Document dV1K2oRDO2KRD419wgJoodmG

OCT 6 1383 MANUFACTURING CHEMISTS ASSOCIATION 1825 CONNECTICUT AVENUE. N W. WASHINGTON. D. C. 20009 (202) 483-6126 October 3, 1969 TO: Food, Drug, and Cosmetic Chemicals Committee SUBJECT: Drugs GMP Gentlemen: Attached is a copy of the notice which appeared in the Federal Register of August 22, 1969. Your comments are requested in the event you 'f,t feel MCA should make a statement in response to <. this notice. Please be sure to send your comments to this office (copy to Bill McCormick) in time for them to be received by Monday, October 13. Sincerely yours, h MMH:sjg Attachment Distribution "B" M. M. Hoover, Secretary Food, Drug, and Cosmetic Chemicals Committee ASI 00002242 PROPOSED RULE MARIN 13555 rrrftw and approval, together with assurance that tha rcrlaw committee doea sot allow participation In lta review and conclusion* by any individual Involved In the conduct of the research activity under review (etoept to provide information to the committee), speciflo the good manufacturing practice regulations for drugs. According, it la proposed that II 193.1 through 133.14 be revised to read as follows: having the authority and responsibility to approve or reject raw materials. Inprocess materials, packaging compo nents, and final products. (8) The term "strength" means (l> thitt the Investigator will report to the com* mtttee for review any emergent problem! or prepoted procedural changee which may af fect the statue of the investigation, and that no changes will ba made without committee approval except where neoeeaery to eliminate apparent Immediate hararde. * (. A general outline of the prelect under taken (ModlfloaUon la permitted on the beats of experience gained, with the approval of the review committee, without advance auhmlsston or the amendment! to the general outline to the sponsor.) 4. Subparagraph (13), Form TO 1573, bp revising division 3 to rend as follows: 133.1- Definitions. ta) As used in this part, "act" mexns the Federal Food, Drug, and Cosmetic Act, eeettona 201-002, 52 Stat. 1082 (21 UJB.C. 321-322), with all amendment* thereto. (b) The definitions and Interpreta tions contained In section SOI of the Fed eral Food, Drug, and Coemetle Act shall be applicable to such term* when used In the regulations In this part. <c) As used in this part: (l> The term "medicated feed" means any "complete feed," "feed additive sup plement," or "feed additive concentrate," the concentration of a known active drug substance in formulation (for example, w/w, w/v. or nnlt dose/volume basis) and/or (ID potency, that is, the specific sbillty or capacity of the product as in dicated by appropriate laboratory testa or by adeauatcly controlled clinical data obtained through lAe administration of the product in the manner intended to effect a given result's) (expressed, for example, in terms of units by reference to a standard). g 123.2 (Ismsi |tsd manufacturfne practice. The criteria In II 1332-113.14, inclu ta. tf any hospital, tnatttuttoa, or research as defined m {121300 of this chapter, sive, shall apply in determining whether lae&tty is involved, an identification of tha whleh feed contains one or more drugs the methods used in, or the facilities or mbs and a description of the peer group committee responsible for Initial and con tinuing review, together with assurance that tha review committee dose not allow partici pation in lta review and conclusions by any Individual involved in the condurt of the as Geflxnd in section 201<g) of the act. Medicated feeds an subject to 11133.100- 133.110,Inclusive. (2) The term "medicated premtr" means asubstance thatmeets the defini 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 research activity under review (except to pro- tion In 4IZL2O0 jpf this chapter tor a drug meets the requUanents of the act ex vlda InfWmaaon to the committee). that the "feed additive premlx," except that it to safety, and has the identity and Investigator will report to tha oommlttaa for review any emergent problems or proposed procedural changes whioh may affect tha atatus of the Investigation and that no changes will be mads without committee approval except where neoeaaary to eliminate apparent lmmadlete hazards. contains one or more drugs as defined In strength and meets the quality and pur section 201(g) of the act and la Intended ity characteristics which It purports or far manufacturing use In the production Is represented to poems, sa required by of a medicated feed. Medicated pro- section 501(a)(2)(B) of the act. The mixes ate subject to II 133.200-133-210. regulations In this part permit the use of inclusive. precision automatic, mechanical, or elec tv A dwcrtptlon of any ollnieal laboratory (d) As used to II 133^-13344 In tronic equipment in the production and fbdUttM that wUl ba uaed. clusive: control of drugs when adequate inspec (ff this Information ha* been submitted to (1) The term "component" draw ma tion and checking procedure* ore used to tha sponsor and reported by him on Foma terial) means any lngredlant intended assure proper performance. PD1871. referenoe to the previous submission , will be adequate.) for use In the manufacturing of drugs, Inctndlng those that may not appear in 8 1332 Buildtack Any interested person may, within 30 days from the date of publication of.this notice in the Federal Ricistex, file with the Hearing Clerk. Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue sw,, Washington, D.C. 30201, written comments (prefer ably In quintupllcate) regarding this proposal. Comments may be accom panied by a memorandum or brief In eupport thereof 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 Buildings shall be maintained tn a clean and orderly manner and ann be of suitable slae. construction, and loca tion in relation to surroundings to facili tate adequate cleaning, maintenance, and proper operations for tbetr Intended purpose--the manufacturing, processing, packing, labeling, or holding of a drug. The buildings shall: <a) Provide adequate space for: (1) Orderly placement of equipment and materials to minimize any risk ot Dated: August is, 1969. in either cam which Is identified toy a mixups between different drugs, drug J. K. Kirk, Associate Commissioner for Compliance. tVJt DOC. 60-0079; Filed. Aug. 01. 1060; a:te am.] distinctive lot number and has uniform character and quality within specified limits. (4) The terms "lot number" or "con trol dumber" mesa any distinctive com bination of letters or numbers, or both, components, in-process materials; pack aging, or labeling, and to mlnlmhe the possibility of cross-contamination of one drug by another drug(s). (2) The receipt, storage, and with holding from use of components pend by which the complete history of the ing sampling, Identification, and testing 121 CFR Part 1331 manufacture, control, packaging, and prior to release by the materials approval distribution'ol a batch or lot of a drug la unit for manufacturing or packaging. DRUGS; CURRENT GOOD MANUFAC determined. (3) The holding of rejected compo TURING PRACTICE IN MANUFAC (5) The term "active Ingredient* nents prior to disposition in such a way TURING, PROCESSING, PACKING, means any substance of a drug which la as to preclude the possibility of their use OR HOLDING intended to furnish pharmacological ac In any manufacturing or packaging tivity or other effect In the diagnosis, procedure. NMkt of Proposed Rule Making cur, mitigation, treatment, or prevention (4) The storage of components ap Pursuant to the provisions of the Fed of disease or to affect the structure or proved for use. eral Food, Drug, and Coemetic Act (secs. Ml. 701 (a), 52 Stat. 1049-50, bus amended, any function of the body of man or other * (5) Any manufacturing and process ing operations performed on the drug. 10SB; 21 UJ3.C. 351, 371(a)) and under I <) The term "Inactive Ingredient" (6) Any packaging and labeling authority delegated to him (21 CFR means any substance other than an "ae- operations. 2.120), the Commissioner of Food and | tlve Ingredient" present to a drug. (7) Storage of containers, packag Druse propoeea to amend Part 133 to (7) Tha term "materials approval ing materials, labeling, sad finished clarify, strengthen, and make men unit" means xn organisational element products. notkAi wotms, vol is, mo. ut--ssay, Auoutr it, mv ASI 00002243 PROPOSED RULE MAKING (8) Control and production-labora and background of education and experi (1 > Approved components are so han tory operations. tb> Provide adequate lighting, ven tilation, and, when necessary for the In tended production or control purposes, ence to assure that the drug has the aafety, identity, strength, quality, and purity that It purports to possess. All per sonnel shall have capabilities commen dled and stored as to guard against their contaminating other drugs by dust or other particles resulting from such handling and storing. Similarly, ap facilities, for adequate air-pressure, surate with their assigned functions, a proved components are so handled and microbiological, dust, screening, filter thorough understanding of the manu stored as to guard against their being ing, humidity, end temperature controls facturing or control operations which contaminated by other preparations. to; they perform, the necessary training and Substances, dust, or other particles re (H Minimise contamination of prod experience relating to Individual prod sulting from such handling and storing. , ucts by extraneous adulterants (includ ucts, and adequate information concern- (2) Approved oomponent* shall be, 1ing cross-contamination of one product ling the reasons for and the application by dust or particles of Ingredients aris p the pertinent provisions of thin part ing from the manufacture, storage, or |tn their respective functions, handling of another drug). (b) Personnel having direct contact (3) Minimise dissemination of micro with drugs shall have periodic health organisms from one area to another. checks, and shall be free from communi (c) Provide for adequate locker facili cable disease and (men lesions on the ties and hot and cold water washing exposed surface of the body. facilities including soap or detergent, air drier or single service towels, and clean 133,6 Components (raw materials). toilet facilities near working areas. Components used in the manufacture <d) Provide an adequate supply of and processing of drugs (including potable water (PHS standards) under those components that undergo