Document BRkKwNLXJq7BEXxL2EBnxy94

JOSEPH E KELLER JEROME H, HECKMAN CHARLES M. MEEHAN WILLIAM H, BOROHESANI, JR. ROBERT H TIERNAN WAYNE V. BLACK THOMAS J. HUGHES, JR DAVID L HILL MARTIN W BEHCOVICI LAW OFFICES Kellee ajstd Heckman 1113 N 5THEET, N. W. WASHINGTON, D C. SOQ36 October 6, 1969 1 TELEPHONE 203 896-2TOO CABLE ADDRESS "KEOLAN Mr. Robert M. Miller Hercules Inc. Delaware Trust Building Wilmington, Delaware Dear Bob: In accordance with your recent instructions, and because we have received a number of inquiries regarding the matters we shall cover in this letter from various mem bers of the Food, Drug and Cosmetic Packaging Materials Committee, the purpose of this com munication will be to inform everyone in a general way about two presently oending rule making proceedings of some interest. Actually, and as I told you, we do not believe that either rule making proceeding calls for formal action by the Committee since, in our opinion, neither will change any substantive responsibility of the industry. The first of the rule makings was announced in the August 14, 1969 Federal Regis ter by the publication of a very comprehensive "Notice of Proposed Rule Making" released by the Consumer and Marketing Service of the Department of Agriculture. In issuing this Notice, the Department pointed out that the Federal Meat Inspection Act was extensively re vised by the Wholesome Meat Act of 1967, and that this revision of the legislation is what has necessitated the making of appropriate and numerous changes in, and additions to, the Federal Meat Inspection Regulations. For all practical purposes, the only portion of this Notice of Proposed Rule Making which has any bearing on packaging materials, ASI-PR 0000704 Mr. Robert. M- Miller October- 6, 1969 Page Two and the traditional clearance thereof by the Technical Services Division of the Consumer and Marketing Service, is Section 317.4. For the convenience of the members of our Com mittee , we have reproduced and are herewith enclosing a copy of Page 13220 of the August 14, 1969 Federal Register, this page being the one which sets forth the proposed new Section 317.4. Shortly after the Department of Agriculture rule making was announced, we were in touch with Mr. R. H. Philbeck of the Technical Services Division to inquire of him as to whether the new Section 317.4 would result in any changes in the way in which he has been handling requests from plastics industry packaging materials suppliers for approvals of their products. As we expected, Mr. Philbeck pointed out that he would be con tinuing to follow the very same procedures he has followed for many years in dealing with data and requests for approvals which allow the use of packaging materials and components in Federally inspected meat and poultry plants. The only change in the present pro cedures contemplated is that, once the new rules.are in effect, the operators of Feder ally inspected establishments (not their suppliers) will be required to file a very simple form (Form CP-481) to make certain that they have the authority they require to use given packages, or packaging components, in their plants. In other words, no change is being made in the Regulations which will affect those who sell finished packages or packaging components, but the meat producers operating Federally inspected establishments will have to file Forms CP-481. ASI-PR 0000705 Mr. Robert M. Miller October 6, 1969 Page Three Incidentally, and again simply for your information, we have obtained a copy of this Form from Mr. Philbeck and one is enclosed herewith. Please forgive the fact that the copy is a rather rough one; the only reason for this is that the Form had not been printed at the time we were in touch with Mr. Philbeck so we were happy to have the reproduction he gave us of an office galley proof copy. - r The one possible change I can think of that might be required in the practices of our membership by the new Technical Services Division procedure, once the rule making is adopted, is that some companies which have not assigned some sort of code number or name to one or all of their products may find it necessary to do so. This will provide the identification Mr. Philbeck's group will need for cross-referencing ''Packaging Composition Statements" received from Federally inspected establishments to the data and approval letters given for specific packaging products , l'* One last point concerning the USDA rule making may be of interest to you. The original deadline data for comments on the entire proposal was October 12, 1969. By means of a notice announced on October 2, 1969 in the Federal Register, the deadline date has now been extended to December 12, 1969. In a totally unrelated area, we would also like to call the attention of the members of the Committee to the fact that, beginning on Page 13553 of the August 22 Federal Register, the Food and Drug Admini stration announced a "Notice of Proposed Rule Making" to amend Part 133 of its drug regulations "to clarify, strengthen, and make more specific the good manufacturing practice regulations for drugs." While it ASI-PR 0000706 Mr. Robert M. Miller October 6, 1969 Page Four should be noted that it is proposed to revise the present Section 133.9 (Product Containers) section of these regulations by the making of a number of editorial changes, having compared the present Section 133.9 with the newly pro posed one, we do not believe that any of these changes will adversely affect the plastics industry. Nevertheless, we have reproduced and are herewith enclosing a complete copy of the FDA proposal. Should any member of the Committee have questions about these proposals, or care to give us any comments on them, we would be most pleased to hear from him. Unless we receive contrary instructions from you, we shall not plan to do anything further about these matters, other than to watch for finali zation of the rule makings so that we can report to the Committee when the rules have been formally amended. enclosures cc SPI Food, Drug and Cosmetic Packaging Materials Committee 0000707 ASI'Pr 13220 PROPOSED RULE MAKING 317-4 Packaging and oilier container*, approval required; conditions anil proftiltin'. (a) Label approval lor any product hall be contingent upon approval of the ickaging ana -ill other containers to bo ased with the roduct. Such approval will be given o:u. If it is found that the containers are i t composed, In whole or in part, of any poisonous or deleterious substance which will directly or Indi rectly render the contents Injurious to health. (b) (1) To request approval of any container, the operator of the establish ment shall submit a completed "Packag ing Composition statement" 3 to the Di rector, Technic, n Services Division, Consumer; and Marketing Service, U.S. Department of Agriculture, Washington, D.C.30250. (2) This form is supplied by the Con sumer and Marketing Service and shall be completed by the