Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try

E P A / 310- R

- 97- 005



### EP A O f f

i ce o f Co m p l i a n ce S ect o r No t e b o o k P r o j ect :


## Pr o f ile o f th e Ph a r m a c e u tic a l M a n u f a c tu r i n g I ndus t r y

Sept em b e r 1997

O ffic e o f C o mp lia n c e Of f i ce o f E n f o r cem en t an d Co m p l

i a n ce A ssur a n c e U. S

. E n v i r o n m en t a l P r o t ect i o n A g en cy 401 M St

. , SW ( M C 2221- A ) W a s h i n gt o n , DC 20460Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try This report is one in a series of volumes published by the U. S. E nvir onmental Pr otection Agency (EPA) to provide informa tion of ge ne ra l inte re s tre ga rding e nvi r o n m e n t a l is s u e s a s s o c i a t e d w ith specific indus tr ial s ector s

. T h e documents wer e developed under c o n t r a c t b y A b t A s s o c i a t e s (Cambridge, M A )
, Science Applications I n ter n ational C o r por ation ( M cL ean, VA)
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. Di r ect t ech n i cal quest i o n s t o t h e “ F eedb ack” b u t t o n at t h e b o ttom of th e w e b p a g e

.

Co v e r ph o t o g r a ph s co ur t e sy o f P h ar maceut i cal Resear ch an d Man u f act ur er s o f A m er i ca.

Sect o r No t e b o o k Pr o j ect ii Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try

Sect or Not e book Cont act s

T h e S e c t or N o t e b ooks we r e

de ve lop e d b y t h e E P A’ s O f f i c e of C o m p lia nc e

. Q u e s t i ons r e la t i ng t o t h e S e c t or N o t e b ook P r oje c t c a n b e dir e c t e d t o :

S e t h H e m i n w a y , C oor d i n a t o r , S e c t or N o t e book P r oj e c t U S EP A O f f i c e o f C o mp lian c e 401 M S t

. , S W (2223-A ) W a s h i n gt o n , D C 20460 (202) 564-7017

Q u e s t i ons a nd c o m m

e nt s r e ga r d ing t h e individu a l doc u m e n t s c a n b e dir e c t e d t o t h e a p p r op r i a t e s p e c ia lis t s lis t e d b e low

.
Doc u m e nt Num b e r I ndus try E P A/ 310-R -95-001. D r y Cl e a n i n g In dus t r y E P A/ 310-R -95-002. E l e c t r o n i c s a n d Co m put e r In dus t r y * E P A/ 310-R -95-003. W o o d F u r n i t u r e a n d F i xt ur e s In dus t r y EP A/ 310-R -95-004. In o r gan i c Ch e mic al In dus tr y * EP A/ 310-R -95-005. Ir o n an d S t e e l In dus tr y E P A/ 310-R -95-006. L u m b e r a n d W o o d P r o duc t s In dus t r y EP A/ 310-R -95-007. F a b r ic ate d M e tal P r o duc ts In dus tr y * EP A/ 310-R -95-008. M e tal M i n i n g In dus tr y E PA/ 310-R -95-009. Mo t o r Ve h i c l e Asse m b l y In dust r y EP A/ 310-R -95-010. N o n f e r r o us M e tals In dus tr y EP A/ 310-R -95-011. N o n

- F u e l
, N o n

- M e tal M i n i n g In dus tr y EP A/ 310-R -95-012. O r gan i c Ch e mic al In dus tr y * E P A/ 310-R -95-013. P e t r o l e u m R e f i n i n g In dus t r y EP A/ 310-R -95-014. P r in tin g In dus tr y E P A/ 310-R -95-015. P u l p a n d P a pe r In dus t r y EP A/ 310-R -95-016. R u b b e r an d P las tic In dus tr y E P A/ 310-R -95-017. S t o n e , Cl a y , G l a s s , a n d Co n c r e t e In dus t r y EP A/ 310-R -95-018. Tr an s p o r tatio n Equipme n t Cle a n i n g In d. EP A/ 310-R -97-001. A i r Tr an s p o r tatio n In dus tr y EP A/ 310-R -97-002. G r o u n d Tr an s p o r tatio n In dus tr y EP A/ 310-R -97-003. W ate r Tr an s p o r tatio n In dus tr y EP A/ 310-R -97-004. M e tal Cas tin g In dus tr y EP A/ 310-R -97-005. P h ar mac e u tic als In dus tr y EP A/ 310-R -97-006. P las tic R e s i n an d M a n

- made F i b e r In d. EP A/ 310-R -97-007. F o s s il F u e l Ele c t r i c P o w e r G e n e r atio n In d. E P A/ 310-R -97-008. S h i p b u i l d i n g a n d R e pa i r In dus t r y EP A/ 310-R -97-009. Te xtile In dus tr y E P A/ 310-R -97-010. S e c t o r N o t e book D ata R e f r e s h -1997 E P A/ 310-R -98-001. A e r o s p a c e In dus t r y E P A/ 310-R -98-002. A g r i c u l t u r a l Ch e m i c a l
, P e s t i c i d e , a n d F e r tilize r I n d u s tr y E P A/ 310-R -98-003. A g r i c u l t u r a l Cr o p P r o duc t i o n In dus t r y E P A/ 310-R -98-004. A g r i c u l t u r a l L i v e s t o c k P r o duc t i o n In d. EP A/ 310-R -98-005. O il an d G a s Explo r atio n an d P r o duc tio n In dus t r y EP A/ 310-R -98-008. L o c al G o v e r n m e n t O p e r atio n s
* S p a n i s h tr an s latio n s av ailab le

. C ontac t P h one (202) J o yc e Ch a n dl e r 564-7073 S t e v e H oove r 564-7007 Bob M a r s h a l l 564-7021 W alte r D e Ri e ux 564-7067 M ar ia M alav e 564-7027 S e t h H e m i n w a y 564-7017 S c o tt Th r o w e 564-7013 J an e En ge r t 564-5021 A n t h o n y R a i a 564-6045 J an e En ge r t 564-5021 Rob L i s c h i n s k y 564-2628 W alte r D e Ri e u x 564-7067 T o m Ri pp 564-7003 G in ge r G o tlif f e 564-7072 S e t h H e m i n w a y 564-7017 M ar ia M alav e 564-7027 S c o t t T h r o w e 564-7013 V i r g in ia L ath r o p 564-7057 V ir gin ia L ath r o p 564-7057 V ir gin ia L ath r o p 564-7057 V ir gin ia L ath r o p 564-7057 J an e En ge r t 564-5021 Emily Ch o w 564-7071 S ally S a s n e t t 564-7074 R a f a e l S a n c h e z 564-7028 A n t h o n y R a i a 564-6045 B e lin da B r e i de n b ac h 564-7022 S e th H e min w a y 564-7017 A n t h o n y R a i a 564-6045 A m y P o r t e r 564-4149

G i n a h M o r t e n s e n (913)551-7864 G i n a h M o r t e n s e n (913)551-7864 D an Ch adw i c k 564-7054

J o h n D o mb r o w s ki 564-7036

Sect o r No t e b o o k Pr o j ect iii Sept em b e r 1997P a g e iv in t e n t io n a lly le ft b l a nk

.Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try


### Tab l e o f Co n t en t s

L i s t o f T ab l e s

.............................................................. v i i

L i s t o f F i g u r e s

............................................................ v i i i

L i s t o f A c r o n ym s

........................................................... i x

I

. I N T R ODUCT I ON T O T H E S E CT OR NOT E B OOK P R OJ E C T

...................... 1 A

. S u m ma r y o f t h e S e c t o r N o t e b o o k P r o j e c t

................................. 1 B

. A d d it i o n a l I n f o r ma t i o n

............................................... 2

I I

. I N T R ODUCT I ON T O T H E P H A R M A CE UT I C A L I NDUS T R Y

..................... 3 A

. I n t r o d u c t i o n , B a c k g r o u n d
, a n d S c o p e o f t h e N o t e b o o k

....................... 3 B. Ch ar act er i zat i o n o f t h e P h ar maceut i cal I n dust r y

............................. 3 1

. P r o d u c t C h a r a c t e r i z a t i o n

........................................ 5 2

. I n d u s t r y S i z e

................................................. 6 3

. G e o g r a p h i c D i s t r i b u t i o n

........................................ 1 1 4

. E c o n o m i c T r e n d s a n d I n t e r n a t i o n a l C o m p e t i t i o n

...................... 1 3

III. INDUST R IA LPR OC E SS DE SC R I PT ION

.................................... 1 7 A

. I n dust r i a l P r o cesses i n t h e P h ar maceut i cal I n dust r y

......................... 1 7 1

. R e s e a r c h a n d D e v e l o p m e n t

..................................... 1 7 2. P r o duct i o n o f Bul k

P h ar maceut i cal S u b s t a n ces

...................... 1 9 3

. F o r m u l a t i o n , M i x i n g , a n d C o m p o u n d i n g

........................... 3 2 B

. R a w M a t e r i a l I np u t s a n d P o ll u t a n t O u t p u t s

............................... 3 8 1

. R a w M a t e r i a l s

............................................... 4 0 2

. A i r E m i s s i o n s a n d C o n t r o l S y s t e m s

................................ 4 3 3

. W a s t e w a t e r

................................................. 4 6 4

. S o l i d W a s t e s

................................................. 5 0 C

. M a n a g e m e n t o f T R I C h e m i c a l s i n t h e P r o d u c t i o n P r o c e s s

.................... 5 1

I V

. C H E M I C A L R E L E A S E A N D T R A N S F E R P R O F I L E

........................... 5 3 A

. E P A T o x i c Rel ease I n v e n t o r y f

o rt h e P h ar maceut i cal I n dust r y

................. 5 7 B

. S u m ma r y o f S e l e c t e d C h e m i c a l s R e l e a s e d

................................ 6 8 C

. O t h e r D a t a S o u r c e s

................................................. 7 2 D

. C o m p a r i s o n o f T o x i c R e l e a s e I n v e n t o r y A m o n g S e l e c t e d I n d u s t r i e s

............ 7 4

V

. P O L L U T I O N P R E V E N T I O N O P P O R T U N I T I E S

............................... 7 7 A

. M a t e r i a l S u b s t it u t i o n s

............................................... 7 9 B

. P r o c e s s M o d i f i c a t i o n s

............................................... 8 3 C

. G o o d O p e r a t i n g P r a c t i c e s

............................................ 8 7 D

. R e c y c l i n g , R e c o v e r y , a n d R e u s e

....................................... 9 0 E

. P o ll u t i o n P r e v e n t i o n R e s e a r c h

......................................... 9 2

Sect o r No t e b o o k Pr o j ect v Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try

V I

. S U M M A R Y O F A P P L I C A B L E F E D E R A L S T A T U T E S A N D R E G U L A T I O N S

...... 9 3 A

. G e n e r a l D e s c r i p t i o n o f M a j o r S t a t u t e s

................................... 9 3 B

. I n d u s t r y S p e c i f i c R e q u i r e m e n t s

....................................... 1 0 5 C

. P e n d i n g a n d P r o p o s e d R e g u l a t o r y R e q u i r e m e n t s

.......................... 1 1 0 D. Ot h e rF e der a l Regul at i o n s A f f ect in g t h e P h ar maceut i cal I n dust r y

............. 1 1 1 E

. Ot h e rS t at ut es an d Regul at i o n s A f f ect in g t h e P h ar maceut i cal I n dust r y

.......... 1 1 4

V I I

. C O M P L I A N C E A N D E N F O R C E M E N T H I S T O R Y

........................... 1 1 7 A

. P h ar maceut i cal I n dust r y Co m p l

i a n ce Hi st o r y

............................. 1 2 1 B

. C o m p a r i s o n o f E n f o r c e m e n t A c t i v i t y B e t w e e n S e l e c t e d I n d u s t r i e s

............. 1 2 3 C

. R e v i e w o f M a j o r L e g a l A c t i o n s

....................................... 1 2 8 1

. R e v i e w o f M a j o r C a s e s

........................................ 1 2 8 2. Suppl em en t a r y E n v i r o n m en t a l Pr o j ect s ( S E P s )

...................... 1 2 9

V III. C O M P L I A N C E A C TIV I TIES A N D IN ITIA TIV E S

........................... 1 3 1 A

. Se c t o r-re l a t e d Pro g ra m s a n d A c t i v i t i e s

................................. 1 3 1 B

. E P A V o l u n t a r y P r o g r a m s

........................................... 1 3 1 C

. T r a d e A s s o c i a t i o n / I n d u s t r y S p o n s o r e d A c t i v it y

........................... 1 3 8 1

. E n v i r o n m e n t a l P r o g r a m s

....................................... 1 3 8 2

. S u m ma r y o f T r a d e A s s o c i a t i o n s

................................. 1 4 0

I X

. C O N T A C T S / A C K N O W L E D G M E N T S / R E F E R E N C E S

......................... 1 4 3

Sect o r No t e b o o k Pr o j ect vi Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try


### Li sto f Tab l es

T ab l e 1: S u m ma r y S t at i s t i cs f o rt h e P h ar maceut i cal I n dust r y

........................... 8 T ab l e 2: P h ar maceut i cal I n dus t r y ( S I C 283) F ac ilit y S i z e

............................. 1 0 T ab l e 3: E m pl o ym e n t S i ze Di st r i b u t i o n f

o r Medi ci n a l s an d Bo t a n i cal s an d P h ar maceut i cal P r epar at i o n s E s t ab l i s h m e n t s

............................................. 1 0 T ab l e 4: T o p U. S

. P h ar maceut i cal Co m p an i e s b y S a l e s

.............................. 1 1 T ab l e 5: E x am pl es o f P h ar maceut i cal P r o duct s b y Bul k

Man u f act ur in g P r o cess

............ 2 0 T ab l e 6: P h ar maceut i cal Do sage F o r m s

.......................................... 3 4 T ab l e 7: S u m ma r y o f T y pi cal Mat e r i al I nput s an d P o ll u t i o n Out put s i n t h e P h ar maceut i cal I n d u s t r y

............................................................ 3 9 T ab l e 8 : S o lv e n t s U s e d i n t h e C h e m i c a l S yn t h e s i s P r o c e s s

............................ 4 1 T ab l e 9 : S o lv e n t s U s e d i n B i o l o g i c a l a n d N a t u r a l P r o d u c t E x t r a c t i o n

.................... 4 2 T ab l e 1 0 : S o lv e n t s U s e d i n F e r m e n t a t i o n P r o c e s s e s

................................. 4 2 T ab l e 11: Ch em i cal s Di sch a r g ed i n W a st ewat erb y t h e P h ar maceut i cal Man u f act ur i n g I n dust r y 4 8 T ab l e 1 2 : W a s t e w a t e r T r e a t m e n t T e c h n o l o g y T r e n d s

............................... 4 9 T ab l e 13: S o ur ce Reduct i o n an d Recy cl i n g A c t i v i t y

f

o rt h e P h ar maceut i cal s I n dust r y

....... 5 2 T ab l e 14: 1995 Rel eas es f o rP h ar maceut i cal F ac ilit ie s ( S I C 2833 & 2834) i n T R I

.......... 5 8 T ab l e 15: 1995 T r an s f er s f o r P h ar maceut i cal F ac ilit ie s ( S I C s 2833 & 2834) i n T R I

......... 6 2 T ab l e 16: T o p 10 T R I Rel easi n g P h ar maceut i cal Man u f act ur i n g F ac ilit ie s

................ 6 6 T ab l e 1 7 : T o p 1 0 T R I R e le a s in g F a c ilit ie s R e p o r t in g P h a r m aceut i cal M a n u f a c t u r i n g S I C C o d e s t o T R I......................................... 6 7 T ab l e 1 8 : A i r P o ll u t a n t R e l e a s e s b y I n d u s t r y S e c t o r ( t o n s / y e a r )

........................ 7 3 T ab l e 1 9 : T o x i c s R e l e a s e I n v e n t o r y D a t a f o r S e l e c t e d I n d u s t r i e s

....................... 7 6 T ab l e 20: F i v e

- Y earE n f o r cem en t an d Co m p l

i a n ce S u m ma r y f

o rt h e P h ar maceut i cal I n dust r y 121 T ab l e 2 1 : F i v e

- Y e a r E n f o r c e m e n t a n d C o m p l

i a n c e S u m ma r y f o r S e l e c t e d I n d u s t r i e s

....... 1 2 4 T ab l e 2 2 : O n e

- Y e a r E n f o r c e m e n t a n d C o m p l

i a n c e S u m ma r y f o r S e l e c t e d I n d u s t r i e s

....... 1 2 5 T ab l e 23: F i v e

- Y earI n spect i o n an d E n f o r cem en t S u m ma r y b y S t at ut e f o rS e l ect ed I n dust r i e s 126 T ab l e 24: On e- YearI n spect i o n an d E n f o r cem en t S u m ma r y b y S t at ut e f o rS e l ect ed I n dust r i e s 127 T ab l e 25: P h ar maceut i cal I n dust r y P ar t i c i p at i o n in t h e 33/ 50 P r o g r a m

.................. 1 3 3

Sect o r No t e b o o k Pr o j ect vi i Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try


### Li sto f F i gu res

F i g u r e 1 : P e r c e n t o f T o t a l V a l u e o f S h i p m e n t s b y S e c t o r

.............................. 8 F i gur e 2: E m pl o ym e n t i n t h e P h ar maceut i cal I n dust r y

................................ 9 F i gur e 3: Geo g r a ph i c Di st r i b u t i o n o f P h ar maceut i cal F ac ilit ie s ( S I C 2833 an d 2834)

........ 1 1 F i gur e 4: W o r l d S a l e s o f P h ar maceut i cal s , 1995

.................................... 1 4 F i g u r e 5 : S i m p l

i f

i e d P r o c e s s F l o w D i a g r a m f o r C h e m i c a l S yn t h e s i s

..................... 2 2 F i gur e 6: T y pi cal Desi gn o f a Ke t t l e- T y pe Bat c h React o r

............................. 2 3 F i g u r e 7 : C r o s s

- S e c t i o n o f T y p i c a l T o p

- S u s p e n d e d C e n t r i f u g a l F i l t e r

................... 2 5 F i g u r e 8 : C r o s s

- S e c t i o n o f T y p i c a l T u m b l e D r y e r

.................................. 2 7 F i g u r e 9 : S i m p l

i f

i e d P r o c e s s F l o w D i a g r a m f o r N a t u r a l / B i o l o g i c a l E x t r a c t i o n

............. 2 9 F i g u r e 1 0 : S i m p l

i f

i e d P r o c e s s F l o w D i a g r a m f o r t h e F e r m e n t a t i o n P r o c e s s

................ 3 0 F i g u r e 1 1 : S i m p l

i f

i e d P r o c e s s F l o w D i a g r a m f o r C o m p o u n d in g a n d F o r m u l a t in g

........... 3 2 F i g u r e 1 2 : S u m ma r y o f T R I R e l e a s e s a n d T r a n s f e r s b y I n d u s t r y

........................ 7 5

Sect o r No t e b o o k Pr o j ect v iii Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try

Li sto f Acr o n y m s

A F S - A I R S F a c ilit y S u b s ys t e m ( C A A d a t ab a s e ) A I RS - A er o m et r i c I n f o r mat i o n Ret r i e v a l S y st em ( C A A dat ab a se) BI F s - B o i l e r s an d I n dust r i a l F u r n aces ( RCRA ) BOD - B i o ch em i cal Ox y g en Dema n d C AA - C l e a n Ai r Ac t C AAA - C l e a n Ai r Ac t Am e n d m e n t s o f 1990 CDE R - Cen t erf o r Dr ug E v al uat i o n an d Resear ch C E R C L A - C o m p r e h e n s i v e E n v i r o n m e n t a l R e s p o n s e , C o mp e n s a t i o n a n d L i ab ilit y A c t CE RCLI S - C E RCLA I n f o r mat i o n S y st em C F C s - C h l or of l u or oc a r b o n s C O - C a r bo n M o no xi d e COD - C h e m i cal Ox y g en Dema n d C S I - C o mmo n S e n s e I n it ia t i v e C T M - C lin ic a l T r ia l M a t e r i a l C W A - C l e a n Wa t e r Ac t D& B - D un an d Br adst r eet Mar k et i n g I n dex E L P - E n v i r o n m en t a l L eader sh i p P r o g r a m E P A - U n i t e d S t at es E n v i r o n m en t a l P r o t ect i o n A g en cy E P C R A - E m e r g e n c y P l a nni ng a n d C o m m

u nit y R i g h t

- t o

- K no w Ac t F D A - F o o d a n d D r u g A d min is t r a t io n F I F R A - F eder al I n sect i c i d e, F u n g i c i d e, an d Ro den t i c i d e A c t F I N D S - F a c ilit y I n d e x i n g S y s t e m HA P s - H azar do us A i rP o ll u t a n t s ( C A A ) HS DB - H azar do us S u b s t a n ces Dat a Bank I D E A - I n t egr a t e d Dat a f

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Sect o r No t e b o o k Pr o j ect ix Sept em b e r 1997Se c t or N o te book P r oje c t P h arm a c e u tic a l I ndus try

N P D E S - N a t io n a l P o llu t i o n D i s c h a r g e E limin a t io n S y s t e m ( C W A ) N P L - N a t io n a l P r io r it i e s L i s t NRC - N at i o n a l Resp o n se Cen t er N SPS - N e w So urc e Pe rf o r ma n c e St a n da rds (C A A ) OA R - O f f i ce o f A i r an d Radi at i o n OE CA - O f f i ce o f E n f o r cem en t an d Co m p l

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i ssi o n s S I C - S t a n d ar d I n dust r i a l Cl assi f i cat i o n SO 2 - S u l f u r D i o x i d e SO
x - S u l f u r O x i d e s T O C - T o t al Or gan i c Car b o n T R I - T o x i c Rel ease I n v e n t o r y T R I S - T o x i c Rel ease I n v e n t o r y S y st em T CRI S - T o x i c Ch em i cal Rel ease I n v e n t o r y S y st em T S C A - T o x i c S u bs t a nc e s C o nt r o l Ac t TSS - T o t a l Sus p e n de d So l i d s U I C - U nd e r g r o u nd I n j e c t i o n C o nt r o l ( S D W A) US T - U n d er g r o u n d S t o r ag e T a nk s ( RCRA ) VOCs - V o l at i l e Or gan i c Co m p o u n d s

Sect o r No t e b o o k Pr o j ect x Sept em b e r 1997P h arm a c e u tic a l I ndus try S e c t or N o te bookP r oje c t

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n e w po l i c y di r ect i o n ar e t h at po ll u t a n t r e l eases t o each en v i r o n m en t a l m e di um ( a i r , wat e r an d l a n d ) af f ect each o t h e r , an d t h at en v i r o n m en t a l st r a t e gi es m u st

a c t i v e l y i d e n t i f y a n d a d d r e s s t h e s e i n t e r-re l a t i o n s h i p s b y d e s i g n i n g p o l i c i e s f o r t h e “ w h o le ” fa c ilit y. O n e w a y t o a c h ie v e a

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r e l a t e d t o pi cs. F o r t h e pur po ses o f t h i s pr o j ect , t h e key el em en t s ch o s en f

o r in c l u s io n a r e : g e n e r a l in d u s t r y in fo r ma t io n ( e c o n o mic a n d g e o g r a p h ic ) ; a de s c r i p t i o n o f i n dus t r i a l pr o ces s e s ; po ll u t i o n o u t put s ; po ll u t i o n pr ev en t i o n
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a le n g t h y v o lu me

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ma n a g e ab le d o c u me n t , t h is pr o j ect f o cus e s o n pr o v i d i n g sum ma r y i n f o r mat i o n f

o r each t o pi c. T h i s f o r mat pr o v i d es t h e r eader wit h a syn o psi s o f each i ssue, an d r e f e r e n ces i f

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r e sear ch ed f r o m a v a r i et y o f so ur ces, an d wer e usuall y

co n d en sed f r o m m o r e det a i l e d so ur ces. T h i s appr o ach all o wed f o ra wi de co v e r a ge o f act i v it i e s t h at

can b e f u r t h e r ex pl o r ed b a sed upo n t h e cit a t i o n s an d r e f e r e n ces l i s t e d at t h e
en d o f t h i s pr o f i l e

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, each n o t e b o o k

wen t t h r o ugh an ex t e r n al r e v i ew pr o cess. T h e Of f i ce o f Co m p l

i a n c e appr eci at es t h e ef f o r t s o f all t h o s e wh o par t i c i p at e d i n t h i s pr o cess wh o

Sect o r No t e b o o k Pr o j ect 1 Sept em b e r 1997P h arm a c e u tic a l I ndus try S e c t or N o te bookP r oje c t

en ab l e d us t o dev e l o p m o r e co m p l e t e , acc u r at e an d up- t o

- d at e sum ma r i es. Man y o f t h o s e wh o r e v i ewed t h i s n o t e b o o k ar e l i s t e d as co n t act s i n S ect i o n X an d ma y b e s o ur ces o f addit i o n al i n f o r mat i o n

. T h e i n di v i dual s an d gr o ups
on th i s l i s t d o n o t n e c e s s a r i l y c o n c u r w ith a ll s t a t e m e n ts w ith in th i s n o te b ook

.
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P r oviding C o m m e nts

OE C A ’ s Of f i ce o f C o m p l

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co m put er di sk t o t h e E P A Of f i ce o f Co m p l

i a n ce, S ect o r No t e b o o k P r o j ect , 401 M S t

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, W a s h in gt o n , DC 20460. C o m m

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. F o ll o w i n st r u ct i o n s i n A ppen d i x A f

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. On ce y o u h a v e l o gged in , pr o cedur es f o r upl o a di n g t e x t ar e av ai l ab l e f r o m t h e
o n

- l i n e E n v i r o $en $ e Hel p S y st em

. Adapt i ng Not e book s t o P a r t icul ar Needs

T h e s c op e of th e i n d u s tr y s e c t or d e s c r i b e d i n th i s n o te b ook a p p r ox i ma te s th e
n a t i o n a l o c c u r r e n c e o f fa c ilit y t y p e s w it h in t h e s e c t o r

. I n ma n y in s t a n c e s , i n dus t r i e s wit h i n s p eci f i c geo g r a ph i c r e gi o n s o r s t a t e s ma y h a v e un i que ch ar act er i s t i cs t h at ar e n o t f u ll y

capt u r e d i n t h ese p r o f i l e s. T h e Of f i ce o f C o m p l

i a n ce en co ur ages st at e an d l o cal en v i r o n m en t a l agen ci es an d o t he r gr o ups t o s uppl em en t o r r e

- p ackage t h e i n f o r mat i o n i n cl uded i n t h i s n o t e b o o k t o in c l u d e mo r e s p e c i fic in d u s t r ia l a n d r e g u l a t o r y in fo r ma t io n t h a t ma y b e
av ai l ab l e. A ddit i o n all y , i n t e r e s t ed s t at es ma y wan t t o s uppl em en t t h e "S um ma r y o f A ppl i cab l e F e der a l S t at ut es an d Regul at i o n s " sect i o n wit h st at e
an d l o cal r e qui r e m e n t s. Co m p l i a n ce o rt ech n i cal assi st an ce pr o v i d er s ma y
a l s o w a n t t o d e v e lo p t h e " P o llu t i o n P r e v e n t i o n " s e c t io n in mo r e d e t a il. P l e a s e
co n t act t h e appr o p r i at e speci al i s t l i s t e d o n t h e o p en i n g page o f t h i s n o t e b o o k if yo u r o ffic e is in t e r e s t e d in a s s i s t in g u s in t h e fu r t h e r d e v e lo p m e n t o f t h e in fo r ma t io n o r p o lic ie s a d d r e s s e d w it h in t h is v o lu me

. I f yo u a r e in t e r e s t e d in

a s s i s t i n g i n t h e dev e l o pm en t o f n e w n o t e b o o k s f o r sect o r s n o t al r eady

co v e r e d, pl eas e co n t act t h e Of f i ce o f C o m p l

i a n ce at 202- 564- 2395.

Sect o r No t e b o o k Pr o j ect 2 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

I I

. I N TRODUCTI O N TO THE P H ARM ACEUTI CAL I NDUS TRY

T h i s sect i o n pr o v i d es b ackgr o u n d i n f o r ma t i o n o n t h e si ze, geo g r aph i c di s t r i b u t i o n , em pl o ym e n t , pr o duct i o n , s a l e s , an d eco n o m i c co n d it i o n o f t h e p h a r ma c e u t i c a l in d u s t r y. F a c ilit ie s d e s c r i b e d w it h in t h is d o c u me n t ar e d e s c ri b e d i nt e rm s o f t h e i r St a n d a rd In d u s t r i a l C l a s s i f i c a t i o n (SIC ) c o d e s

.
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T h e S t an dar d I n dust r i a l Cl assi f i cat i o n ( S I C ) co de est ab l i s h e d b y t h e U. S

. Of f i ce o f M a n a gem e n t an d B udget ( O M B ) t o t r ack t h e f l o w o f go o d s an d

s e r v i ces wit h i n t h e e c o no m y

i s 283 f o r t h e ph ar maceut i cal s in dus t r y

. T h e i n dus t r y i s f u r t h e r cat ego r i zed b y f

o ur 4- di git SI C co des co n s i s t i n g o f :

M e dicinals and B o tanicals ( S I C 2833) P har maceutical P r epar ations ( S I C 2834) I

n V i vo and in V itr o Diagnos tic Subs tances ( S I C 2835) B i ological P r oducts
, except diagnos tics ( S I C 2836)

OMB i s i n t h e pr o cess o f ch an gin g t h e S I C co de sy st em t o a sy st em b a sed o n
s imila r p r o d u c t i o n p r o c e s s e s c a lle d t h e N o r t h A m e r ic a n I n d u s t r ia l Cl assi f i cat i o n S y st e m ( N A I CS )

. I n t h e NA I C sy st em , m e di ci n a l s an d b o t a n i cal s ar e cl as s i f i ed as NA I C 325411 an d ph ar maceut i cal pr epar at i o n s ar e cl as s i f i ed as NA I C 325412.

A cco r d i n g t o t h e U. S. Ce ns us of M anuf actur e r

s , i n 1992 t h e M e di ci n a l s an d Bo t a n i cal s an d P h ar maceut i cal P r epar at i o n s cat ego r i e s acco un t e d f o r 64 per cen t o f e s t a bl i s h m en t s an d 81 per cen t o f t h e v a l u e o f sh i p m e n t s i n t h e i n dust r y

. I n co m p ar i s o n , t h e I n Vit r o an d I n Vi v o Di agn o st i c P r o duct s an d Bi o l o g i cal P r o duct s cat ego r i e s ar e r e l a t i v e l y

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s h ip me n t s in t h e in d u s t r y. I n g e n e r a l, t h e in d u s t r ia l p r o c e s s e s a n d s u b s e q u e n t

en v i r o n m en t a l i m p act s o f t h e I n Vit r o an d I n Vi v o Di agn o st i c P r o duct s an d Bi o l o g i cal P r o duct s cat ego r i e s ar e di f f e r e n t f r o m t h o s e o f t h e Medi ci n a l s an d Bo t a n i cal s an d P h ar maceut i cal P r epar at i o n s cat ego r i e s. T h i s n o t e b o o k

co n cen t r at es o n t h e t w o l a r g er cat ego r i e s ( S I C 2833 an d 2834) wit h i n SI C 283.

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A s def i n e d b y it s S I C Co de, t h e ph ar maceut i cal s i n dus t r y ( S I C 283) co n s i s t s
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m

e di ci n a l ch em i cal s an d ph ar maceut i cal pr o duct s

. T h e i n dust r y al so i n cl udes est ab l i s h m en t s t h at f o r m ul at e ph ar maceut i cal pr o duct s an d ar e i n v o lv ed in g r in d i n g , g r a d in g , a n d millin g o f b o t a n i c a l p r o d u c t s

. T h e C e n s u s o f Man u f act ur er s def i n e s an est ab l i s h m en t as a sin g l e p h y s i c a l l o cat i o n o ra

Sect o r No t e b o o k Pr o j ect 3 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

fa c ilit y w h e r e ma n u fa c t u r in g o c c u r s

. I f mo r e t h a n o n e d i s t i n c t lin e o f

ma n u f act ur i n g o ccur s at t h e s a m e l o cat i o n , t h e Bur eau o f Cen s us r e qui r e s separ a t e r e po r t s f o r each act i v it y

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it s i n du s t r i al pr o ces s e s an d r e gul at o r y r e qui r e m e n t s

. F o r ex am pl e, i n it s i n dust r i a l pr o cesses, t h e ph ar maceut i cal s i n dust r y uses m o r e b a t c h o p er at i o n s t h an t h e ch em i cal s i n dust r y as a wh o l e. S i n ce so m e o f t h e b u l k

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l o w.

T h e ph ar maceut i cal s i n dust r y al so r ecei v e s ex t e n s i v e r e gul at o r y o v er si gh t b y t h e U. S. F o o d an d Dr ug A d m i n i s t r at i o n ( F DA )

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wh i c h 53 wer e n e w m o l ecul a r en t it i es. A cco r d i n g t o t h e Co n g r e ssi o n al Of f i ce o f T ech n o l o gy A s s e s s m en t ( O T A ) i n 1993, it co s t s an av er age o f $359 millio n t o d e v e lo p a

n e w d r u g a n d c o mp le t e t h e d r u g a p p r o v a l p r o c e s s

. T o t a l dr ug dev e l o pm en t an d agen cy r e v i e w t i m e av er aged 15. 3 y ear s f o r dr ugs appr o v ed f r o m 1990 t h r o ugh 1995. M o r e i n f o r mat i o n o n t h e t y pi cal i n dus t r i a l pr o ces s e s an d r e gul at o r y r e qui r e m e n t s o f t h i s i n dus t r y i s pr o v i d ed i n Sect i o n s III a n d V I , re s p e c t i v e l y

.
W h en a ph ar maceut i cal co m p an y di sco v er s a co m p o u n d t h at ma y h a v e
me d i c a l p o t e n t ia l, t h e c o mp a n y u s u a lly a p p lie s fo r a

p a t e n t

. P a t e n t s a r e v a lid f o r 20 y ear s f r o m t h e dat e o f appl i cat i o n

. A n y dr ug ma de f r o m t h e co m p o u n d

m a y b e m a r k et ed o n l y

af t e r a p p r o v al b y t h e f e der a l F o o d an d Dr ug A d min is t r a t io n ( F D A )

. T h e d r u g d e v e lo p m e n t p r o c e s s , b e g i n n i n g w it h in it ia l t o x i c o lo g y t e s t in g , fo llo w e d b y c lin ic a l t r ia ls fo r s a fe t y a n d e ffe c t iv e n e s s , a n d

r e v i ew o f t h e appl i c a t i o n by t h e F D A av er ages f i f

t een y ear s. W h en t h e
co m p an y ’ s pat e n t o r per i o d o f ex cl usi v it y h a s ex pi r e d, o t h e r co m p an i e s ma y
r e l y

o n t h e o r i g i n al ma n u f act ur er ’ s dat a o n saf e t y an d ef f ect i v en ess t o o b t a i n appr o v al t o ma r k e t a gen e r i c v e r s i o n o f t h e dr ug. C o m p an i e s wan t i n g t o
ma n u f act ur e t h e s a m e dr ug o n ce it i s o f f

- pat e n t ar e r e qui r e d t o o b t a i n F D A

m a r k et i n g appr o v al
, b a sed o n ev i d en ce t h at t h e gen e r i c v e r s i o n i s

“ b i o equi v a l e n t , ” i

. e. , di f f e r s i n t h e r a t e an d e x t e nt o f dr ug ab s o r p t i o n b y n o
m

o r e t h an 25 per cen t n o r l e ss t h an t h e 20 per cen t f r o m t h e o r i g i n al dr ug ( F DA
, 1996)

. W h i l e co m p an i e s t h a t s p e c i a l i ze i n t h e dev e l o pm en t an d

ma r k e t i n g o f br a n d

- na me , inno va t o r d r u g s 1 ma y ha ve s u bs i d i a r i e s t h a t

1 Th e te r m “ b r a n d n ame ” is u s e d in te r c h a n g e a b l y w ith “ p io n e e r d r u g ” o r “ i n n o v ato r ’ s d r u g p r o d u c t”. Th e te r m s
r e f l e c t th e f a c t th at th e d r u g p r o d u c t is th e f i r s t to c o n tain a p a r tic u lar ac tiv e in g r e d ie n t o r in g r e d ie n t s to r ecei v e FDA a p p r o v a l f o r a sp e c i f i e du s e

. T h e t e r m “ g e n e r i c ” d r u g i s u s e dt o d e sc r i b e ap r o d u c t t h a t c o n tain s th e s ame
ac tiv e in g r e d ie n t s b u t n o t n e c e s s a r ily th e s ame e x c i p i e n ts ( i n a c tiv e in g r e d ie n t s ) as a s o

- c alle d “ p io n e e r d r u g ”

.
Sect o r No t e b o o k Pr o j ect 4 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

ma n u f act ur e gen e r i c pr o duct s , m o s t gen e r i c dr ug co m p an i e s do n o t co n duct

r e s ear ch i n t e n d ed t o i d en t i f y

an d dev e l o p i n n o v a t o r dr ugs ( P h R M A
, 1997)

.
Because o f t h e h i gh co st an d t i m e t o appr o v al
, ef f ect i v e pat e n t pr o t ect i o n i s
an essen t i a l co m p o n en t i n t h e deci si o n t o i n v e st i n dr ug deve l o p m e n t an d

ma r k e t in g

. T h is is e s p e c i a ll y t r u e fo r in t e r n a t io n a l c o mp a n ie s in t e r e s t e d in

ma r k et i n g dr ugs i n sev e r a l co un t r i e s, each wit h it s o w n appr o v al pr o cedur e
an d ma r k et i n g r e q u i r e m e n t s. W h i l e t h e I n t e r n at i o n a l Co n f er en ce o n H a rm o n i z a t i o ni s p r o p o s in g h a rm o n i z e d ru l e s f o r d r u g re g i s t ra t i o na n d appr o v al f

o rE u r o pe, Ja p a n an d t h e Un it ed S t at es, each co un t r y r e t a i n s it s
o w n appr o v al sy st em

. I n o t h e r co un t r i e s, especi all y

dev e l o pi n g co un t r i e s, t h e i ssue o f adequat e pat e n t pr o t ect i o n i s a cen t r al co n cer n o f ph ar ma c e u t i cal

ma n u f act ur er s ( P h R M A
, 1997)

.
Di sco v er y o f n e w co m p o u n d s f o ll o wed b y f

u r t h e rr e sear ch an d dev e l o pm en t ( R & D ) i s o n e o f t h e pr i ma r y f

u n c t i o n s o f t h e i n dust r y

. T h e ph ar maceut i cal pr o duct i o n pr o cess st ar t s wit h an ex t e n s i v e r e sear ch st age, wh i c h c a n l a st

sev e r a l y ear s. F o ll o wi n g t h e di sco v er y o f a n e w dr u g t h at appear s t o h a v e ef

f i cacy i n t r eat i n g o r pr ev en t i n g illn e s s , p r e

- c lin ic a l t e s t s a n d c lin ic a l t r ia ls a r e
co n duct e d. T h en a New Dr ug A ppl i cat i o n ( NDA ) i s s u b m it t e d t o t h e F D A f o r ap p r o v al

. A cco r d i n g t o a pr i ma r y t r ade asso ci at i o n f

o r ph ar maceut i cal

co m p an i e s pr o d u c i ng b r an d n a m e dr ugs, t h e P h ar maceut i cal Resear ch an d Man u f act ur er s o f A m er i ca ( P h R MA )
, it t a kes an av er age o f 15 y ear s t o b r in g
a n e w dr ug t o ma r k et , f r o m t i m e o f di s c o v er y t o appr o v al ( P h R M A
, 1996)

. I t i s o n l y

af t e rF D A appr o v al h a s b een secur e d t h at ma r k et di st r i b u t i o n i n t h e U

. S

. c a n be g i n.

T h e co m p et it i o n f

o r di sco v er i n g n e w dr ugs an d b r in gi n g t h em t o ma r k et i s
ex t r em el

y h i gh

. A s a r e sul t , a si gn i f i can t pr o p o r t i o n o f t h e i n dust r y ’ s sal e s ar e
r e i n v e st ed i n t o r e sear ch an d dev e l o pm en t ( R & D )

. A cco r d i n g t o P h RMA
, t o t a l R & D e x p e n d it u r e s , b o t h d o me s t ic a lly a n d ab r o a d
, b y it s me mb e r s , w ill b e cl o s e t o $19 b illio n d o lla r s in 1997. Ph R M A es t ima t e s t h at o v er 21% o f t o t a l s a le s w ill b e r e in v e s t e d in t o R & D b y it s me mb e r s ( P h R M A
, 1997)

.
I I

. B

. 1. P r oduct Char act e ri z a t i on

T h e ph ar maceut i cal i n dust r y ma n u f act ur es b u l k

sub s t a n ce ph ar mace u t i cal i n t e r m edi a t e s an d act i v e i n gr edi e n t s wh i c h ar e f u r t h e r pr o cessed i n t o f i n i sh ed pr o duct s

.

M e dicinals and B o tanicals ( S I C 2833)

Co m p an i e s i n t h e Medi cin a l s an d Bo t a n i cal s i n dust r y cat ego r y ar e pr i ma r i l y
en gaged i n 1) ma n u f act ur i n g b u l k

o r gan i c an d i n o r gan i c m e di cin a l ch em i cal s
a n d t h e i r d e r i v a t i v e s a n d 2 ) p r o c e s s i n g ( g r a d i n g , g r in d i n g , a n d millin g ) b u lk b o t a n i cal dr ugs an d h e r b s

. T h e i n d u s t r y i s ma de up o f es t ab l i s h m en t s o r

Sect o r No t e b o o k Pr o j ect 5 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

fa c ilit ie s t h a t ma n u fa c t u r e p r o d u c t s o f n a t u r a l o r ig in
, h o r m o n a l p r o d u c t s , a n d b a si c v it a m i n s, as well as t h o s e t h at i s o l at e act i v e m e di ci n a l pr in ci pal s such as al

kal o i d s f r o m b o t a n i cal dr ugs an d h e r b s ( O M B
, 1987)

. T h es e s u b s t a n ces ar e used as act i v e i n gr e d i e n t s f o rt h e P h ar maceut i cal P r epar at i o n s i n dust r y cat ego r y

. Co m p an i e s o f t e n pr o duce b o t h Medi c i na l s a n d Bo t a n i cal s an d P h ar maceut i cal P r epar at i o n s at t h e sam e f ac ilit y.

P har maceutical P r epar ations ( S I C 2834)

T h e P h ar maceut i cal P r epar at i o n s i n dust r y cat ego r y i s ma de up o f co m p an i e s t h at ma nu f act ur e, f ab r i cat e, an d pr o cess r a w ma t e r i al s i n t o ph ar maceut i cal pr epar at i o n s f o rhu ma n an d v e t e r i n a r y uses. F i n i sh ed pr o duct s ar e s o l d i n
v a r i o u s do sage f o r m s in cl udi n g , f o r ex am pl e, t ab l et s , capsul e s, o i n t m e n t s,
so l u t i o n s, suspen si o n s, an d po wder s. T h ese ar e 1) pr epar at i o n s ai m e d f o r use
ma i n l y b y den t al
, m e di cal
, o rv e t e r i n a r y pr o f essi o n al s, an d 2) t h o s e ai m e d f o r
us e b y pat i en t s an d t h e gen e r a l p u b l i c ( O M B
, 1987)

. A m o r e in dept h di scussi o n o f t h ese f i n i sh ed pr o duct s i s pr o v i d ed i n S ect i o n I I I

. A. 3

. P h ar maceut i cal pr o duct s al so ar e o f t e n cl assi f i ed i n t e r m s o f t h ei r av ai l ab ilit y t o t h e gen e r a l pub l i c

.
Bo t h pr escr i p t i o n an d o v er

- t h e

- c o u n t er ( O T C ) dr ugs ar e av ai l ab l e t o t h e pub li c

. P r escr i p t i o n dr ugs can b e pur ch ased o n l y

wit h a pr escr i p t i o n f

r o m a li cen sed h eal t h

car e pr o f essi o n al aut h o r i zed t o pr e s c r i b e, wh i l e OT C dr ugs
ma y b e p u r c h a s e d w i t h o u t a

p r e s c r ip t i o n

. T h e F D A w ill c o n s id e r a p p r o v in g t h e swit ch o f a dr ug f r o m pr escr i p t i o n t o OT C wh en t h e ma n u f act ur er pr esen t s ev i d en ce t h at co n s um er s can sel f

- d i a gn o s e t h e co n d it i o n f

o r wh i c h t h e dr ug i s appr o v ed, i

. e. , co l d o r seaso n al all e r g y , an d di r ect i o n s f o r use can b e wr i t t e n f

o rt h e co n s um er( P h R M A
, 1997)

.

I

n V i vo and I n V itr o Diagnos tic Subs tances ( S I C 2835) and B i ological P r oducts ( S I C 2836)

T h e I n Vi v o an d I n Vit r o Di agn o s t i c Sub s t a n ces i n dus t r y cat ego r y ( S I C 2835) in c l u d e s fa c ilit ie s t h a t ma n u fa c t u r e in v i v o ( t e s t e d in s i d e a

liv in g o r g a n i s m )

an d i n v it r o ( t est e d o u t s i d e o f a l i v i n g o r gan i sm ) di agn o st i c sub s t a n ces. T h ey pr o duce ch em i cal
, b i o l o g i cal
, an d r a di o act i v e sub s t a n ces used in di agn o sin g
an d m o n i t o r in g h eal t h

. T h e B i o l o g i cal Pr o duct s in dus t r y cat ego r y ( S I C 2836) pr o duces b act er i a l an d v i r u s v acci n e s, t o x o i d s, ser u m s , pl asma s , an d o t h e r bl o o d d e r i va t i ve s f o r hu ma n a n d ve t e r i na r y u s e , o t he r t h a n i n vit r o a n d in vi vo di agn o s t i c s u b s t a n ces ( O M B
, 1987)

.
I I

. B

. 2. I ndus try Siz e

A cco r d i n g t o t h e U. S

. C e n s us of M anuf actur e s f o rt h e ph ar maceut i cal s i n dus t r y as a wh o l e ( S I C 28 3 )
, i n 1992 t h er e wer e a t o t a l o f 1, 425

e s tab l i s h m e n ts e m p l oyi n g 194, 000 peo p l e ( e x c l udi n g Puer t o R i co )

. I t i s p o s s i b l e t h a t s o me o f t h e s ma lle r fa c ilit ie s id e n t i fie d b y t h e C e n s u s a r e a c t u a lly

Sect o r No t e b o o k Pr o j ect 6 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

s a le s , ma r k e t in g o r d i s t r i b u t i o n c e n t e r s in w h ic h n o ma n u fa c t u r in g o p e r a t io n s t a ke pl ace. S u ch po ssi b l e m i s cl assi f i cat i o n s h a v e n o si gn i f i can t ef f ect o n t h e
cen sus st at i s t i cs o t h e rt h an o n t h e n u m b ero f co m p an i e s an d est ab l i s h m en t s

. ( U

. S

. Depar t m e n t o f C o m m

e r ce, 1995) T h e v a l u e o f t o t a l s h i p m e n t s was
o v er $67 b illio n ( s e e T ab l e 1 )

. P h a r maceut i cal P r epar at i o n s ( S I C 2834) was t h e l a r g est sect o ri n t e r m s o f n u m b ero f f

aci l i t i e s ( 48 per cen t )
, em pl o ym e n t ( 6 3 p e r c e n t )
, a n d v a lu e o f s h ip me n t s ( 7 5 p e r c e n t )

. T h e r e ma in in g fa c ilit ie s , e m pl o ym e n t , an d v a l u e o f s h i p m e n t s wer e di v i ded ev en l y

am o n g t h e
r e ma in in g s e c t o r s w it h in t h e in d u s t r y. O n e e x c e p t i o n is t h e I n V i v o a n d I n Vit r o Di agn o s t i c Pr o duct s s ect o r ( S I C 2835) wh i c h cl ai m s a h i gh er po r t i o n
o f

em pl o ym e n t t h an SI C co des 2833 an d 2836. F i gur e 1 di s p l a y s t h e v a l u e
o f

sh i p m e n t s b y sect o r , an d F i gur e 2 di spl a y s em pl o ym e n t b y sect o r

.
A

r e l a t i v e l y

si gn i f i can t n u m b ero f ph ar maceut i cal est ab l i s h m en t s ar e l o cat ed in

P u e r t o R i c o

. T h is i s i n p a r t t h e r e s u lt o f t h e fe d e r a l g o v e r n me n t ’ s p o lic y deci si o n t o en co ur age j o b cr eat i o n b y o f f e r i n g t a x i n cen t i v e s t o ma n u f act ur er s t o l o cat e n e w pl an t s i n P u e r t o R i co

. A 1996 t a x l a w ph as es

- o ut t h o s e t a x i n cen t i v e s o v ert h e n e x t t e n y ear s.

T h e e ffe c t s o f t h e t a xin c e n t i v e a r e illu s t r a t e d b y t h e c o n c e n t r a t io n o f ph ar maceut i cal pl an t s i n P u e r t o Ri co

. A cco r d i n g t o t h e 1992 E c o n o m i c Cen s us o f Out l yin g A r eas, wh i c h co v e r s st at i s t i cs f o r P u er t o Ri co , t h er e wer e a t o t a l o f 88 est ab l i s h m en t s i n P u er t o Ri co

. Of t h ese 88, 74 e s t ab l i s h m en t s
wer e i n t h e P h ar maceut i cal P r epar at i o ns i n d u st r y , 8 wer e i n t h e Medi ci n a l s
an d Bo t a n i cal s i n dust r y , an d t h e r e ma in i n g si x est ab l i s h m en t s wer e i n t h e I n Vit r o an d I n Vi v o Di agn o s t i c Pr o duct s i n dus t r y , an d t h e B i o l o g i cal Pr o duct s , ex cept di agn o st i c sub s t a n ces i n dust r y

. T h e t o t a l v a l u e o f sh i p m e n t s o f t h e 88

es t ab l i s h m en t s l o cat ed i n Puer t o R i co was ab o u t $12 b illio n

. P h a r maceut i cal P r epar at i o n s acco un t e d f o r ab o u t 92 per cen t o f t h i s

. T h e ph ar maceut i cal i n d u s tr y i n P u e r to R i c o e m p l oy e d ab ou t 2 5
, 000 pe op l e i n th e 8 8

es t ab l i s h m en t s i n 1992.

Sect o r No t e b o o k Pr o j ect 7 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

Sect o r No t e b o o k Pr o j ect Sept em b e r 1997 8 

### F i gu re 1: P ercen t o f To t a l Val u e o f S h i p m e n t s b y S ect o r

Sour c e : 1992 U

. S. Ce ns us of Manuf ac t u re r s

. 

### Tab l e 1: S u m m a ry S t at i s t i cs f o r t h e P h arm a ceu t i cal In d u st ry 5 0 S T ATES PUERTO RICO

Indu st r y N u m b er o f Es tab l i s h m e n ts N u m b er o f C o m p a n ies 1 V a lu e o f Shi pm e n t s ( m illio n s o f

d o lla rs ) 2 Em p l o y m e n t (000' s ) N u m b er o f Es tab l i s h m e n ts V a lu e o f Shi pm e n t s ( m illio n s o f

d o lla rs ) 2 E m pl o y m e nt (000' s )

SI C 2833 225 208 6, 438 13 8 N /A 3 N/A 3
SI C 2834 691 585 50, 418 123 74 11, 097 22 SI C 2835 234 205 6, 838 40 5 477 1 SI C 2836 275 193 3, 974 18 1 N /A 3 N/A 3
Total 1, 425 1, 191 67, 668 194 88 11, 924 25 S o u r ce: 1992 Ce ns us of Manuf ac t u re r s , Indus t r y Se r i e s : D r ugs , U S D e par tm e n t of Com m e r c e , B u re au of t h e Ce ns us , 1995 and 199 2 E c onom ic Cens us of O u tlying Areas , Manufacture r s : P u er to Rico, U S

D e par tm ent of Com m e r ce, B u re au of t h e Ce ns us , 1994.

1 D e f i n e d as a b u s i n e s s o r g a n izatio n c o n s is tin g o f o n e e s tab lis h m e n t o r mo r e u n d e r c o mmo n o w n e r s h i p o r c o n t r o l.

2 V alu e o f all p r o d u c ts an d s e r v ic e s s o ld b y e s tab lis h m e n ts in th e p h ar mac e u tic als in d u s tr y

. 3 C e r tain c e n s u s d ata ar e n o t av ailab le f o r P u e r to Ri c o . I n f o r matio n is w ith h e ld to av o i d d i s c lo s i n g d ata f o r in d i v i d u a l f a c ilitie s

.P h arm a c e u tic a l I ndus try I ntr o duc tion

Sect o r No t e b o o k Pr o j ect Sept em b e r 1997 9 

### F i gu re 2: Em p l o y m e n t i n t h e P h arm a ceu t i cal In d u st ry

Sour c e : 1992 U

. S. Ce ns us of Manuf ac t u re r s

.

A s s h o w n in T ab l e 2
, ma n y fa c ilit ie s w it h in t h e p h a r m aceut i ca l i ndus t r y ar e
s ma l l. A lmo s t 7 0 p e r c e n t o f t h e fa c ilit ie s e m p l o y fe w e r t h a n 5 0 p e o p le

. Ho wev e r , a r e l a t i v e l y

smal l n u m b er o f l a r g e co m p an i e s acco un t f o r a l ar g e po r t i o n o f t h e t o t a l v a l u e o f sh i p m e n t s, as well as em pl o ym e n t

. F o r ex am pl e,
acco r d i n g t o t h e 1992 U. S

. Cen s us o f M a n u f act ur er s , o n l y

36 f ac ilit ie s ( l e s s t h an t h r ee per cen t ) em pl o y ed m o r e t h an 1, 000 peo p l e i n t h e 50 s t at es ( i

. e

. , n o t in c l u d i n g P u e r t o R i c o )

. H o w e v e r , t h e s e 3 6 fa c ilit ie s acco un t e d f o r o v er 38%

o f

t h e t o t a l v a l u e o f s h i p m e n t s f o r t h e i n dus t r y

. I n co m p ar i s o n , 968 f ac

ilit ie s ( a lmo s t 7 0 p e r c e n t ) e m p l o y fe w e r t h a n 5 0 p e o p le

. H o w e v e r , t h e s e fa c ilit ie s
acco un t e d f o r l e ss t h an f

o ur per cen t o f t h e i n dust r y ’ s v a l u e o f sh i p m e n t s.P h arm a c e u tic a l I ndus try I ntr o duc tion



### T a ble 2: P h armaceu tical I n du s t ry (SI C 283) F a cility Siz e 1

N um b er o f E m plo y ees N um b er o f F a cilit ies P ercen t o f T o t a l F a c ilit ie s ( % ) P ercen t o f T o ta l Va l u e of

S h i p m e n t s ( % )
f e w e r th a n 10 479 34 0. 6 10 to 49 489 34 3. 2 50 to 249 292 20 19 250 to 999 129 9. 1 3 9 2 1, 000 o r m o r e 36 2. 5 3 8 2
T o ta l 1
, 425 100 100 S o u r ce: 1992 Ce ns us of Manuf ac t u re r s , Indus t r y Se r i e s : D r ugs , B u re au of t h e Ce ns us , 1995. 1 D o e s n o t in c l u d e P u e r to Ri c o - in f o r matio n w ith h e ld to av o i d d i s c lo s i n g d ata f o r in d i v i d u al f a c ilitie s

. 2 S o me in f o r matio n w ith h e ld to av o i d d i s c lo s i n g in d i v i d u al f a c ility d ata. V alu e s may b e s o me w h at h i g h e r

.

M e dicinals and B o tanicals ( S I C 2833) and P har maceutical P r epar ations ( S I C 2834)

T h e est ab l i s h m en t si ze di st r i b u t i o n s f o rP h ar maceut i cal P r epar at i o ns an d M e d i c i n a ls a n d B o t a n i c a l s a r e s imila r ( s e e T ab l e 3 )

. T h e P h a r m aceut i cal P r epar at i o n s sect o r , ho w e v e r , h a s a so m e wh at h i gh er pr o p o r t i o n o f l a r g e fa c ilit ie s

. A s is t h e c a s e w it h t h e p h a r m aceut i cal s i n du s t r y a s a wh o l e, a
r e l a t i v e l y

small n u m b ero f l a r g e est ab l i s h m en t s acco un t f o r t h e ma j o r it y o f t h e t o t a l v a l u e o f sh i p m e n t s f o rt h e P h ar maceut i cal P r epar at i o n s i n dust r y

. Val u e
o f

sh i p m e n t dat a i s n o t av ai l ab l e b y est ab l i s h m en t si ze f o rt h e Medi ci n a l s an d Bo t a n i cal s sect o r

.



### T a ble 3: E m plo y me n t Siz e D i s t r i bu tio n f

o r M e dic i n a ls an d B o tan i c a ls an d P h arm a ceu t i cal P rep arat i o n s E s tablis h m e n ts 1
M e d i ci n a l s an d B o t a n i cal s P h arm a ceu t i cal P r ep ar at i o n s

Num b er o f E m pl o y ees Num b er o f F a c ilit ie s P ercen t o f F a c ilit ie s P ercen t o f Va l u e of Sh i p m e n t s Num b er o f F a c ilit ie s P ercen t o f F a c ilit ie s P ercen t o f Va l u e of Sh i p m e n t s

< t h a n 10 104 46 N/ A 2 225 33 0. 4
10 t o 49 76 34 N/ A 2 211 30 2
50 t o 249 35 16 N/ A 2 142 21 10
250 o r m o r e 10 4 N/ A 2 113 16 88
T o t a l 225 100 100 691 100 100 S o u r ce: 1992 U

. S. Ce ns us of Manuf ac t u re r s

. 1 N o t in c l u d i n g P u e r to Ri c o

. 2 I n f o r matio n h a s b e e n w ith h e ld to av o i d d i s c lo s i n g in d i v i d u al e s tab lis h m e n t d ata.

Sect o r No t e b o o k Pr o j ect 10 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

T ab l e 4 l i s t s t h e l a r g e s t U

. S

. ph ar maceut i cal co m p an i e s i n t e r m s o f U. S

. pr escr i p t i o n sal e s.



### T a ble 4: T o p U

. S. P h ar mac e u tic a l C o mpan ie s by Sale s Rank Com p any 1996 Rx Sal e s ( m i lli o n so f d o lla r s )
1 G la x o W e llc om e 5
, 8 0 3
2 J ohns on & J ohns on 5
, 2 7 5
3 A m e

r i c a n H o m e

P r odu c t s 5
, 2 5 1
4 B r i sto l

- M y e r s S q ui bb 5, 160 5 M e r c k & C o 5, 026
6 P f i z e r 4
, 511
7 N o v a r t i s 3, 786
8 S m i t h K l i n e B eec h a m 3
, 5 8 9
9 L illy 3
, 5 6 7 10 A bbo tt 3, 423
1 1 S c he r i ng- P l ou gh 3
, 2 7 2
12 Ho e c h s t Ma r i o n R o usse l 2
, 474
13 R o c h e 2
, 316
14 A m g e n 1
, 860 15 B a y e r 1, 854 S o u r ce: IMS A m e r i c a

.
I I

. B

. 3. Geogr aphic Dis t ri but ion

T h e U. S

. ph ar maceut i cal s i n dust r y h a s t r adit i o n a ll y b een co n cen t r at ed i n New Jer s ey , Cal i f

o r n i a, an d New Yo r k ( s ee F i gur e 3)

. T h ese t h r ee st at es acco un t fo r ab o u t o n e t h ir d o f t h e fa c ilit ie s , e m p l o y e e s , a n d v a lu e o f s h ip me n t s

. Hi st o r i call y , t h e i n dust r y co n cen t r at ed h e r e b ecause t h ese wer e v o cat i o n a l

cen t e r s

. Ot h e r st at es, such as Massachuset t s , No r t h Car o l i n a an d Mar y l a n d
, h a v e seen r e cen t gr o w t h i n t h e ph ar maceut i cal s i n dust r y , especi all y

i n b i o t ech n o l o gy an d r e sear ch an d dev e l o pm en t

.

Sect o r No t e b o o k Pr o j ect 11 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

F i gur e 3: Geogr aphic Dis t ri but ion of P h arm a ceut i cal F a cil i t i es ( S I C 2833 and 2834)

Pue r t o

Ri c o

0 - 10 1 01 - 12 3
51 - 10 0
11 - 5 0

Sour c e : 1992 U

. S. Ce ns us of Manuf ac t u re r s

.

A

si gn i f i can t n u m b ero f ph ar maceut i cal est ab l i s h m en t s ar e a l s o l o cat ed i n P u er t o Ri co

. A c c o r d i n g t o t h e 1992 E c onomic Ce ns us of Outlying A r eas , wh i c h co v e r s st at i s t i cs f o rP u er t o Ri co , t h er e wer e a t o t a l o f 88 ph ar maceut i cal s est ab l i s h m e n t s i n P u er t o Ri co acco un t i n g f o r al m

o st $12 b illio n in s h ip me n t s

. E i g h t y t w o o f t h e s e e s t ab lis h m e n t s w e r e in t h e P h ar maceut i cal P r epar at i o n s an d Medi c i n a l s an d Bo t a n i cal s sect o r s. T h ese est ab l i s h m en t s acco un t e d f o r 11 per cen t o f all em pl o ym e n t an d 15 per cen t o f t h e v a l u e o f sh i p m e n t s f o rt h ese sect o r s. T h e dr i v i n g f o r ce b e h i n d t h e ph ar maceut i cal s in dust r y co n cen t r at in g in P u er t o Ri co o v ert h e y ear s ar e t a x i n cen t i v e s speci f i call y

di r ect ed at t h e i n dust r y

.
M a n y U

. S

. fi r m s h a v e fa c ilit ie s ab r o a d o r o w n fo r e ig n c o mp a n ie s in w h ic h b o t h R& D an d pr o duct i o n o f ph ar maceut i cal s ar e co n duct e d. A cco r d i n g t o Ph R M A
, i n 1996 it s m e m b er f i r m s em pl o y ed cl o s e t o 165, 000 peo p l e
o v er seas i n t h e pr o duct i o n o f pr escr i p t i o n ph ar maceut i cal s. Of t h ese, ab o u t 42% wer e em pl o y ed i n W e st er n E u r o pe. T h e n e x t l a r g est r e gi o n f

o ro v er seas
em pl o y m e n t b y P h RMA m e m b er co m p an i e s i s L a t i n A m er i ca an d t h e Car i b b ean , wit h 20 per c e n t ( P h R M A
, 1996)

. Recen t l y , a n u m b ero f ph ar maceut i cal co m p an i e s ar e m o v i n g pr o duct i o n t o I r e l a n d

. S imila r l y, ma n y f o r e i g n o w n e d ph ar maceut i cal f i r m s o p er at e ph ar maceut i cal r e sear ch an d d e v e lo p m e n t a n d p r o d u c t i o n fa c ilit ie s in t h e U

. S

.

Sect o r No t e b o o k Pr o j ect 12 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

I I

. B

. 4. E c onom ic T r ends and I n t e r n at ional Com p et it ion

C

hanges in the U. S. Health C a r e I ndus tr y

Dur i n g t h e ear l y

1990s t h e Un it ed S t at es ph ar maceut i cal in dus t r y f

aced ma j o r ch all e n g es asso ci at ed wit h t h e ch an gi n g n a t u r e o f h eal t h

car e del i v er y co upl ed wit h i n t e n s e ma r k et co m p et it i o n

. I n 1995 ab o u t 62 per cen t o f pr es cr i p t i o n s
wer e pai d f o r b y i n s u r i n g t h i r d p a r t i e s , up f r o m 39 per cen t i n 1990. T h i r d par t i e s, i n cl udi n g ma n a ged car e o r gan i zat i o n s an d Medi cai d, co n s i d er co st i n ch o o s in g wh i c h dr ugs ar e appr o v ed f o rr e im b ur s e m e n t

. T ech n i ques s u ch as
s u b s t i t u t i ng gen e r i c dr ugs f o rb r an ded dr ugs ar e al s o us ed. L o w pr i ced gen e r i c dr ugs r a pi dl y

capt u r e a l a r g e sh ar e o f p r escr i p t i o n s o n ce t h e
o r i g i n at i n g dr ug’ s pat e n t ex pi r e s

. L i kewi s e , in t e n s e R & D r i v a l r i e s b e t w een
c o mp a n ie s n o w me a n t h a t n e w p r o d u c t s ma y h a v e ma jo r c o mp e t it io n w it h in

m

o n t h s af t e rt h ei rF D A appr o v al
, as was t h e c a s e f o rt h r ee co m p et i n g pr o t eas e i n h i b it o r s appr o v ed b e t w een Decem b e r 1995 an d A p r i l 1996. Co m p an i e s h a v e r e s p o n d e d t o sh o r t e r pr o duct l i f

e cy cl es an d co st

c o n t a i n m e n t p r e s s u r e s b y fo r min g a n in c r e a s in g n u mb e r o f s t r a t e g i c a llia n c e s
an d m e r g i n g. Ho wev e r , a s t eady s t r eam o f n e w pr o duc t i n t r o duct i o n s h a s
co n t r i b u t e d t o st eady i n dust r y gr o w t h dr i v en b y an i n cr easi n g v o l u m e o f pr es cr i p t i o n s

. I n 1997, r e s ear ch

- b as ed co m p an i e s ’ n e t s a l e s i n t h e Un it ed S t at es ar e pr o j ect ed t o r each $66. 1 billio n , a 5

. 5 p e r c e n t in c r e a s e o v e r 1996 ( P h R M A
, 1997)

.
C

ons olidation of the P har maceuticals I ndus tr y

Co m p et it i v e pr essur e s ar e f o r c i n g ma n y co m p a n i e s t o r e st r u ct ur e an d f o r m
me r g e r s a n d s t r a t e g i c a llia n c e s

. I n c r e a s in g c o mp e t it io n fr o m b o t h d o me s t ic

an d f o r e i g n f

i r m s, as well as f r o m t h e gen e r i c dr ug ma r k et , h a s f o r ced m e r g er s b e t w een t h e l a r g er ph ar maceut i cal co m p an i e s an d m i d

- s i zed co m p an i e s. I n 1989, t h r ee ma j o rm e r g er s o ccur r e d b e t w een l a r g e an d m i d

- s i zed ph ar maceut i cal co m p an i e s

. I n 1995, t h i s n u m b erin cr eas ed t o s e v e n

. I n 1996, t h er e wer e t h r ee m e r g er s.

