Document 3QkVwVqenYELwq9Ydb49N2na3

A RULES A ND REGULATIONS 11865 Title 20-- Employees' Benefits P a rt 405 of Chapter IH of Title 20 of CHAPTER ill-- SOCIAL SECURITY ADMIN ISTRATION, DEPARTMENT OF. HEALTH, EDUCATION, AND WELFARE [Kegs. No. 5, further amended] the Code of Federal Regulations is amended as follows: Paragraph (b) of 405.912 Is revised to read as follows: . 405,912 Collection o f prem ium s ivIiHo PART 4 0 5 -- FEDERAL HEALTH INSUR m onthly benefits arc suspended. ANCE FOR THE AGED AND DISABLED (19 6 5 1 ___ ) (b> Collection of premiums where S ubpart 1-- Prem ium s fo r Supplem entary m onthly benefit paym ents will n ot be re Medical Insurance Benefits sumed during the current taxable year. main categories. One concerns provisions to decrease the potential for Ingestion of asbestos fibers. The other concerns provlslohs. to decrease the potential for 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 th a t S upplement art M edical I nsurance Where an enrollee's monthly title H any food, food packaging material, drag, . B enefits P rem ium B illing benefitpayments (other than age-72 spe drug Ingredient or drug packaging ma On October 2, 1974, there was pub lished in th e F ederal R egister (39 FR 35577 'a notice of proposed rulemaking with a proposed amendment to Subpart I, Regulations No. 5. The proposed regu lation pennits beneficiaries whose title H benefits axe not payable because of work or for other reasons to be billed quarterly for supplementary medical in surance (SMI) premiums, h u t not neces sarily (as is provided under present regu lations) on a calendar-quarter basis. In terested persons were given 30 days within which to submit written com ments or suggestions thereon. The proposed regulation revises section 405.912(b) to permit the Social Security Administration, a t its option, to bill cial payments (see 405.910)) are being suspended for an indefinite period or for a definite period which will no t permit collection of all premiums due from monthly benefits payable in the current taxable year, the enrollee should pay his premiums by direct remittance when he is billed. The first billing will be for whatever premiums are necessary to .place him in a quarterly cycle. There after, assuming such premiums are promptly paid, the enrollee will be billed on a quarterly basis for 3 months' pre miums (see 405.913). If the enrollee, however, wishes to pay premiums for more than 1 quarter a t a time, he may do so. [FR Doc.75-6763 Filed 3-13-75:8:45 am i monthly title H beneficiaries (other than those receiving age-72 special payments), Title 21-- Food and Drugs who are" in suspense status, for any 3 CHAPTER I-- FOOD AND DRUG ADMINIS month quarter instead of restricting such TRATION, DEPARTMENT OF HEALTH, billings to a calendar quarter basis. EDUCATION, AND WELFARE - A suggestion was received but- not adopted th at would allow individuals to be billed annually or' semiannually if they so-desired. This is not within the scope of the proposed amendment, which only conforms the SMI premium billing and collection procedures for beneficiary enrollees with those for nonbeneficiary SU8 CHAPTER C-- DRUGS PART 133-- DRUGS; CURRENT GOOD MANUFACTURING PRACTICE IN MAN UFACTURE, PROCESSING, PACKING, OR HOLDING A sbestos-Form P articles In D rugs fo r Parenteral Injection enrollees. Moreover, experience has The Commissioner of Food and Drugs shown th a t most individuals find it con venient to be billed for premiums on a quarterly basis. In any event, the regula tion expressly provides (and will con tinue to provide) th at any enrollee may published in the F ederal R egister of September 28, 1973 (38 FR 27076), a notice proposing to restrict the utiliza tion of asbestos fijters in the manu facture of parenteral drugs and par pay more t h a n l quarter's premiums a t a enteral drug ingredients, and to pro time if h e so chooses; of course, if his hibit the use of asbestos-containing talc premium for a quarter has been paid, he as a food, or food or drug ingredient, or will not be billedfor th a t quarter. in food and drug packaging materials, - Accordingly, th e proposed amendment within certain analytical restrictions. is adopted without change- as set forth The notice provided for the filing of below. comments within 90 days. terial containing talc th a t is not free from asbestos fibers as determined by a particular analytical method should be deemed adulterated in violation of sec tion 402(a)(1) of the Federal Feed, Drug, and Cosmetic Act. Nineteen comments related to the pro posed analytical