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6 Hazard Avoidance in the Processing of Pharmaceuticals JOHN R. HANDLEY Sterling Organics Division, Sterling Drug Inc., Rensselaer, NY 12144
The batchwise processing of pharmaceuticals always presents the possibility of serious physical hazard. These hazards can usually be avoided with the help of a comprehensive hazard evaluation program such as the one recently installed in our facility. This program involves the physical testing of a process as well as a detailed examination by a Hazard Review Team (consisting of an R & D chemist, safety officer, pilot plant director, environmental co-ordinator, process engineer and hazard evaluation chemist). Physical testing usually entails an examination of heats of reaction, minimum decomposition temperatures, relative thermal stabilities and flammability characteristics associated with a particular process. Some specialized testing (ARC, DSC, etc.) may also be carried out when indicated. We have found that this program is already affording benefits of smoother and safer plant operations.
The S t e r l i n g O r g a n i c s R e n s s e l a e r P l a n t i s a medium-sized c h e m i c a l f a c i l i t y p r o d u c i n g p h a r m a c e u t i c a l s and t h e i r i n t e r m e d i a t e s a s w e l l as some s p e c i a l t y o r g a n i c c h e m i c a l s . P r o d u c t i o n i s g e n e r a l l y on a b a t c h b a s i s i n medium t o l a r g e r e a c t o r s . The S t e r l i n g O r g a n i c s UK p l a n t i s s i m i l a r and i s where, about seven y e a r s ago, t h e concept o f in-house h a z a r d e v a l u a t i o n was conceived. The b e g i n n i n g s o f our h a z a r d e v a l u a t i o n program were f a i r l y low key. F o r y e a r s we had been r u n n i n g a Schiemann r e a c t i o n which i n v o l v e d t h e t h e r m o l y s i s o f an a r o m a t i c d i a z o n i u m f l u o r b o r a t e s a l t (Figure l ) .
0097-6156/ 85/ 0274-0041 $06.00/ 0 © 1985 American Chemical Society
Hoffmann and Maser; Chemical Process Hazard Review ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
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I n t h i s r e a c t i o n the s t a r t i n g s a l t was h e a t e d t o about 90° a t w h i c h p o i n t i t began a slow, c l e a n l i b e r a t i o n of gas. One p a r t i c u l a r b a t c h of s t a r t i n g m a t e r i a l , however, decomposed v i g o r o u s l y a t an u n e x p e c t e d l y low temperature w i t h r a p i d e v o l u t i o n of gas and h e a t . A l t h o u g h no s e r i o u s damage took p l a c e , i t was apparent t h i s f a m i l i a r r e a c t i o n was indeed n o t s a f e even though i t had r u n f o r y e a r s i n the lab and p l a n t w i t h o u t i n c i d e n t . Many r e a c t i o n s cannot be deemed s a f e f o r f u l l s c a l e o p e r a t i o n i n the p l a n t even though no problems were e v i d e n t i n t h e l a b . The p r i m a r y reasons f o r t h i s d i f f e r e n c e i n r e a c t i v e c h a r a c t e r i s t i c s a r e the s c a l i n g e f f e c t s a s s o c i a t e d w i t h much l a r g e r b a t c h size. Simple mass t r a n s f e r e f f e c t s make c o o l i n g a l a r g e r b a t c h a much s l o w e r and more d i f f i c u l t p r o c e s s . Hot s p o t s on the w a l l o f the r e a c t o r v e s s e l o