A s a r e sul t o f g e ne r i c co m p et it i o n , so m e b r an d n a m e f i r m s ar e b eco m i n g i n v o lv ed wit h co m p an i e s t h at ma n u f act ur e gen e r i c dr ugs b y p u r ch asi n g
ex i s t i n g co m p an i e s , s e t t i n g up t h ei r o w n gen e r i c dr ug v e n t ur es , o r f o r m i n g par t n e r s h i ps ( P h R M A
, 1996)

. Al s o , ma n y s mall e r b i o t ech an d R & D

co m p a n i e s ar e m e r g i n g wit h l a r g e ph ar maceut i cal co m p an i e s. S t r a t e gi c
a llia n c e s o f t e n in v o lv e d o me s t ic a n d fo r e ig n p h a r m aceut i cal c o m p an i e s, b i o t ech f

i r m s, un i v er sit y r e se a r c h c e n t e r s , go v e r n m e n t agen ci es such as t h e Nat i o n al I n st it ut e o f Heal t h
, an d co n t r act r e sear ch o r gan i za t i o n s. S u ch

me r g e r s a n d a llia n c e s a llo w c o mp a n ie s t o d r a w u p o n each o t h e r s ’ r e sear ch

ex per t i s e, b r i n g pr o duct s t o ma r k et m o r e r a pi dl y , an d m o r e ef f ect i v el y

ma r k et pr o duct s o n ce t h ey ar e appr o v ed b y F D A

.

Sect o r No t e b o o k Pr o j ect 13 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion

C

hanges in Geogr aphical C oncentr ations

A n i n cr easi n g n u m b ero f est ab l i s h m en t s o w n e d b y U. S

. co m p an i e s ar e l o cat i n g o u t s i d e t h e U. S

. A n u m b ero f f

o r ces ar e dr i v i n g t h ese ch an ges, i n cl udi ng t h e gr o w i n g in t e r n at i o n a l ma r k et f o r ph ar maceut i cal pr o duct s , fo r e ig n r e g i s t r a t i o n r e q u i r e me n t s a n d p a t e n t la w s , la w s a llo w i n g s a le s o n ly if t h e pr o duct s ar e ma n u f act ur ed i n t h e co un t r y ; an d t a x in cen t i v e s.

I

n ter national Tr ade and C o mpetition

T h e U. S

. ph ar maceu t i c a l s i n dust r y acco un t s f o r ab o u t o n e- t h i r d o f all ph ar maceut i cal s ma r k et ed wo r l dwi d e ( s ee F i gur e 4)

. T h e ma j o r U. S

. t r adi n g par t n e r s ar e E u r o pe, Japan
, C a n a da, an d Mex i co

. T h e l a r g est im p o r t e ro f U. S

. ph ar maceut i cal s i s t h e E u r o p ean Co m m

u n i t y

( E C)

. I n 1993, t h e E C al o n e i m p o r t e d ne a r l y 50% o f all U. S. ex po r t s ( I T A
, 1994)

. C a n a da an d Mex i co co m b i n ed im p o r t e d 15 per cen t o f all U. S

. ex po r t s o f ph ar maceut i cal pr o duct s i n 1993. T h e N o r t h A m er i can F

r ee T r ade A g r eem en t ( N A F T A )
, h o wev e r , h a s i n cr eased t h e v o l u m e o f t r ade wit h Can a da an d Mex i co i n r ecen t y ear s.

A l t h o u g h J a p a n s t ill r e ma in s o n e o f t h e lar g e s t imp o r t e r s o f U

. S

. ph ar maceut i cal s, Japan e se ph ar maceut i cal co m p an i e s ha v e b een i n v e st i n g h eavi l y i n t h ei ro w n R& D, t h er eb y r e duci n g Japan ’ s i m p o r t sh ar e o f U. S

. ex po r t s i n r ecen t y ear s.

I n

1993, E u r o pean an d J a pan e s e ph ar maceut i cal co m p an i e s acco un t e d f o r 27 per cen t an d 22 per cen t o f al l ph ar m aceut i cal s m a r k et ed w o r l d w i d e,
r e s p ect i v el y

( P h R M A
, 1996)

. C h i n a an d t h e co un t r i e s o f t h e f o r m er So v i et Un i o n a r e po t e n t i a l l y

l a r g e m a r k et s f o r U. S

. ph ar m aceut i cal s. Ho wev e r , Ch i n a i s al so i n cr easi n g it s pr o duct i o n o f ph ar maceut i cal s a n d t h e f o r m er
co un t r i e s o f t h e S o v i et Un i o n po se so m e ma j o r ch all e n g es f o r U. S

. pr o ducer s in

t e r m s o f t e s t in g a n d lic e n s i n g r e g u l a t io n s ( I n t e r n a t io n a l T r a d e A d m i n i s t r at i o n , 1994)

.
M a jo r is s u e s a ffe c t in g t h e in t e r n a t io n a l c o mp e t it iv e n e s s o f U

. S

. ph ar maceut i c a l f i r m s i n cl ude pr i ce co n t r o l s an d i n t e ll ect ual pr o p er t y pr o t ect i o n ab r o ad. Ot h e r t r ade b a r r i er s i n cl ude f o r e i g n pr i c in g sy st em s t h at f a v o rl o call y

pr o duced ph ar maceut i cal s, di scr imin a t o r y r e g i s t r a t i o n
r e q u ir e m e n t s , a n d r e q u i r e me n t s t h a t fo r e ig n c o mp a n ie s e n t e r in t o jo in t

ve nt u r e s w it h d o m e s t i c f i r m s

.

Sect o r No t e b o o k Pr o j ect 14 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ntr o duc tion



### F i gu re 4: Wo rld Sales o f P h armaceu ticals , 1995

M i ddl e E a s t 2% S o u t h e as t As i a & C h in a 6% C a na da

3% Un i t e d S t at es

30 % A u st r a l a si a 1% Eu r o p e 27 % A fri c a 2%

Ja p a n 22 %

L

a tin A m er

i c a 7%

S o u r ce: P har m a ceutical Res ear c h and Manufactur e r

s of Am er ica, 1997 bas e d on dat a pr ov i d e d by IMS A m e r i c a , 1996.

Sect o r No t e b o o k Pr o j ect 15 Sept em b e r 1997P a g e 1 6 in t e n t io n a lly le ft b l a nk

.P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

III. INDUS TRIAL P R O C ES S DES CRIP T IO N

T h i s sect i o n descr i b e s t h e ma j o rin dust r i a l pr o cesses wi t h i n t h e ph ar maceut i c a l i n dus t r y , i n cl udi n g t h e ma t e r i al s an d equi pm en t us ed, an d t h e pr o ces s e s
em pl o y ed. T h e sect i o n i s desi gn ed f o r t h o s e i n t e r e st ed i n gai n i ng a gen e r a l

u n d e rs t a n d i n g o f t h e i n d u s t r y , a n d f o r t h o s e i n t e re s t e d i nt h e i n t e r-re l a t i o n s h i p b e t w een t h e i n dust r i a l pr o cess an d t h e t o pi cs descr i b e d in sub s equen t sect i o n s
o f

t h i s pr o f i l e - - po ll u t a n t o u t put s , po ll u t i o n pr ev en t i o n o ppo r t un it i e s , a n d F e d e r a l r e g u l a t io n s

. T h is s e c t io n d o e s n o t a t t e mp t t o r e p lic a t e p u b lis h e d

en gi n eer i n g i n f o r mat i o n t h at i s av ai l ab l e f o r t h i s i n dust r y

. Ref e rt o S ect i o n I X f o r a l i s t o f r e f e r e n ce do cum e n t s t h at ar e av ai l ab l e.

T h i s sect i o n speci f i call y

co n t ai n s a descr i pt i o n o f co m m

o n l y used pr o duct i o n pr o cesses, asso ci at ed r a w ma t e r i al s, an d t h e ma t e r i al s eit h er r e c y c l ed o r t r an s f er r e d o f f

- s it e

. T h i s di s c us s i o n , co upl ed wit h s c h e ma t i c dr awin gs o f t h e i d en t i f i ed pr o cesses, pr o v i d es a descr i pt i o n o f wh er e wast es ma y b e pr o duced i n t h e pr o cess. A m o r e i n

- d ept h descr i pt i o n o f t h e ma j o r wast es pr o duced b y ph ar maceut i cal ma n u f act ur in g can b e f o un d i n S ect i o n III.B

.
A d d it i o n a lly, it is imp o r t a n t t o u n d e r s t a n d t h e r e g u l a t o r y fr a m e w o r k in w h ic h ph ar maceut i cal pr o duct s ar e ma n u f act ur ed. T o pr o t ect t h e pub l i c f r o m un saf e
o ri n ef f ect i v e ph ar maceut i cal pr o duct s , Co n g r e ss est ab l i s h e d a st r i n g en t

r e gul at o r y sy st em t o co n t r o l t h e r e sear ch an d dev e l o pm en t , ma n u f act ur e an d

ma r k et i n g o f ph ar maceut i cal pr o duct s

. T h e US F o o d an d Dr ug A d m in i s t r a t i o n ( F D A ) w a s d e le g a t e d t h e r e s p o n s i b ilit y fo r : ( i ) e v a l u a t i n g t h e s a fe t y a n d ef

f i cacy o f n e w dr ugs; ( i i ) det e r m i n i n g i f t h e b e n e f it s o f t h e dr ug o u t w ei gh t h e
r i s k s a n d w a r r a n t a p p r o v a l fo r s a le ; a n d ( iii) r e v i e w in g t o x i c o l o g i c a l per f o r ma n ce o f act i v e ph ar maceut i cal i n gr edi e n t s. F o rm o st n e w ph a r maceut i cal co m p o u n d s, F D A o v er si gh t b e gi n s so o n af t e rt h e di sco v er y
o f

t h e co m p o u n d

.
III. A

. I ndus trial P r oc e s s e s in the P h arm a c e u tic a l I ndus try

T h e pr o duct i o n o f ph ar maceut i cal pr o duct s can b e b r o k en do wn i n t o t h r e e
m a i n st ages: 1) r e sear ch an d dev e l o pm en t ; 2) t h e co n v e r s i o n o f o r gan i c an d

n a t u r a l sub s t a n ces i n t o b u l k

ph ar maceut i cal sub s t a n ces o ri n gr edi e n t s t h r o ugh f e r m en t a t i o n , ex t r act i o n , an d/ o r ch em i cal syn t h e si s; an d 3) t h e f o r m ul at i o n o f t h e f i n a l ph ar maceut i cal pr o duct

.
III. A

. 1

. R e sea r ch a n d D e v e l o p m en t

New dr ug dev e l o pm en t i n v o lv es f o ur pr i n ci pal ph ases: P r e- Cl i n i cal Resear ch

an d Dev e l o pm en t ; Cl in i cal Resear ch an d Dev e l o pm en t ; Rev i ew o f New Dr ug A

p p lic a t io n ; a n d P o s t M a r k e t in g S u r v e illa n c e

. P r e

- C lin ic a l R e s e a r c h a n d Dev e l o pm en t b e gi n s af t e r a pr o m i s i n g co m p o u n d h a s b een di sc o v er ed an d i s o l at ed i n t h e l ab o r a t o r y

. I n t h i s ph ase, t h e co m p o u n d i s sub j ect ed t o

Sect o r No t e b o o k Pr o j ect 17 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

ex t e n s i v e l ab o r a t o r y an d an i ma l t e st s t o det e r m i n e wh et h e r t h e co m p o u n d i s b i o l o g i call y

act i v e an d s a f e

. T h e av er age t i m e t o co m p l e t e t h i s ph ase i s si x y ear s.

A f t e r co m p l e t i n g t h e P r e- Cl in i cal Resear ch an d Dev e l o pm en t an d b e f o r e t e s t in g t h e d r u g in hu ma n s , a n a p p lic a t io n is f

i l e d w it h F D A k n o w n a s a n I n v e s t ig a t io n a l N e w D r u g A p p lic a t io n ( I N D )

. T h e a p p lic a t io n mu s t s h o w t h e
r e sul t s o f t h e pr e- cl i n i cal t e st i n g an d det a i l t h e pl an s f o rhu ma n cl in i cal t e st s. I t m u st al so co n t ai n i n f o r ma t i o n ab o u t t h e ch em i cal st r u ct ur e o f t h e
co m p o u n d an d a gen e r a l descr i pt i o n as t o h o w t h e co m p o u n d i s
ma n u f act ur ed.

Cl i n i cal Resear ch an d Dev e l o pm en t i s t y pi call y

co n duct e d in t h r e e p h a s es, wit h each ph ase i n v o lv i n g pr o g r e ssi v e l y

m o r e peo p l e

. T h e f i r s t ph ase, wh i c h t y

pi call y

l a st s ab o u t a y ear , i s ai m e d at est a bl i s hi ng t h e dr ug’ s saf e t y an d i n v o lv es a small n u m b ero f h eal t h y v o l u n t eer s. T h e seco n d ph ase, wh i c h l a st s ab o u t t w o y ear s, h e l p s t h e sci e n t i s t s det e r m i n e t h e dr ug’ s ef f ect i v en ess. I n t h e t h ir d p h a s e , t h e d r u g i s u s e d in c lin ic s a n d h o s p it a l s , a n d s c ie n t is t s mu s t

co n f i r m t h e r e sul t s o f ear l i e rt e st s an d i d en t i f y

an y adv e r s e r eact i o n s

. A l t o get h ert h e t h r ee ph ases o f Cl in i cal Resear ch an d Dev e l o pm en t t a ke ab o u t si x y ear s.

I n

t h e f i r s t ph ase o f Cl i n i cal Resear ch an d Dev e l o pm en t , a small am o u n t o f t h e
c o mp o u n d is ma n u fa c t u r e d in a

p ilo t p l a n t fo r u s e in t h e c lin ic a l t r ia ls

. T h is b a t c h o f c o mp o u n d is c a lle d C lin ic a l T r ia l M a t e r i a l ( C T M )

. A t t h is t ime
, t h e
ma n u f act ur i n g s t eps o f t h e co m p o u n d ar e al so o p t im i zed an d i m p r o v e d. D u r i n g t h is p h a s e , a t t e n t i o n t o w a s t e min imiz a t io n c o n s id e r a t io n s is mo s t ef

f ect i v e.

A f t e r C l i n i cal Resear ch an d Dev e l o pm en t i s co m p l e t e d, t h e co m p an y f

i l e s, wit h t h e F D A, a New Dr ug A ppl i cat i o n ( NDA ) co n t ai n i n g co m p r e h e n s i v e dat a ab o u t t h e co m p o u n d

. T h e NDA m u st in cl ude dat a t o dem o n s t r at e t h at t h e dr ug i s s a f e an d ef f ect i v e f o r us e un der t h e co n d it i o n s des c r i b e d i n it s l ab e li n g. F D A r e gul at i o n s r e qui r e t h at t h e NDA co n t ai n speci f i c an d det a i l e d i n f o r m at i o n o n : t h e co m p o n en t s an d co m p o s it i o n o f t h e dr ug; t h e m e t h o d s
an d co n t r o l s used i n t h e ma n u f act ur i n g; pr o cessi n g an d packagi n g o f t h e dr ug;
an d, dat a f r o m all pr e- cl i n i cal an d cl i n i cal in v e s t i g at i o n s

. I n 1993, t h e m e di an t o t a l appr o v al t i m e f o r NDA s was 21 m o n t h s

. T h i s h a s b een s i gni f i c a n t l y
r e d u c e d a n d i n 1996
, th e m e d i a n tota l a p p r ov a l ti m e f o r N D A s w a s 1 5

m

o nt hs

.
E ach st ep i n t h e ma n u f act ur i n g pr o cess, an d t h e i d en t i t y

an d qual it y o f each i n gr edi e n t used i n t h e pr o cess, m u st b e speci f i ed i n t h e NDA an d appr o v ed b y t h e F D A

. On ce t h e NDA i s a p p r o v e d
, cer t a i n ch an ges can n o t b e ma de

w it h o u t t h e filin g a n d a p p r o v a l b y t h e F D A o f a

s uppl em en t a l appl i c a t i o n, kn o w n as an S N DA

. T h e l e v e l o f r e po r t i n g depen d s o n t h e t y pe o f ch an ge

Sect o r No t e b o o k Pr o j ect 18 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

a n d m a y r e q u i r e

s u b s t a n t ia l in v e s t me n t o f r e s o u r c e s t o imp le me n t

. F D A appr o v al ma y t a ke s e v e r a l y e a r s t o o b t a in depen d i n g o n t h e n a t u r e o f t h e ch an ge, an d so m e ch an ges ev en r e qui r e n e w cl i n i cal st udi es.

B a s e d o n dat a f

r o m a 1995 s t udy b y t h e C e n t er f o r t h e St udy o f Dr ug Dev e l o pm en t at T u f t s Un i v er sit y , a ph ar maceut i cal R e sear ch an d D e v e lo p m e n t ( R & D ) fa c ilit y d i s c o v e r in g a n d d e v e lo p in g a

n e w me d i c i n a l

a g e n t w ill e v a l u a t e a p p r o x ima t e ly 5
, 000 t o 10, 000 co m p o u n d s

. A b o u t 250

o f

t h ese sub s t a n ces ma y h o l d t h er apeut i c pr o m i s e an d en t e r pr ecl i n i cal t e st in g. H o w e v e r , o n ly ab o u t fiv e w ill g o o n t o limit e d hu ma n c l i n i c a l t e s t i n g

. S u b s e q u e n t ly, o n ly o n e , a f t e r 1 5

. 3 ye a r s o f r e s e a r c h a n d d e v e lo p m e n t , w ill b e i n t r o duced co m m

e r c i a ll y

as a n e w dr ug ( P h R M A
, 1997)

.
Basi c r e sear ch i s r e spo n si b l e f o ri d en t i f yi n g an d i s o l at i n g o r syn t h e si zi n g each

n e w c h e mic a l e n t i t y

t h a t w ill b e e v a l u a t e d fo r it s p o t e n t ia l t h e r a p e u t i c ef

f ect i v en ess. On ce a l ead co m p o u n d h a s b een i d en t i f i ed an d ch ar act er i zed,

s o m e 1, 000 r e l a t e d c h e mi c a ls u b s t a n ces w ill b e s yn t h e s i z e d a n d s t u d i e d b y l ab o r a t o r y assay sy st em s. T h ese assay sy st em s ar e d e si g n ed t o i d en t it y w h i c h

co m p o und s ex h i b it t h e m o st speci f i c an d po t e n t b i o l o g i cal ef f ect

. F o r each

co m p o u n d t e s t e d
, gen e r a ll y

so m e 5- 10 separ a t e ch em i cal r eact i o n s w ill b e
n e e d e d t o s yn t h e s i z e t h e c o mp o u n d

. T h e r e s u lt s o f b i o l o g ic a l t e s t in g w ill t h e n gui de t h e di r ect i o n o f sub s equen t s y nt h e t i c o p er at i o n s

. I f t h e r e sul t s ar e
un sat i sf act o r y , t h en t h e pr o cess st ar t s an ew.

S h o u ld a

s u b s t a n c e s h o w p r o mis e in t h e lab o r a t o r y a s s a ys , limit e d a n im a l st udi e s a r e st ar t e d. I f t h er e i s n o act i v it y i n t h e an i ma l
, o t h e rr e l a t e d

c o mp o u n d s w ill b e e v a l u a t e d o r t h e p r o g r a m w ill b e d i s c o n t i n u e d

. O n c e b i o l o g i call y

act i v e sub s t a n ces ar e i d en t i f i ed, t h e y w i l l un der g o f u r t h e r ch em i cal m o di f i cat i o n t o r e f i n e t h ei r ef f i cacy an d saf e t y

.
O n c e a n a c t i v e c a n d i d a t e h a s b e e n id e n t i fie d
, it w ill b e p r o p o s e d fo r fo r ma l d e v e l o pm en t

. P h ar maceut i cal dev e l o pm en t i n cl udes t h e ev al uat i on of s y n

t h

e t i c
m

e t h o d s o n a l a r g er scal e an d t h e assessm en t o f v a r i o u s way s o f f

o r m ul at i n g t h e d r u g t o p r o v id e o p t imu m d e liv e r y. U p t o t h is p o in t , o n ly s ma ll a m o u n t s h a v e b e e n s yn t h e s i z e d fo r e v a l u a t i o n

. M o r e w ill b e n e e d e d fo r t h e e x t e n s iv e
a n ima l t e s t in g r e q u i r e d b y F D A

. E v e n la r g e r a m o u n t s w ill b e r e q u i r e d fo r t h e
ex t e n s i v e cl i n i cal s t udi es i n hu ma n s r e qui r e d b e f o r e f e der a l appr o v al

.
III. A

. 2

. Pr o d u c t i o n o f B u l k Ph a rma ceu t i ca l Subs tanc e s

Bul k

p h a r m aceut i cal sub s t a n ces t y pi call y

co n s i s t o f st r u ct ur all y

co m p l e x
o r gan i c ch em i cal co m p o u n d s whi c h a r e ma n u f act ur ed v i a a ser i es o f i n t e r m edi a t e st eps an d r eact i o n s un der pr eci se co n d it i o n s

. T h ese sub s t a n ces
a r e used i n t h e ma n u f act ur e o f t h e do sage f o r m o f a f o r m ul at e d ph ar maceut i cal pr o duct an d ar e ma n u f act ur ed b y : ( 1 ) ch em i cal syn t h e si s; ( 2 ) f e r m en t a t i o n ; ( 3 ) i s o l at i o n / r eco v e r y f

r o m n a t u r a l so ur ces, o r( 4 ) a co m b in at i o n

Sect o r No t e b o o k Pr o j ect 19 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

o f

t h ese p r o c e s s e s. E x am pl es o f di f f e r e n t dr ugs pr o duced b y each o f t h ese pr o cesses ar e pr esen t e d i n T ab l e 5.

T a bl e 5: E x am pl e s of P h arm a c e u tic a l P r oduc ts by B u l kM a nuf ac turi ng P r oc e s s

C h e mic al S y n t h e s i s N atu r al P r o d u c t Ex tr ac tio n F e r me n tatio n

A n tib io tic s A n tih is tamin e s C a r d io v a s c u lar A g e n ts C e n t r a l Ne r v o u s Sy st e m ( C NS) S timu lan ts C NS De p r e ssa n t s Ho r m o n e s V itamin s A n tin e o p las tic A g e n ts En zy me s an d D i g e s tiv e A i d s C NS De p r e ssa n t s H e mato lo g i c al A g e n ts I n s u lin V a cci n e s A n tib io tic s A n tin e o p las tic A g e n ts Th e r ap e u tic N u tr ie n t s V itamin s St e r o i d s

M o s t ph arm aceu t i c a l s u bs t a nc e s a r e ma nu f a c t u r e d u t iliz in g “ b a t c h ”p r o c e s s e s

. I n

a b a t c h pr o cess, a par t i c ul ar sub s t a n ce o r “ i n t er m e di at e” 2 i s ma n u f act ur ed in a “ cam pai g n ” f o r per i o d s r a n g in g f r o m a f e w day s t o s e v e r a l m o n t h s un t i l suf f i ci en t ma t e r i al i s ma n u f act ur ed t o sat i sf y

t h e pr o j ect ed sal e s dema n d

. A t t h e en d o f t h e ma n u f act ur in g cam pai g n , an o t h e r ph ar maceut i cal in t e r m edi a t e
o rs u b s t a n ce i s ma de. T h e s a m e equi pm en t wi t h

po t e n t i a ll y

di f f e r e nt

co n f i gur at i o n s an d t h e sam e o p e r at i n g per s o n n e l ar e o f t e n used t o ma ke a d i ffe r e n t in t e r m e d ia t e o r s u b s t a n c e , u t iliz in g d i ffe r e n t r a w ma t e r i a l s , e x e c u t i n g d i f f e r e n t p r o cesses, an dg e n e r a t in g d i f f e r e n t w a st e st r eam s.

W h en t h e sam e equi pm en t i s used f o r ma n u f act ur i n g di f f e r e n t i n t e r m edi a t e s
a n d / o r di f f e r e n t b u l k

sub s t a n ces, t h e equi pm en t i s t h o r o ugh l y

cl ean ed a n d

v a li d at ed pr i o r t o it s r e use. W h er e cl ean i n g o f a speci f i c t y pe o f equi pm en t i s di f f i cul t o r wh er e a suf f i ci en t v o l u m e o f a cer t a i n i n t e r m edi a t e o r b u l k sub s t a n ce i s m a de ev er y y ear , t h e equi pm en t m a y b e dedi cat ed t o t h e b a t c h

m a n u f act ur i n g o f a par t i c ul ar i n t e r m edi a t e o r b u l k

su bst a n ce. W h er e t h e
e q u i p m e n t i s d e d i c a t e d to th e p r oduc ti on of s u ccessi v e b a t c h e s o f t h e sam e i n t e r m edi a t e o rb u l k

sub s t a n ce, t h e equi pm en t ma y n o t b e wash ed an d cl ean ed b e t w e e n b a t c h e s

. I n s t e a d
, t h e c l e a n in g s c h e d u l e w ill d e p e n d o n w h e t h e r t h e r e i s a po t e n t i a l f

o r car r y o v er o f co n t am i n an t s o r degr aded ma t e r i al s t h at co ul d af

f ect t h e f i n a l pr o duct

.
T h e speci f i c m e t h o d s an d ma t e r i al s ( e

. g

. , wat e r , st eam , det e r g en t s , an d/ o r
o r g a n i c s o lv e n t s ) u s e d t o c l e a n t h e e q u i p m e n t a r e b a s e d o n t h e ab ilit y o f t h e cl ean i n g p r o cess t o r e m o v e r e si d u e s o f r a w ma t e r i al s, i n t e r m e d i a t e s, pr ecur s o r s , degr adat i o n pr o duct s , an d i s o m er s ( F DA
, 1996)

.

2 A n in te r m e d iate is a mate r ial p r o d u c e d d u r in g a man u f ac tu r i n g p r o c e s s th at mu s t u n d e r g o f u r t h e r
mo le c u lar c h an g e o r p r o c e s s i n g b e f o r e it b e c o me s a b u lk p h ar mac e u tic al s u b s tan c e

.
Sect o r No t e b o o k Pr o j ect 20 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

Raw m a t e r i al s ar e ch ecked f o rt h ei ri d en t it y an d qual it y b e f o r e use in t h e
ma n u fa c t u r in g p r o c e s s e s

. A d d it i o n a lly, in

- p r o c e s s t e s t in g , a s w e ll a s q u a lit y
a s s u r a n c e / q u a lit y c o n t r o l ( Q A / Q C ) t e s t in g in o n s it e lab o r a t o r i e s , is p e r f o r me d dur i n g dr ug pr o duct ma n u f act ur i n g. I n

- p r o ces s t e s t i n g ma y i n cl ude s i m p l e pH

m

easur e m e n t s o r ch ecks o n co l o r , wh i l e QA / Q C t e st i n g t y pi call y

i n cl udes

m

o r e so ph i s t i cat ed an al y s es such as ch r o ma t o gr aph y

. “ U po n co m p l e t i o n o f t h e ma n u f act ur in g o p er at i o n , b a t c h

- pr o duct i o n r e c o r d s ar e ch ecked b y
co m p et en t an d r e spo n si b l e per s o n n e l f o r act ual yi el d agai n s t t h eo r e t i cal yi el d

o f

a b a t c h an d t o en sur e t h at each st e p ha s b een per f o r m e d an d si gn ed f o r ” ( M c G r a w H ill E n c y c l o p e d ia o f T e c h n o lo g y )

.
C

h emical Synthes i s

Mo st o f t h e co m p o u n d s used t o day as ph ar maceut i cal pr o duct s ar e pr epar ed b y ch em i cal s yn t h e s i s , gen e r a ll y

b y a b a t c h p r o ces s ( W at t h ey , 1992)

. Car d i o v a scul ar agen t s , cen t r a l ner v o u s sy st em agen t s , v it a m i n s, an t i b i o t i c s,
an d an t i h i st am i n es ar e j u st a f e w ex am pl es o f t h e b u l k

ph ar mace u t i cal

s u bs t a nc e s ma d e by t h i s p r o c e s s

.
T h e ma n u f a c t u r e of p h a r m aceut i c a lc o m p ou n d s u s i n g c h e m i c a ls yn t h e s i s i n v o lv es a co m p l e xser i es o f pr o cesses i n cl udin g ma n y i n t e r m edi a t e st ages an d ch em i cal r eact i o n s per f o r m e d i n a st ep- b y

- st ep f a sh i o n

. Depen d in g o n t h e pr o cess, t h e o p er at o r( o r a pr o g r a m m

e d co m put er ) adds r eagen t s , i n cr eases
o r decr eases t h e f l o w r a t e o f ch i ll ed wat e ro r st eam , an d st ar t s an d st o p s pum ps t o dr aw t h e r eact o r co n t en t s i n t o an o t h e rv e ssel

. A t o t h e r st ages i n t h e pr o ces s , s o l u t i o n s ma y b e pum ped t h r o ugh f i l

t er s o r cen t r i f uges , r ecy cl ed

w it h in t h e p r o c e s s , o r p u m p e d t o r e c y c lin g o r d i s p o s a l fa c ilit ie s

. C o

- p r o d u c t s , such as sal t s, ma y b e so l d f o rr e use. S p en t aci ds, m e t a l s , an d cat al y s t s ma y b e re c o v e re d a n d re u s e d o n s i t e o r s o l d f o r re u s e

.
T h e ma t e r i al f

r o m each i n t e r m edi a t e st ep ma y b e i s o l at ed an d t r an sf er r e d t o t h e n e x t st ep o f t h e pr o cess f o r co n t in ued pr o cessi n g un t i l t h e f in a l co m p o u n d i s der i v e d. T h ese st eps ma y b e all co n duct e d at t h e sam e ma n u f act ur i n g sit e , o r if t h e in t e r m e d ia t e is is o l a t e d
, it ma y b e t r a n s f e r r e d t o a n o t h e r s it e fo r f u rt h e r p r o c e s s i n g

.
I t is imp o s s i b l e t o p r o v id e a

s i n g le p r o c e s s flo w d i a g r a m fo r t h is in d u s t r y s i n c e each b u l k

ph ar maceut i cal sub s t a n ce i s di f f e r e n t i n it s ma n u f act ur e an d sev e r a l in t e r m e d ia t e s ma y b e p r o d u c e d in a s t e p

- w is e fa s h io n p r io r t o t h e ma n u fa c t u r e
o f

t h e f i n a l a c t i v e i n gr edi e n t

. Ho wev e r , an ex am pl e ch em i cal syn t h e si s pr o cess h a s b een pr o v i d ed as F i gur e 5 t o sh o w t h e equi pm en t used an d wh er e
w a st es o r em i ssi o n s m i g h t b e g e n e r a t e d

.

Sect o r No t e b o o k Pr o j ect 21 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### F i gu re 5: Simplif ied P r o ces s F l o wDiagram f o r Ch emical Syn t h e s i s

Re a c t i o n

Ve ss e l C h em i cal s ( r eac t a n t s)

R eac t i o n R e s i due s S e al ed - j a c k et fo r c o o lin g / h e a tin g
me di a

Pr oc e s s C onde ns er

Se p a r a t i o n
- e x tra c t io n

- de ca nt i n g
- c e n t rifu g a tio n - filtra t io n

S p e n t s o lv e n ts to
re c o v e ry /d is p o sal A i r E m i s s i ons C ont r o lD e vi ce

So l v en t V a p o rs

W a s t ew at e r T r ea t men t

So l v en t V a p o rs

C r y s ta lliz a t io n Pr oc e s s C onde ns er

W a s t ew at e r T r ea t men t So l v en t V a p o rs
Pu r i fic a tio n
- re c r y s t alliz a tio n
- c e n t rifu g a tio n - filtra t io n Dr y i n g

So l v en t V a p o rs So l v en t

va p o r s

Pr o d u c t So l v en t Va

por s

W a s t ew at er

W a s t ew at er W a s t ew at er

S o u r ce: A d apt e d f r om Ec onom i c I m

pact and R e gul at or y F l e

x i b ility A n a l y s is o f

P r opos e d E

fflu e n t G u id e lin e s fo r th e P

har m a ce ut i c al M anuf act u r i ng I ndus t r y, 1995.

React o r s

T h e m o st co m m

o n t y pe o f r eact o rv e ssel i s t h e ket t l e- t y pe r eact o r

. T h ese
r eact o r s t y pi call y

r a n g e i n capacit y f

r o m 50 t o sev e r a l t h o u san d gall o n s

. T h e
v e ssel s ar e ma de o f eit h er st ai n l ess st eel o r gl ass- l i n ed car b o n st eel

.
A

di agr a m o f a t y pi cal r eact o rv e ssel i s sh o w n i n F i gur e 6

. “R eact o r s ar e
e q u i p p e d t o p r o v id e a

r a n g e o f c a p ab ilit ie s t h a t ma y b e r e q u i r e d d u r in g t h e b a t c h r eact i o n st ep. T h i s equi p m e n t ma y i n cl ude: a j acket f o rh eat i n g an d

co o l in g, h o o kups f o r ch ar gin g r a w ma t e r i al s an d f o r di s c h ar g in g t h e co n t en t s
o f

t h e r eact o r , a n agit at i o n an d r ecy cl e l i n e f o rm i x i n g, co n t r o l sy st em s f o r t e mp e r a t u r e a n d p r e s s u r e , a c o n d e n s e r s y s t e m fo r c o n t r o llin g v e n t lo s s e s , a
r e t u r n l

i n e f o rr e f l ux i n g co n d en sab l es, a st eam ej ect o rf o rv acuum o p er at i o n , a n it r o g en s uppl y

f

o r paddi n g an d pu r g i n g t h e r eact o r , an d a ma n w ay f

o r t a ki n g sam p l e s an d addi n g so l i d cat al y s t s , r eact an t s , an d o t h e r so l i d ma t e r i al s t o t h e r eact o r ” ( U S E P A 1993)

.
Sect o r No t e b o o k Pr o j ect 22 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### F i gu re 6: Typical Des i gn o f a Kettle-Type BatchReacto r

C onde ns e d S t ea m a n d O r ga ni cs Pr e s s u r e Re lie f V alv e

S t ea m- Je t Eje c t o r St e a m

N itro g e n

S o lv e n t, Ra wM a te rial
, an d R eact a n t

A d d itio n

Ma nw a y

R eac t o r Ja ck et St e a m
Co o lin g Wa te r
or

C ool ant

St e a m Tra p

C onde ns e d St ea m Dr a i nVa l v e Ag i t at o r

R eac t o r D i sc h a rg e R ecyc l e

Lin e

Co o lin g Wa te r
or

C ool ant

S o u r ce: A d apt e d f r om C o n t ro l o f

V

o la tile O r gani c C o m pound E m i s s i ons f r om B a t c h P r oce s s e s , E P

A G u i d e l i n e Se r i e s , 1993.

Raw ma t e r i al s o r i ngr edi e n t s, i n cl udi n g so lv en t s , used t o pr o duce t h e i n t e r m edi a t e o rb u l k

sub s t a n ces ar e ch ar ged i n t o t h e r eact o rv e ssel

. L i qui d i n gr edi e n t s ar e dr awn i n t o t h e r eact o r ei t h er b y pum pi n g o r t h r o ugh v acuum f r o m d r u m s an d st o r age t a nk s. S o l i d s ma y b e ch ar ged ma n u all y

o r vi a
m

ech an i cal m ean s such as t h r o ugh a v acuum sy st em

.
On ce t h e r eact o rv e ssel s ar e ch ar ged wit h t h e r a w ma t e r i al s, t h e r eact i o n t a kes p l ace. “ T h e r eact o r can b e o p er at ed at at m o sph e r i c pr essur e , el ev at ed pr essur e , o r un derv acuum

. Because o f t h ei r f l ex i b ilit y, r eact o r s ma y b e used i n a var i et y o f way s

. Besi des h o st i n g ch em i cal r eact i o n s , t h ey can act as
m

i x er s, h e a t e r s , h o l d in g t a nk s, cr y s t a ll i zer s, an d ev apo r at o r s. ” ( U S E P A
, 1979) T y pi cal r eact i o n s per f o r m e d in cl ude al ky l a t i o n s , h y dr o g en at i o n s , b r o m i n at i o n s , et c. T e m p er at ur e, pr e s s u r e , a n d t h e degr ee o f m i x i n g ar e
car ef ull y

m o n it o r e d t o a c h i e v e t h e des i r e d pr o duct an d t o en s u r e wo r k er saf e t y

.
Sect o r No t e b o o k Pr o j ect 23 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

React o r s ar e o f t e n at t ach ed t o pr o cess co n d en ser s t o r eco v e r so lv en t s f r o m pr o cess o p er at i o n s

. T h ey ar e al so o f t e n at t ach ed t o o t h e r ai r po ll u t i o n co n t r o l d e vi c e s t o r e m o ve vo l a t i l e o r g a ni c s o r o t he r c o m p o u nd s f r o m ve nt e d g a s e s

. Depen d i n g o n t h e r eact i o n b e i n g car r i ed o u t , a r eact o rma y al so b e at t ach ed t o a d i s t illa t i o n c o lu mn fo r s o lv e n t s e p a r a t i o n a n d r e c o v e r y

.
Se par a tion

S e v e r a l separ a t i o n m ech an i s m s ar e em pl o y ed b y t h e ph ar maceut i cal in dust r y i n cl udi n g ex t r act i o n , decan t in g , cen t r i f u g a t i o n , an d f i l

t r a t i o n

. T h ese
me c h a n is m s ma y b e e m p l o y e d jo in t l y o r in d i v i d u a lly, in mu lt ip le s t a g e s , t o separ a t e t h e i n t e r m edi a t e o rb u l k

sub s t a n ce f r o m t h e r eact i o n so l u t i o n an d t o
r e mo v e imp u r it ie s

. C r ys t a lliz a t io n is a n o t h e r c o mmo n t e c h n i q u e u s e d t o separ a t e t h e de s i r e d act i v e i n gr edi e n t o rin t e r m edi a t e f r o m t h e r eact i o n
m

i x t u r e

. Because cr y s t a lliz a t io n is w i d e ly u s e d i n c o n j u n c t io n w it h o t h e r
s e par a t i o n t ech n i ques , it i s pr es en t e d s e par a t e l y

f

r o m t h e o t her s e par a t i o n t ech n i ques s h o w n i n F i gur e 5 an d di s c us s e d b e l o w.

E x t r act i o n

. E x t r act i o n i s us ed t o s e par a t e l i qui d m i x t u r e s b y t a ki n g adv a n t age of

d i f f e r e n c e s i n th e s o l u b i l ity of th e m i x tu r e c o m p on e n ts

. A s o lv e n t th a t pr ef er en t i all y

co m b i n es wit h o n l y o n e o f t h e co m p o n en t s i s added t o t h e mix t u r e

. “ T h e r e s u lt in g mix t u r e c o n s is t s o f a n e x t r a c t ( c o n t a in in g t h e pr ef er en t i all y

co m b in ed ma t e r i al ) an d a r a f f in a t e ( c o n t a in i n g t h e r e si dual p h a s e )

. E x t r a c t i o n ma yt a k e pl ace i n a n a g it a t e d r eact i o n v e ssel ( m i x er

set t l er )
, i n a v e r t i cal cy l in der ( w h e r e t h e so lv en t f l o w s upwar d o r do wn war d th

r ough t h e l i q u i d m i x tu r e )
, or i n a c o l u m n w ith i n te r n a l s to m e c h a n i c a ll y
en h a n ce t h e co n t act b e t w een t h e t w o l i qui d ph as es ” ( C r u m e et al

. , 1992)

.
Decan t i n g

. Decan t i n g i s a si m p l e pr o cess used t o separ a t e m i x t u r e s o f a l i qui d

a n d i n s o l u b l e s o l i d t h a t h a s s e t t l e d t o t h e b o t t o m of a r eact or or s e t t l i n g
v e s s e l

. T h e l i qui d o v er t h e s o l i d i s eit h er pum ped o u t o f t h e v e s s e l o r po ur ed f r o m t h e v e ssel l eav in g b e h i n d t h e i n so l u b l e so l i d an d a cer t a i n am o u n t o f l i qui d.

C e n t r i f ugat i o n

. “ C en t r i f uges ar e used t o r e m o v e t h e i n t e r m edi a t e o r pr o duct

s o l i d s f r o m a l i qui d s t r eam ” ( U SE PA 1979)

. C e n t r i f uges wo r k o n t h e pr in ci pl e
o f

cen t r i f ugal f

o r ce, i n wh i c h an o u t w ar d f o r ce i s ex er t e d o n a r o t a t i n g o b j ect

. Cen t r i f uges ar e cy l i n der s wit h r o t a t in g b a sket s wit h i n t h em

. T h e si des o f t h e b a sket ar e per f o r at ed an d co v e r e d wit h f

i l

t erm e di um such as wo v e n f

ab r i c o r
m

e ta l

. A s th e b a s k e t r o ta te s , a s l u r r y s o l u ti on i s f e d i n to th e c e n tr i f u g e v i a a n i n l e t pi pe. T h e cen t r i f ugal f

o r ce push e s t h e sl ur r y agai n s t t h e r o t a t i n g b a sket
, f o r c i n g t h e l i qui d t o pas s t h r o ugh t h e per f o r at i o n s , an d t h e s o l i d s o r f i l

t er cake t o r e ma i n b e h i n d
, accum u l a t i n g o n t h e si des o f t h e b a sket

. “ A f t er all o f t h e sl

ur r y h a s b een f e d t o t h e ch am b e r , a wash l

i qui d ma y b e i n t r o duced t o f o r c e t h e r e m a i n i n g s l ur r y l

i qui d t h r o ugh t h e cake an d f i l

t er m e di um ” ( U SE PA 1993)

. On ce t h e cen t r i f uge i s t u r n ed o f f

, t h e s o l i d s ( i

. e

. , t h e i n t e r m edi a t e s o r

Sect o r No t e b o o k Pr o j ect 24 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

t h e f i n a l b u l k sub s t a n ce) ar e scr a ped o f f t h e si des wit h an in t e r n al scr a pero r
ma n u all y

sco o p ed o u t

. A di agr a m o f a t y pi cal b a sket cen t r i f uge i s sh o w n i n F i gur e 7.



### F i gu re 7: Cro ss- S ect i o n o f Typ i cal To p - S u sp en d e d Cen t ri f u gal F i l t er

Motor

S l u rry In le t

Wa s h In le t

S o lid s Ca k e

P e rfo ra te d

Ba sk e t

R emova bl e V al v e P l at e S o l i d s D i sc h a rg e Ca sin g

F iltra t e D i sc h a rg e Ad j u st a b l e U n l o a d er Kn i f e

S o u r ce: A d apt e d f r om C o n t ro l o f

V

o la tile O r gani c C o m pound E m i s s i ons f r om B a t c h P r oce s s e s , E P

A G u i d e l i n e Se r i e s , 1993.

T h e ex t r em el

y

h i gh speeds an d f r i c t i o n a lf o r ces i n v o lv ed in cen t r i f ugi n g , co m b i n ed wit h t h e po t e n t i a l b u i l d

- up o f co m b ust i b l e so lv en t v a po r s , cr eat e a po t e n t i a l f

o r an ex pl o s i v e en v i r o n m en t t o dev e l o p wit h i n t h e cen t r i f uge. T o
c o n t r o l t h is
, a n in e r t g a s , u s u a lly n it r o g e n , ma y b e i n t r o d u c e d in t o t h e u n it b e f o r e t h e sl ur r y i s f e d i n

. “ C en t r i f uges m u st b e car ef ull y

o p er at ed t o av o i d ai

ri n f i l

t r a t i o n byv o r t exen t r ai n m en t

. T h er ef o r e, t h ey usuall y

ar e o p er at ed

un der n it r o g en b l ank e t a n d kept s eal ed un der o p er at i o n ” ( U SE PA 1993)

. VOC em i ssi o n s ma y o ccur wh en pur gi n g t h e v e ssel b e f o r e l o adi n g an d

un l o adi n g ( U SE PA
, 1993)

.
F ilt r a t i o n

. F ilt r a t i o n is t h e s e p a r a t i o n o f a flu i d

- s o lid s mix t u r e in v o lv in g

Sect o r No t e b o o k Pr o j ect 25 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

pas s a ge o f m o s t o f t h e f l u i d t h r o ugh a po r o us b a r r i er ( t h e f i l

t er m e di um )

w h ic h r e t a in s mo s t o f t h e s o lid p a r t ic u l a t e s c o n t a i n e d in t h e mix t u r e ( P e r r y ’ s 1984)

. I n t h e ph ar ma c e u t i cal in dus t r y , “ f i l

t r a t i o n i s us ed t o r e m o v e s o l i d s f r o m a l i qui d, wh et h e r t h ese so l i d s b e pr o duct
, pr o cess i n t e r m edi a t e s, cat al y s t s
o r car b o n par t i c ul at es ( e

. g

. , f r o m a deco l o r i n g s t ep) ” ( U SE PA 1979)

. B a t c h f i l

t r a t i o n sy st em s wi del y

used b y t h e ph ar maceu t i cal i n dust r y ar e t h e pl at ean d- f r am e f i l

t er , car t r i dge f i l

t er s , t h e n u t s ch e f i l

t er , an d co m b i n at i o n f i l

t er / d r y er s.

“ T h e n o r mal f i l

t r a t i o n pr o cedur e i s sim p l

y

t o f o r ce o r dr aw t h e m o t h erl i quo r t h

r o u g h a filt e r in g me d i u m

. F o l l o w i n g filt r a t i o n , t h e r e t a in e d s o lid s a r e
r e m o v e d” ( U SE PA
, 1979)

. T h e wet cake ma y t h en go t h r o ugh a r e s l ur r y pr o cess wh er e it i s wash ed an d f i l

t er ed agai n

. “ T h i s o p t i o n i s usuall y

car r i ed

o u t wh en a h i gh l y

s p eci al i zed pr o duct r e qui r i n g h i gh pur it y i s des i r e d o r wh en
so l v e n t s w e re n o t re m o v e d a s p a rt o f t h e o r i g i n a l s l u rry f

i l

t ra t i o n (U S E P A
, 1993)

.
C ry s ta l l i z a tio n

A f t e rt h e r eact i o n t a kes pl ace, t h e i n t e r m edi a t e o rf in a l b u l k

sub s t a n ce ( w h i ch i s usuall y

i n so l i d f o r m ) can b e separ a t e d f r o m t h e r eact i o n so l u t i o n b y
c r ys t a lliz a t io n

. C r ys t a lliz a t io n is o n e o f t h e mo s t c o mmo n s e p ar a t i o n t ech n i ques an d i s o f t e n used al o n e o r in co m b in at i o n wi t h

o n e o rm o r e o f t h e separ a t i o n t ech n i ques descr i b e d ab o v e. I n cr y s t a ll i zat i o n , a super s at ur at ed

so l u t i o n i s cr eat ed i n wh i c h cr y s t a l s o f t h e desi r e d c o m p o u n d ar e f o r m ed. S u p e r s a t u r a t io n d e p e n d s o n t h e s o lu b ilit y o f t h e d e s i r e d c o mp o u n d

. I f t h e
c o mp o u n d ’ s s o lu b ilit y in c r e a s e s w i t h

t e mp e r a t u r e , s u p e r s a t u r a t i o n c a n b e
a c h ie v e d b y c o o lin g t h e s o lu t i o n

. I f t h e s o lu b ili t y i s i n d e p e n d e n t o f o r decr eases wit h t e m p er at ur e, t h en e v a p o r a t i n g a po r t i o n o f t h e so lv en t wi ll

cr eat e super s at ur at i o n

. “ I f n e it h e r co o l i n g n o r ev apo r at i o n i s desi r ab l e, super s at ur at i o n ma y b e in duced b y addin g a t h i r d co m p o n en t

. T h e t h i r d

c o mp o n e n t fo r m s a mix w i t h

t h e o r ig in a l s o lv e n t in w h ic h t h e s o lu t e is

co n s i d er ab l y l e s s s o l u b l e” ( U SE PA 1979)

. I f cr y s t a lliz a t io n is d o n e t h r o u g h

c o o lin g o f a

s o lu t i o n t h e r e w ill b e r e la t i v e ly lit t l e V O C e mis s i o n s , e s p e c i a lly i f

t h e equi pm en t i s f u ll y

en cl o s ed. “ H o w ev er , wh en cr y s t a ll i zat i o n i s do n e b y
so lv en t ev apo r at i o n i n a v acuum en v i r o n m en t , t h er e i s a gr eat er po t e n t i a l f

o r
em i s s i o n s ” ( U SE PA 1993)

. F u r t h e r s e par a t i o n o f t h e cr y s t a l s f r o m t h e super s at ur at ed so l u t i o n can b e do n e b y cen t r i f ugi n g o rf i l

t r a t i o n

.
Pu ri fi c a t i o n

On ce t h e i n t e r m edi a t e o r t h e b u l k

sub s t a n ce h a s b een separ a t e d, it ma y n eed t o b e pur i f i e d. Depen d in g o n t h e i n t e r m edi a t e o r t h e b u l k s u b s t a n ce pr o duced, t h er e ma y b e sev e r a l pur i f i cat i o n st eps in v o lv ed t o pr o duce t h e desi r e d act i v e i n gr edi e n t

. I n v it a m i n

pr o duct i o n , f o r ex am pl e, t h er e ar e at l east t h r ee t o f o ur pur i f i cat i o n st eps. P u r i f i cat i o n t y pi call y

i s ach i e ve d t h r o ugh addit i o n al

Sect o r No t e b o o k Pr o j ect 26 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

separ a t i o n st eps such as t h o s e descr i b e d ab o v e. P u r i f i cat i o n i s o f t e n ach i e v e d t h

r o u g h r e c r ys t a lliz a t io n

. W a s h in g w it h a d d it i o n a l s o lv e n t s a n d filt r a t i o n ma y al so b e used.

Dryin g

T h e f i n a l st ep i n t h e ch em i cal syn t h e si s pr o cess i s dr yi n g o f t h e i n t e r m edi a t e
o r

f

i na l bu l k

s u bs t a nc e

. D r yi ng i s d o ne by e v a p o r a t i n g t h e s o lv e n t s f r o m t h e
so l i d s. S o lv en t s r e l eased f r o m dr yi n g o p er at i o n s ma y b e co n d en sed f o rr e use
o r di s p o s al ( U SE PA 1993)

.
T h er e ar e sev e r a l di f f e r e n t t y pes o f dr y e r s used b y t h e ph ar maceut i cal i n dust r y i n cl udi n g t r ay dr y e r s , r o t a r y dr y e r s , dr um o r t u m b l e dr y e r s , o r pr es s u r e f i l

t er dr y e r s

. “ T h e s e l ect i o n o f t h e dr y e r t y pe depen d s pr i ma r i l y

o n t h e ch ar act er i s t i cs o f t h e s o l i d ” ( U SE PA 1993)

.
Pr i o r t o 1980, pr o b ab l y

t h e m o s t co m m

o n t y pe o f dr y e r us ed b y t h e i n dus t r y was t h e v acuum t r ay dr y e r

. I n a v acuum t r ay dr y e r , “ t h e f i l

t er ed so l i d i s pl aced o n t r ay s wh i c h ar e t h en ma n u all y

st acked o n sh elv e s in t h e dr y e r

. W h en t h e d r y e r i s c l o s ed, t h e t r ay s ar e h eat ed t o r e m o v e an y l

i qui ds. A

v acuum i s appl i e d wit h i n t h e dr y e r so t h a t d r y i n g can t a ke pl ace at l o wer t e m p er at ur es wh en n eeded” ( U SE PA
, 1993)

.
Mo r e o f t e n t o day
, t u m b l e dr y e r s o r co m b i n at i o n f i l

t er / d r y er s ar e used. I n a
co m b i n at i o n f i l

t er / d r y er “ t h e equi pm en t n o t o n l y

act s as a f i l

t er , b u t can al so f u n c t i o n as a pr o duct dr y e r af t e rt h e sl ur r y h a s b een co m p r e ssed an d f i l

t er ed i n t o cake f o r m

. Heat i s i n t r o duced t o t h e f i l

t er / d r y ert h r o ugh a h o t gaseo u s
m

e di um wh i c h i s b l o w n up t h r o ugh t h e cake un t i l t h e des i r e d l e v e l o f dr yn es s i s ach i e v e d” ( U S E PA 1993)

. VOC em i s s i o n s ma y o ccurs in ce t h e gas wi ll

en t r ai n ev apo r at ed so lv en t wh i c h m u st b e v e n t ed f r o m t h e dr yi n g f i l

t er / d r y er

.
T u mb le d r ye r s c o n s is t o f r e v o lv in g c o n i c a l s h e lls r a n g in g in c a p a c it y fr o m 2 0 t o 100 gall o n s

. “ T h e r o t a t i o n o f t h e dr y e r t u m b l e s t h e pr o duct t o en h a n c e
so lv en t ev apo r at i o n an d ma y al so per f o r m a b l en di n g f u n c t i o n ” ( U S E P A 1979)

. T h es e dr y e r s ma y b e o p er at ed un der a v acuum o r us i n g h o t ai r ci

r c ul at i o n

. W h en o p er at ed un der a v acuum , h eat i s suppl i e d t h r o ugh

co n duct i o n f

r o m h eat ed sur f aces. S o m e ai r w ill p a s s t h r o u g h t h e e q u i p m e n t d u e t o in w a r d le a k a g e

. T hu s , t h e v a c u u m e x h a u s t w ill c o n t a i n V O C s ( U SE PA
, 1993)

. A di agr a m o f a s i m p l e t u m b l e dr y e r i s s h o w n i n F i gur e 8.

Sect o r No t e b o o k Pr o j ect 27 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### F i gu re 8: Cro ss- S ect i o n o f Typ i cal Tu m b l e Dryer

Chai n Ca s i ng

St e a m or H o t W ate r Inl e t

Conc ret e or St r u ct ur al Foun da t i on Di s c h a r g e Op e n i n g V acu um Conn ect i o n Cove r

S o u r ce: A d apt e d f r om C o n t ro l o f

V

o la tile O r gani c C o m pound E m i s s i ons f r om B a t c h P r oce s s e s , E P

A G u i d e l i n e Se r i e s , 1993.

N

a tur a l and B i ological P r oduct E x tr action

Nat u r a l pr o duct ex t r act i o n , as t h e n a m e s ugges t s , i n v o lv es i s o l at i n g an act i v e i n gr edi e n t f r o m n a t u r a l so ur ces, such as pl an t s , r o o t s, par a sit i c f u n g i o r an i ma l g l a n d s

. T h is p r o c e s s is o f t e n u s e d t o p r o d u c e a lle r g y r e lie f me d i c i n e s , in s u lin
, m

o r p h i n e , an t i

- can cer dr ugs, o ro t h e r ph ar maceut i cal s wit h un i que pr o p er t i es. Bl o o d f r a c t i o n a t i o n , used t o pr o duce pl asma , i s al so par t o f t h e n a t u r a l pr o duct ex t r act i o n pr o ces s ( U SE PA 1995)

. A s i m p l

i f

i e d di agr a m o f n a t u r a l pr o duct ex t r act i o n pr o cesses an d it s asso ci at ed wast es, i s sh o w n i n F i gur e 9.

T h e desi r e d act i v e i n gr edi e n t , u s u a l l y pr esen t i n r a w ma t e r i al s at v e r y l o w
co n cen t r at i o n s , m u st b e ex t r act ed f o rt h e f in a l pr o duct

. T h er ef o r e, a def i n in g ch ar act er i s t i c o f t h i s pr o cess i s t h at t h e v o l u m e o f f i n i sh ed pr o duct i s o f t e n an
o r dero f ma gn it ude small e r t h an t h at o f t h e r a w ma t e r i al s used. A t each st ep i n

t h e ex t r act i o n pr o cess, t h e v o l u m e o f ma t e r i al b e i n g pr o cessed i s r e duced si gn i f i can t l y

. T h i s i n h e r e n t n a t u r e o f t h e pr o cess ma kes it an ex pen s i v e o n e

Sect o r No t e b o o k Pr o j ect 28 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

t o ut i l i ze ( U SE PA 1995)

.


### F i gu r e 9: Simplif ie d P r o c e s s F l o wDiagr am f o r Natu r a l/B io lo gic a l E x tr ac tio n

M i x i n g & Wa s h i n g

Ra

w M a t e r i a l ( a n i m a l ti s s u e p l a n t t i s s ue , ro o t s , p la s m a )

W a s t ew at er ( B OD
, C O D , T S S ) Ex t r ac t i o n H 2 O

Ev a p o r at i o n

W a s t ew at er ( B OD
, C O D, T S S
, a m m oni um
s a lts
, s o lv e n t s ) S l udge ( s o l v e n t s , or

g an i c
ma

t e r i a l ) S o l v e n t va por s ( p h e n o l
, c h l o ro fo rm , me

t h e l y n e c h l o r

. )

Ac

t i v e I ngr e d i e nt

T o C o m pound i n g & F o r m u l a tio n O r ga n i c S o l v e n t s (m e t h e l y n e c h l o r i d e , c h l o ro fo r m , a l c o h o l
, to lu e n e ) S c r ubbe r W a s t ew at er ( aci d i c o r b a s i c , s o lv e n ts )

H 2 O

S o u r ce: A d apt e d f r om Ec onom i c I m

pact and R e gul at or y F l e

x i b ility A n a l y s is o f

P r opos e d E

fflu e n t G u id e lin e s fo r th e P h a r m a c e u tic a l M

anuf act u r i ng I ndus t r y, 1995.

Because o f t h e l a r g e v o l u m e r e duct i o n s i n v o lv ed, an assem b l

y

- l in e pr o cessin g
m

e t h o d
, co n s i s t i n g o f sev e r a l o p er at i o n st at i o n s i s used. A t each sub s equen t

o p er at i o n st at i o n , a l it t l e m o r e o f t h e i n er t ma t e r i al i s r e m o v e d an d t h e act i v e i n gr edi e n t i s ex t r act ed. A s t h e v o l u m e o f ma t e r i al b e in g pr o cessed decr eases, t h e si ze o f t h e co n t ai n e r s car r yi n g t h e ma t e r i al al so decr eases, f r o m co n t ai n e r s capab l e o f car r yi n g 75- 100 gall o n s t o , i n s o m e cas es , l ab o r a t o r y s i ze equi pm en t ( U SE PA 1995)

.
A c t i v e i n gr edi e n t s ar e r eco v e r e d b y pr eci pit a t i o n , pur i f i cat i o n an d so lv en t

e x t r a c t io n me t h o d s

. I n p r e c i p it a t i o n , s o lu b ilit y is c h a n g e d b y p H a d ju s t me n t , sal t f o r mat i o n , o r addit i o n o f an an t i

- s o lv e n t

. S o lv en t s ar e used as ex t r act i v e agen t s t o r e m o v e t h e act i v e i n gr edi e n t f r o m t h e r a w ma t e r i al s, such as pl an t

an d an i ma l t i ssues. S o lv en t s ar e al so used t o r e m o v e f a t s an d o i l s , wh i c h ma y
co n t am i n at e t h e pr o duct ( U SE PA 1995)

. Such s o lv en t s r e m o v e t h e f a t s an d

o ils
, w it h o u t d a ma g i n g t h e e s s e n t ia l a c t iv e in g r e d ie n t ( s ) fo u n d in t h e r a w
m a t e r i a l s. A m m

o n i a i s al so used i n t h e ex t r act i o n st ages as a m e t h o d o f

c o n t r o llin g t h e p H w h e n e x t r a c t in g fr o m a n ima l a n d p l a n t s o u r c e s

. A m m

o n i um sal t s ar e used as b u f f e r i n g ch em i cal s, an d aqueo u s o r an h y dr o u s
a mmo n i a is u s e d a s a n a l k a liz in g a g e n t

. T h e h i g h d e g r e e o f s o lu b ilit y o f

Sect o r No t e b o o k Pr o j ect 29 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

am m

o n i um s a l t s pr ev en t s un wan t ed pr eci pit a t i o n

. A l s o , am m

o n i um s a l t s h a v e t h e adv a n t age o f n o t r eact in g wit h an ima l an d/o r pl an t t i s s u es ( U S E P A 1995)

.

Sect o r No t e b o o k Pr o j ect 30 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

F

e r

m e n tation

Mo st st er o i ds, an t i bi o t i c s, an d cer t a in f

o o d addit i v e s ( s uch as v it a m i n s) ar e
co m m

o n l y

kn o w n ph ar maceut i cal s wh i c h ar e pr o duced b y f e r m en t a t i o n

. I n f e r m en t a t i o n , m i c r o o r gan i sm s ( e

. g

. , b act er i a , y east o r f

u n g i ) ar e t y pi call y i n o c ul at ed i n a l i qui d b r o t h s uppl em en t e d wit h n u t r i e n t s t h at ar e acc lima t e d t o an en v i r o n m en t ( e

. g

. , t e m p er at ur e, pH, o x y g en )
, co n duci v e t o r a pi d gr o w t h )

. T h es e m i c r o o r gan i s m s pr o duce t h e des i r e d pr o duct ( e

. g

. , an t i b i o t i c , st er o i d, v it a m i n , et c. ) as a b y

- p r o duct o f n o r mal m e t ab o l i s m

. F e r m en t a t i o n i n v o lv es t h r ee ma i n st eps: 1) i n o c ul um an d seed pr epar at i o n , 2) f e r m en t a t i o n , an d 3) pr o duct r eco v e r y

. A di agr a m o f a f e r m en t a t i o n pr o cess an d t h e wast es pr o duced in t h i s pr o ces s i s s h o w n i n F i gur e 10.



### F i gu re 10: S i m p l i f i e d P r o cess F l o wDi agram f o r t h e F erm en t a t i o n P r o cess

Fer m e n t a t i o n Br o t h

Se e d

He a t Fi l t e r H 2 O

P r od uc t Di s s o l ve d

o r

P r ecip i t a te d

W a s t ew at er

( s ol ve nt s , c oppe r , z i nc , BO D
, CO D
, T S S
, lo w p H ) S l ud ge ( s uga r s , s t ar ch e s , f e rm e n t a t i o n b r o t h s , co r n s t eep liq u o r ) S epa r a t i on s Ac t i ve In g r e d i e n t

In o c u l a t i o n

Ta

n k N u tr ie nts ( s u g a r s , s t ar ch es ) Ga s (N O 2 CO 2 , s u l f u r )

S o lv en t s o r M e t a l S a lt s (M i B K
, C u , Z n )

Fi l t e r Ca k e O r ga nic S o l v e n ts (a c e t o n e , M i B K
, 1
, 2- di c h l o r o e t ha ne )

T o C o m p ou nd in g & F o r m u l a tio n

W a s t ew at er

( s ol ve nt s )

S o u r ce: A d apt e d f r om Ec onom i c I m

pact and R e gul at or y F l e

x i b ility A n a l y s is o f

P r opos e d E

fflu e n t G u id e lin e s fo r th e P

har m a ce ut i c al M anuf act u r i ng I ndus t r y, 1995.

Sect o r No t e b o o k Pr o j ect 31 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

S eed P r ep ar at i o n

T h e f e r m e n ta ti on p r oc e s s b e g i n s w ith th e in tr od u c ti on of th e m i c r o b i a l s t r a i n t o a p r ima r y s e e d fe r m e n t a t i o n , w h ic h is c o mmo n l y p e r f o r me d u s in g s h a k in g

f l ask cul t ur e t ech n i ques at t h e l ab o r a t o r y scal e. On ce gr o w n , t h e suspen si o n i s t h en t r an sf er r e d t o f u r t he r s eed st ages, wh i c h ma y b e addit i o n al f

l ask f e r m e n ta ti o n s , s t i r r e d ta nk s or b o th

. T h e p u r p o s e of th i s “ s e e d

- t r a i n ” i s to gen e r a t e en o ugh i n o c ul um f o r t h e pr o duct i o n f e r m en t o r ( t y p i call y

1- 10% o f t h e pr o duct i o n t a nk v o l u m e )

. Gen e r a ll y , speci al seed t a nk s ar e used f o rt h e f e r m en t o r i n o c ul um wh i c h ar e m i n i a t u r e v e r s i o ns ( 1

- 10% o f s i ze) o f t h e pr o duct i o n f

e r m en t o r

. I f a seed t a n k b eco m e s co n t am i n at ed, it i s em pt i e d, st er i li zed, an d r e i n o c ul at ed.