applicant for ap proval of the container. (3) The coo ition statement shall include a desci ipuon of the packaging or other containers and a list of their com ponents, each identified by the name of the manufacturer and his identifying trade name and code. Container com ponents shall inc' .de those applied in the establishmentue . as Inks and adhesives. (4) Form CP-481 must be completely filled out by the applicant before the application will oe acted upon. The fol lowing information must be supplied and entered in the spaces in the application form indicated below. (I) In space 1, enter the official es tablishment number, if any. (II) In space 2, enter the name of the roduct as it will appear on the label. (ill) In space 3A, state the size and type of container and how the container will be used In relation to the product. (lv) In space 3B, specify each com ponent part of the material. It is not unusual for a package to have more than one Ink adhesive or coating. (v) In space 3C, enter the name and address of the manufacturer for each of the packaging components shown in 3B. (vt) In space 3D, enter the trade name or manufacturer's code for each of the packaging components shown in 3B. (vii) In space 4. enter date signed by the applicant's representative. (vtil) Space 5 shall contain the signa ture of the authorized representative of the applicant. Spaces 6, 7, and 8 are reserved for use by the Washington office. 317,5 Officer in cliurgc to permit cer tain modifications of approved labels. The officer In charge may permit mod ification of approved labels or markings, under the following circumstances, pro vided the labeling or marking as modified is so used as not to be false or misleading: (a) When all features of the label or marking are proportionately enlarged and the color scheme remains the same. Copy filed with the Office of the Federal Register as pert ot the original document. (b) When changes are made In the for such product by the Administrator: figures denoting the quantity of contents Provided, or when there is substitution of such (a) That the propped labeling ac abbreviations as "lb" for "pound", or cords to the specifications of the foreign "oz." for "ounce", or the word "pound" or purchaser. "ounce" Is substituted for the abbrevia (b) That it is not in conflict with die tion. laws of the country to which the product (c) When a master or stock label Is is intended for export, and approved, from which the name and ad (C) That the outside container is dress of the distributor are omitted and labeled to show that it is intended for such name and address are applied be export: but if such product is sold or fore being used, the words "prepared offered for sale in domestic commerce, for" or similar statement must be shown all the requirements of this subcliapter together with the blank space reserved apply. The inspection legend and the for the Insertion of the name and address establishment number shall in all cases when such labels are offered for approval. appear in English but In addition, may (d) When, during Christmas and appear literally translated in a foreign other holiday seasons, wrappers or other language. covers bearing floral or foliage designs or illustrations of rabbits, chicks, fire works, or other emblematic holiday de signs are used with approved labels or markings. The use of such designs will not make necessary the application of labeling not otherwise required. (e) When there is a slight change in arrangement of directions pertaining to the opening of cans or the serving of the product. (f) When there is a change in the quantity of an ingredient shown in the formula without a change in the order of predominance shown on the label: Provided, That the change In quantity of Ingredients complies with any minimum or maximum limits for the use of such ingredients prescribed in Farts 318 and 310 of this subchapter. 317.8 False or mi'-Iending l.dieling or practices generally; specific prohibi tions and requirements for labels mid containers, (a) No product or any of its wrappers, packaging or other containers .hall bear any false or misleading marking, label or other labeling and no statement, word, picture, design, or device which conveys any false impression or gives any false indication of origin or quality or is other wise false or misleading shall appear in any marking or other labeling. No prod uct shall be wholly or partly enclosed in any wrapper, packaging or other con tainer that is so made, formed, or filled as to be misleading. (b) The labels and containers of prod uct shall comply with the following pro visions, as applicable. 317.6 Approved labels to be used only (1) Terms having geographical sig on products to which they are appli nificance with reference to a locality cable. other than that in which the product is Labels shall be used only on products for which they are approved, and only if they have been approved for such products in accordance with f 317.3: Provided, That existing stocks of labels approved prior to the effective date of this section and which bear the official inspection legend and all other infor mation required by subparagraph (3) and subparagraphs (5) through (11) of paragraph l(n) of the Act and comply with subparagraphs (1) and (2) of para graph l(n> of the Act, and the quantity of which has been identified to the officer in charge as being in storage on said date at the official establishment or other identified warehouse for the account of the operator of the official establishment, may be used until such stocks are ex hausted, but not 'later than 6 months after the effective date of this section unless such labels conform to all the requirements of this part and Part 319 of this subchapter. prepared may appear on the label only when qualified by the word "style." "type," or "brand," as the case may be, in the same size and style of lettering as in the geographical term, and accom panied with a prominent qualifying statement identifying the country, State. Territory, or locality in which the prod uct is prepared, using terms appropriate to effect the qualification. When the word "style" or "type" is used, there must be a recognized style or type of product identified with and peculiar to the area represented by the geographical term and "the product must possess the character istics of such style or type, and the word "brand" shall not be used In such a way as to be false or misleading: pr -ided. That a geographical term wliun has come into general usage as a trade nnme and which has been approved by the Ad ministrator as being a generic term may be used without the qualifications pro vided for in this paragraph. The terms "frankfurter." "Vienna," "bologna," 317.7 Product!) for foreign commerce; "lebanon bologna," "braunschcweigcr," printing labels in foreign language "thuringer." "genoa," "leona," "ber- permissible; other deviations. llner," "holsteln," "goteborg." "milan." Labels1 to be affixed to packages of "polish," and their modifications, as ap product for foreign commerce may be plied to sausages, the terms "brunswick" printed In a foreign language and may and "Irish" as applied to stews, and the show the statement of the quantity of term "boston" as applied to pork shoul contents in accordance with the usage of der butts need not be accompanied with the country to which exported and other the word "style," "type," or "brandor deviations from the form of labeling re a statement identifying the locality in quired under this part may be approved which the product is prepared. FEDERAL REOISTER, VOL 34, N . 