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ASBESTOS INFORMATION ASSOCIATION NORTH AMERICA 1660 L Street, N.W Washington, D C. 20036 / (202) 223^1885 / 14 March 1975 i: '\ ^ j ,! !' Memorandum For: MEMBERS Subject: Asbestos-Form Particles in Drugs for Parenteral Injection h, Pi Enclosed please find regulations for asbestos-form particles---in drugs for parenteral injection, as published in the Federal Register, Vol. 40, No. 51, March 14, 1975. A summary review of this regulation will be forwarded at a later date. R. H. Mereness Executive Director Enclosure UCC 006269 RECEIVED MAR 1 7 1975 0 FRIDAY, MARCH 14, 1975 WASHINGTON, D.C. Volume 40 Number 51 . 'V Pages 11859-12066 PART I HIGHLIGHTS OF THIS ISSUE This listing does not affect the legal status of any document published In this issue. Detailed t table of contents appears Inside. i !. , NONHUMAN PRIMATES--HEW proposes restricting im portation; comments by 4-14--75------- ------------- -------- 11387 _t . EXHAUST EMISSION STANDARDS--EPA grants auto ' manufactures suspension request for 1977 model year____________ _______________________ ______ _____ 11900 ' HIGHWAY SAFETY--DOT criteria for Incentive grants to States for annual fatality rate reductions; effective 3-14-75 _-------------------------- :------------------------------------ 11870 March 14, 1975-- Pages 11859-12066 CAREER EDUCATION PROGRAM-- ' HEW/OE announces dosing data of 4-21-75 for receipt - of funding applications-------------- 11930 HEW/OE proposes fund criteria for FY 1976; comments by 4-14-75---------------------------------------------------------- 11928 ' FOREIGN LANGUAGE AND AREA STUDIES-- HEW/OE sets dosing date of 4-15-75 for receipt of applications------------- 11931 HEW/OE proposes funding criteria for FY 1976; com ments by 4--14--75.... _11930 SUPPLEMENTARY EDUCATIONAL CENTERS-- HEW/OE sets closing date of 4--25--75 for receipt of applications11931 HEW/OE proposes funding criteria for FY 1976; corrv' ments by 4-14-75______________ 1188S ANTIBIOTIC DRUGS--HEW/FDA provides test method ^ot Tetracycline; effective 3-14--75..___ __ __________ _ 11869 ASBESTOS PARTICLES--HEW/FDA restricts use In man ufacture of parenteral infaction preparations; effective 4-14-75 ------------ ---------------------------------------------------- 11865 BtOLOGICS--HEW/FDA proposal changing testing re quirements for Smallpox Vaccine. Live; comments by 4-14-75 ------- ------------------------------ ----- -.------------------- 11884 (Continued Inside) PART H: DRINKING WATER--EPA proposes Interim pri mary standards; comments by 5-16-75____ __ 11989 PART III: I MINIMUM WAGES--Labor/ESA determinations for Federal and federally assisted construction____ 11999 V UCC 006270 RULlS AMD SiGULATiONS Title 21--Food and Drugs ' CHAPTER 1--FOOD AND DRUG ADMIN 15- , TRATION, DEPARTMENT OF HEALTH, : EDUCATION, AND WELFARE ; SUBCHAFTES C--OflUGS ! PART 133--DRUGS; CURRENT GOOO ! MANUFACTURING PRACTICE IN MAN- I UFACTURE, PROCESSING, PACKING, ! OR HOLDING Asbestos-Form Particles In Drugs for 1 ' Parenteral Injection ` j The Commissioner of Food and Drugs . published In the Federal Recistes of September 28. 1973 (38 FR 27078), a; notice proposing to restrict the utiliza- j tlon of asbestos filters In the rnanu- ! facture of parenteral drugs and par- I enteral drug Ingredients, and to pro- 1 hibit the use of asbestos-containing talc i as a food, or food or drug ingredient, or in food and drug packaging materials, \ within certain analytical restrictions, , The notice provided for the filing of 1 comments within 90 days. Asbestos fibers are known to cause cancer when inhaled in large amounts. Also, asbestos and other fibers are con sidered likely to have a similar adverse effect if present in parenteral drugs, although this has not been proven. Be cause of this likelihood, this order pro vides that, whenever possible, asbestoscontaining or other fiber-releasing filters not be used in the manufacture, proc essing or packaging of drugs intended for parenteral Injection In humans. Also, it provides for measures to reduce the amount of fibers present in such prod ucts. where it is not possible to elimi nate these filters in the production of a drug. - The comments made in response to the r September 28, 1973 proposal fall into two uses. mtin categories. One concerns provisions to decrease the potential for Ingestion of asbestos fibera. The other concerns pro visions to decrease the potential lor in jection of asbestos fibers, A. discussion of each category of comments, and the Commission's conclusions, are set forth below. A. Comments on provisions dealing with ingestion potential of asbestos fibers: - 1. The Commissioner proposed that any food, focd packaging material, drug, drug ingredient or drug packaging ma terial containing talc that is not free from asbestos fibers as determined by a particular analytical method should too deemed adulterated in violation of sec tion 402(a) (11 of. thw Federal Food, Drug, and Cosmetic Act. Nineteen comments related to the pro posed analytical method for talc under j 1212008 (21 CTO 