Document 7RvVxvNG4bE5rbRKRk2gm1b98

PLAINTIFF'S EXHIBIT UC-3706 ASBESTOS INFORMATION ASSOCIATION NORTW AMERICA 1660 L Street. MW Washington DC. 20036 , (202) 223^885 14 March 1975 *- K > /. > ti i' t\ i ,< 1 Memorandum For: MEMBERS Subject: Asbestos-Form Particles in Drugs for Parenteral Injection Enclosed please find regulations for asbestos-form partlcJ.es,___ 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 March 14, 1975-- Pages 11859-12066 4) FRIDAY, MARCH 14, 1975 WASHINGTON, D.C. Volume 40 * Number 51 V Pages 11859-12066 FART I HIGHLIGHTS OF THIS ISSUE This Dating does not aifoct the legel status of any document published In this issue. DihM table of contents appears inside. NONHUMAN PRIMATES--HEW proposes restricting im portation; comments by 4-14-75----------- --------- -----11887 EXHAUST EMISSION STANDARDS--EPA grants suto manufactures suspension request foe 1977 model year.11900 HIGHWAY SAFETY--DOT criteria for incentive grant* to States for annual fatality rate reductions; effective 3-14-7511870 CAREER EDUCATION PROGRAM-- HEW70E announces dosing date 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 data of 4-15-75 for receipt of applications ------- ------------- -------------------------------- 11931 HEW/OE proposes funding criteria for FY 1976; com ments by 4-14-75---------------------------------------------------- il930 SUPPLEMENTARY EDUCATIONAL CENTERS-- HEW/OE sets closing date ot 4-25-75 for receipt of applications------------------------------------------------- 11931 HEW/OE proposes funding entasis for FY 1976; com ments by 4-14-751188B XiStOmC DRUGS--HEW/FDA provides test method ^tor Tetracycline; effective 3-14-75____________-- 11869 l/ASABSBBESTOS PARTICLES--HEW/FDA restricts nee In man ufacture of parenteral injection preparations; effective 4-14--75------------------------------------------------------------------ 11869 BSOLDGICS--HEW/FDA proposal changing testing re quirements for Smellpea Vaccine, Live; comments by 4-14-75 --------------------------------------------- -------------------- 11884 (Continued Inside) PART II: DRINKING WATER--EPA propose* Interim pri mary standards; comments by 5-16-75--____ . 11989 PART III: MINIMUM WAGES--Labor/ESA determinations for Federal and federally assisted construction__ -- 11999 UCC 006270 ALiLES .AMD aiGULATiONS ' . . Title 21--Font) and Drugs CHAPTER 1--FOOD AND DRUG ADMIN IS- , TRATION, DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE SUBCHAFTER C--DRUGS PART 133--DRUGS; CURRENT GOOO ! MANUFACTURING PRACTICE IN MAN- i UFACTURE. PROCESSING, PACKING, 1 OR HOLDING j Asbestos-Form Particles In Drugs lor 1 * Parenteral Injection j The Commissioner of Food and Drugs I published In the FsontsL Rstusns of ! September 28, 1973 (38 FR 270781, a 1 notice proposing to restrict the utUlza- : tian of asbestos filters in the m&nu- ! factors of parenteral drugs and par- ! enteral drug Ingredients, and to pro- ! hibit the use of asbestos-containing talc > as a food, or food or drug Ingredient, or I In food and drag packaging materials,! within certain analytical restrictions, i The notice provided for the filing of 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, ft 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 September 28,1973 proposal toll into two j uses main categories. One concerns provisions to decrease the potential for Ingestion of asbestos fibers. The other concerns pro visions to decrease the potential for in jection of asbestos fibers. A discussion of each category of comments, and the Commission's conclusions, ore set forth below. A. Comments on provisions dealing with ingestion potential of asbestos fibers: 1.The Commissioner proposed that any food, food packaging material, drug, drug Ingredient or drug packaging ma terial containing talc that Is not free from asbestos fibers as determined by & particular analytical method should bo deemed adulterated hr violation of sec tion- 402(a) U> of the Federal Food, Drug, and Cosmetic Act. Nineteen comments related to the pro posed analytical method foe talc under1121.2006 <21 CFR 12l.20W>. 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 secting their general experience with optical crystallography or a personal preference for other analytical methods, none at 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 mlcroscoptsta would be capable of using the method with any reasonable accuracy or precisian. Mem bers of one trade association coOabaratlvely studied the method with 10 mtcrosccplsts. each examining seven samples of tale. 