during the period that the written procedures were in effect. The Commissioner has carefully considered the merits of this suggestion and concludes that specific provisions for the dating and retention for all written procedures are not needed at this time. The regulations already contain this type of requirement for certain records such as master and batch production control records. For other procedures, it is preferable for each manufacturer to develop his scheme for dating, replacing, and retaining written procedures. 10. One comment recommended that FDA provide a complete set of correct model forms for use by individual firms in their own recordkeeping. The comment suggested that the model forms could be a part of the CGMP regulations, or FDA could furnish such information separately. The Commissioner does not find sufficient need at this time to warrant development of such model forms. The CGMP regulations, as amended, provide sufficient detail for manufacturers to understand readily what is required for compliance with these regulations. Because of the broad nature of the regulations and the wide variety of manufacturers subject to the CGMP regulations, the Commissioner is not convinced that model forms would be so adaptable as to be useful for a majority of firms. If, however, future experience with these CGMP regulations indicates that model forms issued as guidelines would be helpful, the Commissioner will reconsider the matter. 11. A respondent suggested promulgating the regulations under section 701(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 371(e)) to give opportunities for hearings on, and judicial review of, these regulations before they take final effect. The authority to promulgate the regulations for the enforcement of the current good manufacturing practice provisions of the act rests specifically in section 701(a) of the act. As noted in paragraph 35, Congress voted in 1962 not to require that CGMP regulations be issued under the procedures set forth in section 701(e) of the act. The Commissioner could elect to follow a procedure similar to that in section 701(e) of the act and hold a legislative type of hearing on specific aspects of this proposal under 21 CFR Part 15. After an extensive review of the numerous comments, however, he has decided that there are no particular portions of this regulation which need a further presentation of information or arguments. Any interested person may submit a petition under 21 CFR 10.30 to the Commissioner requesting such a hearing and should identify with specificity and supporting explanations the issues that might be heard. No such petition will, however, automatically delay the effective date of these regulations, as would be the situation under section 701(e) of the act; the Commissioner will grant a delay only if clearly justified. 12. In reference to the proposed requirement in 211.184(a), that the prime manufacturer, if known, be listed, one comment recommended that the CGMP regulations require that the name and lot number of the original manufacturer of the final drug product be part of the labeling. The Commissioner recognizes that a number of interested persons have, at various times, recommended that the labeling of drugs (whether bulk or in dosage form) bear the name of the manufacturer in addition to the distributor or repacker or relabeler. Changes such as this, however, would have such broad effect and would be likely to generate such enormous public and industry interest that the Commissioner does not believe that these final regulations are the proper place to consider them. Moreover, there are questions concerning the legality of such a requirement being adopted under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B)). Therefore, the Commissioner declines to act on this comment at this time. II. TERMINOLOGY AND LANGUAGE IN THESE REGULATIONS 13. Numerous comments were received suggesting changes in language, grammar, terminology, punctuation, sentence structure, and other editorial changes to clarify or improve upon the requirements as stated in the regulations or to eliminate redundancies or inconsistencies. Those proposals that raised significant policy questions, suggested changes in the substance of the regulation, or otherwise required, in the Commissioner's opinion, a specific response, are discussed individually below. Many of the suggested changes, however, were more editorial and stylistic and do not warrant a detailed discussion that would double the length of this preamble. The Commissioner reviewed each of these numerous editorial and language changes to determine whether it offered an improvement in clarity or definition, eliminated an obvious error or redundancy, promoted consistency with other portions of the regulations, or otherwise identified textual problems that were not previously noted by FDA. Where the proposed alternative language or other changes suggested by them were superior to the proposal, they were adopted in substance or verbatim. Where they did not offer any improvement, the Commissioner declined to accept them. 14. One comment recommended consistent usage of the words "drug," "drug product," "phase," "step," and "stage." The comment suggested that confusion can result from using "drug" and "drug product" interchangeably because, in the technical literature, the term "drug" usually refers to the bulk drug and the term "drug product" to the finished dosage form. The comment also pointed out that the words "phase," "step," and "stage" are used interchangeably and may, in fact, describe different aspects of a production operation. The Commissioner finds that Parts 210 and 211, as amended by this order, use "drug" and "drug product" consistently with the definitions in section 201(g) of the act and 210.3(b)(4) of the regulations (21 CFR 210.3(b)(4)); that is, "drug products" refers to only finished dosage forms, while "drug" includes both bulk drugs and drug products. With regard to the words "phase," "step," and "stage," he finds that it is unnecessary to describe various aspects of a production operation by using different words that can have essentially the same meaning in common usage. Therefore, for clarification, the CGMP regulations are revised to use the word "phase" consistently when describing certain aspects of the manufacturing operations. 15. A number of comments concerned use of the phrase "to prevent" throughout the proposed CGMP regulations. The phrase appears in these regulations to indicate that a required procedure must be accomplished, or accomplished in a manner, to preclude a resultant deleterious effect, e.g., "containers shall be opened, sampled, and resealed in a manner to prevent contamination." In several instances, the comments objected to the phrase as being "too absolute," stating that the regulations should allow for variation from the desired objective on occasion because no firm should be expected to prevent undesirable occurrences 100 percent of the time. The phrase "designed to prevent" was suggested as an alternative. A number of comments objected to the phrase "to prevent" when used in conjunction with written procedures on the basis that written procedures in themselves do not prevent anything; they must be implemented to accomplish the desired objective. The phrase "designed to prevent" was again suggested as an alternative phrase. The Commissioner believes that it is not acceptable to allow deviations from practices that could result in adverse effects upon the quality of the drug product, even on occasion. The Commissioner, however, does agree with the comments' contention that written procedures must be implemented to prevent anything and has adopted the phrase "designed to prevent" in the applicable portions of the final regulations. 16. Several comments objected to the use of terminology such as "adequate," "appropriate," "significant," "major" equipment and "long" periods. The objection is that these terms lack the specificity needed and will result in confusion to the manufacturer. The Commissioner has carefully considered the use of these words and other words and phrases that imply absolute requirements in judgmental matters. Except for the changes noted in responding to the comments by specific sections, he concludes that the terminology is appropriate as set forth in the regulations. Words such as "adequate" and "appropriate" do permit reasonable, albeit variable, interpretation by reasonable people, but are necessary and desirable for regulations to have both broad applicability and flexibility. An overwhelming majority of those commenting on the proposal were greatly concerned that the regulations accommodate the wide variability of manufacturing and control systems. In fact, a number of comments recommended additional use of modifying words such as "appropriate" and "adequate" to carry a sense of flexibility in the CGMP regulations. 17. Several comments objected to the use of the word "current" in the title and text of the regulations. Other comments indicated that some of the proposed requirements, such as separation of penicillin operations in the production of veterinary drug products and the proposed statistical testing requirements, are not "current" good manufacturing practice for the industry. Another comment requested that the term "current" be defined. One comment recommended that the word "current" be deleted since it is obvious that the latest regulations to be published are current, and therefore the use of the word "current" is superfluous. Several of these comments reflect, the Commissioner believes, a misunderstanding regarding the use of the word "current." The act itself, in section 501(a)(2)(B), specifies that a drug is deemed adulterated if the methods used in, or the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with "current" good manufacturing practice to assure that such drug meets the requirements of the act as to safety and has the identity and strength, and meets the quality and purity characteristics which it purports or is represented to possess. The Congress intended that the phrase itself have a unique meaning and that the good manufacturing practice regulations represent sound current methods, facilities, and controls for the production of drugs to assure safety, identity, strength, quality, and purity of the product. The agency determines what constitutes "current good manufacturing practice" based upon its experience with the manufacture of drugs through inspectional and compliance activities; upon knowledge gained from reviewing new drug applications, antibiotic forms, biological product and establishment licenses, and other submissions to FDA; and upon consideration of comments from interested persons received in response to proposals to amend CGMP regulations. Although the practices must be "current" in the industry, they need not be widely prevalent. Congress did not require that a majority or any other percentage of manufacturers already be following the proposed mandated practices, as long as it was a current good manufacturing practice in the industry, i.e., that it had been shown to be both feasible and valuable in assuring drug quality. The accumulated knowledge and experience of FDA in the area of current good manufacturing practice is reflected in a body of information, which with the exception of trade secrets and information relating to pending enforcement actions has long been available to the public. This body of information, which is the basis for agency expertise with respect to current good manufacturing practice, is so voluminous that formal inclusion into the administrative record of this proceeding is not practical. Nevertheless, the Commissioner relies on this body of information in promulgating this regulation. The following list describes the information coming to FDA since active preparation of the proposal to revise the CGMP regulations began (in late 1974): (1) FDA investigators conducted approximately 20,000 inspections of establishments in which drugs for human use are processed, and another 6,000 inspections of veterinary drug establishments. After each inspection, an FDA investigator filed an establishment inspection report with the agency. With rare exceptions (for cases subject to active law enforcement investigation), these reports are promptly available as public information under FDA's Freedom of Information regulations (21 CFR Part 20). (2) FDA received approximately 1,000 full new drug