1212008>. The com ments were primarily from representa tives of food, drug, and talc mining firms, but also included four consultant labora tories and two other federal agencies. Al though It is apparent that most of these respondents did not actually use the de signated method, and were,therefore, re flecting their general experience with optical crystallography or a personal preference for other analytical methods, none of the respondents supported th proposed method for compliance pur poses. The predominant objections to the proposed method were that it is difficult to use, laborious, and not practical for its Intended purpose. Several comments offered the opinion that only the most highly trained microscopists. would be capable of using the method with any reasonable accuracy or precision. Mem bers of one trade association collabora tively studied the method with 10 micros copists. each examining sever samples of talc. Four participants admittedly could not use the method to count the samples, and there was obvious incon sistency in the results reported by other microscopists. A number of alternative methods for determining asbestos particles in talc were suggested by the respondents. Al though optical microscopy using disper sion staining was the most frequently suggested method, others suggested x-ray diffraction, spectrophotometry, and sev eral electron microscopy and microprobe techniques as preferred or supportive analytical methods. Many of the re spondents additionally expressed their willingness to Join a Food and Drug Ad ministration analytical task force to evaluate applicable methodology. Although the Commissioner cannot agree that the designated optical crystallographic method is unreliable when used by those experienced in the art, he recognizes that an effective com pliance method must have greater utility and acceptance than indicated by the comments on the proposed method. The Commissioner has, therefore^ decided to delay any final regulation for talc until an acceptable method for deter mining the presence of asbestos particles can be developed for this substance. This FEDERAL REGISTER, VOL 4flf, NO. 51--FRIDAY, MARCH 14, 19?5 UCC 006271 RUUS ANO REGULATIONS area of research currently Is being ac requirements for talc used in the manu man's overall exposure by thpse sub tively pursued by the food find Drug facture of paper and paperboard In stances are small. The comment con Administration. 121.101(h) (21 CFR 121.101(h)). All or tended that evidence is lacking to show 2. Several comments objected to the these comments contended that asbestos, that the ingestion cf small amounts of purity limitations for talc which were es ir. asbestos-containing talc, does not mi asbestos Is safe and that the responsibil tablished by the proposed method. Many grate to packaged food when talc is used ities of the Food and Drug Administra thought that requirements that talc for this purpose. One of these comments tion for promulgation of regulations to be 99.9 percent amphibole-free and 99,99 contained resuhs of recently conducted lessen the total human exposure to as percent chrysotile-free unreasonable, studies which were intended to prove this bestos were not mitigated by the fact that while others insisted that any limitation contention. all human exposure to asbestos cannot was unreasonable unless it could be de After a thorough review of submitted be regulated by the agency. monstrated to reflect known hazard comments, and examination and evalu The Commissioner agrees that uniform levels by ingestion. While one respondent ation of additional requested studies, the and consistent regulations should be calculated that 20,000 amphibole and Commissioner concludes that this com adopted on an industry-wide basis. In 3,900 chrysotile fibers (of 5 micrometers ment has demonstrated the validity of this instance, the lack of available re x i.7 micrometers size) should be permit this contention in a manner consistent producible methodology for determining ted before any talc sample exceeded the with available methodology. In the con asbestos-form fibers in beverages and established limits, another respondent ducted studies, the comment has dem other foods led.the Commissioner to pro observed that individual asbestos par onstrated that dry packaged and shipped pose the regulation of talc before han ticles often vary in size a million-fold, salt contains less than 0.01 part per bil dling other related matters, In any event, thus making it difficult to relate particle lion asbestos when in direct and continu the comment has now become moot since counts to the percentage of asbestos con ous contact with uncoated paper con the Commissioner has decided to delay tamination in talc. taining up to 6 percent tremolitic asbes a final ruling on talc as a direct food or Although the decision of the Com tos. Although detection was limited by drug ingredient. missioner to delay any final regulation on the bulk of ash recovered from other The Commissioner also concludes that talc has rendered these comments moot, products, such