method for talc under 51212006 (21 CFR 1212006J. The com ments were primarily from representa tives of food, drag, and talc mining firms, but also Included four consultant labora tories and two other federal agencies. Al though it is apparent th at 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 the proposed method for compliance pur poses. The predominant objections to the proposed method were th a t i t is difficult to use, laborious, and not practical for its intended purpose. Several comments offered the opinion th a t 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 coliaboratively studied the method with 10 micros copists, each examining seven 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 (Secs. 1102,1840(e), 1871, Social Security Act, Asbestos fibers are known to cause techniques as preferred or supportive as amended; 49 Stat. 647, as. amended; 79 cancer when Inhaled in large amounts. analytical methods. Many of the* re Stat. 307, 331, as amended; (42 TXS.C. 1302, 1395s(e),1395hh)) Also, asbestos and other fibers are con sidered likely to have a similar adverse spondents additionally expressed their willingness to join a Food and Drag Ad Effective dafe. These amendments.wilL be effective on or before April 14,1975. (Catalog of Federal Domestic Assistance Program.No., 13.801. Health Insurance for the Aged. and. Disabled--Supplementary MwUr-nT Insurance.) 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 ministration analytical task force to evaluate applicable methodology. Although the Commissioner cannot agree th at th e designated optical crystallographic method is rnireHahi* when used by those experienced in th e art, h e recognizes th a t an effective com Dated: February24,1975. for parenteral injection in humans. Also, pliance method m ust have greater utility J .B . Cardwell, Commissioner o f Social Security. i t provides for measures to reduce the and acceptance than indicated by th e amount of fibers present In such prod comments on th e proposed method. ucts, where it is not possible to elimi The Commissioner has, therefore, Approved: March 10,1975.. nate these filters in the production of a decided to delay any final regulation fo r Caspar.W -W einberger, drug. talc until an acceptable method fpr deter Secretary o f Health, Education, -The comments made in response to the mining the presence of asbestos particles andW elfare. September 23,1973 proposal fall into two can be developed for this substance. This FEDERAL REGISTER ,-VOL 4 0 , N O . 51-- FRIDAY, MARCH 1 4, 1975 * 11866 RULES A ND REGULATIONS area of research currently is being ac ' requirements for talc used in the manu man's overall exposure by these sub tively pursued by the .Food and Drug facture of paper and paperboard in stances are small. The comment con Administration. 121.101(h) (21 FR 121.101(h)). All Of tended th at evidence is lacking to show 2. Several comments objected to- the these comments contended th at asbestos, th at the ingestion of small amounts of purity limitations for talc which were es in asbestos-coptaining talc, does not mi asbestos is safe and th at the responsibil tablished by the proposed method. Many grate to packaged food when talc is used ities of the Food and Drug Administra thought th at requirements th at talc for this purpose. One of these com m ents tion for-promulgation of regulations to 1be 99.D percent amphibole-free and 99.99 contained results 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 th at while others insisted th at 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 th at uniform levels by ingestion. While one respondent ation of additional requested studies, the and consistent regulations should bo calculated th a t 20,000 amphibole and Commissioner concludes th at this com adopted on an industry-wide basis. In 3,500 chrysotile fibers (of 5 micrometers ment has demonstrated the validity of this instance, the lack of available re x 1.7 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 th at individual asbestos par onstrated th at 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'u n coated 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 oh 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 nonparontoral these comments to clarify his position on milk, rice, and com flakes, the comment drugs by use of asbestos filters nor tho posssible future talc regulations. has also demonstrated th at 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 th at 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 hot proposed in order to Rm. 4-65, 5600 Fishers Lane, Rockville, United States, with some reports th at indicate any known hazard from asbes MD 20852. " the waters of the San Francisco, CA, tos, but was intended to establish a good The Commissioner concludes th a t 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 recont 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 aforementioned products by tho Food and Drug Administration has also th at the comment has demonstrated th at use of filters (Ref. 3). 