F e rm e n ta tio n

On ce t h e f e r m en t o ri n o c ul um i s r eady
, it i s ch ar ged i n t o a st er i l i zed f e r m en t o r

. Dur i n g f e r m en t a t i o n , t h e f e r m en t o ri s usuall y agit at ed an d aer at ed. T h e pH, t e m p er at ur e, an d di sso lv ed o x y g en co n t en t o f t h e f e r m en t a t i o n b r o t h ma y b e
m

o n itor e d d u r i n g f e r m e n ta ti on

. F e r m e n ta ti on ma y l a s t f r om h o u r s to w e e k s , depen d i n g o n t h e pr o cess. A f

e r m en t o r“ b r o t h ” i s p r o d u c e d
, wh i c h i s t h en f i l

t er ed o r cen t r i f uged t o s e par a t e o u t t h e s o l i d s ( U SE PA 1991)

.
P r oduct Recovery

F ilt r a t i o n r e mo v e s a n y la r g e r r e s i d u e s fr o m t h e b r o t h
, b u t it d o e s n o t is o l a t e t h e a c t i v e i n gr edi e n t f r o m t h e r e s i dues

. T h i s m u s t b e do n e b y pr o duct

r eco v e r y pr o cesses. P r o duct r e c o ver y i s ach i e v ab l e t h r o ugh t h r ee di f f e r e n t

m

e t h o d s: so lv en t ex t r act i o n , di r ect pr eci pit a t i o n an d i o n ex ch an ge, o r ads o r p t i o n ( U S E PA 1995)

. So m e t im e s , t h e act i v e ma t e r i al i s co n t ai n e d wi t h i n t h e cell s o f t h e m i c r o o r gan i sm

. Cell wall b r eakage b y h eat o r ul

t r aso u n d
, f o r ex am pl e, ma y b e r e qui r e d t o r eco v e rt h e ma t e r i al

.
I n

so lv en t ex t r act i o n t h e act i v e i n gr edi e n t i s r e m o v e d f r o m t h e aqueo u s b r o t h b y c o n t a c t in g it w i t h

a n o r g a n i c s o lv e n t , in w h ic h t h e p r o d u c t is mo r e s o lu b l e t h an it i s i n wat e r

. Rem o v a l o f t h e act i v e agen t f r o m t h e s o l v e n t c a n b e ach i e v e d b y cr y s t a ll i zat i o n ( U SE PA 1995)

.
T h e di r ect pr eci pit a t i o n m e t h o d o f pr o duct r eco v e r y i n v o lv es pr eci pit a t i o n o f t h e act i v e i n gr edi e n t , as a m e t a l sal t f

r o m t h e b r o t h usi n g, f o r ex am pl e, co pper ( C u) an d/ o r zi n c ( Z n ) as pr eci pit a t i ng a g e n t s

. T h e act ual ch o i ce o f t h e pr eci pit a t i n g agen t depen d s o n t h e pr o p er t i es o f t h e desi r e d act i v e i n gr edi e n t

. T h e b r o t h i s t h en f

i l

t er ed an d t h e pr o duct i s r eco v e r e d f r o m t h e so li d r e si dues ( U SE PA 1991)

.
A ddit i o n all y , i o n ex ch an ge o r adso r p t i o n ma y b e used f o r pr o duct r eco v e r y

. I o n ex ch an ge r e si n ( o r al t e r n at i v el y , act i v at ed car b o n ) i s co n t act ed wit h t h e

Sect o r No t e b o o k Pr o j ect 32 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

b r o t h an d t h e pr o duct ads o r b s o n t o t h e r e s i n

. T h e pr o duct i s r eco v e r e d f r o m t h e r e si n b y usi n g a so lv en t o rb y washi n g t h e r e si n wit h an aci di c o r b a si c
s o l u t i o n

. It i s t h e n c r y s t a ll i z e d

.
III. A

. 3

. Fo rm u l a t i o n , M i x i n g , a n d C o mp o unding

“ T h e p r ima r y o b j e c t i v e o f mix in g , c o mp o u n d in g , o r fo r m u l a t in g o p e r a t io n s
ar e t o co n v e r t t h e ma n u f act ur ed bu l k sub s t a n ces i n t o a f i n a l
, usab l e f o r m

. ” ( U SE P A 1995) F i gur e 11 s h o w s a s i m p l

i f

i e d pr o ces s f l o w di agr a m f

o r
co m p o u n d i n g, f o r m ul at i o n an d packagi n g. C o mm o n do s a ge f o r m s o f p h a r maceu t i c a l p r od u c t s i n c l u d e t ab l e t s , c a p s u l e s , l i q u i d s , c r e a m s a n d

o i n t m e n t s, as well as aer o s o l s, pat c h e s an d i n j ect ab l e do sages. T ab l e 6 l i s t s
co m m

o n ph ar maceut i cal do sage f o r m s an d t h ei r uses.


### Figu re 11: Simp lif ied Pro cess Flo w Diagram f

o r Co m poundi ng a nd F o r m u latin g

Mi xi ng & G

r a nul at i o n

A c tiv eIn g r e d ie n t (D ru g ) T a bl e t i ng & En c a p s u l a tio n Wa s h in g E qui pme n t T a bl e t s and C a

ps ul es N o n

- C ont a c t Co o lin g Wa te r E x ci p i ent s & Bin d e rs (s u g a r s , s t arch es ) Sol v e n t Em is s i o n- V O Cs

W a s t ew at er ( s olv e n ts, d e t erg en t s ) Aqu e ous

- b as ed S o l v e n t s

W a s t ew at er (w as t e s t arch e s , su ga r s BO D
, CO D
, T SS) F u g itiv e e m i s s io n s , ve nt em i s s i ons Ta b l e t Du s t

S o u r ce: A d apt e d f r om Ec onom i c I m

pact and R e gul at or y F l e

x i b ility A n a l y s is o f

P r opos e d E

fflu e n t G u id e lin e s fo r th e P

har m a ce ut i c al M anuf act u r i ng I ndus t r y, 1995.

Sect o r No t e b o o k Pr o j ect 33 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

A s wit h t h e b u l k

ma n u f act ur in g o p er at i o n s , ma n y f i n a l pr o duct s ar e pr o duced in

b a t c h u t iliz in g a

c a m p a ig n r e g ime n

. A t t h e e n d o f t h e p r o d u c t i o n c a m p a ig n , an o t h e r pr o duct ma y b e f o r m ul at ed an d packaged usin g t h e sam e equi pm en t

an d t h e sam e per s o n n e l

. Addit i o n all y , f o r m ul at i o n an d packagi n g i s per f o r m e d i n acco r d an ce wit h “ g o o d m a n u f act ur i n g pr act i ces” ( G MP )

. GMP is

r e g u l a t e d b y t h e F D A a n d s e t s fo r t h t h e min imu m me t h o d s t o b e u s e d in
, a n d t h e fa c ilit ie s a n d c o n t r o ls t o b e u s e d fo r t h e m a n u f a c t u r e , p r o c e s s i n g , packi n g, o r h o l d i n g o f a dr ug t o as s u r e t h a t s u c h d r ug m eet s t h e s a f e t y
r e qui r e m e n t s an d t h e qualit y an d p u r i t y ch ar act er i s t i cs t h at it pur po r t s o r i s
r e pr es en t e d t o po s s e s s

.
F o l l o wi n g f o r m ul at i o n , t h e f i n i sh ed pr o duct m a y b e packaged at t h e sam e sit e
o rit ma y b e t r an sf er r e d t o an o t h e r sit e

. P ackagin g i n cl udes pl aci n g t h e f in a l f o r m ul at ed pr o duct s i n t o co n t ai n e r s , l ab e l i n g, an d pr epar in g f o r s h i ppi n g

.
“ T h e packagi n g co m p o n en t s o f a ph ar m aceut i cal pr o duct ar e v it a l t o it s saf e
an d ef f ect i v e use. Besi des ser v i n g t h e pat i en t as a co n v e n i en t un it o f use, t h e
co m p o s it e package ( u n it co n t ai n e r , l ab e l i n g, an d sh i ppi n g co m p o n en t s ) m u st pr o v i d e appr o p r i at e i d e n t i f i cat i o n an d n ecessar y i n f o r mat i o n f

o r pr o p er use i n cl udi n g wa r n i n g s an d ( p r e ) caut i o n s an d pr eser v a t i o n o f t h e pr o duct ’ s ch em i cal an d ph y s i cal in t e gr i t y ” ( K i r k- Ot h m er , 1994)

.
Bat c h pr o d u c t i o n r eco r d s ar e used an d descr i b e each ma n u f act ur i n g st ep i n det a i l

. A t v a r i o u s st ages i n t h e f o r m ul at i o n an d packagin g pr o c e s s , q u a l it y
co n t r o l ch eck s a r e u t i l i zed. A ll r a w ma t e r i al s ar e ch ecked pr i o rt o use i n a p r o cess an dt h e fi n a l d o s a g e f o r m s r e q u i r e a m y

r i ado f t e st s t o assu r e t h er apeut i c b e n e f it

. F o r ex am pl e, t h e co n t en t un i f o r m it y , co l o r , h o m o gen e it y , d i s s o lu t i o n , s t ab ilit y, id e n t it y , a n d p o t e n c y o f t h e p r o d u c t mu s t b e d e t e r min e d

an d m eet st at ed r a n g es. Repr esen t a t i v e sam p l e s ar e co ll ect ed at t h e en d o f t h e f o r m ul at i o n st age an d sub m it t e d t o t h e ch e mi c a l an d/ o rm i c r o b i o l o g i cal l ab o r a t o r i es f o r

f

i n a l assayi n g

. Repr esen t a t i v e sam p l e s a r e al so co ll ect ed dur i n g packagi n g o p er at i o n s

. T h e qual i t y

co n t r o l un i t o f t h e ph ar maceut i cal

ma n u fa c t u r in g c o mp a n y h a s t h e r e s p o n s i b ilit y a n d a u t h o r it y t o a p p r o v e o r
r e

je c t a ll r a w ma t e r i a l s , in

- p r o c e s s ma t e r i a l s , p a c k a g in g ma t e r i a l s in c l u d in g
co n t ai n e r s , cl o s ur es, an d l ab e l i n g ma t e r i al s, as well as t h e f i n a l pr o duct

.
T h e equi pm en t used t o f o r m ul at e an d package t h e f in a l pr o duct i s cl ean ed,

ma i n t a i n ed, an d san it i zed at appr o p r i at e i n t e r v al s. A c t u al ma i n t e n a n ce an d cl ean i n g s c h e dul es an d r e s u l t s ar e do c u m e nt e d

. A s des c r i b e d un der b u l k

ma n u f act ur i n g, t h e m e t h o d s , e qui pm en t , an d ma t e r i al s us ed ( e

. g

. , wat e r wash
, st eam , det e r g en t s , o r gan i c so lv en t s ) t o cl ean t h e equi pm en t ar e speci f i ed o n a per pr o duct b a si s.

Sect o r No t e b o o k Pr o j ect 34 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

T a bl e 6: P h arm a ceut i cal Dos age F o rm s Do sa g e Co nst i t u e nt s, pr o p e r t i e s Use s Fo r m S o lid s
pow d e r s , c o m m i nut e d o r b l e nde d, di s s o l v e d o r m i x e d w i t h w a t e r e x t e r na l
, i n t e r n a l bu l k
ef

f e r v escen t C O 2 - r el easi n g base i n gr ed i e n t s o r a l
in su f f l a tio n i n s u f f l a t o r p r o p e ls m e d i c a t e d p o w d e r in to b o d y c a v ity b o d y c a v itie s ly o p h iliz e d re c o n s titu tio n b y p h a r m a c i st o f u n s ta b l e p r o d u c ts v a rio u s u s e s in c l u d i n g par e n t er al an d or al

c a p su le s s m a ll- d o se b u lk p o w d e r e n c l o s e d in g e la tin sh e ll, a c tiv e in g r e d ie n t p l u s in te rn a l d ilu e n t

tro c h e s, p r e p a r e d b y p i p i n g a n d c u ttin g o r d i sk c a n d y te c h n o lo g y ; c o m p o unde d w i t h slo w d i sso lu tio n in m o u t h l o zen ges gl y cer ogel a t i n

co m p ressed d i ssol v ed or m i xed w i t h w a t e r ; gr eat v a r i et y of

sh apes an d f o r m u l at i o n s or al an d ext e r n al t a bl et s
p e lle ts f o r p r o l o n g e d a c tio n i m p la n t a tio n
coat ed t a bl et s c oat i n g pr ot ect i v e, sl ow r e l ease o r a l

Liq u i d S o lu tio n s
sy r u ps sw eet en er , sol v en t , m e d i ci n a l agen t f l a v o r i n g agen t , m e d i ci n a l

sp irits a l c o h o l, wa te r, v o la tile su b s ta n c e s f l a v o r o r m e d i c i n a l
col l o d i on s p y r oxy l i n i n et h e r , m e d i ci n a l agen t ( cast o r oi l
, cam ph or ) e xt er n a l f o r cor n s an d bu n i on s
par e n t er al s t er i l e , py r ogen

- f r ee, i s ot on i c , pH cl os e t o t h at of bl ood ; oi l y or aq u e ou s in tra v e n o u s, in tra m u s c u la r,
so lu tio n s so lu tio n su bcu t an eou s i n j ect i o n

o p h th a l m i c s te rile , iso t o n ic , p H c l o s e to th a t o f te a r s; v i sc o s ity b u ild e r e y e tre a t m e n t

n a s a l a q u e ou s , i s ot on i c , pH cl os e t o t h at of n a s a l f l u i d s ; s p r a y s or d r ops n o s e t r eat m e n t

m o ut hw a s h, a q u e o u s, a n tise p tic re f r e s h m e n t, sh o r t te rm gar g l e s bact er i a l con t r o l
i n h a l a t i o n s ad m i n i st er ed w i t h m ech an i cal d e v i ces m e d i cat i o n of t r ach ea or br on ch i o l e s L i q ui d Di sp e rsi o n s

s u s p en s i on s pow d e r s u s p en d e d i n w a t e r , al coh o l
, gl y c ol
, or an oi l o r a l d o s i n g , s k i n appl i cat i o n

em u l sio n s, o il- in

- w a t e r o r wa te r- in

- o il o r a l , e x te rn a l o r in je c tio n lo tio n s S emis o lid a n d p l a s tic d i s

p er s i o n s

o i n t m e n t s h y d ro c a r b o n (o ily ), a d so rp tiv e wa te r- wa sh a b le , o r wa te r- so lu b l e b a se s; ext e r n al

em u l si f y i n g agen t s , gl y c ol s, m e d i cat i n g agen t past es an d o i nt m e nt s w i t h hi g h di s p e r s e d s o l i d s a nd w a x e s , r e s p e c t i v e l y e x t e r na l

cer at es

s u ppos i t o r i es t h eobr om a oi l
, gl y c i n er at ed gel a t i n , or pol y e t h y l en e gl y c ol bas e pl u s in se rtio n in to b o d y c a v ity

m e d i ci n a l agen t S o u r ce: A dapt e d f

r om Z anow ai k
, P

. , 1995, “ P ha r m a c e u tica ls ” in Kir k -O thm e r , Encyclopedia of Chem ical T echnology,

vo l. 1 8
, 4 t h ed itio n

.

Sect o r No t e b o o k Pr o j ect 35 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

Tablets

T ab l et s acco un t f o rt h e ma j o r i t y o f s o l i d m e di cat i o n s t a ken o r all y

i n t h e Un it ed S t at es. “ T ab l e t s can b e ma de t o ach i e v e r a p i d d r ug r e l ease o rt o pr o duce del a y e d, r e peat ed o r pr o l o n g e d t h er apeut i c act i o n ” ( K i r k- Ot h m er , 1994)

. T ab l et s can b e co m p r e s s e d o rm o l d ed, an d ma y b e co at ed.

T o pr epar e a t ab l et , t h e act i v e ph ar maceut i cal i n gr edi e n t i s co m b i n ed wit h a fille r , s u c h a s s u g a r o r s t a r c h
, a n d a

b i n d e r , s u c h a s c o r n s y r u p o r s t a r c h

. T h e f ille r is a d d e d t o e n s u r e t h a t t h e a c t iv e in g r e d ie n t is d ilu t e d t o t h e p r o p e r
co n cen t r at i o n

. A b in d eri s n eeded t o b in d t ab l et par t i c l e s t o get h er

. A l u b r i can t , such as ma gn esi u m st er at e o r po l y et h y l e n e gl y c o l
, ma y b e added t o fa c ilit a t e e q u i p m e n t o p e r a t io n , o r t o s l o w d i s i n t e g r a t i o n o r d i s s o lu t i o n o f t h e act i v e i n gr edi e n t

.
T ab l et s ar e pr o duced b y co m p r e ssi o n o f po wderb l en ds o r gr an ul at i o n s

. I n di

r ect co m p r e ssi o n , t h e i n gr edi e n t s ar e b l en ded an d t h en co m p r e ssed i n t o t h e f i n a l tab l e t w ith ou t m o d i f yi n g th e p h y s i c a l n a tu r e of th e ma te r i a l i t s e l f

. “ T h e
mo s t w i d e ly u s e d a n d mo s t g e n e r a l me t h o d o f t ab l e t p r e p a r a t io n is t h e w e t

gr an ul at i o n m e t h o d ” ( R em i n gt o n , 1995)

. I n wet gr an ul at i o n , t h e act i v e in g r e d ie n t is p o w d e r e d a n d mix e d w it h t h e fille r

. T h is mix t u r e is t h e n w e t t e d

an d b l en ded wit h t h e b i n d er , f o r m i n g a so l u t i o n

. Co ar se gr an ul es f o r m wh i c h

ar e m i x ed wit h l u b r i can t s such as ma gn esi u m st ear at e an d t h en co m p r e ssed i n t o t ab l et s

. Sl uggi n g o r dr y gr an ul at i o n i s us ed wh en t ab l et i n gr edi e n t s ar e
sen s it i v e t o m o i s t u r e o rt e m p er at ur es asso ci at ed wi t h

dr yi n g o r w h e n t h e t abl e ti n g r e d i e nt s ha ve s u f f i c i e n tinhe r e nt bi nd in g o r c o he s i ve p r o p e r t i e s

. D r y gr an ul at i o n i n cl udes wei g h i n g , m i x i ng, s l uggi n g , dr y s c r een i n g, l u b r i cat i o n , an d co m p r e s s i o n

. Sl uggi n g r e qui r e s l a r g e h eav y pr es s e s t o co m p r e s s l ar g er t ab l et s, b e t w een 20- 30 gr am s i n wei g h t

. T h ese l a r g e t ab l et s ar e t h en gr o u n d

a nd scr een ed t o a desi r e d m e sh si ze t h en r eco m p r e ssed i n t o f i n a l t ab l e t s ( U SE PA
, 1991)

.
C o a t in g ma y b e u s e d t o o ffe r p r o t e c t io n fr o m mo is t u r e , o x yg e n , o r lig h t , t o
ma sk un pl easan t t a st e o r appear an ce, an d t o i m p ar t di st i n ct i v e co l o r s t o fa c ilit a t e p a t i e n t r e c o g n it io n

. “ E n t e r ic c o a t in g s ar e u s e d t o d e la y t h e r e le a s e
o f t h e act i v e i n gr edi e n t i n t h e st o mach an d pr o l o n g t h er apeut i c act i v it y

. T h e l a t t e r ar e used f o r dr ugs t h at ar e un st ab l e t o gast r i c pH o re n z y m e s , c a u se
n a usea an d v o m it i n g, o r i r r it a t i o n t o t h e st o mach
, o r sh o u l d b e pr esen t i n h i gh

co n cen t r at i o n s i n t h e i n t e s t in es ” ( K i r k- Ot h m er , 1994)

. C o at i n g i s do n e i n a
r o t a r y dr um

. T h e co at i n g so l u t i o n i s po ur ed o n t o t h e t ab l et s

. I n m a n y
o p er at i o n s , aqueo u s co at i n g so l u t i o n s ar e n o w used i n st ead o f so lv en t b a sed ( u suall y m e t h y l en e ch l o r i de) so l u t i o n s. A s t h e dr um r o t a t e s, t h e t ab l et s b eco m e co at ed. On ce co at ed, t h ey ar e dr i e d i n t h e dr um an d ma y b e sen t t o
an o t h e rr o t a r y dr um f

o rp o l i s hi ng

. P o l i s h i n g wo r k s b y t h e f r i c t i o n cr eat ed

Sect o r No t e b o o k Pr o j ect 36 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

wh en t h e t a bl et s r o t a t e an d r u b agai n s t each o t h e r

. Un

- c o a t e d t ab l et s ma y
a l s o be p o l i s he d

.
O n c e t h e t abl e t s p a s s q u a l i t y

c o nt r o l r e q u i r e m e nt s , t h e y ma y be he l d o r s e nt di

r ect l y

t o packagi n g. Co at ed t ab l et s ar e st am ped wit h i d en t i f yi n g i n f o r mat i o n (e .g ., b r a n d n a m e , c o d e n u m b e r) i n a ro t a ry ink p r e s s

.
C

aps ules

A f t e rt ab l et s, t h e m o st co m m o n so l i d o r al do sage f o r m i s t h e capsul e

. C a p s u l e s c o me in s o ft a n d h a r d s h e lle d v a r i e t ie s

. H a r d c a p s u le s o r “ d r y

- f ille d ”

c a p s u le s a r e fo r m e d b y d i p p i n g me t a l p i n s in t o a s o lu t i o n o f g e la t i n o f a spec i f i c t e m p er at ur e. T h e t e m p er at ur e co n t r o l s t h e v i sco s i t y

o f t h e gel a t i n
an d h e n ce t h e t h i c k n e s s o f t h e capsul e wall s

. W h en t h e pi n s ar e r e m o v e d f r o m t h e so l u t i o n , a h a r d co at in g o f gel a t i n f o r m s o n t h e pi n s

. T h e co at i n g i s d r ie d a n d t r imme d

. “ T h e s e c a p s u le s a r e fille d b y in t r o d u c in g t h e p o w d e r e d

ma t e r i al i n t o t h e l o n g er en d o r b o dy an d t h e capsul e an d t h en sl i ppi n g o n t h e cap. ” ( R em i n gt o n , 1995)

S o ft s h e lle d c a p s u le s a r e fo r m e d b y p l a c i n g t w o c o n t in u o u s g e la t i n films b e t w een r o t a r y di e pl at es. A s t h e pl at es ar e b r o ugh t t o get h er , t h e t w o gel a t i n films jo in a n d s e a l
, fo r min g t h e t w o h a lv e s o f t h e c a p s u le

. A s t h e t w o h a lv e s j o i n , t h e i n gr edi e n t s, wh i c h can b e a l i qui d, past e o r po wder
, ar e i n j ect ed i n t o t h e c a p s u le s

. “ C o mme r c ia lly fille d s o ft g e la t i n c a p s u le s c o me in a

w i d e c h o i c e
o f

s i zes an d s h apes : t h ey ma y b e r o un d, o v al
, o b l o n g , t u b e o r s uppo s it o r y

sh aped” ( R em i n gt o n )

. Liquid Dos age

I n f

o r m ul at i n g a l i qui d pr o duct
, t h e i n gr edi e n t s ar e f i r s t wei g h e d an d t h en di sso lv ed i n an appr o p r i at e l i qui d. T h e so l u t i o n s ar e m i x ed i n gl ass- l i n ed o r st ai n l ess st eel v e ssel s , af t e r wh i c h t h ey ar e st o r ed in t a nk s be f o r e f i n a l packagi n g. P r eser v a t i v e s ma y b e added t o pr ev en t m o l d an d b act er i a l gr o w t h

. I f

t h e liq u i d w ill b e u s e d f o r i n je c t io n o r o p h t h a lmic u s e , s t e r iliz a t io n is

r e qui r e d. I n t h i s case, t h e co n t ai n e r , wh i c h ha s a l s o b een pr ev i o usl y
s t e r iliz e d/ d e p yr o g e n a t e d
, is fille d w it h liq u i d w h ic h h a s e it h e r b e e n r e n d e r e d st er i l e b y asept i c f i l

t r a t i o n i n a st er i l e en v i r o n m en t an d/ o rt h e en t i r e co n t ai n e r
an d it s co n t en t s ar e t e r m i n all y

h eat st er i l i zed i n an aut o cl av e.

Ointments and C r eams

Oi n t m e n t s ar e usuall y

ma de b y b l en di n g t h e b u l k

act i v e in gr edi e n t wit h a b a se, such as a pet r o l eum der i v a t i v e o r wax

. T h e m i x t u r e i s co o l ed, r o ll e d o u t , an d po ur ed i n t o t u b e s b y mach i n es an d packaged ( U SE PA
, 1991)

.

Sect o r No t e b o o k Pr o j ect 37 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

Cr eam s ar e sem i s o l i d em ul si o n s an d ar e eit h ero i l

- i n

- w at ero r wat e r

- i n- o i l
, r a t h ert h an b e i n g pet r o l eum b a sed. “ G en er all y , t h e i n gr edi e n t s o f t h e t w o ph ases ar e h eat ed separ a t e l y , t h en ar e m i x ed an d st i r r e d v i go r o usl y

t o ach i e v e
em ul s i f i cat i o n ” ( K i r k- Ot h m er , 1994)

.
A s wit h al l o t h e r do sage f o r m s , e q u i pm en t i s wash ed an d cl ean ed b a sed o n b a t c h r eco r d r e qui r e m e n t s. Ho wev e r , b ecause o f t h e gr easy n a t u r e o f

o i n t m e n t an d cr eam pr o duct i o n , cl ean in g o f t e n i s do n e wi t h

det e r g en t s

.

Sect o r No t e b o o k Pr o j ect 38 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

III. B

. R a w M a t e ri a l I nputs and P o l l u tant Outputs

P h ar maceut i cal b a t c h pr o cesses use n u m e r o us r a w ma t e r i al s an d gen e r a t e
w a st es an d em i ssi o n s. I n g e n e r a l
, t h e w a st e an d em i ssi o n s g e n e r a t e dd e p e n d

o n t h e r a w ma t e r i al s an d equi pm en t used, as w e ll as t h e ma n u f act ur i n g pr o cess em pl o y ed. I n desi gn i n g b u l k ma n u f act ur i n g pr o cesses, co n s i d er at i o n is

g i v e n t o t h e a v a ilab ilit y o f t h e s t a r t i n g ma t e r i a l s a n d t h e i r t o x i c it y , a s w e ll

a s t h e w a s t e s (e .g ., m o t h e r l i q u o rs , f i l

t e r re s i d u e s , a n d o t h e r b y -p ro d u c t s ) a n d t h e em i ssi o n s gen e r a t e d. A descr i pt i o n o f so m e o f t h e co n s i d er at i o n s gi v e n is

p r o v id e d in S e c t io n V
, P o llu t i o n P r e v e n t i o n O p p o r t u n it ie s

.
W h en b u l k ma n u f act ur i n g r eact i o n s ar e co m p l e t e , t h e so lv en t s ar e ph y s i call y
s e par a t e d f r o m t h e r e s u l t i n g pr o duct

. Due t o pur it y co n cer n s , s o lv en t s o f t e n
a r e n o t r e used i n a ph ar maceut i cal pr o cess. T h ey ma y b e so l d f o r no nph ar maceut i cal uses, used f o rf u el b l en di n g o p er at i o n s , r ecy cl ed, o r dest r o y e d t h

ro u g h i n c i n e ra t i o n

.
T h i s sect i o n descr i b e s t h e r a w ma t e r i al s an d asso ci at ed wast e st r e a m s a n d

so m e o f t h e m o r e co m m

o n t ech n o l o gi es used t o co n t r o l t h ese wast es. Much

o f

t h is in fo r ma t io n is s u mma r i z e d in T ab l e 7

.

Sect o r No t e b o o k Pr o j ect 39 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

T a bl e 7: Sum m a ry of T y pic a l M a te ri al I nputs and P o l l u tion Outputs in the P h arm a c e u tic a l I ndus try P r o ces s I np u t s (ex a m pl es o f

s o me c o mmo n l y

u s e d ch em ica l s pro v i ded) Ai r E m i s s i on s W a s tewa ter R es i d u a l Wa st e s

Che m i c a l Sy nt he si s

- Rea ctio n S o lv e n ts , c ataly s t s , r e ac tan ts , e

. g

. b e n z e n e , c h lo r o f o r m , me th y l e n e
c h lo r i d e , to lu e n e , me th an o l , e t h y le n e g l yc o l , me th y l is o b u ty l ke t o n e (M i B K )
, xy l e n e s , h y d r o c h l o r ic ac id , e t c

. VOC e m i ssi o n s f r o m
r e ac to r v e n t s , man w a y s , mate r ial lo ad in g an d

u n lo ad in g , ac id g a s e s ( h alo g e n ac id s , s u lf u r d i o x id e , n itr o u s o x id e s ) ; f u g itiv e e mis s i o n s , f r o m pum ps , s a m p l e
c o lle c tio n s , v alv e s , tan k s Pr o c e ss w a st e w a t e r s w i t h

s p e n t s o lv e n ts , c ataly s t s , r e ac tan ts ; p u m p s e al w ate r s , w e t s c ru b b e r w a s t e w a t e r; eq u i p m en t cl ea n i n g
w a s t e w ate r ; w a s t e w ate r
m a y b e

h i g h i n B OD, C OD, T S S w i t h pH o f 1-11. R e ac tio n r e s i d u e s
an d r e ac to r b o tto m w a s t e s

- Se par at i o n S e p a r atio n an d e x tr ac tio n
s o lv e n ts , e

. g .. me th an o l
, t o l u en e, h e x a n e s , et c. VOC e m i ssi o n s f r o m f ilte r i n g s y s t e m s w h ic h

ar e n ’ t c o n tain e d ; an d f u g itiv e e mis s i o n s f r o m
v alv e s , tan k s an d

c e n tr if u g e s E q u i p m en t cl ea n i n g w a s h

w ate r s , s p ills , le ak s , s p e n t

s e p a r atio n s o lv e n ts

- P u r ifica tio n P u r i f i c atio n s o lv e n ts e

. g

. . me th an o l , to lu e n e , a cet o n e, h e x a n e s , et c. S o lv e n t v a p o r s f r o m p u r if ic atio n tan k s ; f u g itiv e e mis s i o n s E q u i p m en t cl ea n i n g w a s h

w ate r s , s p ills , le ak s , s p e n t p u r if ic atio n s o lv e n ts

- D r yin g F i n i s h e d a c t i v e dr ug(s ) o r in te r m e d iate s VOC e m i ssi o n s f r o m
man u al lo ad in g an d

u n lo ad in g o f d r ye r s E q u i p m en t cl ea n i n g w a s h

w ate r s , s p ills , le ak s

N a t u ra l P r o d u c t Ex tr ac ti o n P lan ts , r o o t s , an imal tis s u e s , e x tr ac tio n
s o lv e n ts , e

. g .. ammo n ia,

c h l o ro f o rm , p h e n o l
, t o l u en e, et c. S o l v e n t v a po r s & V O C’s f r o m e x tr ac tio n
c h e mic als E q u i p m en t cl ea n i n g w a s h

w ate r s , s p e n t s o lv e n ts ( ammo n ia) ; n atu r al p r o d u c t

e x tr ac tio n w a s t e w ate r h a v e l o w B OD, C OD, T SS a n dp H

o f

6-8. Sp e n t r a w mate r ials ( p lan ts , r o o t s et c. )

F e r m e n tati o n In o c ul um , s uga r s , s tar c h e s , n u tr ie n t s , p h o s p h ate s , f e r m e n tatio n
s o l v en t s , e. g

. . et h a n o l
, amy l alc o h o l , me th an o l
, M i B K
, a cet o n e, et c. Od o r i f e r o u s g a se s,
e x tr ac tio n s o lv e n t v a p o r s , p a r tic u late s S p e n t f e rm e n t o r b r o t h, f e r m e n tatio n w a s t e w ate r
c o n tain in g s u g a r s , s tar c h e s , n u tr ie n t s , e t c

. ; w a s t e w ate r t e nd s t o ha v e hi g h B O D
, CO D
, T S S a n d h a v e pH o f 4- 8. W a s t e f ilte r c a k e , f e r m e n tatio n
r e si d u e s

F o r m u l ati o n A c t i v e dr ug, b i n d e r s (s t a r c h e s ), s uga r , s y r ups , et c. Tab le t d u s ts , o t h e r p a r tic u late s E q u i p m en t cl ea n i n g w a s h

w ate r s ( s p e n t s o lv e n ts )
, s p ills
, le ak s ; w a s h w ate r s ty p i c ally

c o n tain lo w le v e ls o f B O D
, CO D
, T S S a n d h a v e pH o f 6- 8. P a r tic u late s , w a s t e p a ck a g i n g , r e

j e c t e d tab le ts , ca p s u l es et c.

S o u r c e : D e v e lo p m e n t D o c u me n t f o r P r o p o s e d Ef f l u e n t L imitatio n s G u id e lin e s an d S tan d a r d s f o r th e P h ar mac e u tic al M a n u f a c t ur i n g P o i n t S o ur c e Ca t e go r y , U S E P A
, W a s h i n gt o n , D C

. , F e b r ua r y 1995.

Sect o r No t e b o o k Pr o j ect 40 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

III. B

. 1

. R a w M a t e ri a l s

“ T h e ph ar maceut i cal ma n u f act ur i n g i n dust r y dr aws upo n wo r l dwi d e so ur ces f o rt h e m y

r i ad o f r a w ma t e r i al s i t ne e d s t o pr o duce m e di ci n a l ch em i cal s. F e r m e n t a t i o n o p e r a t io n s r e q u i r e ma n y n e w r a w ma t e r i a l s fa llin g in t o g e n e r a l ch em i cal cl assi f i cat i o n s such as car b o h y dr at es, car b o n a t e s, st eep l i quo r s , n

it r o g en , an d ph o s ph o r us co m p o u n d s, an t i

- f o a m agen t s , an d v a r i o u s aci ds an d b a ses. T h ese ch em i cal s ar e used as car b o n an d n u t r i e nt s o u r c e s , as f o am
co n t r o l addit i v e s, an d f o r pH adj u st m e n t i n f

e r m en t a t i o n pr o cesses. Var i o u s
so lv e n t s , aci ds, an d b a ses ar e al so r e qui r e d f o r ex t r act i o n an d pur i f i cat i o n p r o cesses.

Hun d r e ds o f r a w ma t e r i al s ar e r e qui r e d f o r t h e ch em i cal syn t h e si s pr o cesses used b y t h e i n dust r y

. T h ese i n cl ude o r gan i c an d in o r gan i c co m p o u n d s an d ar e used i n gas, l i qui d, an d so l i d f o r m s. P l an t an d an i ma l t i ssues ar e al so used b y t h e ph ar maceut i cal ma n u f act ur i n g i n dust r y t o pr o duce v a r i o u s b i o l o g i cal an d

n a t u r a l ex t r act i o n pr o duct s ” ( E PA
, 1995)

.
E ach ma n u f act ur i n g o r f o r m ul at i o n pl a n t i s speci al
, di f f e r i n g f r o m o t h e r
s imila r p h a r maceut i cal pl an t s i n si ze, t y pes o f in t e r m edi a t e s, b u l k

sub s t a n ces,
o r pr o duct s pr o duced, am o u n t s an d t y pes o f s o lv en t s us ed, an d t hus , i n t h e
r a w ma t e r i al s used an d wast es/ e m i s s i o n s g e n e r a t e d. Mo st b u l k p h a r m aceu t i c a l r eact i o n s r e qui r e o r gan i c so lv en t s t o di sso lv e ch em i cal i n t e r m edi a t e s an d r eagen t s

. Because o f t h e h i gh r eact i v it y o f ma n y ph ar maceut i cal r eagen t s an d i n t e r m edi a t e s, ph ar maceut i cal so lv en t s m u st b e
no n- r eact i v e, pr o v i d e an en v i r o n m en t wh i c h all o ws ef f i ci en t h eat t r an sf e r dur i n g en do t h er m i c o r ex o t h e r m i c r eact i o n s , an d f ac ilit a t e e ffic i e n t e l e c t r o n t r an sf er

. Of t e n h a l o gen a t e d so lv en t s , such as m e t h y l en e ch l o r i de, pr o v i d e t h e op t i m u m c h oi c e f o r p h a r maceu t i c a lr eact i o n s

. T h e m o st co m m

o n l y

used

so lv en t i n t h e ph ar maceut i cal i n dust r y i s m e t h an o l
, an o x y g en at ed o r gan i c
so lv en t

. Ot h e r co m m

o n so lv en t s used ar e et h a n o l
, acet o n e, an d i s o p r o pan o l

. T ab l es 8, 9, an d 10 sh o w t h e t y pi cal so lv en t s ( a n d w h et h e ro rn o t t h ey ar e pr i o r it y po ll u t a n t s o rh azar do us ai r po ll u t a n t s) used i n ch em i cal synt he s i s , b i o l o g i cal an d n a t u r a l ex t r act i o n , an d f e r m en t a t i o n pr o cesses, r e spect i v el y

.
F i n a l b u l k

sub s t a n ces f r o m t h e b u l k

ma n u f act ur i n g pr o cesses ar e used i n f o r m ul at i o n o p er at i o n s , al o n g wi t h

o t h e rr a w m a t e r i al s o ri n gr edi e n t s. T h e p r o d u c t i o n o f t h e s e i n g r e d i e n t s i s d e s c ri b e d u n d e r Se c t i o n III.A

. 2

.

Sect o r No t e b o o k Pr o j ect 41 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### Tab l e 8: S o l v en t s Used i nt h e Ch em i c al S y n t h e si s P r o cess

C h e m ica l P rio rit y P o l l u tan t Unde r t h e C l e a n Wate r Ac t Ha za rd o u s A ir P o llu t a n t

u n d er t h e Cl e a n Ai r Ac t C h e m ica l P rio rit y P o l l u tan t Unde r t h e C l e a n Wate r Ac t Ha za rd o u s Ai r P o l l u tan t

u n d er t h e Cl e a n Ai r Ac t
A cet on e E t h y l en e gl y c ol X Ac e t o n itrile X F o r m a ld e h y d e X A m m o ni a ( a que o u s ) Fo r m a m i d e

n

- A my l acet at e F u r f u r a l Amy l Alc o h o l n

- H e p ta n e An ilin e X n

- H e x a n e X B e n zen e X X I sobu t y r a l d eh y d e 2- B u t a no ne ( M EK ) X I s o p r o p a no l

n

- B u t y l acet at e I sopr opy l acet at e

n

- B u t y l al coh o l I s opr opy l et h e r C h l o r oben zen e X X M et h a n o l X C h lo ro f o rm X X M e th y l a m in e C h lo ro m e th a n e X X M e t h y l c e llu lo se C y an i d e X M e t h y l en e ch l o r i d e X X C y cl oh exan e M et h y l f o r m at e

o- D i ch l o r oben zen e ( 1
, 2

- D i ch l o r oben zen e) X M e t h y l iso b u ty l k e to n e (M iB K ) X

1, 2- D i c h l o r o b e nz e n e X 2- M e t h y l p y r i di ne D i e t hy l a m i e P e t r o l e um na p h t h a D i e t hy l Et he r P he no l X X N,N- Dim e th y l acet am i d e P o ly e t h y le n e g l y c o l 600 D i e t hy l a m i ne n- Pr o p a no l N,N- Dim e th y l a n ilin e X P y r id in eN,NDim e th y l f o rm a m id e X T e t r a hy dr o f ur a n

Dim e th y l su lf o x i d e T o lu e n e X X 1, 4- D i o x a ne X T r i c h l o r o f l o r o m e t ha ne Et ha no l T r i e t hy l a m i ne X E t h y l acet at e X y l en es X

S o u r ce: adapted fr om D evelopm ent D o cum e nt for P r opos ed Effluent G u idelines and Standar ds for the P har m a ceutical Manuf ac t u r i ng P o i n t Sour c e Cat e gor y , 1995 and U S

E

n v i r onm e n t L a w s , 1994.

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### T a ble 9: So lve n ts U s e d in B i o l o g ic al an d N a tu r a l P r o d u c t E x tr ac tio n
C h e m ica ls P rio rit y P o l l u tan ts

u n d er t h e C l e a n Wate r Ac t Ha za rd o u s Ai r P o l l u tan ts

u n d er t h e Cl e a n Ai r Ac t C h e m ica ls P rio rit y P o l l u tan ts

u n d er t h e C l e a n Wate r Ac t Ha za rd o u s Ai r P o l l u tan ts

u n d er t h e Cl e a n Ai r Ac t
A cet on e E t h y l en e gl y c ol X Ac e t o n itrile X F o r m a ld e h y d e X A m m o ni a ( a que o u s ) n- H e p t a n e

n

- A my l acet at e n

- H exan e X A my l al coh o l I s opr opan o l

n

- B u t y l al coh o l I sopr opy l acet at e C h l o r o f o r m X X I s opr opy l et h e r 1, 2- D i c h l o r o e t ha ne X M e t ha no l X D i e t hy l a m i ne M e t h y l e n e ch l o r i d e X X

D i et h y l et h e r P et r o l e u m
n a ph t h aN,ND i e t h y l f o r ma mi d e X P he no l X X

D i m e t h y l s u l f oxi d e n

- P r opan o l 1, 4- D i o x a ne X P y r i d i n e Et ha no l T e t r a hy dr o f ur a n E t h y l acet at e T ol u e n e X X S o u r ce: adapted fr

om D evelopm ent D o cum e nt for P r opos ed Effluent G u idelines and Standar ds for the P har m a ceutical Manuf ac t u r i ng P o i n t Sour c e Cat e gor y , 1995 and U S

E

n v i r onm e n t L a w s , 1994.



### Tab l e 10: S o l v en t s Used i nF erm en t a t i o nP r o cesses
C h e m ica ls P rio rit y P o l l u t a n t s Unde r th e C l e a n Wate r Ac t Ha za rd o u s Ai r P o l l u tan ts

u n d er t h e Cl e a n Ai r Ac t C h e m ica ls P rio rit y P o l l u t a n t s Unde r th e C l e a n Wate r Ac t Ha za rd o u s Ai r P o l l u tan ts

u n d er t h e Cl e a n Ai r Ac t
A cet on e n

- H ept a n e A cet on i t r i l e X n

- H exan e X A m m o n i a ( a q u e ou s ) I s opr opan o l

n

- A my l acet at e I sopr opy l acet at e A my l al coh o l M et h a n o l X

n

- B u t y l acet at e M et h y l

c e llu lo se

n- B u t y l a l c o ho l M e t hy l e ne ch l o r i d e X X

C h lo ro f o rm X X M e th y l iso b u ta n e k e to n e (M iB K ) X

Sect o r No t e b o o k Pr o j ect 43 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### Tab l e 10: S o l v en t s Used i nF erm en t a t i o nP r o cessesN,ND i e t h y l f o r ma mi d e X P e t r o l e u m
n a ph t h a Et ha no l P he no l X X E t h y l acet at e T ol u e n e X X Fo r m a l de hy de X T r i e t hy l a m i ne X S o u r ce: adapted fr om D evelopm ent D o cum e nt for P r opos ed Effluent G u idelines and Standar ds for the P har m a ceutical Manuf ac t u r i ng P o i n t Sour c e Cat e gor y , 1995 and U S

E

n v i r onm e n t L a w s , 1994.

III. B

. 2

. A i r Emi ssi o n s a n d C o n t r o l S y st ems

Bo t h gaseo u s o r gan i c an d i n o r gan i c co m p o u n d s, as well as par t i c ul at es, ma y b e em it t e d dur i n g ph ar maceut i cal ma n u f act ur in g an d f o r m ul at i o n

. S o m e o f t h e v o l a t i l e o r gan i c co m p o u n d s ( VOC) an d in o r gan i c gases t h at ar e em it t e d

ar e cl assi f i ed as h azar do us ai r po ll u t a n t s ( H A P s) un dert h e Cl ean A i rA c t

.
T h e t y pe an d am o u n t o f em i ssi o n s gen e r a t e d ar e depen d en t o n t h e o p er at i o n s
co n duct e d b y t h e f aci l i t y , as well as h o w t h e pr o duct i s ma n u f act ur ed o r f o r m ul at ed. “ E ach ( p h ar maceut i cal ) pl an t i s un i que, d i f f e r in g f r o m o t h e r pl an t s in s i ze, t y pes o f pr o duct s ma n u f act ur ed, am o u n t s an d t y pes o f V O C

us ed, an d ai r po ll u t i o n co n t r o l pr o b l e m s en co un t e r e d” ( E PA
, 1979)

.

B u lk M anuf actur i ng

A s pr ev i o usl y

descr i b e d, t h e i n dust r y ma n u f act ur es m o st b u l k

ph ar maceut i cal sub s t a n ces an d i n t e r m edi a t e s i n cam pai g n s v i a b a t c h pr o cesses. F o ll o wi n g t h e
co m p l e t i o n o f o n e ca m p ai gn , an o t h e rb u l k

sub s t a n ce o ri n t e r m edi a t e i s t y

pi call y

ma de usi n g t h e sam e equi pm en t ( e

. g

. , r eact o r s, f i l

t er s, dr y e r s )

. T h e
r eact an t s an d so lv en t s used i n ma n u f act ur i n g t h e n e x t b u l k

subst a n ce o r in t e r m e d ia t e ma y v a r y g r e a t ly fr o m t h e o n e s p r e v io u s l y u s e d

. W h ile s o me
r eact i o n s ma y r e qui r e t h e use o f h a l o gen a t e d so lv en t s , t h e n e x t r eact i o n ma y
use an o t h e r so lv en t o r n o so lv en t at all

.
T h is w i d e v a r i a t io n s in b u lk ma n u fa c t u r in g ma k e s p r e d ic t i n g t y p i c a l o r a n n u a l

av er age em i ssi o n s di f f i cul t

. T h i s i s b ecause t h e em i ssi o n gen e r a t e d ar e pr edi cat ed o n wh at b u l k sub s t a n ce o rin t e r m edi a t e i s ma n u f act ur ed an d o v er wh at l e n g t h o f t i m e , an d wh i c h equi pm en t an d r a w ma t e r i al s ar e used. S o m e b u lk s u b s t a n c e s a n d in t e r m e d ia t e s a r e ma d e fr e q u e n t ly, w h ile o t h e r s ma y b e
ma de o n l y

o n ce ev er y t w o t o t h r ee y ear s o v er a o n e t o t w o week per i o d

. T h i s h a s o f t e n pr ev en t e d t h e cal cul a t i o n o f t y pi cal emi s s i o n r a t e s f o r each

o p er at i o n

. Ho wev e r , an appr o x i ma t e r a nk i n g o f em i ssi o n so ur ces h a s b een
es t ab l i s h e d b y E P A an d i s pr es en t e d b e l o w in o r der o f decr eas i n g ma gn i t ude. T h e fir s t fo u r s o u r c e s g e n e r a lly w ill acco un t f o rt h e ma j o r it y o f em i ssi o n s f r o m a b u l k

ma n u f act ur i n g pl an t

.

� Dr y e r s

Sect o r No t e b o o k Pr o j ect 44 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

Dr y e r s � React o r s

� D i s t illa t i o n u n it s

� S t o r age an d t r an sf ero f ma t e r i al s

� F ilt r a t i o n

� E x t r act i o n

� C e n t r i f ugat i o n

� C r ys t a lliz a t io n

ar e o n e o f t h e l a r g e s t so ur ces o f VOC em i ssi o n s i n b u l k

ma n u f act ur i n g. I n addi t i o n t o t h e l o s s o f s o lv en t dur i n g d r y i ng, ma n u al l o adi n g an d un l o adi n g o f dr y e r s can r e l ease so lv en t v a po r s i n t o am b i en t ai r , especi all y wh en t r ay dr y e r s ar e used. VOCs ar e al so gen e r a t e d f r o m r eact i o n
an d separ a t i o n st eps v i a r eact o rv e n t s an d ma n w ay s. Cen t r i f u g e s m a y b e a
so ur ce o f VOC em i ssi o n s , especi all y

in t o p l o adi n g t y pes, wh er e so l i d s ar e
ma n u a lly s c o o p e d o u t

.
T y pi cal co n t r o l s f o rt h e s e em i ssi o n so ur ces, ex cl udi n g st o r age an d t r an sf er
o p er at i o n s , i n cl ude co n d en ser s , scr u b b e r s , car b o n ab so r b er s an d, o n o ccasi o n , i n ci n e r a t o r s

. “ S t o r a ge an d t r an sf er em i ssi o n s can b e co n t r o ll e d b y v a po r
r e t u r n l

i n e s , ve ntc o nd e n s e r s , c o ns e r va t i o n ve nt s , ve nts c r u bbe r s , p r e s s u r e t a nk s an d car b o n ab so r b er s. F l o a t i n g r o o f s ma y b e f easi b l e co n t r o l s f o r

l a r g e
v e r t i cal s t o r age t a nk s ” ( E PA
, 1979)

.

F

o r m ulation

B o t h par t i c ul at es an d VOC s m a y be f o r m ed dur i n g m i x i n g, co m p o u n d i n g, f o r m ul at i o n , an d packa g i n g s t eps. Because t h ese co m p o u n d s ma y po se a d a ngert o wo r k er s, t h r o ugh di r ect i n h a l a t i o n , t h ey ar e a pr i n ci pal co n c e r n. Depen d i n g o n t h e pr o cess an d t h e b a t c h r eco r d r e qui r e m e n t s, t h e par t i c ul at es ( e

. g

. , t ab l et dust s ) ma y b e r ecy cl ed b ack i n t o t h e f o r m u l a t i o n pr o cess. Ho wev e r , so m e t i m e s t h e par t i c ul at es ar e co ll ect ed f o r dest r u ct i o n o r di spo s al

.
A s in b u lk ma n u fa c t u r in g , t h e t y p e a n d q u a n t it y o f c o mp o u n d s e mit t e d d e p e n d s o n t h e o p e r a t io n

. F o r e x a m p l e , fo r m u l a t io n fa c ilit ie s ma y o r ma y n o t

em it VOCs. S o m e f o r m ul at i o n o p er at i o n s do n o t r e qui r e t h e use o f so lv en t s , s o m e m a yo n l y

use so lv en t s f o r cl ean in g, an d so m e ma y use so lv en t s i n g r a n u l a t io n a n d c o a t in g o p e r a t io n s

. I n s o me fa c ilit ie s , o r g a n i c c o mp o u n d s , such as et h a n o l o ri s o p r o py l al co h o l
, m i g h t b e used i n t h e f o r m ul at i o n o f t h e pr o duct an d VOC s ma y b e em i t t e d dur i n g m i x i n g, f o r m ul at i o n , an d/o r packagi n g.

A i r P o llution C ontr o l E quipment

Mo r e t h an o n e t y pe o f ai r co n t r o l equi pm en t ma y b e used at an y o n e t im e i n
a n y o n e fa c ilit y. A d e s c r i p t io n o f t h e v a r i o u s e q u i p m e n t u s e d b y t h e in d u s t r y

Sect o r No t e b o o k Pr o j ect 45 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

is

p r o v id e d b e lo w

.
C o nde ns e r s . Co n d en ser s ar e wi del y

used i n t h e ph ar maceut i cal i n dust r y t o
r eco v e r so lv en t s f r o m pr o cess o p er at i o n s ( a pr o cess co n d e n s e r ) an d as ai r p o ll u t i o n c o nt r o l d e vi c e s t o r e m o ve V O C s f r o m ve nt e d g a s e s

. P r o c e s s
co n d en ser s di f f e rf r o m co n d en ser s used as ai r po ll u t i o n co n t r o l dev i ces as t h e pr i ma r y pur po se o f a pr o cess co n d en seri s t o r eco v e rma t e r i al as an in t e gr al par t o f a un it o p er at i o n

. T h e pr o cess co n d en ser i s t h e f i r s t co n d en serl o cat ed af

t e r t h e pr o ces s equi pm en t an d s uppo r t s a v a po r

- t o

- l i qui d ph as e ch an ge f o r t h e va p o r s pr o duced i n t h e pr o ces s equi pm en t

. E x am pl es o f pr o ces s
c o n d e n s e r s in c l u d e d i s t illa t i o n c o n d e n s e r s , r e flu x c o n d e n s e r s , p r o c e s s
co n d en ser s i n l

i n e b e f o r e t h e v acuum so ur ce, an d pr o cess co n d en ser s used i n st r i ppi n g o r f l ash i n g o p er at i o n s

. T h e pr i ma r y pur po se o f a co n d en ser used

a s

a n a i r p o llu t i o n c o n t r o l d e v i c e is t o r e mo v e V O C s p r io r t o v e n t in g

.
C o n d en s a t i o n i s t h e pr o ces s o f co n v e r t i n g a gas o r v a po r t o l i qui d. I n t h i s
m

e t h o d
, gas st r eam s f r o m v e n t s co n t ai n i n g VOCs ar e co o l ed t o b e l o w t h ei r sat u r a t i o n t e m p er at ur es, co n v e r t i n g t h e gas i n t o a VOC l i qui d. T h i s r e m o v e s
s o me V O C s fr o m t h e g a s , b u t s o me r e ma in s

. T h e a m o u n t o f V O C s r e ma in in g in

t h e g a s d e p e n d s o n t h e t e mp e r a t u r e a n d v a p o r

- liq u i d e q u ilib r i u m o f t h e VOC. L o wer i n g t h e t e m p er at ur e o f t h e co n d en ser gen e r a ll y l o w e r s t h e
co n t en t o f VOC i n t h e gas st r eam

.

“ I n t h e m o st co m m

o n t y pe, sur f ace co n d en ser s , t h e co o l an t do es n o t di r ect l y
co n t act co n d en sab l e v a po r s , r a t h erh eat i s t r an sf er r e d acr o ss a sur f ace ( u suall y a t u b e w a l l ) s e p a r a t in g v a po r an d co o l an t

. I n t h i s way t h e co o l an t i s n o t

co n t am i n at ed wit h co n d en sed VOC an d ma y b e di r ect l y

r e used. T h e t y pe o f

co o l an t used depen d s o n t h e degr ee o f co o l i n g n eeded f o r a par t i c ul ar
s i t u a t i o n ” ( E PA
, 1979)

. C o o l an t s in co m m

o n us e ar e wat e r , ch ille d w a t e r , b r i n e, an d gl y c o l

.
Sc rubbe r s . Scr ubbe r s o r g a s ab s o r b er s ar e us ed t o r e m o v e o n e o r m o r e
co n s t it u en t s f r o m a gas st r eam b y t r eat m e n t wit h a l i q u i d

. “ A b s o r pt i o n i s i m p o r t a n t i n t h e ph ar maceut i cal i n dust r y b ecause ma n y VOCs an d o t h e r ch em i cal s b e i n g used ar e so l u b l e i n wat e r o r aqueo u s so l u t i o n s. T h er ef o r e, wat e r , caust i c o r aci di c scr u b b e r s can b e appl i e d t o a v a r i et y o f ai r po ll u t i o n pr o b l e m s ” ( U SE PA 1979)

.
W h e n u s in g a

s c r u b b e r a s a n a i r p o llu t i o n c o n t r o l d e v i c e , t h e s o lu b ilit y o f t h e
c o n s t it u e n t s in t h e g a s s t r e a m in t h e ab s o r b in g liq u i d mu s t b e d e t e r min e d

.
“ T h e r a te of tr a n s f e r of th e s o l u b l e c o n s titu e n ts f r om th e g a s t o t h e l i q u i d ph ase i s det e r m i n ed b y di f f u si o n al pr o cesses o ccur r in g o n each si de o f t h e gas l i qui d i n t e r f ace” ( T h e o d o r e an d Bo n i co r e , 1989)

.
T h e m a i n t y p e s o f scr u b b e r s used ar e packed t o wer , pl at e o rt r ay t o wer ,

Sect o r No t e b o o k Pr o j ect 46 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

v e n t u r i s c ru b b e r, a n d s p ra y t o w e r. Ea c h t y p e o f s c ru b b e r i s d e s i g n e d t o pr o v i d e i n t i ma t e co n t act b e t w een t h e scr u b b i n g l i qui d an d t h e gaseo u s
co n s t it u en t s so t h at ma ss t r an sf er b e t w een ph ases i s pr o m o t ed. T h e degr ee
o f

co n t r o l ach i e v e d i s depen d en t o n t h e r e s i den ce t i m e o f t h e gas an d l i qui ds
, t h e i n t e r f aci al ar ea, and t h e p h y s i cal an d t h er m o dyn a m i c pr o p er t i es o f t h e VOC speci es i n v o lv ed.

Com bus t i on or I n ciner a t i on. A n o t h e r me t h o d u s e d fo r c o n t r o llin g V O C

e mis s i o n s is c o mb u s t i o n o r in c i n e r a t i o n

. “ I n g e n e r a l, fa c t o r s t h a t in flu e n c e t h e ef f i ci en cy o f co m b ust i o n ar e: ( 1 ) t e m p er at ur e, ( 2 ) degr ee o f m i x i n g, ( 3 )

r e si den ce t i m e i n t h e co m b ust i o n ch am b e r , an d ( 4 ) t y pe o f VOC co m b ust e d. S i n ce m o r e wast e st r eam s co n t a i n di l u t e VOC co n cen t r at i o n s , t h ey r e qui r e t h at s uppl em en t a l f

u el ma i n t a i n t h e n eces s a r y co m b us t i o n t e m p er at ur es ” ( E P A
, 1979)

. A l t h o ugh co m b us t i o n s y s t em s can ach i e v e h i gh r e m o va l ef

f i ci en ci es, t h ese sy st em s ar e t y pi call y

m o r e ex pen s i v e t o i n st all
, o p er at e, an d

ma i n t a i n , a nd h a v e seco n d ar y em i ssi o n s asso ci at ed wit h t h ei ro p er at i o n

. A ddit i o n all y , a s c r u b b e r ma y b e r e qui r e d t o co n t r o l in o r gan i c gas e s pr o duced

as b y

- p r o duct s o f co m b us t i o n

.

“ E qui pm en t us ed t o co n t r o l was t e gas e s b y co m b us t i o n can b e di v i ded i n t o t h

r ee cat ego r i e s : d i r ect co m b ust i o n o r f l ar i n g ( n o t o f t e n used b y t h e ph ar m aceut i cal i n dust r y )
, t h er m a l o x i d at i o n , an d cat al y

t i c o x i d at i o n

. A di r ect

co m b ust o r o r f l ar e i s a dev i ce in wh i c h ai r an d all t h e co m b ust i b l e wast e gases
r eact at t h e b u r n er

. I n co n t r a st , in t h er ma l o x i d at i o n , t h e co m b ust i b l e wast e gases pass o v ero r ar o u n d a b u r n erf l am e in t o a r e si den ce ch am b e r wh er e
o x id a t io n o f t h e w a s t e g a s e s is c o mp le t e d

. C a t a lyt i c o x id a t io n is

v e r y s imila r t o t h e r ma l o x id a t io n

. T h e ma in d i ffe r e n c e is t h a t a f t e r p a s s i n g t h r o u g h t h e f l am e ar ea, t h e gases pass o v er a cat al y s t b e d wh i c h pr o m o t es o x i d at i o n at a l o wert e m p er at ur e t h an do es t h er ma l o x i d at i o n ” ( T h e o d o r e an d Bu o n i c o r e, 1989)

. E f f i ci en cy r a t e s o f cat al y

t i c o x i d i zer s i n des t r o yi n g VOCs can r each cl o s e t o 98% ( B uo n i co r e an d Dav i s , 1992)

.
Ads o r p t i on. A d s o rp t i o ni s a n o t h e r m e t h o d f o r re m o v in g V O C s f r o m g a s
s t r e a m s

. T h is me t h o d filt e r s o u t t h e v o la t ile s b y p a s s i n g t h e m t h r o u g h a packed co l u m n

o f act i v at ed car b o n , si l i cat es, al um i n as, al um i n o s i l i cat e s , o r
an y o t h e r sur f ace wh i c h i s po r o us an d h a s a m i c r o cr y s t a llin e s t r u c t u r e

. A s t h e gas st r eam passes t h r o ugh t h e co l u m n , t h e VOCs adso r b t o t h e sur f ace o f t h e
m

e di a. T h e adso r p t i o n ma t e r i al i n t h e co l u m n

ev en t u all y

b eco m e s sat u r a t e d,

an d m u st b e eit h err e gen e r a t e d o r di spo s ed. M o s t so r b en t s ma y b e
r e gen e r a t e d r e peat edl y b y pas s i n g h o t gas o r s t eam t h r o ugh t h e b e d. VOC s
w ill d e s o r b in t o t h e g a s o r s t e a m

. T h e h i g h V O C c o n c e n t r a t io n in t h e g a s o r st eam can t h en b e r e m o v e d t h r o ugh co n d en sat i o n

. A d so r p t i o n can b e ab o u t 98% ef f i ci en t i n r e m o v i n g VOCs i n t h e wast e gas st r eam ( C r u m e an d P o r t zer , 1992)

.

Sect o r No t e b o o k Pr o j ect 47 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

III. B

. 3

. W a s t e w a t e r

P h ar maceut i cal ma n u f act ur er s use wat e rf o r pr o cess o p er at i o n s , as well as f o r
o t h e r n o n

- pr o cess pur po ses. Ho wev e r , t h e use an d di sch a r g e pr act i ces an d t h e c h a r a c t e r is t i c s o f t h e w a s t e w a t e r w ill v a r y d e p e n d in g o n t h e o p e r a t io n s
c o n d u c t e d a t t h e fa c ilit y. A d d it i o n a lly, in s o me c a s e s , w a t e r ma y b e fo r m e d as par t o f a ch em i cal r eact i o n

.
Pr o ces s wat e r i n cl udes an y wat e r t h at , dur in g ma n u f act ur i n g o r pr o ces s i n g , co m e s i n t o di r ect co n t act wi t h

o rr e sul t s f r o m t h e use o f an y r a w ma t e r i al o r pr o duct i o n o f an i n t e r m edi a t e , f i n i s h ed pr o duct
, b y pr o duct
, o r was t e. Pr o ces s wast ewat eri n cl udes wat e rt h at was used o rf o r m ed dur i n g t h e r eact i o n , wat e r
us ed t o c l e a n p r o ces s equi pm en t an d f l o o r s , an d pum p s eal wat e r

. No n

pr o cess wast ewat eri n cl udes n o n c o n t act co o l in g wat e r( e

. g

. , used i n h eat

e x c h a n g e r s )
, n o n c o n t a c t a n c illa r y w a t e r ( e

. g

. , b o ile r b l o w d o w n , b o t t l e wash i n g)
, san it a r y w a s t ewat er , an d wast ewat erf r o m o t h e r so ur ces ( e

. g

. , s t o r m w a t e r ru n o f f )

.
B a s e d o n t h e r e s p o n s e s f r o m 244 f ac ilit ie s t o a 1990 308 Ques t i o n n a i r e, E P A est i ma t e d t h e av er age dai l y

wast ewat er gen e r a t i o n b y t h e ph ar maceut i cal

ma n u f act ur i n g i n dus t r y t o b e 266 millio n g a llo n s

. A d d it i o n a lly, E P A le ar n e d t h a t mo r e t h a n h a l f o f t h e r e s p o n d i n g fa c ilit ie s h a v e imp le me n t e d w a t e r
co n s er v a t i o n m easur es. S u ch m easur es in cl ude: car ef ul

m o n i t o r i n g o f wat e r use, i n st all a t i o n o f aut o ma t i c m o n it o r i n g an d al ar m sy st em s o r i n

- p l a n t di sch a r g es, i m p l e m e n t at i o n o f al t e r n at i v e pr o duct i o n pr o cesses, r e use o f n o n

co n t a c t w a t e r as pr o cess ma keup wat e r an d t r eat m e n t o f co n t act co o l i n g
w a te r to a ll o w r e u s e

.
P h ar maceut i cal ma n u f act ur er s gen e r a t e pr o cess w a s t ewat er co n t ain i n g a
va r i e t y o f c o nve nt i o na l p a r a m e t e r s ( e

. g

. , B O D
, T S S
, a n d p H ) a n d o t he r ch em i cal co n s t it u en t s

. T h e t o p t e n ch em i cal s di sch a r g e d by t h e ph ar maceut i cal i n dust r y ar e pr o v i d ed i n T ab l e 11. Of t h ese co m p o u n d s, t w o
a r e “ p r i o r it y p o llu t a n t s ” 3

. T h e t o p f o ur co m p o u n d s ar e o x y g en at ed o r gan i c
so lv en t s ( e

. g

. , m e t h an o l
, et h a n o l
, acet o n e, an d i s o p r o pan o l )

.

3 P r i o r i t y po l l u t a n t s a r e t h e po l l u t a n t s l i s t e d i n 40 CF R pa r t 403, A ppe n d i x A

.
Sect o r No t e b o o k Pr o j ect 48 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### Tab l e 11: Ch em i c al s Di sch a rged i n Wast e w a t er b y t h e P h arm a ceu t i cal M a nuf a c t u r i ng I n d u s t r y

Co nst i t u e ntNa m e Q u an ti ty Di sc ha r g e d ( l bs/ y r ) P ercen t o f T o t a l Lo ad i n g # o f F a cilit ies R e p o rt in g

Co nst i t u e nt s

M e t h a n o l 15, 388, 273 28 82

E t h a n o l 6, 802, 384 12 97

A c e t o n e 4
, 573, 766 8. 4 5 5

Is o p r o pa n o l 4
, 565, 370 8. 4 8 5

A c e t i c a c i d 4, 328, 691 7. 9 4 4

M e t h y l e n e c h l o r i de 3, 590, 640 6. 6 4 7

F o r m i c a c i d 2, 136, 059 3. 9 9

A m m o n i um h y dr o x i d e 1
, 365, 741 2. 5 3 2

N 1 N

- D ime th y lac e tamide 1
, 046, 333 1. 9 7

T o l u e n e 783, 364 1. 4 4 3 S o u r ce: adapted fr

om D evelopm ent D o cum e nt for P r opos ed Effluent G u idelines and Standar ds for the P har m a ceutical Manuf ac t u r i ng P o i n t Sour c e Cat e gor y , 1995 and U S

E

n v i r onm e n t L a w s , 1994.