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 to tulc 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. sev eral electron microscopy and mlcioprobo techniques as preferred or supportive analytical methods. Many of the re spondents additionally expressed their willingness to loin a Food and Drag 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. ho 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 ITDEKAi UGI5TM, VOL SOT, NO. 51--FklOAT, MAS CM 14, 1975 UCC 006271 RUIS5 ANO REGULATIONS area cf research currently Is being ac requirements for talc used in the manu man's overall exposure by thpse sub tive!? pursued by the Food and Drug Administration. 2. Several comments objected to the purity limitations lor talc '.vhu'h were es facture of paper and paperboard In. { 121.101(h) <21 CfTt 121.101 fh)). All of these comments contended that asbestos, in asbestos-containing talc, does not mi stances are small. The comment con tended that evidence is lacking to show that the ingestion of small amounts of 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 amphlbole-lree and 99.99 contained resup.s of recently conducted lessen the total human exposure to as percent chrysoUle-free unreasonable, studies which were intended to prove this bestos were not mitigated by the fact that virile others insisted that any limitation conization. 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 Inown 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 3.9C0 chrysotile fibers (of 5 micrometers ment has demonstrated the validity of this instance, the lack of available re y 1.7 micrometers size) should be permit this contention in a manner consistent producible methodology lor 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 ir-nki;v? u 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 uncoatcd paper con the Commissioner has decided to delay tamination in talc. taining up to 3 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 cf 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 nonparentera] these comments to clarify his position on milk, nee, and com 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 Rm. 4-65, 5600 Fishers lane, 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 paper and paperboard. claiming little or 'no '.asbestos addition to define the absence of asbestos. The The Commissioner therefore concludes to the aforemehtirmecf'jproducts by the Food and Drug Administration has also that the comment has demonstrated that use of filters (Ref. s'j`. Other reports examined numerous talc samples of un the asbestos content of talc used In the from Canada, which Indicate some in defined grade in the past 2 years, using manufacture of food- or drug-contact creases in the asbestos content of bever the proposed methodology, and finds that paper and paperboard does not represent ages (Ref. 4 and 5) over background approximately two-thirds of such sam a potential contaminant. of packaged water, show that the final levels are com ples are within these limitations. The food or drugs, as assessed by currently parable to the background levels In areas Commissioner therefore concludes that available methodology. Accordingly, the of the United States. Therefore, the Com the proposed particle limitations would Commissioner is withdrawing the analyt missioner has decided to delay the pro not Impose an unreasonable burden on ical limitations proposed for talc in mulgation of any regulation on the pro manufacturers of talc If these limitations ! 121.101(h), unless new methodology or hibition of use of asbestos filters for the are ultimately adopted. toxicological assessment requires further preparation of foods and nonparenteral 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 les3 than a 3-to-l length-to-vidth ratio considerably nar rows the range of permissible particles counted by the proposed method. Con sidering the variation in particle size that may yet be possible, however, a typical particle of .709 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 chrysotlie asbestos fibers. evaluation of this question. 4. The Commissioner stated in the pro posal that it had been decided not to promulgate a proposed regulation gov erning the utilization of asbestos filters In the processing of food and beverages. One comment si.ded that this was in consistent with the Commissioner's pro posed regulation on the asbestos content of food-grade talc, end that attempts to limit asbestos ingestion should apply uniformly to all sources. Another com ment stated that the Commissioner's decision not to regulate the use of as bestos filters in food, beverage and non- parenteral drug preparations was based drugs until more reliable data can be obtained on the background concentra tions of asbestos in drinking water and the role of asbestos filters in regard to the addition of fibers to ir.gestlble products. 