r d u r i n g reagent a d d i t i o n i n a r e a c t o r may a l s o be p o t e n t i a l s o u r c e s o f d i f f i c u l t i e s . Contamination i n p r o d u c t i o n — i r o n , f o r e x a m p l e — i s not a s i g n i f i c a n t problem i n a l a b o r a t o r y environment, but must be a c t i v e l y e x c l u d e d i n the p l a n t . Finally, even a s m a l l k e t t l e has a l a r g e degree o f a d i a b a t i c i t y r e l a t i v e t o a 5 - l i t e r f l a s k . A r e a c t i o n t h a t g e n e r a t e s even a s m a l l amount of h e a t can t h e r m a l l y s e l f - a c c e l e r a t e i f an adequate h e a t - r e m o v a l system i s n o t a v a i l a b l e . The s t a r t i n g m a t e r i a l w h i c h u n e x p e c t e d l y decomposed was examined i n t h e l a b . Samples of t h i s p a r t i c u l a r b a t c h o f m a t e r i a l , as w e l l as b a t c h e s of m a t e r i a l t h a t had r e a c t e d n o r m a l l y , were s u b j e c t e d t o h e a t i n g i n an o i l b a t h a t 2-3°C per minute and t h e i n i t i a l d e c o m p o s i t i o n t e m p e r a t u r e s o b s e r v e d . The temperature d i f f e r e n c e between t h e sample and o i l b a t h was p l o t t e d a g a i n s t t h e o i l b a t h temperature. W i t h t h i s crude equipment, i t was shown t h a t the v i g o r of t h e exotherm was d i r e c t l y r e l a t e d t o t h e q u a l i t y of the f l u o r o b o r a t e . Thus, a pure sample of t h e f l u o r o b o r a t e ( F i g u r e 2) decomposed a t 95°C w i t h smooth e v o l u t i o n of gas and no foaming. W i t h an impure sample the b a t c h decomposed v i o l e n t l y a t 84°C ( F i g u r e 3). As a r e s u l t of t h i s work, s t r i c t c o n t r o l s were p l a c e d on t h e washing and d r y i n g of the f l u o r o b o r a t e s a l t . I n a d d i t i o n , each b a t c h was s u b j e c t e d t o t h i s s i m p l e t e s t t o determine i t s response t o h e a t i n g b e f o r e the p l a n t d e c o m p o s i t i o n was performed. These s a f e guards a l l o w e d t h e s a f e h a n d l i n g of t h i s r e a c t i o n on the p l a n t s c a l e . I n i t i a l Hazard E v a l u a t i o n
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Hoffmann and Maser; Chemical Process Hazard Review ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
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program was developed w i t h the f o l l o w i n g o b j e c t i v e s : 1. E s t a b l i s h a l a b o r a t o r y t o examine the h a z a r d p o t e n t i a l o f a p a r t i c u l a r r e a c t i o n o r compound, i n i t i a l l y u s i n g s i m p l e t e s t s and equipment. 2. P r o v i d e d a t a on the p o t e n t i a l f o r u n c o n t r o l l e d exotherms t o R& D and P r o d u c t i o n groups. 3. Examine a l l new p r o d u c t s e n t e r i n g b o t h P r o d u c t i o n and the P i l o t P l a n t f o r p o s s i b l e unexpected h a z a r d s . 