Mo st pr o ces s w a st ewat err ecei v e s so m e t r eat m e n t , eit h eri n

- p l a n t at t h e p r o c e s s u n it p r io r t o c o mmin g lin g w it h o t h e r fa c ilit y w a s t e w a t e r o r p r io r t o di sch a r g e t o a per m it t e d o u t f all

. T ab l e 12 pr o v i d es a t r en d an al y s i s pr epar ed b y E P A o f wast ewat ert r eat m e n t t ech n o l o gi es used b y t h e ph ar maceut i cal i n dus t r y

. E P A f

o un d t h at “ s i n ce 1986, t h e us e o f n e ut r a l i zat i o n , equal i zat i o n , act i v at ed s l udge, pr i m a r y cl ar i f i cat i o n , m u l

t i m e di a f i l

t r a t i o n , s t eam s t r i ppi n g , seco n d ar y cl ar i f i cat i o n , gr an ul ar act i v at ed car b o n , an d o x i d at i o n h a v e al l i n cr eased, wh i l e t h e use o f aer at ed l a go o n s, ch l o r i n a t i o n , wast e st ab i l i zat i o n po n d s , an d t r i c kl i n g f i l

t er s h a v e decr eas ed s l i g h t l y ” ( U SE PA 1995)

.
M o r e t h a n h a lf o f t h e s u r v e y e d fa c ilit ie s p r o v id e p H a d ju s t me n t o r
n e ut r a l i zat i o n t o adj u st t h e pH pr i o rt o di sch a r g e. A ddit i o n a l l y , because wast ewat ert r eat m e n t can b e sen s i t i v e t o spi k es o f h i gh f l o w o rh i gh

co n s t it u en t co n cen t r a t i o n , ma n y t r eat m e n t sy st em s in cl ude equal i zat i o n

. A d v a n ced b i o l o g i cal t r eat m e n t i s u s e d t o t r eat b i o c h e m i cal o x y g en dema n d (B O D 5 )
, ch em i cal o x y g en dema n d ( C OD)
, t o t a l suspen ded so l i d s ( T S S )
, as well as v a r i o u s o r gan i c co n s t it u en t s

. Bi o l o g i cal sy st em s can b e di v i ded i n t o t w o b a si c t y pes: aer o b i c ( t r eat m e n t t a kes pl ace in t h e pr esen ce o f o x y g en ) an d

an aer o b i c ( t r e a t m e nt t a kes pl aces i n t h e ab sen ce o f o x y g en )

. Ver y f

e w ph ar maceut i cal f

ac ilit ie s ( o n l y t w o ) u s e a n a e r o b ic t r e a t me n t

. H o w e v e r , mo r e t h an 30 per cen t us e aer o b i c s y s t em s s u ch as act i v at ed s l udge, aer at ed l a go o n s , t r i c k l i n g f i l

t er , an d r o t a t i n g b i o l o g i cal co n t act o r s ( RBC)

.

Sect o r No t e b o o k Pr o j ect 49 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption



### Tab l e 12: Wast e w a t er Treat m e n t Tech n o l o gy Tren d s

Tr e atm e n t Te c h n o l o gy P ercen tage o f F a cilities U s i n g Te c h n o l o gy P r i o r to1986 P ercen tage o f F a cilities U s i n g Te c h n o l o gy i n 1989/ 1990

N e u t r alizatio n 2 6

. 0 4 4

. 3
Eq u alizatio n 2 0

. 1 2 8

. 6

A c t i v a t e d s l udge 16. 9 20. 5

S e ttle ab le s o lid s r e mo v a l 1 3

. 3 N A

P r imar y s e d ime n tatio n 1 2

. 0 N A

A e r ate d lag o o n 7

. 5 4 .9

P r imar y c lar if ic atio n 3 .9 9

. 8

C h lo r i n atio n 3 .6 2

. 5

P o l i s hi ng p o nd s 3

. 2 N A

W a s t e s tab ilizatio n p o n d 2

. 9 2 .5

Tr ic k lin g f ilte r 2 .9 2

. 0

M u ltime d ia f iltr atio n 2 .3 6

. 1

S t re a m s t ri p p i ng 1

. 9 5

. 7

Ev ap o r atio n 1 .9 N A

S e c o n d ar y c lar if ic atio n 1 .6 2 0

. 9

G r an u lar ac tiv ate d c a r b o n 1

. 3 3 .3

O x id atio n 1 .0 2

. 0

D i s s o lv e d air f l o tatio n 1 .0 N A
pH a d j u s t m e n t N A 50. 0

P h as e s e p a r atio n N A 1 2

. 3

N o t e : T o t a l p e r c e n t a g e i s no t 100 b ecau se f acilities m a y u s e m u ltip le treatm e n t tech n o lo g i es. NA - No t a v a ila b l e

.
S o u r ce: adapted fr om D evelopm ent D o cum e nt for Pr opos e d Effluent G u idelines and Standar ds for the P har m a ceutical Manufactur i ng P o int Sour ce Categor y, 1995 and U S

Envir onm ent L a w s , 1994.

A l t h o ugh t h e ph ar maceut i cal i n dust r y h a s r o ut i n el y

ut i l i zed r eco v e r y sy st em s t o r e c o v e r a n d r e u s e s o lv e n t s , o n ly fo u r fa c ilit ie s w e r e id e n t i fie d b y E P A a s
us i n g s t r eam s t r i ppi n g t o r e m o ve gas e s an d/o r o r gan i c ch em i cal s f r o m
w a s t e w a t e r s t r e a m s

. S i x t y o n e fa c ilit ie s w e r e id e n t i fie d t h a t u s e d i s t i lla t i o n eit h ert o r eco v e r a speci f i c so lv en t f r o m a pr o cess st r eam o rt o t r eat o n e o r
m

o r e pr o cess wast e st r eam s. Ho wev e r , acco r d in g t o P h RMA
, it i s l i k el y

t h at

Sect o r No t e b o o k Pr o j ect 50 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

t h e s e fa c ilit ie s u s e t h is me t h o d t o r e c o v e r a

s p e c i fic s o lv e n t fr o m a

s p e c i fic pr o cess st r eam r a t h ert h an t o t r eat wast ewa t e r f r o m n u m e r o us o p er at i o n s si n ce t h e t r eat m e n t t ech n o l o gy i s n o t a p p l i c a b l e t o t h e wi de r a n g e o f wast e ch ar act er i s t i cs co m m

o n in t h e ph ar maceut i cal i n dust r y

.
III. B

. 4

. S o l i d W a s t e s

Bo t h n o n h azar do us an d h azar do us wast es ar e gen e r a t e d dur in g all t h r e e st ages o f ph ar maceut i cal ma n u f act ur in g. T h ese wast es can i n cl ude o f f

- spec
o ro b so l e t e r a w ma t e r i al s o r pr o duct s , spen t so lv en t s , r eact i o n r e si dues, used filt e r me d i a , s t ill b o t t o ms , u s e d c h e mic a l r e a g e n t s , d u s t s fr o m filt r a t i o n o r a i r po ll u t i o n co n t r o l equi pm en t , r a w ma t e r i al packagin g wast es, l ab o r a t o r y
w a s t e s , s p ills
, a s w e ll a s w a s t e s g e n e r a t e d d u r in g p a c k a g in g o f t h e fo r m u l a t e d pr o duct

.
F i l t er cakes an d spen t r a w ma t e r i al s ( p l a n t s, r o o t s, an i ma l t i ssues et c. ) f r o m f e r m en t a t i o n an d n a t u r a l pr o duct ex t r act i o n ar e t w o o f t h e l a r g est so ur ces o f

r e si dual wast es i n t h e ph ar maceut i cal i n dust r y

. Ot h e r wast es i n cl ude r eact i o n
r e si d u e s an df i l

t r a t e s f r o m ch em i cal syn t h e si s p r o cesses. T h ese w a st es ma y b e st r i pped o f an y so lv e n t s w h i c h r e ma i n i n t h em , an d t h en di spo s ed as eit h er h azar do us o r n o n h azar do us wast es. T y pi call y , so l i d wast es ar e sh i pped o f f

s ite f o r d i s p os a l or i n c i n e r a ti on

.
A

n u m b ero f pr act i ces ar e i m p l e m e nt ed b y t h e i n dust r y t o r e duce wast e gen e r a t i o n an d ma t e r i al l o ss e s

. T y pi cal pr act i ces i n cl ude pr o cess
o p t im i zat i o n , pr o ducti on s c h e dul in g, ma t e r i al s t r ackin g an d in v e n t o r y co n t r o l
, speci al ma t e r i al h a n d l in g an d st o r age pr o cedur es, pr ev en t i v e m a i n t e n a n c e pr o g r a m s , an d wast e st r eam segr egat i o n

.

Sect o r No t e b o o k Pr o j ect 51 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

III. C

. M a n a g e men to f TR I C h emi c a l s i n t h e Pr o d u c t i o n Pr o cess

T h e Po ll u t i o n Pr ev en t i o n A c t o f 1990 ( PPA ) r e qui r e s f ac ilit ie s t o r e p o r t i n f o r ma t i o n ab o u tt h e ma na g e m e nto f T o xi c s R e le a s e I nve nt o r y ( T R I )

c h e mic a l s in w a s t e a n d e ffo r t s ma d e t o e limin a t e o r r e d u c e t h o s e q u a n t it ie s

. T h ese dat a h a v e b een co ll ect e d an n u all y

i n S ect i o n 8 o f t h e T R I r e po r t i n g F o r m R b e gin n in g wi t h

t h e 1991 r e po r t in g y ear

. T h e dat a s u m mar i zed b e l o w
co v e rt h e y ear s 1 9 94 t h r o ugh 1997 an d ar e m ean t t o pr o v i d e a b a s i c
un der s t a n d in g o f t h e quan t i t i e s o f was t e h a n d l e d b y t h e in dus t r y , t h e m e t h o d s t y

pi call y used t o ma n a ge t h i s wast e, an d r ecen t t r en ds i n t h ese m e t h o d s. T R I wast e ma n a gem e n t dat a can b e used t o assess t r en ds in so ur ce r e duct i o n
w it h in in d i v i d u a l in d u s t r ie s a n d fa c ilit ie s , a n d fo r s p e c i fic T R I c h e mic a l s

. T h is i n f o r m a t i o n co ul d t h en b e us ed as a t o o l i n i d en t i f yi n g o ppo r t un i t i e s f o r po ll u t i o n pr ev en t i o n co m p l

i a n ce assi st an ce act i v i t i e s.

W h i l e t h e quan t it i e s r e po r t ed f o r 1994 an d 1995 ar e es t i m a t e s o f quan t it i e s al

r eady ma n a ged, t h e quan t it i e s r e po r t ed f o r 1996 an d 1997 ar e pr o j ect i o n s
o n ly. T h e P P A r e q u i r e s t h e s e p r o j e c t io n s t o e n c o u r a g e fa c ilit ie s t o c o n s id e r f u t u r e wast e gen e r a t i o n an d so ur ce r e duct i o n o f t h o s e quan t it i e s as well as
m

o v e m e n t up t h e wast e ma n a gem e n t h i er ar ch y

. F u t u r e

- y ear est i ma t e s ar e n o t

c o mmit me n t s t h a t fa c ilit ie s r e p o r t in g u n d e r T R I a r e r e q u i r e d t o me e t

.
T ab l e 13 sh o w s t h at t h e T R I r e po r t i n g ph ar maceut i ca l f ac ilit ie s ma n a g e d ab o u t 382 millio n p o u n d s o f p r o d u c t i o n r e la t e d w a s t e s ( t o t a l q u a n t it y o f T R I ch em i cal s i n t h e wast e f r o m r o ut i n e pr o duct i o n o p er at i o ns in Co l u m n

B) i n 1 9 9 5

. F r o m t h e ye a r ly d a t a p r e s e n t e d in C o lu mn B
, t h e t o t a l q u a n t it y o f pr o duct i o n r e l a t e d was t es i n cr eas ed b e t w een 1994 an d 1995. T h i s i s pr o b ab l y i n

par t b ecause t h e n u m b ero f ch em i cal s o n t h e T R I l i s t a l m o st do ub l e d b e t w een t h o s e y ear s. T h e quan t it y o f wast es gen e r a t e d was al so pr o j ect ed t o i n cr eas e i n 1996 an d 1997. T h e ef f ect o f pr o duct i o n i n cr eas es o n t h e am o u n t

o f

wast es gen e r a t e d h a s n o t b een ev al uat e d.

Val u es i n Co l u m n

C ar e i n t e n d ed t o r e v eal t h e per cen t a ge o f T R I ch em i cal s t h at ar e eit h ert r an sf er r e d o f f

- sit e o r r e l eased t o t h e en v i r o n m en t

. Co l u m n

C i s cal cul a t e d b y di v i di n g t h e t o t a l T R I t r an sf er s a n d r e l eases ( r e po r t ed i n Sect i o n s 5 an d 6 o f t h e T R I Fo r m R ) b y t h e t o t a l quan t it y o f pr o duct i o n

r e l a t e d wast e ( r e po r t ed i n S ect i o n 8 o f F o r m R)

. Co l u m n C sh o w s a decr ease i n

t h e po r t i o n eit h ert r an sf er r e d o f f

- sit e o rr e l eased t o t h e en v i r o n m en t f r o m 50 per cen t i n 1994 t o 46 per c e n t in 1995. T h e was t e r e l eas ed t o t h e
en v i r o n m en t o r t r an s f er r e d o f f

- s it e f o r di s p o s al decr eas ed s l i g h t l y

i n 1995 t o
a b o u t 1 0 p e r c e n t o f t o t a l w a s t e s g e n e r a t e d
, a s s h o w n in C o lu mn J

. T h is decr eas i n g t r en d i s pr o j ect ed t o co n t i n ue t h r o ugh 1997.

Sect o r No t e b o o k Pr o j ect 52 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

T h e ov e r a ll p r op or ti on s o f was t e s ma n a g e d of f

- s ite ( C ol u m n s D
, E
, a n d F )

an d o n sit e ( C o l um n s G, H, an d I ) ch an ge v e r y l

i t t l e f r o m y ear t o y ear

. A b o u t 50 per cen t o f t h e i ndus t r y ’ s T R I was t es wer e ma n a ged o n

- s i t e t h r o ugh

r ecy cl i n g, en er gy r eco v e r y , o rt r eat m e n t as sh o w n i n co l u m n s D, E
, an d F
, r e spect i v el y

. A l m

o st al l o f t h ese o n

- s i t e ma n a ged wast es wer e r ecy cl ed o r t r eat ed o n

- s it e. On l y

ab o u t t w o per cen t wer e used i n en er gy r eco v e r y

. W a st e t h at i s t r an sf er r e d o f f

- sit e can b e di v i ded i n t o po r t i o n s t h at ar e r ecy cl ed o f f

sit e , r eco v e r e d f o r en er gy o f f

- sit e , o r t r eat ed o f f

- si t e as sh o w n i n co l u m n s G, H
, a n d I
, r e s p e c t iv e l y. T h e r e ma in in g p o r t io n o f t h e p r o d u c t i o n r e la t e d wast es, 10 per cen t , sh o w n in co l u m n J, i s eit h err e l eased t o t h e en v i r o n m en t t h

r o ugh di r ect di s c h a r g es t o ai r , l a n d
, wat e r , an d un der g r o un d i n j ect i o n , o r i t i s d i sp o s edo f f

- sit e

.



### Tab l e 13: S o u rce Red u ct i o n an d Recycl i n g Act i vi t y f o r t h e P h arm a ceu t i cal s In d u st ry as Rep o rt ed w i t h i n TRI

A B C O n -S i t e O ff-S i t e J

Ye a r Q u an tity o f P r o duc t i o n

R e late d Wa s t e (10 6 lb s

. ) a % R e le as e d

an d Tr an s f e r r e d b % R e le as e d

an d Di sp o s e d c

O ff- s i t e D E F G H I

% R ecycl ed % E n e r gy R e c o v e r y % Tr e ate d % R ecycl ed % E n e r gy R e c o v e r y % Tr e ate d
1994 324 50% 13. 9% 2. 0% 33. 5% 5. 3% 21. 7% 13. 3% 10. 8%
1995 382 46% 16. 8% 1. 6% 34. 3% 4. 7% 21. 6% 11. 7% 9. 7%
1996 404 N A 18. 7% 1. 6% 37. 1% 5. 1% 18. 8% 10. 4% 8. 4%
1997 414 N A 20. 4% 1. 6% 35. 9% 5. 5% 18. 4% 9. 9% 8. 3% S o u r ce: T o xics Releas e Inventor y D a tabas e, 1995.

a Wi t h i n t h i s i ndus t r y s e c t o r , no n- p r o duc t i o n r e l a t e d w a s t e < 1% o f p r o duc t i o n r e l a t e d w a s t e s f o r 1995. b T o t a l T R I t r an sf er s an d r e l eases as r e por t e d i n S ect i o n 5 an d 6 of F o r m R as a per cen t a ge of pr od u c t i o n r e l a t e d w a st es.

c P e r c e n t a g e o f p r o d u c t i o n r e l a t e d w a s t e r e l e a s e d t o t h e e n v i r o n m e n t a n d t r a n s f e r r e d o ff-s i t e fo r d i s p o s a l

.

Sect o r No t e b o o k Pr o j ect 53 Sept em b e r 1997P h arm a c e u tic a l I ndus try I ndus trial P r oc e s s D e s c ri ption

Sect o r No t e b o o k Pr o j ect 54 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

IV. CH EM ICAL RELEAS E AND TRANS F E R P R O F ILE

T h is s e c t io n is d e s i g n e d t o p r o v id e b a c k g r o u n d in fo r ma t io n o n t h e p o llu t a n t

r e l eases t h at ar e r e po r t ed b y t h i s i n dust r y

. T h e b e st so ur ce o f co m p ar at i v e po ll u t a n t r e l ease in f o r mat i o n i s t h e T o x i c Rel ease I n v e n t o r y ( T RI )

. P u r s uan t to th e E m e r g e n c y P l a n n i n g a n d C o m m

u n ity R i g h t- to- K n o w A c t, T R I in c l u d e s
s e lf- r e p o r t e d fa c ilit y r e le a s e a n d t r a n s f e r

d a t a fo r o v e r 600 t o x i c che mi c al s

. Fa c i l it i e s wit h i n SI C C o des 20 t h r o ugh 39 ( man uf act ur i n g i n dus t r i e s ) t h at h a v e m o r e t h an 10 em pl o y ees, an d t h at ar e ab o v e wei g ht

- b a s e d r e po r t i n g t h

re s h o l d s a r e re q u i re d t o re p o rt TR I o n -s it e re l e a s e s a n d o f f

- s i t e t r a n s f e r s

. T h e i n f o r mat i o n pr esen t e d wit h i n t h e sect o rn o t e b o o k s i s der i v e d f r o m t h e
m

o s t r ecen t l y

av ai l ab l e ( 1995) T R I r e po r t in g y ear ( w h i ch i n cl udes o v er 600 ch em i cal s)
, an d f o cuses pr i ma r i l y

o n t h e o n

- s it e r e l e a s e s r e po r t ed b y each sect o r

. Because T R I r e qui r e s co n s i s t e n t r e po r t i n g r e gar d l e ss o f sect o r , it i s
an ex cell e n t t o o l f

o r dr awi n g co m p ar i s o n s acr o ss i n dust r i e s. T R I dat a pr o v i d e t h e t y pe, am o u n t an d m e di a r ecept o ro f each ch em i cal r e l eased o rt r an sf er r e d.

A l t h o ugh t h i s sec t o r no t e b o o k do es n o t pr esen t h i st o r i cal i n f o r mat i o n
r e gar d i n g T R I ch em i cal r e l eases o v ert i m e , pl ease n o t e t h at i n gen e r a l
, t o x i c ch em i cal r e l eas es h a v e b een decl i n in g. I n f

act , acco r d i n g t o t h e 1995 T o x i c Rel ease I n v e n t o r y P u b l i c Dat a Rel ease, r e po r t ed o n si t e r e l eases o f t o x i c
c h e mic a l s t o t h e e n v i r o n m e n t d e c r e a s e d b y 5 p e r c e n t ( 8 5

. 4 millio n p o u n d s ) b e t w een 1994 an d 1995 ( n o t i n cl udi n g ch em i cal s added an d r e m o v e d f r o m t h e T R I ch em i cal l

i s t dur i n g t h i s per i o d )

. R e po r t ed r e l eas es dr o pped b y 46 per cen t b e t w een 1988 an d 1995. R e po r t ed t r an s f er s o f T R I ch em i cal s t o o f f

s it e l o c a t io n s in c r e a s e d b y 0

. 4 p e r c e n t ( 1 1

. 6 millio n p o u n d s ) b e t w e e n 1994

an d 1995. M o r e det a i l e d i n f o r mat i o n can b e o b t a i n ed f r o m E P A ' s a nnu a l T o x i cs Rel ease I n v e n t o r y P u b l i c Dat a Rel ease b o o k ( w h i ch i s av ai l ab l e t h

r o ugh t h e E P C R A Ho t l i n e at 800- 535- 0202)
, o r di r ect l y

f

r o m t h e T o x i c R e l eas e I n v e n t o r y Sy s t em dat ab a s e ( f o r us er s uppo r t call 202- 260- 1531)

.
W h er ev er po ssi b l e, t h e sect o rn o t e b o o k s pr esen t T R I dat a as t h e pr i mar y i n di cat o ro f ch em i cal r e l ease wi t h in each i n dust r i a l cat e g o r y

. T R I dat a pr o v i d e t h e t y pe, am o u n t an d m e di a r ecept o r o f each ch em i cal r e l eased o r t r an sf er r e d. W h en o t h e r so ur ces o f po ll u t a n t r e l ease dat a h a v e b een o b t a i n ed, t h ese dat a h a v e b een i n cl uded t o augm en t t h e T R I i n f o r mat i o n

.
T R I D a ta L i m i ta tio n s

C e r t a i n limit a t io n s e x is t r e g a r d in g T R I d a t a

. R e le a s e a n d t r a n s f e r r e p o r t in g
a r e limit e d t o t h e a p p r o x ima t e ly 600 ch em i cal s o n t h e T R I l i s t

. T h er ef o r e, a la r g e p o r t io n o f t h e e mis s i o n s fr o m in d u s t r ia l fa c ilit ie s a r e n o t c a p t u r e d b y T R I

. W it h i n so m e sect o r s, ( e

. g

. dr y cl ean in g, pr i n t i n g an d t r an spo r t a t i o n
e q u i p m e n t c l e a n in g ) t h e ma jo r it y o f fa c ilit ie s a r e n o t s u b j e c t t o T R I r e p o r t in g b ecause t h ey ar e n o t co n s i d er ed ma n u f act ur i n g in dust r i e s, o rb ecause t h ey ar e b e l o w TR I re p o rt i n g t h re s h o l d s

. F o r t h e s e s e c t o r s , re l e a s e in f o rma t i o n f r o m

Sect o r No t e b o o k Pr o j ect 55 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

o t h e r s o u r c e s h a s b e e n in c l u d e d

. I n a d d it i o n , ma n y fa c ilit ie s r e p o r t mo r e t h a n
o n e S I C co de r e f l ect in g t h e m u l

t i

p l e o p er at i o n s car r i ed o u t o n sit e

. T h er ef o r e,
r e po r t ed r e l eases an d t r an sf er s ma y o rma y n o t all b e asso ci at ed wi t h t h e in d u s t r ia l o p e r a t io n s d e s c r i b e d in t h is n o t e b o o k

.
T h e r eader sh o u l d al so b e awar e t h at T R I "po u n d s r e l eased" dat a pr esen t e d wit h i n t h e n o t e b o o k s i s n o t equi v a l e n t t o a "r i s k" r a nk i n g f o r each i n dust r y

. W e i g h t i n g each po un d o f r e l ease equall y

do e s n o t f act o r i n t h e r e l a t i v e t o xi c it y o f each ch em i cal t h at i s r e l eased. T h e A g en cy i s i n t h e pr o ces s o f dev e l o pi n g an appr o a c h t o assi gn t o x i co l o gi cal wei g h t s t o each ch em i cal

r e l eased so t h at o n e can di f f e r e n t i a t e b e t w een po ll u t a n t s wit h si gn i f i can t d i ffe r e n c e s in t o x i c it y

. A s a

p r e limin a r y in d i c a t o r o f t h e e n v i r o n m e n t a l imp a c t

o f

t h e i n dust r y ' s m o st co m m

o nl y r e l eased ch em i cal s, t h e n o t e b o o k b r i e f l y
sum ma r i zes t h e t o x i co l o gi cal pr o p er t i es o f t h e t o p f i v e ch em i cal s ( b y wei g h t )

r e po r t ed b y each i n dust r y

.
Def i n i t i on s Associ at ed wi t h S ect i o n IV Dat a Tab l es

Ge ne r a l D e f i nitions

S I C Cod e - - t h e S t an dar d I n dust r i a l Cl assi f i cat i o n ( S I C ) i s a st at i s t i cal cl assi f i cat i o n st an dar d used f o r all est ab l i s h m en t

- b a sed F e der a l eco n o m i c
s t a t is t i c s

. T h e S I C c o d e s fa c ilit a t e c o mp a r is o n s b e t w e e n fa c ilit y a n d in d u s t r y dat a

.
TRI F a ci l i t i es - - a r e ma n u fa c t u r in g fa c ilit ie s t h a t h a v e 1 0 o r mo r e fu ll- t ime

em pl o y ees an d ar e ab o v e est ab l i s h e d ch em i c a l t h r o ugh put t h r e sh o l ds. M a n u fa c t u r in g fa c ilit ie s a r e d e fin e d a s fa c ilit ie s in S t a n d a r d I n d u s t r ia l C l a s s i fic a t io n p r ima r y c o d e s 2 0

- 3 9

. F a c i l it i e s mu s t s u b mit e s t ima t e s fo r a ll ch em i cal s t h at ar e o n t h e T R I l i s t an d ar e ab o v e t h r o ugh put t h r e sh o l ds.

Dat a T a bl e Col u m n Heading Def i nit i ons

T h e f o ll o wi n g def i n it i o n s ar e ba s e d upo n s t an dar d def in it i o n s dev e l o ped b y E P A ’ s T o x i c Rel ease I n v e n t o r y P r o g r a m

. T h e cat ego r i e s b e l o w r e pr esen t t h e po ssi b l e po ll u t a n t dest in at i o n s t h at can b e r e po r t ed.

RELEAS E S - - ar e an o n

- s i t e d i sch a r g e o f a t o x i c ch em i cal t o t h e
en v i r o n m en t

. T h i s i n cl udes em i ssi o n s t o t h e ai r , di sch a r g es t o b o di es o f

w a t e r , r e le a s e s a t t h e fa c ilit y t o la n d
, a s w e ll a s c o n t a i n e d d i s p o s a l in t o
un der g r o un d i n j ect i o n well s

.
Rel e as es t o Air ( P oint and F u git i ve Air E m is s i o n s ) -- In c l u d e a ll a i r
e mis s i o n s fr o m in d u s t r y a c t iv it y. P o in t e mis s i o n s o c c u r t h r o u g h c o n f in e d a i r st r eam s as f o u n di n st ack s, v e n t s, d u c t s , o r p i p e s. F u g i t i v e em i ssi o n s i n cl u d e

Sect o r No t e b o o k Pr o j ect 56 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e equi pm en t l eaks, ev apo r at i v e l o sses f r o m sur f ace i m p o u n d m e n t s an d sp ills
, a n d r e le a s e s fr o m b u ild in g v e n t ila t i o n s y s t e m s

.
Rel e ases t o Wat er ( S u r f a ce Wat er Di sch a r g es)

- - en co m p ass an y r e l eases go i n g di r ect l y

t o st r eam s, r i v e r s , l a kes, o cean s, o ro t h e rb o di es o f wat e r

. Rel eases due t o r u n o f f

, i n cl udi n g st o r m wat e rr u no f f

, ar e al so r e po r t ab l e t o TR I.

Rel e as es t o Lan d - - o c c u r w it h in t h e b o u n d a r i e s o f t h e r e p o r t in g fa c ilit y. R e le a s e s t o la n d in c l u d e d i s p o s a l o f t o x i c c h e mic a l s in la n d fills
, la n d t r eat m e n t / a ppl i cat i o n f

a r m i n g, sur f ace i m p o u n d m e n t s, an d o t h e rl a n d di spo s al

me t h o d s ( s u c h a s s p ills
, le a k s , o r w a s t e p ile s )

.
U nde r g r o und I n je c t ion - - i s a co n t ai n e d r e l ease o f a f l ui d in t o a sub s ur f ace well f

o r t h e pur po se o f wast e di spo s al

. W a st es co n t ai n in g T R I ch em i cal s ar e i n

j ect ed i n t o eit h er Cl ass I well s o r Cl ass V well s

. Cl ass I well s ar e used t o i n

j ect l i qui d h azar do us wast es o r di spo s e o f in dust r i a l an d m u n i ci pal wast ewat er s b e n eat h t h e l o wer m o s t un der g r o un d so ur ce o f dr i nki n g wa t e r

. Cl ass V well s ar e gen e r a ll y

used t o in j ect n o n

- h azar do us f l ui d i n t o o r ab o v e
an un der g r o un d s o ur ce o f dr i nki n g wat e r

. T R I r e po r t i n g do es n o t cur r e n t l y di st i n gui s h be t w een t h ese t w o t y pes o f well s , al t h o ugh t h er e ar e i m p o r t a n t di f f e r e n ces i n en v i r o n m en t a l i m p act b e t w een t h ese t w o m e t h o d s o f i n j ect i o n

.
TRANS F E RS

- - is a t r a n s f e r o f t o x i c c h e mic a l s in w a s t e s t o a fa c ilit y t h a t is g e o g r a p h ic a lly o r p h ys ic a lly s e p a r a t e fr o m t h e fa c ilit y r e p o r t in g u n d e r T R I

. C h e mic a l s r e p o r t e d t o T R I a s t r a n s f e r r e d a r e s e n t t o o ff- s it e fa c ilit ie s fo r t h e pur po se o f r ecy cl i n g, en er gy r eco v e r y , t r eat m e n t , o r di spo s al

. T h e quan t i t i e s
r e po r t ed r e pr esen t a m o v e m e n t o f t h e ch em i cal away f

r o m t h e r e po r t i n g fa c ilit y. E x c e p t fo r o ff- s it e t r a n s f e r s fo r d i s p o s a l
, t h e r e p o r t e d q u a n t it ie s d o
n o t n ecessar i l y

r e pr esen t en t r y o f t h e ch em i cal i n t o t h e en v i r o n m en t

.
Tr a n sfer s t o PO TW s

- - ar e wast ewat ert r an sf er r e d t h r o ugh pi pes o r sewer s t o a p u b lic ly o w n e d t r e a t me n t s w o r k s ( P O T W )

. T r e a t me n t o r r e mo v a l o f a ch em i cal f

r o m t h e wast ewat er depen d o n t h e n a t u r e o f t h e ch em i cal
, as well as t h e t r eat m e n t m e t h o d s pr esen t at t h e P O T W

. No t all T R I ch em i cal s can b e t r eat ed o rr e m o v e d b y a P O T W

. S o m e ch em i cal s, such as m e t a l s , ma y b e
r e mo v e d
, b u t a r e n o t d e s t r o ye d a n d ma y b e d i s p o s e d o f in la n d fills o r di sch a r g ed t o r ecei v i n g wat e r s

.
Tr an sf er s t o Recycl i n g -- a r e s e n t o f f

- s it e f o r t h e p u r p o s e s o f re g e n e ra t in g
o rr eco v e r y b y a v a r i et y o f r ecy cl i n g m e t h o d s, i n cl udi n g so lv en t r eco v e r y , m

e t a l s r eco v e r y , an d aci d r e gen e r a t i o n

. On ce t h ese ch em i cal s h a v e b een
r e c y c l e d
, t h e y ma y b e r e t u r n e d t o t h e o r ig in a t in g fa c ilit y o r s o ld c o mme r c ia lly.

Sect o r No t e b o o k Pr o j ect 57 Sept em b e r 1997- - P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

T r ans f er s t o E n er gy Recovery - - ar e wast es co m b ust e d o f f

- si t e in i n dust r i a l f u r n aces f o r en er gy r eco v e r y

. T r eat m e n t o f a ch em i cal b y i n ci n e r a t i o n i s n o t

co n s i d er ed t o b e en er gy r eco v e r y

.
Tr an sf er s t o Tr eat m en t - - ar e wast es m o v e d o f f

- sit e t o b e t r eat ed t h r o ugh

a v a r i et y o f m e t h o d s, i n cl udi n g n e ut r a l i zat i o n , i n cin e r a t i o n , b i o l o g i cal d e s t r u ct i o n , o r ph y s i cal separ a t i o n

. I n so m e cases, t h e ch em i cal s ar e no t des t r o y e d b u t pr epar ed f o r f u r t h e r was t e ma n a gem e n t

.
Tr a n sfer s t o D i sp o s a l a r e w a s t e s t a k e n t o a n o t h e r fa c ilit y fo r d i s p o s a l gen e r a ll y

as a r e l ease t o l a n d o r as an i n j ect i o n un der g r o un d.

Sect o r No t e b o o k Pr o j ect 58 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

I V

. A

. E P A T o x i c R e l e as e I n ve ntory f o r the P h arm a c e u tic a l I ndus try

T h i s sect i o n sum ma r i zes T R I dat a o f ph ar maceut i cal f ac ilit ie s r e p o r t in g S I C

co des 2833 an d 2834 as t h e pr i ma r y SI C co de f o r t h e f ac ilit y. O f t h e 9 1 6 ph ar maceut i cal est ab l i s h m en t s r e po r t e d by t h e 1992 Ce ns us of M anuf actur e r

s , 200 r e po r t ed t o T R I i n 1995.

A cco r d i n g t o 1995 T R I dat a , t h e r e po r t i n g f ac ilit ie s r e le a s e d ( d is c h a r g e d t o th e a i r , w a te r , or l a n d w ith ou t tr e a t m e n t ) a n d tr a n s f e r r e d ( s h i p p e d of f

- s i te ) a t o t a l o f 177 millio n p o u n d s o f p o llu t a n t s , ma d e u p o f 104 di f f e r e n t ch em i cal s

. T h is r e p r e s e n t s ab o u t 3 p e r c e n t o f t h e 5

. 7 b illio n p o u n d s o f T R I c h e mic a l s
r e l eased an d t r an sf er r e d by all ma n u f act ur er s t h at y ear

. I n co m p ar i s o n , t h e
c h e mic a l in d u s t r y ( S I C 2 8 ) a s a

w h o l e p r o d u c e d 1

. 7 b illio n p o u n d s t h a t ye a r , acco un t i n g f o r ab o u t 30 per cen t o f all r e l eases an d t r an sf er s.

Of t h e ph ar maceut i cal i n dust r y ’ s T R I r e l eases , 57 per c e n t go t o t h e ai r , 25 per cen t t o un der g r o un d i n j ect i o n , 17 per cen t t o sur f ace wat e r s , an d 1 per cen t t o t h e l a n d

. T h is r e le a s e p r o f ile d i ffe r s fr o m o t h e r T R I in d u s t r ie s w h ic h

av er age appr o x i ma t e l y

59 per cen t t o ai r , 30 per cen t t o wat e r , an d 10 per cen t t o l a n d

. T ab l e 14 li s t s t h e ph ar m aceut i cal i n dust r y ’ s T R I r e po r t ed c h e mi cal

r e l eases.

Of t h e ph ar maceut i cal i n dust r y ’ s t r an sf er s , ab o u t 55 per cen t ar e t r an sf er r e d f o r en er gy r eco v e r y o f f

- sit e , 19 per cen t f o rt r eat m e n t o f f

- sit e , 13 per cen t ar e t r an sf er r e d t o P O T W s, 12 per cen t f o r r ecy cl i n g o f f

- sit e , an d ab o u t 1 per cen t f o r di spo s al o f f

- sit e

. T ab l e 15 l i s t s t h e ph ar maceut i cal i n dust r y ' s T R I r e po r t ed t o x i c ch em i cal t r an sf er s.

Of t h e t o p t e n m o st f r equen t l y r e po r t ed t o x i c ch em i cal s o n t h e T R I l i s t , t h e pr ev al en ce o f v o l a t i l e ch em i cal s ex pl ai n s t h e ai rin t e n s i v e t o x i c ch em i cal l o adi n g o f t h e ph ar maceut i cal in dust r y

. S e v e n o f t h e t e n m o st co m m

o n l y
r e po r t ed t o x i c ch em i cal s ar e h i gh l y

v o l a t i l e

. S i x o f t h e t e n ar e v o l a t i l e o r gan i c
co m p o u n d s ( m et h a no l
, di ch l o r o m e t h an e, t o l u en e, et h y l e n e gl y c o l
, N, NDi m e t h y l f o r mam i d e, an d acet o n it r i l e )

. T h ese ar e pr i ma r i l y

so lv en t s used t o
ex t r act act i v e i n gr edi e n t s an d f o r cl ean i n g equi pm en t

. T h e pr i ma r y m ean s o f

r e l ease t o t h e en v i r o n m en t ar e f r o m f

ugit i v e ai r an d po i n t ai r so ur ces. L a r g e quan t it i e s o f m e t h an o l
, N, N- Di m e t h y l f o r mam i d e, an d acet o n it r i l e , h o wev e r , ar e r e l eased v i a un der g r o un d in j ect i o n

. Ot h e r co m m

o n l y r e po r t ed ch em i cal s
r e l eased an d t r an sf er r e d ar e aci ds ( h y d r o ch l o r i c, sulf ur i c , an d ph o s ph o r i c ) wh i c h can b e used f o r pH co n t r o l o r as cat al y s t s

.

Sect o r No t e b o o k Pr o j ect 59 Sept em b e r 1997Sect o r No t e b o o k Pr o j ect 60 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 14:1995 ReleasesforPharmaceuticalFacilities(SIC2833 &2834)in TRI,byNumberofFacilities Reporting(Releasesreportedin pounds/year)�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 61 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 14,cont.:1995 ReleasesforPharmaceuticalFacilities(SICs2833 &2934),in TRIbyNumberofFacilities Reporting(Releasesreportedin pounds/year)������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������ R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 62 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 14,cont.:1995 ReleasesforPharmaceuticalFacilities(SICs2833 &2934)in TRI,byNumberofFacilities Reporting(Releasesreportedin pounds/year)CHEMICAL NAME#REPORTINGCHEMICALFUGITIVEAIRPOINTAIRWATERDISCHARGESUNDERGROUNDINJECTIONLANDDISPOSALTOTALRELEASESAVG. RELEASESPER FACILITYBENZOYL CHLORIDE20200021BENZYL CHLORIDE255000105EPICHLOROHYDRIN229050000340170M-XYLENE21,565571250002,3861,193PHENOL2255255000510255DIETHANOLAMINE25001,0005001,5057531,4-DIOXANE2270260000530265DIMETHYLAMINE223,50015,250250025039,25019,625TETRACHLOROETHYLENE22,23914,00000016,2398,120DIAZINON25278500288144ZINC (FUMEOR DUST)20200021TITANIUMTETRACHLORIDE2510000158HYDROGEN FLUORIDE22508,3500008,6004,300ABAMECTIN2001600168ANTIMONY COMPOUNDS1550001010CHROMIUMCOMPOUNDS100043,000043,00043,000COBALTCOMPOUNDS10000000SELENIUM COMPOUNDS10300033FAMPHUR10000000CARBONTETRACHLORIDE1604006700527527PHENYTOIN10000000DICHLORVOS152505002602601,1,1-TRICHLOROETHANE176,50052,500000129,000129,000BROMOMETHANE150210007171CHLOROETHANE11630000163163CARBONDISULFIDE12,45021,00000023,45023,450PHOSGENE12405050250250DIMETHYLSULFATE10800088ISOBUTYRALDEHYDE111250003636SEC-BUTYLALCOHOL125071,79900072,04972,049METHYLCHLOROCARBONATE12500505260260QUINOLINE1505051515 R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 63 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 14,cont.:1995 ReleasesforPharmaceuticalFacilities(SICs2833 &2934)in TRI,byNumberofFacilities Reporting(Releasesreportedin pounds/year)CHEMICAL NAME#REPORTINGCHEMICALFUGITIVEAIRPOINTAIRWATERDISCHARGESUNDERGROUNDINJECTIONLANDDISPOSALTOTALRELEASESAVG. RELEASESPER FACILITYBIPHENYL15000055O-XYLENE12,400540002,4542,4541,2-DICHLOROBENZENE12442,4900002,7342,7341,2,4-TRIMETHYLBENZENE1250250500505505CUMENE1250250500505505ACETOPHENONE1550001010NITROBENZENE13,8913210004,2124,212ALLYLCHLORIDE132127000348348CHLOROMETHYLMETHYLETHER10000000MALEIC ANHYDRIDE1550501515CHLOROBENZENE112110002323CYCLOHEXANOL1931330002262262-ETHOXYETHANOL12991000120120PROPYLENE1550001010N,N-DIMETHYLANILINE15350004040MALATHION10200022THIABENDAZOLE11753,5040003,6793,679ETHYLCHLOROFORMATE12502505055105101,3-DICHLOROBENZENE11,200800001,2801,280LITHIUMCARBONATE10000000N-METHYL-2-PYRROLIDONE17000077TETRACHLORVINPHOS1555001515TRIFLURALIN16,9002500007,1507,150BENFLURALIN17502500001,0001,000PROMETRYN10000000NICKEL10025000250250THIOPHANATE-METHYL10187000187187SODIUMAZIDE10000000VINCLOZOLIN10000000PERMETHRIN10000000PROPICONAZOLE10000000______________________________________________________________2006,664,93910,500,3584,936,1377,438,370375,27429,915,078149,575 R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 64 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 15:1995 TransfersforPharmaceuticalFacilities(SICs2833 &2834)in TRI,by Numberand FacilitiesReporting(Transfersreportedin pounds/year)������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 65 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 15,cont.:1995 TransfersforPharmaceuticalFacilities(SICs2833 &2834)in TRI,by Numberand FacilitiesReporting(Transfersreportedin pounds/year)���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 66 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 15,cont.:1995 TransfersforPharmaceuticalFacilities(SICs2833 &2834)in TRI,by Numberand FacilitiesReporting(Transfersreportedin pounds/year)CHEMICAL NAME#REPORTINGCHEMICALPOTWTRANSFERSDISPOSALTRANSFERSRECYCLINGTRANSFERSTREATMENTTRANSFERSENERGYRECOVERYTRANSFERSTOTALTRANSFERSAVGTRANSFERPERFACILITYBENZYL CHLORIDE25..10.158EPICHLOROHYDRIN200...00M-XYLENE220..87,14878,059165,22782,614PHENOL2250..548.798399DIETHANOLAMINE21,500...47,91649,41624,7081,4-DIOXANE24,1702.3008,96013,4326,716DIMETHYLAMINE2038,000.2,100.40,10020,050TETRACHLOROETHYLENE20.510.49,00549,51524,758DIAZINON201,060.1,609.2,6691,335ZINC(FUMEORDUST)201,223...1,223612TITANIUMTETRACHLORIDE20....00HYDROGEN FLUORIDE20....00ABAMECTIN20..5,582.5,5822,791ANTIMONY COMPOUNDS1053,200...53,20053,200CHROMIUMCOMPOUNDS1250260.5.515515COBALTCOMPOUNDS12,920....2,9202,920SELENIUM COMPOUNDS1260..13,641.13,90113,901FAMPHUR10..1,540.1,5401,540CARBONTETRACHLORIDE140..45,782.45,82245,822PHENYTOIN1019,300...19,30019,300DICHLORVOS10250.250.5005001,1,1-TRICHLOROETHANE10.106,250..106,250106,250BROMOMETHANE10....00CHLOROETHANE10..2,489.2,4892,489CARBONDISULFIDE11,120..1811,39012,52812,528PHOSGENE10....00DIMETHYLSULFATE10....00ISOBUTYRALDEHYDE10.8,647640.9,2879,287SEC-BUTYLALCOHOL10....00METHYL CHLOROCARBONATE10....00QUINOLINE10..250.250250 R e l e a s e s and T r ans f e r s P r of il eSect o r No t e b o o k Pr o j ect 67 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryTable 15,cont.:1995 TransfersforPharmaceuticalFacilities(SICs2833 &2834)in TRI,by Numberand FacilitiesReporting(Transfersreportedin pounds/year)CHEMICAL NAME#REPORTINGCHEMICALPOTWTRANSFERSDISPOSALTRANSFERSRECYCLINGTRANSFERSTREATMENTTRANSFERSENERGYRECOVERYTRANSFERSTOTALTRANSFERSAVGTRANSFERPERFACILITYBIPHENYL10....00O-XYLENE10..100,00061,800161,800161,8001,2-DICHLOROBENZENE16,480..14,00091,891112,371112,3711,2,4-TRIMETHYLBENZENE14,800....4,8004,800CUMENE11,167....1,1671,167ACETOPHENONE10....00NITROBENZENE15..5,914.5,9195,919ALLYL CHLORIDE10....00CHLOROMETHYLMETHYLETHER10....00MALEIC ANHYDRIDE10....00CHLOROBENZENE10...179,228179,228179,228CYCLOHEXANOL10....002-ETHOXYETHANOL14..25,004.25,00825,008PROPYLENE10....00N,N-DIMETHYLANILINE110,000...328,000338,000338,000MALATHION1026.273.299299THIABENDAZOLE1271...2,1602,4312,431ETHYL CHLOROFORMATE10....001,3-DICHLOROBENZENE11,400....1,4001,400LITHIUMCARBONATE10..750.750750N-METHYL-2-PYRROLIDONE1249,000....249,000249,000TETRACHLORVINPHOS104,200...4,2004,200TRIFLURALIN1018,000...18,00018,000BENFLURALIN1014,000...14,00014,000PROMETRYN10..203.203203NICKEL1018400,000..400,018400,018THIOPHANATE-METHYL10..2,677.2,6772,677SODIUMAZIDE10....00VINCLOZOLIN10..1,030.1,0301,030PERMETHRIN10....00PROPICONAZOLE10..1,025.1,0251,025___________________________________________________________����������20019,119,1791,394,80118,168,78327,330,63381,213,752147,239,047736,195 R e l e a s e s and T r ans f e r s P r of il e1
2
3
4
5
6
7
8
9
10 P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

T h e T R I d a t ab a s e c o n t a i n s a

d e t a ile d c o mp ila t i o n o f s e lf- r e p o r t e d
, fa c ilit ys p e c i fic c h e mic a l r e le a s e s

. T h e t o p r e p o r t in g fa c ilit ie s fo r t h e p h a r m aceut i cal in d u s t r y a r e lis t e d b e lo w in T ab l e s 1 6

. F a c ilit ie s t h a t h a v e r e p o r t e d o n ly th e SI C co des co v e r e d un der t h i s n o t e b o o k as a pr i ma r y SI C co de appear o n t h e fir s t lis t

. T ab l e 1 7 c o n t a in s a d d i t i o n a l fa c ilit ie s t h a t h a v e r e p o r t e d t h e S I C

co de co v e r e d wit h i n t h i s r e po r t , an d o n e o rm o r e S I C co des t h at ar e n o t

w it h in t h e s c o p e o f t h is n o t e b o o k

. T h e r e f o r e , t h e s e c o n d lis t in c l u d e s fa c ilit ie s t h a t c o n duct m u l

t i

p l e o p er at i o n s - - so m e t h at ar e un dert h e sco p e o f t h i s
n o t e b o o k
, a n d s o me t h a t a r e n o t

. C u r r e n t l y , t h e fa c ilit y- le v e l d a t a d o n o t all o w po ll u t a n t r e l eases t o b e b r o k en apar t b y in dust r i a l pr o cess.

T a bl e 16: T o p 10 T R I Rel e as ing P h arm a ceut i cal M a nuf act u ri ng F a cil i t i es a

R a n k F a cilit y T o t a l T R I R elea s e s in P o u nds
P h a r m a c i a & U p

j o h n Co

. , P o r t a g e , M i c h i g a n 8, 307, 190
W ar n e r

- L amb e r t Co

. , H o llan d, M i c h igan 2, 594, 111
Eli L illy & Co

. - Tippe c a n o e L a b s , S h ade lan d, In dian a 2
, 504, 810
U

pj o h n M f g. , Co

. , B a r c e l o n e t a , P u e r t o Ri c o 2, 001, 450
P f

i z e r In c

. , G r o t o n , Co n n e c t i c ut

. 1
, 761, 385
Eli L illy & Co - Clin to n L a b o r ato r i e s , Clin to n , In dian a 1
, 282, 605
A b b o t t Ch e m i c a l s , In c

. , B a r c e l o n e t a , P u e r t o Ri c o 1, 193, 707
P f

i z e r In c

. , S o ut h p o r t , N o r t h Ca r o l i n a 1
, 164, 350
S c h e r i n g-P l o ugh P r o duc t s , In c

. , L a s P i e d r a s , P u e r t o Ri c o 756, 089
B i o k y o w a In c

. , Ca pe G i r a r d e a u, M i s s o ur i 669, 869 S o u r ce: U S

EP A 1995 T o xics Releas e Inventor y D a tabas e.

a B e in g in c l u d e d o n th is lis t d o e s n o t me an th at th e r e le as e is as s o c iate d w ith n o n

- c o mp lian c e w ith e n v i r o n m e n tal law s

.
Sect o r No t e b o o k Pr o j ect 68 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

T a bl e 17: T o p 10 T R I Rel e as ing F a cil i t i es Repor t ing P h arm a ceut i cal M a nuf act u ri ng SI C Cod e s t o TRI a

Ra nk SIC Co de s R e p o rt ed in T R I F a cilit y T o t a l T R I R elea s e s in P o u nds
1 2834 P h a r m a c i a & U p

j o h n Co

. , P o r t a g e , M i c h i g a n 8, 307, 190
2 2819, 2834, 2842, 2865, 2869, 2873, 2879 M o n s a n t o Co

. , L u l i n g, L o ui s i a n a 5
, 698, 031

3 2834 W a r n e r

- L amb e r t Co

. , H o llan d, M i c h igan 2, 594, 111
4 2834 Eli L illy & Co

. - Tippe c a n o e L a b s , S h ade lan d, In di a n a 2, 504, 810

5 2834 U p

j o h n M f g. , Co

. , B a r c e l o n e t a , P u e r t o Ri c o 2, 001, 450
6 2833 P f i z e r In c

. , G r o t o n , Co n n e c t i c ut

. 1
, 761, 385
7 2834, 2869, 2969 E t h y l Co r p

. , O r a n ge b u r g , S o ut h Ca r o l i n a 1
, 284, 456
8 2833, 2834 Eli L illy & Co - Clin to n L a b o r ato r i e s , Clin to n , In di a n a 1, 282, 605

9 2819, 2821, 2824, 2834, 2865, 2869, 2879, 2979 D o w Ch e m i c a l Co

. , M i dl a n d, M i c h i g a n 1, 228, 629

10 2833, 2834 A b b o t t Ch e m i c a l s , In c

. , B a r c e l o n e t a , P u e r t o Ri c o 1, 193, 707 S o u r ce: U S

EP A T o xics Releas e Inventor y D a tabas e, 1995.

a B e in g in c l u d e d o n th is lis t d o e s n o t me an th at th e r e le as e is as s o c iate d w ith n o n

- c o mp lian c e w ith e n v i r o n m e n tal law s

.
Sect o r No t e b o o k Pr o j ect 69 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

IV. B

. S u m m a ry of S e l ect ed Ch em i c al s Rel e ased

T h e fo llo w i n g is a

s yn o p s is o f c u r r e n t s c ie n t ific t o x i c it y a n d fa t e in fo r ma t io n fo r t h e t o p c h e mic a l s ( b y w e ig h t ) t h a t f a c ilit ie s w it h in b o t h S I C 2833 an d 2834 s e l f

- r e po r t ed as r e l eas ed t o t h e en v i r o n m en t b a s e d upo n 1994 T R I dat a

. Because t h i s sect i o n i s b a sed upo n sel f

- r e po r t ed r e l ease dat a , i t do es n o t at t e m p t t o pr o v i d e i n f o r mat i o n o n ma n a gem e n t pr act i ces em pl o y ed b y t h e sect o rt o r e duce t h e r e l ease o f t h ese ch emi c a l s

. I n f o r mat i o n r e gar d i n g po ll u t a n t r e l ease r e duct i o n s o v ert i m e ma y b e av ai l ab l e f r o m E P A ’ s T R I an d 3 3 / 5 0 p r o g r a m s , o r di r ect l y

f

r o m t h e i n dust r i a l t r ade asso ci at i o n s t h at ar e l i s t e d i n Se c t i o nV III o f t h i s d o c u m e n t

. Si n c e t h e s e d e s c ri p t i o n s a r e c u rs o r y , pl ease co n s ul t t h e so ur ces r e f e r e n ced b e l o w f o r a m o r e det a i l e d descr i pt i o n
o f b o t h t h e ch em i cal s descr i b e d i n t h i s sect i o n , an d t h e ch em i cal s t h at appear
o n t h e f u ll l

i s t o f T R I ch em i cal s appear i n g i n S ect i o n I V

. A

.
T h e b r i e f desc r i p t i o ns pr o v i d ed b e l o w wer e t a ken f

r o m t h e Hazar do us S u b s t a n ces Dat a Bank ( H S D B) an d t h e I n t e gr at ed Ri sk I n f o r mat i o n S y st em (IR IS). Th e d i s c u s s i o n s o f t o x i c it y d e s c ri b e t h e ra n g e o f p o s s i b l e a d v e rs e h eal t h e f f e c t s t h at h a v e b een f

o un d t o b e asso ci at ed wit h ex po sur e t o t h ese ch em i cal s. T h ese adv e r s e ef f ect s ma y o rma y n o t o ccur at t h e l e v e l s r e l eased to th e e n v i r o n m e n t. I n d i v i d u a l s i n te r e s t e d i n a m o r e d e ta i l e d p i c t ure of th e ch em i cal co n cen t r at i o n s asso ci at ed wit h t h ese adv e r s e ef f ect s sh o u l d co n s ul t a t o x i co l o gi st o rt h e t o x i cit y l

it er at ur e f o rt h e ch em i cal t o o b t a i n m o r e i n f o r mat i o n

. T h e ef f ect s l i s t e d be l o w m u st b e t a ken i n co n t ex t o f t h ese
ex po sur e assum p t i o n s t h at ar e m o r e f u ll y

ex pl ai n e d wit h i n t h e f u ll ch em i cal pr o f i l e s i n HS DB. F o r m o r e i n f o r ma t i o n o n T OXNE T a
, co n t act t h e T OXNE T h e l p l i n e at 1- 800- 231- 3766.

M e thanol ( C A S : 67- 56- 1)

To x i ci t y . Met h an o l i s r eadi l y

ab so r b ed b y t h e gast r o in t e st in al t r act an d t h e
r e s p i r a t or y tr a c t , a n d i s tox i c to hu ma n s i n m o de r a te to h i g h d o s e s

. I n th e b o dy
, m e t h an o l i s co n v e r t ed i n t o f o r mal deh y de an d f o r m i c aci d. Met h an o l i s
ex cr et ed as f o r m i c aci d. Ob ser v ed t o x i c ef f ect s at h i gh do se l e v e l s gen e r a ll y

a TO X N ET is a c o mp u t e r s y s t e m r u n b y th e N atio n al L i b r ar y o f M e d i c i n e th at in c l u d e s a n u mb e r o f to x i c o lo g i c a l d atab as e s man ag e d b y EP A
, N atio n al C a n c e r I n s titu te , an d th e N atio n al I n s titu te f o r O c c u p atio n al S a f e ty an d H e alth . F o r mo r e in f o r matio n o n T O X N ET, c o n tac t th e TO X N ET h e lp lin e at 800-231-3766. D atab as e s in c l ude d in TO X N ET ar e : C C RI S ( C h e mic al C a r c in o g e n e s is R e s e ar c h I n f o r matio n S y s t e m )
, D A RT ( D e v e l o p me n tal an d R e p r o d u c tiv e To x i c ity D atab as e ) , D B I R ( D ir e c t o r y o f B i o t e c h n o lo g y I n f o r matio n R e s o u r c e s )
, EM I C B A C K ( E n v ir o n me n tal M u tag e n I n f o r matio n C e n t e r B a c k f ile )
, G E N E

- T O X ( G e n e tic To x i c o lo g y )
, H S D B ( H azar d o u s S u b s tan c e s D ata B a n k )
, I RI S ( I n te g r ate d Ri s k I n f o r matio n S y s t e m )
, RTEC S ( R e g is tr y o f To x i c Ef f e c t s o f C h e mic al S u b s tan c e s )
, an d TRI ( T o x ic C h e mic al R e le as e I n v e n t o r y )

. H S D B c o n tain s c h e mic al- s p e c i f i c in f o r matio n o n
man u f ac tu r i n g an d u s e , c h e mic al an d p h y s ic al p r o p e r tie s , s a f e ty an d h a n d lin g , to x i c ity an d b i o m e d ic al e f f e c t s , p h ar mac o l o g y , e n v i r o n m e n tal f ate an d e x p o s u r e p o te n tial, e x p o s u r e s tan d a r d s an d r e g u latio n s , mo n ito r i n g an d

an aly s i s me th o d s , an d ad d itio n al r e f e r e n c e s

.
Sect o r No t e b o o k Pr o j ect 70 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

i n cl ude cen t r al n e r v o u s sy st em dama ge an d b l i n dn ess. L o n g

- t er m ex po sur e t o h i g h le v e l s o f me t h a n o l v i a in h a la t i o n c a u s e liv e r a n d b l o o d d a ma g e in

a n ima ls

.
E c o l o g i call y , m e t h an o l i s ex pect ed t o h a v e l o w t o x i cit y t o aquat i c o r gan i sm s. Co n cen t r at i o n s l e t h al t o h a lf t h e o r gan i sm s o f a t e st po pul at i o n ar e ex pect ed t o ex ceed o n e m g m e t h an o l per l it er wat e r

. Met h an o l i s n o t l i k el y

t o per s i s t i n

wat e ro rt o b i o accum u l a t e in aquat i c o r gan i sm s.

Car c inogenicit y . T h er e i s cur r e n t l y

n o ev i d en ce t o s ugges t t h at m e t h an o l i s
car ci n o gen i c.

E n v i ro n m en t a lF a t e . L i qui d m e t h an o l i s l i k el y

t o ev apo r at e wh en l e f t

ex po sed. Met h an o l r eact s i n ai rt o pr o duce f o r mal deh y de wh i c h co n t r i b u t e s t o t h e f o r mat i o n o f ai r po ll u t a n t s. I n t h e at m o sph e r e i t can r eact wi t h o t h e r at m o sph e r i c ch em i cal s o rb e wash ed o u t b y r a i n

. Met h an o l i s r eadi l y degr aded b y m i c r o o r gan i sm s i n so i l s an d sur f ace wat e r s

.
P h ys ical P r oper t i es . M e t h a n o l i s a c o lo r l e s s , h i g h ly fla mmab l e liq u i d

. M e t h a n o l is mis c i b l e in w a t e r a n d h a s a

b o ilin g p o in t o f 147 degr ees F

.

M e thylene C h lor i de ( D ichlor omethane) ( C A S : 75- 09- 2)

To x i ci t y . S h o r t

- t e r m ex po sur e t o m e t h y l en e ch l o r i de ( M C) i s asso ci at ed wi t h

cen t r al n e r v o u s sy st em ef f ect s, i n cl udi n g he a d ach es, gi ddi n e ss, st upo r , ir r it ab ilit y, a n d n u mb n e s s , a n d t i n g lin g in t h e limb s

. M o r e s e v e r e n e u r o l o g ic a l ef

f ect s ar e r e po r t ed f r o m l o n g er

- t er m ex po sur e , appar e n t l y

due t o i n cr eased

c a r bo n m o no xi d e in t h e bl o o d f

r o m t h e br e a k d o w n o f M C

. C o nt a c tw i t h M C causes i r r it a t i o n o f t h e ey es, ski n , an d r e spi r at o r y t r act

. Occupat i o n al ex po sur e t o MC h a s al so b een l

i nked t o i n cr eased i n ci den ce o f

s p o n t a n e o u s ab o r t i o n s i n wo m e n

. A c ut e dama ges t o t h e ey es an d upper

r e spi r at o r y t r act , un co n s ci o u sn ess, an d deat h wer e r e po r t ed i n w o r k er s
ex po s e d t o h i gh co n cen t r at i o n s o f M C

. Ph o s gen e ( a degr adat i o n pr o duct o f MC) po i s o n i n g h a s b een r e po r t ed t o o ccu ri n sev e r a l cases wh er e MC was used i n t h e pr esen ce o f an o p en f

i r e

.
P o pul at i o n s at speci al r i sk f r o m ex po sur e t o MC i n cl ude o b ese peo p l e ( due t o accum u l a t i o n o f MC i n f

a t )
, an d peo p l e wi t h

i m p ai r e d car di o v ascul a r sy st em s.

Car c inogenit y . M C i s a p r o b ab l e hu ma n c a r c ino g e n vi a bo t h i nha l a t i o n a n d

o r a l e x p o s u r e , b a s e d o n limit e d e v id e n c e in hu ma n s , a n d s u ffic i e n t e v id e n c e in

a n ima ls

.

Sect o r No t e b o o k Pr o j ect 71 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

E n v i r o nm e n ta l F a te

. W h e n s p ille d o n la n d
, M C is r a p i d l y lo s t fr o m t h e s o il

sur f ace t h r o ugh v o l a t i l i zat i o n

. T h e r e ma i n derl each es t h r o ugh t h e sub s o i l i n t o th e g r ou n d w a te r

.
B i o d e g r a d a t i o n is p o s s i b l e in n a t u r a l w a t e r s b u t w ill p r o b ab ly b e v e r y s l o w
co m p ar ed wit h ev apo r at i o n

. L it t l e i s kn o w n ab o u t b i o c o n cen t r at i o n i n aquat i c
o r gan i sm s o r adso r p t i o n t o sedi m e n t s b u t t h ese ar e n o t l i k el y

t o b e si gn i f i can t p r o ces s e s

. Hy dr o l y s i s i s n o t an i m p o r t a n t pr o ces s un der no r m a l

e nvi r o nm e n t a l c o nd i t i o ns

.
MC r e l eased i n t o t h e at m o sph e r e degr ades v i a co n t act wit h o t h e r gases wit h

a

h a lf- life o f s e v e r a l mo n t h s

. A s ma ll fr a c t io n o f t h e c h e mic a l d i ffu s e s t o t h e
s t r a t o s p h e r e wh er e i t r a pi dl y

degr ades t h r o ugh ex po s u r e t o ul t r av i o l e t

r a d i a t io n a n d c o n t a c t w it h c h lo r i n e io n s

. B e in g a mo d e r a t e ly s o lu b l e ch em i cal
, MC i s ex pect ed t o par t i a ll y

r e t u r n t o ear t h i n r a i n

.
P h ys ical P r oper t i es . Met h y l en e ch l o r i de i s a co l o r l ess l i qui d. I t i s so l u b l e t o 2

p e r c e n t in w a t e r a n d h a s a

b o ilin g p o in t o f 104 degr ees F

.

A mmonia a ( C A S : 7664- 41- 7)

To x i ci t y . A n h y dr o u s am m

o n i a i s i r r i t a t in g t o t h e skin , ey es, n o se, t h r o at , an d upperr e s p i r at o r y s y s t em

.
E c o l o g i call y , am m

o n i a i s a so ur ce o f n it r o g en ( a n essen t i a l el em en t f o r aquat i c pl an t gr o w t h )
, an d ma y t h er ef o r e co n t r i b u t e t o eut r o p h i cat i o n o f st an di n g o r sl o w

- m o v i n g sur f ace wat e r , par t i c ul ar l y

i n n it r o g en

- limit e d w a t e r s s u c h a s t h e Ch esapeake Bay

. I n addit i o n , aqueo u s am m

o n i a i s m o der a t e l y

t o x i c t o aquat i c
o r g a n i sm s.

Car c inogenicit y . T h er e i s cur r e n t l y

n o ev i d en ce t o s ugges t t h at am m

o n i a i s
car ci n o gen i c.

E n v i r o nm e n ta l F a te

. A mmo n i a c o mb in e s w it h s u lfa t e io n s in t h e
a t mo s p h e r e a n d is w a s h e d o u t b y r a in fa ll, r e s u lt in g in r a p i d r e t u r n o f a mmo n i a t o t h e so i l an d sur f ace wat e r s

.
A m m

o n i a i s a cen t r al co m p o u n d i n t h e en v i r o n m en t a l cy cl i n g o f n it r o g en

. A m m

o n i a i n l a kes, r i v e r s , an d st r eam s i s co n v e r t ed t o n it r at e.

a Th e r e po r tin g s tan dar d s f o r ammo n ia w e r e c h an ge d in 1995. A mmo n i um s u lf ate is de le te d f r o m th e lis t an d th r e s h o l d an d r e le as e d e te r min atio n s f o r aq u e o u s ammo n ia ar e limite d to 1 0 p e r c e n t o f th e to tal ammo n ia p r e s e n t in s o lu tio n

. Th is c h an g e w ill r e d u c e th e amo u n t o f ammo n ia r e p o r t e d to TRI

. C o mp le te d e tails o f th e r e v i s i o n s
c a n b e f o un d i n 40 CF R P a r t 372.

Sect o r No t e b o o k Pr o j ect 72 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

P h ys ical P r ope r t i e s . A m m

o n i a i s a co l o r l ess gas at at m o sph e r i c pr essur e , b u t i s s h i pped as a l i quef i ed co m p r e s s e d gas

. I t i s s o l u b l e t o ab o u t 34 per cen t in

w a t e r a n d h a s a

b o ilin g p o in t o f - 2 8 d e g r e e s F

. A mmo n i a I t is c o r r o s i v e a n d h a s a pun gen t o d o r

.