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 th at 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 th at the flnol 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 th at 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 tho 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 less than a 3-to-l length-to-width ratio considerably nar rows the range of permissible particles counted by the proposed method. Con sidering the variation in particle size th at 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 a t least 99.99 per cent free of chrysotile asbestos fibers. evaluation of this question. `4. The Commissioner stated in the pro posal th a t 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 stated that this was-inconsistent with the Commissioner's pro posed regulation on the asbestos content of food-grade talc, and that attempts to limit asbestos ingestion should apply uniformly to all sources. Another com m ent stated th at file Commissioner's decision not to regulate the use of as bestos filters in food, beverage and nonparenteral drug preparations was based drugs until more reliable data can bo obtained on the background concentra tions of asbestos in drinking water and the role of asbestos filters in regard to t h e . addition of fibers to ingcstible products. 5. Many comments endorsed or con demned the proposals, or parts of them, with respect to water, food, and bevcrago contamination. Although most of theso 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 th at the amounts conclusion of the Advisory Committeo firms objected to the proposed analytical of asbesots which are contributed to on Asbestos Cancers (Ref. 8) th a t there FEDERAL REGISTER, V L. 4 0, N O . 51-- FRIDAY, MARCH 14, 1975 RULES A ND REGULATIONS 11867 v '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 b,everages;and food, or in fluids used for 1. A number of comments stated th at monthly progress reports thereafter con tiie administration of drugs, and one there is no conclusive evidence th at cerning attempts to implement th e 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) which or th a t asbestos has caused-deleterious maintenance of product quality. reports-no increase of gastrointestinal effects as a result of parenteraHy admin 3. A large number of comments stated and peritoneal cancer among talc istered drugs. th a t many parenteral products would workers exposed to talc dusts, for am ini- Asbestos fibers were fouijd in a number suffer in safety and quality because of a , m um of 15 years. of samples of parenteral drugs by Nichol requirement to replace asbestos-contain From analysis of th e foregoing com son et aL (Ref. 10) and also by a sub ing filters in the manufacturing process; ments received concerning the limita sequent Rood and Drug Administration The Commissioner agrees th a t i t is es tion of asbestos in talc, from thorough investigation of parenterals. Although sential th a t there be no increase in risk re-review of th e scientific evidence avail th e Rood and Drug Administration has to the public os a result of this action. able concerning th e adequacy of the demonstrated th at 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 th e controversial nature cantly reduce the number of fibers pres strating th a t the replacement of asbestos of evidence to demonstrate the hazard ent, the Rood and Drug 'Administration filters or the utilization of a final non- to health-presented by ingestion of the also has direct evidence th at the utili fiber-releasing, non-asbestos-containing amounts of asbestos fibers normally to zation of asbestos filters can cause as filter decreases product quality and effec be expected in talc.used i n food or drugs, bestos contamination. The preliminary tiveness of safety remains th a t of toe 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 m ust be submitted to the ap foods and nonparenteral drugs prepared The evidence of the deleterious effects of propriate bureau of the Food and Drug w ith the use of asbestos filters,* the Com parenteral asbestos administration (Ref. Administration for approval'of the con missioner concludes th at .the promulga 1, 11, 12, and 13) requires th a t the tinued use of the unmodified asbestos tion of regulations on the limitations or amount of contamination in these prod filtration processes. prohibition o f th e use of asbestos filters ucts be minimized. Consequently, the 4. One comment objected to th e utili fo r the preparation of foods' and non- Commissioner has determined th a t It is zation of the terms "membrane filter" parenteral drugs and of the amount of important th a t asbestos-containing fil and "non-fiber-releasing filter," stating asbestos fibers in talc fo r use in food and ters be replaced with non-fiber-releasing th a t the former term was too limiting drugs o r which might migrate into food filters unless it is demonstrated that i t is os a recommendation for a replacement o r drugs from talc-containing-packaging not possible to manufacture a safe and of filters which may release asbestos m aterials is unwarranted until- more effective parenteral drug or parenteral fibers an d th a t th e 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, to the lat media-migration-exhibiting filter." This The Rood and Drug Administration; in te r instance, a final non-fiber-releasing comment claimed t h a t th e term "nan- 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 o fany asbestos-form particles in the drug small quantities of th e fibrous support if long term exposureto ingested asbestos or drug ingredient. Use of an asbestos- used in. many ceUuiose-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 ah additional non-asbestos-contalnlng, from the manufacturing process for is completed o r other data become avail non-fiber-releasing filter shall be permis cartridge and other type filters, a re re able; th e Commissioner has determined sible only upon submission of evidence to leased by cleaning and flushing prior to .th a t a prohibition of the use of asbestos- the appropriate bureau of th e Rood and marketing o f the product. Another com containing filters in the processing of Drug Administration th at substitution ment stated th a t th e proposed regula food and' beverages,- and of asbestos- for th e asbestos filter; of a non-flber-rp- tions did no t contain a definition o f a containing talc as a food or food' additive leasing filter will or is likely to compro non-flber-releasing filter. Comments also or in drugs or drug ingredients is unwar mise th e safety o r effectiveness of the stated t h a t 5133.8 should n o t use the ranted due to lack, of sufficient data. In drug. Use of an asbestos-containing fil term s "fiber-releasing'* and "asbestos- th e 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-containing, non comment objected, to th e synonomous of eliminating th e use of such filters and fiber-releasing filter shall be permissible use of the term s "fiber** and "asbestos talc, and to keep the Rood a n d Drug only upon submission of evidence th a t fiber," - Administration informed about changes neither th e substitution for the asbestos- The Commissioneragrees th at the reg i n formulation a n d processing of this containing filter nor th e use of a sub ulation should n o t specify only one type type. . sequent non-flber-releasing filter can be of filter which would satisfy the new re B. 3h order to deal with, th e Injection accomplished without compromising the quirements, a n d thus has deleted the potential of asbestos fibers, the Com safety o r effectiveness of the drug. term "membrane filter." T he Commis missioner proposed th a t th e good manu 2. One comment noted that, although sioner also concludes th a t, fo r th e p u r facturing practice regulations for drugs there have been several demonstrations poses of these regulations, a. n on-fiber- be amended to requireth a t filtration pro of th e addition of nonasbestos filters as releaslng filter shall be defined as a non- cedures for parenteral drugs shall utilize final filters in th e production of injecta asbestos, nonglass fiber filter which, either a non-fiber-releasing filter such ble biologies, there remains concern th at after any appropriate pretreatm ent such as a membrane filter or, if an asbestos- the replacement of asbestos filters with as washing o r flushing, wifi,n o t continue containing filter is used because i t is non-asbestos-containing filters would up to release fibers into th e drug or drug necessary,- th e procedures shall also set delicate filtration parameters of the ingredient which: is to b e filtered. The utilize an additional non-asbestos-con- product preparation process. An 18- distinction is, therefore, made between tainihg 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 th e minimum level fea m ent of the new processes. the nature of the filter, and filters which, sible unless such a subsequent filter win The Commissioner agrees th a t a spe contain fibers from structural supports compromise the strength, quality, product. safety; identity, or -purity of the cific-period for process development and modification should be provided in the regulations. Therefore. 