as fresh wrapped and fro neither the available data on the addi the Commissioner wishes to respond to zen meat, dry packaged macaroni, dried tion of fibers to foods and nonparenteral these comments to clarify his position on milk, rice, and corn flakes, the comment drugs by use of asbestos filters nor the posssible future talc regulations. has also demonstrated that these prod data on the asbestos content of municipal As indicated in the proposal, the Com ucts contain less than 10 parts per bil water are sufficiently reliable to permit missioner recognizes that the evidence lion asbestos under test and market con promulgation of regulatory controls at concerning the possible hazard from in ditions, The analytical details of these this time. Evidence indicates a wide vari gestion of asbestos particles is contra studies are on file with the Hearing ation of asbestos fiber contamination in dictory and inconclusive. The method Clerk. Food and Drug Administration, the water supply of the cities of the was therefore not proposed in order to Em. 4-65, 5600 Fishers Dane, Rockville, United States, with some reports that indicate any known hazard from asbes MD 20352. the waters of the San Francisco, CA, tos, but was intended to establish a good The Commissioner concludes that the and the Duluth, MN, areas are among manufacturing practice limitation for above reported salt study represents a the highest in asbestos content. How the use of talc in food and drugs until practical upper limit of migration of as ever, the lack of consistency of test meth an assessment of the hazard, if any, of bestos from food-contact paper and pa ods and their applications leads to ques ingested asbestos can be determined. perboard. This conclusion is based upon tions concerning these data. A recent The particle limitation accompanying consideration of the extreme abrasive epidemiological study of cancer mortal the proposed method represents the best nature of salt as compared to other dry ity in Duluth over the last 14 years (Ref, assessment by the Food and Drug Admin foods, and the unusually high tremolitic 2) has concluded that, up to this time, istration of the probability of occurrence asbestos content of the test paper (6 per no carcinogenic "effect could be demon of such particles in natural talc deposits, cent) as compared to reported levels of strated from Ingestion of the municipal the ability of the method to detect such use (0.02-0.4 percent) in food-contact waters. Some reports have been received, particles, and the need to assign a limit to define the absence of asbestos. The Food and Drug Administration has also examined numerous talc samples of un defined grade in the past 2 years, using the proposed methodology, and finds that approximately two-thirds of such sam paper and paperboard. The Commissioner therefore concludes that the comment has demonstrated that the asbestos content of talc used in the manufacture of food- or drug-contact paper and paperboard does not represent a potential contaminant of packaged claiming little or"no'.asbestos addition to the aforemehtianecPjiroducts by the use of filters (Ref. 35", Other reports from Canada, which indicate some in creases in the asbestos content of bever ages (Ref. 4 and 5) over background water, show that the final levels are com ples are within these limitations. The Commissioner therefore concludes that the proposed particle limitations would not impose an unreasonable burden on manufacturers of talc If these limitations are ultimately adopted. The Food and Drug Administration has been aware of the possible extreme variation in asbestos particle size that may occur in natural deposits of talc. Eliminating particles less than 5 microm eters long or with less than a 3-to-l length-to-wklth ratio considerably nar rows the range of permissible particles counted by tike proposed method. Con sidering the variation in particle size that may yet be possible, however, a typical particle of 300 cubic micrometers, weigh ing approximately 1 nanogram (Ref. 1) was used to assure a purity of talc at least 99.9 percent free of amphibole types of asbestos fibers and at least 99.99 per cent free of chrysotile asbestos fibers. food or drugs, as assessed by currently parable to the background levels in areas available methodology. Accordingly, the of the United States. Therefore, the Com Commissioner is withdrawing the analyt missioner has decided to delay the pro ical limitations proposed for talc in mulgation of any regulation on the pro $ 121.101(h), unless new methodology or hibition of use of asbestos filters for the toxicological assessment requires further preparation of foods and nonparenteral evaluation of this question. drugs until more reliable data can be 4. The Commissioner stated in the pro obtained on the background concentra posal that it had been decided not to tions of asbestos In drinking water and promulgate a proposed regulation gov the role of asbestos filters in regard to erning the utilization of asbestos filters the addition of fibers to ingestible In the processing