153--THURSDAY, AUGUST 14, 1949 ASI-PR 0000708 H* * W * (7-1-GS) U, S. HLPAIilMLNT OP AGRICULTURE CONSUMER AND MAfillt- TING SERVCE TECHNICAL SL'KVIC. 5 piMMON WASHINGTON, O. C. 101C0 PACKAGING COMPOSITION STAYC.V.EMT APPLICANT; ?ii!''-mi in lUij'iicnfc to .-uljrcss shown nhovc. I, ESTABLISHMENT IIO. 2. PRODUCT TO UK PACKAGED 3. conv/,i;1: r. r.::scRin ioi: JA. St2 0. USE, CONSTRUCTION 01- CAN. CARTON, CASING, ETC. roiiM approved JtioGCT [pjnlau no. '.o-nUiiz ".V.--.. >?1 f-uu u:.i ur uiUA ACCEPTANCE NO. Jjs'if not occupied, ioc *ki;er.'.ar(;s by U1DA, Y/oshlngtoft, f), C*'r Latov/ 7. DATE m .^'i 10. SIGNATURE O? USOA REPRESENTATIVE 1 ft /, ASI-PR 0000709 (Reprinted from Federal Register of August 22, 1969; 34 F.R. 13553) DEPARTMENT OF HEALTH, EDU CATION, AND WELFARE Food and Drug Administration t 21 CFR Part 133 1 DRUGS; CURRENT GOOD MANUFAC TURING PRACTICE IN MANUFAC TURING, PROCESSING, PACKING, OR HOLDING Notlto of Proposed Rule Making Pursuant to the provisions of the Fed eral Food, Drug, and Cosmetic Act (sees. 501, 701 (a). 52 Stat. 1049-50, as amended. 1055; 21 U.S.C. 351, 371(a)) and under authority delegated to him (21 CFR 2.120), the Commissioner of Food and Drugs proposes to amend Part 133 to clarify, strengthen, and make more specific the good manufacturing practice regulations for drugs. According, it is proposed that If 133.1 through 133.14 be revised to read as follows: 133.1 Definitions* (a) As used In this part, "act" means the Federal Food, Drug, and Cosmetic Act. sections 201-902, 52 Stat. 1052 (21 US.C. 321-392), with all amendments thereto. (b) The definitions and interpreta tions contained in section 201 of the Fed eral Food. Drug, and Cosmetic Act shall be applicable to such terms when used In the regulations in this part, (c) As used in this part: (1) The term "medicated feed" me.ins any "complete feed," "feed additive sup plement," or "feed additive concentrate," as defined in 1 121.200 of this chapter, which feed contains one or more drugs as defined in section 201(g) of the act. Medicated feeds are subject to SI 133 100133.110, inclusive. (2) The term "medicated premix" means a substance that meets the defini tion In 3 121.200 of this chapter for a "feed additive premlx," except that It contains one or more drugs as defined in section 201 <g> of the act and Is Intended for manufacturing use in the production of a medicated reed. Medicated premixes are subject to II 133.200-133.310, Inclusive. (d) As used in 55 133 2-133.14 in clusive: (1) The term "component" (raw ma terial) means any ingredient Intended for use in the manufacturing of drugs, including those that may not appear in the finished product. (2) The term "batch" means a spe cific homogeneous quantity of a drug produced according to a single manufac turing order during the same cycle of manufacture. (3) The term "lot" means a batch or any portion of a batch of a drug or. In the case of a drug produced by a con tinuous process, an amount of drug pro duced in a unit of time or quantity in a manner that assures Its uniformity, and In either case which is identified by a distinctive lot number and has uniform character and quality within specified limits. (4) The terms "lot number" or "con trol number" mean any distinctive com bination of letters or numbers, or both, by which .the complete history of the manufacture, control, packaging, and distribution of a batch or lot of a drug Is determined. (5) The term "active ingredient" means any substance of a drug which is Intended to furnish pharmacological ac tivity or other effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of man or other animals. (8) The term "inactive ingredient" means any substance other than an "ac tive Ingredient" present In a drug. (7) The term "materials approval unit" means an organizational element having the authority and responsibility to approve or reject raw materials, inprocess materials, packaging compo nents, and final products.. (8) The term "strength" means (1) the concentration of a known active drug substance in formulation (for example, w/w, w/v. or unit dose/volume basis) and/or (11) potency, that is, the specific ability or capacity of the product as in dicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner Intended to effect a given reeult(s) (expreeaed, for example, In terms of units by reference to a standard). 133.2 Current good manufariiiring prauite. The criteria in 51 133.3-133,14, inclu sive, 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 adminis tered 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 pur ity characteristics which it purports or is represented to possess, as required by section 501(a)(2)(B) of the act. The regulations in this part permit the use of precision automatic, mechanical, or elec tronic equipment in the production and control of drugs when adequate inspec tion and checking procedures are used to assure proper performance. 133,3 Buildings. Buildings shall be maintained in a clean and orderly manner and shall be of suitable size, construction, and loca tion in relation to surroundings to facili tate adequate cleaning, maintenance, and proper operations for their intended purpose--the manufacturing, processing, packing, labeling, or holding of a drug. The buildings shall; () Provide adequate space for: (1) Orderly placement of equipment and materials to minimize any risk of mlxups between different drugs, drug components, in-process materials, pack aging. or labeling, and to minimize the possibility of cross-contamination of one drug by another drug(s). (2) The receipt, storage, and with holding from use of components pend ing sampling, identification, and testing prior to release by the materials approval unit for manufacturing or packaging. (3) The holding of rejected compo nents prior to disposition in such a way as to preclude the possibility of their use in any manufacturing or packaging procedure. (4) The storage of components ap proved for use. (5) Any manufacturing and process ing operations performed on the drug. () Any packaging and labeling operations. (7) Storage of containers, packag ing materials, labeling, and finished products. ASI-PR 0000710 2- - (8) Control and production-labora tory operations, (b) Provide adequate lighting, ven tilation. and. when necessary for the In tended