chemical continuous positive pressure in a plumb change or are eliminated in the process) ing system free of defects which could shall be withheld from such use until cause or contribute to contamination of they have been Identified, sampled, and the product. Drains shall be of adequate tested for conformance with established alee and, where connected directly to a specifications that are appropriate and aewer, shall be equipped with traps to adequate, and are released by the ma prevent back-slphonagc. terials approval unit. Control of com (e) Provide suitable housing and ponents shall Include the following; apace for the care of all laboratory (a) Bach container of components animals. shall be examined visually for damage (f) Provide for safe and sanitary dis or contamination in transit, including posal of sewage, trash, and other refuse. examination for breakage Of seals when $ 153.4 Equipment, indicated. (b) An adequate number of samples Equipment used for the manufacture, shall be taken from a representative processing, packing, labeling, holding, number of oomponent containers and rotated in such a manner that the oldest A'? stock Is used first. (3) Rejected components shall be w marked and held aa to preclude the pos sibility of their use In any manufactur ing or processing procedure. (4t Appropriate records shall be maintained of the name of the supplier, lot number of each component, date ami amount received, and examinations and tests performed. Said records *h*n also show any components rejected and their disposition. An individual inventory record shall be maintain--! for each com ponent lot showing the amount of com ponent used in each batch of drug manu factured or processed. (h) 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 hall be retained for at least 2 years after distribution of the last dnig lotIncurporating the active Ingredient has been completed, or 1 year after the expiration date of this last drug lot incorporating the active Ingredient, whichever is short est. testing, or control of drugs shall be main shall be subjected to one or more iden | 133.7 Master-fennela and batch-pro tained in a clean and orderly manner tity tests, Including at least one labora duction record*. 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 ns to alter the safety. Identity, strength, quality, or purity of the drug or its com- j 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. (o> 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 teetlng, meas uring, mixing, weighing, or other procemlng or storage operations. | 133..', IVmonnrl. (,\> vhe personnel responsible for di recti' the manufacture and control of the -.Iruf shell be adequate in number tory test for Identity. (c) 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. (d) Representative aamples 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. (e) 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 oomxments subject to microbiological conlamination (such as those of animal and xitanlcal origin) shill 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 neerosary to assure that they conform to appropriate specifications of Identity, strength, quality, and purity at time of use. This requires the following: (a> To assure drug batch uniformity, 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 lest drug batch produced uring the masterformula record, or 1 year after the ex piration date of this 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 formula 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 rccotd prior to the reproduction of the batch records.) Also included tii&ll be copies of the final 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 approvine the draft (3) The name and weight or measure of each Ingredient per dosage unit or per RDERAL REGISTER, VOL *4, NO. Ul--FRIDAY, AUGUST >3, 1947 ASI 00002244 PROPOSED RULE MAKING msr. unit of weight or measure of the finished aethm shall be taken. Said record shall contamination of nonpenicillin products drug, end e statement of the total weight indicate the evaluation and action. by penicillin in these establishments that or measure of any dosage unit. (3) A complete list of ingredients 1133.fi Production and control proce dure*. manufacture, store, or handle penicillin as well as nonpenieUlin products. designated by names or codes sufficiently 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 doeage form provided that the variations are stated in the nwWw formula; an appropriate statement oon* doming any calculated excess or 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 eoutalners, edosurea, and packaging, and finishing ttiterifti*. (8) Manufacturing and control ln- atruettotts. procedures, specifications, special notations; and precautions to be followed. <b) Readily accessible records teiall be prepared for each batch of drug pro duced end teiall include complete In formation relating to the production d control of each such batch, feid reccedf tewll be retained for at leate 3 yean after batch dlsbrlbtitton is comgfefce, or 1 year after the batch expira tion date, whichever Is shortest. The records relating to production. Including P+rireginf, labeling, and control of each balrh. pile 