applications (including original submissions, resubmissions, and amendments), 1,500 abbreviated new drug applications, and 6,900 new animal drug applications. Each application contains information pertaining to the manufacturing processes to be used in producing the drug subject to the application. In addition, about 10,000 supplements to approved applications, many relating to manufacturing processes, were submitted. FDA must review and approve these processes before an application may be approved. The contents of approved new drug applications, except those portions that constitute trade secrets, are available for public inspection. (21 CFR 314.14, 431.71, 514.11, and 601.51.) (3) FDA monitored more than 1,200 recalls of drugs for human use and 275 recalls of veterinary products. In each recall resulting from a product defect, FDA investigates to determine the manufacturing control problems that led to the defect. These investigations, generally embodied in establishment inspection reports, are also publicly available upon completion of regulatory activities. (4) FDA brought over 500 legal proceedings--criminal proceedings, seizures, and injunctions--involving drugs for human use and veterinary products. Again, in those proceedings arising from product defects, a full investigation has been conducted to support the agency's case. In addition to the establishment inspection reports, testimony, documented evidence, and court papers are publicly available. Furthermore, FDA representatives have participated in numerous activities-- meetings, seminars, and workshops (regarding CGMP's, industry practices, and agency policies)--with organizations such as Parenteral Drug Association, the Proprietary Association, the National Association of Pharmaceutical Manufacturers, Pharmaceutical Manufacturers Association, the Packaging Institute, University of Wisconsin Industrial Pharmacy Management Conference, and the American Society for Quality Control. These activities further contribute to the knowledge and experience of FDA. Many of the organizations sponsoring these activities publish publicly available proceedings of these meetings, e.g., Journal of the Parenteral Drug Association and Proprietary Association Manufacturing Controls Seminar Presentations. For additional information summarizing FDA's activities for the past several years, see 1975-1977 Annual Reports and fiscal year 1979 Justification of Appropriation Estimates for Committee on Appropriations. (Copies have been placed on file with the office of the Hearing Clerk, FDA.) 18. Several comments asserted that CGMP regulations must reflect the "current" practices of manufacturers of a particular type of drugs. Others objected to the absence of findings specifically supporting the conclusion that a particular practice was a "current" practice of the manufacturers of a particular type of drug product. Among the drug products cited as the appropriate measure for current good manufacturing practice were veterinary drugs, medical gases, radio-pharmaceuticals, and cosmetic-type drug products. The Commissioner recognizes that different types of drug products may require specialized manufacturing and control procedures or may not be appropriate to the application of certain procedures that are otherwise generally applicable to drug products. For this reason, he has announced his intention to issue specialized current good manufacturing practice regulations for particular types of drug products and, in fact, has already issued one such proposal regarding large volume parenteral drug products. The regulations set forth in Part 211 (21 CFR Part 211) are designed to be applicable to all drug products in finished dosage form. They are based on practices widely used throughout the industry for manufacture of many finished drug products. The Commissioner rejects the idea that FDA must establish that each CGMP requirement is a current practice of the manufacturers in each subset of drug products covered by the general requirements of Part 211. As noted elsewhere in this preamble, the Commissioner has evaluated whether this requirement is appropriate for particular types of drug products in response to specific comments. Where he has found it to be inappropriate, he has exempted the products from the requirement; otherwise the Commissioner has concluded that all manufacturers of finished drug products should be subject to the requirements of Part 211. The Commissioner believes this is the only feasible way to approach such general current good manufacturing practice regulations. There is no consensus on the various subgroups of finished drug products, and therefore a requirement that the currency of practice must be documented for each subgroup would ultimately amount to establishing that it was a current practice by each manufacturer of each drug product, a burden which would be impossible to establish and unnecessary for purposes of regulation. Therefore, the Commissioner rejects these comments. III. AMENDMENTS REGARDING PLACEMENT OF EXPIRATION DATE ON DRUG PRODUCT LABELS 19. A substantial number of comments objected to the proposed requirement in 201.17 that the expiration date appear on the shipping carton. The majority objected on the grounds that it is common practice for shipping containers to contain different drug products or similar drug products with different expiration dates. Some persons recommended that the expiration date be required on the shipping carton only when the carton is for one drug product. The Commissioner recognizes that there are valid reasons for comingling various drug products, or different lots of the same drug product, within a single shipping carton. In such instances it may not always be practical for each different expiration date to appear on the shipping carton. Because of significant differences in the use and labeling of shipping cartons, the Commissioner concludes that a requirement for the expiration date to appear on the shipping carton when such shipping carton is not the immediate container should not be a part of the regulations at this time, and this requirement is deleted from 201.17. Manufacturers are encouraged, however, to provide appropriate information to the extent possible on all shipping cartons to facilitate handling, reduce the possibility of mixups, and allow easy identification of lots that are being recalled or withdrawn from the marketplace. 20. Several comments were received regarding expiration dating of shipping cartons containing radio-pharmaceuticals. Generally, the comments were that such drugs usually have several separate component parts each with a different expiration date. One comment requested an exemption from the entire section, while another comment asked for an exemption for the shipping carton. The Commissioner believes that 201.17, as revised, will accommodate the special problems encountered in the handling of radiopharmaceuticals. 21. Several comments suggested that the heading of this section be revised by changing the title word from "drugs" to "drug product" to conform to the drug product definition in 210.3(b)(4). The Commissioner finds that the word "drugs" in the heading of 201.17 is more consistent with the terminology used in Part 201. The term "drug product," as defined in 210.3(b)(4), is intended specifically for use in Part 211 to convey a meaning more limited than the general term "drug" as defined in section 201(g) of the act. However, to clarify that 201.17 applies to drug products under Parts 210 and 211, the final regulation in 201.17 is revised to refer to both drugs and drug products. 22. A number of comments recommended that the expiration date not be required on outer retail package labeling, such as display cartons, if the expiration date appearing on the immediate container is visible. The Commissioner agrees that it was his intention to require that the expiration date be visible under usual and customary conditions of packaging. He notes that section 201(k) of the act provides for label information that is easily legible through the outside container or wrapper. Section 201.17 is revised to allow such alternative placement of the expiration date. 23. One comment said the proposed section does not clearly cover a situation where the producer does not package the material in a retail package, but markets drug products in bulk containers. Although the Commissioner believes that the situation described is covered by the proposed regulations, the final regulation as rewritten clearly specifies that when the expiration date of a drug, including drug products, is required, it shall appear on the immediate container. There is no exemption for drug products in bulk containers. 24. One comment recommended that 201.17 specifically exclude "wrappers" for individual tablets, lozenges, and suppositories from the requirement of bearing an expiration date. The Commissioner finds that it is generally understood that protective wrappers for individual dosage forms that are further packaged in immediate containers are not required to bear an expiration date. Because only one comment about protective wrappers was received requesting a statement in the regulations and no information was submitted that the issue raised has actually been a problem, the Commissioner concludes that further clarification of this section is not now warranted. 25. Several comments asked about the acceptability of placing the expiration date on the crimp of the drug product tube. Because of the wide variety of available methods and techniques of applying and presenting expiration dating information on the immediate container, the Commissioner has not attempted to specifically evaluate and list individual methods. In general, he finds that the expiration date should be readily seen under usual and customary circumstances. The tube crimp has been used for placing the lot or control number (as provided for under 201.100(b)(6)) and for placing the expiration date for some products. No known problems have been associated with such information appearing on the crimp of the dispensing tube and, therefore, this method is an acceptable way to comply with 201.17. 26. Several comments objected to the provisions in 201.17 that when single-dose containers are packed in individual cartons, the expiration date may properly appear on the carton only. Several respondents noted that ampules are sometimes removed from the outer carton, particularly in hospitals, and that valuable information that is not a part of the immediate container labeling is lost. The provision in this section regarding single-dose containers has been in effect for a number of years and was based on information that such an allowance was necessary for single-dose containers, primarily glass ampules, because of technical problems in labeling glass ampules on a batch-by-batch basis. Some manufacturers are now placing expiration dates on single-dose containers; however, no information has been presented that expiration dating for all single-dose containers, particularly glass ampules, is feasible. Although the Commissioner recommends this activity, it was not his intent to propose revocation of the exemptions for single-dose containers as part of this revision of FDA regulations. Based on the few comments received which recommended additional revisions in this section, the Commissioner will not revoke these exemptions at this time, but will consider the recommendations for revisions for a future proposal. 27. Several comments recommended that for drugs which are also cosmetics (see also paragraph 42(h)) expiration dates should only be placed on the shipping carton and outer retail package because such products are typically purchased by the user with the outer retail package intact and the product is consumed in a relatively short period of time. The Commissioner advises that under the interim provisions of 211.137(f), most of these types of products will be exempted from the expiration dating requirements. But the so-called "drug-cosmetic" type of products are not free from stability problems; therefore, unless such products are stable for at least 3 years, expiration dating is required (see also paragraph 353 of this preamble). IV. AMENDMENTS REGARDING DRUG LISTING AND ESTABLISHMENT REGISTRATION REQUIREMENTS FOR DRUG PRODUCT SALVAGING OPERATIONS 28. Several comments suggested that the word "human" be inserted between the words "licensed" and "biologicals" in 207.3(b) because veterinary biologicals are regulated by the U.S. Department of Agriculture. The Commissioner agrees with these comments and is amending the paragraph accordingly. 