genzyme allston 483 11-20-09 purged(3)

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DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATION

DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

1 Montvale Ave Stoneham, MA 02180 781-596-7700 10/8/09 - 11/13/09

FEI NUMBER

1000305672

NAME AND TITLE OF INDIVIDUAL TO \lVHOM REPORT IS ISSUED

TO: Henri A. Termeer, Chairman, Pr es id en t , and CEOFIRM NAME STREET ADDRESS

Genzyme Corpora t ion 500 Sold ier s Field Road

CITY. STATEANo ZIP CODE TYPE OF ESTABLISHMENT INSPECTED

A l l s to n , MA 02134 Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE{S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE lNSPECTIONAL

OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE . IF YOU HAVe AN OBJECTION REGARDING AN

OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS THE

OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE{S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY QUESTIONS. PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM-tij'(WE) OBSERVED:

1. The Vice Pres iden t of Quali ty Operations US Therapeut ics conf i rms t h e r e is no

es tabl ished s t andard opera t ing procedure to desc r ibe the per iod ic review! and the conten t s

of the revievJ, of devia t ions and i nves t iga t ions performed by the Qual i ty Unit. The Quali ty

Unit per forms i n d iv id u a l rev iews and a p p r o v a l . However! t h e r e i s no o v e ra l l assessment of

th e dev ia t ions and inves t iga t ions with r e s p ec t to t h e i r impact on the manufactur ing

o p er a t i o n s and Quali ty Controls to p r e v e n t t h e i r reoccur rence .

• For example , the firm has rece ived many Product Event Intake Repor t s for the presence of

p a r t i c l e s in the f inished drug product . In the inves t iga t ion i n to th e source of the

p a r t i c l e s in the drug produc t has found the following types o f p a r t i c l e s : meta l

p a r t i c u l a t e s ! colored an d t r an s p a r en t f i b e r s (cot ton and p o l y es t e r ) , rubber l i ke pa r t i c l e s !

and g l a s s p a r t i c l e s . The f irm has not completely ident i f ied the source o f a l l fo re ign

mat t e r contaminants or implemented cor r ec t ive measures to reduce the fo re ign mat t e r in

f ina l drug product .

2. There i s a f a i lu r e to thoroughly review the f a i lu r e o f a batch o r any o f its components

to meet any of its s p ec i f i ca t i o n s whether o r not the batch has been already di s t r ibu ted .

Sp ec i f i ca l l y !

a. In v es t i g a t i o n s in to meta l p a r t i c l e contaminat ion in f i n i s h ed drug produc t concluded

equipment used in the asept ic f i l l process sheds meta l p a r t i c u l a t e s i n t o v i a l s before drug

product i s f i l l ed based on the equipment des ign and intended use . The equipment i s used

for f i l l i ng o f Myozyme! Fabrazyme, Cerezyme! and Thyrogen. Your follow up to th is

conc lus ion i s inadequate because it f a i l s to address preve nt ion contaminat ion before long.

term cor r ec t ive ac t io n s a re implemented in 2010 an d 2011., ' - .

f (\

SEE / DATE ISSUED~ L O Y E E ( S ) S I G N A T U ~ E . I', r f fkOYEE{S) NAME A N D ~ or Type)REVERSE _ ~ . ~ ~ ~ < " ' l - < \ V - " ' ) \-\,0 1Jv-J\':3> ~ " \" , \N....-.J,OF THIS

Debra Emerson, I nves t iga to r 11/13/2009PAGE ~ - " ' " ' : ~

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(b) (4)(b) (4)

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION


1 Montvale Ave Stoneham I MA 02180 781-596 -7700 10 / 8 / 09 - 11 /13 /09

FEI NUMBER

1000305672

NM'lE AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

TO : Henri A. Termeer, Chairman, President , and CEO

FIRM NAME

Genzyme Corporation

CITY, STATE AND ZIP CODE

Alls ton , MA 02134

STREET ADDRESS

500 Soldiers Field Road

TYPE OF ESTABLISHMENT INSPECTED

Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MAOE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONALOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN

OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THE

OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTlON. OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

(b) (4

DURING AN INSPECTION OF YOUR F I ~ ~ P ( W E ) OBSERVED:

b. Inves t iga t ions into part icu late matter in f in ished drug product fai led to ident i fy

c o r r e c t iv e ac t ions for def ic ienc ies noted in your f irm/s v i su a l inspec t ion process us ing the

at a rate of ,I I V i a l S ~ For example, i n ve s t i ga t i on noted dif f erences

e ween your inspect ion method an e me t od used by Genzyme Japan which inc lude pacing l

l igh t source , the distance of examinat ion and that p ar t i c l e s found by the secondary

inspect ion were approximately than those detected using your current

(b) (4)

(b) (4)

method. On multiple occasions, fore ign matter has been found during Genzyme Japan's v i s u a l

inspect ion o f f in ished drug product which has been prev ious ly v i su a l ly inspected an d

(b) (4)

which you have ident i f ied as

re leased by your firm.