5. Many comments endorsed or con demned the proposals, or parts of them, with respect to water, food, and beverage contamination. Although most of these comments did not supply any additional data or Information, a current asbestos feeding study by J. M. G. Davis (Ref. 6) and a 1967 study by G. M. Bonser and D. B. Clayton (Ref. 7) were cited as fur ther evidence of no harm from Ingested asbestos. Other comments cited the 1972 3. Three comments from industrial on the unproven notion that the amounts conclusion of the Advisory Committee firms objected to the proposed analytical of asbesots which are contributed to on Asbestos Cancers (Ref. 8) that there FEDERAL REGISTER, VOt. 40, NO. SI--FRIDAY, MARCH 14, 197S UCC 006272 RULES AND REGULATIONS 1186T was no evidence of an increased risk of lection potential of asbestos fibers, are months ot 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. Messlte, and Z&ki (Ref. 9) which or that asbestos has caused deleterious maintenance of product quality. reports no increase of gastrointestinal effects as a result of parenterally 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 llmita- 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 wtth 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 evidence 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 fiber-relearing. non-asbestos-containlng amounts of asbestos fibers normally to zation of asbestos filters can cause as filter decreases'})roduct 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, II, 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 `tfnr preparation of foods and non- Commissioner has determined that it Is zation of the terms "membrane filter" parenteraT drugs and of the amount of Important that asbestos-containing fil and "non-ftber-releasing filter," stating asbestos fibers in talc for use in food and ters be replaced with non-fiber-releastng 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-exhibitlng filter." This The Food and Drug Administration, in ter instance, a final non-flber-releaslng 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 membrana fibers represents a definitive hazard to containing filter with subsequent use of filters, as. anil 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 uon-fiber-releasing filter shall be permis cartridge and other type filters, are re able. the Commissioner ha3 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 notf-eontala a definition of a containing talc as a food or food additive leaslng 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 }>133:8 Should not use the ranted due to lack of sufficient data. In drug. Use of an asbestos-containing fil terms "flber-relaaslngri 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 lor 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 tair.iug or non-fiber-releasing filter such month period was suggested as the allow filters which release fibers by media mi os a membrane filter to reduce asbestos able period of time for technical develop gration, l.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 The Commissioner agrees that a spe contain fibers from structural supports compromise the strength, quality, product. safety, identity, or purity of the cific period for process development pnd modification should be provided in the regulations. Therefore. 18 months will be and contamination. The utilization of nonasbestos, nonglass fiber filters In the Comments received in response to this allowed for compliance. Firms not con latter category will be permitted pro part of the notice, dealing with the in forming to these regulations within 12 vided that appropriate pretreatmeat. FE0ERAL REGISTER, VOL 40, NO. 51--FRiDAV, MARCH 14, 14/5 UCC 006273 11S68 RULES AND RSGUtATiONS which eliminates fiber contaminant re than by individual evaluation by knowl 17) have demonstrated mesotheliomas In lease. has been accomplished. As the edgeable' scientists. No automatic de rats and rabbits from pleural ahd peri similarity between the carcinogenicities cision scheme was suggested in the com toneal injections of both chrysotlle and of asbestos and fibrous glass has been ment. Therefore, the responsibility for crocidollte fibers. Further studies have noted, fibrous gias3 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 tile effects of parenteral widespread conversion from astescos to manufacturer and the responsibility for injections of chrysotlle fibers In experi this type of filter (Ref. 11 and 15). A accepting or rejecting the request for use mental animals. fiber is defined as "any particle vita of asbestos-containing filters will rest 10. One comment indicated that. In length at least tluee times greater than with the appropriate bureau In the Food the study of parenteral administration of iU width" i.ter. 