Tolue n e ( C A S : 108- 88- 3)

To x i ci t y . I n h a l a t i o n o r i n gest i o n o f t o l u en e can cause h eadach es, co n f usi o n , weakn e ss, an d m e m o r y l o ss. T o l u en e ma y al so af f ect t h e way t h e ki dn ey s an d liv e r fu n c t i o n

.
React i o n s o f t o l u en e ( s ee en v i r o n m en t a l f

a t e ) i n t h e at m o sph e r e co n t r i b u t e t o t h e f o r mat i o n o f o z o n e i n t h e l o w e r at m o sph e r e

. Ozo n e can af f ect t h e
r e s p ir a t o r y s y s t e m , e s p e c i a lly in s e n s it iv e in d i v i d u a ls s u c h a s a s t h ma o r a lle r g y
s u f f e re rs

.
S o m e

s t u d i e s ha ve s h o w n t h a tu nbo r n a n i ma l s w e r e ha r m e d w h e n hi g h l e ve l s
o f t o l u en e wer e i n h a l e d b y t h ei rm o t h er s, al t h o ugh t h e sam e ef f ect s wer e n o t

seen wh en t h e m o t h er s wer e f e d l a r g e quan t i t i e s o f t o l u en e. No t e t h at t h ese
r e s u lt s ma y r e fle c t s imila r d i ffic u lt ie s in hu ma n s

.
Car c inogenicit y . T h e r e i s cur r e n t l y

n o ev i d en ce t o s ugges t t h at t o l u en e i s
car ci n o gen i c.

E n v i r o nm e n ta l F a te

. A po r t i o n o f r e l eases o f t o l u en e t o l a n d an d wat e r wi ll

ev apo r at e. T o l u en e ma y al so b e degr aded b y m i c r o o r gan i sm s

. On ce
v o la t iliz e d
, t o lu e n e in t h e lo w e r a t mo s p h e r e w ill r eact wit h o t h e r at m o sph e r i c
co m p o n en t s co n t r i b u t i n g t o t h e f o r mat i o n o f gr o u n d

- l ev el o z o n e an d o t h e r ai r p o llu t a n t s

.
P h ys ical P r oper t i es . T o l u en e l i qui d wit h a s w eet , pun gen t o d o r

. I t i s s o l u b l e t o 0

. 0 7 p e r c e n t in w a t e r a n d h a s a

b o ilin g p o in t o f 232 degr ees F

.

Sect o r No t e b o o k Pr o j ect 73 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

I V

. C

. Othe r D a ta Sour c e s

T h e t o x i c ch em i cal r e l ease dat a o b t a i n ed f r o m T R I capt u r e s ma n y o f t h e fa c ilit ie s in t h e p h a r m aceut i cal in dust r y

. I t al so all o ws f o r a co m p ar i s o n
a c r o s s ye a r s a n d in d u s t r y s e c t o r s

. R e p o r t e d c h e mic a l s a r e limit e d h o w e v e r t o t h e appr o x i ma t e l y

600 r e po r t ed ch em i cal s

. M o s t o f t h e h y dr o car b o n
em i ssi o n s f r o m ph ar maceut i cal f

ac ilit ie s a r e n o t c a p t u r e d b y T R I

. T h e E P A Of f i ce o f A i r Qual it y P l an n in g an d S t an dar d s ha s co m p i l e d ai r po ll u t a n t

e mis s i o n fa c t o r s fo r d e t e r min in g t h e t o t a l a i r e mis s i o n s o f p r io r it y p o llu t a n t s (e .g ., t o t a l h y d r o c a r b o n s , S O 2 , N O 2 , CO, p a r t i c ul at es, et c. ) f r o m ma n y ch em i cal ma n u f act ur i n g so ur ces.

Th e EPAO f f i c e o f A i r’ s A e ro m e t r i c In f o rma t i o nR e t r i e v a l Sy s t e m (A IR S)

co n t ai n s a wi de r a n g e o f i n f o r mat i o n r e l a t e d t o st at i o n a r y so u r c e s o f ai r p o llu t i o n , in c l u d i n g t h e e mis s i o n s o f a

n u mb e r o f a i r p o llu t a n t s w h ic h ma y b e
o f

co n cer n wit h i n a par t i c ul ari n dust r y

. W it h t h e ex cept i o n o f v o l a t i l e o r gan i c
co m p o u n d s ( VOCs)
, t h e r e i s l it t l e o v er l a p wit h t h e T R I ch em i cal s r e po r t ed ab o v e. T ab l e 1 8 s u m ma r i zes an n u al r e l eases o f car b o n m o n o x i de ( C O)
, n itr og e n d i ox i d e ( N O 2 ), p a rt i c u l a t e ma t t e r o f 1 0 m i c ro n s o r l e s s (PM 10 )
, tota l par t i c ul at e ( P T )
, s u l f ur di o x i d e ( S O 2 )
, a n d v o la t ile o r g a n i c c o mp o u n d s ( VOCs )

.

Sect o r No t e b o o k Pr o j ect 74 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e



### Tab le 18: Air P o llu tan t Re le as e s b y I n d u s t r y S e c t o r (to n s / y e ar )

I ndus try Se c t or CO NO 2 PM 10 PT SO 2 VOC

M e ta l M i ning 4,670 39,849 63,541 173,566 17,690 915

No nme t a l M i ning 25,922 22,881 40,199 128,661 18,000 4,002

L

u mbe r a nd W o o d P r o duc tio n 122,061 38,042 20,456 64,650 9,401 55,983

F u r n itur ea nd F i x t ur e s 2,754 1,872 2,502 4,827 1,538 67,604

P u lp a nd P a pe r 566,883 358,675 35,030 111,210 493,313 127,809

P r inting 8,755 3,542 405 1,198 1,684 103,018

I n o r ga nic C h e mic a l s 153,294 106,522 6,703 34,664 194,153 65,427

Or ga nic C h e mic a l s 112,410 187,400 14,596 16,053 176,115 180,350

P e tr o l e u m R e f i ning 734,630 355,852 27,497 36,141 619,775 313,982

R ubbe r a nd M i s c . P l a s tic s 2,200 9,955 2,618 5,182 21,720 132,945

S t o n e , C l a y a nd C o nc r e te 105,059 340,639 192,962 662,233 308,534 34,337

I r o n a nd S t e e l 1,386,461 153,607 83,938 87,939 232,347 83,882

No nf e r

r o us M e ta ls 214,243 31,136 10,403 24,654 253,538 11,058

F a br ic a t e d M e ta ls 4,925 11,104 1,019 2,790 3,169 86,472

E l e c tr o nic s a nd C o mpute r s 356 1,501 224 385 741 4,866

M o to r Ve hic l e s , B o die s , P a r t s an d A c c e sso r i e s 15,109 27,355 1,048 3,699 20,378 96,338

Dr y C l e a ning 102 184 3 2 7 155 7,441

G

r o und T r a n s p o r ta tio n 128,625 550,551 2,569 5,489 8,417 104,824

M e ta l C a s ting 116,538 11,911 10,995 20,973 6,513 19,031

P h ar m a c e u t i c a ls 6,586 19,088 1,576 4,425 21,311 37,214

P l a s tic R e s i ns a n d M a nma d e F i be r s 16,388 41,771 2,218 7,546 67,546 74,138

T e x tile s 8,177 34,523 2,028 9,479 43,050 27,768

P o we r G e ne r a tio n 366,208 5,986,757 140,760 464,542 13,827,511 57,384

S h ipbuilding a nd R e pa ir 105 862 638 943 3,051 3,967

S o ur c e : U.S

. E P A Of f i c eo f Air a nd R a dia tio n, AI R S Da ta ba s e , 1997.

Sect o r No t e b o o k Pr o j ect 75 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

I V

. D

. C o m p aris on of T o x i c R e l e as e I n ve ntory A m ong Se l e c t e d I ndus trie s

T h e f o ll o wi n g i n f o r mat i o n i s pr esen t e d as a co m p ar i s o n o f po ll u t a n t r e l ease
an d t r an sf er dat a acr o ss i n dust r i a l cat ego r i e s. I t i s pr o v i d ed t o gi v e a gen e r a l

sen s e a s t o t h e r e l a t i v e scal e o f r e l eases an d t r an sf er s wit h i n each sect o r pr o f i l e d un der t h i s pr o j ect

. P l ease n o t e t h at t h e f o ll o win g f i gur e an d t ab l e do

n o t co n t ai n r e l e a s e s a n d t r an sf er s f o ri n dust r i a l cat ego r i e s t h at ar e n o t i n cl uded i n t h i s p r o j ect , an d t hus can n o t b e used t o dr aw co n c l u si o n s
r e gar d i n g t h e t o t a l r e l ease an d t r an sf e r a m o u n t s t h at ar e r e po r t ed t o T R I

. S imila r in fo r ma t io n is a v a ilab l e w it h in t h e a n n u a l T R I P u b lic D a t a R e le a s e B ook

.
F i gur e 12 i s a gr aph i cal r e pr es en t a t i o n o f a s u m ma r y o f t h e 1995 T R I dat a f

o r t h e ph ar m aceut i cal i n dust r y an d t h e o t h e r sect o r s pr o f i l e d i n separ a t e
n o t e b o o k s. T h e b a r gr aph pr esen t s t h e t o t a l T R I r e l eases an d t o t a l t r an sf er s
o n t h e v e r t i cal ax i s

. T h e gr aph i s b a sed o n t h e dat a i n T ab l e 19 an d i s m ean t t o fa c ilit a t e c o mp a r is o n s a m o n g t h e r e la t i v e a m o u n t s o f r e le a s e s , t r a n s f e r s , a n d r e l e a s e s p e r fa c ilit y b o t h w it h in a n d a m o n g t h e s e s e c t o r s

. T h e r e a d e r
s h o u ld n o t e , h o w e v e r , t h a t d i ffe r e n c e s in t h e p r o p o r t i o n o f fa c ilit ie s c a p t u r e d by T R I ex i s t am o n g i n dust r y sect o r s. T h i s can b e a f act o ro f po o rS I C

ma t c h i n g a n d r e la t i v e d i ffe r e n c e s in t h e n u mb e r o f fa c ilit ie s r e p o r t in g t o T R I f r o m t h e v a r i o u s s ect o r s

. I n t h e cas e o f t h e ph ar maceut i cal i n dus t r y , t h e 1995 T R I dat a pr es en t e d h e r e co v e r s 200 f ac ilit ie s

. O n ly t h o s e fa c ilit ie s l i s t i ng p r ima r y S I C c o d e s fa llin g w it h in S I C 2833 an d 2834 wer e us ed.

C o mp a r is o n s o f t h e r e p o r t e d p o u n d s r e le a s e d o r t r a n s f e r r e d p e r fa c ilit y i n T ab l e 19 dem o n s t r at e t h at t h e ph ar maceut i cal i n dust r y i s ab o v e av er age i n it s p o llu t a n t r e le a s e s a n d t r a n s f e r s p e r fa c ilit y w h e n c o mp a r e d t o o t h e r T R I i n d u s tr i e s

. O f th e tw e n ty ma n u f a c t u r i n g S I C c o d e s l i s te d i n th e T R I d a tab a s e , t h e me a n a m o u n t o f p o llu t a n t r e le a s e p e r fa c ilit y ( i n c lu d i n g p h a r m aceut i cal fa c ilit ie s ) w a s a p p r o x i m a t e ly 101, 000 po un ds

. T h e T R I r e l eas es o f t h e
av er age ph ar maceut i cal f

ac ilit y ( S I C 2833 an d 2834) wer e 150, 000 po un ds
, ma k i n g t h e in d u s t r y 1

. 5 t ime s h i g h e r in p e r f a c ilit y r e le a s e s t h a n fo r o t h e r i n dust r i e s. F o rt r an sf er s, t h e m ean o f ph ar maceut i cal f ac ilit ie s w a s ab o u t 4

. 6 t ime s a s mu c h a s t h a t o f a ll T R I ma n u fa c t u r in g fa c ilit ie s ( 1 6 1
, 000 po un ds t r a n s f e r r e d o ff- s it e p e r fa c ilit y c o mp a r e d t o 7 3 6 , 0 0 0 p o u n d s p e r ph ar maceut i cal f

ac ilit y)

. T h is c o mp a r is o n is d i ffic u lt t o in t e r p r e t d u e t o t h e di v e r g en t n a t u r e o f t h e i n dus t r i e s l i s t e d in T ab l e 19 an d t h e di f f e r e n ces i n t h e
r a w ma t e r i al s an d pr o cess e s used t o ma n u f act ur e t h e speci f i c i n dust r y ’ s pr o duct s

. T h e b a t c h n a t u r e an d l a r g e v o l u m e s o f r a w ma t e r i al s u s ed t o pr o duce t h e r e l a t i v e l y

small am o u n t s o f h i gh pur it y ph ar maceut i cal pr o duct s
ma y acco un t f o rt h e h i gh err a t e r e l eased an d t r an sf er r e d b y t h e ph ar maceut i cal i n dus t r y

.

Sect o r No t e b o o k Pr o j ect 76 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e 

### F i gu re 12: S u m m a ry o f TRI Rel e ases an d Tran sf ers b y In d u st ry

0 10 0 20 0 30 0 40 0 50 0 60 02224252611-26312711-27892812-28192821, 2823, 28242833, 28342861-286929113032331332, 336333, 33434363713731

S I C R

a ngeTotal Pounds (millions)

T o t a l R

e le as es T o t a l T r a n s f er s

Sour ce : U S

E

P

A 1995 Toxi cs R e l e as e I n ve nt or y D a t abas e

.

SI C Ra n g e I n du s t ry S ecto r S I C Ra n g e I n du s t ry S ecto r S I C Ra n g e I n du s t ry S ecto r

2 2 T e x tile s 2833, 2834 P h arm a ceu t i cal s 333, 334 N o nf e r r o us M e t a l s

24 L u m b e r a nd Wo o d Pr o duc t s 2861- 2869 O r gan i c C h em

. M f g. 3 4 F a br i cat ed M e t a l s

25 Fur n i t u r e a nd Fi x t ur e s 2911 Pe t r o l e u m R e f i ni ng 36 El e c t r o ni c Equi p

. a n d Co m p

. 2611- 2631 Pul p a nd Pa p e r 3 0 R ub b e r a nd M i s c

. P l a s tic s 371 M o t o r V e hi c l e s , B o di e s , P a r t s, an d A ccessor i es 2711- 2789 Pr i n t i n g 3 2 S t o ne , C l a y , a n d Co n c r e t e 3731 Shi p b u i l d i n g

2812- 2819 I n o r g a ni c C h e m i c a l M a nuf a c t ur i n g 331 I r o n a nd St e e l

Sect o r No t e b o o k Pr o j ect 77 Sept em b e r 1997P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

2821, 2823, 2824 P l ast i c R e si n s an d M a n m ad e F i ber s 332, 336 M e t a l C a s t i n g

Sect o r No t e b o o k Pr o j ect 78 Sept em b e r 1997Sect o r No t e b o o k Pr o j ect 79 Sept em b e r 1997 P h arm a c e u tic a lI ndus tryIndustrySectorTable19: ToxicsReleaseInventory Data forSelectedIndustriesSICRange# TRIFacilitiesTRIReleasesTRITransfersTotal Releases+Transfers(millionlbs.)Average Releases +Transfers per Facility(pounds)TotalReleases(millionlbs.)Ave.ReleasesperFacility(pounds)TotalTransfers(millionlbs.)Ave.Trans.per Facility(pounds)Textiles2233917.853,0007.021,00024.874,000Lumber and Wood Products2439730.076,0004.110,00034.186,000FurnitureandFixtures2533637.6112,0009.929,00047.5141,000PulpandPaper2611-2631305232.6763,00056.5185,000289.1948,000Printing2711-278926233.9129,00010.440,00044.3169,000InorganicChem.Mfg.2812-281941360.7468,00021.7191,000438.5659,000Plastic Resinsand ManmadeFibers2821,2823,282441064.1156,000192.4469,000256.5625,000Pharmaceuticals2833,283420029.9150,000147.2736,000177.1886,000OrganicChemicalMfg.2861-2869402148.3598,000208.6631,000946.81,229,000PetroleumRefining291118073.8410,00029.2162,000103.0572,000RubberandMisc.Plastics301,947143.173,000102.653,000245.7126,000Stone,Clay,andConcrete3262343.970,00031.851,00075.7121,000IronandSteel33142390.7214,000513.91,215,000604.61,429,000MetalCasting332,33665436.055,00073.9113,000109.9168,000NonferrousMetals333,334282201.7715,000164582,000365.71,297,000FabricatedMetals342,67683.531,000350.5131,000434.0162,000Electronic Equip. andComp.364074.311,00068.8169,00073.1180,000Motor Vehicles, Bodies,Parts, and Accessories37175479.3105,000194257,000273.3362,000Shipbuilding3731432.456,0004.195,0006.5151,000 R e l e a s e s and T r ans f e r s P r of il eSource:USEPA ToxicsReleaseInventoryDatabase,1995.P h arm a c e u tic a l I ndus try R e l e a s e s and T r ans f e r s P r of il e

Sect o r No t e b o o k Pr o j ect 80 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V. PO LLUTIO N PREVENTIO N O PPO RTUNITIES

T h e b e st way t o r e duce po ll u t i o n i s t o p r ev en t i t i n t h e f i r s t pl ace. S o m e
co m p an i e s h a v e cr eat i v el y im p l e m e n t ed po ll u t i o n pr ev en t i o n t ech n i ques t h at imp r o v e e ffic i e n c y a n d in c r e a s e p r o f it s w h ile a t t h e s a me t ime min imiz in g
e n v i r o n m en t a l i m p act s. T h i s can b e do n e in ma n y way s , such as r e d u c i n g
ma t e ri a l i n p u t s , re -e n g i n e e r in g p r o c e s s e s t o re u s e b y -p ro d u c t s , i m p ro v i n g
ma n a gem e n t pr act i ces, an d em pl o yi n g sub s t it u t i o n o f t o x i c ch em i cal s. S o m e
s ma lle r fa c ilit ie s a r e ab le t o a c t u a lly g e t b e lo w r e g u l a t o r y t h r e s h o l d s ju s t b y
r e duci n g po ll u t a n t r e l eas es t h r o ugh aggr es s i v e po ll u t i o n pr ev en t i o n po l i c i e s

.
T h e Po ll u t i o n Pr ev en t i o n A c t o f 1990 es t ab l i s h e d a n a t i o n al po l i c y o f

ma n a gi n g wast e t h r o u g h so ur ce r e duct i o n , wh i c h m ean s pr ev en t i n g t h e gen e r a t i o n o f wast e. T h e P o ll u t i o n P r ev en t i o n A c t al so est ab l i s h e d as n a t i o n al po l i c y a h i er ar ch y o f wast e ma n a gem e n t o p t i o n s f o r sit u at i o n s i n wh i c h so ur ce
r e d u c t i o n c a n n o t b e imp le me n t e d fe a s ib ly. I n t h e w a s t e ma n a g e me n t h i er ar ch y , i f so ur ce r e duct i o n i s n o t f easi b l e t h e n e x t al t e r n at i v e i s r ecy cl i n g
o f

wast es, f o ll o wed b y en er gy r eco v e r y , an d wast e t r e a t m e n t as a l a st al

t e r n at i v e.

I n o r dert o en co ur age t h ese appr o ach es, t h i s sect i o n pr o v i d es b o t h gen e r a l

an d co m p an y

- speci f i c descr i pt i o n s o f po ll u t i o n pr ev en t i o n act i v it i e s t h at h a v e b een i m p l e m e n t ed w i t h i n t h e ph ar maceut i cal i n dust r y

. W h i l e t h e l i s t i s n o t

ex h a ust i v e , it do es pr o v i d e co r e i n f o r mat i o n t h at can b e used as t h e st ar t i n g p o in t fo r fa c ilit ie s in t e r e s t e d in b e g i n n in g t h e i r o w n p o llu t i o n p r e v e n t i o n pr o j ect s. W h en po ssi b l e, t h i s sect i o n pr o v i d es i n f o r mat i o n f

r o m r eal act i v it i e s t h at can b e , o r ar e b e in g, i m p l e m e n t ed b y t h i s sect o r- - i n cl udi n g a di scussi o n
o f

asso ci at ed co st s, t i m e f r am es, an d ex pect ed r a t e s o f r e t u r n

. T h i s sect i o n p r o v id e s s u mma r y in fo r ma t io n fr o m a c t iv it i e s t h a t ma y b e , o r a r e b e in g imp le me n t e d b y t h is s e c t o r

. P l e a s e n o t e t h a t t h e a c t iv it ie s d e s c r i b e d in t h is

s e c t io n d o n o t n e c e s s a r ily a p p l y t o a ll fa c ilit ie s t h a t fa ll w it h in t h is s e c t o r

. F a c ilit y- s p e c i fic c o n d it io n s mu s t b e c a r e f u lly c o n s id e r e d w h e n p o llu t i o n pr ev en t i o n o p t i o n s ar e ev al uat e d, an d t h e f u ll im p act s o f t h e ch an ge m u st b e
ex am i n ed t o det e r m i n e h o w each o p t i o n af f ect s ai r , l a n d an d wat e r po ll u t a n t

r e l eases.

T h e b u l k

ma n u f act ur i n g pr o cesses o f t h e ph ar ma c e u t i c a l in dust r y ar e ch ar act er i zed b y a l o w r a t i o o f f

i n i sh ed pr o duct t o r a w ma t e r i al

. T h er ef o r e, l a r g e quan t it i e s o f r e si dual wast e ar e gen e r a t e d, especi all y

i n f

e r m en t a t i o n an d

n a t u r a l p r o d u c t ex t r act i o n

. Ch em i cal syn t h e si s p r o cesses g e n e r a t e w a st es
co n t ai n i n g h azar do us spen t so lv en t s an d r eact an t s , co m b i n ed wit h r e si dual wast es such as r eact i o n r e si dues. E qui pm en t cl ean i n g wat e r an d r e si due, o f t e n
co n t ai n i n g h azar do us ch em i cal s, al so ar e a ma j o r wast e st r eam ( U

. S

. E P A
, 1991)

.

Sect o r No t e b o o k Pr o j ect 81 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

S o ur ce r e duct i o n i s o n e m e t h o d b y wh i c h t h e i n dust r y ai m s t o r e duce t h ese wast es. Ho wev e r , so ur ce r e duct i o n m e t h o d s s u c h as pr o cess m o di f i cat i o n s
a n d ma te r i a l s u b s titu ti on s ma y n o t b e a s e a s i l y im pl e m e n te d in th e ph ar maceut i cal i n dust r y a s i n o t h e rma n u f act ur i n g sect o r s. T h i s i s b ecause
an y si gn i f i can t ch an ge t o t h e pr o duct i o n pr o cess o f an ex i s t i n g pr o duct
, ma y
n eed appr o v al f r o m t h e F o o d an d Dr ug A d m i n i s t r at i o n ( F DA )

. I f a co m p an y wi sh es t o ch an ge t h e m e t h o d o f ma ki n g a dr ug o r act i v e i n gr edi e n t t h at go es i n t o it , t h e F D A r e qui r e s t h e co m p an y t o pr o v e t h at t h e ‘ n ew’ dr ug i s o f t h e
s a me o r b e t t e r q u a lit y a s t h e o l d d r u g a n d t h a t a n y r e fo r m u l a t io n w ill n o t

a d v e r s e l y a ffe c t t h e id e n t i t y , s t r e n g t h
, q u a lit y, p u r it y, o r b i o a v a ilab ilit y o f t h e dr ug. T h e pr o ces s o f gat h er i n g i n f o r mat i o n t o s uppo r t t h e ch an ge an d await i n g F D A r e v i ew an d app r o v a l c a n b e l e n g t h y , t i m e

- c o n sum i n g an d

ex pen s i v e.

A s a r e sul t , ma n y ph ar maceut i cal co m p an i e s ar e l o o k in g at way s t o m i n imiz e wast e i n f

u t u r e pr o duct i o n pr o cesses at t h e r e sear ch an d dev e l o pm en t st age. I n co r p o r at i n g po ll u t i o n pr ev en t i o n at t h e st ar t o f a n e w dr ug dev e l o pm en t pr o cess i s m u ch m o r e eco n o m i cal
, ef f i ci en t , an d en v i r o n m en t a ll y so un d ( s ee S ect i o n VI

. D. f o r f u r t h e r det a i l s )

. T h e f act o r s af f ect i n g t h e ph ar maceut i cal in d u s t r y’ s p o llu t i o n p r e v e n t i o n e ffo r t s w e r e d o c u me n t e d b y P h R M A me mb e r s i n

a 1997 do cum e n t en t it l ed P har maceutical I ndus tr y W a s t e M i n i m i z a tion Initiativ e s

.
Man y ph ar maceut i cal co m p an i e s h a v e al r eady i m p l e m e n t ed po ll u t i o n p r e v e n t i o n p r o g r a ms i n t h e i r ma n u fa c t u r in g fa c ilit ie s

. A l t h o u g h p o llu t i o n pr ev en t i o n ma y n o t al way s b e a sub s t it u t e f o r co n t r o l t ech n o l o gi es, it i s o f t e n vi ab l e an d i s an in cr easin gl y

po pul arm e t h o d f o rm eet in g en v i r o nm e n t a l

co m p l

i a n ce r e qui r e m e n t s. S o m e ex am pl es o f i n n o v a t i v e wast e r e duct i o n pr o g r a m s t h at i n co r p o r at e so ur ce r e duct i o n as well as r ecy cl i n g an d r e use ar e pr esen t e d i n t h e case st udi es t h at appeari n t h i s sect i o n

.

Sect o r No t e b o o k Pr o j ect 82 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V

. A

. M a te ri al Subs titutions

S u b s titu ti n g r a w ma te r i a l s to l e s s e n th e v o l u m e a n d/ or tox i c ity of w a s t e gen e r a t e d i s a t y pe o f s o ur ce r e duct i o n ( U

. S

. E P A
, 1991)

. On e o f t h e m o s t

co m m

o n o ppo r t un it i e s f o rm a t e r i al sub s t it u t i o n s i n t h e ph ar maceut i cal s i n dust r y i s f o un d i n t h e t ab l et co at i n g pr o cess. Un t i l r ecen t l y , ma n y t ab l et

c o at i n g o p er at i o n s i n v o lv ed t h e use o f m e t h y l en e ch l o r i de an d o t h e r
c h lo r i n a t e d s o lv e n t s

. B y s w it c h in g t o a q u e o u s

- b a s e d c o a t in g films
, ma n y f i r m s h a v e r e duced t h e h azar do us wast e co n t en t i n t h ei r ai r an d ef f l uen t wast e st r eam s, as well as t h e co st o f pur ch asi n g ch em i cal s. A queo u s

- b a s e d cl ean i n g
so l u t i o n s ar e al so b e i n g used m o r e f r equen t l y

f

o r equi pm en t cl ean in g i n st ead

o f

s o lv en t

- b a s e d s o l u t i o n s ( U

. S

. E P A
, 1991)

.

Sect o r No t e b o o k Pr o j ect 83 Sept em b e r 1997S c e r n o e t w n o t ma wh s r o C- a o
ar maceut Cs ar a r n e s I

c h o y ugus a b r e dr u e C s 134a do depl

o ma n h e b a v e l A

g. o er an o n a cl e an m s T h o r d n h ch n e b at ed wi ay i g. s h wat an
a i ed. I n al o n t m o s a

ye a a s a e $ o g r a d o o h

A t s P in t A e k e v e d e n e ( duct i o o at i T C r f d o h n
o er s , pr i n i n an ur n b t u o r
n en o i g equi t a pet

s t e m wh er gy eco n an o f t e

� A t e c e r c u d p e n o h o s a me c r s d o u
a een e t v er i h n i i a f e a t n o n n e t g en a l e ss- do

o v o c e en o n m b a
n n o n r i duct ki an d co o r r e r

t h r o k a i n k o p e a n ve f a t ch em i sub t e o e T h e n
cen e i o n n d t er f e addi n
o u e i o l a t an o r eco v e t h n t v equi

o o co n o o t t h ey cr i

l P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

PO LLUTIO N PREVENTIO N CAS E S T UDIES

M a te r i al Subs titution

� h i g

- P l ugh P h ar maceut i cal s w ill ma r k a n e in h a le r fo r t h e t r e a t me t f a s h
, i c h i f r ee o f ch l o r o f l uo car b o n s ( C F C s)

. T h e CF f r ee i n h l e r was dev e l ped b y 3M P h i cal s. CF e used as a pr o p ell n t i n m e t e e d- do se i h a l r ( M DI )

. n a n e w M D I
, wh i was appr v ed b t h e F D A i n A t , 1996, CF Cs h v e een pl aced b y h y o f l o r o a l k an e- 134a ( H F A

- 134a)

. Un l i k F C
, HF A

­ es n o t et e t h e
o z o n e

. T h e p r d u c t w ill b e r k e t e d u d e r t r a n d n me P r o n t i ® HF

.

� Sc h e ri n g -Pl o u g hL ab o ra t o ri e s i s s w it c h i n g t o a c o a t e d n a t u ra l kr a f t (C N K ) p a p e rb o a rd f o r i t s packagi n CNK i s st r n g d l e ss ex pen s i v e t h an t h e pr ev i us packagi g m t e r i al
, as well as r ecy ab l d co p o t ab l e. e paper b a i s o t b l each ed wi t l o r i
, u t i s
co t h wh it e cl co at n I n st ead o f m i n er al

- b ased v a r n i e s an d i nks, e r d so y

b s e d ma t e r al s ar e us New J e r s ey e, h e co p an y i s ex pect ed t v e $225, 000 p e r r n d c o u l d v u p t o 1

. 2 millio n if t h e p r m e x p a n s t t e r d i v i s i o n s

.

� it W e s t o , P
, fa c ilit y, M r c r mo 1
, 1
, 1

- T r ic h l o r o t h a T C A ) fr o m it s pr o n p er o n s

. A was used i n st i ppi n g l ab e l s o f b o t t l es an t e r cl ean i g p at i o n t g , d ma n u f act i g. A cit r us­ ased so lv en t was sub s i t t e d f cl ean i g packagin g equi pm t

. F r cl ean in g ma n u f act ur n pm en , r o l eum

- b a sed

so lv en t was sub t it u d, t h e wast e f r o i c h i s used f o r en r v e r y i f

- si fa c ilit y.

t h s a me fa ilit y, M k s u b s t it t e h l fo r t ime r l, a r u y- b a e c o mp n d

. T h i m e r o sal h d b used as a b i o c i d o i n act i at e b act a dur i n g t e i t l st ages o f

r m en t i o n i t h e pr o duct i o f a v acci

. S u b s t i u t i n ph o l
, h azar us, F D A

appr ed b i i d ab l e d M e r c k t ach i e v e an 85 per cen t r e duct i o i n e r c ur y

­ s e d wast e. I addit i o , t h e sub s t it u t i e sul t ed i n n cr eased pr o yi el ds, i m p r o v e d m i c r o b i al

n e t i cs, st sav i n g s f a w ma t i al s.

� Ati s C e e e p l n t R i ve r s i d e , P A
, M e r c d e ve l d i nno va t i ne w ma nu c u r i n g
s t r y wh i c h s t i u t s t o l u en e f r di ch l o r o m t h an e. e ch an ge h a s r sul t ed i a 98 per t r duct i r e l eases an r an sf s o di ch l o r o m t h an e. I n t i o , b ecause t l en s l e ss v i l e d m r e easi l y r e d, e co r o l s an d r eco e r y pm en t o n t h e n e w pr cess ar e ab l e t t r l t l u en e r e l eases such h at h a v e i n eased o n l y
s lig h t ly. M a te r i al Subs titution (c ont. )

� Ri kerL ab o r a t o r i es i n No r t h b r i dge, CA r ecen t l y

r e pl aced sev e r a l di f f e r e n t o r gan i c so lv en t

co at i n g ma t e r i al s used o n m e di ci n e t ab l et s wit h a wat e r

- b ased co at i n g ma t e r i al

. Di f f e r e n ces i n t h e n e w co at i n g ma t e r i al r e qui r e d t h at n e w spr a y equi pm en t b e i n st all e d. Ho wev e r , t h e co m p an y s a v e s $15, 000 pery earn o t pur ch as i n g t h es e o r gan i c s o lv en t s an d det e r m in ed t h at $180, 000 in po ll u t i o n co n t r o l equi pm en t was n o l o n g ern eeded. T h ey
e s t ima t e t h a t t h e in v e s t me n t w ill p a y fo r it s e lf in le s s t h a n o n e ye a r

. T h e s u b s t i t u t i o n pr ev en t s 24 t o n s pery eari n o r gan i c so lv en t em i ssi o n s, r e duced ex po sur e r i sks t o wo r k er s,
an d h a s ma de i t easi e r f

o r

t h e co m p an y t o co m p l

y

wit h st r i ct Cal i f

o r n i a ai r em i ssi o n st an d a r d s.

� I n p r o d u c in g t h e a n t i

- v ir a l d r u g 6

- a min o p e n ic illa n i c a c i d
, B r is t o l- M y e r s S q u i b b u s e d t o
e x t r a c t t h e in t e r m e d ia t e , p e n i c illin V fr o m a n a q u e o u s fe r m e n t a t i o n b r o t h

. T h e b r o t h w a s f i l

t er ed an d t h e i n t e r m edi a t e t h en was ex t r act ed i n sev e r a l cen t r i f uge st eps usi n g t h e t o x i c
s o lv e n t me t h yl is o b u t yl k e t o n e ( M iB K )

. T h e e x t r a c t io n w a s a

ma jo r s o u r c e o f fu g it i v e
em i ssi o n s. T h e b r o t h n o w i s f l t er ed t h r o ugh a m e m b r a n e an d t h e i n t e r m edi a t e i s ex t r act ed usi n g n

- b u t y l acet at e, a n o n

- t o x i c ch em i cal
, i n cl o s ed cen t r i f uges, r e ducin g f ugit i v e
em i s s i o n s

. T h e o v er all capit al i n v e s t m e n t f o rt h i s pr o j ect cam e t o al m

o s t $10 millio n

. Ho wev e r , t h e an n u al o p er at i n g co st r e duct i o n s, co upl ed wit h a 10 per cen t i n cr ease i n t h

r o u g h p u t , g e n e r a t e $ 4

. 9 millio n in a d d i t i o n a l c a s h flo w

. B a s e d o n t h is
, t h e p r o j e c t w ill gen e r a t e a r e t u r n o n i n v e s t m e n t o f 28 per cen t an d a pay b ack per i o d o f 2. 7 y ear s

. I n addi t i o n t h e pr o j ect r e duced h azar do us was t e b y 20, 000 po un ds an d e limin a t e d o v e r o n e millio n p o u n d s o f M i B K r e le a s e s t o t h e a i r a n d w a t e r

.

� G l a x o

- W e llc o m e , I n c

. d e v e lo p e d a n in n o v a t i v e a q u e o u s c o a t in g me t h o d t h a t e limin a t e d t h e use o f m e t h y l en e ch l o r i de, i s o p r o py l al co h o l
, m e t h an o l
, an d et h a n o l i n t h ei rZ a n t ac t ab l e t c o a t in g o p e r a t io n s p e r f o r me d a t t h e i r Z e b u lo n , N o r t h C a r o lin a fa c ilit y. G l a x o

W e ll c o m e o v er cam e a n u m b ero f o b st acl es b e f o r e usi n g t h e aqueo u s- b a sed co at i n g
ma t e r i al o n t h e Z a n t ac pr o duct i o n l

i n e. F i r s t , t h e ph ar maceut i cal act i v e r eadi l y

degr aded at t h e ex t r em e h eat an d m o i s t u r e en co un t e r e d dur i n g aqueo u s co at i n g. A l so , t h e ph ar maceut i cal act i v e m i g r a t e s t h r o ugh t h e aqueo u s co at i n g causi n g di sco l o r i zat i o n an d d e g r a d a t io n o f t h e t ab l e t c o a t in g film. T o imp le me n t t h e u s e o f t h e s u b s t i t u t e ma t e r i a l s , Gl ax o

- W e ll c o m e h a d t o ma ke ex t e n s i v e ch an ges t o t h e co at er spr a y assem b l

i e s, r e v a m p ed t h e co at er ai rh a n d i n g sy st em wit h l a r g erf a n s an d h eat in g co i l s , an d i n st all e d a d e hu mid ifyin g s y s t e m

. T h e c a p it a l in v e s t me n t fo r t h is e q u i p m e n t w a s $ 1

. 5 millio n

. Ho wev e r , t h e co m p an y an n u all y

s a v e s $286, 800 i n o r gan i c s o lv en t pur ch as es an d $322, 900 i n di s p o s al co s t s o f t h e m o r e t h an 479 t o n s o f h azar do us was t e gen e r a t e d b y t h e
o l d sy st em ev er y y ear

. T h e est i ma t e d pay b ack per i o d f o rt h e m o di f i cat i o n s i s t h r ee y ear s. I n

addi t i o n , t h e n e w s y s t em cut VOC em i s s i o n s t o t h e ai r f r o m al m

o s t 15, 000 po un ds per y eart o zer o

.

Sect o r No t e b o o k Pr o j ect 84 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

M a te r i al Subs titution (c ont. )

� T h e P h ar maci a an d Upj o h n , I n c. S t er i l e Man u f act ur i n g ar ea in K a l a mazo o h a s r ecei v e d F D A appr o v al f

o r a T h i m e r o sal

- f r ee f o r m ul at i o n o f o n e o f it s pr o duct s

. T h i s n e w fo r m u l a t io n w ill e limin a t e t h e u s e o f T h ime r o s a l, a me r c u r y b a s e d p r e s e r v a t i v e , in t h e
ma n u fa c t u r e o f t h e d r u g A t g a m. A t g a m w ill b e ma n u fa c t u r e d w it h o u t a n y p r e s e r v a t i v e usi n g n e w cl o s ed co l u m n

ch r o ma t o gr aph y an d Rest r i ct i v e A ccess Bar r i ert ech n o l o gy

. A t gam i s used t o pr ev en t o r gan t r an spl a n t r e j ect i o n an d i n t h e t r eat m e n t o f apl a st i c an em i a

.

� T h e E li L illy C l e a n in g T e c h n o lo g y C e n t e r in la t e 1996 i n it i a t e d a f o r mal s c r een i n g pr o g r a m t o i d en t i f y

po t e n t i a l aqueo u s b a sed cl ean er s as r e pl acem en t s f o rt h e v a r i o u s
o r gan i c an d ch l o r i n a t e d so lv en t s cur r e n t l y

used i n b u l k

ph ar maceut i cal ma n u f act ur i n g equi pm en t cl ean in gs

. I n o n e pr o duct l in e, 8, 700 l i t er s o f acet o n e per cl ean in g was r e pl aced wi t h

an al kal in e aqueo u s b a s e d cl ean erf o r an es t ima t e d an n u al r e duct i o n o f 17, 400 l i t er s o f acet o n e. A n aci d aqueo u s b a sed cl ean err e pl aced m e t h an o l i n an o t h e r pr o duct l i n e,
r e s u l t in g in m e t h an o l r e duct i o n s o f 25, 800 l i t er s pery ear

. I n cl ean in g o p er at i o n s
as s o ci at ed wi t h

an o t h e r pr o duct
, an al kal in e aqueo u s b a s e d cl ean err e pl aced 117, 000 l i t er s
o f

m e t h an o l an d 600 l i t er s o f et h y l e n e di ch l o r i de per cl ean in g. T h i s r e s u l t ed in an
es t ima t e d an n u al r e duct i o n o f 368, 000 l i t er s o f m e t h an o l an d 1, 200 l i t er s o f et h y l e n e di ch l o r i de.

Sect o r No t e b o o k Pr o j ect 85 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V. B

. P r ocess M o d i f i cat i on s

P r o cess m o di f i cat i o n s ar e al t e r a t i o n s t o o rm o der n i zat i o n o f ex i s t i n g pr o cess e s t o r e duce wast e gen e r a t i o n

. P r o cess m o di f i cat i o n s can in v o lv e r e

- d esi g n i n g
c h e mic a l t r a n s f e r

s y s t e m s t o r e d u c e s p illa g e a n d o t h e r ma t e r i a l lo s s e s

. F o r
ex am pl e, i n b a t c h o p er at i o n s , each l o adi n g an d un l o adi n g o f t h e r eact o r s an d

o t h e r e q u i p m e n t in c r e a s e s t h e r i s k o f c h e mic a l s p ills a n d s o lv e n t v ap o r
r e l eases. Bat c h o p er at i o n s o f t e n r e qui r e m o r e f r eque n t r eact o r cl ean o u t s
u s in g s i g n ific a n t v o lu me s o f c l e a n in g s o lu t i o n a n d s o lv e n t s

. W it h c o n t in u o u s
o p er at i o n s , t h e r eact o ri s l o aded o n ce an d so lv en t s an d r eact an t s ar e f e d in t o t h e r eact o r co n t i n uall y , t h er eb y r e duc i n g t h e r i sk o f po ll u t a n t r e l eases ( U S E P A
, 1991)

.
T hus s w it ch i n g f r o m b a t c h t o co n t i n uo us o p er at i o n s f o r cer t a in pr o duct s ma y p o t e n t ia lly r e d u c e la r g e v o lu me s o f w a s t e s

. S w it c h in g t o a c o n t in u o u s o r p a r t ia lly c o n t in u o u s p r o c e s s ma y b e p o s s i b l e fo r a

fa c ilit y t h a t is t h e p r ima r y pr o ducer o f a pr o duct wh i c h i s in co n s t a n t dema n d

. F o r ex am pl e, Ho f f man n L a R o c h e ’ s fa c ilit y in N u t l e y , N J is o n e o f t h e p r ima r y p r o d u c e r s o f V it a min E i n t h e co un t r y

. C o n s equen t l y , m u ch o f t h ei r v it a m in pr o duct i o n equi pm en t i s dedi cat ed an d r u n as sem i

- co n t i n uo us o p er at i o n s

.
P r o cess ch an ges t h at o p t i m i ze r eact i o n s an d r a w ma t e r i al use ca n r e duce

was t e an d r e l eas es t o t h e en v i r o n m en t ( U S E P A
, 1995)

. M o di f i cat i o n s as si m p l e as car ef ul

m o n it o r i n g o f r eact i o n par a m e t e r s ( t em per a t u r e s, pH, et c. )

can dr amat i call y

i m p r o v e ma n u f act ur in g ef f i ci en cy

. P r o duct i o n i n ma n y o f t h e l a r g e p h a r m aceut i c a l c o m p a n i e s i s c o m p u t e r i z e d a n d h i g h l ya u t o ma t e d

. C o m put er s equi pped wit h co m put er a i ded des i gn ( C A D ) pr o g r a m s v i s u all y si m u l a t e t h e pr o duct i o n pr o cess o n t h e scr een

. T h e aut o ma t e d sy st em all o ws pr o duct i o n ma n a ger s t o t u r n o n t h e b a t c h pr o cess an d co n t r o l t e m p er at ur es, pr essur e , an d o t h e r pr o cess par a m e t e r s , f r o m t h e key b o a r d

. W h i l e , t h e sy st em
r u n s , pr o duct i o n per s o n n e l ar e f r e e t o d o o t h e rt h i n gs such as ch eck equi pm en t o rt a ke pr o duct s a m p l e s

. Such car ef ul

aut o ma t e d m o n i t o r in g ma y i n sur e agai n s t t h e f o r mat i o n o f f

o ul i n g wast e at t h e b o t t o m o f r eact o rv e ssel s , t h er eb y r e duci n g t h e n eed f o r addit i o n al cl ean i n g, as well as l e ssen i n g t h e r i sk

o f dama ged b a t c h e s o f pr o duct wh i c h h a v e t o b e di s p o s ed ( U S E P A
, 1991)

.

Sect o r No t e b o o k Pr o j ect 86 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

PO LLUTIO N PREVENTIO N CAS E S T UDIES

P

r

o cess Mo d i f

i ca ti o n s

� A s par t o f t h ei r “ E n v i r o n m en t 2000" pr o g r a m , B r i s t o l

- M y er s Squi b b h a s s t ar t e d t o l o o k at P r o d u c t L i fe C y c l e ( P L C ) ma n a g e me n t a s a

w a y t o imp le me n t p o llu t i o n p r e v e n t i o n

. P L C i n v o lv es i n v e st i g at i n g t h e en v i r o n m en t a l i m p act s o f a pr o duct at ev er y st age o f pr o duct i o n : R& D, ma n u f act ur i n g, an d packagin g. P o ll u t i o n pr ev en t i o n o p t i o n s ar e n o w b e i n g in v e s t ig a t e d a t t h e v e r y b e g i n n i n g o f d r u g d e v e lo p m e n t

. T h is e limin a t e s t h e p o s s i b ilit y o f l e n g t h y Suppl em en t a r y Dr ug A ppr o v al appl i cat i o n s wi t h

F D A

. Us i n g PL C ma n a gem e n t , Br i s t o l

- My er s S qui b b di sco v er ed t h e use o f a f i l

t r a t i o n m e m b r a n e f o rt h ei r 6-

a min o p e n ic illa n i c a c i d p r o d u c t i o n ( s e e S e c t io n V

. A

. C a s e S t u d i e s )

.

� A t it s E a s t H a n o v e r , N J fa c ilit y, S a n d o z P h a r m aceut i cal Co

. ch an ged pr o cesses i n it s
r eact o r s, t o r e duce so lv en t usage. A n i n er t at m o sph e r e ab o v e t h e r eact i o n m i x t u r e i s used dur i n g syn t h e si s t o pr o t ect t h e r eact i o n f

r o m ex po sur e t o o x y g en

. I n t h e pr ev i o us pr o cess,
n i

t r o g en f

l o w ed co n t i n uo usl y

o v ert h e m i x t u r e , car r yi n g away wit h it a cer t a i n am o u n t o f

so lv en t v a po r s

. T h e n it r o g en gas b l anket i n g pr o cess uses a n o n

- f l o w in g n it r o g en l a y e rt h at

o n l y

b l eeds o u t a v e r y small am o u n t o f n i t r o g en an d so lv en t

.

� I n t h ei r ma i n dr ug dev e l o pm en t l ab i n T i ppecan o e , I N
, E l i L illy a n d C o mp a n y h a s i m p l e m e n t ed a po ll u t i o n pr ev en t i o n pr o g r a m

. Begi n n i n g i n t h e R& D ph ase, t h e co m p an y assesses t h e en v i r o n m en t a l i m p act s o f ev er y n e w pr o duct an d det e r m i n es wh er e wast es can b e min imiz e d

. A s a

r e s u lt
, E li L illy d e v e lo p e d a

n e w p r o c e s s w h ic h e limin a t e d t h e u s e o f

m

e t h y l en e ch l o r i de, al um i n um wast es, use o f an o d o r i f er o u s r a w ma t e r i al
, an d all d i s t illa t i o n s t e p s fr o m p r o d u c t i o n o f a

d r u g u n d e r d e v e lo p m e n t fo r t h e t r e a t me n t o f

os te op or os i s

.

� On e o f Ho f f man n L a Ro ch e’ s ma j o rma n u f act ur i n g pr o cesses uses gl y c o l et h e r as an
ex t r act i v e so lv en t , m u ch o f wh i c h h a d t o b e di spo s ed o f as wast ewat er

. A f t e rt h e pr o duct is

r e c o v e r e d
, t h e g l yc o l e t h e r is d i s t ille d a n d r e u s e d

. T h e o v e r h e a d fr o m t h e d i s t illa t i o n is pr i ma r i l y

wat e r wit h so m e gl y c o l et h e r wh i c h i s di spo s ed as wast ewat er

. T h e pr o cess was
r e d e s i g n e d t o in c r e a s e p e r p a s s r e c y c l e o f t h e g l yc o l e t h e r in t h e d i s t illa t i o n c o lu mn b y 12%

. A s a r e sul t , use o f t h e ch em i cal was r e duced b y ab o u t 60% an d so lv en t r e l eases decr eas ed b y 300, 000 po un ds per y ear an d t h e b a t c h cy cl e t i m e was r e duced b y f

o ur h o ur s

. A n n u al s a v i n g s ar e $250, 000.

Sect o r No t e b o o k Pr o j ect 87 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

P

r

oces s M odif i cations ( c ont. )

� A t o n e o f it s fa c ilit ie s , H o ffma n L a R o c h e w a s u s in g 110, 000 gall o n s o f m e t h an o l pery ear f o r cl ean i n g equi pm en t dur i n g pr o duct ch an geo v er s

. M e t h an o l was b e in g us ed f o r all cl ean i n g an d r i n s i n g st ages. T o r e duce m e t h an o l usage an d t h e asso ci at ed wast e di spo s al

co st s, a n e w m e t h o d was dev e l o ped wh er eb y a t w o

- st age wat e r

- b ased cl ean i n g i s do n e b e f o r e a f i n a l m e t h an o l r i n s e. T h i s r e duced t h e am o u n t o f m e t h an o l us ed t o ab o u t 30, 000 gall o n s per y ear an d s a v e s ab o u t $49, 000 per y ear

.

� I n o n e o f it s ma n u f act ur i n g pr o cesses, Ho f f man L a Ro ch e ex t r act ed a syn t h e si zed ph ar maceut i cal i n t e r m edi a t e f r o m t o l u en e i n t o wat e r , an d t h en f

r o m wat e ri n t o ch l o r o f o r m

. Because t o l u en e was so l u b l e i n t h e ex t r act i o n , it co n t am i n at ed t h e ch l o r o f o r m an d cr eat ed a

w a s t e s t r e a m o f t h e mix e d s o lv e n t s

. T h e c o mp a n y e limin a t e d t h e w a s t e s t r e a m b y s t e a m

d i s t illin g t h e t o lu e n e fr o m t h e w a t e r s o t h a t t h e t o lu e n e n e v e r c a m e in c o n t a c t w it h t h e ch l o r o f o r m

. Ch l o r o f o r m use decr eased b y 76 per cen t wh i c h was suf f i ci en t t o r e m o v e t h i s
ma t e r i a l fr o m t h e lis t o f c h e mic a l s t h e fa c ilit y w a s r e q u i r e d t o in c l u d e in it s T o x i c R e le a s e I n v e n t o r y r e po r t

. T h e pr o j ect s a v e d $22, 000 per y ear

.

� A t it s W e s t P o in t , P A fa c ilit y, M e r c k C o

. ma d e a

s imp le c h a n g e in t h e s e q u e n c e o f p r o c e s s st eps used t o ma n u f act ur e a v acci n e , wh i c h r e sul t ed i n a sub s t a n t i a l r e duct i o n o f m e r c ur y

b a sed wast es. T h i m e r i so l
, a m e r c ur y

- b a sed ch em i cal
, was used as a pr eser v a t i v e dur i n g an i n t e r m edi a t e pr o cess st ep. T hus an y wast e st r eam pr o duced dur i n g t h e r e st o f t h e pr o cess
was co n t am i n at ed wit h m e r c ur y

. A pr o cess ch an ge was i n it i a t e d t o add t h im e r o sal at t h e en d

o f

t h e p r o c e s s

. B y e lima t i n g me r c u r y in w a s t e s t r e a m s g e n e r a t e d p r io r t o t h e a d d i t i o n o f t h ime r i s o l, me r c u r y c o n t a min a t e d w a s t e s g e n e r a t e d d u r in g ma n u fa c t u r in g w e r e d r a ma t ic a lly

r e duced.

� A t it s F l i n t Ri v e r pl an t i n A l b a n y , Geo r gi a, Mer c k used st eam j e t s t o pr o duce a v acuum i n t h e p r o c e s s v e s s e l d u r in g t h e p r o d u c t i o n o f a n a n t i b i o t ic

. T h is r e s u lt s in d i c h lo r o me t h a n e b e i n g m i x ed wit h st eam an d sub s equen t l y

ev apo r at in g i n t o t h e ai r

. T h e st eam j e t s wer e
r e pl aced wit h l

i qui d r i n g v acuum pum ps wh i c h r e duced ai r em i ssi o n s. Di ch l o r o m e t h an e
em i s s i o n s wer e f u r t h e rr e duced b y ma in t a in in g t h e v acuum pum p s eal f

l ui d at s u b zer o t e m p er at ur es wh i c h co n d en ses t h e di ch l o r o m e t h an e v a po r so i t can b e r ecy cl ed an d r e used.

� P h ar maci a an d Upj o h n ’ s wast ewat ert r eat m e n t pr o cess was m o di f i ed t o si gn i f i can t l y

r e duce

was t e di s p o s ed b y it s Un der g r o un d I n j ect i o n C o n t r o l o p er at i o n

. A m o di f i cat i o n s ugges t ed b y
a n e m p l o y e e e limin a t e d ab o u t 1 millio n p o u n d s o f s o lid w a s t e

. T h is mo d i fic a t io n in v o lv e d sub s t i t u t i n g a b a g f i l

t erf o r a pr eco at v acuum f

i l

t er

. T h e pr eco at v acuum f

i l

t er used a di at o maceo us f i l

t erm e di um , wh i c h gen e r a t e d l a r g e v o l u m e s o f so l i d wast e. T h e b a g f i l

t er
cr eat es m u ch l e ss wast e perv o l u m e o f l

i qui d f i l

t er ed. T h e used f i l

t erb a gs ar e i n cin e r a t e d o n
s it e , t h e r e b y g r e a t ly r e d u c in g la n d fill w a s t e s

.

Sect o r No t e b o o k Pr o j ect 88 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

P

r

oces s M odif i cations ( c ont. )

� I n co n v e r t i n g t o a n e w pr o cess f o rb i o c o n v e r s i o n o f a st er o i d i n t e r m edi a t e , P h ar maci a an d U p jo h n , I n c

. h a s e limin a t e d a p p r o x ima t e ly 9 0
, 000 po un ds o f di m e t h y l f o r mam i d e was t e an d appr o x i ma t e l y

190, 000 po un ds o f f

i l

t er ai d was t e per y ear

. I n addit i o n , s o lv en t h a n d l i n g was
r e d u c e d fr o m ab o u t 6 millio n p o u n d s t o ab o u t 600, 000 po un ds an d aqueo u s was t e was
r e d u c e d mo r e t h a n 4 millio n p o u n d s p e r ye a r

.

Sect o r No t e b o o k Pr o j ect 89 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V. C. Good Oper at ing P r act i ces

On e o f t h e easi e st an d m o st eco n o m i cal way s t o ach i e v e so ur ce r e duct i o n i s t o i m p l e m e n t go o d o p er at in g pr act i ces. P h ar maceut i cal co m p an i e s al r eady fo llo w a

lis t o f G o o d M a n u fa c t u r in g P r a c t ic e s ( G M P ) g u i d e lin e s o u t lin e d b y t h e F D A

. I n so m e cases t h ese i n v o lv e go o d o p er a t i n g pr act i ces t h at wi ll

r e duce r a w ma t e r i al s use an d wast e gen e r a t i o n

. A s a r e sul t , ma n y co m p an i e s h a v e d e v e lo p e d e n v i r o n m e n t a l p o lic ie s fo r a ll o f t h e i r fa c ilit ie s , b o t h in t h e U. S

. an d ab r o ad. T y pi call y , po l i c i e s ma y b e wr it t e n f

o r em pl o y ee t r ai n i n g , em pl o y ee h eal t h

an d saf e t y , h azar do us ch em i cal sp ill c l e a n u p p r o c e d u r e s , equi pm en t ma i n t e n a n ce pr o cedur es, l eak det ect i o n , an d em er gen c y r e spo n se pr o cedur es

.
M a n a g e me n t c o mmi t m e n t

. Go o d o p e r a t i ng pr act i ces st ar t wit h o n

- s it e
c o mmit me n t a n d u n d e r s t a n d in g o f t h e n e e d a n d me t h o d s fo r p o llu t i o n p r e v e n t i o n , fr o m t o p ma n a g e me n t le v e ls t o t h e p l a n t flo o r

. W it h o u t fa c ilit ywi de ef f o r t s t o r e duce po ll u t i o n , s o ur ce r e duct i o n ma y n o t b e s u cces s f ul

( U S E P A
, 1991)

.
E m pl oye e tr aining. A n em pl o y ee t r ai n i n g pr o g r a m i s essen t i a l t o t h e success
o f

a s o ur ce r e duct i o n pr o g r a m

. E m pl o y ees s h o u l d b e t r ai n e d i n s a f e h a n d l i n g
o f

equi pm en t , ch em i cal s, a n d wast es. T h ey sh o u l d al so b e i n f o r m ed o f an y po t e n t i a ll y

h a r m f u l

h eal t h

ef f ect s o f t h e h azar do us ch em i cal s t h ey h a n d l e

. A s well as b e i n g t r ai n e d i n pr o p ero p er at i o n o f equi pm en t an d ch em i cal h a n d l in g,
e m p l o y e e s s h o u ld b e t r a i n e d in s p ill c l e a n u p a n d me t h o d s fo r d e t e c t in g ch em i cal r e l eas es ( U S E P A
, 1991)

.
M a inte nanc e pr ogr am s . M a in t e n a n c e p r o g r a ms s h o u ld t a r g e t b o t h pr ev en t i v e an d co r r ect i v e ma in t e n a n ce o f equi pm en t

. T h i s m ean s t h at equi pm en t sh o u l d b e r e gul ar l y

ch ec ked an d cl ean ed t o i n sur e it s pr o p er f u n c t i o n i n g, an d dama ged equi pm en t s h o u l d b e r e pai r ed qui ckl y

. R o ut i n e cl ean i n g, m i n o r adj u st m e n t s, t e st i n g an d r e pl acem en t o f par t s, sh o u l d b e a par t

o f

t h e ma i n t e n a n ce pr o g r a m

. A ddi t i o n all y , go o d r eco r d keepi n g o f equi pm en t ch ecks, r e pai r s, cl ean i n g, an d equi pm en t f a i l u r e w i l l h e l p t o r e duce t h e li

k eli h o o d o f f

u t u r e equi pm en t b r eakdo wn s an d an y asso ci at ed po l l u t i o n
r e l eas es ( U S E P A
, 1991)

.
I n vent ory cont r o l

. T h e wi de r a n g e o f ch em i cal s used i n t h e ph ar maceut i cal in d u s t r y ma k e s it e s s e n t ia l t o in s t ig a t e a n e ffic i e n t in v e n t o r y t r a c k in g s y s t e m , such as a “ f i r st

- i n , f i r s t

- o u t ” po l i c y an d ch em i cal s m u st b e pr o p er l y

l ab e l e d wit h t h ei rn a m e , dat e o f pur ch ase, an d dat e o f ex pi r a t i o n

. T h i s h e l p s t o i n sur e t h at o l der
, un

- u s e d c h em i cal s do n o t h a v e t o b e n eedl e s s l y

di s car ded ( U S E P A
, 1991)

. I n addi t i o n , h a v in g o n e per s o n r e s p o n s i b l e f o rt h e di s t r i b u t i o n o f ch em i cal s an d suppl i e s i n sur e s a m o r e ef f i ci en t t r acki n g sy st e m ( U S E P A
, 1995)

. I n v e n t o r y t r acki n g i s a v a l u ab l e an d eas y m e t h o d f o r r e duci n g was t es

.

Sect o r No t e b o o k Pr o j ect 90 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s Spil l pr e v e n tion and s t o r a g e . S p ill a n d le a k p r e v e n t i o n a r e c r it ic a l t o po ll u t i o n pr ev en t i o n

. T i gh t l y

secur e d st o r age t a nk s ar e a key t o av o i d i n g
s p ills

. C o n t a i n e r s s h o u ld h a v e g o o d v a lv e s w it h t i g h t s t o p p i n g d e v i c e s t o
a v o i d t h e s p illin g o r d r ip p in g o f h azar d o u s ch em i cal s. S t o r age co n t ai n e r s sh o u l d h a v e l e gi b l e si gn s i n di cat i n g t h e co n t en t s o f t h e co n t ain e r , h eal t h h azar d war n i n g s ( w h e r e n ecessar y )
, an d sp ill c l e a n u p p r o c e d u r e s in c a s e o f

em er gen c i e s. L a r g e dr um s can b e r a i s ed ab o v e t h e gr o u n d t o av o i d co r r o si o n

. A n o r g a n i z e d s t o r a g e a r e a fa c ilit a t e s fa s t a n d e a s y r e mo v a l o f c h e mic a l s , a s
w e ll a s r e d u c t i o n a n d c l e a n u p o f s p ills ( U

. S

. E P A
, 1991)

.

Sect o r No t e b o o k Pr o j ect 91 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

PO LLUTIO N PREVENTIO N CAS E S T UDIES
Good Oper ating P r

actices

� A t it s Ke n ilw o r t h
, N J fa c ilit y, S c h e r i n g

- P lo u g h P h a r m aceut i cal s h a s a cen t r al war e h o use wit h a co m put er i zed i n v e n t o r y sy st em

. Raw ma t e r i al s co m e i n t o t h e war e h o use i n l a r g e
v o l u m e s. Mat e r i al s ar e wei g h e d acco r d in g t o b a t c h r e qui r e m e n t s, l ab e l e d, an d t h en sen t t o d i ffe r e n t p r o c e s s a r e a s t h r o u g h o u t t h e fa c ilit y. T h is e limin a t e s e x c e s s r a w ma t e r i a l wast es an d en sur e s t h at o n l y

t h e am o u n t s n eeded ar e used.

� S a n d o z P h ar maceut i cal s h a s al so dev e l o ped a sy st em t o i m p r o v e sch e dul i n g o f b a t c h

o p e r a t io n s in t h e i r fa c ilit ie s w o r l d w id e a n d d o me s t ic a lly. A c c u r a t e s c h e d u lin g r e d u c e s t h e ch an ces o f ex cess wast es an d co st s, wh i c h o ccur wh en a b a t c h ch an geo v ert a kes pl ace.

� A t it s Nut l ey , NJ pl an t , Ho f f man n L a Ro ch e was ab l e t o i d en t i f y

an d r e pai rm o r e t h an 900

so ur ces o f f

ugit i v e em i ssi o n s. I n addit i o n , t h e co m p an y in st all e d ul t r a- l o w t e m p er at ur e
co n d en ser s t o r e m o v e so lv en t s f r o m v e n t st r eam s. T h e capt u r e d so lv en t s ar e r ecy cl ed o r t r eat ed o f f

- sit e

.

� T h e P h ar maci a an d Upj o h n , I n c. P u er t o Ri co T ech n i cal Oper at i o n s gr o up was t h e f i r s t

o ffs h o r e lo c a t io n t o imp le me n t t h e c o mp a n y’ s p o llu t i o n p r e v e n t i o n p r o g r a m. T h e lo c a l po ll u t i o n pr ev en t i o n t eam h e l p s t h e pl an t set po ll u t i o n pr ev en t i o n go al s. T h e t eam r e po r t s pr o g r e ss t o war d m eet i n g go al s an n u all y

. A s a r e sul t , t h e But y l A l co h o l r eco v e r y ef f i ci en cy
a t

t h e fa c ilit y h a s b e e n in c r e a s e d t o 9 5 % a n d A c e t o n e t o 9 6 %

. T h e fa c ilit y h a s b e e n t r acki n g was t e i n di ces ( T o n s o f was t e gen e r a t e d v s

. K i l o gr am s o f pr o duct pr o duced) an d

re s u l t s f o r s e v e ra l w a s t e s s h o w re d u c t i o n s o v e r a f o u r-y e a r p e ri o d

. Th e p o ll u t i o n pr ev en t i o n pr o g r a m h a s b een f

u ll y

i m p l e m e n t ed at all P h ar maci a an d Upj o h n U. S

. sit e s. Un der t h e pr o g r a m i n di v i dual b u s i n e s s un it s s e t go al s an d r e po r t o n pr o g r e s s an n u all y

. M o r e t h an 300 po l l u t i o n pr ev en t i o n pr o j ect s , m a n y o f t h em i n t h e r e s ear ch an d dev e l o pm en t ar eas , h a v e b een r eco r d ed s i n ce t h e pr o g r a m s t ar t e d i n 1990.

� T h e Ch em i cal an d F e r m en t a t i o n o p er at i o n at P h ar maci a an d Upj o h n , I n c. i n K a l a mazo o h a s b e gun usi n g i n t e r l o c ked v a lv e sy st em s o n j acket ed co o l er s. T h e n e w v a lv e sy st em s h e l p pr ev en t t h e i n adv e r t en t di sch a r g e o f m e t h an o l
, used as r e f r i g er an t , t o sur f ace wat e r s

. T h e y a l s o h a v e b e g u n u s in g n e w d r ip

- l e s s p i p e c o u p l e r s t o r e d u c e s o lv e n t lo s s e s a n d s p ills f r o m ho s e c o nne c t i o ns

.

Sect o r No t e b o o k Pr o j ect 92 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V. D. Recycl in g, Recovery , an d Reu s e

“ R eco v e r y an d r ecy cli n g i n cl ude di r ect r e use o f w a s t e m a t e r i al
, r eco v e r i n g
u s e d m a t e r i al s f o r a separ a t e use, an d r e m o v in g i m pur it i e s f r o m wast e t o
o b t a i n r e l a t i v e l y

pur e s u b s t a n ces ” ( E PA 1991)

. A l t h o ugh “ s t r i c t qual it y
co n t r o l r e qui r e m e n t s o f t h e ph ar maceut i cal i n du s t r y o f t e n r e st r i ct r e use
o ppo r t un it i e s , s o m e do ex i s t ” ( E PA 1991) an d ar e co n s i d er ed v a l u ab l e b y t h e i n dust r y si n ce t h ey r e duce t h e v o l u m e o f r a w ma t e r i al s used an d t h e am o u n t

o f

was t e gen e r a t e d an d di s p o s ed.

