Document NeY4RMrDVO6ongbLyOowMvBkE

D ecem ber 21, 1973 1 HYLAND DIVISION T R A V E N O L L A B O R A T O R IE S, INC. Post Office Box 2214 3300 Hyland Avenue Costa Mesa, California 92626 {714) 540-5000 Hearing Clerk Food and Drug Administration 5600 Fish ers Lane Rockville, Maryland 20852 Dear Sir: As m anufacturers of biological products, holding establishment licen se num ber 140, we w ish to com m ent on the P r o p o s e d Rule concerning A sb estos P a rtic le s in Food and D rugs, published at 38 F R 2707 6 on S e p t e m b e r 28, 197 3. We would like to point out that: 1. T h e r e i s no e v id e n c e that a s b e s t o s in the q u an titie s p u r p o r t e d to be p resen t in som e p aren terally ad m in istered drugs has ever caused a d v e rse effects in human recip ien ts, despite the fact that a s b e s t o s has been a component of m a t e r ia ls used in p r o c e ssin g such drugs for m any d e c ad e s. The only evidence of ill effect follows exposure by inhalation and (possibly) by contact and ingestion, and then only following relativ ely high exposure becau se of o ccupa tion or unusual environment. 2. A s b e s t o s is u biqu itou s, a s noted in the p r e a m b l e of the p r o p o s a l . 3. T h e r e i s no a c c e p t e d p r a c t i c a l m e t h o d to d e m o n s t r a t e the p r e s e n c e (or, m o re important, the absence) of a sb e sto s in p aren teral drugs. We have no objection, h ow e ve r, to a tte m p t to p re v e n t u n n e c e s s a r y exposure to the p resen tly unknown hazard, providing that the quality and e fficac y of often life - sa v in g drugs a r e not im p a ire d in such an attem pt. In acco rd an ce with this attitude, we have had an active project, r7P*SUe[ Hearing Clerk Food and Drug Adm inistration D ecem ber 21, 1973 Page 2 opened in O ctober 1972, to find w ays of elim inating a s b e s t o s and asb e sto s-c o n tain in g m a t e r ia ls fro m all sta g e s of the p ro c e ssin g of the in jectab le p r o d u c ts we m a k e . We have no m e a n s to d e m o n strate either the p resen c e or absen ce of a sb e sto s in our products; th e refo re the study has been directed so lely to the elim ination of asbestos-containing m aterials (filters) so far as possible from all processing steps. Our injectable produ cts a r e a ll d e riv a tiv e s of human p la s m a and the diluents with which such products as are furnished in dry form are reconstituted for administration. The diluents are all prepared with out the use of a sb e s t o s or asb esto s-c o n tain in g m a t e r ia ls . A sb e sto s containing filters have been used for years to achieve the sharp separations of fractions of human p lasm a proteins needed for purity and p h y s i c i a l s t a b i l i t y of p r o d u c t s and to r e a c h the fi n a l p r o d u c t c l a r i t y required by present FDA regulations. Dozens of candidate substitutes for asbestos-containing filter m aterial have been found ineffective in our study. Only in recen t months has p a r t i a l s u c c e s s b e en a c h ie v e d . We have been able to u se fin al m e m b r a n e filtration for all our products, and for som e products we have been able to eliminate asbestos-containing filters entirely. However, for other produ cts, we have not yet been able to find an acceptable substitute during the p ro cessin g . We should again mention that we have no inform ation a s to whether or not the number of a sb e sto s p artic le s, if present, has been reduced by the final m em brane filtration. Although it is not c le a r, the descrip tio n of the FD A su rv ey and study in the p r e a m b l e of the p r o p o s a l ( p a g e 2 7 0 7 7 , c o l u m n 3, to p a g e 27078 to p of c o l u m n 1) s e e m s to s a y t h a t a s b e s t o s w a s d e m o n s t r a t e d in m a n y products which were never exposed to asb esto s during processing. Thus it m a y be futile to expect to achieve com plete ab sen ce of a s b e s t o s . * Hearing Clerk Food and Drug Administration D ecem ber 21, 1973 Page 3 The present FDA regulations and requirem ents for clarity and stability of p a r e n t e r a lly - a d m in iste r e d human p la s m a d e riv a tiv e s a r e b a s e d on what has been p o ssib le with the use of a sb e sto s-c o n ta in in g filte r s, not upon any knowledge of harm ful effects or lack of effectiveness of p r e p aration s l e s s c le a r or l e s s stable with r e s p e c t to the form ation of insoluble m a t e r ia l on aging. B a s e d upon the above con sideration s, we feel that the issu an ce of any regulations such as those in proposed Section 133. 3 (j) is prem ature and should await: 1. P r a c t i c a l m e th o d s of d e m o n s t r a t i n g and quantitating a sb e sto s p artic les in such biologicals as human p lasm a derivatives. 2. Knowledge that the p resen t p rep aration s, which may or m ay not contain very slight trace amounts of a sb e sto s , have any undesirable side effects attributable to asb esto s. 3. K n o w l e d g e a s to w h e th e r or not the p r e s e n t l y r e q u i r e d degree of clarity and physical stability are needed for reaso n s other than esthetic. If it should be determ ined that so m e kind of regulation s in this m atter is needed, we have the following com m ents concerning the proposed fo rm of Section 133. 8 (j): F i r s t sentence: T h is sentence would regulate the filter, not the use of the filter. A better choice of sentence f o r m might be; " F i l t e r s w h i c h r e l e a s e f i b e r s s h a l l not be u s e d in the m a n u f a c t u r e ---------------- . " Second sentence: This d irectly contradicts the f ir s t sentence, saying that such filters m ay be used under certain circum stan ces. Further, dem onstration that something is not p ossib le is an a lm o st im p ossible task ; the p o ssib ility changes with advan cem en t of the art, a m atter l a r g e l y in the hands of the filte r m a n u f a c t u r e r s , not the b io lo g ic a l m a n u factu rers, although the latter adm ittedly can stim ulate the fo rm e r. Hearing Clerk Food and Drug Administration D ecem ber 21, 1973 Page 4 Third and fourth sentences; The proposed requirem ent to furnish evi dence that the final (m e m b ra n e ) filter a ctu ally re d u c e s the content of a sb e sto s p a rtic le s se e m s unreasonable, and we feel it is am ple to require that such a filter be used. The demonstration of reduction re q u ires equipment not easily or usually available to a biologies m anu fa c tu r e r, and the re fe r e n c e cited is a lm o st en tirely concerned with much larg e r num bers of particles than might be expected under any condition in a parenteral solution. This proposed requirem ent would require proof only that safety or effectiveness is (or might be - a purely subjective conjecture) com p ro m ise d . It does not co n sid e r that c la rity and p h y sic a l stability, which a r e a p a r t of the p r e s e n t r e q u ir e m e n ts for our p ro d u c ts, m ight be affected with no effect on safety or e ffe c tiv e n e ss, yet products would not be satisfactory by present re le a s e standards. In sum m ation, we fee l that a g reat deal of inform ation needs to be gathered before regulations such as those proposed for Section 133. 8(j) can be considered. Respectfully, J o h n W. P a l m e r , P h . D. Vice P resident and D irector of L aboratories gt