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 fiber-releasing filter ex that the regulations were limited to the related to asbestos since they were cludes the pcssibUity of the use of an release of asbestos and asbestos-form sarcomas rather than mesotheliomas. asbestos or fibrous glass filter locked into fibers and suggested that all extraneous, Although mesotheliomas are closely re a matrix which precludes the release of material such as dlatomaceous 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 fiiay occur as a result of releasing filter is appropriate for this ticulate contamination in parenteral exposure to a particular carcinogen de regulation and that, shouid 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 not possible to manufacture a drug with other particulates prior to developing applicable regulations. A call for scien demonstrating that membrane filtration was capable of removal of all asbestos out the use of such a filter" be replaced tific information In this regard will be particles from his asbestos-filtered prod by "when an asbestos-containing filter published in the Fxsxui. RxmsTza ha the uct (beer) as measured by electron mi is utilized, a suitable after-fiiter 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 poeaibUity of del eterious effects, and although an afterfilter 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, be 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-flber-releaslng filter or the utiliza tion of a final or after-filter is non-flberreleasing 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 possible 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. 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. Tills and one otber 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 Focd 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 ot a nonflber-releastng filter of 0.22 micron maximum pore size is added to this regu lation (0.15 micron maximum. If the manufacturing conditions so dictate). 9. One comment claimed that it Is inappropriate to control all types of asbestos :Yc. rs uniformly, as asbestos filters arc c moored primarily of chrysottie which is less hazardous to human 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 Poor' and Drug Administration has found asbestos particles in parenteral drags produced by manufacturers who do not nse 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 be filtered through nonfiber-releasing filters equivalent to those required for post-aibestoadfilter filtration to remove lnherenT-fiber^eontamination. 12. The Environmental Impact Anal ysis Report (EtAR> and other relevant materials have been reviewed and It has been determined that the proposed use will not have a significant environmental impact. Copies of'Ehe E1AR are available in the office of the Assistant Commis sioner for Public Affairs, Rm. 15B-43, or the office of the Hearing Clerk, Rm, 4-65, Pood 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 Clerki 1. "Parenteral Preparations. Pyrogens," In Remington's Pharmaceutical Sciences, 14th ed.. Chapter 82. p. 1542.1S70. 2. Mason. T. J.. P. W. McKay and R. w. Miller. "Asbestos-Lire Fibers In Duluth Water Supply: Relation to Cancer Mortality," Vou.-nai of the American Medical Associa tion." 228:1020, May 20. 1974. The Commissioner concludes that there is no more reasonable method by which to make a determination of the impossibility of aclueving the desired product quality r r.d effectiveness without health than amphiboles. The Commissioner concludes that this differential In hazard has not been es tablished for parenterally administered 3 Comment from Asbestos Research Coun cil. March 1. 1974. 4. Cunningham, H. M and It. Pontefract: (a) "Asbestos Fibers In Beverages and Drlnldng Water," "Nature" 232:332-833, the use of aifcc.tos-containing filters asbestos. Studies by Reeves et al. (Ref, 1971. KDHA1 REGISTM. VOl. 40, NO. 3)--FRIDAY, MARCH 14, 1475 UCC 006274 a DIES AND REGULATIONS 11869 p) "Sysipcsi'Jin on Iudiutrtftl Chemicals aa Food CoQtamtoauta/* "Journal of the AbsocUtion of OQciat Analytical Cliemlati/* 56:973-981. 