E x cept f o ri n

- p r o cess r ecy cl in g, E P A do es n o t co n s i d er r ecy cl i n g, r eco v e r y , an d r e use t o b e so ur ce r e duct i o n t ech n i ques. Ho wev e r , i n

- p r o cess r ecy cl i n g, wh i c h i n cl udes t h e r e use o rr eci r c ul at i o n o f a ch em i cal wit h i n a pr o cess an d

ma y i n cl ude r eco v e r y o r r e c l amat i o n , i s co n s i d er ed a so ur ce r e duct i o n t e c hni q u e

. T h e ph ar maceut i cal i n dust r y o f t e n uses t h i s f o r m o f r ecy cl i n g wh i c h i s dedi cat e d t o an d ph y s i call y

in t e gr at ed wi t h

t h e ph ar maceut i cal

ma n u f act ur i n g pr o cess b y m ean s o f pi pin g o r an o t h e rf o r m o f co n v e y a n ce.
Recy cl i n g an d r eco v e r y pr o v i d es t h e ph ar maceut i cal in dust r y a gr eat op p o r t u n it y to r e d u c e th e v o l u m e a n d tox i c ity of s p e n t s o lv e n ts

. A s descr i b e d i n S ect i o n 3, so lv en t s ar e used f o r a wi d e r a ng e o f appl i cat i o n s , f r o m syn t h e si s, ex t r act i o n , an d pur i f i cat i o n o f act i v e i n gr edi e n t s t o cl ean i n g pr o cess equi p m e n t

. T h e t y pes o f so lv en t r eco v e r y em pl o y ed i n cl ude d i s t illa t i o n , e v a p o r a t io n , d ecan t a t i o n , cen t r i f ugat i o n , an d f i l

t r a t i o n

. Ho wev e r , limit a t io n s e x is t w it h b o t h o n a n d o ff- s it e r e c y c lin g a n d r e c o v e r y s i n c e s e v e r a l t y

pes o f so lv en t s ( i n c l udi n g wat e r )
, r eact an t s , an d o t h e r co n t am i n an t s ma y b e pr esen t

. T h ese ma t e r i al s m u st b e ex t r act ed t o all o w t h e so lv en t t o b e r e used eit h eri n a ph ar maceut i cal pr o cess o ri n an o t h e r pr o cess. A ddit i o n all y , speci al t e c h n i ques an d equi pm en t m u st b e used t o b r eak azeo t r o p es f o r m ed dur in g t h e ch em i cal r eact i o n s

.
I n

addit i o n t o s o l v e n t s , so m e r e si dual wast es ma y al so b e r eco v e r e d an d

r e used. F o r ex am pl e, f i l

t er cakes f r o m f

e r m en t a t i o n pr o cesses ar e usuall y d i s p o s e d o f in la n d fills

. A n a l t e r n a t iv e b e in g u s e d in s o me fa c ilit ie s is t o
co ll ect t h e wast e f i l

t er cakes, r eco v e r an y v a l u ab l e b y

- p r o duct s , an d t h en sell t h e cakes t o b e used as f e r t i l i zer s o r so i l addit i v e s. T o b e used as a f e r t i l i zer , t h e nit r o g en , ph o s ph o r us , an d po t a s s i um co n t en t m u s t b e gr eat er t h an 5%
, w h ic h s o me t ime s c a n b e a c h ie v e d b y r e d u c in g t h e mo is t u r e c o n t e n t in t h e f i l

t er cake ( U S E P A
, 1991)

.

Sect o r No t e b o o k Pr o j ect 93 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

PO LLUTIO N PREVENTIO N CAS E S T UDIES
Recycl i n g, Recovery, an d Reu s e

� Ny co m e d I n c. ma n u f act ur es b u l k

ph ar maceut i cal pr o duct s b y b a t c h pr o cessi n g

. I n pr o cessi n g a pr o duct f o rm e di cal di agn o st i c i ma gi n g , t h e co m p an y i n st all e d cl o s ed l o o p d i s t illa t i o n u n it s t o r e c o v e r a ll o f it s me t h a n o l w a s h e s a n d me t h a n o l

- c o n t a in in g w a s t e w a t e r

. T h e me t h a n o l r e c o v e r y s y s t e m c a n d i s t ill a p p r o x ima t e ly 2
, 000 gall o n s per day o f 70 per cen t

m

e t h an o l t o m o r e t h an 99. 5 per cen t m e t h an o l
, wh i c h can b e r e used i n t h e sam e pr o cess. N y c o me d I n c

. e limin a t e d w a t e r d i s c h a r g e s o f me t h a n o l
, r e d u c e d h azar do us wast e, an d

s a v e d appr o x i ma t e l y

680, 000 po un ds o f m e t h an o l i n t h e f i r s t h a l f o f 1992, s a v i n g $54, 438 in

t h e s a me p e r i o d

.

� T h e P h ar maci a an d Upj o h n , I n c. Ch em i cal an d F e r m en t a t i o n o p er at i o n i n K a l a mazo o
r e us es m o r e t h an 195 millio n p o u n d s o f s o lv e n t a n n u a lly. A p p r o x ima t e ly 8 0 % o f t h e s it e ’ s t o t a l s o lv e n t r e q u i r e me n t a n d 9 0 % o f t h e s i t e ’ s c h lo r i n a t e d s o lv e n t r e q u i r e me n t is me t b y
r e used so lv en t

. T h e r e used so lv en t dema n d i s m e t t h r o ugh a co m b i n at i o n o f i n pr o cess
s o lv en t r e us e ( 150 millio n p o u n d s ) a n d d i s t illa t i o n ( 4 5 millio n p o u n d s )

. T h e r e a r e n o w s i x
c e n t r a liz e d d i s t illa t i o n u n it s

. O n s it e s o lv e n t r e u s e a n d r e c o v e r y in c h e mic a l p r o c e s s e s h e l p ed t h e co m p an y ex ceed it s 33/ 50 P r o g r a m go al s. T h e ach i e v e m e n t was co m m

e m o r a t e d b y a Nat i o n al P e r f o r ma n ce Rev i ew E n v i r o n m en t a l Ch am pi o n A w ar d gi v e n t o t h e co m p an y b y Vi ce Pr es i d en t A l Go r e in 1995.

� P h ar maci a an d Upj o h n , I n c. Ch em i cal P r o cess Resear ch an d Dev e l o pm en t dev e l o ped a p r o p r i e t a r y d i s t illa t i o n p r o c e s s fo r s p lit t i n g T e t r a h yd r o fu r a n fr o m a

mix t u r e o f a l c o h o l, wat e r , an d o t h e r wast es. W it h o u t t h e n e w pr o cess, T e t r ah y d r o f u r a n f

o r m s azeo t r o p i c mix t u r e s w it h a l c o h o l w h ic h c a n n o t b e d i s t ille d

. T h is p r o c e s s n o w r e c o v e r s a p p r o x ima t e ly 1 millio n p o u n d s o f T H F p e r ye a r

.

� P h a r ma c i a a n d U p jo h n , I n c

. is e v a l u a t in g t h e p o s s i b ilit ie s o f r e u s in g w a s t e s o lv e n t

co n d en sat e pr o duced f r o m t h ei r cr y o gen i c ai r po ll u t i o n co n t r o l equi pm en t

. T h ey h a v e id e n t i fie d o n e me t h yle n e c h lo r i d e r i c h s t r e a m t o r e c o v e r a s a

t r ia l. A n e s t ima t e d 2

. 5 millio n po un ds o f t h i s wast e so lv en t i s gen e r a t e d an n u all y

. Reco v e r y b y an o f f

- sit e r ecy cl ero ro n sit e r ecl amat i o n ar e b e i n g f u r t h e r ev al uat e d.

Sect o r No t e b o o k Pr o j ect 94 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

V. E

. P o l l u t i on P r event i on Res e ar ch

Because o f co m p r e h e n s i v e r e gul at i o n s f r o m b o t h t h e F D A a nd t h e E P A
, ph ar maceut i cal co m p an i e s ar e co n t i n uo usl y r e sear ch i n g n e w an d i n n o v a t i v e way s t o r e duce t h ei r wast es. Man y co m p an i e s ar e st ar t in g t o l o o k at po ll u t i o n pr ev en t i o n o p t i o n s ear l y

i n d e ve l o pm en t an d ar e co ll ab o r a t i n g wit h

un i v er sit i es an d o t h e rr e sear ch in st i t ut i o n s t o dev e l o p n e w t ech n o l o gi es t h at

w ill h e lp r e d u c e o r e limin a t e w a s t e s

. S o me o f t h e s e t e c h n o lo g i e s , s t ill in t h e
r e sear ch an d t e st in g st ages, ar e di scussed b e l o w.

Solvent M i nimiz a tion

On e po t e n t i a l r e sear ch ar ea wh i c h h a s b een i d en t i f i ed i s in supe r c r i t i c a l

so lv en t s

. S uper c r it i cal f l ui ds ar e kn o w n t o b e v e r y ef f ect i v e so lv en t s an d can f u n c t i o n as an al t e r n at i v e t o t r adit i o n a l ch l o r i n a t e d an d o t h e rt o x i c so lv e n t s used i n ph ar maceut i cal separ a t i o n s. T h ese so lv en t s ar e in a super c r it i cal st at e,
m

ean i n g t h at t h ey ar e at a v e r y h i gh t e m p er at ur e an d/ o r pr essur e

. A

r e l a t i v e l y

small ch an ge i n t h e t e m p er at ur e an d/ o r pr essur e i n super c r it i cal st at e
c a n l e a d t o la r g e c h a n g e s in t h e s o lu b ilit y o f c h e mic a l s in t h e s o lv e n t

. T h i s in c r e a s e i n s o lu b ilit y is id e a l fo r s e p a r a t i o n s b ecause t h e o v er all v o l u m e o f

s o lv en t n eeded i s r e duced ( N J I T
, 1991)

. Separ ation I m

pr ovements

S e par a t i o n o f act i v e i n gr edi e n t s f r o m so lv en t s i s o n e o f t h e m o s t i m po r t an t pr o cesses i n t h e ph ar maceut i cal i n dust r y

. R e sear ch h a s b een co n duct e d t o f i n d s e p a ra t i o n m e t h o d s w h i c hg e n e ra t e f e w e r b y -p ro d u c t s a n d l e s s w a s t e

.
On e t ech n o l o gy wit h such a po t e n t i a l i s i n o r gan i c m e m b r a n e r eact o r s. “ T h e y
ar e i n ef f ect r eact o r s wit h b u i l t

- i n separ a t o r s wh i c h ma y h a v e po t e n t i a l f

o r
r eact i o n s e quen ces wi t h

m u ch b e t t e rr eact o r ut i l i zat i o n an d pr o duct

co n cen t r at i o n s ” ( N J I T
, 1991)

. I n o r gani c m e m b r a n e s en ab l e a co n t i n uo us
r e m o v a l o f pr o duct an d a co n t r o ll e d addit i o n o f r eact an t

. T h i s i n cr eases t h e po t e n t i a l f

o rh i gh eryi el ds an d gr eat er sel ect i v i t y

b y ch em i cal s , wh i c h co ul d

r e duce t h e v o l u m e o f so lv en t s r e qui r e d, t h er eb y r e duci n g co st s an d wast es. A l so , b ecause t h e r eact i o n an d separ a t i o n ar e co m b i n ed i n a si n g l e st ep, t h e
em i ssi o n s asso ci at ed wit h t h e t r adi t i o n a l t r an sf ers t ep b e t w een r eact i o n an d

s e p a r a t i o n a r e e limin a t e d ( N J I T
, 1991)

.

Sect o r No t e b o o k Pr o j ect 95 Sept em b e r 1997P h arm a c e u tic a l I ndus try P ol l u tion P r e v e n tion Oppor t unitie s

Sect o r No t e b o o k Pr o j ect 96 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

VI

. S U M M ARY OF AP P L I CAB LE F E DERAL S T ATUTES AND REGULATI ONS

T h i s sect i o n di scu sses t h e F e der a l r e gul at i o n s t h at ma y appl y

t o t h i s sect o r

. T h e p u r p o s e o f t h is s e c t io n is

t o h i g h lig h t a n d b r ie fly d e s c r i b e t h e a p p lic ab le F e d e r a l r e q u i r e me n t s , a n d t o p r o v id e c it a t i o n s fo r mo r e d e t a ile d in fo r ma t io n

. T h e t h r ee f o ll o wi n g sect i o n s ar e i n cl uded:

S ect i o n VI

. A co n t ai n s a gen e r a l o v er v i ew o f ma j o r st at ut es S ect i o n VI

. B co n t ai n s a l i s t o f r e gul at i o n s speci f i c t o t h i s i n dust r y S ect i o n VI

. C co n t ain s a l i s t o f pen d in g an d pr o p o s ed r e gul at i o n s S ect i o n VI

. D co n t ain s a gen e r a l o v er v i ew o f o t h e rf e der a l st at ut es appl i cab l e to th e i n d u s tr y S ect i o n VI

. E

. co n t ai n s a gen e r a l o v er v i ew o f st at e r e gul at i o n s af f ect i n g t h e i n dus t r y

.
T h e des c r i pt i o n s wit h in Sect i o n VI ar e i n t e nded s o l e l y

f o r gen e r a l i n f o r m a t i o n. D e pen d i n g upo n t h e n a t u r e o r sco p e o f t h e act i v it i e s at a p a r t ic u l a r fa c ilit y, t h e s e s u mma r i e s ma y o r ma y n o t n ecessar i l y

d e scr i b e a l l appl i cab l e en v i r o n m en t a l r e qui r e m e n t s. Mo r e o v er , t h ey do n o t co n s t it u t e f o r mal i n t e r p r e t a t i o n s o r cl ar i f i cat i o n s o f t h e st at ut es a n d r e gul at i o n s

. F o r f u r t h e ri n f o r mat i o n r eader s sh o u l d co n s ul t t h e Co de o f F e der a l Regul at i o n s
an d st at e o rl o cal r e gul at o r y agen ci es. E P A Ho t l i n e co n t act s ar e al so pr o v i d ed f o r each ma j o r st at ut e.

V I

. A

. Ge ne r a l D e s c ri ption of M a jor Statute s

R e source Conservat i on A nd R ecovery A c t (

R CR A )

RCRA o f 1976, wh i c h am en ded t h e S o l i d W a s t e Di s p o s al A c t , addr es s e s s o l i d ( S ub t it l e D) an d h azar do us ( S ub t it l e C) wast e ma n a gem e n t a c t i v i t i e s. T h e Hazar do us a n d S o l i d W a s t e A m en dm en t s ( H S W A ) o f 1984 s t r e n g t h en ed RCRA ’ s wast e ma n a g e m e n t p r o v i s i o n s an d ad d e d S u b t it l e I
, wh i c h g o v e r n s
un der g r o un d s t o r age t a nk s ( U ST s )

. Reg u l at i o n s p r o m u l g a t e d p u r s u a n t t o S u b t i t l e C o f RCRA ( 4 0 CF R P ar t s 260- 299) es t ab l i s h a “ c r a dl e- t o

- g r a v e” s y s t em go v e r n i n g h azar do us was t e f r o m t h e po i n t o f gen e r a t i o n t o di spo s al

. RCRA h azar do us wast es i n cl ude t h e
s p e c i fic ma t e r i a l s lis t e d in t h e r e g u l a t io n s ( c o mme r c ia l c h e mic a l p r o d u c t s , desi gn at ed w i t h t h e co de "P " o r "U"; h azar do us wast es f r o m speci f i c i n dust r i e s/ so ur ces, desi gn at ed wit h t h e co de "K "; o rh azar do us wast es f r o m
n o n

- speci f i c so ur ces, desi gn at ed wi t h

t h e co de "F ") o rma t e r i al s wh i c h ex h i b it a h azar do us w a s t e c h a r act er i s t i c ( i gn it ab ilit y, c o r r o s i v it y , r eact i v it y , o rt o x i cit y
an d desi gn at ed wit h t h e co de "D")

. Regul at ed en t it i es t h at g e ne r a t e h azar do us wast e ar e sub j ect t o wast e
accum u l a t i o n , ma n i f e st i n g, an d r eco r d keepi n g st an da r d s

. F ac ilit ie s mu s t

Sect o r No t e b o o k Pr o j ect 97 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

o b t a i n a per m it eit h erf r o m E P A o rf r o m a S t at e agen cy wh i c h E P A h a s
a u t h or i z e d t o i m p l e m e n t t h e p e r m it t i n g p r og r a m i f t h e y s t or e h azar d o u s
w a s t e s fo r mo r e t h a n 9 0 d a ys b e fo r e t r e a t me n t o r d i s p o s a l

. F a c ilit ie s ma y t r eat h azar do us wast e st o r ed i n l e ss- t h an

- n i n et y

- day t a nk s o r co n t ai n e r s
w it h o u t a p e r mit

. S u b t it le C p e r mit s c o n t a i n g e n e r a l fa c ilit y s t a n d a r d s s u c h

as co n t i n gen c y pl an s, em er gen c y pr o cedur es, r eco r d keepi n g an d r e po r t i n g
r e qui r e m e n t s, f i n a n c i a l assur a n ce m ech an i s m s , an d un i t

- s peci f i c st an dar d s. RCRA al s o co n t ai n s pr o v i s i o n s ( 40 CF R P a r t 264 S u b p ar t S an d §264. 10) f o r
co n d u c t i n g co r r ect i v e act i o n s wh i c h go v e r n t h e cl ean up o f r e l eases o f h azar do us wast e o r c o n s t it u en t s f r o m so l i d wast e ma n a gem e n t un it s at RCRA

- r e g u l at ed f ac ilit ie s

.
A l t h o u g h RCRA i s a F e d e r a l st at u t e, ma n y S t at es i m p l e m e n t t h e R CRA p r o g r a m. C u r r e n t ly, E P A h a s d e le g a t e d it s a u t h o r it y t o imp le m e n t v ar i o u s p r o v i s i o n s o f RCRA t o 4 7 o f t h e 5 0 S t at es an d t o t w o U. S

. t e r r i t o r i es. D e l e g a t i o n ha s no t be e n g i ve n t o Al a s k a , H a w a i i
, o r I o w a

.
Mo st RCRA r e q u i r e m e n t s ar e n o t i n d u s t r y sp eci f i c b u t ap p l y

t o an y co m p an y t h at ge ne r a t e s, t r an spo r t s , t r eat s, st o r es, o r di spo s es o f h azar do us wast e. Her e ar e so m e i m p o r t a n t RCRA r e g u l at o r y r e q u i r e m e n t s:

I d ent i f i cat i on of Sol i d and Haz a r d ous Was t e s ( 40 C F RPar t 261) l a y s o u t t h e pr o cedur e ev er y gen e r a t o r sh o u l d f o ll o w t o det e r m i n e
w h e t h e r t h e ma t e r i a l i n q u e s t i o n c r e a t e d i s c o n s i d e r e d a h azar d o u s wast e, so l i d wast e, o ri s ex em pt ed f r o m r e gul at i o n

.
S t a n d a rd s f

o r G e n e ra t o rs o f H a za rd o u s W a s t e ( 40 C F RPar t 262)

e s t ab lis h e s t h e r e s p o n s i b ilit ie s o f h azar do us wast e gen e r a t o r s i n

c l

udi n g
o b t a i n i n g an E P A I D n u m b er , pr epar i n g a ma n i f e st , en sur i n g pr o p er packagi n g an d l ab e l i n g, m eet i n g st an dar d s f o r wast e accum u l a t i o n
un i t s , an d r eco r d keepin g an d r e po r t in g r e qui r e m e n t s

. Gen e r a t o r s can
accum u l a t e h azar do us was t e f o r up t o 90 day s ( o r 180 day s depen d in g
on th e a m ou n t of w a s t e g e n e r a te d ) w ith ou t ob ta i n i n g a p e r m i t

.
L a nd D i s p os al R e s t ri c t ions ( L DR s ) ( 40 C F RPar t 268) ar e
r e g u l a t i o n s pr o h i b it i n g t h e di spo s al o f h azar do us wast e o n l a nd

w it h o u t p r io r t r e a t me n t

. U n d e r t h e L D R s p r o g r a m, ma t e r i a l s mu s t

m

eet L D R t r eat m e n t st an dar d s pr i o rt o pl acem ent i n a RCRA l a n d d i s p o s a l u n it ( l a n d f ill, la n d t r e a t me n t u n it
, w a s t e p i le
, o r s u r f a c e imp o u n d me n t )

. G e n e r a t o r s o f w a s t e s u b j e c t t o t h e L D R s mu s t p r o v id e
n o t i fic a t io n o f s u c h t o t h e d e s i g n a t e d T S D fa c ilit y t o e n s u r e p r o p e r t r eat m e n t pr i o rt o di spo s al

.
U s e d Oil M a nage m e nt Stand a r d s ( 40 C F RPar t 279) i m p o s e
ma n a gem e n t r e qui r e m e n t s af f e c t i n g t h e st o r age, t r an spo r t a t i o n ,

Sect o r No t e b o o k Pr o j ect 98 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

b u rn i n g , p r o c e s s i n g , a n d re -re f in in g o f t h e u s e d o i l

. F o r p a rt i e s t h a t

me r e ly g e n e r a t e u s e d o il, r e g u l a t io n s e s t ab lis h s t o r a g e s t a n d a r d s

. F o r a par t y co n s i d er ed a used o i l pr o cesso r , r e

- r e f in e r , b u r n er , o rma r k et er ( o n e wh o gen e r a t e s an d sell s o f f

- speci f i cat i o n used o i l )
, addit i o n al t r acki n g an d paper w o r k r e qui r e m e n t s m u s t b e s a t i s f i e d.

RCRA co n t ai n s u n it

- s p eci f i c st an d a r d s f o r all u n it s u s edt o st o r e, t r eat , o r di spo s e o f h azar do us w a st e, i n cl udi n g T a nk s and C o ntaine r s

. T a nk s an d co n t ai n e r s used t o s t o r e hazar do us wast e
w it h a h i g h v o la t ile o r g a n i c c o n c e n t r a t io n mu s t me e t e mis s i o n
s t an dar d s un der RCRA

. Regul at i o n s ( 40 CF R P a r t 264- 265, S u b p ar t C C ) r e q u i r e g e n e r a tor s to te s t th e w a s t e to d e te r m i n e th e
co n cen t r at i o n o f t h e wast e, t o sat i sf y

t a nk an d co n t ai n e r em i ssi o n s st an dar d s, an d t o i n spect a n d m o n i t o rr e gul at ed un it s. T h ese
r e g u l a t io n s a p p l y t o a ll fa c ilit ie s t h a t s t o r e s u c h w a s t e , in c l u d i n g la r g e quan t it y gen e r a t o r s accum u l a t i n g wast e pr i o rt o sh i p m e n t o f f

- sit e

.
U nde r g r o und Stor age T a n k s ( U S T s) co n t ai n in g pet r o l eum an d h azar do us sub s t a n ces ar e r e gul at ed un derS u b t i t l e I o f RCRA

. Sub t it l e I r e gul at i o n s ( 4 0 C F R P a r t 280) co n t ain t a nk des i gn an d

r e le a s e d e t e c t io n r e q u i r e me n t s , a s w e ll a s fin a n c ia l r e s p o n s i b ilit y a n d

co r r ect i v e act i o n st an dar d s f o r US T s

. T h e US T pr o g r a m al so i n cl udes upgr ade r e qui r e m e n t s f o r ex i s t i n g t a nk s t h at m u s t b e m e t b y Decem b e r 22, 1998.

B o il e r s and I ndus trial F u r n ac e s (B IF s ) t h a t u s e o r b u rnf u e l

co nt ai n i n g h azar do us wast e m u st co m p l

y

wi t h

st r i ct desi gn an d

o p er at i n g s t an dar d s

. B I F r e gul at i o n s ( 40 C F R Par t 266, Sub p ar t H) addr es s un i t des i gn , pr o v i d e per f o r ma n ce s t an dar d s , r e qui r e em i s s i o n s
m

o n it o r i n g , an d r e st r i ct t h e t y pe o f wast e t h at ma y b e b u r n ed.

E

P

A ' s R C R

A

/

Super f

und/UST Hotline, at ( 800) 424- 9346, r e s

ponds to ques tions and dis t r i butes gui d a n c e r e gar ding all R C R

A r e gulations

. The R C R

A Hotline oper a tes w eekdays f r

om 9: 00 a. m. to 6: 00 p. m. , E T
, excluding F

e der a l holidays

.
C

o mpr e hens ive E n vir onmental R e s pons e, C o mpens a tion, A nd Liability A c t ( C E

R C LA )

C E R C L A
, a 1980 l a w co m m

o n l y

kn o w n as Super f un d, aut h o r i z e s E P A t o
r e spo n d t o r e l eases, o r t h r eat en ed r e l eases, o f h azar do us sub s t a n ces t h at ma y
en dan g er pub l i c h eal t h
, wel f ar e, o r t h e en v i r o n m en t

. CE RCL A al so en ab l e s E P A t o f o r ce par t i e s r e spo n si b l e f o r en v i r o n m en t a l co n t am i n at i o n t o cl ean it up o r t o r e i m b ur s e t h e Super f un d f o r r e s p o n s e co s t s i n cur r e d b y E P A

. T h e Super f un d A m en dm en t s an d R eaut h o r i zat i o n A c t ( S AR A ) o f 1986 r e v i s e d

va r i o u s s e c t i o ns o f C E R C L A, e x t e nd e d t h e t a xi ng a u t h o r it y f

o r

S u p e r f u n d
,

Sect o r No t e b o o k Pr o j ect 99 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

a n d c r e a t e d a f r e e

- s t a n d i n g l a w , SA R A Tit l e III, a l s o k n o w na s t h e E m e r g e nc y P l a nni ng a n d C o m m

u nit y R i g h t

- t o

- K no w Ac t( E P C R A )

.

T h e CE RCLA h a za rd o u s s u b s t a n c e re l e a s e re p o rt i n g re g u l a t i o n s ( 40 C F R Par t 302) di r ect t h e per s o n i n ch ar ge o f a f aci l i t y t o r e p o r t t o t h e Nat i o n al Respo n se Cen t er( N RC) an y en v i r o n m en t a l r e l ease o f a h azar do us sub s t a n c e wh i c h equal s o r ex ceeds a r e po r t ab l e quan t it y

. Repo r t ab l e quan t it i e s ar e def i n e d an d l i s t e d i n 40 C F R §302. 4. A r e l eas e r e po r t ma y t r i gger a r e s p o n s e b y E P A
, o rb y o n e o r m o r e F e der a l o rS t at e em er gen c y r e spo n se aut h o r it i e s.

E P A imp le me n t s h a z a r d o u s su b s t a n ce r e sp o n ses acco r d i n g t o pr o cedur es
o u t li n ed i n t h e Nat i o n al Oi l an d Hazar do us S u b s t a n ces P o l l u t i o n Co n t i n gen c y Pl an ( N C P ) ( 40 C F RPar t 300)

. T h e NC P i n cl udes pr o v i s i o n s f o r per man en t

c l ean ups, kn o w n as r e m e di al act i o n s , an d o t h e r cl ean ups r e f e r r e d t o a s "r em o v al s. " E P A gen e r a ll y

t a kes r e m e di al act i o n s o n l y

at s i t e s o n t h e Nat i o n al Pr i o r it i es L i s t ( N PL )
, wh i c h cur r e n t l y

i n cl udes appr o x i ma t e l y

1300 sit e s. Bo t h E P A an d s t at es can act at o t h e r sit e s; h o wev e r , E P A pr o v i d es
r e s p o n s i b l e par t i e s t h e o ppo r t un it y t o co n duct r e m o v a l an d r e m e di al act i o n s
an d en co ur ages co m m

u n it y i n v o lv em en t t h r o ugh o u t t h e S uper f un d r e spo n se p r o cess.

E P A ' s R C R

A

/

Super f

und and E P C R

A Hotline, at ( 800) 424- 9346, ans w e r s ques tions and r e f

e r

e nces guidance per tai n i ng to the Super f

und pr ogr am. The C E

R C LA Hotline oper a tes w eekdays f r

om 9: 00 a. m. to 6: 00 p. m. , E T
, excl udi ng F e deralhol i days.

E

m er gency P l anning A nd C o mmunity R i ght- T o- K now A c t ( E P C R

A )

T h e S u p e r f u n d A m e n d m e n ts a n d R e a u th or i z a t i o n A c t ( S A R A ) o f 1986

c r e a t e d EPC R A , a l s o k n o w na s SA R A Tit l e III, a s t a t u t e d e s i g n e d t o i m p ro v e
co m m

u n it y access t o i n f o r mat i o n ab o u t ch em i cal h azar ds an d t o f ac ilit a t e t h e deve l o pm en t o f ch em i cal em er gen c y r e spo n se pl an s b y S t at e an d l o cal go v e r n m e n t s. E P CRA r e q u i r e d t h e est ab l i s h m en t o f S t at e em er gen c y
r e sp o n se co m m

i ssi o n s ( S E RCs)
, r e s p o n si b l e f o r co o r d i n a t in g cer t a i n
em er gen c y r e spo n se act i v it i e s an d f o r appo i n t i n g l o cal em er genc y pl an n i n g
co m m

it t ees ( L E P Cs)

.
E P C R A an d t h e E P C R A r e gul at i o n s ( 40 C F RPar t s 350- 372) es t ab l i s h f

o ur t y

p e s o f r e p o r t in g o b lig a t io n s fo r fa c ilit ie s w h ic h s t o r e o r ma n a g e s p e c i fie d ch em i cal s:

E P CRA §302 r e q u i r e s fa c ilit ie s t o n o t i fy t h e S E R C a n d L E P C o f t h e pr esen ce o f an y "ex t r e m e l

y

h azar do us sub s t a n c e " ( t h e l i s t o f such

s u b s t a n ces i s i n 40 C F R Par t 355, A ppen d i ces A an d B ) i f it h a s s u ch sub s t a n ce i n ex cess o f t h e sub s t a n ce' s t h r e sh o l d pl an n i n g quan t it y , an d

Sect o r No t e b o o k Pr o j ect 100 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

d i

r e c t s t h e fa c ilit y t o a p p o in t a n e m e r g e n c y r e s p o n s e c o o r d i n a t o r

.
E P CRA §304 r e q u i r e s t h e fa c ilit y t o n o t i fy t h e S E R C a n d t h e L E P C i n

t h e ev en t o f a r e l ease equal i n g o r ex ceedin g t h e r e po r t ab l e quan t it y
o f

a CE RCL A h azar do us s u bs t a nce o r an E P CRA ex t r em el

y h azar do us sub s t a n ce.

E P CRA §311 and §312 r e q u i r e a fa c ilit y a t w h ic h a h azar do us ch em i cal
, as def i n e d b y t h e O c c upat i o n al S a f e t y an d Heal t h

A c t , i s pr esen t i n an am o u n t ex ceedi n g a speci f i ed t h r e sh o l d t o sub m it t o t h e S E RC, L E P C an d l o cal f

i r e depar t m e n t ma t e r i al saf e t y dat a sh eet s ( M S D S s ) o rl i s t s o f MS DS ' s an d h azar do us ch em i cal i n v e n t o r y f

o r m s ( a l s o kn o w n as T i erI an d I I f o r m s)

. T h i s i n f o r mat i o n h e l p s t h e l o cal g o v e r n me n t r e s p o n d in t h e e v e n t o f a

s p ill o r r e le a s e o f t h e c h e mic a l

.
E P CRA §313 r e q u i r e s ma n u fa c t u r in g fa c ilit ie s in c l u d e d in S I C c o d e s 20 t h r o ugh 39
, w h i c h h a v e t e n o r m o r e em pl o y ees , an d wh i c h

ma n u f act ur e, pr o cess, o r use speci f i ed ch em i cal s i n am o u n t s gr eat er t h an t h r e sh o l d quan t it i e s, t o sub m i t an an n u al t o x i c ch em i cal r e l ease
re p o rt

. Th i s re p o rt , c o m m

o n l y k n o w n a s t h e F o rm R
, c o v e rs re l e a s e s
a n d t r a n s f e r s o f t o x i c c h e mic a l s t o v a r i o u s fa c ilit ie s a n d e n v i r o n m e n t a l

m

e di a, an d all o ws E P A t o co m p i l e t h e n a t i o n al T o x i c Rel ease I nve nt o r y ( T R I ) d a t aba s e

.
A ll in fo r ma t i o n s u b mit t e d p u r s u a n t t o E P C R A r e g u l a t io n s is p u b lic ly accessi b l e, un l e ss pr o t ect ed b y a t r ade secr et cl ai m

.

E

P

A ' s R C R

A
, Super f

und and E P C R

A Hotline, at ( 800) 424- 9 346, ans w e r s ques t i o n s and dis t r i butes guidance r e gar ding the emer gency planning and

c o mmunity r i ght-to-k now r e gulations

. The E P C R

A Hotline ope r a te s
w eekdays f r

om 9: 00 a. m. t o 6: 00 p. m. , E T
, excl udi ng F e deralhol i days.

C l e a n Wa t e r A c t (C WA )

T h e p r ima r y o b je c t iv e o f t h e F e d e r a l W a t e r P o llu t i o n C o n t r o l A c t , c o mmo n l y
r e f e r r e d t o as t h e CW A
, i s t o r e st o r e an d ma i n t a i n t h e ch em i cal
, ph y s i cal
, an d b i o l o g i cal i n t e gr it y o f t h e n a t i o n ' s sur f ace wat e r s

. P o ll u t a n t s r e gul at ed un der t h e C W A i n c l u d e " p r i o r it y" p o ll u t a nt s a n d va r i o u s t o xi c p o ll u t a nt s ;

" c o nve nt i o na l " p o ll u t a nt s , s u c h a s bi o c he m i c a l o x y g e n d e ma nd ( B O D )
, t o t a l

s u s p en ded so l i d s ( T S S )
, f ecal co l i f

o r m , o i l an d gr ease, an d pH; and " n o n

co n v e n t i o n a l " po ll u t a n t s wh i c h ar e po ll u t a n t s n o t i d en t i f i ed as eit h er
c o nve nt i o na l o r p r i o r i t y

.

T h e CW A r e gul at e s b o t h di r ect an d i n di r ect di sch a r g es. T h e Nat i onal P o l l u tant D i s c har g e E l im ination Sys t e m (N P D E S ) pr o g r a m ( C W A §402)

Sect o r No t e b o o k Pr o j ect 101 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

co n t r o l s di r ect di sch a r g es i n t o n a v i gab l e wat e r s

. Di r ect di sch a r g es o r "po i n t

so ur ce" di sch a r g es ar e f r o m so ur ces such as pi pes an d sewer s

. NP DE S per m it s, i ssued b y eit h erE P A o r an aut h o r i zed S t at e ( E P A h a s aut h o r i zed 42 S t at es t o adm i n i s t e rt h e NP DE S pr o g r a m )
, co n t ai n in dust r y

- speci f i c, t e c h n o l o g y

- b a s e d a n d/ o r w a t e r q u a lit y- b a s e d limit s , a n d e s t ab lis h p o llu t a n t

mo n it o r i n g r e q u i r e me n t s

. A fa c ilit y t h a t in t e n d s t o d i s c h a r g e in t o t h e n a t i o n ' s
w a t e r s mu s t o b t a in a p e r mit p r io r t o i n i t i a t i n g it s d i s c h a r g e

. A p e r mit appl i can t m u s t p r o v i d e quan t it at i v e an al y

t i cal dat a i d en t i f yi n g t h e t y pes o f p o llu t a n t s p r e s e n t in t h e fa c ilit y' s e fflu e n t

. T h e p e r mit w ill t h e n s e t fo r t h t h e
c o n d it i o n s a n d e fflu e n t limit a t io n s u n d e r w h ic h a fa c ilit y ma y m a k e a di s c h a r g e.

A

N P D E S p e r mit ma y a l s o in c l u d e d i s c h a r g e limit s b a s e d o n F e d e r a l o r S t a t e wat e r qual it y cr it er i a o r st an dar d s t h at wer e desi gn ed t o pr o t ect desi gn at ed

us es o f s u r f ace wat e r s , s u ch as s uppo r t in g aquat i c l i f

e o r r ecr eat i o n

. T h es e
s t an dar d s , un l i k e t h e t ech n o l o gi ca l s t an dar d s , gen e r a ll y

do n o t t a ke in t o
acco un t t ech n o l o gi cal f

easi b ilit y o r c o s t s

. W a t e r q u a lit y c r it e r ia a n d s t a n d a r d s
v a r y f r o m st at e t o st at e, an d si t e t o sit e , depen d i n g o n t h e use cl assi f i cat i o n
o f

t h e r ecei v i n g b o dy o f wat e r

. Mo st st at es f o ll o w E P A gui del i n e s , wh i c h pr o p o s e aquat i c l i f

e an d hu ma n h eal t h

cr it er i a f

o rma n y o f t h e 126 p r i o r it y p o llu t a n t s

.
St o r m W a t e r D i s c h a rg e s

I n

1987 t h e C W A was am en ded t o r e qui r e E P A t o es t ab l i s h a pr o g r a m t o addr es s s t o r m wat e r di s c h a r g es

. I n r e s p o n s e , E P A pr o m ul gat e d t h e NPDE S st o r m wat e r per m it appl i cat i o n r e gul at i o n s

. T h ese r e gul at i o n s r e q u i r e t h at fa c ilit ie s w it h t h e fo llo w in g s t o r m w a t e r d i s c h a r g e s a p p l y fo r a n N P D E S p e r mi t : ( 1 ) a di sch a r g e asso ci at ed wit h i n dust r i a l act i v it y ; ( 2 ) a di sch a r g e fr o m a

la r g e o r me d i u m mu n i c i p a l s t o r m s e w e r s y s t e m ; o r ( 3 ) a d i s c h a r g e wh i c h E P A o rt h e S t at e det e r m in es t o co n t r i b u t e t o a v i o l at i o n o f a wat e r q u a l it y s t a n d a r d or i s a s i g n i f i c a n t c o n t r i b u tor of p o ll u ta n t s to w a te r s of th e Un it ed S t at es.

T h e t e r m "st o r m wat e r di sch a r g e asso ci at ed wit h i n dust r i a l act i v it y " m ean s a
s t o r m w a t e r d i s c h a r g e fr o m o n e o f 1 1 c a t e g o r ie s o f in d u s t r ia l a c t iv it y d e fin e d at 40 C F R 122. 26. Si xo f t h e cat ego r i e s ar e def i n e d b y SI C co des wh i l e t h e
o t h e rf i v e ar e i d e n t i f i ed t h r o ugh n a r r a t i v e descr i pt i o n s o f t h e r e gul at ed i n d u s t r i a l a c t i v it y

. I f t h e p r i ma r y S I C c o d e o f t h e fa c ilit y is o n e o f t h o s e id e n t i fie d in t h e r e g u l a t io n s , t h e fa c ilit y is s u b j e c t t o t h e s t o r m w a t e r p e r mit

a p p lic a t io n r e q u i r e me n t s

. I f a n y a c t iv it y a t a fa c ilit y is c o v e r e d b y o n e o f t h e f i v e n a r r a t i v e cat ego r i e s, st o r m wat e r di sch a r g es f r o m t h o s e ar eas wh er e t h e act i v it i e s o ccur ar e sub j ect t o st o r m wat e r di sch a r g e per m it appl i cat i o n
re q u i re m e n t s

.

Sect o r No t e b o o k Pr o j ect 102 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

T h o s e fa c ilit ie s / a c t iv it ie s t h a t a r e s u b j e c t t o s t o r m w a t e r d i s c h a r g e p e r mit appl i cat i o n r e qui r e m e n t s ar e i d en t i f i ed b e l o w. T o det e r m i n e wh et h e ra p a r t ic u l a r fa c ilit y fa lls w i t h in o n e o f t h e s e c a t e g o r ie s , t h e r e g u l a t io n s h o u ld b e
co n s ul t e d.

Cat e gory i: F a c ilit ie s s u b j e c t t o s t o r m w a t e r e fflu e n t g u i d e lin e s , n e w
so ur ce per f o r ma n ce st an dar d s, o rt o x i c po ll u t a n t ef f l uen t st an dar d s.

Cat e gory ii: F a c ilit ie s c l a s s i fie d a s S I C 2 4

- lu mb e r a n d w o o d p r o d u c t s ( e x c e p t w o o d k it c h e n c ab in e t s ) ; S I C 2 6

- p a p e r a n d a llie d pr o duct s ( e x cept paper b o a r d co n t a in e r s an d pr o duct s ) ; SI C 28-

c h e mic a l s a n d a llie d p r o d u c t s ( e x c e p t d r u g s a n d p a in t s ) ; S I C 291- p e t r o l e u m r e f i ni ng ; a n d S I C 3 1 1

- le a t he r t a nni ng a n d f

i ni s h i n g , 3 2 ( e x cept 323)

- s t o n e , cl ay , gl as s , an d co n c r e t e , 33- pr i ma r y m e t a l s , 3441- f ab r i cat ed s t r u ct ur al m e t a l
, an d 373- s h i p an d b o at b u i l d i n g an d

r e p a ir in g

.
Cate gory iii: F a c ilit ie s c l a s s i fie d a s S I C 1 0

- me t a l min in g ; S I C 1 2

- c o a l min in g ; S I C 1 3

- o il a n d g a s e x t r a c t io n ; a n d S I C 1 4

- n o n m e t a llic min e r a l min in g

.
Cat e gory iv: Hazar do u s wast e t r eat m e n t , st o r age, o r di spo s al fa c ilit ie s

.
Cat e gory v: L a n d fills
, l a nd a p p l i c a t i o n s i t e s , a n d o p e n d u m p s t h a t

r ecei v e o rh a v e r ecei v e d in dust r i a l wast es.

Cat e gory vi: F a c ilit ie s c l a s s i fie d a s S I C 5015- us ed m o t o r v e h i cl e par t s ; an d SI C 5093- aut o m o t i v e s c r a p an d was t e ma t e r i al r ecy cl in g fa c ilit ie s

.
Cat e gory vii: S t e a m e l e c t r i c p o w e r g e n e r a t i n g fa c ilit ie s

.
Cate gory viii: F a c ilit ie s c l a s s i fie d a s S I C 4 0

- r a ilr o a d t r a n s p o r t a t i o n ; SI C 41- l o cal pas s e n g er t r an s p o r t a t i o n ; S I C 42- t r ucki n g an d

war e h o us i n g ( e x cept pub l i c war e h o us i n g an d s t o r age) ; SI C 43- U. S. P o s t a l S e r v i c e ; S I C 4 4

- w a te r tr a n s p or ta ti on ; S I C 4 5

- tr a n s p or ta ti on b y ai

r ; an d SI C 5171- pet r o l eum b u l k

s t o r age s t at i o n s an d t e r m i n al s

.
Cat e gory ix : S e wage t r eat m e n t wo r k s

.
Cat e gory x : Co n s t r uct i o n act i v it i e s ex cept o p er at i o n s t h at r e sul t i n t h e di st ur b a n ce o f l e ss t h an f

i v e acr es o f t o t a l l a n d ar ea.

Sect o r No t e b o o k Pr o j ect 103 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

Cat e gory x i : F a c ilit ie s c l a s s i fie d a s S I C 2 0

- fo o d a n d k i n d r e d pr o duct s ; S I C 21- t o b acco pr o duct s ; S I C 22- t e x t i l e mill p r o d u c t s ; S I C 23- appar e l r e l a t e d pr o duct s ; SI C 2434- wo o d kit c h e n cab i n et s
ma n u f act ur i n g; SI C 25- f u r n i t ur e an d f i x t ur es ; SI C 265- paper b o a r d

co n t ai ne r s an d b o x e s ; SI C 267- co n v e r t ed paper an d paper b o ar d p r o d u c t s ; S I C 2 7

- p r in t i n g , p u b lis h i n g , a n d a llie d in d u s t r ie s ; S I C 283- d r u g s ; S I C 2 8 5

- p a in t s , v a r n is h e s , la c q u e r , e n a m e l s , a n d a llie d pr o duct s ; SI C 30- r ubbe r an d pl as t i cs ; SI C 31- l eat h e r an d l eat h e r pr o duct s ( e x cept l eat h e r and t a n n in g an d f i n i s h i n g) ; SI C 323- gl as s pr o duct s ; SI C 34- f ab r i cat ed m e t a l pr o duct s ( e x cept f ab r i cat ed

s t r u c t u r a l me t a l) ; S I C 3 5

- in d u s t r ia l a n d c o mm e r c ia l ma c h in e r y a n d

co m put e r e qui pm en t ; S I C 36- el ect r o n i c an d o t h e r el ect r i cal equi pm en t an d co m p o n en t s ; S I C 3 7

- t r an spo r t a t i o n equi pm en t ( e x cept

s h i p an d b o at b u i l d i n g an d r e pai r i n g) ; SI C 38- m eas ur i n g, an al y z i n g,
a n d c o n t r o llin g in s t r u me n t s ; S I C 3 9

- mis c e lla n e o u s ma n u fa c t u r in g i n dus t r i e s ; an d SI C 4221- 4225- pub l i c war e h o us i n g an d s t o r age.

P r et r eat m e n t P r o g r a m

A n o t h e rt y pe o f di sch a r g e t h at i s r e gul at ed b y t h e CW A i s o n e t h at go es t o a pub l i c l y

- o wn ed t r eat m e n t wo r k s ( P OT W s )

. T h e n a t i o n al pr e t r e atm e nt pr ogr am ( C W A §307( b ) ) co n t r o l s t h e i n di r ect di s c h a r g e o f po ll u t a n t s t o P O T W s b y " i n d u s t r ia l u s e r s

. " F a c ilit ie s r e g u l a t e d u n d e r §307( b ) m u s t m eet

cer t a i n pr et r eat m e n t st an dar d s. T h e go al o f t h e pr et r eat m e n t pr o g r a m i s t o pr o t ect m u n i ci pal wast ewat ert r eat m e n t pl an t s f r o m dama ge t h at ma y o ccur wh en h azar do us, t o x i c, o ro t h e r wast es ar e d i s c ha r g ed i n t o a sewer sy st em
an d t o pr o t ect t h e qual it y o f s l udge gen e r a t e d b y t h es e pl an t s

. Di s c h a r g es t o
a P O T W ar e r e gul at ed pr i m a r i l y b y t h e P O T W it sel f
, r a t h er t h an t h e S t at e o r EPA

.
E P A h a s dev e l o ped t ech n o l o gy

- b as ed s t an dar d s f o r i n dus t r i a l us e r s o f P O T W s. Di f f e r e n t st an dar d s appl y t o ex i s t i n g an d n e w so ur ces wit h i n each cat ego r y

. "Cat ego r i cal " pr et r eat m e n t st an dar d s appl i cab l e t o an i n dust r y o n
a n a t i o n wi de b a s i s ar e dev e l o ped b y E P A

. I n addi t i o n , an o t he r k i nd o f p r e t r e a t me n t s t a n d a r d
, " l o c a l limit s , " a r e d e v e lo p e d b y t h e P O T W in o r d e r t o
a s s i s t t h e P O T W in a c h ie v i n g t h e e fflu e n t limit a t io n s in it s N P D E S p e r mit

. Regar d l e ss o f wh et h e ra S t at e i s aut h o r i zed t o i m p l e m e n t eit h ert h e NP DE S

o r

t h e p r e t r e a t me n t p r o g r a m, if it d e v e lo p s it s o w n p r o g r a m, it ma y e n fo r c e
re q u i re m e n t s m o re s t ri n g e n t t h a nF e d e ra l s t a n d a rd s

.
S p ill P r e v e n t i o n , C o n t r o l a n d C o u n t e r m e a s u r e P l a n s

T h e 1990 Oi l Po ll u t i o n A c t r e qui r e s t h at f ac ilit ie s t h a t c o u l d r e a s o n ab ly b e
e x p e c t e d t o d i s c h a r g e o il in h a r m fu l q u a n t it ie s p r e p a r e a n d imp le me n t mo r e

Sect o r No t e b o o k Pr o j ect 104 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

r i g o r o u s S p ill P r e v e n t i o n C o n t r o l a n d C o u n t e r m e a s u r e ( S P C C ) P l a n r e q u i r e d

un der t h e C W A ( 40 C F R §112. 7)

. T h er e ar e al s o cr imin a l a n d c i v il p e n a lt ie s fo r d e lib e r a t e o r n e g lig e n t s p ills o f o il. R e g u l a t io n s c o v e r i n g r e s p o n s e t o o i l di s c h a r g es an d co n t i n gen c y pl an s ( 40 C F R Par t 300)
, an d F ac ilit y R e s p o n s e Pl an s t o o i l di s c h a r g es ( 40 C F R§112. 20) an d f o r PC B t r an s f o r m e r s an d PC B

co n t ai n i n g it em s wer e r e v i s e d an d f i n a l i zed i n 1995.

E

P

A ’ s Of f

i ce of W a ter , at ( 202) 260- 5700, w ill dir ect caller s w ith ques tions about th e C W A t o t h e appr opr iate E P

A of f

i ce. E P

A als o maintains a bibliogr aphic databas e of Of f

i ce of W a ter p u b lications w h ich can be

acces s e d thr ough the Gr ound W a ter and Dr inking W a ter r

e s our ce center , at ( 202) 260- 7786.
Saf e Dr inking W a ter A c t ( S DW A )

T h e S D W A ma n d at es t h at E P A est ab l i s h r e gul at i o n s t o pr o t ect hu ma n h eal t h fr o m c o n t a min a n t s in d r ink i n g w a t e r

. T h e la w a u t h o r iz e s E P A t o d e v e lo p
n a t i o n al dr i nki n g wat e r st an dar d s an d t o cr eat e a j o i n t F e der a l

- S t at e sy st em t o en sur e co m p l

i a n ce wit h t h ese st an dar d s. T h e S D W A al so di r ect s E P A t o p r o t ect un der g r o un d s o ur ces o f dr i nki n g wat e r t h r o ugh t h e co n t r o l o f

un der g r o un d i n j ect i o n o f l

i qui d was t es

.
E P A h a s dev e l o ped pr i ma r y an d s eco n d ar y dr i nki n g wat e r s t an dar d s un der it s S D W A aut h o r it y

. E P A an d aut h o r i zed st at es en f o r ce t h e pr i ma r y d r i n k in g
w a t e r s t a n d a r d s , w h i c h a r e , c o n t a min a n t

- s p e c i fic c o n c e n t r a t io n limit s t h a t

a p p l y t o c e r t a in p u b lic d r ink i n g w a t e r s u p p lie s

. P r ima r y d r ink i n g w a t e r
s t a n d a r d s c o n s is t o f ma x imu m c o n t a min a n t le v e l g o a l s ( M C L G s )
, w h ic h a r e
n o n

- en f o r ceab l e h eal t h

- b ased go al s, an d ma x i m u m co n t am i n an t l e v e l s ( M C L s )
, w h i c h ar e en f o r ceab l e limit s s e t a s c l o s e t o M C L G s a s p o s s i b l e , c o n s id e r in g c o s t a n d fe a s ib ilit y o f a t t a in me n t

.
Th e SD W A U nde r g r o und I n je c t ion C o ntr o l (U IC ) p r o g ra m (4 0 C F R Pa rt s 144- 148) i s a per m it pr o g r a m wh i c h pr o t ect s un der g r o un d s o ur ces o f dr i nki n g
w a t e r b y r e g u l a t in g fiv e c l a s s e s o f in je c t io n w e lls

. U I C p e r mit s in c l u d e des i gn , o p er at i n g, i n s p ect i o n , an d m o n i t o r in g r e qui r e m e n t s

. W e ll s us ed t o i n

j ect h azar do us wast es m u st al so co m p l

y

wit h RCRA co r r ect i v e act i o n st an d a r d s i n o r d e r t o h a v e RCRA p e r m it b y r u l e st a t u s , an dm u st m eet ap p l i cab l e RCRA l a n d d i sp o s al r e st r i ct i o n s st an d a r d s. T h e UI C p e r m it pr o g r a m i s pr i ma r i l y

st at e- en f o r ced, si n ce E P A h a s aut h o r i zed all b u t a f e w st at es t o adm i n i s t e rt h e pr o g r a m

.
T h e S D W A a l s o p r o v id e s fo r a F e d e r a lly- imp le me n t e d S o le S o u r c e A q u i fe r p r o g r a m, w h ic h p r o h ib it s F e d e r a l fu n d s fr o m b e in g e x p e n d e d o n p r o j e c t s t h a t

ma y co n t am i n at e t h e so l e o r pr i n c i p a l so ur ce o f dr i nki n g wat e rf o r a gi v e n

Sect o r No t e b o o k Pr o j ect 105 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

ar ea, an d f o ra S t at e- i m p l e m e n t ed W e ll h ead P r o t ect i o n pr o g r a m , desi gn ed t o pr o t ect dr inkin g wat e r well s an d dr inkin g wat e rr ech ar ge ar eas.

E

P

A ’ s Saf e Dr inking W a ter Hotline, at ( 800) 426- 4791, ans w e r s ques tions and dis t r i butes g u i d a n ce per taining to SDW A s tandar ds

. The Hotline oper a tes f r

om 9: 00 a. m. thr ough 5: 30 p. m. , E T
, excluding F e der a l holidays

.
Toxic Subs tances C ontr o l A c t ( T SC A )

T S CA gr an t e d E P A aut h o r it y t o cr eat e a r e gul at o r y f

r am ewo r k t o co ll ect dat a
o n ch em i cal s i n o r dert o ev al uat e , ass e s s , mi t i g at e, an d co n t r o l r i sks wh i c h

ma y b e po sed b y t h ei r ma n u f act ur e, pr o cessi n g , an d use. T S CA pr o v i d es a
v a r i et y o f co n t r o l m e t h o d s t o p r e v e n t ch em i cal s f r o m po sin g unr easo n ab l e ri s k

.
T S CA st an dar d s ma y appl y

at an y po i n t dur i n g a ch em i cal ’ s l i f

e cy cl e. Un der T S C A § 5
, E P A ha s e s t abl i s he d a n i nve nt o r y o f c h e m i c a l s u bs t a nc e s

. I f a ch em i cal i s n o t al r eady o n t h e i n v e n t o r y , an d h a s n o t b een ex cl uded b y T S CA
, a pr eman uf act ur e n o t i ce ( P MN) m u st b e su bm it t e d t o E P A pr i o rt o
m a n u f act ur e o ri m p o r t

. T h e P M N m u st i d en t i f y

t h e ch em i cal an d pr o v i d e
av ai l ab l e i n f o r mat i o n o n h eal t h

an d en v i r o n m en t a l ef f ect s. I f av ai l ab l e dat a
ar e n o t suf f i ci en t t o ev al uat e t h e ch em i cal s ef f e c t s, E P A can i m p o s e
r e s t r i ct i o n s pen d in g t h e dev e l o pm en t o f i n f o r mat i o n o n it s h eal t h

an d

en v i r o n m en t a l ef f ect s. E P A can al so r e st r i ct si gn i f i can t n e w uses o f ch em i cal s b a sed upo n f

act o r s such as t h e pr o j ect ed v o l u m e an d use o f t h e ch em i cal

.
Un derT S CA §6, E P A can b a n t h e ma n u f act ur e o r di st r i b u t i o n in co m m

e r ce, limit t h e u s e , r e q u i r e lab e lin g , o r p l ace o t h e rr e st r i ct i o n s o n c h e mi cal s t h at po se unr easo n ab l e r i sks. A m o n g t h e ch em i cal s E P A r e g u l at es un der §6 aut h o r it y ar e asb e st o s , ch l o r o f l uo r o car b o n s ( C F C s)
, an d po l y ch l o r i n a t e d b i

p h e n y l s (PC B s ).

E

P

A ’ s TSC A A s s i s tance I n

f

o r m ation Ser v ice, at ( 202) 554- 1404, ans w e r s ques tions and dis t r i butes guidance per taining to Toxic Subs tances C ontr o l A c t s tandar ds

. The Ser v ice oper a tes f r

om 8: 30 a. m. thr ough 4: 30 p. m. , E T
, excl udi ng F e deralhol i days.

C l e a n Ai r Ac t ( C AA)

T h e C AA an d it s am en dm en t s , in cl udi n g t h e Cl ean A i rA c t A m en dm en t s ( C AAA) o f 1990, ar e des i gn ed t o “p r o t ect an d en h a n ce t h e n a t i o n ' s ai r
r e so ur ces so as t o pr o m o t e t h e pub l i c h eal t h an d wel f ar e an d t h e pr o duct i v e capacit y o f t h e po pul at i o n

. ” T h e CA A co n s i s t s o f si xsect i o n s , kn o w n as T it l es, wh i c h di r ect E P A t o est ab l i s h n a t i o n al st an dar d s f o r am b i en t ai r qual it y
an d f o rE P A an d t h e S t at es t o im p l e m e n t , ma i n t a i n , an d en f o r ce t h ese
s t a n d a r d s t h r o u g h a va r i e t y o f m e c h a n i s m s

. U n d e r t h e C AAA, ma ny f

a c ilit ie s

Sect o r No t e b o o k Pr o j ect 106 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

w ill b e r e q u i r e d t o o b t a in p e r mit s fo r t h e fir s t t ime

. S t a t e a n d lo c a l go v e r n m e n t s o v er see, ma n a ge, an d en f o r ce ma n y o f t h e r e qui r e m e n t s o f t h e C AAA. C AA r e g u l a t i o ns a p p e a r a t 4 0C F R P a r t s 5 0

- 9 9

. P u r s u a n t to T itl e I of th e C A A
, E P A h a s e s tab l i s h e d n a t i o n a l a m b i e n t a i r q u a lit y s t a n d a r d s ( N A A Q S s ) t o limit le v e ls o f " c r i t e r i a p o llu t a n t s , " in c l u d i n g
car b o n m o n o x i de, l ead, n it r o g en di o x i d e, par t i c ul at e ma t t e r , v o l a t i l e o r gan i c
co m p o u n d s ( VOCs)
, o z o n e, an d sul f ur di o x i d e. Geo g r a ph i c ar eas t h at m eet NA A Q S s f o r a gi v e n po ll u t a n t ar e cl assi f i ed as at t a i n m e n t ar eas; t h o s e t h at do

n o t m eet NA A Q Ss ar e cl as s i f i ed as n o n

- at t a i n m e n t ar eas

. Un der §110 o f t h e CA A
, each S t at e m u st dev e l o p a S t at e I m pl em en t a t i o n P l an ( S I P ) t o i d en t i f y
so ur ces o f ai r po ll u t i o n an d t o det e r m in e wh at r e duct i o n s ar e r e qui r e d t o m eet F e der a l ai r qual i t y

s t an dar d s

. R e v i s e d NA A Q Ss f o r par t i c ul at es an d o z o n e
wer e pr o p o s ed in 1996 an d ma y go in t o ef f ect as ear l y

as l a t e 1997.

T it l e I al so aut h o r i zes E P A t o est ab l i s h New S o ur ce P e r f o r ma n ce S t an dar d s (N SPSs ), w h i c h a r e n a t i o n a ll y

un i f o r m e m i s s i o n s t a n da rds f o r n e w s t a t i o n a ry
s o u r c e s fa llin g w it h in p a r t ic u l a r in d u s t r ia l c a t e g o r ie s

. N SPSs a r e b a s e d o n t h e po ll u t i o n co n t r o l t ech n o l o gy av ai l ab l e t o t h at cat ego r y o f i n dust r i a l so ur ce.

Un derT it l e I
, E P A est ab l i s h e s an d en f o r ces Nat i o n al E m i ssi o n S t an dar d s f o r Hazar do us A i rP o ll u t a n t s ( N E S HA P s )
, n a t i o n all y un i f o r m st an dar d s o r i e n t ed t o w a r d s c o n t r o llin g p a r t i c u l a r h azar do us ai r po ll u t a n t s ( H A P s)

. T it l e I
, s ect i o n 112( c) o f t h e C A A f u r t h e r di r ect ed E P A t o dev e l o p a l i s t o f s o ur ces t h at em it an y o f 189 HA Ps
, an d t o dev e l o p r e gul at i o n s f o r t h es e cat ego r i e s o f

s o ur ces

. T o dat e , E P A h a s l i s t e d 174 cat ego r i e s an d dev e l o ped a s c h e dul e f o r t h e e s t ab lis h m e n t o f e mis s i o n s t a n d a r d s

. T h e e mis s i o n s t a n d a r d s w ill b e d e ve l o p e d f

o r bo t h ne w a n d e x i s t i ng s o u r c e s ba s e d o n " ma x i m u m a c h i e vabl e
co n t r o l t ech n o l o gy ( M A C T )

. " T h e MA CT i s def i n e d as t h e co n t r o l t e c h n o lo g y a c h ie v i n g t h e ma x imu m d e g r e e o f r e d u c t i o n in t h e e mis s i o n o f t h e HA P s , t a ki n g i n t o acco un t co st an d o t h e rf act o r s.

T it l e I I o f t h e CA A per t ai n s t o m o b i l e so ur ces, such as car s, t r uck s , bu s e s,
an d pl an es. Ref o r m ul at ed gaso l i n e, aut o m o b i l e po ll u t i o n co n t r o l dev i ces, an d

v a po r r eco v e r y n o zzl es o n gas pum ps ar e a f e w o f t h e m ech an i s m s E P A uses t o r e gul at e m o b i l e ai r em i ssi o n so ur ces.

T it l e I V o f t h e CA A est ab l i s h e s a sul f ur di o x i d e em i ssi o n s pr o g r a m desi gn ed t o r e duce t h e f o r mat i o n o f aci d r a in

. Reduct i o n o f sul f ur di o x i d e r e l eases wi ll b e o b t a in e d b y g r a n t i n g t o c e r t a in s o u r c e s limit e d e mis s i o n s a llo w a n c e s , wh i c h
, b e gi n n i n g in 1995, w ill b e s e t b e lo w p r e v io u s le v e ls o f s u lfu r d i o x id e
r e l eases.

T it l e V o f t h e C A A o f 1990 cr eat ed a per m it pr o g r a m f

o r all " maj o r s o ur ces " ( a n d cer t a i n o t h e r so ur ces) r e gul at ed un dert h e CA A

. On e p u r po se o f t h e
o p e r a t in g p e r mit is t o in c l u d e in a s i n g le d o c u me n t a ll a i r e mis s i o n s
r e q u i r e me n t s t h a t a p p l y t o a g i v e n fa c ilit y. S t a t e s a r e d e v e lo p i n g t h e p e r mit

Sect o r No t e b o o k Pr o j ect 107 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

pr o g r a m s i n acco r d an ce wit h gui dan ce an d r e gul at i o n s f r o m E P A

. On ce a S t a t e p r o g r a m is ap p r o v e d b y E P A
, p e r mit s w ill b e is s u e d a n d mo n i t o r e d b y t h at S t at e.

T it l e VI o f t h e CA A i s i n t e n d ed t o pr o t ect st r a t o sph e r i c o z o n e b y ph asin g o u t t h e ma n u f act ur e o f o z o n e- depl et i n g ch em i cal s an d r e st r i ct t h ei r us e an d di s t r i b u t i o n

. Pr o duct i o n o f C l as s I s u b s t a n ces , i n cl udi n g 15 ki n d s o f ch l o r o f l uo r o car b o n s ( C F C s) an d ch l o r o f o r m , wer e ph ased o u t ( e x c ept f o r
es s e n t i a l us es ) i n 1996.

E

P

A ' s C l ean A i r Technology Ce nter , at ( 919) 541- 0800, pr ovides gener a l

as s i s tance and inf o r m ation on C A A s tandar ds

. The Str a tos pher i c Oz one I

n

f

o r m ation Hotline, at ( 800) 296- 1996, pr ovides gener a l inf o r m ation about

r

e gulations pr omulgated under Title V I o f t h e C A A
, and E P

A ' s E P C R

A Hotline, at ( 800) 535- 0202, ans w e r s ques tions about accidental r e leas e pr evention under CA A §112( r )

. I n a d d i t i on, the C l ean A i r Technology Center ’ s w e bs ite includes r ecent CA A r u les
, E P

A guidance documents
, and update s o f

E P

A activities ( www. e p a

. g o v /ttn then s e lect Dir ector y and then CA T C

)

.

Sect o r No t e b o o k Pr o j ect 108 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

V I

. B

. I ndus try Spe c i f i c R e quir e m e nts

T h e ph ar maceut i cal i n dust r y i s af f ect ed b y sev e r a l ma j o rf e der a l

en v i r o n m en t a l st at ut es. I n addit i o n , t h e i n dust r y i s sub j ect t o n u m e r o us l a ws
an d r e gul at i o n s f r o m st at e an d l o cal go v e r n m e n t s desi gn ed t o pr o t ect an d imp r o ve t h e na t i o n ’ s he a l t h
, s a f e t y , a n d e nvi r o nm e n t

. A s u m ma r y o f t h e
ma j o rf e der a l r e gul at i o n s af f ect i n g t h e ph ar maceut i cal in dust r y f

o ll o ws.

C l e a n Ai r Ac t ( C AA)

T h e o r ig in a l C A A a u t h o r iz e d E P A t o s e t limit s o n p h a r m aceut i cal pl an t

e m i s s i o n s

. So m e o f t h e s e n e w s o urc e pe rf o r ma n c e s t a n da rds (N SPS) appl y t o ph ar maceut i cal ma n u f act ur er s i n cl udi n g t h o s e f o rf l ar es ( 40 CF R P a r t 60 Sub p ar t A )
, an d s t o r age o f v o l a t i l e o r gan i c l i qui ds ( 40 C F RPar t 60 Sub p ar t K

b )

. T h e C l ean A i r A c t A m en dm en t s o f 1990 s e t co n t r o l s t an dar d s b y i n dus t r i a l s o ur ces f o r 41 po ll u t a n t s t o b e m e t b y 1995 an d f o r 148 o t h e r po ll u t a n t s t o b e r e a c h e d b y 2003. Un der t h e ai r t o x i cs pr o v i s i o n s o f t h e C AAA, m o r e s o u r c e s a r e c o ve r e d i n c l u d i ng s ma ll bu s i ne s s e s

. T h e H azar do us Or gan i c Nat i o n a l E m i ssi o n s S t an dar d f o r Hazar do us A i rP o ll u t a n t s, al so kn o w n as HON, co v e r s hu n d r e ds o f ch em i cal s an d t h o u s a n d s o f pr o ces s un i t s

. T h e ph ar maceut i cal i n dust r y i s af f ect ed b y st an dar d s f o r equi pm en t l eaks ( 4 0 CF R P a r t 63 S u bp ar t H)
, equi pm en t l eaks f r o m ph ar maceut i cal pr o cesses
us in g car b o n t e t r ach l o r i de o rm e t h y l en e ch l o r i de ( 40 C F RPar t 63 Sub p ar t I )
, an d s t an dar d s f o r em i s s i o n s f r o m h a l o gen a t e d s o lv en t cl ean in g ( 40 C F R Par t 63 S u b p ar t T )

. T h e HON al s o i n cl udes i n n o v a t i v e pr o v i s i o n s s u ch as
e mis s i o n s t r a d in g , t h a t o ffe r in d u s t r y fle x ib ilit y in c o mp lyin g w it h t h e r u le ' s
em i ssi o n s g o al s.

