(a) Retail pharmacies in any State that are licensed and operating under applicable local laws regulating dispensing of prescription drugs, and who do not manufacture, prepare, propagate, compound, or process drugs for sale other than in the regular course of their business of dispensing and selling drugs at retail. (b) Practitioners in any State who are licensed by law to prescribe or administer drugs and who manufacture, prepare, propagate, compound, or process drugs solely for use in the course of their professional practice. (c) Persons in any State who manufacture, propagate, compound, or process drugs solely for use in research, teaching, or chemical analysis and not for sale. (d) Wholesale drug establishments that do not repackage or otherwise change the container or wrapper labeling of any drug packages, except that they may receive shipping cartons containing a number of individually and fully labeled packages of drugs the individual units of which they distribute without change. (e) Manufacturers of harmless excipients, colorings, and flavorings that become components of drugs, and who otherwise would not be required to register under the provisions of this part 132. (f) Manufacturers in any State of a virus, serum, toxin, or analogous product intended for treatment of domestic animals, who hold an unsuspended and unrevoked license issued by the Secretary of Agriculture under the animal virusserum-toxin law of March 4, 1913 (37 Stat. 832: 21 U.S.C. 151 et. seq.), and who would not otherwise be required to register under this section because of other drugs produced. (g) Manufacturers in any State of a virus, therepeutic serum, toxin, antitoxin, or analogous product intended for the prevention, treatment, or cure of diseases or injuries of man, who hold an unsuspended and unrevoked license issued by the Secretary of Health, Education, and Welfare under the Public Health Service Act of July 1, 1944 (58 Stat. 62 as amended; 42 U.S.C. 201 et seq.), and who would not otherwise be required to register under this section because of other drugs produced. The Commissioner of Food and Drugs hereby oïers an opportunity to all interested persons to submit their views in writing with reference to this proposal to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington 25, D.C., within 30 days from the date of publication of this notice in the FEDERAL REGISTER Views and comments should be submitted in triplicate. Dated: February 8, 1963. GEO. P. LARRICK, [F.R. Doc. 63-1569; Filed, Feb. 13, 1963; 8:45 a.m.] DRUGS; CURRENT GOOD MANUFACTURING PRACTICE, IN MANUFACTURE, PROCESSING, NOTICE OF PROPOSED RULE MAKING Under the provisions of the Federal Food, Drug, and Cosmetic Act (secs. 501 (a) (2) (B), 701(a); 52 Stat. 1050 as amended 76 Stat. 780, 781; 1055; 21 U.S.C.A. 351 (a) (2) (B), 371(a)), and the authority delegated to him by the Secretary of Health, Education, and Welfare (25 F.R. 8625), the Commissioner of Food and Drugs proposes the promulgation of the following regulations to establish criteria for current good manufacturing practice in the manufacture, processing, packing, and holding of drugs, to effect compliance with section 501(a)(2) (B) of the act: PART 133-DRugs; Current GOOD MANUFACTURING PRACTICE IN MANUFACTURE, PROCESSING, PACKING, OR HOLDING AUTHORITY: 133.1 to 133,13 issued under secs. 501, 701; 52 Stat. 1050 as amended 76 Stat. 780, 781; 1055; 21 U.S.C.A. 351, 371. § 133.1 Definitions. DEFINITIONS (a) As used in this Part 133, "act" means the Federal Food, Drug, and Cosmetic Act, sections 201-902, 52 Stat. 1052 (21 U.S.C. 321-392), with all amendients thereto. (b) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act shall be applicable to such terms when used in the regulations in this Part 133. FINISHED PHARMACEUTICALS; MANUFACTURING PRACTICE § 133.2 Current good manufacturing practice. The criteria in §§ 133.3-133.13, inclusive, shall apply in determining whether the methods used in, or the facilities or controls used for, the manufacture, processing, packing, or holding of a drug conform to or are operated or administered in conformity with current good manufacturing practice to assure that a 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, as required by section 501(a)(2)(B) of the act. § 133.3 Buildings. Buildings in which drugs are manufactured, processed, packaged, labeled, or held shall be of suitable design, size, construction, and location in relation to surroundings to facilitate maintenance and operation for their intended purpose in a manner that is orderly and clean. The buildings shall: (a) Provide adequate space for the orderly placement of equipment and materials used in any of the following operations for which it is employed, to minimize any risk of mix-ups between different drugs, their components, packaging, or labeling: (1) The receipt, sampling, and storage of raw materials. (2) Any manufacturing and processing operations performed on the drug. (3) Any packaging and labeling operations. (4) Storage of containers, packaging materials, labeling, and finished products. (5) Control, research, and production-laboratory operations. (b) Provide adequate lighting and ventilation, and when necessary for the intended production, control, or research purposes, adequate screening, filtering, dust, humidity, temperature, and bacteriological controls, as for example, to prevent contamination of products by extraneous adulterants; to prevent the dissemination of microorganisms from one area to another; to facilitate the sterilization of special work areas, such as those used for production of parenteral preparations, to provide suitable housing for any animals; and to avoid other conditions unfavorable to the safety and integrity of the product. (c) Provide for adequate washing, cleaning, toilet, and locker facilities. (d) Provide accessibility and kind of construction appropriate to the sound maintenance and cleanliness of buildings, materials, and equipment. § 133.4 Equipment. Equipment used for the manufacture, processing, packaging, labeling, holding, or control of drugs shall be of suitable design, size, construction, and location in relation to surroundings to facilitate maintenance and operation for its intended purpose in a manner that is orderly and clean. The equipment