Document jpKjQ3xXvog9o7O2yK9Ky245

MOUNT SINAI SCHOOL OF MEDICINE of The City University ofNew York P I P T H A V E N U E AND 100TH S T R E E T N E W YORK, N.Y. 10029 DepartmentofCommunityMedicine M a y 9, 1972 Mr. John Tuit Columbia Filter Company, Inc. 199 Seventh Avenue Hawthorne, New Jersey 07507 Dear Mr. Tuit: I am sorry that you have not yet received an answer to your letter of March 15. I had asked some of our laboratory staff to answer your specific questions; something may have gone awry. I will bring this once more to their attention. Pending their response, I will add several comments of my own. First, the chrysotile fibers do not have a strong negative charge; this was a transcription error and was corrected in the manuscript some time ago. They have a positive charge. Second, we have no knowledge of the source of other foreign fibers and particles, which were present in the drugs tested. These have not been identified and, failing such identifica tion, their properties have not been explored. I believe this subject is of some importance and agree with the sugges tion I infer, that investigation of such particles is in order. It would be. I accept, too, that it would be useful to investigate chemical contamination from synthetic membrane filter media. As you know, this area is one in which some research is being done, primarily insofar as tubing or con tainers are concerned, with plasticizers and stabilizers the objects of such study. I d o n 't know whether filter material is also under scrutiny. Do you know whether they are? I have reviewed the question of phthallates with colleagues work ing in the field and find that trace amounts are not unusual in blood samples taken in some areas, although the source and significance of these findings are unstudied. I c a n 't agree that it is important to investigate whether asbestos in paren teral drugs can cause cancer in humans; pari passu with administration of parenterals so contaminated. It would seem prudent to avoid such drugs. Mr. John Tuit May 9, 1972 It is conceivable that asbestos filters could be used, because of their unique and valuable properties, provided further treat ment of the filtrate would remove those fibfils that are added. This is a technical matter, however, and I am sure that you know much more about it than we do. Finally, I d o n 't believe that the paper claimed that we had evidence that asbestos contamination at levels mentioned con stitute a threat to health. Indeed, I thought we made clear that cancers associated with asbestos in humans have so far been observed only in other circumstances, presumably at levels considerably higher than those associated with paren teral drug contamination. Indeed, we cannot even guarantee that the asbestos we have found in the particular drug samples tested by us came from asbestos filters in the production lines concerned; it is conceivable that contamination occurred at some point after filtration. However, we have ascertained that asbestos can be found in the filtrate of at least some production lines. We would be interested in such evidence as you might have that the filters made by your company cio not shed fibers or fibrils to contaminate the filtrate. Sincerely yours, IJS:sa co: W.J. Nicholson, Ph.D. C. Maggiore, Ph.D. March 15# 1972 RTEL ENG'N. corp. Irving J. Sclikoff# M. D. 750 Broadway Paterson# New Jersey Dear Dr* Selikoffs An manufacturers of asbestos-cellulose filter pads, we are interested in more details regarding your paper# "Asbestos in Parenteral Drugs." The first item io your mention of the asbestos fibers# as used in the pharmaceutical industry, having a strong negative charge. Ar you certain about this"? Further# wo note that your preparation procedures wore carried out with a laminar flow filtered air hood. Please advise uo of the male and stylo unit employed# as well as rche make and typo of final filter used. In your findings# you refer in passing to other foreign fibers and particles which wore present in the $rugs tested. To what do you attribute this# and what problems might they cause? At this point# we do not believe that your paper presents conclusive proof that liquids may become contaminated with asbestos during filtration# or that such possible contamination at the levels mentioned constitute a threat to health* Have you investigated the alternatives? It would be interesting to investigate the possibility of absorption of chemical contamination# such as plasticiisors# from the synthetic membrane filter media also widely used. This potential may exist# and is pointed out