18 months win be and contamination. T he utilization of nonasbestos, nonglass fiber filters in the '- -Comments received in response to-this allowed for compliance. Firms not con latter category wifi be permitted pro-1 p a r t of-the notice, dealing with the in forming to these regulations within 12 Tided th a t appropriate pretreatment; FEDERAL REGISTER, V O L 4 0 , N O . 51-- FRIDAY, MARCH 14, 1975 11868 RULES A N D 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. No automatic de rats and rabbits from pleural and peri similarity between the carcinogenicities cision scheme was suggested in the com toneal injections of both chrysotilo 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 from asbestos to manufacturer and the responsibility for injections of chryeotile 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 a t least three times greater than with the appropriate bureau in the Food the study of parenteral administration of its width" (Ref. 15"and 16). and Drug Administration.' asbestos to animals by Schmahl (Ref. The Commissioner realizes th at the 7. Two comments objected to the fact 11), the tumors th at occurred were not definition of a fiber-releasing filter ex th at the regulations were limited to the related to asbestos since they woro- cludes the possibility 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 th at all extraneous Although mesotheliomas are closely re a matrix which precludes the release of material such* as diatomaceous earth, lated to inhalation of asbestos, thoro 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 th at there is tion. As with other carcinogens, several concludes th at the definition of a fiber- reason to be concerned about all par- types of tumors may occur as a result of releasing filter is appropriate for this . ticulate contamination in parenteral exposure to a particular carcinogen de regulation and that, should a method for drugs, but concludes th at this problem pending upon the route of exposure. The production of such a non-fib'er-releasing should be considered separately from the Commissioner therefore concludes th at asbestos or glass containing filter become subject regulations. Therefore, except for the data in this reference ore 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 th at the degree of other types of contamination of soft tissues, namely, sarcomas. proposed requirement th at "no asbestoscontaining filter .may be used unless it is and the possible health effects of such other particulates prior to developing 11. One commenter presented data 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 this regard will be particles from his asbestos-filtered prod by "when an asbestos-containing filter published in the F ederal R egister 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." 8. One comment objected to the re- tainer for this product was subjected to The Commissioner concludes th at 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 th a t 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 th at 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 th at the use cf an asbestos filter will be .permissible only upon a demon stration by the manufacturer th a t the replacement of an asbestos filter by a non-fiber-releasing filter or the utiliza tion of a final or after-filter is non-fiberreleasing adversely affects the quality, safety, and effectiveness of the product. 