29. One comment recommended that the definition of "establishment" under 207.3(b) be broadened to include additional categories such as bulk sales by practitioners, antique shops, and dealers and trustees handling estate sales and/or bankruptcies. The Commissioner agrees that these are all examples of establishments that could engage in drug-salvaging operations, but believes that the proposed definition of "establishment" is preferred in order to provide coverage for any type of establishment that engages in drug product salvaging operations, including those identified in the comment. 30. Two comments suggested deletion of the word "may" in the phrase "may have been subjected to" improper storage conditions in the proposed 207.3(k) because the statement is too general and the requirement should only apply when the drug product has actually been exposed to adverse conditions. The Commissioner rejects this suggestion because it may not be possible in every instance to establish clearly the exact nature of the adverse circumstance to which a drug product has been exposed. Therefore, in some instances, the salvager may only have sketchy information about improper storage conditions, such as unusual temperatures, and must assume that such conditions may have occurred in order to handle the salvaging operations properly. 31. Three comments concerned the proposed exemption of drug product salvagers from drug listing in 207.20. Two of the comments recommended that drug product lists be submitted prior to salvaging and one respondent recommended that a drug product list need not be submitted, but should be maintained by the salvager. The Commissioner agrees that an inventory of drugs subjected to salvaging operations should be maintained, but does not agree that salvagers should submit a drug list under Part 207 (21 CFR Part 207). To clarify that an inventory of drugs involved in salvaging operations shall be maintained, provisions are added in 211.208 for maintenance of records for drug products subjected to salvaging operations. 32. One comment considered the registration requirement for a drug salvaging firm to be a waste of taxpayers' money and recommended that the recycling of any and all drugs and pharmaceuticals be prohibited. The Commissioner disagrees with this opinion. He does not agree that drug product salvaging should be prohibited where the integrity of the drug product is not compromised. Otherwise costs to consumers might be increased. Individual firms are in a better position to determine the financial feasibility of a salvaging operation. The costs of registration, both to the Government (and the taxpayer) and to the registrant, are quite insignificant and probably less than the added costs that would result from the needless destruction of salvageable drug products. V. LEGAL STATUS OF CGMP REGULATIONS 33. Several comments requested deletion of the word "drugs" in the title and insertion of the words "drug products" in order to be consistent with the title of Part 211 and the definition of 210.3(b)(4) and 210.1(a). Part 210 applies to all parts between Parts 211 and 229. Part 211 deals with finished dosage forms, but other parts may not. Therefore, the Commissioner finds that the more general term "drugs" applies better to the various types of drugs that are likely to be covered in Parts 211 to 229. 34. A number of comments objected, on diverse grounds, to use of the word "minimum" to describe the requirements in these regulations. Several respondents believed that current good manufacturing practice cannot be considered in terms of a "minimum" because that implies that firms adhering to the regulations are then merely at a threshold level of compliance. Other respondents suggested that "minimum" means that normal practices represent a higher standard and that there is an implication that the standards of these regulations fall below an acceptable level. Some comments recommended that "minimum" not be used because no such reference to CGMP regulations is in the act. The Commissioner does not agree with these comments. The legislative history of the Drug Amendments of 1962 shows that section 501(a)(2)(B) of the act was included to raise the standards of drugs manufacturing by all manufacturers to the level of the current good manufacturing practice in the industry. Congress was quite concerned about the uneven and sometimes unacceptable quality of drug products from some portions of the pharmaceutical industry. The purpose of section 501(a)(2)(B) of the act is to provide assurance that drug product quality would not fall below that which was feasible and available under contemporary technology. There is no implication that the standards represented by these regulations are less than acceptable or below the industry's norm. On the other hand, there is no prohibition in the regulations against the manufacturing of drug products using better, more efficient, and innovative methods. In fact, the Commissioner encourages use of such methods because it benefits the consumer. Although the word "minimum" does not appear in section 501(a)(2)(B) of the act, its use is necessary in the CGMP regulations because of their binding legal nature (discussed in paragraph 35); that is, failure to meet the minimum standards of the regulation results in the product's being adulterated. BINDING DRUG CGMP REGULATIONS 35. Several comments argued that 210.1 should be deleted because it is based on the erroneous proposition that CGMP regulations can be substantive. The comments urged that regulations issued under section 501(a)(2)(B) of the act are only interpretive. In support of their argument, many referred to the legislative history of the Drug Amendments of 1962. One commented stated the following: Section 501(a)(2)(B) was enacted as part of the Drug Amendments of 1962, and, as reported by House Committee, those amendments would have included a provision empowering the FDA to issue GMP regulations under it formal section 701(e) rulemaking authority. (H.R. 11581, 87th Congress, Second Session.) The House Committee Report explained: "The promulgation of these regulations would be subject to opportunity for hearing and judicial review. Thus, legal action could be brought against firms failing to abide by these standards and against the products they ship." (H.R. Rep. No. 2464, 87th Congress, Second Session, 2(1962).) The present form of section 501(a)(2)(B) was first enacted by the Senate. The Senate Committee Report made clear that the provision was intended to authorize the FDA to issue "interpretative" regulations that would constitute only prima facie evidence of adulteration. (S. Rep. 1744, 87th Congress, Second Session, 9(1962).) In floor action on September 27, 1962, the House amended H.R. 11581 to be consistent with the Senate bill. (108 Congressional Record 19916 (daily edition 1962).) Most of those relying on the legislative history argument quoted from the same Senate Committee Report. Other comments objecting to FDA's authority to issue binding CGMP regulations asserted that the four judicial decisions cited in the preamble to the February 13, 1976, proposal in fact did not support that authority. One comment reviewed the history of all four proceedings and concluded: All of the cases cited by the Commissioner * * * recognize that the court cannot reach a conclusion contrary to Congressional intent. In those cases, there was no clear Congressional intent and the courts allowed the FDA to issue substantive regulations under section 701(a) of the Act. The legislative history with respect to the proposed CGMP regulations is crystal clear and does not permit the Commissioner to issue substantive regulations. Because of the fervor reflected by these objections and because the Commissioner foresees identical objections being made to proposals to issue binding CGMP regulations for specific classes of drug products in the future, the Commissioner has decided that a lengthy exposition of the basis for his concluding that FDA has legal authority to promulgate such regulations is warranted. The Commissioner intends that this statement will be definitive, and he does not contemplate reconsidering the issue of FDA's legal authority to issue substantive CGMP regulations in the future unless new materials, not discussed below, are brought to his attention. The question of whether a particular regulation should be issued as binding or interpretive, of course, may always be raised, and comments on the wisdom of making these CGMP regulations binding are discussed in paragraph 36 below in this preamble. With regard to the legislative history of the Drug Amendments of 1962, the Commissioner finds that none of the comments provided a complete or accurate picture of the enactment of the current section 501(a)(2)(B) of the act. Because of the emphasis placed by the persons objecting to "substantive" CGMP regulations on Congressional intent, the Commissioner believes a detailed review is necessary. On July 19, 1962, the Senate Judiciary Committee reported out S. 1552, the Senate version of what ultimately became the Drug Amendments of 1962. Section 5 of the July 19 bill would have amended section 501(a)(2) of the act to read as follows: (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packaging, or holding do not conform to current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. The Secretary is authorized to issue interpretative regulations, upon notice and in accordance with the procedures set forth in section 4 of the Administrative Procedure Act (5 U.S.C. 1003), which shall, in any proceeding involving this paragraph, be prima facie evidence of what constitutes current good manufacturing practice. The accompanying bill report (S. Rep. No. 1744, 87th Cong., 2d Sess. (July 19, 1962)), described this section at page 9, emphasizing that the "Secretary would be authorized to issue interpretative regulations as to what constitutes current good manufacturing practice, and these regulations would be prima facie evidence in any proceeding under this section of the Food, Drug, and Cosmetic Act." On August 3, 1962, President Kennedy submitted a series of amendments to the Senate Judiciary Committee. In response to this and to the public controversy then erupting over thalidomide, the Committee reconsidered S. 1552 and, on August 21, 1962, reported out a revised version of the bill. One change was to reword section 5 of the bill so that section 501(a)(2) would be amended to read as follows: (2)(A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. The Judiciary Committee issued a second report to explain its proposed changes in S. 1552 (S. Rep. No. 1744, Pt. 2, 87th Cong., 2d Sess. (Aug. 21, 1962)). On pages 3 and 4, it discussed the revision of section 5 as follows: The President, in the recommendations submitted for the consideration of the committee with his letter of August 3, 1962, proposed a revised version which included the following principal amendments to the reported bill: (1) It proposed to replace the provisions on regulations with prima facie evidentiary effect with a provision that the adequacy of the quality controls be determined "in accordance with regulations promulgated by the Secretary on the basis of good manufacturing practice" after formal rulemaking procedures, i.e., after affording an opportunity for hearing, and for judicial review on the basis of the hearing record, with respect to such regulations. * * * * * The explanation accompanying the recommendations of the President expressed concern lest the language as to interpretative regulations with prima facie evidentiary effect invite endless de novo litigation on the question of what constitutes a good manufacturing practice each time there is enforcement action under the new quality control provisions. The committee acceded to the President's request for elimination of the "prima facie" regulatory authority in the bill. It felt, however, on balance, that there was no need for inserting provisions for regulations through formal rulemaking on the subject of what is good manufacturing practice. Section 701(a) (21 U.S.C. 371(a)) now vests in the Secretary "authority to promulgate regulations for the efficient enforcement of this Act." This permits the Department to issue such regulations as it desires and their scope and effect will