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: Cl> An accurate reproduction of the appropriate master-formula record cheeked 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, ln-process and laboratory-control results, and the endorsements of the In dividual actively performing and the in dividual actively supervising or checking each step in the operation. <8> A batch number that permits de termination of all laboratory-control procedures and results on the batch, and aO lot or control numbers appearing on the labeling of drugs from that batch, tnclmhng copies of the labeling bearing the lot or control numbers used on the final contablets of the batch. product!cm end control procedures shall Include all reasonable precautions. Including the following, to assure that the drugs produced have the safety. Iden tity, strength, quality, and purity they purport to possess; (a) .Each critical step In the process, such as the selection, weighing, and measuring of components, the addition of active ingredloits during the process, weighing and measuring during various stages of the processing, and the determi nation of the finished yield, shall be per formed by a competent; responsible Individual and cheeked by a second com petent, raponslble individual; or if such steps In ths processing are controlled by precision automatic, mechanical, or electronic equipment, their proper per formance is adequately cheeked by one or more competent, responsible individ uals. The written record at the critical stepe in the process shall be inii'-i'-i by the individual performing the f-.Mcai step and also initialed by the :r,;\-'"ial chargedwith checking each cri< '-v step. tb) AH 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 content*, the stage of processing, and the batch. For equipment and tines, placement of this identification bii in clude. when applicable, input lines, out put lines, and operator controls. AQ containers, lines, and equipment used In producing a batch of drugs shall be stored and handled in a manner adequate to prevent mtxups or contamination with other drugs, <o equipment, utensils, and con tainers shall be thoroughly cleaned a^d properly stared and have previous be`oh Identification removed between batches, or at suitable intervals in eontlnr^'S production operations, to minimiTM the hazard of contamination with ir*-reorganism* and to prevent other cor.' nattou and mlxups. Equipment being employed for oooseeutive identical prod uct batches shah be thoroughly cleaned at suitable intervals. AH equipment used In the handling of sterile product* be appropriately denned and, when necessary, sterilized prior to use. <d> Appropriate procedures, such as the following, shall be lmka> to minimise the hazard cf oonteminetton with micro organisms in the production of paren teral drugs, opthaimie eolations, and aay other drugs purporting to be sterile: (1) Filling operations shall be per formed with adequate physical Kfrotatlon from similar operationson any other drugs to avoid cross-contamiiiattoQ. (f) To arnure the uniformity and Integrity of products, there shall be ade quate ln-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, and the clarity of solutions. Such ln-process testing shall be done at appro priate intervals during each individual operation, when practicable, using read ily accessible, adequate, end su.table equipment. A written record of all such tests 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. <g> Competent end responsible per sonnel shall cheek actual against theo retical yield of each batch of drug, 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 also contain a state ment on criteria used. In accepting at rejecting such a batch. (h In-procen batches of drugs found unacceptable to the firm shall be held u"t;i a determineUon as to their dlspo- hLV.'T. has been made. Appropriate recurOs shall be maintained which re flect tire reason!*) lot un&cceptattfity and the ultimate disposition of this material. (1) Certifiable antibiotics and insulin are to be withheld from distribution until the certification certificate is actually received unless exempted by Part 144 of this chapter. All other drags shall be withheld from distribution until released by the materials approval unit on the basis of satisfactory control testa. <J) Returned goods shall be so identi fied and held. If the condition of the container, carton, or labeling is such as to cast doubt on the identity, strength, quality, or purity of the drag, the re turned goods shall be destroyed or sub jected to the complete protocol of test ing <to assure that the material will meet all appropriate standards and specifications) before being returned to stock for warehouse distribution or re packing. No returned goods shall be reprocessed utdern they have been found by appropriate teste not to have under gone any significant physical, chemical, (4) A record with complete Investiga tive history of any mirupe, errors, and unsatisfactory drug products found dur ing and otter drag manufacturing, proc- easing, packaging, labeling, testing, controlltag. and distributing of the batch, TMs investigative history shaU be evalu C2> Proper control of air movaneat and air filtration prior to entry and dis charge shall be provided in all sterile sre.