Document MLL7M1nqzNkGEqNkqmXYe0zM

NDTJMr i S A RU / i - V TO : Ar mand R. C a s o l a , P h . D . C h i e f Chemi s t Bureau of Drugs DEPARTMENT o f h e a l t h , e d u c a t i o n , a n d w e lf a PUBLIC HEALTH SERVICE - FOOD a n d d r u g a d m i n i s t r a t i o n DATE: M a y 10, 1972 FROM : P h a r m a c o l o g i s t Bureau of Drugs SUBJECT: R e p o r t o f a S e m i n a r A t t e n d e d May 10, 1972 The B u r e a u o f Drugs s e m i n a r f o r t h i s dat e was e n t i t l e d " P a r t i c u l a t e M a t t e r i n Pa r e n t e r a 1s , " and was g i v e n by Dr. S a l v a t o r e J . T u r c o o f the C o l l e g e of Pharmacy, Temple U n i v e r s i t y , P h i l a d e l p h i a . It should be o f i n t e r e s t to y ou r committee on a s b e s t o s , e s p e c i a l l y w i t h regard to methodology on l i g h t m i cr os co p y. Dr. T u r c o p o i n t e d o u t t h a t p a r e n t e r a l s s h o u l d be s t e r i l e , p y r o g e n f r e e and f re e o f p a r t i c u l a t e matter. Dr. Turco began with a review of the l i t e r a t u r e on the s u b j e c t , and t he two pa per s by G a r v i n and Gunner o f A u s t r a l i a in 1963 and 1964. T h e r e have been more than 1 0 0 p a p e r s r e l a t e d to the s u b j e c t s i n c e thac time, i n c l u d i n g 3 on w h i c h Dr. T u r c o was c o - a u t h o r . FDA hel d a Symposi um on the s u b j e c t J u l y 2 8 - 2 9 , 1966 at whi ch t i me Dr . J . D. L o c k h a r t r e v i e w e d t h e me d i c a l l i t e r a t u r e a n d Dr. A. G r o s s presented h i s stu dies on dogs f o llo w in g in je ctio n IV of ground f i l t e r paper particle s. The human s t u d i e s i n d i c a t e d t h a t p a r t i c u l a t e m a t t e r c o u l d be f i b e r s o r c r y s t a l l i n e m a t e r i a l , o r e v e n f u n g i . ( D r u g a d d i c t s who u s e t a b l e t s I V can have s t a r c h and t a l c gr a nu l om as . ) The lung is the most frequent s i t e o f d e p o s i t , w i t h f i b r o u s p n e u m o n i t i s and granul omas produced by a g g l u t i n a t e d p l a t e l e t s and t h r o m b i c f o r m a t i o n . P a r t i c l e s can a l s o be found in the o c c ip i t a l lobe, or in the blood v e s s e ls of the eye. P a r t i c l e s in p a r e n t e r a l s vary from one manufacturer to another, and from year to y e a r , depending on q u a l i t y c o n t r o l s . The problem extends beyond la rg e volume IV i n f u s i o n s , f or IV a n t i b i o t i c s and o p h t h a l m i c s o l u t i o n s a r e i n v o l v e d . T h e r e a r e many p a r t i c l e s i n a n t i b i o t i c s , more in t h e d r y powder t han in l y o p h i l i z e d p r e p a r a t i o n s a c c o r d i n g to Beckerman o f UCLA. Norman J a f f e r epo r t e d eye granul omas from p a r t i c l e s in ophthalmic s o l u t i o n s , e s p e c i a l l y those used in eye surgery. T e c h n i q u e s o f d e t e c t i o n may be d e s t r u c t i v e o r n o n - d e s t r u c t i v e . The n o n d e s t r u c t i v e a r e v i s u a l i n s p e c t i o n , the most s o p h i s t i c a t e d being, w i t h a T i n d a l l beam and p h o t o m u l t i p l i e r tubes. The " s e n s i t i v i t y " o f v i s u a l methods is p a r t i c l e s o f j T > 2 5 _ 50 p f o r the unaided eye, orjj> 5~600 p f o r t h e T i n d a l l beam. The Emha