be the same as that of other regulations issued under such general authority. Numerous regulations have been issued under section 701(a) and have been the subject of consideration and application in the courts in actions arising under the various provisions of the act not now subject to formal rulemaking procedures. During the floor debate on S. 1552 on August 23, Senator Eastland, Chairman of the Judiciary Committee, elaborated on the meaning of section 501(a)(2) as it would be amended by the bill: Section 5, as it would read under the August 20 amendments, is designed to assure that drugs are manufactured according to good manufacturing practice. It would deem a drug to be adulterated and thus subject to seizure if made under facilities, methods, or controls that are inadequate to assure that the drug meets the specifications of a quality product. Adulteration could also be found if such facilities, methods, or controls were not operated or administered in conformity with good manufacturing practice. Since the competitive position of responsible manufacturers depends in large part on the confidence of the medical profession and the public, it will be in their own interest to maintain high standards of current good manufacturing practice which will provide a readily determinable basis for enforcement proceedings against any substandard operator. The Secretary could use his general rulemaking authority under section 701(a) of the act to announce what he, in the administration of the act, considers to be good manufacturing practice insofar as methods, facilities, controls, and their operation and administration are concerned. As in the case of other regulations, the court in the final analysis will pass upon the scope and effect of such regulations. (108 Cong. Rec. 16303-4 (Aug. 23, 1962).) Senator Kefauver concurred in this change, stating, "This provision has been strengthened considerably in comparison to the bill which was reported in July." (Id., at 16306-7). The Commissioner thus concludes that when it unanimously approved S. 1552 on August 23, 1962, the Senate obviously believed that the problem identified by the President--"endless de novo litigation * * * each time there is enforcement action"--had been resolved. The Senate must, therefore, have intended that regulations issued under section 501(a)(2)(B) of the act be more than merely prima facie evidence of what constitutes current good manufacturing practice, i.e., that they be given at least the same force as any other regulation issued under section 701(a) of the act. He also finds that the statement relied upon by most comments as proof that only interpretive regulations could be issued appeared in the first Senate Report and was explicitly reversed in the second Senate Report. One month later, the House Interstate and Foreign Commerce Committee reported out H.R. 11581, the House bill that preceded the Drug Amendments of 1962. (H.R. Rep. No. 2464, 87th Cong., 2d Sess. (1962)). Section 101(a) of this bill proposed to amend section 501(a)(2) of the act to read as follows: (2)(A) if it has been prepared, packed, or held under unsanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice (as determined in accordance with regulations promulgated by the Secretary) to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. In addition, paragraph (b) of section 101 would have amended section 701(e) of the act to provide that regulations under section 501(a) would be issued by formal rulemaking procedures (rather than the informal procedures under section 701(a) of the act). The Committee Report accompanying H.R. 11581 explained this provision as follows (H. Rep. 2464, 87th Cong., 2d Sess. 2 (Sept. 22, 1962)): Section 101 of the reported bill would amend section 501(a)(1) [sic] of the Federal Food, Drug, and Cosmetic Act to deem a drug to be adulterated if the methods, facilities, or controls used in its manufacture, processing, packaging, or holding fail to conform to, or are not operated or administered in conformity with, good manufacturing practices as determined in accordance with regulations to be issued by the Secretary of Health, Education, and Welfare which are designed to assure that the drug is safe and has the identity and strength and meets the quality and purity characteristics which it purports or is represented to possess * * * The promulgation of these regulations would be subject to opportunity for hearing and judicial review. Thus, legal action could be brought against firms failing to abide by these standards and against the products they ship. The House of Representatives debated H.R. 11581 on September 27, 1962. Congressman Schenck offered several amendments that day, one of which would delete the parenthetical element in section 101(a), and all of section 101(b), from the bill. He explained this amendment as follows: My amendment to section 101 of the bill, which was approved by the committee, provides simply that the drug will deem[sic: be deemed] to be adulterated and subject to seizure if the methods, facilities, or controls used in the manufacture of the drug do not conform with current good manufacturing practice, as determined in accordance with regulations promulgated by the Secretary. The purpose of this provision is to enable the Secretary to require all companies producing drugs to observe the high standards that are now followed by the better manufacturers. It is intended that the Secretary's regulations will define minimum standards of good manufacturing practice, rather than setting forth an exclusive method by which some particular drug product may be made. Manufacturers whose methods, facilities, and controls exceed the minimum standards will not be required to lower their own standards, so long as they can show that their own practices meet or exceed these minimum requirements. The principal purpose of the provision is to assure that the same high manufacturing standards are followed in making so-called old drugs that the law now requires in the making of so-called new drugs. Before any manufacturer is permitted to make a new drug he must file complete details of his manufacturing process with the Food and Drug Administration. It is not intended that the regulations issued under section 101 will apply to the manufacturer of new drugs insofar as the methods, facilities, or controls used in making these new drugs but that the Food and Drug Administration will require that such drugs meet the requirement of this act as to safety, and has the identity and meets the quality and purity characteristics which it purports or is represented to possess. The committee adopted an amendment which would make the formal rulemaking procedures of section 701(e) of the Federal Food, Drug, and Cosmetic Act applicable to regulations referred to which may be made pursuant to the above amendment. I am opposed to the amendment in section 101(b) of the bill which would require the Secretary to hold a formal hearing under section 701(e) of the Federal Food, Drug, and Cosmetic Act in order to issue regulations as to what constitutes 'current good manufacturing practice.' I favor the approach adopted by the Senate under which this determination is made pursuant to section 701(a) of the act. This procedure permits the Secretary to issue such regulations as he desires and their scope and effect will be the same as that of other regulations, issued under such general authority. This procedure is more flexible. Numerous regulations have been issued under this section and they have been the subject of consideration and application in the courts in actions arising under the various provisions of the act not now subject to formal rulemaking procedures. (108 Cong. Rec. 19895-6 (Sept. 27, 1962).) The Schenck amendment was concurred in by Congressman Harris, Chairman of the House Commerce Committee, who observed that the amendment "is taken, in part, from the Senate bill, S. 1552 * * * The gentleman from Ohio [Mr. Schenck] has advised me of the need not to tie this provision in with section 701(e) * * *" 108 Cong. Rec. 19916 (Sept. 27, 1962). The amendment was agreed to and, as approved by the House of Representatives, the legislation would amend section 501(a)(2) to read: (2)(A) if it has been prepared, packed, or held under unsanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. The Commissioner finds from this history that the House of Representatives believed that CGMP regulations would have the same legal status as other FDA regulations, and moved to revise language to conform to S. 1552, as passed, solely to eliminate the requirement that CGMP regulations be issued pursuant to the formal rulemaking procedures of section 701(e) of the act. Because there was no difference between the House and Senate bills insofar as the amendment of section 501(a)(2) of the act was concerned, it was not a subject of the Conference Report (H. Rep. No. 2526, 87th Cong. 2d Sess. (Oct. 3, 1962)), nor was it modified or debated further by either the Senate or the House when each voted to approve the Drug Amendments of 1962 (on October 3 and 4, 1962, respectively). Based on this complete review of the legislative history of section 501(a)(2)(B) of the act, the Commissioner concludes that there is no support for the proposition that Congress intended that CGMP regulations should be merely interpretive. At the least, Congress wanted CGMP regulations to have the same force and effect as other regulations issued under section 701(a) of the act. (See the second Senate Report and Rep. Schenck's description of his amendment, above). To the extent that a stronger Congressional mandate can be gleaned from the various reports, amendments, and debates, it appears that binding standards were to be issued by FDA and issued through the less cumbersome notice-and- comment rule making procedures of section 701(a) of the act rather than the more complex section 701(e) mechanism. Therefore, the Commissioner rejects the argument that 210.1 exceeds the authority conferred by Congress under sections 501(a)(2)(B) and 701(a) of the act. With respect to judicial interpretations of FDA's authority to issue substantive rules, the Commissioner believes that the cases cited in the February 13, 1976 preamble and decisions handed down since February 13, 1976 are directly relevant to, and further support, his conclusion that CGMP regulations can be issued as binding standards. In 1973, the Supreme Court reviewed the legality of two interrelated FDA regulations. One, now codified in 21 CFR 314.111(a)(5), set forth in detail the scientific principles that the Commissioner believed are part of the requirement in section 505(d) of the act that the effectiveness of a drug be demonstrated by "substantial evidence consisting of adequate and well-controlled studies." The second regulation, now codified in 21 CFR 314.200, contained standards for FDA to determine whether a request for a hearing on the denial or withdrawal of approval of a new drug application (NDA) presented a genuine and substantial issue of fact. At stake in the case of Weinberger v. Hynson, Westcott and Dunning, Inc., 412 U.S. 609(1973), was whether an applicant was entitled to a full evidentiary hearing on the approvability of its product, and at such a hearing could offer whatever evidence it felt met the statutory standards of effectiveness, or whether FDA could summarily deny or withdraw approval of the NDA because the agency found that the applicant's evidence did not meet the standards in the regulations for evidence of effectiveness. Manufacturers contended that FDA's regulations could not serve as the basis for denying them a full evidentiary hearing under section 505 of the act. The agency believed that the regulations were a reasonable method of screening out unnecessary hearings and thereby managing an otherwise overwhelming workload. The Supreme Court concluded that both of the regulations were within the authority of the Commissioner under section 701(a) of the act and therefore FDA could act on NDA's without a full hearing where evidence failed to satisfy the FDA regulations. It said (id. at 622): The standard of 'well-controlled investigations' particularized by the Regulations is a protective measure designed to ferret out those drugs for which there is no affirmative, reliable evidence of effectiveness. The drug manufacturers have full and precise notice of the evidence they must present to sustain their NDA's, and under these circumstances we