-.s to minimize microbiological ooni&ranatloiw particulate matter, and crons-contamination of one drug with an.'1'' n\ or microbiological degradation and not to have become oonlaminated with ex traneous substances or filth. Records at returned goods tenth be maintained and shall indicate the amount returned, date, and actual disposition of the product, ated by competent and responsible per ie> Appropriate procedures shall ba such sa reprocessed, destroyed, or re sonnel and, where indicated, appropriate taken to minimize the hazard of croas- turned to stock. mciua SSOISm, VOW 84, NO. Ut-antKMV, AUOUST gg, m* ASI 00002245 PROPOSED R(HE MAKING 153.$ Product container*. fixed to them s specimen of the label repacker said drug compiled with the Suitable specifications, test methods, cleaning procedures, and. when Indi cated, sterilisation procedures shall be used: to assure that containers, closures, and other component parts -of drug packages are suitable for their Intended use. The container shall comply with applicable compendial requirements when used for an official product. Con tainers. closures, and other component parts of drug packages shall not be re active. additive, or absorptive so as to iter the safety, identity, strength, qual ity. or purity of the drug or Its com ponents beyond tne official or other established requirements, and shall provide adequate protection against de terioration or contamination of th 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. or labeling they contain or some other adequate means ofWentillcation to avoid mlxtvs. ' - <51 A perpetual check of current labels and package labeling. Stocks of outdated and obsolete labels and other package labeling shall be destroyed. Restrict access to labels and pack age labeling storage areas to persons responsible far them.' (d) Provide strict central of the pack age labeling issued for use with the drug. Such issue shall be earefully checked by a competer*. responsible person tot identity and conformity to ths labeling specified In th-_- hr uu production records. Said reoords r'.'.nii identify the labeling and the quantT' ^ tr ued 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 evented any significant, act. (3) A labeled sample package of the drug, tor which the manufacturer fur nishes protocol(s) of laboratory teste showing that the drug meets appropriate Standards of Identity, strength, quality, and purity, and which sample package bean a label 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 sad a suffi cient number of finished ia-ifvi con tainers of the repacked drug to contain at least as much drug as contained in the sample package ate to be retained for at least 2 years after drug distribution has been completed, or 1 year after the S 133.10 Packaging and labeling. unexplained discrepancy, distribution of drug's expiration date, whichever Is 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 mixups between drugs during the filling, peckaging, 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 end eentrol of the batch. The lot or control number shall be identified as such on the label. An hour, day, or shift code la appropriate as a lot or control number 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 d -ga In a manner adequate to avoid Two or more packaging ond/or lauding operations having tiro as. 'ontaiuers, or labeling similar ,n at >r?<vvance shall not be in process shnultan-'ously on adjacent or nearby lines unless these op erations are separated by a physical barrier. (b) Provide for an Inspection of the facilities prior to use to assure that all other drugs and previously used labeling have been removed. (0) Include the following labeling controls: (1) The holding of labels and package labeling upon receipt plus review end proofing against an approved final copy 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 aa determined by appropriate Investigation, and ths resultant action shall also be entered on the batch record of the batch 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 ih ths finishipy operations and to pre vent distribution at 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 esse of, and only fit the case Of, those tablet or capsule dosage forma of drugs which. In addition to having had all necessary laboratory tests on the bulk (but unpackaged drug), are 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 fortes 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 shortest. (4) Prior to repacking, a visual com parison is conducted by a competent, re sponsible person to assure ut the drug to be repacked from bulk is identical In appearance to that bi the sample pack age and that the labeling of the bulk package and the ample package show the same drug identity sod composition. (6) The repacker labels the drug with a suitable expiration date (In accordance with the stability requirements of 1133.13) to assure that the drug meets appropriate standards of Identity, strength, quality, and purity at time of nee. (6) The label of the repacked drug bears a lot or oontrol number and the repacker maintains records lor 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 alse and have identical or similar