of food and beverages. products. One comment stated that this was in 5, Many comments endorsed or con consistent with the Commissioner's pro demned the proposals, or parts of them, posed regulation on the asbestos content with respect to water, food, and beverage of food-grade talc, and that attempts to contamination. Although most of these limit asbestos ingestion should apply comments did not supply any additional uniformly to all sources. Another com data or Information, a current asbestos ment stated that the Commissioner's decision not to regulate the use of as feeding study by J. M. G. Davis (Ref. fli and a 1967 study by G. M. Bonser and D. B. Clayton (Ref. 7) were cited as fur bestos filters in food, beverage and non- ther evidence of no harm from ingested parenteral drug preparations was based asbestos. Other comments cited the 1972 3. Three comments from industrial on the unproven notion that the amounts conclusion of the Advisory Committee fums objected to the proposed analytical of asbesots which are contributed to on Asbestos Cancers (Ref. 8) that there FEDERAL REGISTER, VOl. 40, NO. 31--FRIDAY, MARCH 14, 1975 UCC 006272 RULES AND REGULATIONS 11867 was no evidence of an Increased risk of jection potential of asbestos fibers, are months of the date of publication of this cancer from asbestos fibers in water, as follows: regulation will be-required to submit beverages, and food, or In fluids used for 1.A number of comments stated that monthly progress reports thereafter con the administration of drugs, and one there is no conclusive evidence that cerning attempts to implement the re comment cited a recent study by Klein- asbestos filters add fibers to the filtrate, quired procedures and any difficulties in feld. Messite. and Zaki (Ref. 9) whictl or that asbestos has caused deleterious maintenance of product quality. reports no increase of gastrointestinal effects as a result of parenteraily admin 3. A large number of comments stated and peritoneal cancer among talc istered drugs. that many parenteral products would workers exposed to talc dusts for a mini Asbestos fibers were found in a number suffer in safety and quality because of a mum of 15 years. of samples of parenteral drugs by Nichol requirement to replace asbestos-contain From analysis of the foregoing com son et al. (Ref. 10) and also by a sub ing filters in the manufacturing process. ments received concerning the limita sequent Food and Drug Administration The Commissioner agrees that it is es tion of asbestos in talc, from thorough Investigation of parenterals. Although sential that there be no Increase in risk re-review of the scientific evidence avail the Food and Drug Administration has to the public as a result of this action. able concerning the adequacy of the demonstrated that filtration through as The regulation provides for continued use available methodology to determine the bestos of a water sample highly contami of asbestos filters where no alternative amount of asbestos in talc, and from nated with asbestos fibers can signifi is feasible. The responsibility for demon consideration of the controversial nature cantly reduce the number of fibers pres strating that the replacement of asbestos of erideace to demonstrate the hazard ent, the Food and Drug Administration filters or the utilization of a final non- to health presented by ingestion of the also has direct evidence that the utili flber-releaslng, non-asbestos-containlng amounts of asbestos fibers normally to zation of asbestos filters can cause as- filter decreasesiiroduet quality and effec oe expected in talc used in food or drugs, -bestos contamination. The preliminary tiveness of safety remains that of the or in food or drug packaging materials report of the latter study Is on public manufacturer. Evidence for such product containing talc, or in beverages, other display in the office of the Hearing Clerk. alteration must be submitted to the ap foods and nonparenteral drugs prepared The evidence of the deleterious effects of propriate bureau of the Food and Drug with the use of asbestos filters, the Com parenteral asbestos administration (Ref. Administration for approval of the con missioner concludes that the promulga 1, 11, 12, and 13) requires that the tinued use of the unmodified asbestos tion' of regulations on the limitations or amount of contamination in these prod filtration processes. prohibition of the use of asbestos filters ucts be minimized. Consequently, the 4. One comment objected to the utili for" the_ preparation of foods and non- Commissioner has determined that it is zation of the terms "membrane filter* parenterar drugs and of the amount of Important that asbestos-containing fil and "non-flber-releasing filter," stating asbestos fibers in talc for use in food and ters be replaced with non-fiber-releasing that the former term was too limiting drugs or which might migrate into food filters unless it is demonstrated that it is as a recommendation for a replacement or drugs from talc-containing packaging not possible to manufacture a safe and of filters