r t A u t o s c a n i s u s e d by t he P a r e n t e r a l Drug A ssoc ia tio n. Page 2 D e s t r u c t i v e methods are the C o u l t e r c ount er and the m i l l i p o r e f i l t e r with l i g h t microscope counting. The o b j e c t i o n to the C o u l t e r counter is that is does not d i s t i n g u i s h between shapes, or s i z e s . A " c o u n t " r e l a t e s to " ma s s " , a long t h i n f i b e r be i ng g i ve n the same v a l u e as a smal l sphe r e. A l s o a clump o f p a r t i c l e s w i l l be c o u n t e d as one. I d e a l l y a method s h o u l d i n d i c a t e the number, s i z e and shape of p a r t i c l e s as well as the i d e n t i t y ( c e l l u l o s e , c o tt o n, a s b e s t o s , e t c ) . The m i l l i p o r e f il t e r collection plus light microscope will give f a ir ly accurate ( t l O % ) c o u n t s on p a r t i c l e s j3>5 ju, and w i t h t h e e l e c t r o n m i c r o s c o p e the met hod may be e x t e n d e d t o p a r t i c l e s b e l o w 5 u. Dr. T u r c o ' s s t u d i e s repor t e d here r e p r e se n t 6 months w o r k and 500 samples. The r e s u l t s a r e p u b l i s h e d i n Am. J. Hos p . Pharm. 28_: 6 2 0 - 6 2 3 , ( Aug. 1 3 7 1 ) . A s i m i l a r study, done in 1969 on products o f 4 firms i d e n t i f i e d o n ly by A . B . C . D . c ode, was c o mpa r e d. The t e c h n i q u e s u s e d wer e t h e same. Two f i r m s , Abbott and Baxter, supported f i n a n c i a l l y the 1970 study. In the 1970 study there were a ls o reported r e s u l t s of a " f i n a l f i l t e r " in the a d m i n i s t r a t i o n s e ts , fo r Baxter and fo r Abbott. The te chn iq ue in vol ves use o f a lami n ar flow hood, c a r e f u l c l e a n i n g of the c o n t a i n e r s and components of the m i l l i p o r e c o l l e c t i o n device with p a r t i c l e - f r e e Freon TF s o l v e n t and the running o f " b l a n k s " a f t e r every 6 samples to control t e c h n i q u e s . The m i l l i p o r e f i l t e r is removed a f t e r vacuum f i l t r a t i o n o f l i t e r f l a s k s of IV f l u i d s , s t o r e d in u l t r a c l e a n P e t r i p l a t e s , and examined w i t h t h e l i g h t m i c r o s c o p e a t A0 and 100X m a g n i f i c a t i o n . C o u n t s a r e made f o r p a r t i c l e s , by s i z e , and the f i b e r s are g i ven s p e c i a l a t t e n t i o n because o f the p o t e n t i a l fo r thrombus formation. A f i b e r is de fin ed as being a t l e a s t 10 X as l o n g as i t i s t h i c k . An aut omat ed method o f c o u n t i n g , u s i n g a " TTMC" s y s t e m w i t h TV m o n i t o r and c o mpu t e r modul e was used some t i m e s ( i t was b o r r o w e d ) . R e s u l t s we r e much t h e same as p u b l i s h e d . The f i r m s wer e r a t e d : A b b o t t T > B a x t e r j > C u t t e r McGaw f o r r e l a t i v e f r e e d o m from p a r t i c u l a t e s . Each fir m had improved over 1969- The a d d it io n of a d m i n i s t r a t i o n se ts , o r a d d i t i v e s such as KC1, or v i t a m i n s , added m a t e r i a l l y to the p a r t i c l e count. The use of a f i n a l f i l t e r , downstream, was v e r y e f f e c t i v e in r e d u c i n g the p a r t i c l e co unt , and most o f the p a r t i c l e s we r e v e r y s m a l l ( pg. 622 o f t h e A u g . 