production or control purposes, facilities for adequate air-pressure, microbiological, dU3t. screening, filter ing, humidity, and temperature eontiols to: <1> Minimize contamination of prod ucts by extraneous adulterants (includ ing cross-contamination of one pioduct by dust or particles of Ingredients aris ing from the manufacture, storage, or handling of another drug'. (2) Minimize dissemination of micro organisms from one area to another. <c) Provide for adequate locker facili ties and hot and cold water washing facilities Including soap or detergent, air drier or single service towels, and clean toilet faculties near working areas. <d> Provide an adequate supply of potable water (PHS standards) under continuous positive pressure In a plumb ing system free of defects which could cause or contribute to contamination of the product. Drains shall be of adequate size and, where connected directly to a sewer, shall be equipped with traps to prevent back-siphonage. (e> Provide suitable housing and space for the care of all laboratory animals. (f) Provide for safe and sanitaiy dis posal of sewage, trash, and other refuse. 133.4 Equipment. Equipment used for the manufacture, processing, packing, labeling, holding, testing, or control of drugs shall be main tained In a clean and orderly manner and shall be of suitable design, size, con struction, and location In relation to sur roundings to facilitate cleaning, main tenance, and operation for Its Intended purpose. The equipment shall: (a) Be so constructed that all surfaces that come Into contact with a drug shall not be reactive, additive, or absorptive so as to alter the safety. Identity, strength, quality, or purity of the drug or its com ponents. beyond the official or other established requirements <b) Be so constructed that any sub stances required for operation of the equipment, such as lubricants or cool ants, do not contact drug products. (c) Be constructed and installed to fa cilitate adjustment, disassembly, clean ing, and maintenance as necessary to assure the reliability of control proce dures. uniformity of production, and exclusion from drugs or contaminants (for example, pesticides, lubricants), In cluding contaminants from previous and current operations (for example, crosscontamination with penicillin or any other drug). (d) Be of suitable type, size, and accuracy for any Intended testing, meas uring. mixing, weighing, or other proc essing or storage operations. fi 133.5 IVr-onncl (a) The personnel responsible for di recting the manufacture and control of the drug shall be adequate in number and background of t un Mton and experi ence to a.ssuie that the drug lias the safety, identity, slienglh, quality, and purity that it pin ports pi possess All per sonnel shall have capabilities commen surate with their assigned functions, a thorough understanding of the manu facturing or control operations which they pcrfoim, the necessary training and experience vcloling to Individual prod ucts, and adequate Information concern ing the reasons for and the application of the pertinent provisions of this part to their respective functions, <b) Personnel having direct contact with drugs shall have periodic health checks, and shall be free from communi cable disease and open lesions on the exposed surface of the body. 133.(1 (ImiiHUW'iiU (rmv material..). Components used In the manufacture and processing of drugs (Including those components that undergo chemical change or arc eliminated in the process) shall be withheld from such use until they have been identified, sampled, and tested for conformance with established specifications that are appropriate and adequate, and are released by the ma terials approval unit. Control of com ponents shall Include the following: (a) Each container of components shall be examined visually for damage or contamination In transit. Including examination for breakage of seals when Indicated. <b) An adequate number of samples shall be taken from a representative number of component containers and shall be subjected to one or more iden tity tests, including at least one labora tory test for identity. ic) Representative samples of all components shall be appropriately exa mined, including when Indicated micro scopic examination, for evidence of filth, Insect Infestation, or other extraneous contamination. id) Representative samples of com ponents particularly liable to contami nation with highly toxic substances (for example, heavy metals), as Indicated by tests for such substances In monographs of the official compendia, shall be tested to assure that official compendia or other appropriate limits for such Impurities are not exceeded. le) Representative samples of all components intended to be used as active ingredients shall be tested to determine their strength per unit of weight or measure to assure compliance with ade quate specification for such strength. (f) Representative samples of com ponents subject to microbiological con tamination (such as those of animal and botanical origin) shall be subjected to microbiological tests. Such samples shall contain no micro-organisms which are objectionable In view of the intended use of the components. (g) Approved components shall be ap propriately marked and retested as nec essary to assure that they conform to appropriate specifications of Identity, strength, quality, and purity at time of use. This requires the following: < 1) Approved components are so han dled and stored os to guard against their contaminating other drugs by dust or other particles resulting from such handling and storing. Similarly, ap proved components are so handled and stored as to guard against their being contaminated by other preparations, substances, dust, or other particles re sulting from such handling and storing (2) Approved components shall be rotated in such a manner that the oldest stock is used first. (3) Rejected components shall be so marked and held as to preclude the pos sibility of their use in any manufactur ing or processing procedure. (4) Appropriate records shall be maintained of the name of the supplier, lot number of each component, date and amount received, and examinations and tests performed. Said records shkll also show any components rejected and their disposition. An Individual Inventory record shall be maintained for each com ponent lot showing the amount of com ponent used In each batch of drug manu factured or processed. ih) A reserve sample of all active in gredients consisting of at least twice the quantity necessary for all required tests of Identity, quality, purity, and strength shall be retained for at least 2 years after distribution of the last drug lot incor porating the active ingredient has been completed, or l year after the expiration date of this last drug lot Incorporating the active Ingredient, whichever Is short est, 133.7 IMu-ier.forfinilii arid fxit<ii-pm. flilcliun records, tai To assure diug batch