shall: (a) Be so constructed that any surfaces that come into contact with drugs are nonreactive, nonadditive, and nonabsorptive to the components or finished products. (b) Be so constructed that any substances required for the operation of the equipment, such as lubricants or coolants, may be employed without hazard of becoming additive to drag products. (c) Be constructed to facilitaté adjustment, cleaning, and maintenance as necessary to assure the reliability of control procedures, to assure uniformity of production, and to assure the exclusion from drugs of contaminants, including those from previous and current manufacturing operations. (d) Be of suitable size and accuracy for use in any intended measuring, mixing, or weighing operations. § 133.5 Personnel. The key personnel involved in the manufacture and control of the drug shall have a background of education and experience appropriate for assuming responsibility to insure that the drug has the safety, identity, strength, quality, and purity it purports to possess. § 133.6 Raw materials. Raw materials used in the manufacture and processing of drugs shall be identified, stored, examined, tested, inventoried, handled, and otherwise controlled in a manner to insure that they conform to appropriate standards of identity, strength, quality, and purity, and are free of dirt, vermin, and other contaminants at time of use, and to provide that appropriate records are maintained of their origin, receipt, examination, testing, disposition, and use in drug manufacture or processing. § 133.7 Master-formula and batch-production records. (a) For each drug product, a master-formula record shall be prepared, independently checked, and reconciled, endorsed and dated by at least two competent and responsible individuals. The record shall include: (1) The name of the product, a description of its dosage form, and a specimen or copy of the label and each other portion of the labeling contained in a retail package of the drug. (2) The weight or measure of each ingredient per dosage unit or per unit of weight or measure of the finished drug, and a statement of the total weight or measure of any dosage unit. (3) A complete batch formula for each batch size to be produced from the master-formula record, including a complete list of ingredients designated by names sufficiently specific to indicate any special quality characteristic; an accurate statement of the weight or measure of each ingredient, regardless of whether it appears in the finished product; an appropriate statement concerning any calculated excess of an ingredient; appropriate statements of theoretical weight or measure at various stages of processing; and a statement of the theoretical yield. (4) A description of the containers, closures, packaging, and finishing materials. (5) Manufacturing and control instructions, procedures, specifications, special notations, and precautions to be followed. (b) A separate batch-production and control record shall be prepared for each batch of drug produced and shall be retained for at least 2 years after all the batch has been distributed. The batch-production and control record shall include: (1) An accurate reproduction of the master-formula record, checked and endorsed by a competent, responsible individual. (2) A record of each step in the manufacturing, processing, packaging, labeling, and controlling of the batch, including dates, specific identification of each batch of raw material used, weights or measures of raw materials and products in course of processing, in-process and laboratory-control results, and the endorsements of each individual performing and checking each step in the operation. (3) A batch number that permits determination of all laboratory-control procedures and results on the batch and all lot or control numbers appearing on the labeling of drugs from the batch. $133.8 Production and control procedures. Production and control procedures, shall ir lude all reasonable precautions, including the following, to insure that the drugs produced have the identity, strength, quality, and purity they purport to possess: (a) Each critical step in the process, such as the selection, weighing, and measuring of raw materials; the addition of active ingredients during the process; weighing and measuring during various stages of the processing; and the determination of the finished yield shall be performed by a competent, re sponsible, individual and checked by a second competent, responsible individual. (b) All containers and equipment used in producing a batch of drugs shall be clearly labeled at all times to identify fully and accurately their contents, the stage of processing, and the batch, and shall be adequately segregated physically to prevent mixup with other drugs. (c) Equipment, utensils, and reused containers shall be thoroughly cleaned and previous identification removed between batches to prevent cross-contamination and mixups. (d) Appropriate procedures to minimize the hazard of contamination with microorganisms in the production of parenteral drugs, ophthalmic solutions, and any other drugs purporting to be sterile. (e) There shall be adequate in-process control to insure the uniformity and integrity of products, such as checking the weights and disintegration time of tablets, checking fill of liquids, and checking the adequacy of mixing, the homogeneity of suspensions, and the clarity of solutions. (f) Competent and responsible key personnel shall check actual against theoretical yield of a batch of drug, and in the event of any significant unexplained discrepancies shall prevent distribution of the batch in question and other associated batches of drugs that may have been involved in a mixup with it. § 133.9 Product containers. Suitable specifications, test methods, cleaning procedures, and, when indicated, sterilization procedures shall be used to insure that containers, closures, and other component parts of drug packages are suitable for their intended use so that the container is nonreactive, nonadditive, and nonabsorptive to the drug and furnishes adequate protection against its deterioration or contamination. § 133.10 Packaging and labeling. Packaging and labeling operations shall be adequately controlled to insure that only those