6. One comment objected to the state ment in the proposal th at the use of asbestos filters in parenteral drug manu facturing is prohibited "unless i t is not possible to manufacture th at drug or drug ingredient without the use of such a filter," claiming th at the lack of a more specific statement will lead to capricious regulatory decisions. The Commissioner concludes th a t there is no more reasonable method by which to make a determination of the impossibility of achieving the desired product quality and effectiveness without ' 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 th at un til these studies are completed, the evi dence for 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 ten t 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 th a t it is inappropriate to control all types of asbestos fibers uniformly, as asbestos filters are composed primarily of chrysotile which is less hazardous to human health than amphiboles. The Commissioner concludes th at this differential in hazard has n o t been es tablished for parenterally administered a final rinse by municipal v/ater, tho packaged product contained a significant number of asbestos fibers. Similarly, tho Foot' and Drug Administration has found asbestos particles in parenteral drugs 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 th at cleansing and rinse water for the containers for paren teral drugs shall be filtered through non fiber-releasing filters equivalent to thoso required for post-asbestos-fllter filtration to remove inherent fiber contamination. 12. The Environmental Impact Anal ysis Report (EIAR) and other relevant materials have been reviewed and it has been determined that the proposed uso will not have a significant environmental impact. Copies of the EIAR are available in the office of the Assistant Commis sioner for Public Affairs,' Rm. 15B-42, or the office of the Hearing Clerk, Rm. 4-65,. Food and Drug Administration, 6600 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 tho Hearing Clerk: 1. "Parenteral Preparations, Pyrogons," in Remington's Pharmaceutical Sclonccs, 14th ed.. Chapter 82, p. 1542,1070. - 2. Mason, T . J,, P. w . McKay and R. W . Miller, "Asbestos-Like Fibers In Duluth Water Supply: Relation to Cancor Mortality," "Journal of the American Medical Associa tion," 228:1020, May 20,1074. 3. Comment from Asbestos Research Coun cil, March 1,1974. 4. Cunningham, H. M. and R. Pontefract: (a) "Asbestos Fibers In Bovoragoa and Drinking Water," "Naturo" 232:332-333, the use of asbestos-containing filters asbestos. Studies by Reeves et al. (Ref. 1971. FEDERAL REGISTER, V O L , 4 0 , N O . 51--rfRIDAY, MARCH 14, 1975 , _f r r 'rules and regulations ' 11869 *O (b) ^Symposium on Industrial Chemicals s Food- Contaminants," "Journal o the As sociation of Official Analytical Chemists," 56:976-981,1973. * 5. Pontefract, R., and H. M. Cunningham, `Penetration of Asbestos through the Diges tive Tract of Rats," "Nature," 243:352-353, products unless It is not possible to m an ufacture that drug product or component without the use of such a filter. Filtra tion, as needed, shall be through a non fiber-releasing filter. For the purposes of this regulation a non-fiber-releasing (Sacs. 501, 502,701, 5a S ta t. 1043-1051, 1.Q55-: 1056, 03 am ended; (21 TDS.C. 351, 352, 3 7 1 ))- Dated: February 28,1975. A. M . S chmidt, Commissioner o f Food and Drugs; 1973. . filter is defined as a nonasbestos, non (PR Dsc.75-6733 F iled 3-13-75;8:45 am ] _ 6. Davis, J.M . G., Institute of Occupational glass fiber filter whfch, after any appro Medicine Edinburgh, Scotland, unpublished report. - 7. Bonser, G. M., and D. B. Clayton, "Feed ing of Blue Asbestos to Rats," 1967 Annual Report, British Empire Cancer Campaign for Research, p. 242. - 8. "Report of the Advisory Committee on priate pretreatment such as washing or flushing, will not continue to release fibers into the drug protluct or compo nent which iEbelng filtered. A fiber is de fined as any particle with length a t least three times greater than Its width. [Recodlflcation Docket No. 6] SUBCHAPTER D --DRUGS FO R'HUMAH USE PART 4 3 6 -- TESTS AND METHODS OF ASSAY OF ANTIBIOTIC AND ANTIBI OTIC-CONTAINING DRUGS --Asbestos Cancers to the Director of the In ternational Agency for Research on Cancer," "British Journal of Industrial Medicine," 30:180-186.1973. 9. Kleinfeld, M., J. Messlte, and M. H. Zahl, "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 (2) If iise of a fiber-releasing filter is required, an additional non-fiber-releas ing 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 asbestos-containing filter with or with Reorganization and Republication; Correction * I n FR Doc. 74-12338 appearing a t page 18921 in the F ederal R eg ister of May 30, 1974, the heading for 436.206 appearing on page 18959 Is corrected to read " 436.206 Test for m etal particles in ophthalmic ointments." Parenteral Drugs," "Science," 177:171-173, 1972. - 11. Schmahl, D., "Carcerogene Wlrklng von Asbest bei Implantation von Hatten," "Zeit schrift. f r Krebsforschung," 62:561-567, 1958.. .12. Roe. F. H. C.; R. L. Carter, M. A. Walters and J. S. Harrington, "The Pathological'ef out subsequent use of a specific non--" 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-releasing filter will, or is likely to, compromise the safety or electiveness of Dated: March 11,19.75. Sam D. F ine, Associate Commissioner * * fo r Compliance., [FR DOC.75-6853Filed 3-13-75;8:45 am] fects of Subcutaneous Injections of Asbestos the drug. Fibers In Mice: Migration of Fibers to Sub- (3) Substitution for a fiber-releasing PART 444-- OLIGOSACCHARIDE mesothelial Tissues and Inuction of Meso theliomas," "International Journal of Can cer," 2:628-638, 1967. . 