unifoinuty, a master-formula record for each drug product and each batch .size of such drug product shall be prepared, endorsed, and dated by a competent and responsible individual and shall be Independently checked, reconciled, endorsed, and dated by a second competent and responsible Individual. Master-formula records shall be retained for a period of at least 2 years after distribution of the lost drug batch produced using the masterformula record, or 1 year after the ex piration date of tills last drug batch, whichever Is shortest. The masterformula record shall Include: (1) The name of the product, a descrip tion of Its dosage form, and a specimen or copy of each label and all other label ing contained In a retail package of the drug (In private foitnula production, upon receipt of a written order for a portion of the drug stored In bulk form, a specimen or copy of the label to be used in filling that order shall be at tached to the master-formula record prior to the reproduction of the batch records.) Also Included shall be copies of the fiiml draft of each label and all other labeling contained In a retail pack age of the drug and their printing au thorization, dated and endorsed by the responsible person or persons approving the draft. (3) The name and weight or measure of each Ingredient per dosage unit or per A5I"PR 0000711 I 3 unit of weight or measure of the finished drug, and a statement of the totai weight or measure of any doeage unit. <3> A complete list of Ingredients designated by names or codes sufficiently specific to Indicate any special quality characteristic: an accurate statement of the weight or measure of each ingre dient regardless of whether it appears In the finished product, except that reason able variations may be permitted In the amount of components necessary in the preparation in dosage form provided that the variations are stated in the master formula; an appropriate statement con cerning any calculated excess of an in gredient: and 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, and packaging, and finishing materials. (5) Manufacturing and control in structions, procedures, specifications, special notations, a : precautions to bo followed. (b) Readily accessible records shall be prepared for each batch of drug pro duced and shall Include complete In formation relating to the production and control of each such batch. Said records shall be retained for at least 2 years after batch distribution is com plete, or 1 year after the batch expira tion date, whichever Is shortest Tire records relating to production, including packaging, labeling, and control of each batch, plus copies of the labeling bearing the lot or control numbers used on the batch, shall be readily available during such retention period. The batch records shall Include: (1) An accurate reproduction of the appropriate master-formula record checked and endorsed by a competent, responsible Individual. (2) Records of each step In the manu facturing, processing, packaging, label ing. testing, and controlling of the batch, Including dates, individual major equip ment and lines employed, specific Identi fication of each batch of components used, weights or measures of components and products used in course of proc essing, in-process and laboratory-control results, and'the endorsements of the In dividual actively performing and the In dividual actively supervising or checking eadh step in the operation. (3) A batch number that permits de termination of all laboratory-control procedures and results on the batch, and all lot or control numbers appearing on the labeling of drugs from that batch, Including copies of the labeling bearing the lot or control numbers used on the final containers of the batch. (4) A record with complete Investiga tive history of any mlxups, errors, and unsatisfactory drug products found dur ing and after drug manufacturing, proc essing, packaging, labeling, testing, controlling, and distributing of the batch. This investigative history shall be evalu ated by competent and responsible per sonnel and, where indicated, appropriate action shall be ` - u, ;-ul 1 it.i,; shall r ,nt;vnd: ": m -if im >i '-'Iffijln t?rod'irM indicate the evitiu *' '-m and -,u lion by penicillin In tb eslabllslunenta Li.:''- 133.il IVimIij'O dun-s. * ," .nnlrol jiior/'- Production an I : ul procedures shall Include all roa-w , aide precautions, including the following, to assure that the drugs produced have (hf safety, Iden tity, strength, quality and purity they purport to possess1 (fti Each critical slop in the process, such as the selection, weighing, and measuring of components, the addition of active Ingredients during the process, weighing and mensuring during various stages of the processing, and the determi nation of the finished yield, shall be per formed by a competent, responsible Individual and checked by a second com petent, responsible individual; or if such steps In the processing are controlled by precision automatic, mechanical, or electronic equipment, their proper per formance is adequately checked by one or'more competent, responsible Individ uals. The written record of the critical steps in tlie process shall be initialed by the individual poriormlng the critical step and also Initliilod by the Individual charged with checking each critical step, (b) All containers, lines, and equip ment used in producing a batch of drugs shall be distinctly labeled at all times to identify accurately and completely their' contents, the stage of processing, and the batch. For equipment and Unos, placement of tlvis identification shall in clude, where applicable. Input lines, out put lines, and operator controls. All containers, lines, and equipment used in producing a batch of drugs shall be stored and handled In a manner adequate to prevent mlxups or contamination with other drugs. (cl Equipment, utensils, and con tainers shall be thorougirly cleaned and nmnufacture, >l-ire, or handle penicillin as well 03 notuvnirlllln products. (f) To assure the uniformity and Integrity of products, there shall be an quale in,process controls, such as check ing the weights and disintegration time of tablets, the fill of liquids, the adequacy of mixing, the homogeneity of suspen sions, ami the clarity of solutions. Such in-process testing shall be done at appro priate intervals during each Individual operation, when practicable. Using read ily accessible, adequate, and suitable equipment. A written record of all sw !, teats shall be maintained, including the date and time of each test, the product name and batch number, the quantity tested, the results, and the Initials of the person performing the test. (gi Competent and responsible per sonnel shall check actual against theo retical yield of each batch of drqg, or at appropriate Intervals in continuous pro duction operations, and In the event of any significant unexplained discrepan cies shall prevent distribution