4. F i n a l l y , and p r o b a b l y most i m p o r t a n t l y , educate and t r a i n c h e m i s t s , e n g i n e e r s and managers on the r o l e of the h a z a r d s l a b i n achieving safer in-plant operating conditions. Two p r i o r i t y s c h e d u l e s were developed t o determine i n what o r d e r compounds and p r o c e s s e s s h o u l d be t e s t e d . The f i r s t p r i o r i t y l i s t i n g covered the t e s t i n g which was needed i n a s h o r t t i m e , t h a t i s , those p r o c e s s e s which c o u l d pose a r e a l , immediate t h r e a t t o p l a n t p e r s o n n e l . These i n c l u d e d : 1. A l l p l a n t p r o c e s s e s where concern e x i s t e d r e g a r d i n g the r e a c t i o n * s c o n t r o l l a b i l i t y o r r e a c t i o n s which had, i n the p a s t , shown any e v i d e n c e of v a r i a b l e exothermic b e h a v i o r . 2. Residues from d i s t i l l a t i o n s o f p r o d u c t s o r i n t e r m e d i a t e s which were s u b j e c t e d t o temperature i n excess o f 250°C. 3. Raw m a t e r i a l s , i n t e r m e d i a t e s o r p r o d u c t s which c o n t a i n e d f u n c t i o n a l groups known from e x p e r i e n c e t o have p o t e n t i a l f o r instability. 4. A l l p l a n t p r o c e s s e s i n v o l v i n g n i t r a t i o n s o r s t r o n g l y o x i d i z i n g c o n d i t i o n s and p r o c e s s e s w i t h h i g h r a t e s o f gas e v o l u t i o n . A f t e r c o m p l e t i o n of t h i s stage o f our t e s t i n g program, l o n g term p r i o r i t i e s were a d d r e s s e d . These a r e : 1. Examine a l l p r o c e s s e s e n t e r i n g the P i l o t P l a n t f o r the f i r s t time. 2. Examine a l l p r o c e s s e s c u r r e n t l y i n o p e r a t i o n i n t h e p l a n t . Hazard Review Team O r g a n i z a t i o n R e c e n t l y , a f o r m a l i z e d h a z a r d assessment procedure has been i n i t i a t e d f o r a l l p r o c e s s e s t o be r u n i n the P i l o t P l a n t . To d a t e , the t e s t i n g methodology has been found t o be q u i t e e f f e c t i v e a t i d e n t i f y i n g p o t e n t i a l h a z a r d s . For the remainder o f t h i s paper, I w i l l e l a b o r a t e on t h i s p r o c e d u r e , d e t a i l i t s s t e p - b y - s t e p format as w e l l as t h e r e s p o n s i b i l i t i e s o f the i n d i v i d u a l s i n v o l v e d . The h a z a r d e v a l u a t i o n program r e q u i r e s the e x p e r t i s e o f a number of d i f f e r e n t d i s c i p l i n e s as w e l l as the c o o r d i n a t i o n and r e c o n c i l i a t i o n of the p r o j e c t s c h e d u l e w i t h f a c t o r s such a s equipment s u i t a b i l i t y , p e r s o n n e l , t r a i n i n g and e f f l u e n t c o n s i d e r a t i o n s . O b v i o u s l y , t o t a k e i n t o account a l l o f the d i f f i c u l t i e s a s s o c i a t e d w i t h s t a r t i n g and r u n n i n g an u n f a m i l i a r p r o c e s s i n a d d i t i o n t o examining the p o t e n t i a l h a z a r d s o f the p r o c e s s i s a c o m p l i c a t e d t a s k . The format d e s c r i b e d h e r e w i l l work f o r most m a n u f a c t u r i n g operations. The r e s p o n s i b i l i t y f o r h a z a r d assessment f o r new p r o d u c t i n t r o d u c t i o n l i e s w i t h the Hazard Review Team. The Hazard Review Team f o r a p a r t i c u l a r p r o j e c t g e n e r a l l y c o n s i s t s o f t h e f o l l o w i n g people: 1. The P i l o t P l a n t D i r e c t o r who c o o r d i n a t e s h a z a r d r e v i e w s c h e d u l i n g , p r e p a r e s a h a z a r d r e v i e w summary and keeps comprehensive r e c o r d s of a l l i n f o r m a t i o n p e r t i n e n t t o a p r o c e s s .