find the FDA hearing regulations unexceptionable on any statutory or constitutional ground. The Supreme Court, in this and related cases, discussed FDA's authority to determine whether a drug was a "new drug" under section 201(p) of the act (and thus subject to the requirements of section 505 of the act). It described favorably the review of over-the-counter (OTC) drugs under the procedures set forth in 21 CFR 330.10, by which OTC drugs are being classified as "new" or "generally recognized as safe and effective and not misbranded," the latter not subject to the new drug provisions of the act. These procedures were also promulgated under the authority of section 701(a) of the act. The Court stated, in Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973) that: We think that it is implicit in the regulatory scheme, not spelled out in haec verba, that FDA has jurisdiction to decide with administrative finality, subject to the types of judicial review provided, the 'new drug' status of individual drugs or classes of drugs. The deluge of litigation that would follow if 'me-too' drugs and OTC drugs had to receive de novo hearings in the courts would inure to the interests of manufacturers and merchants in drugs, but not to the interests of the public that Congress was anxious to protect by the 1962 amendments, as well as OTC drugs and drugs covered by the 1972 (Drug Listing) Act. We are told that FDA is incapable of handling a caseload of more than perhaps 10 or 15 de novo judicial proceedings in a year. Clearly, if FDA were required to litigate, on a case-by-case basis, the 'new drug' status of each drug now marketed, the regulatory scheme of the act would be severely undermined, if not totally destroyed. Moreover, a case-by-case approach is inherently unfair because it requires compliance by one manufacturer while his competitors marketing similar drugs remain free to violate the Act * * *. In a third case decided at the same time, Ciba Corp. v. Weinberger, 412 U.S. 640 (1973), the Court said (id. at 643-4) that "the definition of new drug as used in section 201(p)(1) involves a determination of technical and scientific questions by experts. The agency is therefore appropriately the arm of Government to make the threshold determination of the issue of coverage * * *." The Commissioner notes that even prior to these rulings, most major manufacturers of OTC drugs had recognized the reasonableness as well as legal propriety of the OTC review as a mechanism within the authority of section 701(a) of the act to classify drugs as "new" or "not new." Indeed, for over 5 years now, these firms have been participating in this review, and the Commissioner expresses his gratitude for this cooperation. Subsequent to these rulings by the highest Federal court, another case arose over the issue of whether FDA could promulgate regulations under section 701(a) of the act that represented binding rules relating to prescription drugs under section 503(b) of the act. The specific issue was whether FDA could, by regulation, declare products containing more than certain amounts of vitamin A or D to be prescription drugs. The opponents of the regulation, in an interesting parallel to the comments on the CGMP regulations, argued that only regulations issuable under section 701(e) of the act procedures could be binding and that the legislative history of section 503(b) of the act demonstrates that FDA could issue only interpretive regulations. The United States Court of Appeals for the Second Circuit rejected these contentions in National Nutritional Foods Ass'n. v. Weinberger, 512 F.2d 688 (1975). It stated: We have come to recognize that, if the administrative process is to be practicably effective, specific regulations promulgated pursuant to general statutory delegation of authority must be treated as authoritative, whether labeled "substantive" or "interpretive," especially in areas where the agency possesses expertise not shared by the courts. In the event its views are unlikely to be distributed by the court in an enforcement proceeding * * *. Whatever doubts might have been entertained regarding the FDA's power under 701(a) to promulgate binding regulations were dispelled by the Supreme Court's recent decision in Weinberger v. Hynson, Westcott, & Dunning * * * and its companion cases * * *. (id. at 696). * * * * * Surely an agency which possess the power to determine administratively what products are "new drugs" has the authority to decide what products are "prescription drugs". (id. at 699). The decisions in the National Nutritional Foods, Hynson, Bentex, and Ciba were cited by the Commissioner because he believes that they conclusively rule that regulations issued under section 701(a) of the act are binding and that the justifications for issuing substantive regulations in other areas are directly applicable to CGMP regulations. Similar to the Court's observations in Hynson quoted above, the statutory standard of "current good manufacturing regulations" can and should be particularized as a protective measure to identify those manufacturing practices which are at a minimum necessary to assure drug quality. The drug manufacturers have full and precise notice of the CGMP requirements they must fulfill to sustain the acceptability of their products under section 501(a)(2)(B) of the act, as the Commissioner noted in the February 13, 1976, preamble. Substantive regulations also provide greater certainty about the agency's expectations because, in promulgating such regulations, the agency must carefully distinguish standards it seriously intends to enforce from those it finds desirable but not essential. The Commissioner also stated in the 1976 proposal that binding CGMP regulations would assist courts and expedite enforcement proceeding under the act. As with "new drug" determinations discussed in Bentex, if each CGMP requirement has to receive a de novo hearing in each and every enforcement proceeding, the burden of litigation that would result would not be in the public interest, nor would it be equitable to competing manufacturers who where not involved in such litigation. President Kennedy and the second Senate Report made the same arguments in deleting the reference to interpretive regulations from S. 1552. The agency has avoided this problem over the last several years because agency priorities have been concentrated in areas other than drug CGMP enforcement; it is not anticipated that this allocation of resources will continue indefinitely and, with the issuance of these regulations, more regulatory proceedings are probable. In Ciba, the Court noted the technical and scientific expertise appropriate for at least the threshold determination of "new drug" status. The Commissioner believes that determination of what is the "current good manufacturing practice" in the drug industry also requires technical and scientific expertise, as well as a unique ability to observe the entire industry. These CGMP regulations were developed with the participation of pharmaceutical chemists employed by FDA, individuals qualified by formal training as well as by valuable experience in reviewing the good (and bad) current (and past) production and control techniques set forth in original NDA's and abbreviated NDA's, supplemental applications, antibiotic certification forms, biological establishment and product licenses, new animal drug applications, and proposed and final compendial standards. In addition, FDA investigators who conduct and/or review inspections of manufacturers under the act also participated in preparing this document. Although, as one comment noted, FDA does not manufacture drugs, it does not follow that FDA cannot determine current good manufacturing practice for drugs. On the contrary, FDA may be uniquely able to do so, because it and it alone has had access to the facilities and records of every manufacturer of pharmaceuticals in this country. Given the fact that many production and control processes are considered by individual firms to be trade secrets, it is unlikely that competitors or independent private third parties such as compendial authorities have the same ability as FDA to discover what non-public practices other than their own are current and which of these are good. Subsequent to the February 1976 proposal, other courts have considered and affirmed FDA's authority to promulgate binding of substantive regulations pursuant to section 701(a) of the act. See, e.g., Cosmetic, Toiletry and Fragrance Association v. Schmidt, 409 F. Supp. 57 (D.D.C., Feb. 3, 1966), appeal docketed No. 76-1242 (D.C. Cir., Feb. 5, 1976)(regulation requiring warning labels on aerosolized products, issued under sections 201(n), 602(a), and 701(a) of the act, upheld; American Frozen Food Institute v. Mathews, 413 F. Supp. 548 (D.D.C. March 30, 1976), aff'd sub nom. American Frozen Food Institute v. Califano, 555 F.2d 1059 (D.C. Cir. May 12, 1977)(regulations establishing common and usual names for nonstandardized foods, issued under sections 403(i) and 701(a) of the act, upheld); National Confectioners Ass'n. v. Mathews, CCH Food, Drug & Cos. L. Rep. 38,062 (D.D.C. April 14, 1976), aff'd sub nom. National Confectioners Ass'n v. Califano, Docket No. 76-1617 (D.C. Cir. Jan. 20, 1978)(CGMP regulations for cocoa products and confectionery relating to lot coding on finished product packages and shipping containers and to distribution records of lots, issued under sections 502(a)(4) and 701(a) of the act, upheld); Federation of Homemakers v. Schmidt, 385 F. Supp. 362(D.D.C. 1974), aff'd 539 F.2d 740 (D.C. Cir. June 10, 1976)(regulation establishing requirements for "imitation" foods, issued under sections 403(c) and 701(a) of the act, upheld); Almay, Inc. v. Weinberger, 417 F. Supp. 758 (D.D.C. June 30, 1976), rev'd on the grounds, No. 76-1718 (D.C. Cir. Dec. 21, 1977) authority to issue regulations regarding labeling and supporting evidence of cosmetics claiming to be "hypoallergenic," under sections 301(b), 602(a) and (b) and 701(a) of the act upheld); United States v. Nova Scotia Food Prod. Corp., 417 F. Supp. 1364 (E.D.N.Y., Aug. 17, 1976), rev'd on the grounds, No. 76-6169 (2d Cir. Dec. 15, 1977)(CGMP regulations regarding brining and heating of fish in the production of smoked fish may be promulgated under sections 402(a)(4) and 701(a) of the act). The Commissioner notes that two of the cases dealt specifically with the validity of CGMP regulations issued under the statutory standards relating to adulterated foods, which do not explicitly refer to "current good manufacturing practice." It would indeed be anomalous that those regulations could be issued as legally binding if regulations amplifying section 501(a)(2)(B) could not be. The Commissioner interprets much of the concern over FDA's authority to issue binding regulations as reflecting a belief that the CGMP regulations can be arbitrary, need not be based upon actual current practice, and may exceed what is necessarily "good" for drug quality. There also seems to be a belief that binding regulations cannot be changed and are beyond review by the courts. These perceptions are in error. The Administrative Procedure Act clearly provides that regulations which are arbitrary or capricious may be overturned by a reviewing court. 