by the recont disclosure of a situation where IV solutions have been found to absorb plasticiEiors from their synthetic containers# with possible harmful results. It appears that w ar at a point where asbestos media id guilty of contamination of pharrnacouticals by inference and ^ conjecture# rather than by proof. Rather than not knowing if # Irving J. Selihoff, H* D. ** 2 - # March 15, 1972 asbestos in injectables can cause cancer in humans, which is your stated preference, I think that it is important to investigate the matter thoroughly to a definitive conclusion. To prefer ignorance in this matter detracts from the credibility of your vjorh. If asbestos media is truly a factor in contamination of pharmaceuticals, with resultant disease, we fchUTa bo the staunchest advocate of- the search for a superior substitute. Wo loot forward to receipt of your comments, and would welcome the opportunity to meet with your to discuss the matter in detail. Very truly yours, COLUMBIA FILTER CO,, INC, JT/pm John Tuit, President n D E P A R TMM S W OF HEALTH, EDUCATION, AN D Wi PU BLIC H EALTH S E R V IC E N A TIO N A L IN S T IT U T E S OP H EA LTH B E T H E S D A , |M A R Y LA N D 20014 *ARE June 27, 1972 We apologize for the delay in answering your letter of March 22, 1972. This delay had resulted from the new delegation of authority to the Division (copy enclosed) which requires proof of efficacy of all products. On May 31, 1972, . a meeting was held at the Division in which experts in the field of allergy were present to study the matter of efficacy for allergenic products. No final decisions were made at that time..However, when current problems ' 'associated with the determination of \efficacy are resolved, we will undertake , a review of all allergenic products. . We have a few' additional comments concerning your pending license application amendment for freeze^dried pollen extracts. r . ' . '. . n License Application ' 0/ Item 8 - Since it has been shown that' asbestos particles can be carcino- 1^ , genic, and t h a a s b e s t o s filters (Seitz, Ertel) adsorb considerable v * amounts of the active ingredients, we recommend that a millipore filter or similar type of filter be used for the sterilization of your aller genic extracts. t Item 10 - A stability study"'should be initiated using at least three lots of product fron\. ,each allergen category (pollen, mold, dust, etc.). Moisture and vacuum determinations should be made every six months for . ... the entire dating period. Such data should be submitted to the Division as collected. Item 16 - Our test results.on your submitted sample of American Elm Pollen Extract, //92-20-1F1 for residual moisture content was 1.26%. Please retest another final container of this lot and forward to us a copy of your results, along with another final container. ., We are returning under separate cover, your labeling for freeze-dried pollen extracts with our comments. ,* ' \, 11 Page 2 1 I! Our records do not indicate that we have received the information requested in our letter of February 29, 1972, regarding the manufacture of freeze-dried mold and house dust extracts. In our letter of April, 18, 1972, we accepted your method for carrying out the sterility test on final' containers as described in your letter of March 16, 1972. The sterility test procedure has been subject to a new review. In . order to establish the minimum acceptable level of sensitivity for the test, the minimum volume o final container material to be tested in each culure * medium should be 1.0 ml. rather than 0.5 ml. Therefore, we recommend that 1 your sterility test procedure be revised accordingly... Sincerely yours, ^ 1 , , 't'v- {' -v ' Jr *'A M'SU - ' - f San^T. Gibson, M.D. -'Assistant Director ^ ' Division of Biologies Standards Enclosure -V A., ( - " . I' O (,'  DEPARTM ENT OF HEALTH. EDUCATION, AND W ELFARE ` '. . P U B LIC H EA LTH S E R V IC E . ' FO O D AND D R U G A D M IN ISTR A TIO N . ' , R O C K V I L L E . M A R Y L A N D 20852 `\ * May 23, 1973 #. TO: All Licensed Manufacturers SUBJECT: Asbestos-containing Filters Asbestos contamination of parenteral drugs was reported recently by Nicholson et al, (Science 177:171, 1972). * These findings come at a time when there is concern over the presence of asbestos in the environment because of the association of high exposure to asbestos with tumors in man,. . Asbestos-containing filters are used in the manufacture of biologies, . as well as other parenteral drugs, either for "in-process" filtration or for final filtration. We are asking each manufacturer to