Document 6w7YLDRv9eLZkX7yZ3yVVb5R4

P A L .L . G L E N C O V E , L. I., N. Y. 1 1 3 4 2 , U .S.A . (S I 6 ) 7 1 - 4 0 0 0 TWX 1 0 -2 2 3 -0 6 0 TELEX I 2 0 3 2 2 CABLE: PALLCO GLEN COVE Food and D rug A dm inistration H earing C lerk, Room 7-86 5600 F ish e rs Lane R ockville, M aryland 20852 D ecem b er 7, 1973 Subject: P ro p o sed R egulation, P a rt 21, P a r. 133.8, F ed. R e g is te r V ol, 38 No. 188 - S ep tem b er 28, 1973 G entlem en: In re sp o n se to the in v itatio n fo r co m m en ts on the p ro p o sed reg u la tio n #21, P a r . 133. 8, we a r e en clo sin g a p o sitio n p a p e r and su g g e ste d change in w ording of the p ro p o sed reg u latio n . O ur p o sitio n p ap e r is d ire c te d p r i m a rily tow ard clarify in g the usage of the w ords "m em b ran e filte rs " , in o rd e r to avoid m is in te rp re ta tio n w hich w ould r e s u lt in a d v e rs e effg ct on the sa les of w idely used n o n -asb esto s-co n tain in g P a ll C o rp o ratio n U ltip o r^ ) M em branes. To b riefly su m m arize our position, we resp e ctfu lly re q u e st the follow ing ch an g es in P a r . 133. 8(j): (1) F i r s t s e n te n c e : " F ilte rs used in the m anufacture of a p a re n te ra l drug or p aren teral drug ingredient shall not ex hibit p article or fib er m igration from constituents of the filte r m edium . F ilte rs should be sufficiently clean ed a fte r m an u factu re or p rio r to u se to a s s u re a high degree of effluent clean lin ess. " (2) S eco n d se n te n c e : "No asb esto s-co n tain in g or fib e r-re le a sin g f ilte r .." to: "No asb esto s-co n tain in g o r m edia m ig ratio n exhibiting filte r. . . " *As you m ay know, P a ll C o rp o ratio n w ith its p re se n t annual filte r sa les volum e exceeding $30, 000, 000, is a m a jo r su p p lier of fine f ilte rs to the p h a rm a c e u tic a l and rela ted in d u strie s. The enclosed annual re p o rts fro m 1972-73, the listin g of P a ll patents and the listin g s of selected p h arm aceu tical and food in d u strie s using P a ll filte rs m ay be of in te re s t in your evaluation of our com m ents. 1SP.WS(Appendix IV) Engineered Products For The Control Of Fluids & Environments REGIONAL CORPORATE OFFICES U S A S : Far East: Pall Corporation, Glen C o \e, L .I., N Y , U S A. Fnrope A M iddle East- Pall (U .K .) Ltd., Portsmouth, England Latin America Pall S A Mexico, D F C anada Pall <Canada) L td M ontreal. Canada PALL CORPORATION Food and Drug A dm inistration page -2- D ecem b er 7, 1973 (3) T h ir d s e n te n c e : d e le te r e f e r e n c e to " m e m b r a n e f i l t e r " (4) F if th s e n te n c e : c h a n g e " . . . n o n - a s b e s to s - c o n t a in in g m e m b r a n e filte r .." to "non-asbestos-containing filter" The a tta ch e d p o sitio n p a p e r ex p lain s in g r e a te r d e ta il the b ack g ro u n d on which our com m ents are based. Your consideration in this m atter is greatly appreciated. P lease let us know if you require any further inform ation. Sincerely yours, E A K :cm enclosures E rw in A. K irnbauer C orporate Consultant Contam in ati on V PALL CORPORATION POSITION PA PER DISCUSSION ON P A L L CORPORATION RECOMMENDED CHANGES TO PROPOSED P A R A G R A P H 133. 8 O F C F R P A R T 21 It is our understanding that the in ten t of P a r . 133. 8 is to elim in ate a sb e sto s c o n ta in in g -filte rs as a so u rc e of a sb e sto s fib e rs in p a re n te r a l d ru g s or p a r e n te ra l drug in g red ien ts. P a r. 133. 8 as p re se n tly w ritten also sp ecifies that the filte r used in the production of p a re n te ra ls should not re le a s e fib er, citing a m em b ran e filte r as an e x a m p le , and la te r specifying the use of a m em brane filte r as an asb esto s fib er rem o v al device to be used subsequent to an a sb e s to s containing filter under p rescrib ed conditions. We feel that fu rth er clarification of the te rm "non-fiber releasing" p ro p erties and of the usage of the w ord "m em b ran e filte r" is re q u ire d to avoid possible m isin te rp re ta tio n , which could a d v erse ly affect P a ll C orporation sales of the widely used U ltipor m em branes. This clarification will also avoid