of the batch In question and other associated batches of drugs that may have been in volved. A satisfactory explanation for any significant discrepancy between the oretical and actual yields shall be entered on the batch record and signed by the person who Investigated the discrepancy. This record shall also contain a state ment on criteria used In accepting or rejecting such a batch. (h) -In-process batches of drugs found unacceptable to the firm shall be held until a determination as to their dispo sition has been made. Appropriate records shall be maintained which re flect the reason(s) for unacceptability and the ultimate disposition of this material. properly stored and have previous batch (I) Certifiable antibiotics and insulin identification removed between batches, are to be withheld from distribution or at suitable intervals In continuous until the certification certificate is production operations, to minimize the actually received unless exempted by hazard of contamination with micro Part 144 of this chapter. All oilier drugs organisms and to prevent other contami shall be withheld from distribution until nation and mixups. Equipment being released by the materials approval unit employed for consecutive Identical prod on the basis of satisfactory control tests. uct batches shall be thoroughly cleaned (J) Returned goods shall be so identi at suitable Intervals. All equipment used fied and held. If the condition of the in the handling of sterile products shall container, carton, or labeling is such as be appropriately cleaned and. when to cast do*ibt on the identity, strength, necessary, sterilized prior to use. quality, or purity of the drug, the re (d) Appropriate procedures, such as turned goods shall be destroyed or sub the following, shall be taken to minimize jected to the complete protocol of test the hazard of contamination with micro ing (to assure that the material will organisms In the production of paren meet all appropriate standards and teral drugs, opthalmlc solutions, and any specifications i before being returned to other drugs purporting to be sterile: stock for warehouse distribution or re (1) Filling operations shall be per packing. No returned goods shall be formed with adequate physical segrega reprocessed unless they have been found tion from similar operations on any other by appropriate tests not to have under drugs to avoid cross-contamination. gone any significant physical, chemical, (2) Proper control of air movement or microbiological degradation and not and air filtration prior to entry and dis to have become contaminated with ex charge shall be provided in all sterile areas to minimize microbiological con tamination, particulate matter, and cross-contamination of one drug with another. traneous substances or filth. Records of returned goods shall be maintained and hall indicate the amount returned, date, and actual disposition of the product, (e> Appfoprlate procedures shall be such as reprocessed, destroyed, or re taken to minimize the hazard of cross- turned to stock. ASI-PR 0000712 4 - | 133.*) I'owl itrl < oulmnriM, /'"* Suitable specifications, tent nwUiodn, / cleaning procedures, ami. when ludlI catcd, sterilisation procedures shall be I used to assure that containers, closures, 1 and other component parts o drug \ packages are suitable fur their intended 1 Use, The container shall comply with l applicable compendial requh ements 1 when used for an oflicinl product ConI talners, closures, and other component J parts of drug packages shall not be rey active, additive, or absorptive ,so as to S alter the safety, Identity, strength, qual ity, or purity of the drug or Its com ponents beyond the official or other established requirements, and shall provide adequate protection against de terioration or contamination of the drug. Containers, closures, and other com ponent parts of drug packages shall be handled and stored In a manner to pro tect them from contamination and \ deterioration and to avoid mlxups. 13*133.10 Packaging and lulieling. Packaging and labeling operations shall be adequately controlled: To assure that only those drug products that have met the standards and specifica tions established In the master-formula 'records shall be distributed; to prevent mlxups between drugs during the filling, packaging, and labeling operations; to assure that correct labels and labeling 'are employed for the drug; and to iden tify the finished product with a lot or control number that permits determina tion of the history of the manufacture and control of the batch. The lot or control number shall be Identified as such on the label. An hour, day, or shift code Is appropriate as a lot or control numbe- for the drug products manu factured or processed in continuous production equipment. Packaging and labeling operations shall: (a> Be separated (physically or'spa tially >, from operations on any other drugs In a manner adequate to avoid mlxups. Two or more packaging and/or lab> ling operations having drugs, contr : ers, or labeling similar in appearance si ill not be in process simultaneously on i j iacent or nearby lines unless these opi rations are separated by a physical 1 irrier. (b) Provide for an inspection of the /acuities prior to use to assure that all other drugs and previously used labeling have been removed. (c) Include the following labeling controls: (1) The hoi ling of labels and package labeling upon receipt plus review nnd proofing against an approved final copy by a competent, responsible Individual to assure that they are accurate in respect to identity, content, and conformity with the approved copy before release to Inventory. (2) The maintenance and storage of each type label and package labeling rep resenting different products, strengths, or dosage forms in separate compart ments, drawers, or containers suitably identified. Said compartments, drawers, or containers shall have prominently al ii -. a io ii.oi*" ,i or labeling the, of lie, label i or some other adequate means f c ,i ov mu to avoid mix ups. (3) A perpetual cl' ' r of i pi i ent labels ami package labelins .stocks of outdated and obsolete Inb'*1:. and other package labeling shall be drM nyed (4) Restrict access to labc.'s and pack age labeling storage areas to persons responsible for them, id) Provide strict i ontrol of the pack age labeling issued for use with the diug. Such Issue shall be carefully checked by a competent, responsible person for Identity and conformity to the labeling specified m the bateh production records. Said records shall identify the labeling and the quantities issued and used and shall reasonably reconcile any discrep ancy between the quantity of drug finished and the quantities of labeling issued. All excess package labeling bear ing lot or control numbers shall be destroyed In the event of any significant, unexplained discrepancy, distribution of the batch in question and other asso ciated batches of the drugs that may have been involved in such discrepancy shall be prevented, A statement regard ing the discrepancy, the facts under lying the discrepancy, an explanation as determined by appropriate investigation, and the resultant action shall also be entered on the natch record of the bitch or batches in question and shall be signed by a competent, responsible Individual. 