Document Ea829XgkXyRaXB70o6QL6qQb

! 'f \: m *\ II DEPAR'i M i-N T O f E 'A L M , E D U C A T IO N , AN D W E IL F A R E PUDLIC rl-AL'H S rR V IC r FO O D AND D R U G ADM iKI/l NATION ROCKVILLE. MARYLAND 2C112 APR J l 1376 Mr. Joseph Stehler President Pharmaceutical Manufacturers Association 1155 Fifteenth Street, N.W. Viashington, D.C. 20005 Dear Mr. Stehler: This is in reply to yoor petition relating to the final regulation published in the Federal Register of March 14, 1975, entitled "Asbes tos-Form Particles in Drugs for Parenteral Injection". Your petition requested (1) withdrav/ing two subsections of the final regulation that you allege were not included as part of the original proposal., (2) recording the subsection relal.jjig to subsequent use of a non-fiber releasing'filter, and (3) delaying the effective date of the regulation. Our response to your requested actions is as follows: 1. Definition of non-fiber-releasing filter to include non-glass , fiber filters in 211.i0~(j7~(T)T~ '' f Both your petition and a submission by Johns-Manville allege that the Commissioner issued the final regulations contrary to the rule making provisions of Lie Administrative Procedure Act in tirt the final regulations included a substantive provision not set forth in the proposed regulation. Specifically, you allege that although the proposed regulations did not make any reference to glass fiber filters, the final regulation prohibits their use in preparing drugs for injection into humans. As a result of the failure to mention glass fiber filters in the proposal, you allege that interested persons were precluded from presenting written data, views, and arguments concerning such filters. It is our conclusion that, although the terms of the notice are broad enough to include glass filters, the lack of carments on the proposal with respect to the glass fiber filter issue indi cates that the proposal may not have provided sufficient notice \ 7dT/ ? I Mr. Joseph S cetier 2 that the phrase "asbestos-containing or fiber-releasing filter" embraces glass fiber filters. Therefore, to eliminate the pos sibility of a legal, challenge to the regulations on the grounds that the proposal was inadequate, an amendment to c 311.40 (j) (1) v/i.11 be published in the Ftyerdl register to delete non-rla .s fiber fillers from the definition of non fiber-releasing io J to: .. Howove we maini: in that the scientific data 'suggest that the preson of glass fibers in parenteral drugs is of sufficient public health concern to require agency action. Therefore, in the very near future we intend to propone in amendment to pro hibit the use of glass fiber filters ini the manufacture of paren-feral drugs for human use. 2. Request for rewording of 211.40 (j) (2). . Your petition requests that 211.40(j)(2) be amended to indicate that the use of asbestos-containing filter with subsequent use of a specific non-fiber releasing fib ter be routinely permissible. As published, the regulation permito the use of an asbestos con taining filter with subsequent use of a specific non-fiber-relcas ing filter only upon submission of preof to FDA that the use of a non-fiber releasing filter alone will, or is likely to, compro mise the safety and effectiveness of the drug product. Your pe tition states that a non-fiber-releasing filter will filter out any fibrous materials, thus meeting the agency's objective of eliminating fibers from the drug product. Therefore, since the agency's objective is met, you contend that it should not be necessary to demonstrate that the use of only a non-fiber-releas ing filter will compromise tlse safety of efficacy of the drug. We conclude that such a change would be unacceptable since the purpose of these regulations is to minimize to the greatest de gree possible the amount of asbestos or asbestos-form fibers in parenteral drugs, thereby minimizing the possibility of deleteri > ous effects. Although a non-fiber-releasing filter used after an asbestos-containing filter will substantially reduce the num ber of fibers in the product, one cannot be sure that it will remove all of this material. Therefore, the best means to elim inate asbestos contamination from parenteral drugs is by removal of tlie asbestos 'filters from the process whenever possible. 3. Filtration of wash-water ( 211.55). Your petition also contends that 211.55 adds a new requirement that was not contained in the proposal. Specifically, your pe tition states that the specification that wash water used to clean Mr. Joseph Stetler 3 containers for parenteral, drug products and their components must be filtered through a 0.22 micron filter (0.45 micron if the manu facturing conditions so dictate) was not in the proposal and there fore should be withdrawn or published as a proposed regulation. hi issue is not th- racersitg for filL.ation of w h water, but the pore sire of the noi,-fiber--.? elec sing filter that v?ill b- r e quired in water lines carrying wafer to be used for the irr.1 rin io Or containers tor parenteral drugs and their co.vm e .ifs. In addition to tire 3l.lG.gati.cn that the filter pore size was not included in the proposal, your petition states that the filter pore size specified is unreasonably small without the .inclusion of an appropriate test method to determine the effect of filuna tion cind that the large volumes of water involved in the cl caus ing and rinsing operations con pose many practice! problems in terms of increased time involved and needless costs. It is our conclusion that the proposal contains sufficient .infor mation to pornat specification, in the final regulation, of the pore size of filters used to prepare v.vter for cleaning and rins ing containers for parenteral drugs and their components. There fore, _we reject your request to withdraw this requirement. Your petition did nov. object to the pore size-; requirement for filter ing drugs but only to that requirement as it pertains to the wash water. TO require a filter with a pore size of 0.22 micron (0.45 micron if the nnnufactoring conditions so dictate) for