5 U.S.C. 706. The legislative history of section 501(a)(2)(B) of the act and cases involving enforcement of CGMP regulations, e.g., United States v. An Article of Drug * * * "White Quadrisect", 484 F.2d 748 (7th Cir. 1973)) established that the regulations must be based on current industry practice, although not necessarily on the predominant practice in the industry. The agency is directed to consider the current "good" practices. In determining current practice, the agency has relied upon the knowledge and expertise of FDA staff developed from the review of NDA's and ANDA's, antibiotic certification forms, biological licenses, and compendial standards submitted to the agency, and from establishment inspections made during the last half decade. A "good" practice was included in these regulations only if it is feasible for manufacturers to implement the practice, if the practice contributes to assuring the safety, quality, and purity of the drug product, and if the value of the contribution or added assurance exceeds the cost, in terms of dollars and/or other burdens, of implementing or continuing the practice. The Commissioner does not believe it is legally required that, in addition to reliance upon agency expertise, he must include in the record specific examples of each practice mentioned in these regulations. Regarding judicial review of regulations, the Commissioner notes that such review is assured by the Administrative Procedure Act whether the regulations are deemed interpretive or substantive. Judicial review is available in any enforcement proceeding brought against a particular manufacturer or product. Pre-enforcement review is also available. Abbott Laboratories v. Gardner, 387 U.S. 136 (1976). Thus, the Commissioner believes that the fears that substantive, binding CGMP regulations somehow deprive individuals of legal protections are unfounded. As noted at the outset of this discussion, the Commissioner does not intend in the future to reconsider the legal authority of FDA to promulgate binding CGMP regulations under section 701(a) of the act, unless new material, not discussed above, is presented to him that raises substantial doubt as to the correctness of the analyses and conclusions he set forth above. For reasons discussed in this paragraph and in paragraph 36 below, the Commissioner has also decided that these CGMP regulations shall be issued as binding. The Commissioner advises that any person who still questions FDA's authority to do this is welcome to seek prompt pre-enforcement judicial review of this authority. 36. A number of comments suggested, in effect, that whether or not FDA could lawfully issue "binding" CGMP regulations, it would be unwise for the agency to do so. These individuals cited the complexity and variability of manufacturing control processes, emphasizing the variety of options available and the need for freedom of choice among these options by various manufacturers depending on cost and technological factors. They further complained that FDA lacked the expertise to determine which practices were best and that, by "freezing-in" techniques, FDA would discourage innovation and development of new procedures which might increase the assurance of product quality. The comments objected to the presumption that would follow from a technical violation of the CGMP regulations that the product was therefore adulterated and that individuals, under the legal doctrine of strict criminal liability under the Federal Food, Drug, and Cosmetic Act, were criminally responsible for these violations. Binding regulations would, in their opinion, provide the agency no flexibility for discretion in enforcement of the act. Finally, the comments objected that there was no need for binding regulations because there were only a few large pharmaceutical manufacturers involved in production of most drugs; because these were subject to frequent inspections by FDA; and because in the past, these firms had been subject to few problems, few recalls, and rare legal proceedings. This history suggested that most firms were in substantial compliance with the regulations regardless of whether they were classified as substantive or interpretive. The Commissioner has evaluated these objections and found that, although some have merit, none is so serious as to outweigh the benefits from making CGMP regulations binding. Recognizing the diversity of manufacturing and control procedures, the Commissioner has endeavored wherever possible to state CGMP regulations in the terms of objectives to be attained, rather than methods of attaining such objectives. Procedures have been specified only where essential to assure product quality under the act. Thus, these regulations provide flexibility to manufacturers to select the methods and processes that will be most suitable to the products and operations of the individual firms. This flexibility should also permit the development of novel approaches to attaining the same objectives. In those few cases where precise procedures are set forth in these regulations, individuals who believe that alternative mechanisms may also be acceptable are invited to petition the Commissioner to amend the specific regulation to permit such alternatives. As discussed in paragraph 35 of this preamble, the Commissioner does not believe that FDA lacks sufficient expertise to develop and promulgate CGMP regulations and advises that the public procedures for commenting on these proposed CGMP regulations, together with the opportunity to petition the agency for changes in the regulations, provide individual manufacturers with an opportunity to correct any errors in FDA's information. Thus, the Commissioner does not believe the agency lacks sufficient information to justify making CGMP regulations binding rather than interpretive. With regard to the alleged lack of flexibility in the enforcement of "binding" CGMP regulations, the Commissioner believes that the comments have confused the question of whether a violation exists with the question of whether FDA will take action upon the violation. In numerous areas, FDA has established tolerances for actionable offenses and is currently in the process of establishing regulations setting forth agency policy with regard to prosecutions for violations of the act. It should be noted, however, that even in the absence of any CGMP regulations, whether binding or not, the doing of or failure to do any particular act which is inconsistent with current good manufacturing practice results in the product being legally adulterated, even if no legal action is brought. That is to say, the existence of CGMP regulations does not create violations of the law where they did not previously occur. The question rather is whether the violator will be prosecuted or enjoined and/or the product seized, an issue beyond the scope of this rule making. Finally, with regard to the objection that there is no need to make these regulations binding since most major pharmaceutical manufacturers are in substantial compliance with the current regulations, the Commissioner believes that this is simply not relevant to the question of whether CGMP regulations should be binding or interpretive. The most significant justification for having the regulations binding is to minimize the burden on the government and on the courts in a case where a violation does occur. When the regulations are merely interpretive, the agency must provide expert testimony in each trial to demonstrate what the current good manufacturing practice in the industry is, notwithstanding the regulation. The cost of locating and preparing such expert witnesses and bringing them to the trial, as well as the judicial time taken in hearing these witnesses, would be eliminated by having binding regulations. In the event that a challenge is raised about the validity of the regulation, FDA can present to the court the administrative record underlying the regulation in lieu of any expert testimony. Thus, it is not the proportion of manufacturers who are in compliance with the regulations but the number who are out of compliance and whose noncompliance justifies regulatory action that necessitates making these regulations binding. For these reasons the Commissioner has concluded that insofar as he has discretion to issue CGMP regulations as either binding or interpretive, he elects to make them binding. 37. Several comments suggested the words "where applicable" be inserted in the first sentence of 210.1(a). The comments argued that, as proposed, conformance to every requirement regardless of the need to do so. The Commissioner concludes that there are numerous examples of flexibility built into the CGMP regulations. Words like "appropriate" and "as necessary" are used in the regulations to make it clear that requirements which are not relevant to a given manufacturer's operation do not apply. In addition, a new paragraph (b) is established in 210.2 to clarify that the requirements apply only to those operations subject to the CGMP regulations in which the manufacturer is engaged. 38. Two comments recommended that the references in this section be Parts 210 through 226 instead of Parts 210 through 229, since 229.25 was being revoked. Since the Commissioner has reserved all parts between 210 and 229 for current good manufacturing practice regulations, the reference is appropriate. Even though 229.25 has been revoked, Part 229 may be used in the future. 39. One comment suggested insertion of the phrase "and testing and quality control thereof" after the words "the manufacture, processing, packing, or holding of a drug product" in 210.1(d). Because "manufacture, processing, packing, or holding of a drug product" is defined in 210.3(b)(12) to include testing and quality control of drug products, the Commissioner rejects this comment. 40. A large number of comments recommended that the personal liability statement in 210.1(b) be eliminated. Some comments suggested that an individual should be held responsible only if actual contamination has occurred. Others recommended modifying the liability statement by requiring willful and knowing intent to violate the law. One comment said this was unclear as to who was covered by the section and that it was not useful in clarifying the requirements of the act. Another asked about the definition of "responsible." The Commissioner notes that actual contamination of a drug does not have to occur for the article to be deemed adulterated under section 501 (a)(2)(B) of the act. Further, the act does not require a showing of intent for a person to be held accountable under the act. United States v. Dotterweich, 320 U.S. 277, (1943); United States v. Park, 421 U.S. 658 (1975). It would be contrary to public policy and congressional intent, as well as beyond the Commissioner's authority, to require the showing of actual contamination or intent. Congress purposely did not do so in order to provide the maximum protection of the public health. With regard to clarifying "person," the Commissioner advises that the word "person" is defined in section 201(e) of the act to include corporations and partnerships as well as individuals. Under section 301(d) of the act, the adulteration of any drug is a prohibited act, and under section 303(a) "any person who violates a provision of section 301" is subject to criminal penalties. Thus, the reference to "the person" in 210.1(b) merely parallels the statutory language. The reference to the word "responsible" is in accord with interpretations of the act by the Supreme Court of the United States. See United States v. Park, 421 U.S. 658 (1975). Thus, the Commissioner does not believe that this language is unclear or misleading. He also believes that, although 210.1(b) is not essential to the regulations and merely reflects the legal position of the agency, it is a useful exposition of FDA policy with regard to failure to comply with the CGMP regulations. For this reason, the language is retained in the final order. 