S p eci f i c i n dust r i e s ar e r e gul at ed un dero t h e r Nat i o n al E m i ssi o n S t an dar d s f o r Hazar do us A i r P o ll u t a n t s ( N E S HA P )

. T h ese st an dar d s ar e b e in g dev e l o ped f o rt h e pha r m a c e ut i cal i n dust r y ( s ee S ect i o n VI

. C)

. T it l e V o f t h e CA A in t r o d u c e s a

n e w p e r mit s y s t e m t h a t w ill r e q u i r e

a ll ma jo r s o u r c e s t o o b t a in

o p er at i n g per m it s t o co v e r all appl i cab l e co n t r o l r e qui r e m e n t s. S t at es wer e
r e qui r e d t o dev e l o p an d i m p l e m e n t t h e pr o g r a m i n 1993 an d t h e f i r s t per m it s
wer e i s s u ed i n 1994. I n Decem b e r 1994, S c h e r i n g

- P l o ugh P h ar maceut i cal ’ s fa c ilit y in Ke n ilw o r t h
, N e w J e r s e y , w a s t h e fir s t in t h e n a t i o n t o r e c e i v e a fa c ilit y- w i d e p e r mit u n d e r t h is T it l e V p r o g r a m.

C l e a n Wa t e r A c t (C WA )

T h e C l ean W a t e r A c t , f i r s t pas s e d i n 1972 an d am e nded i n 1977 an d 1987, gi v e s E P A t h e aut h o r it y t o r e gul at e ef f l uen t s f r o m sewage t r eat m e n t wo r k s, ch em i cal pl an t s , an d o t h e rin dust r i a l so ur ces i n t o wat e r s

. T h e act set s “ b est

av ai l ab l e” t ech n o l o gy st an dar d s f o rt r eat m e n t o f wast es f o r b o t h di r ect an d i n d i re c t (t o a Pu b l i c l y

O w n e d Tre a t m e n t W o rk s (PO T W )) d i s c h a r g e s

. In 1983, E P A pr o p o s ed ef f l ue n tgui del i n es f o r t h e ph ar maceut i cal ma n u f act ur i n g

Sect o r No t e b o o k Pr o j ect 109 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

po i n t so ur ce cat ego r y

. T h ese gui del in es ar e cur r e n t l y

un der g o i n g r e v i si o n s ( s ee S ect i o n VI

. C)

. T h e i m p l e m e n t at i o n o f t h e gui del i n es i s l e f t t o t h e st at es
w h o is s u e N a t i o n a l P o llu t a n t D i s c h a r g e E limin a t io n S y s t e m ( N P D E S ) p e r m it s f o r each f

ac ilit y.

T h e ph ar maceut i cal ma n u f act ur i n g ef f l uen t gui del in es f o r po i n t so ur ce cat ego r y ( 40 C F RPar t 439) i s di v i ded in t o pr o ces s s p eci f i c ef f l uen t gui del in es
a s fo llo w s :

F e r m en t a t i o n - 40 C F RPar t 439 Sub p ar t A
, Nat u r a l pr o duct ex t r act i o n - 40 C F RPar t 439 Sub p ar t B
, C h em i cal s yn t h e s i s - 40 C F RPar t 439 Sub p ar t C
, M i x i n g , co m p o u n d i n g, f o r m ul at i o n - 40 C F RPar t 439 Sub p ar t D, an d R e s ear ch - 40 C F RPar t 439 Sub p ar t E

.
E a c h S u b p a r t c o n s is t s o f e fflu e n t limit a t io n s r e p r e s e n t i n g t h e a m o u n t o f ef

f l uen t r e duct i o n po s s i bl e b y us i n g ei t h er b e s t pr act i cab l e co n t r o l t e c hno l o g i e s ( B P T )
, be s tc o nve nt i o na l p o ll u t i o n t e c hno l o g i e s ( B C T )
, o r be s t

av ai l ab l e t ech n o l o gi es ( B A T )

. BP T s ar e used f o r di sch a r g es f r o m e x i s t i n g p o i n ts o u r c e s t o c o nt r o l c o nve nt i o na l a n d no n- c o nve nt i o na l p o ll u t a nt s a s w e ll

as so m e pr i o r it y po ll u t a n t s. BCT s ar e used f o r di sch a r g es f r o m po i n t so ur ces t o c o n t r o l c o n v e n t io n a l p o llu t a n t s

. F i n a lly, B A T s a r e u s e d t o c o n t r o l p r io r it y p o ll u t a nt s a n d no n- c o nve nt i o na l p o ll u t a nt s w h e n d i r e c t l y

d i s c ha r g e d i n t o t h e
n a t i o n ’ s wat e r s

. S t an dar d s ar e pr o v i d ed f o r cy an i d e, b i o l o g i c o x y g en dema n d ( B OD)
, ch em i cal o x y g en dema n d ( C OD)
, t o t a l suspen ded so l i d s ( T S S ) an d pH. Gui d el i n es f o r BCT an d BA T f o rt h e r e s ear ch cat ego r y , n e w so ur ce pe rf o r ma n c e s t a n da rds (N SPS), a n d pre

- t r e a t m e n t s t a n da rds f o r n e w a n d

ex i s t i n g so ur ces, ar e b e in g r e v i sed an d ar e i n t h e f i n a l r u l e st age ( s ee S ect i o n VI

. C)

.
T h e S t o r m W a t e r Rul e ( 40 CF R §122. 26) r e qui r e s ph ar maceut i cal f

ac ilit ie s di s c h a r g i n g s t o r m wat e r as s o ci at ed wit h i n dus t r i a l act i v it i e s ( 40 C F R§122. 26 (b )(1 4 )(x i )) t o a p p l y

f

o r s t o r m w a t e r p e rm it s

. Saf e Dr inking W a ter A c t Under g r ound I n

jection C ontr o l P r ogr am

Th e f e d e ra l U n d e rg ro u n d In j e c t i o nC o n t ro l (U IC ) p r o g ra m w a s e s t ab l i s h e d

un der t h e pr o v i s i o n s o f t h e SDW A o f 1974. T h i s f e der a l pr o g r a m pr es cr i b es min imu m r e q u i r e me n t s fo r e ffe c t iv e s t a t e U I C p r o g r a ms

. S i n c e g r o u n d w a t e r i s a ma j o r so ur ce o f dr i nki n g wat e ri n t h e Un it ed S t at es, t h e U I C p r o g r a m
r e qui r e m e n t s wer e des i gn ed t o pr ev en t co n t am in at i o n o f Un der g r o un d S o u r c e s o f D r ink i n g W a t e r ( U S D W ) r e s u lt in g fr o m t h e o p e r a t io n o f in

je c t io n
w e lls

. A U S D W is d e fin e d a s a n “ a q u i fe r o r it s p o r t io n w h ic h s u p p lie s a n y pub l i c wat e r sy st em o r co n t ain s a suf f i ci en t quan t it y o f g r o u n d wat e rt o
s uppl y

a pub l i c wat e r s y s t em , o r co n t ai n s l e s s t h an 10, 000 millig r a ms p e r lit e r t o t a l di sso lv ed so l i d s an d i s n o t an ex em pt ed aqui f e r

. ”

Sect o r No t e b o o k Pr o j ect 110 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

S i n ce t h e passage o f t h e S a f e Dr inki n g W a t e r A c t , st at e an d f e der a l r e gul at o r y agen ci es h a v e m o di f i ed ex i s t i n g pr o g r a m s o r dev e l o ped n e w st r a t e gi es t o p r o t e c tg r o u nd w a t e r by e s t abl i s hi ng r e g u l a t io ns t o c o nt r o l t h e p e r m it t i ng , c o ns t r u c t i o n , o p er at i o n , m o n it o r i n g , an d cl o s ur e o f in j ect i o n well s

. I n Mi ch i g an , wh er e all f

i v e o f t h e ph ar maceut i cal in dust r y ’ s i n j ect i o n well s ar e l o cat ed, t h e st at e h a s n o t so ugh t aut h o r it y t o i m p l e m e n t t h e f e der a l UI C pr o g r a m b u t do es r e gul at e use o f i n j ect i o n well s t h r o ugh st at e l a w. T h e E P A is t h e r e s p o n s i b l e r e g u l a t o r y a g e n c y fo r imp le me n t in g t h e U I C p r o g r a m in t h e st at e.

T h e f i v e well s used b y t h e ph ar maceut i cal co m p an i e s in Mi ch i g an ar e t e r m ed h azar do us Cl ass I i n j ect i o n well s sin ce t h e y i n j e ct h azar do us wast e i n t o f o r mat i o n s b e l o w t h e US DW

. T h e pr o cess o f sel ect in g a sit e f o r a Cl ass I d i s p o s a l w e ll in v o lv e s e v a l u a t i n g ma n y c o n d it io n s w it h t h e mo s t i m p o r t a n t b e i n g t h e det e r m i n at i o n t h at t h e un der g r o un d f o r mat i o n s po s s e s s t h e n a t u r a l

ab ilit y t o c o n t a i n a n d is o l a t e t h e in je c t e d w a s t e

. A d e t a ile d s t u d y is

c o n d u c t e d t o d e t e r min e t h e s u it ab ilit y o f t h e u n d e r g r o u n d fo r ma t io n fo r d i s p o s a l

. T h e
r ecei v i n g f o r mat i o n m u st b e f a rb e l o w an y usab l e gr o u n d wat e r s an d b e separ a t e d f r o m t h em b y co n f in i n g l a y e r s o f r o ck, wh i c h pr ev en t f l ui d

m

i g r a t i o n i n t o t h e gr o u n d wat e r

. T h e i n j ect i o n zo n e i n t h e r ecei v i n g f o r mat i o n m u st b e o f suf f i ci en t si ze an d h a v e suf f i ci en t po r e space t o accept

an d ma i n t a i n t h e i n j ect ed wast es.

C l as s I i n j ect i o n well s ar e r e gul at ed i n 40 C F RPar t 146, Sub p ar t G. Sub p ar t G

r e q u i r e s fa c ilit ie s w it h in je c t io n w e lls t o s u b mit o p e r a t in g r e p o r t s a n d t o sub m it pl an s f o rt e st in g an d m o n it o r i n g t h e wast es, h y dr o g eo l o gi c co n d it i o n s , co n d it i o n o f t h e well ma t e r i al s, m ech an i cal i n t e gr it y o f t h e well
, an d am b i en t

co n d it i o n s i n adj acen t aqui f e r s

. S u b p ar t G al so set s cr it er i a f

o r sit i n g Cl ass I h azar do us wast e i n j ect i o n well s , c o nst r uct i o n r e qui r e m e n t s, co r r ect i v e act i o n pr o cedur es, o p er at i n g r e qui r e m e n t s, an d cl o s ur e pl an s.

R e s our ce C ons er vation and R ecover y A c t ( R C R

A )

T h e Res o ur ce Co n s er v a t i o n an d Reco v e r y A c t ( RCRA ) was en act ed i n 1976 t o a ddr ess pr o b l e m s r e l a t e d t o h azar do us an d so l i d wast e ma n a gem e nt

. RCRA gi v e s E P A t h e aut h o r it y t o est ab l i s h a l i s t o f so l i d an d h azar do us wast es an d t o est ab l i s h st an dar d s an d r e gul at i o n s f o r t h e t r eat m e n t , st o r age,
an d d i sp o s al o f t h ese wast es. Reg u l at i o n s i n S u b t i t l e C o f RCRA ad d r ess t h e i d en t i f i cat i o n , gen e r a t i o n , t r an spo r t a t i o n , t r eat m e n t , st o r age, an d di spo s al o f h azar do us was t es

. T h es e r e gul at i o n s ar e f o un d in 40 CF R P a r t 124 an d CF R P ar t s 260- 279. Un der RCRA
, per s o n s wh o gen e r a t e was t e m u s t det e r m in e wh et h e r t h e wast e i s def in e d as so l i d wast e o rh azar do us wast e. S o l i d wast es
ar e co n s i d er ed h azar do us wast es i f t h ey ar e l i s t e d b y E P A as h azar do us o ri f t h ey ex h i b it ch ar act er i s t i cs o f a hazar do us wast e: t o x i ci t y , i g n it ab ilit y,
co r r o si v it y , o rr eact i v it y

.

Sect o r No t e b o o k Pr o j ect 111 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

Pr o duct s , i n t e r m edi a t e s , an d o f f

- s p eci f i cat i o n pr o duct s po t e n t i a ll y

gen e r a t e d at ph ar m aceut i cal f

ac ilit ie s t h a t a r e c o n s id e r e d h azar do us wast es ar e l i s t e d i n 40 C F RPar t 261. 33( f )

. So m e o f t h e h a n d l i n g an d t r eat m e n t r e qui r e m e n t s f o r RCRA h azar do us was t e gen e r a t o r s ar e co v e r e d un der 40 CF R P a r t 262 an d i n cl ude t h e f o ll o wi n g : det e r m i n i n g wh at co n s t i t u t e s a RCRA h azar do us wast e ( S ub par t A ) ; ma n i f e st i n g ( S ub par t B) ; packagi n g, l ab e l i n g, an d accum u l a t i o n t ime limit s ( S u b p a r t C ) ; a n d r e c o r d k e e p in g a n d r e p o r t in g ( S u b p a r t D )

.
Man y ph ar maceut i cal f ac ilit ie s s t o r e s o me h azar do us wast es at t h e f ac ilit y fo r
mo r e t h a n 9 0 d a ys , a n d a r e t h e r e f o r e , a s t o r a g e fa c ilit y u n d e r RCRA

. S t o r ag e fa c ilit ie s a r e r e q u i r e d t o h a v e a RCRA t r eat m e n t , st o r ag e, an d d i sp o s al f ac ilit y ( T S D F ) per m it ( 40 CF R P a r t 262. 34)

. S o m e ph ar maceut i cal f

ac ilit i e s a r e
c o n s id e r e d T S D F fa c ilit ie s a n d a r e s u b j e c t t o t h e fo l l o w in g r e g u l a t io n s
c o v e r e d u n d e r 4 0 C F R P a r t 264: con t i n g e n c y p l a n s a n d e m e r g e n c y pr o cedur es ( 40 C F RPar t 264 Sub p ar t D) ; ma n i f e s t i n g, r eco r d keepi n g, an d

r e po r t i n g ( 40 C F R Par t 264 Sub p ar t E ) ; us e an d ma n a gem e n t o f co n t ai n e r s ( 40 C F RPar t 264 Sub p ar t I ) ; t a nk s y s t e m s ( 40 C F RPar t 264 Sub p ar t J ) ;
s u r f ace i m p o u n d m e n t s ( 40 CF R P a r t 264 S u b p ar t K ) ; l a n d t r eat m e n t ( 40 CF R P a r t 264 S u b p ar t M ) ; co r r ect i v e act i o n o f h azar do us was t e r e l eas es ( 40 CF R Par t 264 Sub p ar t S) ; ai r em i s s i o n s s t an dar d s f o r pr o ces s v e n t s o f pr o ces s e s t h at pr o ces s o r gen e r a t e h azar do us was t es ( 40 CF R P a r t 264 S u b p ar t A A ) ;
em i ssi o n s st an dar d s f o rl eaks i n h azar do us wast e h a n d l i n g equi pm en t ( 40 CF R Par t 264 Sub p ar t B B ) ; an d em i s s i o n s s t an da r d s f o r co n t ai n e r s , t a nk s , an d

sur f ace i m p o u n d m e n t s t h at co n t ai n h azar do us wast es ( 40 CF R P a r t 2 6 4 S u b p ar t CC)

.
A

n u m b er o f RCRA wast es h a v e b een p r o h i b it edf r o m l a n d d i sp o s al u n l e ss t r eat ed t o m eet sp eci f i c st an d a r d s u n d e r t h e RCRA Lan d Di sp o s al Rest r i ct i o n ( L DR) p r o g r a m

. T h e wast es co v e r e d b y t h e RCRA LDRs a r e l i st ed i n 4 0 C F RPar t 268 Sub p ar t C an d in cl ude a n u m b er o f was t es co m m

o n l y

gen e r a t e d at ph ar m aceut i cal f

ac ilit ie s

. S t a n d a r d s fo r t h e t r e a t me n t a n d s t o r a g e o f

r e st r i ct ed wast es ar e descr i b e d i n S u b p ar t s D an d E
, r e spect i v el y

.
Man y ph ar maceut i cal ma n u f act ur in g f a c i l i t i es ar e al so sub j ect t o t h e
un der g r o un d s t o r age t a nk ( U S T ) pr o g r a m ( 40 C F RPar t 280)

. T h e UST

r e g u l a t io n s a p p l y t o fa c ilit ie s t h a t s t o r e e i t h e r p e t r o l e u m p r o d u c t s o r h azar do us sub s t a n ces ( e x cept h azar do us wast e) i d en t i f i ed un dert h e C o mp r e h e n s iv e E n v i r o n m e n t a l R e s p o n s e , C o mp e n s a t i o n , a n d L i ab ilit y A c t

. US T r e gu l a

t i

o n s addr ess desi gn st an dar d s, l eak det ect i o n , o p er at i n g pr act i ces,
r e spo n se t o r e l eases, f in a n c i a l r e spo n s i bi l it y f o rr e l eases, an d cl o s ur e st an d a r d s.

Sect o r No t e b o o k Pr o j ect 112 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

C

o mpr e hens ive E n vir onmental R e s pons e C o mpens a tion and Liability A c t ( C E

R C LA )

T h e C o m p r e he ns iv e E n v i r o n m e n t a l R e s p o n s e C o mp e n s a t i o n a n d L i ab ilit y A c t

o f 1980 ( C E R C L A ) an d t h e Super f un d A m en dm en t s an d R eaut h o r i zat i o n A c t

o f

1986 ( S A R A) p r o v i d e t h e b a s i c l e gal f r am ewo r k f o r t h e f e der a l

“ S uper f un d” pr o g r a m t o cl ean up ab an do n e d h azar do us wast e sit e s ( 40 CF R Par t 305)

. T h e 1986 SA R A l e gi s l at i o n ex t e n d ed t h es e t a x e s f o r f i v e y ear s an d ado p t e d a n e w b r o a d- ba s e d c o r p o r at e en v i r o n m en t a l t a x , appl i cab l e t o t h e
a llie d c h e mic a l s ( S I C 2 8 ) in d u s t r y, w h ic h in c l u d e s t h e p h a r maceut i cal s in dus t r y

. I n 1990, C o n g r e s s pas s e d a s im p l e r eaut h o r i zat i o n t h at di d n o t

s u b s t a n t i a ll y

ch an ge t h e l a w b u t ex t e n d ed t h e pr o g r a m aut h o r i t y

un t i l 1994

a n d th e ta x i n g a u th or i t y u n ti l th e e n d of 1995. A c o m p r e h e n s i v e
r eaut h o r i zat i o n was co n s i d er ed i n 1994, b u t n o t pas s e d. Si n ce t h e ex pi r a t i o n
o f

t h e t a x i n g aut h o r it y o n Decem b e r 31, 1995, t a x e s f o r S uper f un d h a v e b een t e m p o r ar i l y

suspen ded. T h e t a x e s can o n l y

b e r e i n st at ed b y r eaut h o r i zat i o n
o f

S u p e r f u n d o r a n o m n i

b u s r e c o n c ilia t i o n a c t w h ic h c o u l d s p e c i fic a lly

r eaut h o r i ze t a x i n g aut h o r it y

. T h e all i e d ch em i cal i n dus t r y pay s ab o u t $300 milli o n a

y e a r i n S u p e r f u n d c h e m i c a l f

e e d s t o c k t a xe s

. S u p e r f u n d ’ s l i ab ilit y st an d a r di s su ch t h at P o t e n t i a ll y

Resp o n si b l e P a r t i e s ( P RP s) ma y p a y t h e
en t i r e co st o f cl ean

- up at sit e s, ev en t h o ugh t h ey ma y b e r e spo n si b l e f o ro n l y a f r act i o n o f t h e wast e.

T it l e III o f t h e 1986 SA R A a m e n dm e n t s (a l s o kn o w n a s E m e r ge n c y R e s p o n s e
a n d C o mmu n it y R i g h t

- t o

- K n o w A c t , E P C R A ) r e q u i r e s a ll ma n u fa c t u r in g fa c ilit ie s , in c l u d i n g p h a r m aceut i cal f

ac ilit ie s , t o r e p o r t a n n u a l in fo r ma t io n t o t h e pub l i c ab o u t st o r ed t o x i c sub s t a n ces as well as r e l ease o f t h ese sub s t a n ces i n t o t h e en v i r o n m en t ( 42 U. S. C

. 9601)

. T h i s i s kn o w n as t h e T o x i c R e l eas e In v e n t o r y (TR I). EPC R A a l s o e s t ab l i s h e s re q u i re m e n t s f o r f e d e ra l
, s t a t e , a n d l o c a l go v e r n m e n t s r e gar d i n g em er gen c y pl an n i n g

. I n 1994, o v er 300 m o r e ch em i cal s wer e added t o t h e l i s t o f ch em i cal s f o r wh i c h r e po r t i n g i s r e qui r e d.

Toxic Subs tances C ontr o l A c t ( T SC A )

T h e ph ar maceut i cal i n dust r y i s speci f i call y

ex cl uded f r o m so m e o f t h e
r e qui r e m e n t s o f T S C A

. A n y dr ugs ma n u f act ur ed, pr o ces s e d, an d di s t r i b u t e d i n

co m m

e r ce ar e ex cl uded b y def i n it i o n f

r o m t h e I n v e n t o r y Repo r t i n g R e gul at i o n s ( 40 C F RPar t 710. 4( c) ) an d t h e Pr e- M a n u f act ur in g No t i ce
r e qui r e m e n t s ( 40 C F R720. 30( a) ) o f T S C A

.

Sect o r No t e b o o k Pr o j ect 113 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

V I

. C

. P e nding and P r opos e d R e gul a tory R e quir e m e nts

C l e a n Ai r Ac t ( C AA)

Un dert h e Cl ean A i rA c t , Nat i o n al E m i ssi o n s S t an dar d s f o r H a z a r d o u s A i r P o ll u t a n t s ( N E S HA P S ) ar e b e i ng dev e l o ped f o rt h e ph ar maceut i cal

ma n u f act ur i n g i n dus t r y

.
C l e a n Wa t e r A c t (C WA )

A s par t o f t h e Cl ean W a t e rA c t r e v i si o n pr o cess, t h e ef f l uen t gui del i n es f o r t h e ph ar maceut i cal i n dus t r y ( 40 CF R 439) a r e c u r r e n t l y

b e i n g r e v i s e d an d

r e v i e w e d

. A ma jo r p a r t o f t h e r e v i e w c o n s id e r s t h e in c l u s io n o f limit a t io n s f o r

t o xi c a n d no n- c o nve nt i o na l vo l a t i l e o r g a ni c p o ll u t a nt s

. Ad d it i o n a ll y , t h e 1 983 N e w S o u r c e P e r f o r ma nc e S t a n d a r d s ( N SPS) f o r c o n v e n t i o n a l po ll u t a n t s
w ill a l s o b e r e e v a l u a t e d

.

Sect o r No t e b o o k Pr o j ect 114 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

V I

. D

. Othe r F e de r a l R e gul a tions A f f e c t ing the P h arm a c e u tic a l I ndus try

F

ood and Dr ug A d minis t r a tion ( F DA )

T h e F o o d an d Dr ug A d m i n i s t r at i o n ( F D A ) i s par t o f t h e Depar t m e n t o f Heal t h

an d Huma n S e r v i ces. F D A h a s t h e st at ut o r y aut h o r it y t o r e gul at e a wi de r a n g e o f pr o duct s s u ch as pr es cr i p t i o n an d o v er

- t he

- c o u nt er dr ugs , f o o d s, b i o l o g i c s ( e

. g

. , b l o o d pl asma , v accin e s)
, m e di cal dev i ces ( e

. g

. , n eedl e s, h ear t v a lv es)
, v e t e r i n a r y dr ug s, co sm et i c s an d co n s um er go o d s t h at em it

r a d i a t i o n. T h i s a u t h o r it y ha s be e n g r a n t e d t o FD A by C o ng r e s s u n d e r va r i o u s la w s in c l u d i n g t h e F e d e r a l F o o d
, D r u g a n d C o s m e t ic A c t a n d t h e P u b lic Heal t h

S e r v i ce A c t

.
T h er e ar e f i v e Cen t er s wit h i n F D A t h at deal wit h F D A

- r e gul at ed ar t i cl e s : Cen t erf o r Dr ug E v al uat i o n an d Resear ch ( C D E R )
, C e n t erf o r Bi o l o g i c s E v al uat i o n an d Resear ch ( CBE R)
, Cen t erf o r Vet e r i n a r y Medi ci n e ( C VM)
, Cen t erf o r Dev i ces an d Radi o l o g i c a l H e a l t h

( C DRH)
, an d Cen t erf o rF o o d S a fe t y a n d A p p l i e d N u t r it io n ( C F S A N )

. T h e C e n t e r s r e v i e w s c ie n t ific i n f o r mat i o n pr o v i d ed b y per s o n s wi sh in g t o pl ace F D A

- r e gul at ed ar t i cl es i n t o i n t e rs t a t e c o m m

e rc e i n o r d e r t o d e t e rm in e w h e t h e r re g u l a t o r y re q u i re m e n t s
ar e m e t

. F D A h a s o f f i c e s t h r o ugh o u t t h e U. S

. wh er e t e st i n g o f F D A

r e gul at ed ar t i cl es i s per f o r m e d an d wh er e i n v e st i g a t o r s ar e b a sed. I n v e s t ig a t o r s g o t o U

. S

. a n d fo r e ig n ma n u fa c t u r in g fa c ilit ie s a n d o t h e r t y p e s
o f

fa c ilit ie s i n v o lv e d in F D A

- r e g u l a t e d a c t iv it ie s t o v e r i fy t h a t t h e y ar e in

co m p l

i a n ce wit h F D A r e gul at i o n s

.
F D A ’ s g e n e r a l a p p r o a c h t o r e g u l a t in g v a r i o u s a r t i c l e s is s imila r , h o w e v e r , d u e t o t h e di v e r s e n a t u r e o f t h ese pr o duct s , t h er e ar e r e g u l a t o r y r e qui r e m e n t s t a i l o r e d t o each t y pe o f F D A

- r e gul at ed ar t i c l e

. B e l o w i s a sum mar y o f in f o r mat i o n r e l a t in g t o t h e t y pe o f pr o duct s r e gul at ed b y C D E R

. A ddi t i o n al i n f o r mat i o n o n o t h e rF D A

- r e gul at ed ar t i cl es ma y b e l o cat ed i n 21 CF R o rb y
co n t act i n g F D A di r ect l y

.
T h e ma n u fa c t u r in g fa c ilit ie s t h a t p r o d u c e d r u g s fo r hu ma n u s e a r e r e g u l a t e d b y C D E R

. T h e me t h o d s , fa c ilit ie s , a n d c o n t r o ls u s e d fo r t h e m a n u fa c t u r e , pr o cessi n g , an d packi n g o f a dr ug ar e r e v i ewed b y F D A t o det e r m i n e wh et h e r t h ey ar e adequat e t o en sur e an d pr eser v e t h e dr ug’ s i d en t it y , st r e n g t h
, qual it y
an d pur it y

. T h ese ch ar act er i s t i cs ar e cr it i cal t o en sur e t h e saf e t y an d ef f i cacy
o f

a dr ug f o r hu m a n us e. C D E Rco n duct s a s c i e n t i f i c r e v i ew o f

ma n u f act ur i n g m e t h o d s an d pr o ces s co n t r o l s f o r t h e dr ug s u b s t a n ce an d dr ug pr o duct

. F i el d i n v e st i g at o r s co n duct o n

- s it e r e v i ews t o v e r i f y

t h e accur acy
o f

t h e in fo r ma t io n s u b mit t e d t o C D E R a n d t o d e t e r min e fa c ilit y c o mp lia n c e wit h F D A ’ s Go o d Man u f act ur i n g P r act i ces ( G MP s)

.
F D A ’ s r e v i ew o f a ph ar maceut i cal f ac ilit y d o e s n o t i n c l u d e a u d it i n g
co m p l

i a n ce wit h r e gul at i o n s per t ai n i n g t o t h e pr o t ect i o n o f t h e en v i r o n m en t

.
Sect o r No t e b o o k Pr o j ect 115 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

Ho wev e r , i n acco r d an ce wi t h

t h e Nat i o n al E n v i r o n m en t a l P o l i c y A c t o f 1969 ( N E P A )
, wh i c h r e qui r e s all F e der a l agen ci es t o a s sess t h e en v i r o n m en t a l i m p act s o f t h ei r act i o n s , CDE R h a s i n t e gr at ed t h e c o n s i d er at i o n o f t h e
en v i r o n m en t a l im p act s o f appr o v i n g dr ug pr o duct appl i cat i o n s in t o it s
r e gul at o r y pr o ces s ( 21 C F RPar t 25)

. W h en an en v i r o n m en t a l r e v i ew un der NE P A i s r e qui r e d, t h e r e v i ew f o cuses o n t h e en v i r o n m en t a l i m p act s o f

co n s um er us e an d di s p o s al o f t h e dr ug an d i s b a s e d o n i n f o r mat i o n s u b m it t e d b y t h e ma n u f act ur er s, o ro n a ma n u f act ur er ’ s cer t i f i cat i o n t h at an appl i cat i o n f a ll s wit h i n an est ab l i s h e d cat ego r y o f appl i cat i o n s e x c l uded f r o m t h e
r e q u i r e me n t t o s u b mit in fo r ma t io n

.
A f t e rt h e o r i g i n al appr o v al f

r o m CDE R
, an appl i can t ma y wi sh o rn eed t o
ma ke ch an ges i n t h e m e t h o d o f ma n u f act ur e, t e st in g, et c. descr i b e d i n t h ei r appl i cat i o n

. A n appl i can t i s r e qui r e d t o n o t i f y

F D A ab o u t each ch an ge in each

c o n d it io n e s t ab lis h e d in a n a p p r o v e d a p p lic a t io n ( e

. g

. , in g r e d ie n t s , s o lv e n t s , pr o cesses) b e y o n d t h e v a r i at i o n s al r eady pr o v i d ed f o rin t h e appl i cat i o n ( 2 1 C F R§314. 70( a) )

. Depen d i n g o n t h e t y pe o f ch an ge, t h e appl i can t n o t i f i es F D A ab o u t it i n ( 1 ) a s uppl em en t r e qui r i n g F D A appr o v al b e f o r e t h e ch an ge i s ma de ( §314. 70( b ) )
, ( 2 ) a s uppl em en t f o r ch an ges t h at ma y b e ma de b e f o r e F D A appr o v al ( §314. 70( c) )
, o r ( 3 ) an an n u al r e po r t ( §314. 70( d) )

. C h an ges
r e qui r i n g F D A appr o v al b e f o r e t h ey ar e ma de ma y i n cl ude ch ang e s i n t h e
s yn t h e s i s o f t h e dr ug pr o duct o r ch an ges in s o lv en t s ; t h e addi t i o n o r del e t i o n
o f

an i n gr edi e n t ; an d ch an ges i n t h e m e t h o d o f ma n u f act ur e o rin

- p r o cess
co n t r o l o f t h e dr ug pr o duct ma n u f act ur in g pr o ces s

. T h e r e gul at i o n s s p eci f y t h e m e t h o d o f r e po r t in g cer t a in ch an ges. CDE Ral so pr o v i d es addit i o n al gui dan ce o n t h e m e t h o d o f r e po r t i n g ch an ges an d do cum e n t at i o n n eeded t o
s uppo r t ch an ges in gui dan ce f o rin dus t r y ( e

. g

. , “ G ui dan ce f o rI n dus t r y , I m m

e di at e Rel ease S o l i d Or al Do sage F o r m s, S cal e- Up an d P o st A ppr o v al C h a n g e s : C h e mis t r y M a n u fa c t u r in g a n d C o n t r o ls
, In V itr o D i sso l u t i o n T e s t i n g an d In V i v o B i o e qui v a l e n ce Do cum e n t at i o n , ” No v e m b er 1995)

.
T h e ch an ges i n a ma n u f act ur in g pr o cess t h at a ma nu f a c t ur erma y wi sh t o
un der t ake t o pr ev en t o r r e duce po ll u t i o n wo ul d m o s t l i k el y

b e r e po r t ed i n a
s uppl em en t r e qui r i n g F D A appr o v al b e f o r e t h e ch an ge co ul d b e ma de ( e

. g

. , §§314. 70( b ) ( 1 ) ( i v ) an d 314. 70( b ) ( 2 ) ( v ) )

. C h an ges s u ch as t h es e o f t e n r e qui r e t h e ma n u f act ur er , b e f o r e s u b m it t in g t h e s uppl em en t a l appl i cat i o n t o t h e F D A
, t o g e ne r a t e dat a t h at dem o n s t r at e t h e pr o p o s ed ch an ge do es n o t adv e r s el y af

f ect t h e i d en t it y , st r e n g t h
, qual it y o r pur it y o f t h e dr ug. A n appl i can t ma y
as k F D A t o ex pedi t e i t s r e v i ew i f a del a y in ma kin g t h e ch an ge wo ul d im p o s e
an ex t r ao r d i n ar y h a r d s h i p o n t h e appl i can t ( §314. 70( b ) )

. F o r ch an ges r e l a t i n g t o po ll u t i o n pr ev en t i o n , “ e x p e d i t ed r e v i ew” i s t y pi call y

r e ser v ed f o rt h o s e ch an ges ma ndat e d b y t h e F e der a l
, S t at e o rl o cal en v i r o n m en t a l pr o t ect i o n
a g en ci es, wh i c h m u st b e acco m p l

i s h e d wit h i n a speci f i ed t i m e f r am e. T h e gr an t i n g o f an ex pedi t e d r e v i ew do es n o t ch an ge t h e t y pe o f do cum e n t at i o n t h at n eeds t o b e s u b m i t t e d t o C D E R t o s uppo r t t h e ch an ge.

Sect o r No t e b o o k Pr o j ect 116 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

Summar y of F D

A R e gulations A pplicable to the P har maceutical I ndus tr y

St at ut ory Aut h orit y

T h e F e der a l F o o d Dr ug an d C o s m et i c A c t , pr i n ci pall y

Sect i o n s 201, 301, 501, 502, 503, 505, 506, 507, 512, 701, 704.
CDER Regu l a t i on s

21 C F RPar t s 300- 499

M a nuf ac turi ng I n f o rm ation Subm ittal

M a n u fa c t u r in g I n fo r ma t io n S u b mit t e d t o C D E Rin I n v e s t ig a t io n a l N e w D r u g A

ppl i cat i o n s ( I NDs )
, New Dr ug A ppl i cat i o n s ( NDA s )
, A n t i b i o t i c A

p p lic a t io n s , A b b r e v ia t e d N e w D r u g A p p lic a t io n s ( A N D A s )
, a n d Abbr e v i a t e d Ant i bi o t i c D r u g Ap p l i c a t i o ns ( AAD As )

I NDs : §312. 23( a) ( 7 ) ( i )

Ot h e r appl i cat i o n s : §§314. 50( d) ( 1 ) ( i ) an d 314. 50( d) ( 1 ) ( i i ) ( a )

R e por t ing C h ange s in M a nuf ac turi ng M e thods and C o ntr o l s to C D E R

I ND I n f o r mat i o n am en dm en t s : §312. 31
Suppl em en t s an d o t h e r ch an ges t o an appr o v ed appl i cat i o n : §314. 70

Good M a nuf act u ri ng P r act i ces ( G M P s )

Cur r e n t Go o d Man u f act ur i n g P r act i ce i n Man u f act ur i n g, P r oc e s s i n g , P acki n g,
o r Ho l d i n g o f Dr ugs ; Gen e r a l
, Par t 210

Cur r e n t Go o d Man u f act ur i n g P r act i ce f o rF i n i sh ed P h ar maceut i cal s: P a r t 211

Sect o r No t e b o o k Pr o j ect 117 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

V I

. E

. Othe r Statute s and R e gul a tions A f f e c t ing the P h arm a c e u tic a l I ndus try

State Statutes and R e gulations

M o s ts t a t e s ha ve l o ng

- e s t ab l i s he d br o a d

- ba s e d e nvi r o nm e n t a l r e g u l a t o r y pr o g r a m s

. Man y o f t h ese r e gul at o r y sch e m e s wer e en act ed t o i m p l e m e n t f e der a l pr o g r a m s an d ha ve be en gr an t e d l o cal pr i macy b y t h e USE P A

. Gen e r a ll y , t h e st at e pr o g r a m s ar e all o wed t o b e m o r e r e st r i ct i v e t h an f

e der a l

r e qui r e m e n t s an d, i n so m e cases, t h ey ar e.

S o m e st at es wit h h i gh co n cen t r at i o n s o f ph ar maceut i cal ma n u f act ur in g fa c ilit ie s , h a v e t h e i r o w n r e g u l a t i o n s p e r t a i n i n g s p e c i fic a lly t o t h e in d u s t r y. F o r ex am pl e, b o t h New Yo r k an d New Jer s ey h a v e Reaso n ab l y

A c h i ev ab l e C o n t r o l T e c h n o lo g y ( R A C T ) r e q u i r e me n t s fo r p r o c e s s s p e c i fic v o la t ile

o r g a n i c c o mp o u n d ( V O C ) e mis s i o n s

. O t h e r s t a t e s ma y h a v e s imila r
re q u i re m e n t s u n d e r t h e i r o w n St a t e Im p l e m e n t a t i o n Pl a n s (SIPs )

.

I

n ter national Standar ds

T h e U. S

. P h ar maceut i cal i n dust r y i s l a r g el y

an i n t e r n at i o n a l i n dust r y i n wh i c h

ma n y c o mp a n ie s h a v e ma n u fa c t u r in g fa c ilit ie s a n d s a le s a n d d i s t r i b u t i o n
o p er at i o n s i n co un t r i e s o t h e rt h an t h e U. S

. I n addit i o n t o U. S

. f e der a l st at ut es
an d r e gul at i o n s t h er e ar e i n t e r n at i o n a l l a ws, r e gul at i o n s , t r eat i e s, co n v e n t i o n s
a n d in it ia t i v e s w h ic h a r e d r iv e r s o f t h e e n v i r o n m e n t a l p r o g r a ms o f ph ar maceut i cal co m p an i e s

. T h e Bas e l Co n v e n t i o n , I S O 14000 s t an dar d s , t h e
en v i r o n m en t a l r e qui r e m e n t s o f NA F T A
, an d t h e ev o lv i n g E u r o pean Un i o n Di r ect i v es an d Regul at i o n s ar e a f e w ex am pl es o f i m p o r t a n t in t e r n a t i o n a l

en v i r o n m en t a l st an dar d s an d pr o g r a m s wh i c h af f ect t h i s in dust r y

.

Dr ug En f

o r cement A d minis t r a tion R e gulations

P h ar maceut i cal m a nu f act ur i n g o p er at i o n s ma y al so b e r e gul at ed un dert h e Co n t r o ll e d S u b s t a n ces A c t

. T h i s A c t r e gul at es t h e ma n u f act ur e, di st r i b u t i o n , an d di spen si n g o f co n t r o ll e d sub s t a n ces an d i s en f o r c e d by t h e Dr ug E n f o r cem en t A d m i n i s t r at i o n ( D E A )

. E x am pl es o f ph ar maceut i cal pr o duct s
r e g u l a t e d u n d e r t h i s A c t in c l u d e D e me r o l, P e r c o d a n , R it a lin
, V a liu m, a n d Dar v o n

. A l

i s t o f co n t r o ll e d sub s t a n ces can b e f o un d i n � 1308 o f 21 C F R

.

Sect o r No t e b o o k Pr o j ect 118 Sept em b e r 1997P h arm a c e u tic a l I ndus try F e d e r al Statute s and R e gul a tions

T h e st at ut e pr o v i d es “ c l o sed” sy st em f o rv i r t uall y

ev er y per s o n wh o le g it ima t e ly h a n d le s c o n t r o lle d s u b s t a n c e s , o t h e r t h a n t h e u l t ima t e u s e r

. A s
a

me a n s o f c o n t r o llin g t h e d i s t r i b u t i o n o f r e g u l a t e d p r o d u c t s , D E A s e t s q u o t a s limit in g t h e q u a n t it ie s w h ic h ma y b e ma n u fa c t u r e d o r p r o d u c e d t o t h a t

am o u n t wh i c h i s n ecessar y t o m eet t h e l e gi t ima t e n eeds o f t h e Un it ed S t at es. T h e r e gul at i o n s set speci f i c r e qui r e m e n t s f o rh o w such c o m p o u n d s ar e h a n d le d a n d s t o r e d a t a

ma n u fa c t u r in g fa c ilit y. I n a d d it i o n , w h e n d i s p o s e d o f
, t h ese sub s t a n ces m u st b e dest r o y e d i n t h e pr esen ce o f DE A per s o nne l i n
acco r d an ce wit h t h e r e gul at i o n s f o un d i n 21 CF R, S ect i o n 1307. 21.

Sect o r No t e b o o k Pr o j ect 119 Sept em b e r 1997Page 116 in t e n t i o n a ll y

l e f t b l ank.P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

VI I

. COM P LI ANCE AND ENF O RCEM E NT HI S T ORY

B a ck gr ound

Un t i l r ecen t l y , E P A h a s f o cused m u ch o f it s at t e n t i o n o n m easur i n g
co m p l

i a n c e w i t h speci f i c en v i r o n m en t a l st at ut es. T h i s appr o ach all o ws t h e A g en cy t o t r ack co m p l

i a n c e wit h t h e Cl ean A i rA c t , t h e Reso ur ce Co n s er v a t i o n a n d Reco v e r y A c t , t h e Cl ean W a t e rA c t , an d o t h e r
en v i r o n m en t a l st at ut es. W it h i n t h e l a st sev e r a l y ear s, t h e A g en cy h a s b e gun t o s uppl em en t s in g l e

- m edi a co m p l

i a n ce i n di cat o r s wi t h

f ac ilit y- s p e c ific
, mu lt ime d i a in d i c a t o r s o f c o mp lia n c e

. I n d o in g s o , E P A is in a b e t t e r p o s it i o n t o t r a c k c o mp lia n c e w it h a ll s t a t u t e s a t t h e fa c ilit y le v e l, a n d w it h in s p e c i fic in d u s t r ia l s e c t o r s

.
A

ma jo r s t e p in b u ild in g t h e c a p a c it y t o c o mp ile mu lt ime d i a d a t a fo r in d u s t r ia l sect o r s was t h e cr eat i o n o f E P A ' s I n t e gr at ed Dat a f

o rE n f o r cem en t A n al y s i s ( I D E A ) sy st em

. I D E A h a s t h e capacit y t o “ r ead i n t o ” t h e A g en cy ' s sin g l e

m

e di a dat ab a ses, ex t r act co m p l

i a n ce r eco r d s, an d ma t c h t h e r eco r d s t o in d i v i d u a l f a c ilit ie s

. T h e I D E A s y s t e m c a n ma t c h A i r , W a t e r , W a s t e , T o x i cs/ P est i ci des/ E P CRA
, T R I
, an d E n f o r cem en t Do cket r eco r d s f o r a gi v e n fa c ilit y, a n d g e n e r a t e a

lis t o f h i s t o r ic a l p e r mit
, in s p e c t io n , a n d e n fo r c e m e n t

a c t iv it y. I D E A a l s o h a s t h e c a p ab ilit y t o a n a l yz e d a t a b y g e o g r a p h ic ar e a a n d

co r p o r at e h o l d er

. A s t h e capaci t y

t o gen e r a t e m u l

t i m e di a co m p l

i a n ce dat a imp r o v e s , E P A w ill ma k e a v a ilab l e mo r e in

- d e p t h c o mp lia n c e a n d

en f o r cem en t i n f o r mat i o n

. A ddit i o n all y , s e c t or

- s p e c i f i c m easur es o f success f o r
co m p l

i a n ce assi st an ce ef f o r t s ar e un der dev e l o pm en t

.
Com p l i an ce an d En f o r cem en t P r of i l e Descri p t i o n

Usi n g i n spect i o n , v i o l at i o n , an d en f o r cem en t dat a f

r o m t h e I D E A sy st em , t h i s sect i o n pr o v i d es i n f o r mat i o n r e gar d i n g t h e h i st o r i cal co m p l

i a n ce an d

e n f o r c e m e n t a c t i v it y o f t h i s s e c t o r

. I n o r d e r t o m i r r o r t h e f

a c ilit y u n i v e r s e
r e po r t ed i n t h e T o x i c Ch em i cal P r o f i l e , t h e dat a r e po r t ed wit h in t h i s sect i o n
co n s i s t s o f r eco r d s o n l y

f

r o m t h e T R I r e po r t in g un i v er se. W it h t h i s deci si o n , t h e sel ect i o n cr it er i a ar e co n s i s t e n t acr o ss sect o r s wit h cer t a i n ex cept i o n s. F o r t h e s e c t o r s t h a t d o n o t n o rma ll y

re p o rt t o t h e TR I p r o g ra m , d a t a h a v e be e n p r o v i d e d f

r o m E P A's F a c ilit y I n d e xi ng S y s t e m ( F I N D S ) w h i c h t r a c k s fa c ilit ie s in a ll me d i a d a t ab a s e s

. P l e a s e n o t e , in t h is s e c t io n , E P A d o e s n o t

a t t e mp t t o d e fin e t h e a c t u a l n u mb e r o f fa c ilit ie s t h a t fa ll w it h in each sect o r

. I n s t e a d
, t h e s e c t io n p o r t r a ys t h e r e c o r d s o f a

s u b s e t o f fa c ilit ie s w i t h i n t h e sect o rt h at ar e well def in e d wit h i n E P A dat ab a ses.

As a c h eck o n t h e r e l a t i v e si ze o f t h e f u ll sect o r un i v er se, m o st n o t e b o o k s
c o n t a i n a n e s t i ma t e d n u mb e r o f fa c ilit ie s w i t h in t h e s e c t o r acco r d i n g t o t h e B u r e a u o f C e n s u s ( S e e S e c t i o n II). W i t h s e c t o r s d o m i n a t e d b y s ma ll b u si n e sses, su ch as m e t a l f

i n i sh er s an d p r i n t e r s , t h e r e p o r t i n g u n i v er se w it h i n

Sect o r No t e b o o k Pr o j ect 121 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

t h e E P A d a t ab a s e s ma y b e s ma ll in c o mp a r is o n t o C e n s u s d a t a

. H o w e v e r , t h e g r o u p s e le c t e d fo r in c l u s io n in t h is d a t a a n a l ys is s e c t io n s h o u ld b e c o n s is t e n t wit h t h i s s ect o r ' s gen e r a l ma keup.

F o l l o wi n g t h i s i n t r o duct i o n i s a l i s t def i n i n g each dat a co l u m n

pr esen t e d wit h i n t h i s sec t i o n. T h ese v a l u es r e pr esen t a r e t r o s pect i v e sum mar y o f i n spect i o n s an d en f o r cem en t act i o n s , an d so l e l y

r e f l ect E P A
, S t at e, an d l o cal

co m p l

i a n ce assur a n ce act i v i t i e s t h at h a v e b een en t e r e d i n t o E P A dat ab a ses. T o i d en t i f y

an y ch an ges in t r en ds, t h e E P A r a n t w o dat a quer i es, o n e f o rt h e f i v e cal en dar y ear s ( A pr i l 1, 1992 t o M a r c h 31, 1997) an d t h e o t h e r f o rt h e
m

o s t r ecen t t w elv e

- m o n t h per i o d ( A pr i l 1, 1996 t o M a r c h 31, 1997)

. T h e f i v e

- y ear an al y s i s g i ves an av er age l e v e l o f act i v it y f

o rt h at per i o d f o r
co m p ar i s o n t o t h e m o r e r ecen t act i v it y

.
Because m o st i n spect i o n s f o cus o n si n g l e

- m edi a r e qui r e m e n t s, t h e dat a quer i es pr esen t e d i n t h i s sect i o n ar e t a ken f

r o m si n g l e m e di a dat ab a ses. T h ese dat ab a ses do n o t pr o v i d e dat a o n wh et h e r i n spect i o n s ar e st at e/ l o cal o rE P A

l e d. Ho wev e r , t h e t ab l e b r eaki n g do wn t h e un i v er se o f v i o l at i o n s do es gi v e t h e r eader a cr ude m easur em en t o f t h e E P A ' s an d st at es' ef f o r t s wi t h i n each

me d i a p r o g r a m. T h e p r e s e n t e d d a t a illu s t r a t e t h e v a r i a t io n s a c r o s s E P A Regi o n s f o r cer t a in sect o r s. a T h is v a r i a t io n ma y b e a t t r ib u t ab le t o s t a t e / lo c a l d a t a e n t r y v a r i a t i o n s , s p e c i fic g e o g r a p h ic c o n c e n t r a t io n s , p r o x imit y t o po pul at i o n cen t e r s , sen s it i v e eco sy st em s, hi gh l y

t o x i c ch em i cal s used i n p r o d u c t i o n , o r hi s t o r i c a l no nc o m p l

ia nc e

. H e nc e , t h e e xhi bit e d d a t a d o no t

r a nk r e gi o n al per f o r ma n ce o rn ecessar i l y

r e f l ect wh i c h r e gi o n s ma y h a v e t h e
mo s t c o mp lia n c e p r o b le ms

.
Com p l i an ce an d En f o r cem en t Dat a Def i n i t i on s

Ge ne r a l D e f i nitions

F a c i l i ty I nde x i ng Sys t e m (F I N D S ) - - t h is s y s t e m a s s i g n s a

c o mmo n fa c ilit y
n u m b ert o E P A si ng l e

- m edi a per m i t r eco r d s. T h e F I NDS i d en t i f i cat i o n
n u mb e r a llo w s E P A t o c o mp ile a n d r e v i e w a ll p e r mit
, c o mp lia n c e , e n fo r c e m e n t a n d p o llu t a n t r e le a s e d a t a fo r a n y g i v e n r e g u l a t e d fa c ilit y.

I n t e gr at ed Dat a f o r E n f o r cem ent Anal ys is ( I DE A) - - is a

d a t a in t e g r a t io n sy st em t h at can r e t r i e v e in f o r mat i o n f

r o m t h e ma j o rE P A pr o g r a m o f f i ce d a tab a s e s

. I D E A u s e s th e F I N D S i d e n ti f i c a t i o n n u m b e r to l i nk s e p a r a te d a ta

r eco r d s f r o m E P A ’ s d a t ab a ses. T h i s all o w s r e t r i e v a l o f r eco r d s f r o m acr o s s

a EP A R e gio n s in c l ude th e f o llo w i n g s tate s : I (CT, M A
, M E
, RI
, N H
, V T ); II (N J
, N Y
, P R
, V I); III (D C, D E
, M D
, PA, VA, W V ) ; I V ( A L
, FL
, GA, KY, MS, NC
, SC
, T N ) ; V ( I L
, I N
, MI
, MN, OH
, W I ) ; VI ( A R
, L A
, NM, OK, T X ); V II (IA
, K S
, M O
, N E ); V III (CO
, M T
, N D
, S D
, UT
, W Y ); IX (A Z
, CA
, H I
, N V
, P a c i f i c T r us t T e r r i t o r i e s ); X ( AK, I D
, OR
, W A )

.

Sect o r No t e b o o k Pr o j ect 122 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

me d i a o r s t a t u t e s fo r a n y g i v e n fa c ilit y, t hu s c r e a t in g a � ma s t e r lis t ”o f

r e c o r d s fo r t h a t fa c ilit y. S o me o f t h e d a t a s y s t e m s accessi b l e t h r o ugh I D E A

a r e : A I R S ( A ir F a c ilit y I n d e x i n g a n d R e t r ie v a l S y s t e m , O ffic e o f A i r a n d Rad i at i o n )
, P C S ( P er m it Co m p l

i a n ce S y st em , O f f i ce o f W a t e r )
, RCRI S ( R eso u r ce Co n s er v a t i o n an d Reco v e r y I n f o r mat i o n S y st em , Of f i ce o f S o l i d W a st e)
, NCDB ( N at i o n a l Co m p l

i a n c e Dat a Base, Of f i ce o f P r ev en t i o n , P e st i c i d es, an d T o x i c S u b s t a n ces)
, CE RCL I S ( C o m pr eh en s i v e E n v

i r o n m en t a l

a n d L i ab ilit y I n f o r ma t io n S y s t e m , S u p e r f u n d )
, a n d T R I S ( T o x ic R e le a s e I n v e n t o r y S y st em )

. I D E A al so c o nt ai n s i n f o r mat i o n f

r o m o u t s i d e so ur ces such as Dun an d Br adst r eet an d t h e Occupat i o n al S a f e t y an d Heal t h A d min is t r a t io n ( O S H A )

. M o s t d a t a q u e r i e s d i s p la ye d in n o t e b o o k s e c t io n s I V an d VI I wer e co n duct e d us i n g I D E A

.
Dat a T a bl e Col u m n Heading Def i nit i ons

F a ci l i t i es i n S e ar ch - - ar e b a sed o n t h e un i v er se o f T R I r e po r t er s wit h i n t h e l i s t e d SI C co de r a n g e. F o r i n dus t r i e s n o t co v e r e d un der T R I r e po r t i n g
r e q u i r e me n t s ( m e t a l min i n g , n o n m e t a llic min e r a l min in g , e l e c t r i c p o w e r g e n e r a ti on , g r ou n d tr a n s p or ta ti on , w a te r tr a n s p or ta ti on , a n d d r y c l e a n i n g )
, or in d u s t r ie s in w h ic h o n ly a v e r y s ma ll fr a c t io n o f fa c ilit ie s r e p o r t t o T R I ( e

. g

. , pr i n t i n g )
, t h e n o t e b o o k uses t h e F I NDS un i v er se f o r ex ecut i n g dat a quer i es. T h e S I C co de r a n g e sel e c t e d f o r each sear ch i s def i n e d b y each n o t e b o o k ' s sel ect ed S I C co de co v e r a ge descr i b e d i n S ect i o n I I

.
F a ci l i t i es In sp ect ed --- i n d i c a t e s t h e l e v e l o f E P A a n d s t a t e a g e n c y in s p e c t io n s fo r t h e fa c ilit ie s in t h is d a t a s e a r c h

. T h e s e v a lu e s s h o w w h a t p e r c e n t a g e o f t h e fa c ilit y u n iv e r s e is in s p e c t e d in a

o n e

- ye a r o r fiv e

- y e a r per i o d

.
Nu m b er of In sp ect i o n s - - m easur es t h e t o t a l nu m b e r o f i n spect i o n s
co n duct e d i n t h i s sect o r

. A n i n spect i o n ev en t i s c o u n t e d each t i m e it i s
e n t e r e d in t o a s i n g le me d i a d a t ab a s e

.
Aver age Ti m e B e t w een In sp ect i o n s - - pr o v i d es an av er age l e n g t h o f t i m e , e x p r e s s e d in mo n t h s , b e t w e e n c o mp lia n c e in s p e c t io n s a t a fa c ilit y w it h in t h e def i n e d un i v er s e

.
F a ci l i t i es wi t h O n e or M o r e En f o r cem en t Act i on s

- - ex pr esses t h e n u m b er
o f fa c ilit ie s t h a t w e r e t h e s u b j e c t o f a t le a s t o n e e n fo r c e m e n t a c t io n w it h in t h e d e fin e d t ime p e r i o d

. T h is c a t e g o r y is b r o k e n d o w n fu r t h e r in t o fe d e r a l a n d

s t a t e a c t io n s

. D a t a a r e o b t a in e d fo r a d min is t r a t iv e , c i v il/ ju d i c i a l
, a n d c r imin a l

en f o r cem en t act i o n s

. A d m i n i s t r at i v e act i o n s i n cl ude No t i ces o f Vi o l at i o n ( NOVs )

. A f

ac ilit y w it h mu lt ip le e n fo r c e m e n t a c t io n s is o n ly c o u n t e d o n c e in

t h is c o lu mn , e

. g

. , a fa c ilit y w it h 3 e n fo r c e m e n t a c t io n s c o u n t s a s 1 fa c ilit y.

Sect o r No t e b o o k Pr o j ect 123 Sept em b e r 1997- - P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

T o ta l E n f o r c e m e n t A c tio n s

- - descr i b e s t h e t o t a l n u m b er o f en f o r cem en t act i o n s i d en t i f i ed f o r an in dust r i a l sect o r acr o ss all en v i r o n m en t a l st at ut es. A fa c ilit y w it h mu lt ip le e n fo r c e m e n t a c t io n s is c o u n t e d mu lt ip le t ime s , e

. g

. , a fa c ilit y w it h 3 e n fo r c e m e n t a c t io n s c o u n t s a s 3

.
St at e L e ad Act i o n s s h o w s wh at per cen t a ge o f t h e t o t a l en f o r cem en t act i o n s ar e t a ken b y st at e an d l o cal en v i r o n m en t a l agen ci es. Var yin g l e v e l s
o f

u s e b y s t a t e s o f E P A d a t a s y s t e m s ma y limit t h e v o lu me o f a c t io n s
r eco r d ed as st at e en f o r cem en t act i v it y

. S o m e st at es ex t e n s i v el y

r e po r t

en f o r cem en t act i v it i e s i n t o E P A dat a sy st em s, wh i l e o t h e r st at es ma y use t h ei r
o w n d a t a sy st em s.

F e der a l L e ad Act i ons - - sh o w s wh at per cen t a ge o f t h e t o t a l en f o r cem en t act i o n s ar e t a ken b y t h e Un it ed S t at es E n v i r o n m en t a l P r o t ect i o n A g en cy

. T h i s v a l u e i n cl udes r e f e r r a l s f r o m st at e agen ci es. Man y o f t h ese act i o n s r e sul t f r om c oor d i n a te d or j o in t s t a t e / f e d e r a l e f f o r t s

.
En f o r cem en t t o In sp ect i o n Rat e - - i s a r a t i o o f en f o r cem en t act i o n s t o i n spect i o n s , an d i s pr esen t e d f o r co m p ar at i v e pur po ses o n l y

. T h i s r a t i o i s a
r o ugh i n di cat o ro f t h e r e l a t i o n sh i p b e t w een i n spect i o n s an d en f o r cem en t

. I t

r e l a t e s t h e n u m b er o f en f o r cem en t act i o n s an d t h e n u m b ero f i n spect i o n s t h at

o c c u r r e d wit h i n t h e o n e- y earo rf i v e

- y ear per i o d

. T h i s r a t i o in cl ude s t h e i n spect i o n s an d en f o r cem en t act i o n s r e po r t e d u n d e rt h e Cl ean W a t e rA c t ( C W A )
, t h e Cl ean A i rA c t ( C A A ) an d t h e Reso ur ce C o ns e r v a t i o n an d Reco v e r y A c t ( RCRA )

. I n sp ect i o n s a n d act i o n s f r o m t h e T S CA / F I F RA / E P CRA dat a b a se ar e n o t f act o r ed in t o t h i s r a t i o b ecause m o st o f t h e act i o n s t a k e n u n d e r t h e s e p r o g r a ms a r e n o t t h e r e s u l t o f fa c ilit y in s p e c t io n s

. A l s o , t h i s r a t i o do es n o t acco un t f o r en f o r cem en t act i o n s ar i s i n g f r o m n o n

in s p e c t io n c o mp lia n c e mo n it o r i n g a c t iv it ie s ( e

. g

. , s e lf- r e p o r t e d w a t e r di sch a r g es) t h at can r e sul t i n en f o r cem en t act i o n wit h in t h e CA A
, CWA
, an d RCRA

.
F a ci l i t i es wi t h O n e o r M o r e Vi ol at i o n s Id en t i f i ed - - i n di cat es t h e per cen t a ge o f i n spect ed f aci l i t i e s h a v i n g a v i o l at i o n i d en t i f i ed i n o n e o f t h e fo llo w i n g d a t a c a t e g o r ie s : I n V i o l a t io n o r S i g n ific a n t V i o l a t io n S t a t u s ( C A A ) ; R e p o r t ab le N o n c o m p l

i a

nc e , C u r r e nt Y e a r N o n c o m p lia n c e , S i g n ific a n t N o n c o m p lia n c e ( C W A ) ; N o n c o m p lia n c e a n d S i g n ific a n t N o n c o m p lia n c e (F IF R A
, T S C A
, a n d EPC R A ); U nre s o lv e d V i o l a t i o na n d U nre s o lv e d H i g h P r i o r it y Vi o l at i o n ( RCRA )

. T h e v a l u es p r esen t e d f o r

t h i s co l u m n

r e f l ect t h e
ex t e n t o f n o n c o m pl

i a n ce wit h i n t h e m easur ed t im e f r am e, b u t do n o t di st i n gui sh b e t w een t h e sev e r it y o f t h e n o n c o m pl

i a n ce. Vi o l at i o n st at us ma y b e a pr ecur s o rt o an en f o r cem en t act i o n , b u t do es n o t n ecessar i l y

i n di cat e t h at

a n e n fo r c e m e n t a c t io n w ill o c c u r

.

Sect o r No t e b o o k Pr o j ect 124 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

M e d i a B r eak d own of En f o r cem en t Act i on s an d In sp ect i o n s -- f o u r
co l u m n s i d en t i f y

t h e pr o p o r t i o n o f t o t a l i n spect i o n s an d en f o r cem en t act i o n s wit h i n E P A A i r , W a t e r , W a st e, an d F I F R A / T S CA / E P CRA dat ab a ses. E ach

co l u m n

i s a per cen t a g e o f eit h ert h e � T o t a l I n spect i o n s , ” o rt h e � To t a l A c t i o n s ”c o lu mn

.
V I I

. A

. P h arm a c e u tic a l I ndus try C o m p l i anc e His tory

T ab l e 20 pr o v i d es an o v er v i ew o f t h e r e po r t ed co m p l

i a n ce an d en f o r cem en t dat a f

o rt h e ph ar maceut i cal in dus t r y o v ert h e pas t f i v e y ear s ( A pr i l 1992 t o A

p r i l 1997)

. T h es e dat a ar e al s o b r o k en o u t b y E P A R e gi o n t h er eb y per m it t i n g geo g r a ph i cal co m p ar i s o n s. A f

e w po i n t s ev i d en t f r o m t h e dat a ar e lis t e d b e lo w

.

� Regi o n I I h a s m o r e t h an t w i ce t h e n u m b ero f ph ar maceut i cal f

ac ilit ie s t h a n
an y o t h e r Regi o n an d m o r e t h an h a l f o f all i n spect i o n s n a t i o n all y

wer e car r i ed

o u t in t h is R e g i o n

. T h e h i g h r a t e o f in s p e c t io n s in r e la t i o n t o t h e n u mb e r o f fa c ilit ie s is r e fle c t e d i n t h e R e g i o n ’ s r e la t i v e ly lo w a v e r a g e t ime b e t w e e n in s p e c t io n s ( 6 mo n t h s )

� Regi o n s VI h a d o n l y

f

i v e ph ar maceut i cal f

ac ilit ie s ( i d e n t ifie d b y t h e I D E A sy st em ) an d a r e l a t i v e l y h i gh av er age t i m e b e t w een i n spect i o n s

. Ho wev e r , i n t h e p a s t fiv e ye a r s fo u r e n fo r c e m e n t a c t io n s w e r e b r o u g h t a g a i n s t fa c ilit ie s in t h e Regi o n , gi v i n g it o n e o f t h e h i gh est en f o r cem en t t o in spect i o n r a t e s.

� Regi o n X ha d o n l y

o n e ph ar maceut i cal f

ac ilit y id e n t i fie d b y t h e I D E A

s y s t e m

. I n t h e p a s t fiv e ye a r s t h is fa c ilit y w a s in s p e c t e d t w ic e a n d h a d t w o
en f o r cem en t act i o n b r o ugh t again s t it

.

Sect o r No t e b o o k Pr o j ect 125 Sept em b e r 1997------

Sect o r No t e b o o k Pr o j ectTable20:Five-YearEnforcement and ComplianceSummaryforthePharmaceuticalIndustryABCDEFGHIJRegionFacilitiesinSearchFacilitiesInspectedNumber ofInspectionsAverageMonthsBetweenInspectionsFacilitieswith1orMoreEnforcementActionsTotalEnforcement ActionsPercentStateLeadActionsPercentFederalLeadActionsEnforcementtoInspectionRateI851144000%0%II60536246219584%16%0.15III18161111033100%0%0.03IV2417227641283%17%0.05V221614394560%40%0.03VI551718140%100%0.24VII128371911100%0%0.03VIII652216000%0%IX83769000%0%X112301250%50%1.00TOTAL1641291,20183512280%20%0.10 P h arm a c e u tic a lI ndus try

126 Sept em b e r 1997 C om pl ianc e and E n f o r c e m e n t His toryP h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

V I I

. B

. C o m p aris on of E n f o r c e m e n t A c tivity B e tw e e n Se l e c t e d I ndus trie s

T ab l es 21 an d 22 all o w t h e co m p l

i a n ce h i st o r y o f t h e ph ar maceut i cal i n dust r y t o b e co m p ar ed wit h t h e o t h e ri n dust r i e s co v e r e d b y t h e i n dust r y sect o r
n o te b ook s

. C o m p a r i s on s b e tw e e n T ab l es 21 an d 22 per m i t t h e i d en t i f i cat i o n
o f

t r en ds i n co m p l

i a n ce an d en f o r cem en t r eco r d s o f t h e i n dust r y b y co m p ar i n g dat a co v e r i n g t h e l a st f i v e y ear s t o t h at o f t h e past y ear

. S o m e po i n t s ev i d en t f r o m t h e dat a ar e l i s t e d b e l o w.

� T h e ph ar maceut i cal i n dust r y h a d o n e o f t h e h i gh est i n spect i o n r a t e s a s i n di cat ed b y it s r e l a t i v e l y

l o w av er age t i m e b e t w een i n spect i o n s ( 8 m o n t h s )

co m p ar ed t o o t h e ri n dust r i e s.