which may release asbestos materials is unwarranted until more effective parenteral drug or parenteral fibers and that the latter phrase should reliable data can be obtained concerning drug ingredient without the use of such be changed to "asbestos-containing or these matters." " , an asbestos-containing filter. In the lat medla-migration-exfaibiting filter." This The Food and Drug Administration, in ter Instance, a final non-fiber-releasing comment claimed that the term "non conjunction with other agencies. Is plan filter shall be used to reduce the content fiber-releasing" should be replaced since ning extensive experiments to determine of any asbestos-form particles in the drug small quantities of the fibrous support If long term exposure to ingested asbestos or drug ingredient. Use of an asbestos- used in many cellulose-ester membrane fibers represents a definitive hazard to containing filter with subsequent use of filters, as well as fibers and particles human health. As noted, until this study an additional non-asbestos-containing, from the manufacturing process for Is completed or other data become avail lion-fiber-releasing filter shall be permis cartridge and other type filters, are re able, the Commissioner has determined sible only upon submission of evidence to leased by cleaning and flushing prior to that a prohibition of the use of asbestos- the appropriate bureau of the Food and marketing of the product. Another com containing filters in the processing of Drug Administration that substitution ment stated that the proposed regula food and beverages, and of asbestos- for the asbestos filter of a non-flber-re- tions did notr-contain a definition of a containing talc as a food or food additive leasing filter will or is likely to compro non-fiber-releasing filter. Comments also or in drugs or drug ingredients is unwar mise the safety or effectiveness of the stated that f 133:8 Should not use the ranted due to lack of sufficient data. In drug. Use of an asbestos-containing fil terms "fiber-refgasingh and "asbestos- the interim, maufacturers of food and ter without subsequent use of an addi containing" interchangeably, and one drugs are urged to Investigate all means tional non-asbestos-containlng, non comment objected to the synonomous of eliminating the use of such filters and fiber-releasing filter shall be permissible use of the terms "fiber" and "asbestos talc, and to keep the Food and Drug only upon submission of evidence that fiber." -* Administration informed about changes' neither the substitution for the asbestos- The Commissioner agrees that the reg In formulation and processing of this containing filter nor the use of a sub ulation shouldmot specify only one type type. sequent non-fiber-releasing filter can be of filter which would satisfy the new re B. In order to deal with the Injection accomplished without compromising the quirements, and thus has deleted the potential of asbestos fibers, the Com safety or effectiveness of the drug. term "membrane filter." The Commis missioner proposed that the good manu 2. One comment noted that, although sioner also concludes that, for the pur facturing practice regulations for drugs there have been several demonstrations poses of these regulations, a non-fiber- be amended to require that filtration pro of the addition of nonasbestos, filters as releasing filter shall be defined as a non cedures for parenteral drugs shall utilize final filters in the production of injecta asbestos. nonglass fiber filter which, either a non-fiber-releasing filter such. ble biologies, there remains concern that after any appropriate pretreatment such as a membrane filter or, if an asbestos- the replacement of asbestos filters with as washing or flushing, will not continue containing filter Is used because it Is non-asbestos-containing filters would up to release fibers into the drug or drug necessary, the procedures shall also set delicate filtration parameters of the ingredient which is to be filtered. The utilize an additional non-asbestos-con product preparation process. An 18- distinction is, therefore, made between taining or non-fiber-releasing filter such month period was suggested as the allow filters which release fibers by media mi as a membrane filter to reduce asbestos able period of time for technical develop gration, i.e., continuous release due to fiber content to the minimum level fea ment of the new processes. the nature of the filter, and filters which sible unless such a subsequent filter will compromise the safety, identity, strength, quality, or purity of the product. Comments received in response to this The Commissioner agrees that a spe cific period for process development ami modification should be provided in the regulations. Therefore, 18 months will be allowed for compliance. Firms not con contain fibers from structural supports and contamination. The utilization of nonasbestos, nonglass fiber filters In the latter category will be permitted pro part of the notice, dealing with the in forming to these regulations within 12 vided that