format and/or color schemes. '| 133.11 Laboratory wntfok. Laboratory controls shall Include the establishment of scientifically sound and appropriate specifications, standards, and test procedures (for example, iden tity, weight variation, disintegration, homogeneity) to assure that components, by a competent, responsible Individual to lowing conditions: drug preparations in the course of proc asroro that they are accurate In respect (l) The drug received by the repacker essing, and finished products conform to to td^Eltty, content, and conformity with in bulk containers is readily distinguish appropriate standards of identity, r- - roved copy before release to1 able visually from all other drugs In his strength, quality, and purity. Laboratory possession and In the possession of the controls shall include: 1 V -o maintenance and storage of supplier of the drug. (a) The establishment of master rec .. *- , anti package label*">r rep- >?. i Tie r<*p*ck*,'r has in his posses ords containing appropriate specifica s.r-ug'hs, sion. an-, i ir g*x*> faith relies 'in a valid tions for the acceptance of each lot of ......* '-v 'r'us it. secarate eomosrt- guarantee o.- un-i-utar itg 'ref.-w-sd ro,. components, containers, and closures - -s or ciLcair-or! sn'taMy In aertloti spic,-) -2: of t.)'act' ;; ->m the used In drug production and packaging ........ \l uonirurho'mts, drawers, manufacturer ol the bulk drug setting and a description at the sampling and u -r -u::ers shall have prominently af- forth that at the tune ofdelivery to tits testing procedures used for them. Bald FIDIkAl UOISTI1, VOL 34, NO. Ul--MlftAY, AUdUfT 22, lfSt ASI 00002246 PROPOSED RULE MAKING 13557 samples shall be representative and ade pyrogens. Identification of this sample of controlled drugs subject to Dmj quately identified. Such records shall shall include the labeling used on the Abuse Control Amendments of 1965. see also provide lor appropriate retesting of finished product. 9 320.16, Chapter H, Title 21.) components, containers, and closures (h> Provision for retaining complete g 953.13 Stability. subject to deterioration, . <(b) A reserve sample of all active in gredients and aU components which ap- records of all data, including analytical raw data, concerning laboratory testa performed, Including the dates and en There shall be assurance of the stabil ity of components, drag preparations in Ipear In significant quantities In the finished drug produot. These reserve samples shall consist of at least twloe the quantities necessary to perform all required testa. Said sample shall be re dorsements of Individuals obtaining the samples, making the tests, releasing lota (component and finished material) from storage, and provision for specifically relating the tests to each batch or lot of the course of processing, and flnislied drug*. The stability shall be: <a) Determined by reliable, meaning ful, and speeifie test metljod* (b) Determined on product* In the tained for at least 2 years after distribu tion of the last drug lot incorporating such active ingredient or component drug, component, and animals to which they apply. Buch records shall be re tained for at least 2 years after drug dis containers in which they are marketed to assure, among other things, that jhe container Is not reactive, additive, or ab 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. tribution has been completed, or 1 year after the drug's expiration date, which ever Is shortest, except for stability data aa provided for by 9133.13(f). sorptive so as to alter the safety, identity, strength, quality, or purity of the drug or Its components beyond the official or other established requirements. (0) The establishment of master rec ords, when needed, containing specifica tions and a description of samp and tasting 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 for 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 required 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 tasted 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 (I) Provision that firms which manu facture nonpenlclllin products. Including certifiable antibiotic products, on the same premises or use the same equipment as that used for manufacturing penicillin products or that operate under any cir cumstances that may reasonably be re tarded as conducive to contamination of other drugs by penicillin, shall test such nonpenlclllin products to determine whether any have become cross-contam inated by penicillin. Such products-shall not be marketed 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 a 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. (J) Provision that animals used in laboratory tests and procedures shall be adequately housed, fed. and maintained under suitable conditions of temperature and humidity. They shaU 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. 