'e) Provide for adequate examination and laboratory testing of an adequate number of representative samples of fin ished products after packaging and labeling to safeguard against any error in the finishing operations and to pre vent distribution of any batch until all specified tests have been met. Manufac turers. however, may perform adequate examination of an adequate number of representative samples of their finished drug products after packaging and label ing in lieu of laboratory testing in the case of, and only in the case of, those tablet or capsule dosage forms of drugs which, in addition to having lmd all necessary laboratory tests on the bulk (but unpackaged drug), aie not similar in physical appearance to any other final dosage form product found within that manufacturing establishment. Repack ers who, in accordance with the practice of the trade, repack tablet or capsule dosage forms of drugs In substantial quantities at establishments other than those where originally processed or packed may meet these requirements of adequate examination and laboratory testing by complying with all of the fol lowing conditions; (1) 'The drug received by the repacker In bulk containers Is readily distinguish able visually from all other drugs In his possession and In the possession of the supplier of the drug. (2) Tiie repucker has In his posses sion, and in good faith relies on. a valid guarantee or undertaking (referred to in section 303(c) (2) of the act) from the manufacturer of the bulk drug setting forth that at the time of delivery to the repacks'r said di ug omphed with i, e act (3) A labcli 1 sample package of (lie drug, for which the manufacturer fur nishes protocol is) of laboratory tests showing that the drug meets approprla'e standards of Identity. strength, quality, and purity, and which sample package brnis a lalx-l identical (except for the quantity of contents statement) to the label on the bulk package of the capsules or tablets, is shipped by the manufac turer to the repacker for comparison with the appearance and labeling of the article In the bulk container. Such sam ple package contains at least twice the quantity of drug required to conduct all the tests performed on the batch of the drug The sample package and a suffi cient number of finished labeled con tainers of the repacked drug to contain at least os much drug as contained In the sample package are to be retained for at least 2 years after drug distribution has been completed, or 1 year after the drugs expiration date, whichever Is shortest. (4) Prior to repacking, a visual com parison Is conducted by a competent, re sponsible person to assure that the drug to be repacked from bulk Is identical In appearance to that in the sample pack age and that the labeling of the bulk package and-the sample package show the same drug Identity and composition. (5) Tlie repacker labels the drug with a suitable expiration date (In accordance with the stability requirements of 5 133 13) to assure that the drug meets appropi iatr standards of identity, strength, quality, and purity at time of use (6) The label of the repacked drug bears a lot or control number and the repackcr maintains records for at least 2 years after drug distribution has been completed, or 1 year after the drug's ex piration date, whichever Is the shortest, from which the lot or control number of the bulk drug used In the repacking can be ascertained. (f) Gang printing of cut labels or car tons should be avoided, especially when the labels or cartons for different prod ucts or different strengths of the same product are of the same size and have identical or similar foimat and or color schemes, 133.1 1 Labm-anu-} control*. Laboratory controls shall Include the establishment of scientifically sound and appropriate specifications, standards, and test piocedures (for example. Iden tity, weight variation, disintegration, homogeneity) to assure that components, drug preparations In the course of proc essing, and finished products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall Include: (a) The establishment of master rec ords containing appropriate specifica tions for the acceptance of each lot of components, containers, and closures used in drug production and packaging and a description of the sampling and testing procedures used for them. Bald ASI~PR 0000713 f 5 samples shall be representative and ade quately Identified. Such records shall also provide for appropriate retesting of components, containers, and closures subject to deterioration. Ib> A reserve sample of all tu five In gredients nnd all components which ap pear In significant quantities In the finished diug product. These reserve samples shall consist of at lead twice the quantities necessary to perform all required tests. Said sample shall be re tained for at least 2 years after distribu tion of the last drug lot incorporating such active Ingredient or component has been completed, or 1 year after the expiration date of this last drug lot In corporating such active Ingredient or component, whichever Is shortest <c) The establishment of master rec ords. when needed, containing specifica tions andva description of sampling and testing procedures for in-process drug preparations. Such samples shall be ade quately representative and properly marked <d> The establishment of master rec ords containing a description of sam pling procedures, testing procedures, and appropriate specifications for finished drug products. Such samples shall be adequately representative and properly marked. (e) Adequate provision for checking the Identity and strength foi all active Ingredients of drug products and for assuring: (1) Compliance with satisfactory cri teria for assuring sterility of drugs pur porting to be sterile. (2) Compliance with satisfactory cri teria of nonpyrogenlcity as requited by an official compendium or as Indicated by the manner In which, the drug Is to be used. (3) Freedom of ophthalmic ointments from foreign particles, such as metal, plastic, or other harsh and abrasive sub stances, to the'extent possible under current good manufacturing practice. (4) That the drug release pattern of sustained release products is tested by laboratory methods used in establishing appropriate specifications related to clin ical safety and effectiveness to assure conformance to such specifications. (5) That all components are ade quately tested to conform to such speci fications, for example particle size, as are necessary to assure reasonably uni form rates of absorption, biological