appropriate pretreatment. FEDERAL REGISTER, VOL 40, NO. 5T--FRiDAlf, MARCH 14, 197S UCC 006273 11S68 RULES AND REGULATiONS which eliminates fiber contaminant re than by individual evaluation by knowl 17) have demonstrated mesotheliomas In lease, has been accomplished. As the edgeable' scientists, Ho automatic de rats and rabbits from pleural ahd peri similarity between the carcinogenicities cision scheme was suggested in the com toneal injections of both chrysotile and of asbestos and fibrous glass has been ment. Therefore, the responsibility for crocidolite fibers. Further studies have noted, fibrous glass filters have been submission of the evidence required for been initiated by the Food and Drug Ad added to this definition to prevent the this determination will rest with the ministration on the effects of parenteral widespread conversion irom asbestos to manufacturer and the responsibility for injections of chrysotile fibers in experi this type of filter (Ref. 14 and 15). A accepting or rejecting the request for use mental animals, fiber is defined as "any particle with of asbestos-containing filters will rest 10. One comment indicated that, in length at least tliree times greater than with the appropriate bureau in the Food the study of parenteral administration of its width" iRef. 15 and 16). and Drug Administration, asbestos to animals by Schmahl (Ref. The Commissioner realizes that the 7. Two comments objected to the fact 11), the tumors that occurred were not definition of a niter-releasing filter ex that the regulations were limited to the related to asbestos since they were cludes the possibility of the use of an release of asbestos and asbestos-form sarcomas rather than mesotheliomas. asbestos or fibrous glass filter Inched into fibers and suggested that all extraneous, Although mesotheliomas are closely re a matrix which precludes the release of material such as diatomaceous earth, lated to inhalation of asbestos, there fibers. However, no such technology was carbon, silica, micro-fiberglass, etc., also also has been an association of carci presented as feasible by any of the com be regulated. _ noma of the lung with asbestos Inhala ments. Therefore, the Commissioner The Commissioner agrees that there is tion. As with other carcinogens, several concludes that the definition of a fiber reason to be concerned about all par types of tumors tjiay occur as a result of releasing filter is appropriate for this ticulate contamination in parenteral exposure to a particular carcinogen de regulation and chat, should a method for drugs, but concludes that this problem pending upon the route of exposure. The production of such a non-fiber-releasing should be considered separately from the Commissioner therefore concludes that asbestos or glass containing filter become subject regulations. Therefore, except for the data in this reference are valid and . available, the definition will be subject to fibrous particulates, the Commissioner may possibly implicate asbestos in the review. ' has decided to await clarification of the development of these malignant tumors 5. One comment suggested that the degree of other types of contamination of soft tissues, namely, sarcomas. proposed requirement that ."no asbestos- and the possible health effects of such 11. One commenter presented data containing filter may be used unless it is other particulates prior to developing demonstrating that membrane filtration not possible to manufacture a drug with applicable regulations, A call for scien was capable of removal of all asbestos out the use of such a filter" be replaced tific information in thl3 regard will he particles from his asbestos-filtered prod by "when an asbestos-containing filter published In the Federal Regisxzb in the uct (beer) as measured by electron mi is utilized, a suitable after-filter must future. croscopy. However, even though the con also be utilized to retain fibers." The Commissioner concludes that such a change would be unacceptable since the purpose of these regulations is to minimize the amount of asbestos or asbestos-form fibers in parenteral drugs thereby minimizing the possibility of del eterious effects, and although an after filter will substantially reduce the num ber of these fibers in the product, it can not be assumed that it will remove all of this material. Hence, the Commissioner has determined that the best means to eliminate asbestos contamination from parenteral drugs is by removal of the asbestos filters from the process when ever possible. As stated In paragraph B.3. of this preamble, the Commissioner agrees that there must be no increase in risk to the public from any product the manufacturing process of which is re quired to be changed. However, he re iterates that the use cf an asbestos filter will be permissible only upon a demon stration by the manufacturer that the replacement of an asbestos filter by a non-fiber-reieasing filter or the utiliza tion of a final or after-filter is non-fiber releasing adversely affects the quality, safety, and effectiveness of the product. 