specifying, by im plication, cellulose e ste r m em branes, which have their m ain application in the analytical field, and which in m any cases are not optim al for bulk-volum e sterile process applications. In o rd e r to c lea rly state our position on this, the following detailed discussion is offered: 1. R e g a r d in g F i b e r R e l e a s i n g P r o p e r t i e s of F i l t e r s : We feel that the specific intent of this p roposed re q u ire m e n t is to prohibit the use of asbestos filters with the latent intent of elim in ation of filters which add contam ination, i. e . , p artic le s or fibers CORPORATION page -2- to the filte re d product. T h e re a re two re a so n s fo r a filte r exhibiting this condition: (a) F il te r m edium m ig ra tio n , i, e. , continuous re le a s e of fib e rs o r p a rtic le s constituting a p a rt of the filte r m edium , due to inadequate o r no bonding of the filte r m a trix . T his can o ccu r under both steady state o r under pulsating flow conditions. (b) " B u ilt-in " c o n tam in atio n . T h is c o n s is ts of p a r tic u la te and fib ro u s d e b ris picked up during m anufacturing. T hese can be p a rtic u la rly h arm fu l if they a re located d o w n stream of the filterin g elem ent. To reduce this type of contam ination it is n e c e ssa ry to m anufacture the filter under contam ination controlled environm ental conditions and to clean the filte r after m anufacture until the d e sired level is re a c h e d . T h is clean in g o p e ra tio n can be re a d ily a cc o m p lish e d if the filter m a te ria l lends itself to high velocity flushing with w ater o r other fluids, a m anufacturing step w hich can not be used on cellulose e ste r m em branes, since it would rem ove the p lasticizer on w hich these m em branes depend for their m echanical integrity. M anufacturing of c a rtrid g e type high a re a elem en ts under clean conditions, without flushing after com pletion, w ill resu lt in m oderate to high levels of built in contam ination. This is the case because cellulose e s te r m e m b ra n es, like m ost o th er types of filte rs, being inherently m echanically weak, require a dow nstream fibrous support, as w ell as m eans for providing flow p assages for the filtered fluid. PALL CORPORATION page -3- Depending upon w hether the m edium is pleated, w rapped around a sim ple cylinder core or sp irally w rapped around a co re, one or m o re fibrous lay ers m ay be used. It is difficult - and indeed m o s t people fa m ilia r w ith th is a r t would say im p o s sib le - to guarantee that these layers will not release fibers or particulates, and for this reaso n the ability to apply a high velocity flush is extrem ely im portant. F lush cleaning of cellulose e ste r m em brane cartridges after m anufacture can not be readily accom plished due to rem o v a l of the p la stic iz e r. Ultipor AB F ilte rs can be readily flush cleaned after m anufacture until the d esired cleanliness level is reached, and this is our norm al m anufacturing p ro cess. The enclosed Pall C orporation Bulletin A B -8 0 0 (T a b le 2) s h o w s ty p ic a l p a r t i c l e c o u n t le v e l s of v a r io u s c a rtrid g e s tested in 1972. Although the data a re of lim ited natu re, they show clearly the difference between "m edia-m igration" and " b u i l t - i n c o n ta m in a tio n . " F o r e x a m p le , f i l t e r s ty p e Q, R, S, and T show high in itial fib er and p a rtic le counts, and they continue to show high fib e r and p a rtic le counts a fte r the in itia l 20 lite r e f fluents, and therefore they exhibit m edia m igration. The other types of filters show relatively low initial effluent counts and even lo w e r (su b stan tially z ero ) counts a fte r the f i r s t 20 lite r effluent. The initial count of these low count filters is due to "built-in con tam inant" which can be reduced by cleaning the filter cartridge after m anufacture to a degree of effluent cleanliness as outlined in A PPEN D IX II. R eview of the data fro m a filte r m a te ria l con- PALL CORPORATION page -4- stru c tio n point of view shows th at the c le a n lin e ss le v els of the n o n -m ig ra tin g v a rie tie s of f ilte r s te s te d is not a function of the filte r m a te ria l com position and low levels a re not re s tric te d to cellulose e ste r m em branes only. F o r exam ple, com paring sp ecim en V, W, and P a ll 0. 