drugs that have met the specifications established in the masterformula records shall be finished; to prevent mixups between drugs during the packaging and labeling operations; to insure that correct labeling is employed for the drug; and to identify finished products with lot or control numbers that permit determination of the history of the manufacture and control of the batch of drug. Packaging and labeling operations shall: (a) Be performed with adequate physical segregation of such operations from operations on any other drugs to avoid mixups. (b) Provide that each type of labeling used shall be stored in a manner that avoids mixups between labelings and shall be carefully checked for identity and conformity to the labeling specified in the batch-production records. (c) Provide adequate control of the quantities of packaging and labeling materials issued for use in finishing a batch of drug. (Competent, responsible key personnel shall reconcile any discrepancy between the quantity of drug finished and the quantity of packaging and labeling materials issued. In the event of any significant unexplained discrepancy, such personnel shall prevent distribution of the batch in question and other associated batches of drugs that may have been involved in a mixup.) (d) Provide for adequate examination and laboratory testing of adequately representative samples of finished products after packaging and labeling to safeguard against any error in the finishing operations, and to prevent distribution of any batch until all specified tests have been met. § 133.11 Laboratory controls. Laboratory controls shall include the establishment of adequate specifications and test procedures to insure that raw materials, drug preparations in the course of processing, and finished products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: (a) The establishment of master records containing appropriate specifications for each kind and quality of raw material used in drug production and a description of the test procedures used to check them, including provision for testing adequately representative samples. Such records shall also provide for appropriate retesting of materials subject to deterioration. (b) The establishment of appropriate specifications, when needed, for drag preparations in the course of processing, and a description of the test procedures to check them, including provision for testing adequately representative samples. (c) The establishment of appropriate finished-product specifications and a description of laboratory test procedures to check them, including provision for testing adequately representative samples. 37-272-64-pt. 1—————7 (d) Adequate provision for checking the identity and strength of all active ingredients of drugs, for insuring the sterility of articles purporting to be sterile, and the freedom from pyrogens of articles that should be tested for freedom from pyrogens. (e) Adequate provision to check the reliability, accuracy, and precision of any unverified laboratory test procedures used. (f) Provision for complete records of all data concerning laboratory tests performed, including the dates and endorsements of individuals making the tests, and provision for specifically relating the tests to each batch of drug to which they apply. Such records shall be retained for at least 2 years after all the batch to which they relate has been distributed. §133.12 Distribution records. Complete records shall be maintained of the distribution of each batch of drug in a manner that will facilitate its recall if necessary. Such records shall be retained for at least 2 years after all the batch has been distributed and shall include the name and address of the consignee, the date and quantity shipped, and the lot or control numbers identifying the batch of drug. §133.13 Stability. Adequate provision shall be made for testing the stability of raw materials, drug preparations in the course of processing, when needed, and finished drugs. Such stability tests shall: (a) Make adequate provision for determining the reliability and specificity of stability test methods employed. (b) Make adequate provision to determine the stability of products in the containers in which they are marketed to insure, among other things, that the container is nonreactive, nonadditive, and nonabsorbtive to the drug. (c) Provide for stability studies of any solutions prepared as directed in the drug labeling at time of dispensing. (d) Provide for suitable expiration dates to appear in the labeling of the drug when needed to insure that the drug meets appropriate standards of identity, strength, quality, and purity at time of use. These proposed regulations have been prepared primarily to establish criteria of current good manufacturing practice for the production of finished pharmaceuticals. It is recognized that some modification of these proposed concepts is indicated in connection with their application to the manufacture of chemicals and other raw materials used as components of finished drugs and in connection with their application to the production of such drugs as medicated feeds for administration to animals, in which current practice involves less rigid conditions. Consideration is being given to additional proposed regulations dealing with these areas. The Commissioner of Food and Drugs hereby offers an opportunity to all interested persons to submit their views in writing with reference to this proposal to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington 25, D.C., within 45 days from the date of publication of this notice in the FEDERAL REGISTER. Views and comments should be submitted in triplicate. Dated: February 11, 1963. GEO. P. LARRICK, Commissioner of Food and Drugs. [F.R. Doc. 63-1612; Filed, Feb. 13, 1963; 8:45 a.m.] [For release to drug trade journals, Apr. 4, 1968] Washington, D.C. REGULATIONS ISSUED FOR REGISTRATION OF DRUG FIRMS The Food and Drug Administration today announced its new regulations governing registration of drug establishments, and reminded firms that initial registration must be completed by May 1 Registration forms are being mailed to all persons on FDA's drug trade mailing lists, and are available on request at FDA headquarters in Washington and from its 18 field district offices. |