13. Kanazawa, K., M. S. C. Blrbeck. R. B. Carter and F. J. C. Roe, "Migration of As bestos Fibers from Subcutaneous Injection Sites In Mlcei" "British Journal of Cancer," filter shall be achieved on or before Sep 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 ANTIBIOTIC DRUGS PART 4 4 6 -- TETRACYCLINE ANTIBIOTIC DRUGS Otic and O phthatm ic/Otic Preparations The Commissioner of Food and Drugs 24:96-106,1970. , / manufacturing procedures so as to uti is amending Parts 444 and 446 to delete 14. "Symposium on Occupational Exposure to Fibrous Glass," sponsored by National In stitute for Occupational Safety and Health, -University of Maryland, June 26-27, 1974. . 15. Stanton, Mearl F., `Fiber Carcinogene sis: Is Asbestos the Only Hazard?" "Journal of th e National'Cancer Institute," 52:633 (1974). lize non-fiber-relealng filters in place of 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 two sections th a t refer to drugs no longer being certified, to delete a section th at has been superseded, and to amend a section to provide for a test method. The final order for DESI 8583 et al., published in the F ederal R egister of September 19, 1974 (39 FR 33665), re 6.' "Occupational Exposure to Asbestos," loss of the safety or effectiveness of the voked the provisions for otic use from ' Criteria document, XJB. Public Health Serv ice, National Institute for Occupational Safety and Health, Chapter VIII, pg. 6, 1972. . 17. Reeves, A.-J.. H. E. Puro, R. G. Smith and A. J. Vorwald, "Experimental Asbestos Carcinogenesis," "Environmental Research," 4:496-511,1971. drug. 2. By revising 33.9 to read as follows: 133.9 Product containers and their components. 444.342g and 446.367c. m addition, it amended. 446.367e by separating It into two sections, 446.367e for the ophthal mic dosage form and a new 446.467dfor the otic dosage form. However, the docu ment failed to account for sections de Therefore, pursuant to provisions of the Federal Food, Drug, 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), F art 133 is amended as follows: . 1. By amending 133.8 by adding new paragraph (j), to repd as follows: 133.8 Production and control proce dures. * * ' "* * . (j) Use of asbestos-containing or other fibr-Teleasing filters: (1) Filters used in the manufacture, processing or pack' aging of components of drug products for parenteral injection in humans shall 'not release fibers into such products. No' asbestos-containing or other fiber-re Suitable specifications, test methods, cleaning procedures, and when indicated, sterilization procedures shall be used to assure th at 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 equivalent to th at Indicated In 133.8(j) (2). Product containers and their com ponents shall not be reactive, additive, 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 external factors th at can cause deterio ration or contamination of the drug. scribing products for both eye and ear use th a t appear twice In the regulations, as recodified May 30,1974 (39 FR 18922) In the subpart for ophthalmic dosage forms and in the subpart for otic dosage forms. As a result, P art 444 now con tains 444.442e th a t refers to drug prod ucts th at are no longer being certified. P art 446 contains 446.467c th a t refers to drug products no longer being cer tified and 446.467b th at has been super seded by a new section. Therefore, these three sections should be revoked. In addition, the amendment to 446.367e in the order of September 19,1974 inadvertently omitted the test method for sterility. I t Is provided for below. Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (secs. 502, 507, 52 Stat; 1050-1051, os amended. 59 Stat. 463, as amended; leasing filter may bemused in-the manu Effective date. This order shall be ef 21 U.S.C. 352, 357) and under authority facture, processing or packaging of such fective April 14, 1975. delegated to the Commissioner (21 CFR FEDERAL REGISTER, V O L . 4 0 , N O . 51-- FRIDAY, MARCH 14, 1975