parenteral dnicjo but to allow a filter of greater pore size to be used for the wash water would defeat the purpose of the regulation. If a filter of larger pore size than that used for the product were permitted, the filtered product could be free of fibers but the rinsed container could have fibers in it of a size that can pass through the filter used as a result of the known inherent fiber contamination of water. As a result, when the product comes into contact with the rinsed surfaces of such a container, the drug product, could become contaminated. Such a result would clearly be contrary to the stated intent of the proposed regulation, i.e., to minimize the possibility of deleterious effects resulting from injecting asbestos fibers into man. Even when asbestos filters are not used by a manufacturer, asbestos particles have been found in parenteral drugs. We recognize that the specific pore size to b e used in filtering parenteral drugs, as well as to be used in filtering the wash water, was not mentioned in the proposal. The devious and logical intent was that the same size filter should b e used for both. The proposal did, however, contain the requirement that if an asbestos filter was required in preparing the product, "an additional nonasbostos-containing or non--fiber--releasing filter such as membrane Mr. Joseph Stetler 4 filter shall subsequently be used to reduce the content of any asbestos-form particles in the drug or drug ingredient. Evidence for reduction shall be based on the use of the methods described in Criteria for a Res snrp.endrd Stendard-Dccupational E posare to Asbesto.;, Report of 1 :vicw Cun;' t.tce, National Ins tit. to for Orca; ai.:ianal altb, P eolica tic;n bo. HE: 5 72-10"'-: (1972) iv;o cc.. ::iit C.vji to tills pro: :eo rc .;i.rc ox proof of reduction cc frescos fibers for the reason that eho test vns inadequeto q iLitalively to dsr.onsfrate reduction ari is immensely difficult to perform. In issuing the final regula tion, the Conxoicsioner agreed that better methodologies for these analyses were needed. He therefore emitted proof of reduction from the final re.cjvdation. ar substituted the recnrLrcm.ont for use of a filter of 0.22 micron pore size (0.45 micron if the m nu- facturing conditio is so dictate) which is what was m i n t };y a raambi'ane. filter in the proposal. That the wording of a final regulation differs from the proposed regulation is not sufficient reason to require that the former be published as a new proposal.. The important issue is whether the proposal adequately put interested persons on notice as to the intent of the regulation. In this instance -the proposed regulation clearly gave notice that all reasonable attempts to exclude asbestos fibers from parenteral drug products would be required. It was also obvious that filters with comparable pore size would be necessary to preclude asbestos fibers from finding their way into tire final drug product. 4. Delay of Effective Date of Regulation. Your petition indicates that many parenteral products, especially biological products, have historically been filtered, through as bestos filters or cannot be filtered through known non-fiber releasing filters. Therefore, you. allege that the requirements placed on manufacturers to prove that the use of non-asbestos > containing membrane filters will compromise the safety or potency of their products, before the use of asbestos filters is sanctioned, is unreasonable and would require considerable time and expense. Moreover, it is asserted, that FDA has not indicated what type of evidence will be considered proof tiiat the use of a non-fiber releasing filter will be likely to compromise the safety or effec tiveness of a drug. Therefore, until such criteria have been defined, you request a delay in the effective date of the regula tions. Specifically, you request that 211.40(j)(3) be amended to read as follows: Mr. Joseph Stetler 5 o ln "Substitution for a fiber-releasing filter shall be achieved 180 days after FDA has established the criteria necessary to prove that use of a norv-fiber-releasing filter will be litely to compromise the safety or effec tiveness of a drug." having reconsidered the issue of \hat. constitutes proof oi a c-c .v p r a t sc1 of the sazety or of fcctivonsss of a brag, we reaffirm ib statement in pnrigraph B.3. of the preamble to die .March 14, 197 publication to the effect tliat the responsibility remains with tlie manufacturer to demonstrate tliat the replacement of asbestos filters or the utilization of a final non-fiber-releasing, nenasbeston-cr>nl:aining filter decreases product quality, effective ness or safety. Presumably each m:-mufl;cLu::or hr.ows the charac teristics of his product. Based on that }a.o.\dedge, and the bvcwIcxlgc of her; the product is manuuac trued, the lranefactuier is in tlie best position to determine how his produce will lie adverse]^ affected by not using in asbestos filter and can pattern his evi dence accordingly, the data necessary for one type of product could conceivably be quite different them tliat needed for another product. As pointed out by your petition, the use of asbestos filters with viral biological products may be to absorb undesir able components in tissue culture vaccines. Further, you also state that asbestos filters are used with viscous blood products, such as Normal Hunan Serum Albumin, because they c-.unot be fil tered through membranes at temperatures required to prevent pos sible development of pyrogens. Cbviously, data demonstrating a ccapromi.se of the safely or effectiveness of tissue culture1 vac cines will be quite different from data demonstrating a similar ccxipromise for viscous blood products and is best elicited by the manufacture in each case. As a result of a comment on the proposal, the final regulations provided for an 18-month period to allow for compliance. We con sider this sufficient time for a manufacturer to either submit the necessary data or develop any new processes. Sincerely yours, Sam D. Fine Associate Carmissioner for Gompliance