review the manufacturing procedures for each of the products for which your establishment is licensed, and to submit to the Bureau a list of those products for which the production includes the use of asbestos-containing filters for either "in-process" or final filtration. Preparation of . water for glassvrare washing is considered an in-process step. In addition, the type of filter used for final filtration of each -product should be provided. This information should be submitted within 90 days from the date of this memorandum. Your comments on the use of asbestos-containing filters in the. manufacture of your products and the problems associated with the use of other types of filters for final filtration are requested. . Harry M. Meyer, Jr. , M.\h Director Bureau of Biologies  DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PU BLIC H EALTH SER V IC E FQ O D AND D R U G A D M IN ISTR A TIO N W A SH IN G TO N , D .C . 20204 January 26, 1973 This rep lie s to your le tte r of January 16, 1973 concerning the use of asbestos f ilt e r s in the food industry. , The Food and Drug Administration is currently in v e stiga tin g the use of asbestos f ilt e r s in the food industry. We have recently. hacPa meeting with several firms from the food industry and representativer of the asbestos manufacturing firms to discuss the problem of asbestos, including the technological aspects of the use o f any types or forms of asbestos in food processing applications. , I t is our view that food should be free of asbestos form p article s such as Tremo!ite or Chrysolite. Food manufacturers should assure themselves that the fin a l consumer product is free of asbestos. Manufacturers of asbestos f ilt e r s should take what ever steps are necessary to insure that use o f these f i lt e r s w ill not re su lt in contamination of food with asbestos form p a rtic le s. Sincerely yours Pat T. Adamo A ssista n t to the Director D ivision of Regulatory Guidance O ffice of Compliance Bureau of Foods *v * ^DEPAF.TSViWT Q F X T sT K E TREASURY. X , ? Dj]i WBNuuamsrhbeoinnagtu7o2n-o,3f1D.AC.22c0o22S4Oioat3,TOocbtoabcerci1/0a^n9d72Fiioasrns FOREIGN SUBSTANCES IN BOTTLED ALCOHOLIC BEVERAGES Proprietors of distilled spirits plants, bonded wine cellars, breweries,' taxpaid wine bottling houses, and others concerned: |. "We are becoming increasingly concerned about the reported finding of foreign .substances in bottled alcoholic beverages* Among the materials found have been asbestos and cellulose fibers and glass* Because we know of your interest in having your products meet consumer protection standards, we are issuing this circular to make you aware of this problem, and to suggest that you evaluate your operations and take every precaution to see that your products, when shipped for sale, are free of foreign substances, some of which may be hazardous* , In the future, we shall make it a practice to keep you-informed of pending investigatory studies concerning the effects of human ingestion of various materials* As you know, studies of this type frequently result in a declaration of probable hazard to health, with a resultant banning of use. cVe, of course, must enforce such bans at any of the plants regulated by this Bureau* Any questions you may have on this subject should be forwarded to tb^ Director, , Bureau of Alcohol, Tobacco and Firearms, Attention: Regulatory Enforcement* zSs Rex D* Davis Director JL'l.Tr T' \ 'p T 0 *J y Sootion 3 .3 Pager; from Pierilisution - Doain-iVi'-tion -- Fone.ervioruug - Cheroother^pie by Dr. JC,D. WalD^eusser (Frenkfirt/M. - Iloenhst) ,(Wid Professor Dr. H, Schmidt ( Wahern b, Bern) tvTyjTOUT1 flOaftTOWP 3 .3 , The Removal of Fyroaers by Filtroti on. Pyrogens aro, in the min, constituents of the col1 walls of bacte^ie . of which something towo^is DCfa aro hound to the cqIIn, They ran only be detected by animal experiments (see page /]91). At temperatures over 200C they are destroyed in approximately 30 minutes, A pre-condition of their somraiion by filtration is the removal of .11 `bacterial cells including those that liave been killed by hoot r,m Further, steps must be taken with injection solutions that arc serr-it- to microbial infection, to prevent bacterial reproduction and combin'.i. therewith, accumulation of pyrogens, The strongest pyrogen fonvur ;? the gram-negative bacteria, Pseudomonas types, E, coli and so on althougl gram-positive bacteria and viruses can also play a part. Although the "genuine" pyrogens can induce temperature increases wi -,>>:o 3o minutes in animal experiments, the. virus pyrogens lag behind nem^vf.