41. One comment said the CGMP regulations, as proposed, set up FDA as both prosecutor and judge and deprive persons of due process. The Commissioner finds that penalties for violation of these regulations (i.e., seizure of violative products, injunctive sanctions, and criminal prosecution) are imposed by judicial proceedings in United States courts, where the U.S. Department of Justice serves as prosecutor, Federal judges preside, and in criminal cases there is a right to trial by jury. The role of FDA is twofold: First, it establishes standards amplifying the statutory language (through issuance of CGMP regulations after public comment); and second, it investigates to determine whether these standards have been violated. Affected persons have full legal rights, including the right to challenge the regulations as being beyond the authority of the act. The Commissioner finds no rationale to suggest these CGMP regulations compromise any person's right to due process. VI. APPLICABILITY OF CGMP REGULATIONS; EXEMPTIONS 42. Many comments said there should be exemptions or waivers from the CGMP regulations for certain classes of drugs or specialized kinds of manufacturing activities. These comments came from manufacturers of bulk drugs, veterinary drug products, radiopharmaceutical drug products, biological drug products, so- called "drug-cosmetic" products, and wholesalers and retail dispensers of drug products. These comments, except one, asserted that the CGMP regulations were inappropriate, unnecessary, excessive, or not part of current industry practice when applied to the type of product identified; the exception (discussed in paragraph g. below), together with one comment regarding a particular product line, questioned FDA's legal authority to apply CGMP regulations to certain types of businesses or products. As discussed in the preamble to the February 13, 1976 proposal, the Commissioner intends to propose at future times CGMP regulations for specific classes of drug products such as small volume parenterals, compressed medical gases, and radiopharmaceuticals. (See, e.g., the proposal regarding LVP's published in the FEDERAL REGISTER of June 1, 1976 (41 FR 22202).) In addition, regulations for certain kinds of manufacturing activities such as manufacturing of bulk drug components, repacking, or relabeling will be proposed. Generally, these future regulations will supplement, and in some situations supersede, the more general CGMP regulations. As these proposals are issued, the need for waivers from or modifications in the general CGMP regulations should be diminished. After considering these plans and the comments regarding exemptions for specialized drug products or manufacturing activities, the Commissioner has reached the following conclusions: a. Bulk drugs. It is first necessary to distinguish between (1) "drug products" (i.e., finished dosage forms) that may be held in bulk containers, and (2) bulk drug "components" (i.e., ingredients intended for use in the manufacture or processing of a drug product). The CGMP requirements set forth in Part 211 are intended to apply to the preparation of a finished dosage form, whether or not in packaged form. This is clearly set forth in the regulations (210.3(b)(4) and 211.1(a)). Although these CGMP regulations are not applied to the manufacture of bulk drug components, there are numerous instances where good manufacturing practices for bulk drug components would parallel the requirements set forth in Part 211. For this reason. FDA will utilize the standards of Part 211 as guidelines during inspections of manufacturers of bulk drug components under the jurisdiction of the act. b. Veterinary drug products. Veterinary drug products shall continue to be subject to the general CGMP regulations for all drug products, with certain specific exceptions, namely 211.42(d), 211.46 (d), and 211.72. Comments regarding the appropriateness of individual provisions of these regulations to veterinary drug products have been considered and responded to under the sections involved. When the provisions of a section in the regulations do not apply to veterinary drug products, exemptions for such products are stated in that section. c. Radiopharmaceutical drug products. The general CGMP regulations are suitable requirements for the preparation of radiopharmaceutical drug products. When the Commissioner was aware of situations where the requirements are not appropriate, exemptions were made from these final regulations. Supplemental requirements specific for radiopharmaceuticals will be proposed in the future. d. Biological drug products. The Commissioner notes that section 902(c) of the act parallels section 351(g) of the Public Health Service Act (42 U.S.C. 262(g)), which provides that section 351 does not affect, modify, repeal, or supersede the Federal Food, Drug, and Cosmetic Act. The agency has consistently interpreted these provisions to be additive; that is, although they preclude duplicative or inconsistent regulation under the two acts, where one statute speaks to a matter regarding biological products and the other statute is silent, the express statutory provisions govern, regardless of the statute in which they appear. Thus, for example, the provisions of section 505(i) of the act regarding investigational use of new drugs have been consistently held to apply to biological products because no part of section 351 of the Public Health Service Act addresses investigational use of biologics (21 CFR 312.1(g)). Because section 351 of the Public Health Service Act does not refer to current good manufacturing practice and because biological products are considered to be drugs subject to section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, the Commissioner believes it is consistent with both laws to apply current good manufacturing practices to biological drug products. Biological products are now manufactured according to current good manufacturing practice and regulated under parts 600 through 680 (21 CFR parts 600 through 680), in particular the establishment license and product license provisions. Sections 210.2 and 211.1 clearly provide that the more specific biologic regulations prescribed in 21 CFR Parts 600 through 680 will supplement or supersede, where appropriate, the more general drug CGMP regulations. The Commissioner believes it possible that provisions in the general CGMP regulations may be inappropriate for certain biological products and would make appropriate changes to assure that the CGMP requirements would not increase manufacturing costs without a commensurate increase in safety, purity, potency, or efficacy. However, no specific examples were submitted to FDA in response to the proposal that can be considered as areas for exempting biological drug products. The Commissioner invites interested persons to submit petitions under 10.30 to amend particular provisions of the CGMP regulations to account for the special technologies or incompatabilities of biologics. e. Compressed medical gases. The agency will propose specific CGMP regulations for compressed medical gases. Until such regulations can be proposed for public comment, comments received and evaluated, and a final regulation published, however, the Commissioner concludes that the requirements in the more general CGMP regulations, with certain stated exceptions, are applicable. It would not be in the public interest to delay a final regulation based on the February 13, 1976 proposal until FDA can promulgate specific CGMP regulations for compressed medical gases. f. Repackaging and relabeling. Only certain portions of the general CGMP regulations apply to repackaging and relabeling operations. For example, the requirements pertaining to labeling control apply to repackers and relabelers, while the requirements for compounding a drug product do not apply since repackers/relabelers do not compound drug products. The CGMP regulations apply to repackaging and relabeling operations at locations that are different from the place of manufacture. Supplemental CGMP regulations regarding this unique type of drug processing will be proposed in the future. g. Wholesalers. Section 501(a)(2)(B) of the act provides that a drug shall be deemed to be adulterated if "the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to current good manufacturing practice * * *." This section, through the operation of section 301(k) of the act, applies to wholesalers, retailers, pharmacies, and hospitals, as well as to manufacturers. However, the CGMP regulations set forth in part 211 apply only to establishments engaged in the preparation of a drug product. Therefore, these regulations do not apply to the wholesalers, retailers, pharmacies, and hospitals engaged in activities that are traditional to those establishments. The wholesaler, however, is a particularly important link in the distribution chain between manufacturer, retailer, and consumer. The Commissioner encourages wholesalers to adopt applicable provisions of the CGMP regulations to insure that drug products are handled and stored in a manner that will not contribute to loss of identity, strength, quality and purity. In addition, they are responsible for being able to identify the distribution of drug products that are subject to recall or market withdrawals. Recall strategy will frequently involve wholesalers as consignees and intermediate distributors when recalls are to the retail or consumer levels. In the FEDERAL REGISTER of June 16, 1978 (43 FR 26202), FDA published regulations to provide guidance to manufacturers and distributors in this area. It is especially important for wholesalers to maintain adequate records to assure effective recall or market withdrawal. If future experience indicates to FDA that recalls and market withdrawals are being adversely affected by inadequate recordkeeping on the part of the wholesalers, the Commissioner will give further consideration to the need for specific CGMP regulations for wholesalers. h. Drugs that are also cosmetics. A number of comments, including a petition to the Commissioner, were received regarding the applicability of the proposed general CGMP regulations to a class of products identified as "cosmetic-drug products" and described as those which: (1) Meet the definitions of both "drug" and "cosmetic" under section 201 of the act; (2) represent a minimal health or safety risk; and (3) are marketed over-the-counter for regular and frequent consumer use without dosage limitations. Examples of these products were described as medicated skin creams, anti-bacterial soap, antiperspirants, and topical sunburn prevention products. Specifically, the comments requested separate CGMP regulations for this alleged class of drugs, and one comment submitted a proposed new part 213 for drug-cosmetic products, drafted in the style and format of other CGMP regulations for drugs. Another comment recommended that, because the drug-cosmetic products were so similar to related cosmetic products, CGMP regulations for those two classes of products be proposed and adopted together, separate from those relating to drug products generally. The Commissioner has concluded that these regulations, except expiration dating for certain human OTC drug products described in paragraph 353 of this preamble, must apply to all products meeting the definition of drug products, whether the drug products are highly potent prescription drugs or are OTC drugs of the type described as "cosmetic-type." Past experience of the agency has demonstrated that the public has been put in a hazardous situation because of manufacturing errors in OTC products, such as by the substitution of spirits of camphor for castor oil. Further, the Commissioner notes that there are very few clearly innocuous drug products or components in the OTC area. Several examples can be given: If appropriate stability study requirements and manufacturing controls required by CGMP regulations are not met for fluoride toothpaste, there could be a question of effectiveness of the products because of the unavailability of fluoride in a toothpaste. In the case of aerosolized products, control of the particle size and identity and purity of components are important for the safety of the user. In the case of topical cosmetic-type drugs, the incidence of allergic reactions may be lessened by the assurance of uniform quality of these products. That many of the general CGMP regulations are applicable to and reasonable for cosmetic-type drug products is evidenced by the fact that a majority of the specific suggestions submitted by the petitioner and others as applicable for cosmetic-type drug products duplicated in substance, a number of comments submitted by other OTC manufacturers and manufacturers of prescription drug products and the proposed text of part 211. Although he declines to provide a broad exemption for cosmetic-type drugs products, the Commissioner points out that a number of changes proposed by the comments are adopted in the final regulations. These suggested changes were appropriate for application to the manufacture of all drugs products, however, and not merely cosmetic-type drug products. In many instances the suggested changes that were adopted do not alter the original intent of the regulations, but clarify it or provide flexibility in complying. In a few cases, the proposed requirements were deleted or changed where the Commissioner concluded that they were not necessary to assure the quality of drug products, cosmetic- type or otherwise. i. Drug products that are also foods. Although no specific requests were received to exempt OTC drug products that are also human foods from Part 211, the Commissioner has tentatively concluded that there may be a few such products that would more appropriately be regulated under the good manufacturing practice regulations for food. He believes that the type of OTC drug products that could be exempted from Part 211 are those that are ordinarily marketed and consumed as human foods which may also fall within the legal definition of drugs by virtue of their intended use. Therefore, elsewhere in this issue of the FEDERAL REGISTER, the Commissioner is proposing to exempt such products if the products and all their ingredients are ordinarily consumed as human foods. Examples of products that the Commissioner foresees being covered by the proposed exemption are (1) Some candy cough drops formulated entirely of ingredients ordinarily consumed as human foods or ingredients of human foods; and (2) sodium bicarbonate labeled for use as an antacid but ordinarily use as an ingredient of human foods under the more common "baking soda" label. In proposing this exemption for certain OTC drug products, the Commissioner has considered, first, the inadvisability of applying drug CGMP regulations that are not necessary to ensure appropriate quality characteristics in view of the intended use of a product and, second, the reasonableness of applying food GMP regulations to a product manufactured, handled, and ordinarily consumed as a human food. Therefore, the Commissioner has stated under 211.1(c) that, pending considered of the proposal, the requirements of Part 211 will not be enforced for OTC drugs that meet the proposed definition. During the interim and until further notice, regulations under Part 110 (21 CFR Part 110) and, where applicable, Parts 113 to 129 (21 CFR Parts 113 to 129) shall be applied in determining whether these products are manufactured, processed, packed, or held under current good manufacturing practice. 