2 m ic r o m e te r f ilte r s show s c le a n lin e s s le v e ls of the sa m e o rd e r of m agnitude, w ith the P a ll 0. 2 m ic ro m e te r units som ew hat clean er than the cellulose e ste r m em b ran e c a rtrid g e s. T h erefo re, the w ord "non-fiber re leasin g " is not to be equated w ith "m em brane filter" (as im plied in the proposed regulation) but should be related to the d eg ree of effluent clean lin ess levels which can be achieved in n o n -m ig ratin g type filte rs . B ased on the above d iscu ssio n , we strongly recom m end the word "fiber releasing" in the proposed regulation be changed to "p article or fiber m igration", sim ilar to the p ro p o sed w ording in A PPEN D IX I. 2. R egarding usage of the w ord " M e m b ra n e -F ilte r": It is com m only accepted by many, if not m o st filter u se rs that the designation "m em b ran e filte r" re fe rs specifically to cellulose e ste r filte rs, and to m o st of th ese, it m eans "M illipore f ilte r ." As an exam ple, see D r. S. T u rco 's p ap er , w hich defines m em b ran e filter as being "chem ical com positions of cellulose e s te rs . " M any other lite ra tu re citations with s im ila r connotation can be m ade. In co n sid erab le p a rt, this acceptance stem s from the wide use of M illipore m em b ran es in lab o rato ry p ro ced u res. *TURCO, S. J. e t al, C o m p a ris o n of F in a l F iltra tio n D e v ice s, B ulletin of the P a re n te ra l D rug A sso ciatio n , S e p t., O c t., 1973, Vol. 27, No. 5, page 209. PALL CORPORATION page -5- P all products are not so widely recognized because th eir principal are a of use has been in plant scale applications. As you m ay know, P a ll C o rp o ra tio n is a m a jo r in te rn a tio n a l s u p p lie r of 0. 2 m ic r o m e te r s te riliz in g f ilte r s and of c o a r s e r f ilte r s , w hich em ploy the patented non-asb esto s-co n tain in g U ltipor inorganic fiber m em brane, corrugated into high a re a filte r elem ent c artrid g e s. The U ltipor m e m brane has pore size distribution sim ilar to and som ewhat n arro w er than cellulose este r m em branes, with better m axim um pore size control as shown in the attached paper by Dr. P all (presented at the P a re n te ra l D rug A s s o c ia tio n N atio n al M eeting of N o v e m b e r 2, 1973. ) The U ltip o r m em branes are non-m igrating (non-fiber releasing) and are m anu factured under clean conditions. Among their advantages over cellulose e s te r m em b ra n es, they can be nin -situ " steam steriliz ed , exhibit longer life and higher stru ctu ral strength, and have w ider solvent com patibility. They a re w ell suited fo r ste rile p ro cess filtratio n to rem ove b acteria and asbestos p articles from liquids and gases in pharm aceutical application, and a re p a rtic u la rly useful for filtration of p a re n te ra l drugs and p a re n teral drug ingredients. M aterial used in construction of these filte rs a re listed at the FDA under DMF 2063. N ote: P r e l i m i n a r y t e s t s a t P a l l C o r p o r a tio n l a b o r a t o r i e s show th a t the 0. 2|j.m a b s o lu t e a n d 3. 0jj,m a b s o lu t e U ltip o r m e m b r a n e s q u a n tita tiv e ly r e m o v e a s b e s t o s fib ers (obtained from standard asb estos filters used for pyrogen rem oval) in the m ic ro s c o p ic ra n g e , w hen using p h a se c o n tra s t m ic ro s c o p y p e r N10SH pu b licatio n No. HSM 72-10267. F u r th e r stu d ies on c o a r s e r g ra d e s of s im ila r m e m b ra n e s a re presently being conducted. A sbestos rem oval efficiency tests have also been con ducted by using SEM & XREDAS system s for analysis. A discussion of these m ethods and d a ta obtained to date a r e s u m m a riz e d in A P P E N D IX III. PALL CORPORATION page -6- B ecau se a la rg e p ro p o rtio n of p o ten tial u s e r s accep t the w ord "m em brane filter" to denote a cellulose e ste r, we feel that the basic intent of the proposed regulation will be m isunderstood by m