8 153.12 FtnMicd-goods warehouse con, Irol 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 (c> Determined on any solution of a drug product which Is to be prepared, as directed in its labeling, at the time of dispensing. (d) Determined in relation to specifi cations necessary to assure reasonably uniform rate* of absorption and the bio logical availability of the drug produet as well as in relation to the specifica tions for composition and physical char acteristics of tha drug product. fe> Expressed as an expiration date with related conditions of storage on the drug label. When the drug Is marketed in the dry state for use in 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 justified 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 drag that Ifalls below Its professed standards of (safety. Identity, strength, quality, or pujrity prior to the expiration date is recalled from channels of distribution. Ex piration dates, including the redating of drug products, shall be calculated from the time of Inception of the latest set of pertinent laboratory teste. 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. 8 133.14 Cnaqblu file*. the reliability, accuracy, precision, and facturer or repacker. Records within the Records shall be maintained of all performance of laboratory test proce system shall contain the name and ad written or verbal complaints regarding dural and laboratory instruments used. dress of the consignee, date and quantity each product. Complaints shall be eval (g) A properly identified reserve sam shipped, and lot or control number of the uated by competent and responsible ple (Including at least two labeled con drug. Records shall be retained for at personnel and. where Indicated, appro tainers of the final dosage form) of at least 2 years after drug distribution has priate action shall be taken. The record least twice the quantity of the finished be*n completed, or l year after the drug's shall Indicate the evaluation and action drug lot required to conduct aU appro expiration date, whichever is shortest. Bald complaint files shall be maintained priate testa performed shall be retained Finished-goods warehouse control ShaU for at least 2 yean after drag distribu for at least 2 years after drug distribu also include a system whereby the oldest tion has been completed, or 1 year after tion has been completed, or 1 year after approved stock is distributed first, when the drug's expiration date, whichever is the drug's expiration date, whichever Is ever possible, to assure the quality of the shortest. Shortest. The reserve sample need not product. (For regulations relating to Any Interested person may, within 60 aontaln units for sterility testing and manufacturing and distribution reoords days from the date of publication of this no. lei- FEDEIAl (MISTER, VOL >4, NO. 1*1--TODAY, AUOUS1 22, m ASI 00002247 13538 PROPOSED RULE MAKING notice In the Psdeaal Recur**, flle with the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington, D.C. 30301, written com ments (preferably In aulntupUcate) re garding this proposal. Comments may be accompanied by a memorandum or brief In support thereof. Dated: August 13,1969. Heuekt L. Lrr, Jr, Commissioner of Food and Drugs. (r'-R. Doe. 00-6980; TOW,, Aug. 31, 1808; > S;46 SJB.J FEDERAL MARITIME COMMISSION t 46 cm Parts 503, 510 ] (Oensnl Orders , 33: Docket Me. Of-ill PIES FOR SERVICES) LICENSE FEE ' Notice of Proposed Rule Making Notice Is hereby given that pursuant to section 4 of the Administrative Pro cedure Act (5 U.S.C. 553) and section 43, Shipping Act, 191V (48 tJJS.C. 841(a)). and ln,, accordance with the Act ol August ll, 1051 (31 UB.C. 483(a)), as lmpletneraed by the Bureau of the Budget Clreular no. A-39 dated Septem ber 33.1959, the Federal Maritime Com mission -is considering the revision of certain existing chargee to recover the costs of services, as set forth below. A recent evaluation, taking Into con sideration estimated direct and Indirect costa to the Government In accordance with criteria established by the Bureau of the Budget, Indicates that an Increase la the fee schedule Is warranted and Is hereby piwueed for the fallowing aervloes. In paragraph <aJ of 1903.43 Pees for services In Oeneral Order 33 <46 cm 503.41) the rate lor copying of record# and documents Is proposed to be in* created from 88 mate per pegs to 80 In paragraph (b> of 1603.43 the rate far certification and validation with the Federal Maritime OOtamtmon seal is propoeed to be increased from 41 to $3. m paragraph (e)(1) 1603.43 the rate for records-eeanfii by clerical personnel Is proposed to be Increased from 84 per person per hour to 84-90 per person per hour. . m paragraph (c)(3) of (803.43 thd minimum charge for record search is proposed to be deleted with the under standing that chargee for records search will not be Imposed for the first one-half hour. m paragraph (f) of 1510.5 Reowtre- mentsfor licensing, in General Order 4 (46 CFR 510.5) the freight forwarder application fee of 8100 Is proposed to be Increased to $123. Interested persons may submit com ments pertaining to this proposal by filing with the Secretary. Federal Mari time Commleslon. Washington, DC 20573, within 15 days of publication of this notice In the Fttmasi. Rscisns an original and 15 copies of their view* or comments. In the absence of comments, the Com mission intends to adopt the proposed changes to be effective October 1, 1969. By the Commission. Isbal] Thomas List, Secretary. {FJt. Doc. 08-10011; TOsd. Aug. 21. 1969; 8:48 in] ASJ 00002248 TEDEftAL mBTIftg VOL U, NO, U1--ftIDAY, AUGUST 22, 19*9