43. One comment from a university school of pharmacy asked whether future proposed CGMP regulations would specifically state their applicability to such situations as (1) personnel at hospital "A" strip-packaging drug products for its own use as well as for use in hospitals "B" and "C"; (2) personnel at the warehouse of a chain of pharmacies who repackage and relabel quantities of drug products from manufacturers' original commercial containers for different units in the drug store chain; and (3) similar repackaging and relabeling by individual pharmacists as members of informal buying groups. As noted in paragraph 42(g) above, section 501(a)(2)(B) of the act applies to retail establishments, pharmacies, and hospitals, but the specific regulations in Part 211 do not. When CGMP regulations for repackers and relabelers are proposed, some of these questions posed in the comment will be addressed. Regarding pharmacies and hospitals in particular, however, it is the policy of FDA not to inspect routinely for compliance with section 501(a)(2)(B) of the act establishments that operate within State or local laws governing the practice of pharmacy. Nor has FDA ever sought to issue specific CGMP regulations for pharmacies engaged in traditional activities of dispensing or selling drugs at retail. This policy is consistent with statutory exemptions provided for pharmacies regarding establishment registration in section 510(g) of the act and regarding establishment inspection in section 704(a) of the act. When a hospital or pharmacy is engaged in drug repacking or relabeling operations that are beyond the usual conduct of dispensing or selling drugs at retail, however, the exemptions in the act cease to apply; the establishment is required to register and is subject to regular inspections under section 704 of the act. Furthermore, appropriate current good manufacturing practice must be complied with. 44. Several comments expressed concern about the applicability of CGMP regulations to foreign drug manufacturers. One comment said foreign drug manufacturers may not uniformly be subject to the stringent controls of United States manufacturers and that sampling of foreign drug products at the point of importation is not sufficient to assure the quality of those drugs. Two foreign drug manufacturers indicated that CGMP regulations had a significant impact on their operations. Another foreign manufacturer said their facilities were inspected annually by FDA with respect to antibiotic certification and new drug approvals. The act applies to drugs introduced into interstate commerce in the United States, including drugs imported from other countries. It does not, of course, apply to manufacturing of drugs in other nations if the drugs are not brought into the United States. Many foreign countries, however, have adopted requirements similar to CGMP regulations, and foreign manufacturers may be subjected to inspection by their own governments. International organizations such as the World Health Organization and the European Free Trade Association provide manufacturing standards and reciprocal agreements between participating countries. Overseas pharmaceutical manufacturers who export to the United States are inspected by FDA or under reciprocal inspection agreements as part of the new drug application approval process and antibiotic drug certification, and individual drug products are subject to intensive examination, including testing, before being allowed into the United States. If, for example, there is a question regarding the safety, identity, strength, quality, or purity of a drug product offered for import, FDA has authority to deny entry of the article unless factory inspection is permitted or inspectional information is available about those firms covered under reciprocal inspection agreements. The United State currently has reciprocal inspection agreements under which governments will exchange inspection information about domestic firms in lieu of conducting overseas inspections. These agreements are with Sweden, Switzerland, and Canada. Therefore, the Commissioner finds that there is adequate coverage of imported drugs to assure compliance with CGMP regulations. 45. Several comments referred to provisions in the Medical Device Amendments of 1976 and requested that FDA consider providing for exemptions from or variances to the CGMP regulations and special advisory assistance as Congress specifically mandated regarding FDA regulation of small manufacturers of medical devices. Along the same lines, a substantial number of comments were received from "small" drug manufacturers or organizations representing "small" drug manufacturers who strenuously oppose most of the proposed changes in the CGMP regulations. The tenor of the majority of the comments was that the proposed changes would seriously affect the initial and continuing costs of a "small" drug manufacturer but probably have little economic impact on, or could more easily be absorbed by, a "large" pharmaceutical manufacturer. Several comments expressed concern that generic drug manufacturers might be eliminated because they could not meet all the requirements of the proposed CGMP regulations and still compete in the marketplace. Arguments were presented that, because small manufacturers very often are involved with the manufacture of a small number of products (frequently less potent over-the-counter preparations) and almost by definition have small physical facilities, limited equipment, and few personnel, extensive formal quality control procedures are unnecessary to assure high quality of the drugs manufactured. One comment, apparently from a small manufacturer, agreed in principal with the proposed CGMP regulations, felt that size had very little to do with achieving good manufacturing practice, and offered comments on specific sections of the proposed CGMP regulations. The Commissioner rejects the contention that quality control procedures are unnecessary in the case of small firms; FDA's experience is that quality control procedures falling below those described in these regulations, in firms of great or small size, are often responsible for lack of drug product quality. The Commissioner also rejects the argument that less control need be exerted over so-called "less potent over-the-counter preparations," which respondents stated are often manufactured by small firms, for the reasons explained in paragraph 42(h) above. The Commissioner believes that the final regulations will be no more burdensome for small manufacturers than for others. Many interpretations offered in comments on specific sections strongly suggested that the intent of the proposed regulations had been misunderstood. The language has been clarified in the final regulations. In other instances the requirements were reworded to provide for more flexibility for the varieties of procedures and controls that may be utilized by various manufacturers. The Commissioner does not believe a specific provision within the CGMP regulations for variances to these regulations is necessary for small manufacturers. A mechanism already exists, however, in 21 CFR 10.30 for firms to petition for variances to or amendments in any regulation when the requirements are not reasonably attainable. For many years FDA has conducted and participated in numerous seminars and workshops designed to assist drug firms in interpreting and carrying out the requirements of CGMP regulations. Additionally, the agency has made films and publications available that are also designed to assist drug firms in their efforts to comply. The agency is committed to continuing these voluntary compliance efforts especially designed to assist small businesses. 46. Several comments noted that the current good manufacturing practice regulations do not pertain to veterinary biological products. One respondent suggested that the section specifically state that these regulations apply only to human biological products. The Commissioner believes that the section as proposed clearly establishes applicability to pertinent biological drug regulations, but for consistency with references elsewhere in the CGMP regulations to human biological drug products, he is revising 210.2 to specifically include reference to biological drug products for human use. 47. Several comments requested clarification of the last sentence of 210.2 to show that conflicting or contradictory regulations would be superseded by the one specifically applicable to the drug product. The Commissioner finds that the proposed wording clearly states his intent. Certainly, in the case of conflicting or contradictory regulations, it will be impossible to comply with all regulations and the regulation that is specifically applicable to the drug product in question would apply. 48. A comment suggested that if medicated premixes are meant to be excluded from Part 210, then Part 226 should be specifically excluded. The meaning of this comment, as it relates to 210.2 is not clear. The Commissioner advises that Part 210 applies to all the regulations in Parts 211 through 229. 49. One person proposed that the term "drug product" be replaced with the words "commercial dosage form" to exempt drugs undergoing development from the requirements of these regulations. The Commissioner finds that, as stated in 211.1, these CGMP regulations apply to the preparation of any drug product for administration to humans or animals, including those still in investigational stages. It is appropriate that the process by which a drug product is manufactured in the development phase be well documented and controlled in order to assure the reproducibility of the product for further testing and for ultimate commercial production. The Commissioner is considering proposing additional CGMP regulations specifically designed to cover drugs in research stages. VII. DEFINITIONS The Commissioner received hundreds of comments regarding definitions. General comments are listed immediately below; comments regarding specific definitions follow in numerical order. 50. One respondent said this section is inconsistent because certain terms such as "drug" and "establishment" which are defined in the act are not defined here, while other terms which are defined elsewhere are also defined here. The Commissioner believes that the length of part 210 would be unnecessarily increased by including in this part the definitions of terms that are well known or already defined in the act. Other terms the meaning of which may not be as readily recognized, or may vary in other regulations because of context and needs, are defined in part 210 as a standard reference. 51. One comment suggested that all terms defined in part 210 be highlighted in the running text. The Commissioner is not convinced that highlighting defined words in the running text offers any advantages over the more usual manner of printing. For example, some persons might interpret highlighting as adding emphasis that is not intended to a particular word or phrase. This suggestion cannot be adopted. 52. One respondent sugg