6. One comment objected to the state ment in the proposal that the use of asbestos filters in parenteral drug manu facturing is prohibited "unless it is not possihie to manufacture that drug or drug ingredient without the use of such a filter," claiming that the lack of a more specific statement will lead to capricious regulatory decisions. The Commissioner concludes that there is no more reasonable method by which to mate a determination of the impossibility of acliieving the desired product quality rr.d effectiveness without 8. One comment objected to the re quirement of proof of reduction of asbes tos fibers by the use of subsequent non asbestos-containing filters In the manu facture of a parenteral drug or drug ingredient when submitting a request for approval of a process in which asbestos filters are used. This and one other com ment claimed that the national Institute for Occupational Safety and Health (NIOSH) analytical method, as well as other analytical methods for determina tion of asbestos-form fibers in parenteral drugs, is Inadequate quantitatively to demonstrate reduction and is immensely difficult to perform. The Food and Drug Administration and other government agencies are pres ently attempting to develop reproducible, practical and useful methodologies for these analyses, and amendments to these regulations will be promulgated upon the satisfactory completion of this research. The Commissioner has decided that un til these studies are completed, the evi dence lor reduction of asbestos-form fiber content need not be obtained if adequate downstream filtration is ac complished. Thus, the requirement of proof of reduction of asbestos fiber con tent is omitted and the use of a non fiber-releasing filter of 0,22 micron maximum pore size is added to this regu lation (0.45 micron maximum, if the manufacturing conditions so dictate). 9. One comment claimed that it is inappropriate to control all types of asbestos fibers uniformly, as asbestos filters arc composed primarily of ebrysotile which is less hazardous to human health than amphiboles. The Commissioner concludes that this differential In hazard has not been es tablished for parenterally administered tainer for this product was subjected to a final rinse by municipal water, the packaged product contained a significant number of asbestos fibers. Similarly, the Food and Drug Administration has found asbestos particles in parenteral drags produced by manufacturers who do not use asbestos filters in their processes. These indications of substantial con tamination of the product from typical liquid containers have led the Commis sioner to conclude* that cleansing and rinse water for the containers for paren teral drugs shall bk filtered through nonfiber-reieasing filters equivalent to those required for post-aibestojSfilter filtration to remove inherent'-fibertoontamination. 12. The Environmental Impact Anal ysis Report (EIAR) and other relevant materials have been reviewed and it has been determined that the proposed use will not have a significant environmental impact. Copies or file EIAR are available in the office of tftfe Assistant Commis sioner for Public Affairs, Rm. 15B-42, or the office of the Hearing Clerk, Rm. 4-65, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852. The indications to references set forth in the preamble are to the following, which are on display in the office of the Hearing Clerk: 1. "Parenteral Preparations. Pyrogens," in Remington's Pharmaceutical Sciences, I4th ed., Chapter S3, p, 15+2, 1970. 2. Mason. T. J., P. W. McKay and R. W. Miller. "Asbestos-LlKe Fibers In Duluth Water Supply: Relation to Cancer Mortality," "Journal of the American- Medical Associa tion,1' 228:1020,. May 20. 1974. 3. Comment from Asbestos Research Coun cil. March 1, 1971. 4. Cunningham, H, M. and R. Pontefract: (a) "Asbestos ' Fibers In Beverages and Drinking Water," ''Nature'' 232:332-333, the use of asbestos-containing filters asbestos. Studies by Reeves et al. (Ref. 1971- FEDERAL REGISTER, VOL. 40, NO. 51---FRIDAY, MARCH 14, 1975 UCC 006274 RULHS AND REGULATIONS 11869 (*o) "Symposium on Industrial Chemicals aa Food Coataiotaants/'' "Journal of the As sociation of O&cial Analytical Chemists/' 56:9713-981, 1973. 5. Pontefract, ft., and H. M. Cunningham* "Fenetraa^r. of Asbestos through the Diges tive Tries of Rats,'* "Nature," 243:352-353, 1373. 6. Davis, J. M. G., Institute of Occupational MeUicLne Eiiinburgh, Scotland, unpublished report. 7. Eonser, O. M., and D. B. Clayton, "Feed ing of Blue Asbestos to Rats/' 1967 Annual Report. British Raiptre Cancer Campaign for Research, p. 2-42, 8. "Report of the Advisory Committee on Asbestos cancers to the Director of the In terna Uottal Agency for Research on Cancer,'* products unless it is not possible to man (Secs. 501, 502. 701, 52 Stat. 1049-1051. 