>v. and only show a significant fever effect after 1 - 2 hours. (flV' standard for control - Ljpopolysaccho,ride Pyrem l prepared by the /h.'iV- Company causes in rabbits when used in a concentration of 0,23 efe, ' substance in 0,5 ml of distilled wator a temperature rise of 0,8 - l.'/'o within 30 mlnuteo.) According to Siogert and colloboro torn (S.--D. Cos, Ford, gen, Katuv.rj:/, (ihrburg) 8 3 , 1/2; 84, 1 (l961/62), 255) there are cigni.ib.c ><> difforoncoo botwoon bacterial and vtrue pyrogens. Whereas i - iter can bo separated from tnc cell wall (soluVlo ) and aro only drsiu <>71 ' after heating for a longer time (3 0 minutes) at 200C, the batoe: bo separated from the virus particles, thoy are more readily '<t -1 -' by heating and can be neutralised by anti--bodies. The bacterial , are not volatile in steam but, nevertheless, substances tve ..... on distillation which do result in a fever reaction, although g several hours. It is probable that the products carried cu bacterial breakdown products such as aminen end other nitre yu<- compounds. 1 Cent - The removal of the p.vrogons "bound, to tlv' hooteriel cells or frr-i on te thereof can be effected by filtration through a membrane filter (maximum pore size 250 m micron) (Schmidt, B,, V. Bias?; Z. hyg, 142 (1955/5^) 183| 298), or Seitz filter sheets (Wilke, H,, H.E, Voss: ArznoimittolForsch. 4 (1954) 8; K,D, Rudat; Zbl. Bakt. I.Abt. Orig. 164 (1955) 370). The removal of the "free" partly roln.bl e pyrogens is far more difficult. These car only be eliminated by means of adsorptive action filters end, when necessary, by repeated filtration processes. The loading limit (the available adsorptive surface) is, aoeording to Wilke and Vo.uo for 1000 cm filter surface (EKS) some 2000m , the composition (and particularly the protein content) of the solution to be processed and the pyrogen content all play significant roles. If the loading limit is exceeded then the pyrogens will pass through. 'Sn any case proving experiments should be used to clarify the cor.rospending relationships. In general it can be said that with watery solutions whir; do not contain too much high molecular weight substancen all pyregnnn (up to 1 tflg/i) Will lid iHsffloVed in the COUfb of tii bidiHliirig i i i r 1. Colloids (serum, proteins etc.), high viscosity solutione (plasm? substitute) as well as surface active agents substances (Saponins, preservation additives etc.) hinder quite significantly the pyrogen adsorption process. With surface active substances the small amounts of pyrogens remaining in the filter sheets after manufaciure can even be eluted out. These smell omounte of pyrogens can normally be disregarded owing to the high adsorptive action of the filter sheets. The best safety measure is, in any case, to use the greatest possible filtering surface and this should always be done, especially with infusion solutions. hextran solutions (molecular weight approximately 50000) can be satisfactorily depyrogenised through EKS sheets at a loading of 500 litres per square metre. A1burr-on hydrolysates are more difficult, and whores.1 hydrolysates prepared by acid liydrolynis can be adequately depyrogenised by double filtration through EKS?, this i.s not; adequate for the'high r 'Locular weight products obtained by the enzymatic splitting of albumen. A. protreat mont with ion exchange resins (e.g. Amberlite ` oC ftoehm -b Hons) is of assistance. IN this case the EKS filter sheet is oeyered with a 5/l0 cm thick layer of the ion exchange resin. According to Kuntochor, H., W. Fahrig, the b o lubib pyrogens in conccntrsLi c ranging from 10 to 100ji 100/ml can be adequately removed by filtration --.orr-i'2 a single sheets (Seitz-EK) of 100 cm surface and a volume of 25 litres. 2- Continued According to a rcc/mt ropo^t: 'from the G^it :>-hbrkr' a 1<y(h gamr.c'globulin h o Ih I;ion a prefi.ltration through five clientb 0 x /]0^m Graclo AK34 (thedr sheets whioh are Rome 5 mm thick contain in addition to cellulose and asbestos fibres as the hasio Giructnre a high content of very fine activated carbon to increase the filtration effect and to prevent the washing through of the activated carbon carry on the outlet side a nuitable filter paj>er that will, hold it up) erd a finishing nterili cation with 15 EK3 sheets proved satisfactory. Investigations of Kienholz, M. (Arznoimittel-I('orbcli. 14 (19^4) 125?) w2 have shown that 1 rn of Seitz EKS shdet is adequate to depyrogonree $0approximately water with a pyrogen content of some, 500 from added E. coli-Lipopolysaccharide. GO/Dili) 5.12.1^73. 3