Hoffmann and Maser; Chemical Process Hazard Review ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
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2. The R&D Chemist most i n t i m a t e l y i n v o l v e d i n the p r o j e c t . He p r o v i d e s a b a s i c r e a c t i v e sequence summary, o f f e r s h i s o p i n i o n as t o t h e r e l a t i v e h a z a r d p o t e n t i a l of s p e c i f i c o p e r a t i o n s and c h e m i c a l s p e c i e s , and p r e p a r e s f o r m a l i z e d p r o c e s s d i r e c t i o n s . 3. The Hazard E v a l u a t i o n Chemist q u a n t i f i e s the a c t u a l p o t e n t i a l h a z a r d s i n v o l v e d i n an o p e r a t i o n - h e a t s of r e a c t i o n , gas e v o l u t i o n r a t e s , minimum d e c o m p o s i t i o n t e m p e r a t u r e s , e t c . 4. The P r o c e s s E n g i n e e r i s i n v o l v e d when an a c t u a l p o t e n t i a l h a z a r d i s i d e n t i f i e d . He suggests methods f o r m i n i m i z i n g o r e l i m i n a t i n g such a h a z a r d . 5. The E n v i r o n m e n t a l C o o r d i n a t o r d e c i d e s the u l t i m a t e f a t e of s o l i d and l i q u i d waste p r o d u c t s from the p r o c e s s . 6. The P l a n t S a f e t y O f f i c e r i d e n t i f i e s the t o x i c h a z a r d s o f c h e m i c a l s p e c i e s i n v o l v e d i n a p a r t i c u l a r p r o c e s s . He a l s o recommends what p r o t e c t i v e equipment may be r e q u i r e d t o p r e c l u d e p e r s o n a l injury. Hazard Review T e a m — P r o c e s s E x a m i n a t i o n F i g u r e 4 i s a f l o w c h a r t o u t l i n i n g the u s u a l p r o g r e s s i o n of i n f o r mation and r e s p o n s i b i l i t y f o r a t y p i c a l h a z a r d r e v i e w . B r i e f l y , the h a z a r d r e v i e w p r o c e s s i s as f o l l o w s : When a d e c i s i o n i s made t o p i l o t a p r o c e s s , the P i l o t P l a n t D i r e c t o r s c h e d u l e s the r e v i e w sequence and n o t i f i e s the R&D Chemist who p r o v i d e s a p r o c e s s summary t o i n d i v i d u a l members o f the Hazard Review Team. The S a f e t y O f f i c e r w i l l then examine t h e p r o c e s s f o r the presence of p o s s i b l e t o x i c o r i r r i t a t i n g compounds w h i l e the E n v i r o n m e n t a l C o o r d i n a t o r d e c i d e s the u l t i m a t e f a t e of any p r o c e s s waste streams. The Hazard E v a l u a t i o n Chemist i d e n t i f i e s any t h e r m a l or r e a c t i v e h a z a r d s a s s o c i a t e d w i t h the p r o c e s s . I f a h a z a r d i s i d e n t i f i e d , the P r o c e s s E n g i n e e r d e t e r m i n e s the s u i t a b i l i t y of a p a r t i c u l a r r e a c t o r g r o u p i n g t o h a n d l e the s p e c i f i c c o n d i t i o n s involved. Once every member of the Review Team has had a chance t o examine the p r o c e s s , the e n t i r e Team meets t o d e c i d e upon the s a f e s t o p e r a t i n g p r o c e d u r e s . From the n o t e s o f t h i s m e e t i n g , a Hazard Review Summary i s p r e p a r e d . The R&D Chemist uses t h i s Summary t o p r e p a r e a f i n a l i z e d s e t of m a n u f a c t u r i n g d i r e c t i o n s . A t t h i s p o i n t the p r o c e s s i s c o n s i d e r e d ready f o r p i l o t i n g . An i m p o r t a n t c o n t r o l l i n g f e a t u r e of the h a z a r d r e v i e w procedure i s the Hazard Assessment Form ( F i g u r e 5 ) . T h i s Form i s s i m p l y a c h e c k l i s t by which i n d i v i d u a l r e s p o n s i b i l i t i e s and suggested c o m p l e t i o n d a t e s a r e a s s i g n e d f o r the f o l l o w i n g i t e m s : 1. Hazard and o p e r a b i l i t y assessment 2. P r o c e s s h a z a r d e v a l u a t i o n 3. Implementation of r e a c t o r m o d i f i c a t i o n s 4. E f f l u e n t d i s c h a r g e c o n s i d e r a t i o n s 5. S a f e t y and t o x i c i t y s c r e e n i n g 6. S p e c i a l m a t e r i a l h a n d l i n g c o n s i d e r a t i o n s 7. Hazard r e v i e w summary 8. Approved Batch Record p r e p a r a t i o n . An i n d i v i d u a l s i g n s the Hazard Assessment Form o n l y when he i s s a t i s f i e d t h a t a p r o c e s s can be r u n s a f e l y i n the p l a n t .
Hoffmann and Maser; Chemical Process Hazard Review ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
6. H A N D L E Y
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