3, Equipment used in th e manufacture processing l packing or holding of drug products i s not

of appropriate design to fac i l i ta te operations for i t s intended use, Specifical ly,

• Your firm i s using v i a l pans used in the depyrogenation process of drug product v i a l s

a source o f metal p ar t i c l e contamination in f inished drugproduct because of metal-on-metal contact with the trays and prep components such a meta l

basel l id , or r ing .

• Your firm upgraded the refr igerat ion skid which i s used to run the lyophil izer in January

2003 . This included the repla an d computer upgrades. There are II1IIyophi l i zer . Th e Operational Qual i f ica t ion

performed on the system did not inc lude funct ional t e s t s fo r a l l c r i t i c a l s teps . There was

an error in one o f the bi ts for compressor .. . This b it was entered as

s t ar t compressor #1 condenser coo l in ' and th e b it should have been entered as

-. Due to th i s error ,

there was an issue on 5 / 15 / 07 during the lyophil izer cycle for Cerezyme lo t A7034 which did

not allow the compressor to c yc l e o f f an d required manual in tervent ion .

• The f i l l ing l in e has been in place an d in use s ince 1994 , The f i l l ing

l i ne has not been cal ibrated for l i ne speed, stopper bowl. speed, or volumetric control .

(\.

DATE ISSUEDREVERSE ,

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Debra Erne , I n v e s t i g a t o r 11 / 13 / 2009AGE I ~ . . . " " " ' FORM FDA 483 (4103) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS P A G E ~ O F * P A G E S



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conducted by





FEl NUMBER

1000305672

TO: Henri A. Termeer, Chairman, President, and CEOFiRMNMAE STREET ADDRESS

NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

500 Sold iers Field Road

(b) (4)

Genzyme Corporat.:i.on

eln'. STATE AND ZIP CODE. TYPE OF ESTABLISHMENT INSPECTED

Alls ton, MA 02134 Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL

OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN

OBSERVATION. OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS THE

OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF


DURING AN INSPECTION OF YOUR FIRM;t{(WE)OBSERVED:

4. Control procedures are not

(b) (4)

established which monitor the output or val idate the

performance of those manufacturing processes that may be responsible for causing variabi l i tyin the character ist ics of in-process material and the drug product. Speci f ica l ly ,

• Validat ion of the f i l l process for low volume products i s inadequate in that fu l l s ize

val idat ion runs have not been executed since process and equipment parameter changes have

been implemented to prevent low f i l l volumes.

• The 100% visual inspection conducted by your ! irm on a ll f inished drug products i s cannot

r e l i ab ly de tec t and r e j ec t v i a l s conta in ing fore ign mat ter including, but not l imi ted to

metal par t ic le s . F o example, on multiple occas ions released drug product ha s been rejected

and returned af ter a second 100% inspect ion, a consignee. Your investigation

noted di f ferences in the inspection methods including pacing, l ight source, the distance of

examination and that part ic les found by the secondary . inspection were approximately . . . . .

" l I l I l I l I l I l I l I l I th a n those detected using you current method.

• The f i l l he ight vi sua l inspec t ion conducted on 100% of f inished product

i s cannot re l iably assure out of speci f i cat ion low volume drug products are rejected. Your

f i rm concluded t ha t the inspect ion can only re l iabl .y detec t fill volumes ifolume

products such as Fabrazyme Smg and Thyrogen. Furthermore,

inspec t ion i s capable of detec t ing a fill he ight di f fe rence of

difference o f l l l l l l l r a 1 1 s outside the -potency range for low volume products.

5. Routine ca l ibrat ion of mechanical and electronic equipment i s not performed according to

a written program designed to assure proper performance.

• Speci f i ca l l .y , a wri t ten program has not been es tabl i shed for ca l ib ra t ion of the proper

performance of thelllllllllfill equipment. The fill equipment has been in place an d

in use s ince 1994 and used fo r f i l l i ng of drug products inc luding , Myozyme, Fabrazyme,Cerezyme, and Thyrogen. The equipment ha s not been calibrated for fill volume or speed.

the

but a

your firm concluded

SEE PLOYEE(S) SIGNATURE EMP OYEE(S) NAME A N : l \ ~ Y } : : ; : n l q; Typol DATE ISSUED

REVERSE \ ) ' \1 \ / , / /0- ' J - ' - ' - ~ " \ """"'" c::> , \1/'-.VF THIS ' : - - : . . - - ,~ "' . • Debra Emerson, InvesEigator 11/13/2009PAGE

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPJ:CTIONAL OBSERVATioNSPAGE+ -OF#PAGES



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FOOD AND DRUG ADMINISTRATlON

DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S)OF INSPECTION

1 Montvale Ave Stoneham, MA 02180 781-596-7700 10/B/09 - 11/13/09

FEI NUMBER

1000305672


TO: Henr i A. Termeer, Chairman, Pres iden t , an d CEOFIRM NAME

Genzyme Corpora t ion

CITY. STATE AND ZIP CODE

Alls ton , MA 02134

STREET ADDRESS

50 0 Sold iers Fie ld Road


Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL

OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGAR.DlNG AN

OBSERVATION. OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTiON IN RESPONSE TO AN OBSER.VATION, YOU MAY DISCUSS THE