107J. 5. P^rueCrac*.. R,, and H. M. Cunningham, *,r,*rjtftriti3" of Asbestos through tha Dlgea- tiv* True: of RaLs/* "Nature/* 243:353-353, 1373 6 Darla. j M. O.. Institute of Occupational products unless it is not possible to mao- ufacture that drug product or component without the use of such a filter. Filtra tion. as needed, shall be through a nonEber-releastag filter. For the purposes of thi3 regulation a non-fiber-releaslng filter is defined as a nonasbestos, non glass fiber filter which, alter any appro (Secs. sot. 503. toi, 52 stat. 100-1051, ioss1056, as amended; (2i U3.C. 351, 352, 371)) Dated: February 28,1975. A. M. SenseDT. Commissioner of Food and Drugs. [FR Doc.75-0733 Filed 3-J3-76;8:M am] Medic u Eoinburgb, Scotland, unpublished report. V. Bonder. O. M., and D. B. Clayton, "Feed* lng of Blue Asbestos to Rats/* 1957 Annual Report. British Empire Cancer Campaign lor Research. p. 242. 8. "Report of the Advisory Committee on AiteV-Os Cancers to the Director of the In* ternailohal Agency for Research on Cancer,'* priate pretreatment such as washing "or . Bushing, will not continue to release fibers 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- "Bri'-ush Journal of Industrial Medicine,** 30-lBO-ie5. 1973. ' 9. KlelD.'tld. M.. J. Mewlt,. and M. H. Zald, "McrtaJ tty Experiences Among Talc Work ers: A Follow-up study/* "Journal of Oc cupational Medicine/*. 18:345-34. *974. 10. Nicholson. W. H., C. J. Maggtare and l. J. SellkoJ., "Asbestos Contamination of Parenteral Drugs/* "Science/* 177:171-173, tng filter of maximum pore size of 0.22 : microns (0.45 microns if-the manufac- ! turing conditions so dictate) shall sub sequently be used to reduce the content of any asbestos-form particles in the drug product or component. Use of an 1 asbestos-containing filter with or with out subsequent use of a specific non- i 1973. 11. Schxnahl, D.t "Carcerogene `Wlrklng von Ashest bei implantation von Ratten,** "Zeltcchrlft fur Krebsforschung/* 63:581-687, 1358. 13. Roe. F. H. C.. R. L. Carter, M. A. Walters and J. S. Harrington. "The Pathological ef fects of Subcutaneous injections of Asbestos Fibers in Mice: Migration of Fibers to SubmesotheLlai Tissues and Induction of Meso theliomas,'* "International Journal of Can cer," 2:628-633.1967. 13- Kanazawa, K., M. S. C. Birbeck, R. L. Carter and F. J. C. Roe, "Migration of As bestos Plbe^y from Bubcutaneoua Injection Sites In Mice/' "British Journal of Cancer,** 24:96-108.1970. 14. "Symposium on Occupational Exposure fiber-releasing filter Is permissible only . upon submission ol proof to the appro priate bureau of the Food and Drug Ad ministration that use.of a non-flber-re- leaslng filter will, or is likely to, : compromise the safety or eleettveness of ' the drug. I (3) Substitution for a fiber-releasing j filter shall be achieved on or before Sep- 1 tember 14, 1976. If such substitution is ' 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 lize non-fiber-releasing filters in place of \ to Fibrous Class.** sponsored by National In stitute for Occupational Safety and Health, University of Maryland. June 26-37, 1974. 15. Stanton. Wear! F., "Fiber Carcinogene sis: Is Asbestos the Only Hazard?** "Journal of the National Cancer Institute," 62:633 (1974). 16. `'Occupational Exposure to Asbestos." Criteria document. OB. Public Health Serv ice. National Institute for Occupational Safety and Health. Chapter VTH. pg. Q, 1972. 17. Reeves. A. J., H. B. Puro. R. Q. Smith 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 drug. 2. By revising 9 133.9 to read as - | follows; I . it l-.'.O tt. ts Vi- and A. J. Vorwald, "Experimental Asbestos Carcinogenesis/' `'Environmental Research/' 4:496-511. 1971. 133.9 Product containers and their components. ( Therefore, pursuant to provisions of the Federal Food. Dfiug. and Cosmetic Act (secs. 501. 502, 701, 52 Stat. 10491051. 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 9 133.8 by adding new paragraph (J), to read as follows; Suitable specifications, test methods, ' cleaning procedures, and when indicated, sterilization procedures shall be used to i assure that containers, closures, and other component parts of drug packages are suitable for their Intended use. Con- , tainera 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 3 133.3 Production and control proce equivalent to that indicated in 3 133.8(J> , dure. (2). Product containers and their com- ; * * , * . ponents shall not be reactive, additive, j (j) Use of 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 1 j j 1 r.ot release fibers into such products. No externa! factors that can cause deterio 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. i KDERAL REGISTER, VOL 40, NO. 51--FRIDAY, MARCH 14, 1975 UCC 006275