� Co m p ar ed t o o t h e r sect o r s, t h e ph ar maceut i cal i n dust r y h a d a r e l a t i v e l y

h i gh

e n fo r c e m e n t t o in s p e c t io n r a t e ( 0

. 0 7 ) a n d a

r e la t i v e ly h i g h p e r c e n t o f fa c ilit ie s i n s p ect ed wit h v i o l at i o n s ( 105 per cen t )

.
T ab l es 23 an d 24 pr o v i d e a m o r e i n

- d ept h co m p ar i s o n b e t w een t h e ph ar m aceut i cal i n dust r y an d o t h e r sect o r s b y b r eaki n g o u t t h e co m p li a n ce an d

en f o r cem en t dat a b y en v i r o n m en t a l st at ut e. A s i n T ab l es 21 an d 22, t h e dat a
co v e rt h e l a st f i v e y ear s ( T ab l e 23) an d t h e pr ev i o us y ear( T ab l e 24 ) t o fa c ilit a t e t h e id e n t i fic a t io n o f r ecen t t r en ds. A f

e w po i n t s ev i d en t f r o m t h e d a t a a r e lis t e d b e lo w

.

� Ov ert h e past f i v e y ear s, ab o u t 80 per cen t o f t h e i n dust r y ’ s i n spect i o n s wer e f o r CA A an d RCRA

. Ov er t h e p a st y ear CA A an d RCRA i n sp ect i o n s
acco un t e d f o r al m

o st 90 per cen t o f i n spect i o n s

. T h i s t r en d i s pr i ma r i l y due t o a n i n cr ease i n CA A i n spect i o n s an d a decr ease i n CW A and F I F R A / T S CA / E P CRA / O t h er in sp ect i o n s

.

� T h e per cen t a ge o f CA A en f o r cem en t act i o n s i n cr eased f r o m 49 per cen t o v er th e p a s t f i v e y e a r s to 7 1 p e rc e n t i n th e p a s t y e a r

. A t th e s a m e ti m e th e per cen t a ge o f CW A en f o r cem en t act i o n s decr eased f r o m 25 per cen t t o 14 per cen t

.

Sect o r No t e b o o k Pr o j ect 127 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His toryTable 21:Five-Year Enforcementand Compliance Summaryfor Selected IndustriesJEnforcementtoInspectionRate0.070.040.050.050.060.100.040.100.060.080.090.100.110.080.250.060.080.070.080.110.080.060.070.130.060.090.100.060.02IPercentFederalLeadActions47%11%21%23%10%30%19%20%12%26%24%20%35%26%32%18%25%29%29%22%25%20%18%16%16%39%12%24%5%HPercentStateLeadActions53%89%79%77%90%70%81%80%88%74%76%80%65%74%68%82%75%71%71%78%75%80%82%84%84%61%88%76%95%GTotalEnforcementActions111132309622832659147842823521912246810276327627730519117460025141332774709778966FFacilitieswith1or MoreEnforcementActions6388149385531346515023889933515347124178971211136836515025320375364840355EAverageMonthsBetweenInspections4652462515151364698861232511516722171393638271495DNumber ofInspections1,6003,7486,07112,8261,4652,7672,3794,6307,6913,0872,4301,2014,2941,2933,0814,3833,4744,4762,5351,6407,9144,5005,91224312,90481697314,2103,813CFacilitiesInspected3787411,9022,8032674733864302,0922862631293551641489813882754241611,858863927373,2631922312,1662,360BFacilitiesinSearch1,2323,2564,6765,2563557124994845,8624413291644252631561,8186153496692032,9061,2501,260447,7865144443,2706,063AIndustrySectorMetalMiningCoalMiningOilandGasExtractionNon-MetallicMineral MiningTextilesLumberandWoodFurniturePulpandPaperPrintingInorganicChemicalsResinsandManmadeFibersPharmaceuticalsOrganicChemicalsAgriculturalChemicalsPetroleumRefiningRubberandPlasticStone,Clay,GlassandConcreteIronandSteelMetalCastingsNonferrousMetalsFabricatedMetalProductsElectronicsAutomobileAssemblyShipbuildingandRepairGroundTransportationWaterTransportationAirTransportationFossilFuelElectricPowerDryCleaning

Sect o r No t e b o o k Pr o j ect 128 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

Sect o r No t e b o o k Pr o j ect Sept em b e r 1997 129Table 22:OneYear Enforcementand Compliance Summaryfor Selected IndustriesACDEFGHFacilitieswith1orMoreViolationsFacilitieswith1ormoreEnforcementActionsTotalEnforcementActionsIndustry SectorFacilitiesinSearchFacilitiesInspectedNumber ofInspectionsNumberPercent*NumberPercent*EnforcementtoInspectionRateMetalMining1,23214221110272%96%100.05CoalMining3,2563627659025%206%220.03OilandGasExtraction4,6768741,17312715%263%340.03Non-MetallicMineral Mining5,2561,4812,45138426%735%910.04Textiles3551722959656%106%120.04LumberandWood71227950719269%4416%520.10Furniture49925445913654%94%110.02PulpandPaper48431778824878%4314%740.09Printing5,8628921,36357765%283%530.04InorganicChemicals44120054815578%1910%310.06ResinsandManmadeFibers32917341915288%2615%360.09Pharmaceuticals1648020984105%810%140.07OrganicChemicals42525983724394%4216%560.07AgriculturalChemicals26310520610297%55%110.05PetroleumRefining15613256512998%5844%1320.23RubberandPlastic1,81846679138983%337%410.05Stone,Clay,GlassandConcrete61525567815159%197%270.04IronandSteel34919786617488%2211%340.04MetalCastings669234433240103%2410%260.06NonferrousMetals2031083109891%1716%280.09FabricatedMetal2,9068491,37779694%637%830.06Electronics1,25042078040296%276%430.06AutomobileAssembly1,2605071,05843185%357%470.04ShipbuildingandRepair4422511986%314%40.08GroundTransportation7,7861,5852,49968143%855%1030.04WaterTransportation514841415363%1012%110.08AirTransportation444961516972%88%120.08FossilFuelElectricPower3,2701,3182,43080461%1008%1350.06DryCleaning6,0631,2341,43631425%121%160.01*Percentages in Columns E and F are based on the number of facilities inspected (Column C).e violations and actions canoccur without a facility inspection.Table 23:Five-Year Inspection and EnforcementSummarybyStatute for Selected IndustriesIndustrySectorFacilitiesInspectedTotalInspectionsTotalEnforcementActionsCleanAirActCleanWaterActRCRAFIFRA/TSCA/EPCRA/Other%ofTotalInspections% ofTotalActions%ofTotalInspections% ofTotalActions%ofTotalInspections% ofTotalActions%ofTotalInspections% ofTotalActionsMetalMining3781,60011139%19%52%52%8%12%1%17%CoalMining7413,74813257%64%38%28%4%8%1%1%OilandGasExtraction1,9026,07130975%65%16%14%8%18%0%3%Non-MetallicMineral Mining2,80312,82662283%81%14%13%3%4%0%3%Textiles2671,4658358%54%22%25%18%14%2%6%LumberandWood4732,76726549%47%6%6%44%31%1%16%Furniture3862,3799162%42%3%0%34%43%1%14%PulpandPaper4304,63047851%59%32%28%15%10%2%4%Printing2,0927,69142860%64%5%3%35%29%1%4%InorganicChemicals2863,08723538%44%27%21%34%30%1%5%ResinsandManmadeFibers2632,43021935%43%23%28%38%23%4%6%Pharmaceuticals1291,20112235%49%15%25%45%20%5%5%OrganicChemicals3554,29446837%42%16%25%44%28%4%6%AgriculturalChemicals1641,29310243%39%24%20%28%30%5%11%PetroleumRefining1483,08176342%59%20%13%36%21%2%7%RubberandPlastic9814,38327651%44%12%11%35%34%2%11%Stone,Clay,GlassandConcrete3883,47427756%57%13%9%31%30%1%4%IronandSteel2754,47630545%35%26%26%28%31%1%8%MetalCastings4242,53519155%44%11%10%32%31%2%14%NonferrousMetals1611,64017448%43%18%17%33%31%1%10%FabricatedMetal1,8587,91460040%33%12%11%45%43%2%13%Electronics8634,50025138%32%13%11%47%50%2%7%AutomobileAssembly9275,91241347%39%8%9%43%43%2%9%ShipbuildingandRepair372433239%25%14%25%42%47%5%3%GroundTransportation3,26312,90477459%41%12%11%29%45%1%3%WaterTransportation1928167039%29%23%34%37%33%1%4%AirTransportation2319739725%32%27%20%48%48%0%0%FossilFuelElectricPower2,16614,21078957%59%32%26%11%10%1%5%DryCleaning2,3603,8136656%23%3%6%41%71%0%0%BPercentages can exceed 100% becausP h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His toryTable 24:OneYear Inspection and EnforcementSummarybyStatute for Selected IndustriesFIFRA/TSCA/EPCRA/Other% ofTotalActions30%0%0%0%0%40%9%1%0%6%5%0%0%9%10%0%0%0%0%7%0%5%0%0%1%9%0%0%0%%ofTotalInspections0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%0%RCRA% ofTotalActions30%5%24%2%8%25%45%7%23%25%5%14%34%36%15%23%30%24%35%30%57%53%47%50%44%45%25%5%38%%ofTotalInspections8%4%9%3%17%44%32%14%33%39%38%45%47%30%34%35%28%26%30%41%43%43%41%35%26%38%57%9%30%CleanWaterAct% ofTotalActions40%14%9%9%17%5%0%19%0%9%38%14%13%0%8%13%7%29%8%20%2%5%6%50%10%36%42%21%6%%ofTotalInspections40%40%10%10%17%6%2%32%4%26%24%11%13%22%17%10%10%23%10%15%11%14%7%11%11%24%15%32%1%CleanAirAct% ofTotalActions0%82%68%89%75%30%45%73%77%59%51%71%54%55%67%64%63%47%58%43%41%37%47%0%46%9%33%73%56%%ofTotalInspections52%56%82%87%66%51%66%54%63%35%38%43%40%48%49%55%62%52%60%44%46%44%53%54%64%38%28%59%69%TotalEnforcementActions102234911252117453313614561113241273426288343474103111213516TotalInspections2117651,1732,4512955074597881,3635484192098372065657916788664333101,3777801,058512,4991411512,4301,436FacilitiesInspected1423628741,48117227925431789220017380259105132466255197234108849420507221,58584961,3181,234Industry SectorMetalMiningCoalMiningOilandGasExtractionNon-MetallicMineral MiningTextilesLumberandWoodFurniturePulpandPaperPrintingInorganicChemicalsResinsandManmadeFibersPharmaceuticalsOrganicChemicalsAgriculturalChemicalsPetroleumRefiningRubberandPlasticStone,Clay,GlassandConcreteIronandSteelMetalCastingsNonferrousMetalsFabricatedMetalElectronicsAutomobileAssemblyShipbuildingandRepairGroundTransportationWaterTransportationAirTransportationFossilFuelElectricPowerDryCleaning

Sect o r No t e b o o k Pr o j ect 130 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

VI I

. C. Review of M a j o r L e gal Act i ons

T h i s sect i o n pr o v i d es sum ma r y i n f o r mat i o n ab o u t ma j o r cases t h at h a v e af

f ect ed t h i s s ect o r , an d Suppl em en t a r y E n v i r o n m en t a l Pr o j ect s ( S E P s )

. S E P s a r e c o mp lia n c e a g r e e m e n t s t h a t r e d u c e a fa c ilit y' s s t ip u l a t e d p e n a lt y in

r e t u r n f

o r an en v i r o n m en t a l pr o j ect t h at ex ceeds t h e v a l u e o f t h e r e duct i o n

. Of t e n , t h ese pr o j ect s f u n d po ll u t i o n pr ev en t i o n act i v i t i e s t h at can si gn i f i can t l y
r e d u c e t h e fu t u r e p o llu t a n t lo a d in g s o f a

fa c ilit y.

VI I

. C. 1. Review of M a j o r Cas e s

A s i n di cat ed i n E P A ’ s En f

o r cement A ccomplis hments R e por t, F Y 1995 and F Y 1 996 p u b l i c a

t i o n s , 5 si gn i f i can t en f o r cem en t act i o n s wer e r e so lv ed b e t w een 1994 an d 1996 f o r t h e ph ar maceut i cal i n dus t r y

.
In t h e Ma t t e r o f

Ci b a - G e i g

y, In c. : On No v e m b er 7, 1994, R e gi o n I I i s s u ed

an adm i n i s t r at i v e co n s en t o r dert o Ci b a

- G e i g y , I n c. , assessi n g a pen a l t y

o f $130, 000 f o r v i o l at i o n s o f E P C R A at i t s T o m s R i v e r , New J e r s ey , f ac ilit y. T h e o r d e r w a s b a s e d u p o n a n in s p e c t io n o f C i b a

- G e i g y ’ s fa c ilit y t h a t r e s u lt e d i n

a si x t een co un t co m p l a i n t all e gi n g t h at Ci b a

- G ei gy f a i l e d t o r e po r t t h at it used cer t a i n o f t h e f o ll o wi n g : co pper co m p o u n d s; gl y c o l et h e r s ; ch r o mi um
c o mp o u n d s ; c o b a lt c o mp o u n d s ; C

. I

. D i s p e r s e Y e llo w 3 ; d i e t h a n o la min e a n d et h y l e n e gl y c o l dur i n g t h e cal en dar y ear s 1988 t h r o ugh 1991.

C

i ba-Ge igy S u p e r fund Site : On Oct o b e r 18, 1995, R e gi o n I I i s s u ed an adm i n i s t r at i v e o r der o n co n s en t un der Sect i o n s 104, 107, a n d 122 o f C E R C L At o t h e C i b a -G e i g y C o rp o r a t i o n

. Th e o r d e r re q u i re s C i b a -G e i g y t o p e r f o r m, u n d e r E P A o v e r s i g h t , a fe a s ib ilit y s t u d y fo r O p e r ab le U n it T w o t o dev e l o p a nd ev al uat e r e m e di al al t e r n at i v es f o r appr o x i ma t e l y

t w en t y

- o n e po t e nt i a l so ur ce ar eas o f gr o u n d wat e r co n t am i n at i o n o n t h e sit e

. T h e
e s t i ma t e d c o s to f t h e w o r k t h a tC i ba

- G e i g y w ill p e r f o r m i s $20 millio n

. I n
a d d it i o n , C i b a

- G e i g y w ill a l s o p a y a ll o f E P A ’ s u nr e imb u r s e d p a s t r e s p o n s e
co s t s , $797, 000, pl us all o f E P A ’ s f u t u r e r e s p o n s e co s t s , in cl udin g o v er s i gh t

co st s.

T h e sit e i s o n t h e Nat i o n al P r i o r it i es L i st an d l o cat ed i n T o m s Ri v e r , Ocean Co un t y , New Jer s ey

. Gr o u n d wat e r at t h e sit e i s co n t am i n at ed wi t h

o r gan i c
an d i n o r gan i c co m p o u n d s, an d eman at es f r o m sur f ace an d sub s ur f ace f o r m er di s p o s al ar eas o n t h e s it e

. Pur s uan t t o a s e t t l em en t wit h E P A in 1994, C i b a

Gei g y i s cur r e n t l y r e m e di at i n g t h e gr o u n d wat e r co n t am i n at i o n

. E P A r ecen t l y
co m p l e t e d a b a sel i n e pub l i c h eal t h

r i sk assessm en t o r so ur ce ar ea sur f ace
so i l s , as well as a r e m e di al i n v e st i g at i o n t o ex am in e t h e n a t u r e an d ex t e n t o f t h e c o n t a min a t io n in t h e s o u r c e a r e a s a t t h e s it e

. I n p e r f o r min g t h e fe a s ib ilit y st u d y f

o rt h e so ur ce ar eas, Ci b a

- G ei gy h a s agr eed t o ado p t E P A ’ s r i sk

assessm en t an d r e m e di al i n v e st i g at i o n r e po r t

.

Sect o r No t e b o o k Pr o j ect 131 Sept em b e r 1997P h arm a c e u tic a l I ndus try C om pl ianc e and E n f o r c e m e n t His tory

T

akeda C h em ical P r

oducts USA , I n c. ( N C ) : On A ugus t 31, 1995, R e gi o n I V en t e r e d i n t o a co n s en t agr eem en t / co n s en t o r der( C A C O) r e so lv i n g cl ai m s ag ai n s t T a k e d a Ch em i cal P r o d u c t s US A
, I n c. , f o r v i o l at i o n s o f RCRA at it s
v i t a min ma n u fa c t u r in g p l a n t in W ilmin g t o n , N o r t h C a r o lin a

. A s p a r t o f a
s o lv en t ex t r act i o n pr o ces s , T a keda gen e r a t e d a b y

- p r o duct r e f e r r e d t o as DA S

- f u el
, wh i c h T a keda i n t e n d ed t o b u r n f

o r en er gy r eco v e r y

. P r i o r t o
r ecei v i n g an y per m it s t o b u r n t h e DA S

- f u el
, T a keda gen e r a t e d DA S

- f u el an d st o r ed it o n

- s it e f o r a per i o d i n ex cess o f 90 day s wi t h o u t a per m it o ri n t e r i m
s t a t u s , a n d l a te r s h i p p e d it of f

- s ite

. E P A d e te r m i n e d th a t th e D A S

- f u e l ( e s s e n t ia lly s p e n t t o lu e n e mix e d w it h D A S w a t e r a n d p o lyme r s ) w a s F 0 0 5 h azar do us was t e. A s a r e s u l t , o n S e pt em b e r 24, 1994, R e g i o n I V i s s u ed a

c o mp la in t fo r ille g a l s t o r a g e o f h azar do us wast e, f a i l u r e t o ma ke a h azar do us wast e det e r m i n at i o n , an d f a i l ur e t o ma n i f e st t h e DA S

- f u el sh i pped o f f

- sit e

. T h e C A C O r e qui r e s T a keda t o pay a ci v i l pen a l t y

o f $99, 000, b u t all o w s T a keda t o b r i n g DA S- f u el b ack o n

- s i t e f o r r e pr o ces s i n g , pr o v i d ed T a keda

ma n a ges an y wast e it pr o duces as a r e sul t as a h azar do us wast e.

A bbott L abor ator ies : A co n s en t agr eem en t an d f i n a l o r der was si gne d i n Sept em b e r 1995, co n cer n i n g A b b o t t L ab o r a t o r i es C o r p o r at i o n ’ s v i o l at i o n s o f RCRA st an dar d s appl i cab l e t o t h e b u r n i n g o f h azar do us wast e i n b o i l e r s an d i n dust r i a l f u r n aces ( B I F ) at it s No r t h Ch i cago , I llin o i s fa c ilit y. N e g o t i a t io n s wit h A b b o t t L ab o r a t o r i es a f t e ri s s u an ce o f t h e co m p l a i n t i n F e b r uar y 1994

r e s u l t ed in a pen a l t y

o f $182, 654. A b b o t t al s o agr eed t o co n duct a
s uppl em en t a l en v i r o n m en t a l pr o j ect ( S E P ) t h at w ill a llo w A b b o t t t o r e c o v e r
an d r ecy cl e t h e m e t h y l en e ch l o r i de pr o duced i n it s ma n u f act ur i n g pr o cesses
a n d w ill r e d u c e f

u g it i ve m e t h y l e n e c h l o r i d e e m i s s i o n s

. T h e S E P i nvo lv e s t h

r e e s e p a r a t e , a l b e it s imila r , o p e r a t io n s , r e p l a c in g “ w e t ”v a c u u m p u m p sy st em s wit h “ d r y ” pum ps an d h i gh ef f i ci en cy co n d en ser s

. T h e pr o j ect ed co st

o f

t h e SE P i s $480, 000.

V I I

. C

. 2. Suppl e m e n tary E n vir o nm e n tal P r oje c t s (SE P s )

S upp l e m e nt al en v i r o n m en t a l pr o j ect s ( S E P s) ar e en f o r cem en t o p t i o n s t h at

r e q u i r e

t h e n o n

- c o mp lia n t fa c ilit y t o c o mp le t e s p e c i fic p r o j e c t s

. I n fo r ma t io n
o n S E P cases can b e accessed v i a t h e in t e r n et at E P A ’ s E n v i r o $en $ e web s it e: h t t p ://e s

. i n e l

. g o v /s e p

.

Sect o r No t e b o o k Pr o j ect 132 Sept em b e r 1997Page 130 in t e n t i o n a ll y

l e f t b l ank. VIII. CO M P LIANCE ACTIVITIES AND INITIATIVES

T h is s e c t io n h i g h lig h t s t h e a c t iv it ie s u n d e r t a k e n b y t h is in d u s t r y s e c t o r a n d pub l i c agen ci es t o v o l u n t ar i l y

i m p r o v e t h e sect o r ' s en v i r o n m en t a l per f o r ma n ce. T h ese act i v it i e s i n cl ude t h o s e in depen d en t l y

in i t i a t e d b y i n dust r i a l t r ade as s o c i a t i o n s

. I n t h i s sect i o n , t h e n o t e b o o k al so co n t ai n s a l i s t i n g an d descr i pt i o n o f n a t i o n al an d r e gi o n al t r ade asso ci at i o n s

.
V III. A

. S ect o r - r el a t ed Pr o g r a m s a n d A c t i v i t i es

T h e P h ar maceut i cal Resear ch an d Man u f act ur er s o f A m er i ca ( P h R MA ) an d E P A ar e co n s i d er i n g dev e l o pi n g co m p l

i a n ce an d r e gul at i o n s g u i d es,
co n c e r nin g t h e in t e r act i o n s o f E P A an d F D A r e gul at i o n s f o rt h e ph ar maceut i cal i n dust r y

.
V III. B

. EPA V o l u n t a ry Pr o g r a m s

33/50 P r ogr am

T h e 33/50 Pr o g r a m i s a gr o u n d b r eaki n g pr o g r a m t h at h a s f o cus e d o n
r e duci n g po ll u t i o n f

r o m s e v e n t een h i gh

- p r i o r it y ch em i cal s t h r o ugh v o l u n t ar y par t n e r s h i ps wit h i n dus t r y

. T h e pr o g r a m ' s n a m e s t em s f r o m it s go al s : a 33%

r e duct i o n i n t o x i c r e l eas es an d t r an s f er s b y 1992, an d a 50% r e duct i o n by 1995, agai n s t a b a s e l i n e o f 1. 5 b illio n p o u n d s o f r e le a s e s a n d t r a n s f e r s in 1988. T h e r e s u l t s h a v e b een i m p r e s s i v e : 1
, 3 00 co m p an i e s h a v e j o i n ed t h e 33/50 Pr o g r a m ( r e pr es en t in g o v er 6, 000 f ac ilit ie s ) a n d h a v e r each ed t h e
n a t i o n al t ar g et s a y ear ah ead o f s c h e dul e. T h e 33% go al was r each ed in 1991,

an d t h e 50% go al - - a r e duct i o n o f 745 millio n p o u n d s o f t o x i c w a s t e s - - w a s
r each ed i n 1994. T h e 33/50 P r o g r a m can pr o v i d e cas e s t udi es o n ma n y o f t h e
co r p o r at e acco m p l

i s h m en t s in r e duci n g wast e.

T ab l e 25 l i s t s t h o s e co m p an i e s p a r t i c i p a t in g i n t h e 33/50 pr o g r a m t h at

r e po r t ed t h e SI C co des 2833 an d 2834 t o T R I

. S o m e o f t h e co m p an i e s
s h o w n a l s o lis t e d fa c ilit ie s t h a t a r e n o t p r o d u c in g p h a r ma c e u t i c a l s

. T h e
n u mb e r o f fa c ilit ie s w it h in each co m p an y t h at ar e par t i c i p at i n g i n t h e 33/ 5 0 pr o g r a m an d t h at r e po r t ph ar maceut i cal S I C co des i s sh o w n

. W h er e av ai l ab l e
an d quan t i f i ab l e agai n s t 1988 r e l eas es an d t r an s f e r s , each co m p an y ’ s 33/50 g o a l s f o r 1995 an d t h e act ual t o t a l r e l eas es an d t r an s f er s an d per c e n t

r e duct i o n b e t w een 1988 an d 1994 ar e pr es en t e d. A t t h e t i m e o f pub l i cat i o n
o f

t h i s do cum e n t ( A ugus t 1997) 1995 33/50 Pr o g r a m T R I dat a wer e n o t

av ai l ab l e.

T ab l e 20 s h o w s t h at 34 co m p an i e s co m p r i s e d o f 160 f ac ilit ie s r e p o r t in g S I C 2833 an d 2834 ar e par t i c i p at ed i n t h e 33/50 pr o g r a m

. F o r t h o s e co m p an i e s sh o w n wit h m o r e t h an o n e ph ar m aceut i cal m a n u f act ur i n g f ac

ilit y, a ll fa c ilit ie s
ma y n o t b e par t i c i p at i n g i n 33/50. T h e 33/50 go al s s h o w n f o r co m p an i e s wit h

m

u l

t i

p l e ph ar maceut i cal f

ac ilit ie s , h o w e v e r , a r e c o mp a n y- w i d e , p o t e n t ia lly

a g g r e g a t in g mo r e t h a n o n e fa c ilit y a n d fa c i l i t i e s n o t c a r r yin g o u t ph ar maceut i cal o p er at i o n s

. I n addit i o n t o co m p an y

- wi de go al s, i n di v i d u a lP h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

fa c ilit ie s w it h in a c o mp a n y ma y h a v e t h e i r o w n 3 3 / 5 0 g o a l s o r ma y b e speci f i call y

l

i s t e d as n o t par t i c i p at i n g i n t h e 33/ 50 pr o g r a m

. S i n ce t h e act ual p e r c e n t r e d u c t i o n s s h o w n in t h e la s t c o lu mn a p p l y t o a ll o f t h e c o mp a n ie s ’ ph ar m aceu t i c a lma n u f a c t u r i n g f a c ilit i e s a n d o n l y p h a r m aceut i cal

ma nu f a c t u r i n g f a c ilit i e s , d i r e c tc o m p a r i s o n s t o t h o s e c o m p a n y g o a l s i n co r p o r at i n g n o n

- ph ar maceut i cal f

ac ilit ie s o r e x c l u d i n g c e r t a in fa c ilit ie s ma y
n o t b e p o s s i b l e

. F o r in fo r ma t io n o n s p e c i fic fa c ilit ie s p a r t ic ip a t in g in 3 3 / 5 0
, co n t act Dav i d Sar o ki n ( 202- 260- 6907) at t h e 33/50 Pr o g r a m Of f i ce.

Sect o r No t e b o o k Pr o j ect 134 Sept em b e r 1997- -

-- P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s



### Tab l e 25: P h arm a ceu t i cal In d u st ry P a rt i c i p at i o n i n t h e 33/ 50 P r o g ram
P a r e n t C o m p an y (H e a dquar t e r s L o c atio n ) C o mp an y

- O w n e d P h ar mac e u tic al F a c ilitie s R e po r t i n g 33/ 50 C h e mic als C o mp an y

- w i d e % R e duc t i o n Go a l 1 (1988- 1995) 1988 T RI R e le as e s an d Tr an s f e r s o f 33/ 50 Ch e m i c a l s (po un ds ) 1994 T RI R e le as e s an d Tr an s f e r s o f 33/ 50 Ch e m i c a l s (po un ds ) A c tu al % R e duc t i o n f o r P h ar mac e u tic al F a c ilitie s (1988 - 1994)
3M M i nne s o t a M i ni ng & M f g .. Co m p a n y - St

. Pa ul
, M N 2 7 0 885, 011 194, 850 78

A bbot t L a bor at or i e s - N o r t h C h i cago, I L 6 2 0 3
, 017, 869 2, 869, 793 5. 0

A m er i can H o m e P r od u c t s C o r por at i o n - M a di s o n , N J 19 50 1, 828, 970 930, 992 49

A n abol i c I n cor por at ed - Ir v i n e , C A 1 7 5 39, 602 0 100

B a x t e r I n te rn a tio n a l I n c

. - D eer f i el d
, I L 8 8 0 921, 282 33, 312 96

B o eh r i n g er I n gel h ei m C o r p

.

- R i d g e f ie ld , C T 2 5 0 198, 500 247, 166 -24. 5

B r isto l- M y e r s S q u i b b C o . - Ne w Yo r k , NY 15 50 4, 876, 002 2, 305, 269 53

B u r r o ug hs We l l c o m e C o

. - Du r h a m , NC 2 2 6 469, 075 193, 171 59

C i ba- G ei gyC o m p an y- T a r r y to wn , NY 14 50 2, 613, 266 1, 179, 471 55

C o at i n g P l ace I n cor por at ed - Ve r o n a , W I 1 *** 149, 000 0 100

D o w C h em i cal C o m p an y- M i dl a nd, M I 1 5 0 115, 000 109, 100 5

Ea s t m a n K o da k C o m p a n y - R o ch est e r , N Y 1 5 0 87, 350 15, 766 82

E li L illy a n d C o m p a n y - I ndi a n a p o l i s , I N 7 5 0 5
, 749, 879 1, 194, 760 79

Fi s o ns C o m p a n y - R o ch est e r , N Y 1 *** 3, 395 2, 229 34

G a n e s C h em i cal s I n c. - Ca r l s t a d t , NJ 2 *** 67, 018 19, 586 71

H o ech st C e l a n e se C o m p an y

- Co r p u s Ch r i s t i
, T X 1 5 0 0 0

H o f f m an n

- L a R o ch e I n c. - Nu tle y , NJ 5 6 2 2
, 154, 667 1, 230, 361 43

J o hns o n & J o hns o n - Ne w Br u n s wic k , NJ 2 6 5 258, 090 234, 444 9

M a llin c kro d t G r o u p I n c

. - S a in t L o u i s, M O 1 5 0 0 500

Sect o r No t e b o o k Pr o j ect 135 Sept em b e r 1997--

-- P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s



### Tab l e 25: P h arm a ceu t i cal In d u st ry P a rt i c i p at i o n i n t h e 33/ 50 P r o g ram

M e r c k & C o m p an yI n c. - W h ite h o u s e S t a tio n , NJ
M o n s an t o C o m p an y- S a in t L o u i s, M O 7

3 5 0

2 5 5
, 863, 293 927, 225 84

9
, 200 3, 480 62

P a r P h ar m aceu t i cal I n c. - S p r i n g Va lle y , NY 1 *** 194, 099 0 100

P e r r i go C o m p an y- Alle g a n , M I 2 9 5 638, 235 0 100

P f

i zer I n cor por at ed - Ne w Yo r k , NY 10 50 2, 492, 314 3, 250, 940 -30

S a n d o z C o r por at i o n Ne w Yo r k , NY 18 50 572, 915 100, 439 82

Sc he r i ng

- P l o ug h C o r p

. - M a di s o n, N J 7 7 0 3
, 181, 202 1, 867, 558 41

S m i t h kl i n e B eech am A m er i cas - P h ila d e lp h i a , P A 6 8 1 2
, 882, 573 35, 469 99

S o l v ayA m er i ca I n c. - H o us t o n, T X 1 * 0 36, 474

S y n t ex U S A I n cor por at ed - P a lo Alto , C A 3 3 3 1
, 093, 051 393, 493 64

T i s h c o n C o r p o r a t i o n - W e s t b u r y , NY 2 * * 3
, 900 113, 000 -2797

Un ite d Or g a n i c s Co r p . - W illia m s to n , NC 1 * 0 5
, 950

U p j o hn C o m p a n y - K a l a m azoo, M I 3 5 0 7
, 128, 339 5, 654, 150 21

U p s h er

- S m i t h L a bor at or i e s In c

. - Mi n n e a p o l i s , MN 1 100 94, 000 320, 000 -240

W a r n er

- L am ber t C o m p an y- M o rris P l a i n s , N J 4 4 0 197, 540 242, 638 -22

To t a l 160 47, 784, 637 23, 711, 586 50 S o u r ce: U S

EP A 33/50 P r ogr am O ffice, 1996. 1995 33/50 T R I data w a s not available at tim e of publication.

1 C o m p a n y

- wid e R e d u c tio n G o a l s a g g r e g a t e a ll c o m p a n y

- o w n e d f a c ilitie s wh ic h m a y in c l u d e f a c ilitie s n o t p r o d u c in g ph ar m aceu t i cal s.
* = R e duc t i o n g o a l no t qua nt i f i a b l e a g a i ns t 1988 T R I da t a

. ** = U s e r e d u c t i o n goal on l y

. *** = N o n u m er i c r e d u c t i o n goal

.

En vir onmental Leader s h ip P r ogr am

T h e E n v i r o n m e n t a l L e a d e r s h ip P r o g r a m ( E L P ) is a n a t i o n a l in it ia t i v e d e ve l o p e d by E P A t h a tf o c u s e s o n im p r o vi ng e nvi r o nm e n t a l p e r f o r ma nc e , e n c o u r a g in g v o lu n t a r y c o mp lia n c e , a n d b u ild in g w o r k in g r e la t i o n s h ip s w i t h

s t akeh o l der s

. E P A i n it i a t e d a o n e y ear pi l o t pr o g r a m i n 1995 b y s e l ect i n g 12 p r o j e c t s a t in d u s t r ia l fa c ilit ie s a n d fe d e r a l in s t a lla t i o n s t h a t d e mo n s t r a t e t h e

Sect o r No t e b o o k Pr o j ect 136 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

pr i n ci pl es o f t h e E L P pr o g r a m

. T h ese pr i n ci pl es in cl ud e : e nvi r o n m en t a l

ma n a g e me n t s y s t e m s , mu lt ime d i a c o mp lia n c e a s s u r a n c e , t h ir d

- p a r t y
v e r i f i cat i o n o f co m p l

i a n ce, pub l i c m easur es o f acco un t ab ilit y, p o llu t i o n pr ev en t i o n , co m m

u n it y in v o lv em en t , an d m e n t o r pr o g r a m s

. I n r e t u r n f

o r par t i c i p at in g, pi l o t par t i c i p an t s r ecei v e d pub l i c r eco gn i t i o n an d wer e gi v e n a per i o d o f t i m e t o co r r ect an y v i o l at i o n s di sco v er ed dur i n g t h ese ex per i m e n t al pr o j ect s.

E P A is ma k i n g p l a n s t o la u n c h it s fu ll

- s c a l e E n v i r o n m e n t a l L e a d e r s h ip Pr o g r a m i n 1997. T h e f u ll

- s cal e pr o g r a m w ill b e fa c ilit y- b a s e d w it h a

6

- ye ar p a r t ic ip a t io n c y c l e

. F a c ilit ie s t h a t me e t c e r t a in r e q u i r e me n t s w ill b e e lig ib le t o par t i c i p at e, such as h a v i n g a co m m

u n i t y o u t r each / e m p l o y ee i n v o lv em en t p r og r a m s a n d a n e n v i r o n m e n t a l ma n a g e m e n t s y s t e m ( E M S ) i n p l ace f o r 2 y e a r s

. (C o n t a c t : h t t p ://e s

. i n e l

. g o v /e l p o r De b b y T h o m a s , E L P De put y Di r ect o r , at 202- 564- 5041)

P r oj ect X L

P r oj e c t X L w a s i n it i a te d i n M a r c h 1995 a s a p a r t of P r e s i d e n t C l i n ton ’ s R e inv e n ting En v i r onme n tal R e gulation i n it i a t i v e

. T h e pr o j ect s seek t o ach i e v e co st ef f ect i v e en v i r o n m en t a l b e n e f i t s b y pr o v i d i n g par t i c i p an t s
r e g u l a t o r y fle x ib ilit y o n t h e c o n d it io n t h a t t h e y p r o d u c e g r e a t e r e n v i r o n m e n t a l b e n e fit s

. E P A a n d p r o g r a m p a r t ic ip a n t s w ill n e g o t i a t e a n d s i g n a

F i n a l P r o j e c t A g r e e m e n t , d e t a ilin g s p e c i fic e n v i r o n m e n t a l o b je c t iv e s t h a t t h e r e g u l a t e d

e n t it y s h a ll s a t i s f y. E P A w ill p r o v id e r e g u l a t o r y fle x ib ilit y a s a n in c e n t i v e fo r t h e par t i c i p an t s ’ super i o r en v i r o n m en t a l per f o r ma n ce. P a r t i c i p an t s ar e
en co ur aged t o s eek s t akeh o l der s uppo r t f r o m l o cal go v e r n m e n t s , b u s i n e s s e s , a n d e n v i r o n m e n t a l g r o u p s

. E P A h o p e s t o imp le me n t fift y p ilo t p r o j e c t s in fo u r c a t e g o r ie s , in c l u d i n g in d u s t r ia l fa c ilit ie s , c o mmu n it i e s , a n d g o v e r n me n t fa c ilit ie s r e g u l a t e d b y E P A

. A p p lic a t io n s a r e b e in g accept e d o n a r o llin g b a si s.

I n

1996, E P A accept e d a pr o p o s al b y M e r c k t o del i v er s upe r i o r
e n v i r o n m e n t a l p r o t e c t io n w h ile a llo w i n g fle x ib le o p e r a t io n a t it s ph ar maceut i cal ma nu f act ur i n g f ac ilit y n e a r E l k t o n , V i r g in ia

. M e r c k
, a l o n g
w it h it s s t a k e h o l d e r s , d e v e lo p e d a s imp lifie d a i r p e r mit fo r t h e fa c ilit y t h a t w ill cap t o t a l ai r em i ssi o n s o f cr it er i a po ll u t a nt s a t l e ss t h an r ecen t act ual l e v e l s
a n d a ll o w t h e f

a c ilit y t o ma k e c h a n g e s a n d a d d i t i o n s t o it s ma nu f a c t u r i n g pr o cesses as so o n as t h ey ar e n eeded wit h o u t pr i o r a p p r o v al

. T h e upf r o n t

e n v i r o n m e n t a l b e n e fit w h ic h w ill e n ab le M e r c k t o o p e r a t e fle x ib ly u n d e r t h e
e mis s i o n s c a p w ill c o me fr o m c o n v e r t in g t h e c o a l b u r n i n g p o w e r h o u s e t o
n a t u r a l g a s

. T h is c o n v e r s io n w ill r e d u c e t h e s i t e ' s a c t u a l a i r e mis s i o n s b y o v e r 900 t o n s per y ear o f cr it er i a po ll u t a n t s , an d 50 t o n s pery ear o f h azar do us ai r p o llu t a n t s

.
Un der t h e pr o p o s al
, E P A an d t h e Vi r g i n i a Depar t m e n t o f E n v i r o nm en t a l

Sect o r No t e b o o k Pr o j ect 137 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s
Q u a l it y ( V A D E Q ) w ill a d o p t t h e P r e v e n t i o n o f S i g n ific a n t D e t e r i o r a t io n ( PSD) per m it t h r o ugh di f f e r e nt m ech an i s m s un der t h ei r r e s p ect i v e j u r i s d i c t i o n s

. E P A pl an s t o pr o m ul gat e a s it e

- s peci f i c r u l e ma ki n g i n o r der t o
ma k e a d j u s t me n t s t o c u r r e n t a p p lic ab le r e g u l a t io n s t o a llo w fo r t h e fle x ib le

o p e r a t io n o f t h e p e r mit

. T h e V i r g in ia S t a t e A i r P o llu t i o n C o n t r o l B o a r d w ill pr o m ul gat e a v a r i an ce t o ma ke t h e P S D per m it l e gall y

en f o r ceab l e un der st at e l a ws. T h ese pr o p o s ed act i o n s an d t h e dr af t per m it wer e sub j ect t o pub l i c
c o mm e n t a n d it is e x p e c t e d t h a t t h e p e r mit w ill b e is s u e d t o M e r c k d u r in g 1997.

F o r addit i o n al i n f o r mat i o n r e gar d i n g XLpr o j ect s , i n c l udi n g appl i cat i o n pr o cedur es an d cr it e r i a , s e e t h e M a y 23, 1995 F e der a l R e gi s t er No t i ce. ( C o n t act: F a x

- on

- D e m a

n d Ho t l i n e 202- 260- 8590, W e b : h t t p ://www. epa. go v / P r o j ect XL
, o r Ch r i st o p h e rK n o p es at E P A ’ s Of f i ce o f P o l i c y , P l an n i n g an d E v al uat i o n 202- 260- 9298)

C limate W i s e P r ogr am

C lima t e W i s e is h e lp in g U S in d u s t r ie s t u r n e n e r g y e ffic i e n c y a n d p o llu t i o n pr ev en t i o n i n t o a co r p o r at e as s e t

. Suppo r t ed b y t h e t ech n i cal as s i s t an ce, fin a n c in g in fo r ma t io n a n d p u b lic r e c o g n it io n t h a t C lima t e W i s e o f f e r s , p a r t ic ip a t in g c o mp a n ie s a r e d e v e lo p i n g a n d la u n c h in g c o mp r e h e n s iv e i n dust r i a l en er gy ef f i ci en cy an d po ll u t i o n pr ev en t i o n act i o n p l an s t h at sav e
m

o n e y an d pr o t ect t h e en v i r o n m en t

. T h e n ear l y

300 C lima t e W i s e c o mp a n ie s
ex pect t o s a v e m o r e t h an $300 millio n a n d r e d u c e g r e e n h o u s e g a s e mis s i o n s by 1 8 millio n m e t r i c t o ns o f c a r bo n d i o x i d e e q u i va l e nt by t h e y e a r 2000. S o m e o f t h e act i o n s co m p an i e s ar e un der t aki n g t o ach i e v e t h ese r e s u l t s in c l u d e : p r o c e s s imp r o v e me n t s , b o ile r a n d s t e a m s y s t e m o p t imiz a t io n , a i r
co m p r e sso r sy st em i m p r o v e m e n t s, f u el swit ch i n g, an d wast e h eat r eco v e r y
me a s u r e s in c l u d i n g c o g e n e r a t i o n

. C r e a t e d a s p a r t o f t h e P r e s id e n t ’ s C lima t e C h a n g e A c t i o n P l a n , C lima t e W i s e is jo in t l y o p e r a t e d b y t h e D e p a r t me n t o f E n er gy an d E P A

. Un dert h e P l an ma n y o t h e r pr o g r a m s wer e al so l a un ch ed

o r upgr aded in cl udin g Gr een L i gh t s , W a s t eW i $ e an d Do E ’ s M o t o r C h all e n g e P r o g r a m

. C l ima t e W i s e p r o v id e s a n u m b r e lla fo r t h e s e p r o g r a ms w h ic h

en co ur age co m p an y par t i c i p at i o n by p r o v i d in g i n f o r mat i o n o n t h e r a n g e o f par t n e r s h i p o ppo r t un i t i e s av ai l ab l e. ( C o n t act : Pam e l a Her man , E P A
, 202- 260- 4407 o r J a n Ver n et , Do E
, 202- 586- 4755)

En er gy Star B u ildings P r ogr am

EPA ’ s E NE RG Y S TA R B u ild in g s P r o g r a m is a

v o lu n t a r y, p r o f it

- b a s e d p r o g r a m desi gn ed t o i m p r o v e t h e en er gy

- e f f i ci enc y i n co m m

e r c i a l an d i n dust r i a l b u i l d i n gs

. E x pan d in g t h e s u cces s f ul

Gr een L i gh t s Pr o g r a m , E NE RG Y S TA R B u i l d i n g s w a s l a un ch ed i n 1995. T h i s pr o g r a m r e l i e s o n a 5- s t age s t r a t e gy d e s i g n e d t o ma x imiz e e n e r g y s a v i n g s t h e r e b y lo w e r in g e n e r g y b ills
, imp r o v i n g
o ccupan t co m f o r t , an d pr ev en t in g po ll u t i o n - - all at t h e sam e t i m e

. I f

Sect o r No t e b o o k Pr o j ect 138 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s imp le me n t e d in e v e r y c o mme r c ia l a n d in d u s t r ia l b u ild in g in t h e U n it e d S t a t e s , E NE RG Y S TA R B u ild in g s c o u l d c u t t h e n a t i o n ’ s e n e r g y b ill b y u p t o $25 b illio n
a n d p r e v en t up t o 35% o f car b o n di o x i d e em i s s i o n s

. ( T h i s i s equi v a l e n t t o t a k i n g 6 0 millio n c a r s o f t h e r o a d )

. E NE RG Y S TA R B u ild in g s p a r t ic ip a n t s i n cl ud e co r p o r at i o n s ; small an d m e di um si zed b u si n e sses; l o cal
, f e der a l an d st at e go v e r n m e n t s; n o n

- pr o f it gr o ups; sch o o l s; u n i v er sit i es; an d h eal t h

car e f aci l it i e s

. E P A pr o v i d es t ech n i cal an d n o n

- t ech n i cal s uppo r t i n cl udi n g
so f t war e , wo r k s h o p s , ma n u al s, co m m

u n i cat i o n t o o l s, an d an i n f o r mat i o n h o t l i n e. E P A ’ s Of f i ce o f A i r an d Radi at i o n ma n a ges t h e o p er at i o n o f t h e E NE RG Y S TA R Bui l d i n gs P r o g r a m

. ( C o n t act : Gr een L i gh t / E n er gy S t ar Hot l i ne at 1- 888- ST A R

- Y E S o r M a r i a T i ko f f Var g as , E P A Pr o g r a m Di r ect o r at 202- 233- 9178 o r v i s it t h e E NE RG Y S TA R B u ild in g s P r o g r a m w e b s it e a t h t t p ://www. epa. go v / appds t a r / b u i l d i n gs /)

Gr een Lights P r ogr am

E P A ’ s Gr een L i gh t s pr o g r a m was in it i a t e d i n 1991 a n d has t h e go al o f pr ev en t i n g po l l u t i o n b y en co ur agi n g U. S

. i n st it ut i o n s t o use en er gy

- e f f i ci en t l i g h t in g t e c hno l o g i e s

. T h e p r o g r a m s a ve s m o ne y f o r bu s i ne s s e s a n d

o r g a n i zat i o n s an d cr eat es a cl ean er en v i r o n m en t b y r e ducin g po ll u t a n t s
r e l eas ed in t o t h e at m o s p h e r e

. T h e pr o g r a m h a s o v er 2, 345 par t i c i p an t s wh i c h in c l u d e ma jo r c o r p o r a t io n s , s ma ll a n d me d i u m s i z e d b u s i n e s s e s , fe d e r a l, s t a t e
an d l o cal go v e r n m e nt s , n o n

- pr o f i t gr o ups , s c h o o l s , un i v er s it i es , an d h eal t h

c a r e fa c ilit i e s

. E a c h p a r t ic ip a n t is r e q u i r e d t o s u r v e y t h e i r fa c ilit ie s a n d upgr ade l i g h t i n g wh er ev er it i s pr o f it ab l e

. A s o f M a r c h 1997, par t i c i p an t s h a d lo w e r e d t h e i r e l e c t r i c b ills b y $289 millio n a n n u a lly. E P A p r o v id e s t e c h n i c a l

as s i s t an ce t o t h e par t i c i p an t s t h r o ugh a deci s i o n s uppo r t s o f t war e package,

wo r k sh o p s an d ma n u al s, an d an i n f o r mat i o n h o t l i n e. E P A ’ s Of f i ce o f A i r an d Radi at i o n i s r e spo n si b l e f o r o p er at i n g t h e Gr een L i gh t s P r o g r a m

. ( C o n t act : Gr een L i gh t / E n e r g y S t ar Ho t l i n e at 1- 888- ST A R YE S o r M a r i a T i ko f f Var g ar , E P A Pr o g r a m Di r ect o r , at 202- 233- 9178 t h e )

W

a s t eW i$e P r ogr am

T h e W a s t eW i $ e Pr o g r a m was s t ar t e d i n 1994 b y E P A ’ s Of f i ce o f So l i d W a s t e
a n d E m e r g e n c y R e s p o n s e

. T h e p r o g r a m is a ime d a t r e d u c in g mu n i c i p a l s o lid wast es b y p r o m o t i n g wast e pr ev en t i o n , r ecy cl in g co ll ect i o n an d t h e
ma n u f act ur i n g an d pur ch as e o f r ecy cl ed pr o duct s

. A s o f 1997, t h e pr o g r a m h a d ab o u t 500 co m p an i e s as m e m b er s , o n e t h i r d o f wh o m ar e F o r t un e 1000

co r p o r at i o n s

. Mem b er s agr ee t o i d en t i f y a n d i m p l e m e n t act i o n s t o r e duce t h e i r s o l i d was t es s e t t in g was t e r e duct i o n go al s an d pr o v i d i n g E P A wi t h ye a r ly p r o g r e s s r e p o r t s

. T o me mb e r c o mp a n ie s , E P A
, in t u r n , p r o v id e s t ech n i cal assi st an ce, pub l i cat i o n s , n e t w o r ki n g o ppo r t un it i e s, an d n a t i o n al an d

r e gi o n al r eco gn it i o n

. ( C o n t act : W a s t eW i $ e Ho t l i n e at 1- 800- 372- 9473 o r J o an n e Ox l e y , E P A Pr o g r a m M a n a ger , 703- 308- 0199)

Sect o r No t e b o o k Pr o j ect 139 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

NI CE 3

T h e U

. S

. D e p a r t me n t o f E n e r g y is

a d min is t e r in g a g r a n t p r o g r a m c a lle d T h e Nat i o n a l I n dust r i a l Co m p et it i v en ess t h r o ugh E n er gy , E n v i r o n m en t , an d Ec o n o m i c s (N IC E 3 )

. B y pr o v i d i n g gr an t s o f up t o 45 per cen t o f t h e t o t a l pr o j ect co st , t h e pr o g r a m en co ur ages i n dust r y t o r e duce i n dust r i a l wast e at it s so ur ce an d b eco m e m o r e en er gy

- e f f i c i en t an d co st

- c o m pet it i v e t h r o ugh wast e m i n i m i zat i o n ef f o r t s. Gr an t s ar e used b y i n dust r y t o desi gn , t e st , an d dem o n s t r at e n e w pr o ces s e s an d/ o r e qui pm en t wit h t h e po t e n t i a l t o r e duce p o l l u t i o n an d i n cr ease en er gy ef f i ci en cy

. T h e pr o g r a m i s o p en t o a l l in d u s t r ie s ; h o w e v e r , p r io r it y is g i v e n t o p r o p o s a l s fr o m p a r t ic ip a n t s in t h e f o r e st pr o duct s , ch em i cal s, pet r o l eum r e f i n i n g , st eel
, al um in um , m e t a l cast in g
an d gl as s ma n u f act ur i n g s ect o r s

. ( C o n t act : h t t p //www. o it

. do e. go v / acces s /

n i ce3, C h r i s Si f r i
, DOE
, 303- 275- 4723 o r E r i c Has s , DOE
, 303- 275- 4728)

Des i gn f o r the En vir onment ( D

f

E)

D f E is w o r k in g w it h s e v e r a l i n d u s t r ie s t o id e n t i fy c o s t

- e ffe c t iv e p o llu t i o n pr ev en t i o n st r a t e gi es t h at r e duce r i sks t o wo r k er s an d t h e en v i r o n m en t

. Df E he l p s b u si n e sses co m p ar e an d ev al uat e t h e per f o r ma n ce, co st , po ll u t i o n pr ev en t i o n b e n e f it s , an d hu ma n h eal t h

an d en v i r o n m en t a l r i sks asso c i at ed wit h

ex i s t i n g an d al t e r n at i v e t ech n o l o gi es. T h e go al o f t h e s e pr o j ect s i s t o
en co ur age busi n esses t o co n s i d er an d use cl ean er pr o duct s , pr o cesses, an d t ech n o l o gi es

. F o r m o r e i n f o r mat i o n ab o u t t h e Df E Pr o g r a m , call ( 202) 260- 1678. T o o b t a i n co pi es o f Df E ma t e r i al s o r f o r gen e r a l i n f o r m at i o n ab o u t Df E
, co n t act E P A ’ s Po ll u t i o n Pr ev en t i o n I n f o r mat i o n C l ear i n gh o u s e at ( 202) 260- 1023 o r v i s it t h e Df E W e b s it e at h t t p ://es

. i n el

. g o v /df e

.

V III. C

. Tr a d e A sso ci a t i o n / I ndus try Spons or e d A c tivity

V III. C

. 1

. En v i r o n m en t a l Pr o g r a m s

T h e P h ar maceut i ca l s Resear ch an d Man u f act ur er s o f A m er i ca ( P h R MA )

c o o r di n a t e s t h e r e sear ch

- b ased ph ar maceut i cal i n dust r y ’ s r e spo n se t o i n dust r y

- speci f i c en v i r o n m en t a l i ssues, such as t h e ph ar maceut i cal MA CT

. P h RMA wo r k s t h r o ugh an en v i r o n m en t a l co m m

it t ee, a ser i es o f sub c o m m

it t ees r e spo n si b l e f o r r e gul at o r y ar eas such as wat e r an d ai r , an d ad h o c wo r k gr o ups t o addr es s n a r r o wl y

- f o cus e d i s s u es

.
T h e r e sear ch

- b ased ph ar maceut i cal i n dust r y al so r e l i e s o n o t h e rb r o a d- b a sed t r ade asso c i a t i o n s f o r

i ssues t h at af f ect t h e l a r g er b u si n e ss co m m

u n i t y

. S e v e r a l o f t h e P h RMA m e m b er s ar e al so m e m b er s o f t h e Ch em i c a l Manu f act ur er s A sso ci at i o n ( C MA ) an d t h er ef o r e ar e par t o f CMA ’ s Resp o n si b l e Car e ® I n i t i a t i v e

.

Sect o r No t e b o o k Pr o j ect 140 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

I n

addit i o n , ma n y ph ar maceut i ca l c o m p an i e s h a v e b een i m p l e m e n t i n g t h ei r
o w n en v i r o n m en t a l pr o g r a m s an d i n it i a t i v e s t o r e duce t h e envi r o n m en t a l i m p act s o f t h ei r pr o duct s an d ma n u f act ur i n g pr o cesses. T h ese pr o g r a m s ar e b o t h c o mp a n y- w i d e a n d a t t h e fa c ilit y l e v e l

. M o r e in fo r ma t io n o n s u c h p r o g r a ms c a n b e o b t a in e d b y c o n t a c t in g in d i v i d u a l c o mp a n ie s a n d fa c ilit ie s

.

Sect o r No t e b o o k Pr o j ect 141 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

V III. C

. 2

. S u mma ry o f Tr a d e A sso ci a t i o n s

P h ar maceut i cal Resear ch an d Man u f act ur er s
o f

A m er i ca ( P h R MA ) 1100 15t h St r eet , NW W a s h i n gt o n , D. C

. 20035 Ph o n e: ( 202) 835- 3400 F a x : ( 202) 835- 3414 B udget : $20, 000, 000 S t a ff: 8 0 Mem b er s: 40 co m p an i e s A ffilia t e s : 3 0 c o mp a n ie s

T h e

P h ar maceut i cal Resear ch an d Man u f act ur er s o f A m er i ca ( P h R MA ) i s a n o n

- pr o f it

o r gan i zat i o n wh i c h was es t ab l i s h e d i n 1958. I t s ma i n f

u n c t i o n i s t o as s i s t r e s ear ch

b a sed ph ar m aceut i cal co m p an i e s i n di sco v er y , dev e l o pm en t , a n d m a r k et i n g o f n e w dr ugs f o rhu ma n s

. Co m p r i sed o f m o st o f t h e l a r g est ph ar maceut i cal co m p an i e s i n t h e Un it ed S t at es, P h RMA m e m b er s ar e pr i ma r i l y

en gaged i n r e sear ch an d dev e l o pm en t

o f

n e w m e di ci n e s. T o b e a m e m b ero f P h RMA
, a co m p an y m u st b e h eav i l y

in v o lv ed i n

r e sear ch an d dev e l o pm en t ( R & D ) an d m u st al so ma n u f act ur e an d ma r k et f i n i sh ed do s a ge- f o r m dr ugs un der t h ei r o w n b r an d n a m e

. Ph R M A m e m b er co m p an i e s in v e s t

n ear l y

$19 b illio n a

ye a r in d i s c o v e r in g a n d d e v e lo p i n g n e w d r u g s

. A d d it i o n a lly, P h RMA m e m b er s acco un t f o r appr o x ima t e l y

90% o f t o t a l ph ar maceut i cal sal e s i n t h e Un it ed S t at es.

Gen e r i c P h ar maceut i cal I n dust r y A sso ci at i o n 1620 I St r eet , NW W a s h i n gt o n , D. C

. 20006- 4005 Ph o n e: ( 202) 833- 9070 F a x : ( 202) 833- 9612

T h e Gen e r i c P h ar maceut i cal I n dust r y A sso ci at i o n B udget : $1- 2, 000, 000 S t a ff: 6 Mem b er s: 46 co m p an i e s

( G P I A ) i s a pr i ma r y t r ade

asso ci at i o n f o r ma n u f act ur er s an d di st r i b u t o r s o f gen e r i c dr ugs. I t s ma i n pub l i cat i o n i s “ G P I A News ”.

Nat i o n al P h ar maceut i cal A llia n c e (N PA ) 421 K i n g St r eet , Suit e 222, A l ex an dr i a , VA 22314 Ph o n e: ( 703) 836- 8816 B udget : $250- 500, 000 F a x : ( 703) 549- 4749 M e m b er s : 165 co m p an i e s

T h e Nat i o n al P h ar maceut i cal A llia n c e ( N P A ) is a n o r g a n i z a t io n w h ic h r e p r e s e n t s t h e i n t e r e st s o f small ph ar maceut i cal co m p an i e s an d a llie d in d u s t r ie s

. M e mb e r s o f N P A dev e l o p b i o e qui v a l e n t v e r s i o n s o f ma j o r b r an ded pr o duct s , cr eat e pr o duct s o f al

t e r n at i v e co m b i n at i o n s , st r e n g t h s, an d/ o r do sage f o r m s, an d ma r k et pr o duct s wh i c h

ar e n o t pr o duced b y l a r g er co m p an i e s an d wh i c h wo ul d n o t b e av ai l ab l e t o t h e pub l i c

Sect o r No t e b o o k Pr o j ect 142 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

o t h e r w i s e. NP A assi st s i n m eet in g t h ese go al s f o rit s m e m b er co m p an i e s. NP A al so p u b lis h e s a

b i

- m o n t h ly jo u r n a l c a lle d “ N P A & N e w s , W a s h in g t o n R e p o r t

. ”

A m er i can P h ar maceut i cal A sso ci at i o n (A Ph A ) 2215 C o n s t it u t i o n A v e. NW W a s h i n gt o n , DC 20037 Ph o n e: ( 202) 628- 4410 B udget : $12, 000, 000 F a x : ( 202) 783- 2351 M e m b er s : 44, 000

T h e A m er i c an P h ar maceut i cal A sso ci at i o n ( A P h A ) i s a pr o f essi o n al so ci et y t h at i n cl udes ph ar maci st s i n all pr act i ce set t i n g s, educat o r s, st uden t s, r e sear ch er s, edit o r s
an d pub l i s h e r s o f ph ar maceut i cal l

i t er at ur e, ph ar maceut i cal ch em i s t s an d sci e n t i s t s , an d f o o d an d dr ug o f f i ci al s. A P h A pr o m o t es qual it y h eal t h

car e an d co m p r e h e n s i v e ph ar maceut i cal car e t h r o ugh t h e appr o p r i at e use o f ph ar macy ser v i ces. A P h A wo r k s t o : r e pr esen t t h e i n t e r e st s o f t h e pr o f essi o n b e f o r e go v e r n m e n t al b o di es; i n t e r p r e t s an d di ssem i n at es i n f o r mat i o n o n dev e l o pm en t s in h eal t h

car e; an d assur e qual it y ph ar macy
ser v i ces an d pat i en t car e. A P h A f

o st er s pr o f essi o n al edu c a t i o n an d t r ai n i n g o f p h a r ma c i s t s ; s uppo r t s th e A c a d e m y

of P h a r maceut i cal Resear ch an d S c i e n ce, t h e A cadem y

o f P h ar macy P r act i ce an d Man a gem e n t , an d t h e A cadem y o f S t uden t s o f P h ar m a c y

. A P h A al so pub l i s h e s a quar t er l y

n e wsl e t t e r , A c ademy R e por ter , a n d

mo n t h l y jo u r n a ls in c l u d i n g , A m e r ican P har macy ( Jour nal of the A m er ican P har maceutical A s s o ciation ) an d Jour nal of P har maceutical Sciences

.

Un it ed S t at es P h ar maco pei a l C o nve nt i o n ( U S P ) 12601 T w i n b r o o k Pky

. R o c k v ille
, M D 20852 Ph o n e: ( 301) 881- 0666 B udget : $20, 000, 000 Mem b er s: 3 9 5 F a x : ( 301) 816- 8247

T h e Un it ed S t at es P h ar maco pei a l Co n v e n t i o n ( U S P ) i s a r eco gn i zed aut h o r it y i n
me d i c i n e , p h a r ma c y , a n d a llie d s c ie n c e s

. U S P r e v i s e s a n d p u b lis h e s le g a lly

r eco gn i zed co m p en di a o f dr ug st an dar d s i n cl udi n g t h e N a tional F o r m ular y

.

Sect o r No t e b o o k Pr o j ect 143 Sept em b e r 1997P h arm a c e u tic a l I ndus try A c t ivitie s and I n itiative s

Nat i o n al A sso ci at i o n o f P h ar maceut i cal Man u f act ur er s ( N A P M) 320 Ol d C o un t r y R o ad - Suit e 205 Gar d en C it y , NY 11530 Ph o n e: ( 516) 741- 3699 F a x : ( 516) 741- 3696

N o n p r e scr i p t i o n D r u g Man u f act u r er s A sso ci at i o n 1150 C o n n ect i c ut A v en ue, NW W a s h i n gt o n , DC 20036 Ph o n e: ( 202) 429- 9260 F a x : ( 202) 223- 6835

Nat i o n al W h o l es al e Dr uggi s t ’ s A s s o ci at i o n 1821 M i ch ael F ar a day Dr i v e Sui t e 400 R e s t o n , VA 22090 Ph o n e: ( 703) 787- 0000 ex t

. 240 F a x : ( 703) 787- 6930

Sect o r No t e b o o k Pr o j ect 144 Sept em b e r 1997P h arm a c e u tic a l I ndus try C ontac t s and R e f e r e nc e s

I X

. CONTACTS / ACK NOWLEDGM ENTS /REF ERENCES

F o rf u r t h e ri n f o r mat i o n o n sel ect ed t o pi cs wi t h i n t h e ph ar maceut i cal i n dust r y a l i s t o f pub l i cat i o n s an d co n t act s ar e pr o v i d ed b e l o w:

Con t act s a

N a m e Or ganiz ation T e l e phone Subje c t E m ily C how EP A / OEC A ( 202) 564- 7071 C h e m i c a l I n d u str y B r a n c h
, R e g u l a t o ry re q u i r e m e n t s an d

c o m p l i a n c e a ssi sta n c e Jo a n n e B e r ma n EP A / OEC A ( 202) 564- 7064 C h e m i c a l I n d u str y B r a n c h
, R e g u l a t o ry re q u i r e m e n t s an d

c o m p l i a n c e a ssi sta n c e F r a n k

Hun d EP A / OW ( 202) 260- 7182 R e g u l a to r y R e q u i r e m e n ts ( C W A )
R a ndy M c D ona ld E P A/ O A ( 919) 541- 5402 R e g u l a to r y R e q u i r e m e n ts ( C A A )
U m e s h Dh o l a k i a EP A R e g i o n I I ( 212) 637- 4023 R e g u l a to r y R e q u i r e m e n ts ( C A A )
N a nc y S a ge r F D A

- C e nt e r f

o r

D r u g E v al u a t i o n an d Re se ar c h ( 301) 594- 5629 I n f o r ma t i o n o n Huma n Dr ug s

D a nie l K e a r ns F D A - C e nt e r f

o r B i ologic s E v a l u a t i on
a nd R e s e a r c h ( 301) 827- 3031 I n f o r ma t i o n o n B i o l o g i c s

C h a r l e s E. Ei r k so n , III F D A - C e n t e r fo r Vet e r i na r y M e dic i ne ( 301) 594- 1683 I n f o r ma t i o n o n V ete r i n a r y M e dic i ne M e rv i n P a rk e

r F D A - C e n t e r f o r De v i ce s a n d R a diologic a l H e a l t h ( 301) 594- 2186 I n f o r ma t i o n o n m e d i c a l d e v i c e s
a nd r a diologic a l he a l t h

B u zz L. Ho ffma n F D A - C e n t e r fo r F ood S a f et y a n d A

p p lie d N u t r it ion ( 202) 418- 3005 I n f o r ma t i o n o n f

oods

T o m W h i t e P h R MA ( 202) 835- 3546 En v i r o n m e n ta l A f f a i r s C AA: C l e a n Ai r Ac t CW A : Cl ean W a t e r A c t OE CA : Of f i ce o f E n f o r cem en t an d Co m p l

i a n ce A ssur a n c e OA : Of f i ce o f A i r OW : Of f i ce o f W a t e r F D A : F o o d a n d D r u g A d min is t r a t io n P h RMA : P h ar maceut i cal Resear ch an d Man u f act ur er s o f A m er i c a

a M a n y of t h e c o n t a c t s l i s t e d a bove h a ve p r ovi d e d va l u a b l e ba c k g r ou n d i n for matio n an d c o mme n t s d u r in g de v e lo pme n t o f th is do c u me n t

. EP A appr e c iate s th is s uppo r t an d ac kn o w le dge s th at th e in div i duals lis te d do n o t

n e c e s s a r ily e n d o r s e all s tate me n t s mad e w ith in th is n o tebook

.

Sect o r No t e b o o k Pr o j ect 145 Sept em b e r 1997P h arm a c e u tic a l I ndus try C ontac t s and R e f e r e nc e s

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s f o r Dr ugs , I ndus tr y Ser i es , U S Depar t m e n t of C o m m

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