availability, and the stability of the drug products. <f) Adequate provision for auditing the reliability, accutacy, precision, and performance of laboratory test proce dures and laboratory instruments used. (g) A properly Identified reserve sam ple (Including M least two labeled con tainers of the fitfal dosage form) of at least twice the quantity of the finished drug lot required to conduct all appro priate tests performed shall be retained for at least 2 years after drug distribu tion has been completed, or 1 year after the drug's expiration date, whichever is shortest. The reserve sample need not contain units for sterility testing and pyrogens. Identification of this sample shall Include the labeling used on the finished product. (h) Provision for retaining complete records of all o < ' 1 i11<1 i. - '.MMytiral raw data, com'1 'v : hjo it,,iy tests perfurmer! hv ::;n, q' dates and --ii- tiot.sciMcuLs '<i U!t(' ' obtaining the samples, milking Lie releasing lots (rompon-nt anti flnHie 1 material) from storage, and provision for pertfinilly relating ilu* i'1'1.-, m tarh hatch or lot of ding, component rind animals to which they appl,-. Stnli re-suds shall be re tained for at least 2 yeans after diug dis tribution lias been completed, or 1 year after t.he drugs expiration dale, which ever Is shortest, exrept for stability data as provided for by } 13131ft. ti> Provision that firms which manu facture nonpcnfcltlln products, including certifiable antibiotic products, on the snmc premises or use the same equipment as that used lor manufacturing penicillin pioducUs or that operate under any cir cumstances that may reasonably be re garded as conducive to contamination of other drugs by penicillin, shall test such nonpenicillin products to determine whether any have become cross-contam inated by penicillin Such products shall not be mat keted if intended for use by man and the product is contaminated with an amount of penicillin equivalent to 0 05 unit or more of penicillin G per maximum single dose recommended In the labeling of a drug intended for parenteral administration, or an amount of penicillin equivalent to 0.5 unit or more of penicillin G per maximum single dose recommended In the labeling of a drug intended for oral use. ()> Provision that animals used In laboratory tests and procedures shall be adequately housed, fed. and maintained under suitable conditions of temperature and humidity. They shall be identified and records maintained as to use and date and time of use. (k) Adequate regular retesting and recording of results on products and components subject to deterioration. 133.12 I-iiii-hrd-goiids warehouse con trol distribution records. Finished-goods warehouse control and distribution records shall Include an adequate perpetual Inventory control system or other suitable system for ware housed finished goods so that the dis tribution of each lot of drug. Identified by lot or control number, can be readily determined to facilitate its recall. If nec essary, from all consignees of the manu facturer or repacker. Itecoids within the system shall contain the name and ad dress of the consignee, date and quantity shipped, and lot or control number of the drug. Records shall be retained for at least 2 years after drug distribution has been completed, or 1 ycai after the drug's expiration date, whichever is shortest. Finished-goods warehouse control shall also Include a system whereby the oldest approved stock is distributed first, when ever possible, to assure the quality of the product. (For regulations relating to manufacturing and distribution records of controlled drugs subject to Drug Abuse Control Amendments of 1985, see { 320.16, Chapter II, Title 21.) 133.13 Stability. There shall be assurance of the stabil ity of compancnts, drug preparations in the course of processing, and finished drugs. The stability shall be: . c i n-',r'ii,1rlii by reliable meaning ful Mid -pecsite test methods <b) O'-h-mined on products In the i" aitfUncrs in which they are marketed tofciissure, among other things, that the container Is not reactive, additive, or ab sorptive so ns to alter the safety, Identity, strength, q : hiy, or purity of the drug or its c.mpm.eptbrvond the official or other established requirements. tc) Determined on any solution of a drug product which Is to be prepared, ns dftcctcd In Us labeling, at the time of dispensing. td.) Detennined Ln relation to specifi cations necessary to assure reasonably uniform rates of absorption and the bio logical availability of the drug product as well as ln relation to the specifica tions for composition and physical char acteristics of the drug product. (e> Expressed as an expiration date with related conditions of storage on the drug label. When the drug Is marketed ln the dry state for use ln preparing a solu tion or suspension, the labeling shall bear an expiration period for such solution or suspension as well as an expiration date for the dry product Expiration dates and periods shall be Justlfind by (1) readily available data from stability studies or (2) readily available data showing that samples from each marketed batch of the drug are laboratory tested at appropriate Intervals so that any batch of drug that falls beb'w Its professed standards of safety, Identity, strength, quality, or pu rity prLor to the expiration dale Is re called fiom channels of distribution. Ex piration dates, including the redatlng of drug products, shall be calculated from the time of Inception of the latest set of pcttlnent laboratory tests An expiration date shall assure that the drug main tains Its safety, Identity, strength, qual ity, and purity until that date If related conditions of storage are met. (f) Records shall be maintained of the expiration dates and periods used in the labeling of each batch or lot of drug and said records shall be maintained for at least 2 years after drug distribution has been completed or 1 year after the drug's expiration date, whichever Is shortest. 133.lt Complaint files. Records shall be maintained of nil written or verbal complaints regarding each product. Complaints shall be eval uated by competent and responsible personnel and, where Indicated, appro priate action shall be taken. The record shall Indicate the evaluation and action. Said complaint files shall be maintained for at least 2 years after drug distribu tion has been completed, or 1 year after the drug's expiration date, whichever Is shortest. Any Interested person may, within 60 days from the date of publication of this notice in the Federal Register, file with the Heating Clerk, Department of Health, Education, and Welfare. Room 5440, 330 Independence Avenue SW,, Washington, D.C, 20201, written com ments (preferably ln qumtupllcate) re garding this proposal. Comments may be accompanied by a memorandum or brief ln support thereof. Dated: August 13,1909. Herbert L. Lev, Jr. Commissioner of Food and Drugs. ASI-PR 0000714