any filter u s e rs , who w ill in te rp re t the regulation as proposed to m ean that cellulose este r m em branes are p re fe rre d over Ultipor m em branes, or sintered porcelain filter candles. This, we believe, is certainly not the intent of this regulation. We a re fu rth er concerned that u ser in terp retatio n of this proposed regulation (without the m odifications, p e r A PP E N D IX I) w ill r e s u l t in undue h a rd s h ip , p ro d u c tio n d e la y s, and higher costs to those cu sto m ers who have found it advantageous to u se U ltipor m e m b ra n e s, som e of w hom w ill e rro n e o u sly conclude fro m the p re se n t phrasing of the proposed regulation that they are r e quired to use cellulose e ste r m em b ran es. This also would re su lt in an ad v erse effect on P all C orporation sales of asb esto s free U ltipor m e m b ra n e c a rtrid g e s , w hich we and m any of our c u sto m e rs feel is a stip erio r pro d u ct and w hich c ertain ly satisfy the intent of the proposed regulation to achieve a sb e sto s-fre e and clean p a re n teral and p a re n teral drug ingredients by the m ost p ractical m eans. T h erefo re, we respectfully req u est that the w ord "m em brane" in the proposed regulation be replaced with "non p article or non-fiber m igrating filter m ed iu m ", sim ila r to the proposed w ording in APPENDIX I of this docum ent. UCR A,v Pbbr>i PKOPOG:'';) F u R t l N G p-MirjKG FTT,T F i l t e r s u s e d in t h e m e n u f a c l u r o o f a p a r e n t e r a l clrv or p a r e n t o r a ] d r u a i n q r e d 1 on i: s i i a j l n o t e x h i b i t p a r t i c l e o r f i b e r i n i g r a t i o r f r o m c o n s t i t u - - u t i o f 1h e f i 1 1"c;r roe d 1.ure. h e s u f f i c i e n t l y c l c o n e d n ' t o ' r :i.uf a c t u r e or p r i o r I n u s - t o r s o n r e a h~; oh c l o q r r o f o f f l u e - ' d , . l e e ; ) } nss Ro a s b e s t o s - c o n l a i n i n g o r m e d i a r.e r e : a t . i o n exl.3 h j. ti iK -: i l i or ruoy b e u s e d i n t h e inanuf a c l u v e o f a 'o a r e r , t o r s i d r u g o r p a r e n t s r a l d r e g i n g r e d i e n t u n l e s s i t i s not p o ssib le to Manufacture th at drug or drug in gred ien t w ithout the use o f such a f i l t e r . I f use o f such a f i l t e r i s required, an a d d i t i o n a l n o n - a s b e s t o s c o n t a i n i n g f i l t e r v fiich d o e s n o t e x h i b i t p a r t ic le or fib er m igration s h a ll subsequently be used to reduce th e c o n te n t o f any a sb e sto s-fo r m par t i d e s in th e drug or drug i n g r e d i e n t . E v id e n c e fo r r e d u c t i o n s h a l l be b a se d on th e u s e o f t h e m e t h o d s d e s c r i b e d i n *c r i t e r i a f o r a Recommended S t a n d a r d -- O ccupational Exposure to A sbestos", Report of Review Committee, R a tio n a l I n s t i t u t e for O c c u p a tio n a l S a f e t y and H e a lth , P u b lic a t io n N o . HSM 7 2 - 1 0 2 6 7 ( 1 9 7 2 ) . U s e o f an a s b e s t o s c o n t a i n i n g f i l t e r without subsequent use of the additional non-asbestos containing  .5 - f i l t e r i s p e n i s r.' b l e o n l y u p o n s u b m i s s i o n o f p r o o f t o i h o F o o d a n d D r u g c!:a.i n i c t r a t ' o n t h a t u s e o f a n o n - a s b e s ' . e- c o n t u i n i n g f i l t e r w i l l , i s l i k e l y t o c o r .pi r>ui.i s e t h e s a f e t y o r e f f e c t i v e n e s s ox the. d r u g . I n te r e ste d per sens m y , on o r b e f o r e December 67, 1973, i]r w i t h t h e He? n y C l o i r l , pox. f r e d Dj . ng 7br ni r , : n I r a l i o n , i n . 7 - 8 6 , 5 6 0 0 F i s h e r . 1- L en a , Ro< k v.i ' ~ )/*'. "0C52, w r i t t e n c o n me ; l.r> ( p r e - f e x a b l y ii i c / a i n t u p l i c a t o ) :: `d '- ;g t h e p e t i t i o n and t h e Comm i s s i o n e r 1a p r o p o s e ] . Comm on i s i ay b e a c c o m p a n i e d b y o metfitorandum or b r i e f i n s u p p o r t t h e r e o f . 'j h e p e t i t i o n , b a c k g r o u n d i n f o r m a t i o n r e f e r r e d t o i n t h i s p r o p o s e 1, and comments r e c e i v e d may b e s e e n in t h e above o f f i c e d u r in g w ork in g h o u r s , Monday th rou gh F r id a y .