1065 ufacture that drug product or component 1056, os amended; (31 UJ9.C. 351, 353, 371)) without the use of such a filter. Filtra tion, as needed, shall be through a non- Dated: February 28,1975. fiber-releastng filter. For the purposes of this regulation a non-fiber-releasing A M. Schmidt, Commissioner of Food and Drugs. filter is defined as a nonasbestos, non [FR Doc.75-6733 Filed 3-13-75:8:45 am] glass fiber filter which, after any appro priate pretreatment such as washing'or r flushing, will not continue to release fiberg into the drug product or compo- ; nent which is being filtered, A fiber is de fined as any particle with length at least three times greater than its width. : (2) If use of a fiber-releasing filter Is required, an additional non-fiber-releas- . "British Journal of Industrial Medicine/1 30:180-185,1973. ' 9. Klelnleld, M., J. Measlte, and M. H. Zakl, 'Mortality Experiences Among Talc Work ers: A Follow-up study," "Journal of Oc cupational Medicine." ,16:345-349, 1974. 10. Nicholson, W. H,, C. J. Magglare and I, J, Selikoff., "Asbestos Contamination of ing filter of maximum pore size of 0.22 microns (0.45 microns lf-the manufac turing conditions so dictate) shall subsequer.tly be used to reduce the content of any asbestos-form particles in the drug product or component. Use of an ! asbestos-containing filter with or with Parenteral Drugs," "Science," 177:171-173, out subsequent use of a specific non- I 1973. 11. Schmnhl, D., "Carcerogene WIrktng von Asbest bei Implantation von Patten," "Zeltschrlft fur Krebsforscliung," 63:561-587, 1958. 12. Roe, F. H. C., It. L. Carter, M. A, Walters and J. S. Harrington, "The Pathological ef fects of Subcutaneous Injections of Asbestos fiber-releasing filter Is permissible only : upon submission of proof to the appro priate bureau of the Food and Drug Ad ministration that use-of a non-fiber-re- i leasing filter will, or is likely to, i compromise the safety or eleettveness of j the drug. * [ Fibers In Mice: Migration of Fibers to Sub- (3) Substitution for a fiber-releasing mesothellal Tissues and Induction of Meso theliomas," "International Journal of Can cer," 2:628-603. 1967. 13. Hanazawa, K,, M. S. C. Blrbeck, R. L. Carter and F. J. C. Roe, "Migration of As bestos Plbecj from Subcutaneous Injection Sites In Mice," "British Journal of Cancer," 24:96-108. 1970. ' filter shall be achieved on or before Sep- ! tember 14, 1976. If such substitution is 1 not achieved on or before March 14, 1976, the manufacturer of the drug prod uct for parenteral injection who requires the additional 6 months to develop new manufacturing procedures so as to uti 14. "Symposium on Occupational Exposure lize non-fiber-releasing filters in place of to Fibrous Glass." sponsored by National In stitute for Occupational Safety and Health, University of Maryland, June 28-27, 1974. 15. Stanton, Mearl F., "Fiber Carcinogene sis: 13 Asbestos the Only Hazard?" "Journal of the National Cancer Institute," 52:633 (1974). 16. "Occupational Exposure to Asbestos," fiber-releasing filters shall submit monthly reports to the appropriate bu reau of the Food and Drug Administra tion indicating progress in substituting the new filters. Such a substitution shall be shown to have been effected without loss of the safety or effectiveness of the Criteria document, UB. Public Health Serv ice, National Institute for- Occupational Safety and Health, Chapter Vllf, pg, 6, 1972. 17. Reeves. A. J., H. E. Puro, B. Q. Smith drug. ' 2. By revising 3133.9 to read asfollows: and A. J. Vcrwald, "Experimental Asbestos Carcinogenesis," "Environmental Research," 4:49.6-511,1971. ., 133.9 Product containers and their . components. Therefore, pursuant to provisions of the Federal Food, DYug, and Cosmetic Act (secs. 501, 502, 701, 52 Stat. 1049 1051, 1055-1056, as amended; 21 U.S.C. 351, 352, 371) and under the authority delegated to the Commissioner (21 CFR 2.120;, Part 133 is amended as follows: 1. By amending 5133.8 by adding new paragraph (j), to read as follows; Suitable specifications, test methods, cleaning procedures, and when Indicated, sterilization procedures shall be used to assure that containers, closures, and other component parts of drug packages are suitable for their Intended use. Con- tainers for parenteral drugs, drug prod ucts or drug components shall be cleansed with water which has been fil tered through a non-fiber-releasing filter : , | 133.8 Production and control proce equivalent to that indicated in 3 133.8(j) , dures, (2). Product containers and their com- i * * ponents shall not be reactive, additive, i (j) Use oT asbestos-containing or other fiber-releasing filters: (1) Filters used in the manufacture, processing or pack aging of components of drug products for parenteral injection in humans shall or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug or its components beyond the official or established requirements and shall provide adequate protection against j i not release fibers Into such products. No external factors that can cause deterio- I asbestos-containing or other fiber-re ration or contamination of the drug. leasing filter may be used in the manu Effective date. This order shall be ef facture, processing or packaging of such fective April 14, 1975. * FEDERAL REGISTER, VOL, 40, NO. 51--FRIDAY, MARCH 14, 1975 UCC 006275