71 p u b l i c a t i o n ) . T e mp l e U. P h a r ma c y d i s t i l l e d w a t e r g a v e 361 p a r t i c 1e s / 1 i t e r , and a community pharmacy d i s t i l l e d water gave 933- Tap water qave almost 2 8 ,000/1 i t e r. A f ew a n a l y s e s o f f i b e r s we r e done by W a l t e r C. Me Cone A s s o c i a t e s o f C h i c a go . Rubber p a r t i c l e s pr edomi nated, f o l l o w e d by red i r o n o x i d e and l i m e s t o n e , g l a s s , p a p e r f i b e r s , e t c . Dr. T u r c o s t a t e d he t h o u g h t some a s b e s t o s f i b e r s were p r e s e n t but he co ul d not s p e c i f y which kind. The A b b o t t f i n a l f i l t e r i s an a c e t a t e , w i t h 1 ju p o r e s i z e , w h i l e t h e Baxter final f i l t e r is m illip o re , 0.45 p pore size. E le c tro n micrographs of the pores show they are t o rtu ou s, not s t r a i g h t pores. S o u r c e s o f p a r t i c l e s c o u l d be the i n g r e d i e n t s , t he p a c k a g e and c omponents , o r t h e a d m i n i s t r a t i o n s e t s , o r a d d i t i v e s . T h e r e may be r e a c t i o n p r o d u c t s , a l s o , bec aus e p a r t i c l e s ar e more numerous w i t h long s h e l f - l i f e . M a n i p u l a t i o n s at the b e d s i d e add more p a r t i c l e s . ,No s y s t e m a t i c s t u d i e s f o r a d v e r s e e f f e c t s have been do ne i n t h e USA, but a program of autop sie s is being s t a r t e d at Temple, on p e r s o n s having i n f u s i o n s who l a t e r di e. Dr. Turco a dv o ca t es use o f f i n a l f i l t e r s e t s , e s p e c i a l l y when a d d i t i v e s a r e u s e d , o r t h e r e a r e m u l t i p l e i n f u s i o n s . He a l s o a d v o c a t e s s e t t i n g o f s t a n d a r d s (by USP and FDA) f o r t o l e r a n c e s o f p a r t i c l e s i n p a r e n t e r a l s . Dr. T ur c o s t a t e d h i s s t u d i e s had d e f i c i e n c i e s , in t h a t t h e s a m p l i n g was not o f a l l p r o d u c t i o n n a t i o n w i d e , in 1969 and 1970. A t h i r d s tu d y is b e i n g conducted w i t h b r o a d e r s a m p l i n g . H i s t e c h n i q u e mi g h t be improved, i n t h a t r e p l i c a t e c o u n t s by t he same p e r s o n show w i t h V I 0 % v a r i a t i o n , and the s t u d ie s were not " b l i n d e d , " but t think these are t r i v i a l c r i t i c i s m s . He p l a n s t o s t u d y p e r i t o n e a l d i a l y s i s f l u i d s s o o n . Dr. T u r c o th en i n t r o d u c e d h i s g r a d u a t e s t u d e n t , Mr. S t e v e Lamancha. who h a s s t u d i e d o p h t h a l m i c s o l u t i o n s , b o t h OTC and Rx, and b o t h t o p i c a l and f o r e y e s u r g e r y . He u s e d t h e same t e c h n i q u e , w i t h c o n t r o l b l a n k s u s u a l l y z e r o . T h e r e was t r e m e n d o u s v a r i a t i o n among t h e v a r i o u s p r o d u c t s , w i t h some s h o w i n g a s few as 1 0 - 1 2 , o t h e r s s h o w i n g 535 p a r t i c 1e s / m l . In some c a s e s t h e s m a l l p a r t i c l e s wer e t o o n u mer o us t o c o u n t . He s u g g e s t e d us e o f Swinnex m i l l i p o r e f i l t r a t i o n (2.2p) of a ll s o l u t i o n s f o r use in eye surgery. Both spea kers s ta ted that p l a s t i c c o n t a i n e r s had g e n e r a l l y less p a r t i c l e s t h a n t h o s e made o f g l a s s .