OBJECTION OR ACTION WITH T H FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY au ESTlONS, PLEASE CONTACT FDA AT TH E PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR Fl RM %<WE) OBSERVED:

6. No appropr ia te inves t iga t ion was conducted when a re tu rned drug product appeared to

impl ica te assoc ia ted batches of drug products . Spec i f i ca l ly ,

• I nves t iga t ions a re inadequate in t h a t they do in to inc lude evalua t ion o f a l l pe r t inen t

d a t a c o l l e c t i v e l y . For example lo t A90l3 Cerezymel l l l u n i t s p e r v i a l underwent 100%

inspec t ion p r i o r to re lease w i t h l l l v i a l s re jec ted fo r fo re ign mat te r and I11III v ia l s

re leased by your Qual i ty depar tment t h i s r a te did not exceed your i n t e r na l a l e r t l imi t . A

t o t a l o f of these re leased v ia l s underwent a second 100% inspect ion a n d ' " v i a l s were

r e jec ted fo r foreign matter , which equates to a r e jec t r a te of which does exceed your

. i n t e r n a l a l e r t l imi t . By combining th e r e j e c t s from th e pre- re lease 100% inspect ion and the

second 100% inspect ion the t o t a l r e j ec t s r i s es to'" This doesn ' t account fo r the

v i a l s re leased which never underwent a second 100% inspec t ion .

• I nves t iga t ions into returned drug produc t are inadequate in t h a t they are l imi ted to

inves t iga t ion of a product spec i f i c l o t . For example wa s i n i t i a t ed based on re turn

of Cerezymel l l l u n i t s / v i a l l o t A9013 fo r par t i cu la te mat ter . The inves t iga t ion was l imi ted

to the manufactur ing records , t e s t ing and inspect ion records , r e tu r ns , inves t iga t ions , e t c .

r e l a t i n g to only lo t A9013. Your f i rm did not cons ider , as p a r t of the inves t iga t ion , o ther

products which have been r e tu rned fo r p a r t i c u l a t e contaminat ion, or other lo t s which have

been r e t u rn ed fo r pa r t i cu l a t e contaminat ion, or the f requency of re tu rns fo r par t i cu la te

contaminat ion in any product or l o t .

7. Th e ~ C e r t i f i c a t i o n & Re- ce r t i f i c a t ion of the Aseptic Fi l l ing Processes a t Alls ton

Landing", document VP-026-15, i s es t ab l i shed , ~ T prov ide a procedure for describing th e

requirements fo r cer t i fy ing new asep t ic f i l l i n g processes and r e -cer t i fy ing ex i s t ing a sep t i c

f i l l i ng processes ." ~ N o t more than one contaminated v i a l may be detec ted fo r a fill to be

cons idered success fu l . " ' I f more than one contaminated v i a l i s detected, t h i s i s consideredan ~ A c t i o n Level" , which requ i res t h a t an inves t iga t ion be performed, and cor rec t ive ac t ions

t aken before r e - i n i t i a t i n g the c e r t i f i c a t i o n process ." (Note: t h i s document i s app l icab le

fo r a l l media f i l l s used to suppor t th e asep t i c f i l l i n g process of the Cerezyme (NDA #

020367), Fabrazyme, (BLA #103979) and Myozyme (BLA # 125141) f in ished products manufactured

a t th e Alls ton f ac i l i ty ) .

\~ M P L O Y E E ( S ) SIGNATURE \ E M P ~ Y E E ( S ) NAME AND TIl.:E(Ptinl or Type) DATE ISSUEDEE

REVERSE ( --\(\." D \ ( . ~ ' C ' \ t \. Vv'RS;) 1\."0\--:z." \ i\,'ojOF THIS

Debra Emerson, I nves t lga to r 11/13/2009~ " ' 1 ~ 7 . ... .....JAGE

FORM FD A 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS



(b) (4)

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1 Montvale Ave

Stoneham MA 02180

(b) (4)

FEI NUMBER781-596-7700 1000305672

(b) (4)

10/8/09-11/13/09

NAME AND TITLE OF INDNIDUAl TO WHOM REPORT IS ISSUED

TO:Henri A.

Tenneer, Chairman, President, and CEOFIRM NAME

Genzyme CorporationSTREET ADDRESS


TYPE OF ESTABLISHMENT INSPECTEDITY, STATE AND ZIP CODE

(b) (4)

Drug Manufacturerllston, MA 02134

DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED;

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN DISCUSS TOBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THI S INFORMATION TO TO FDA AT THE ADDRESS ABOVIF YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED:

(b) (4)

RESPONSE TO AN OBSERVATION, YOU MAY

(b) (4)

The following table lists media filled batches used in support of the 2008 & 2009 aseptic filling processes prefonned at the Allston

FilllFinish suite. As summarized below not all media filled vials are incubated for the requisite time and temperature, i.e., discardevials absent an assignable cause for their reject ion, which precludes the Quality Unit from confirming that, "The results of the Medi

Fill Qualification were evaluated to determine if the aseptic process met the criteria stated in the protocol" and fl.-om" .. .certifying

new aseptic filling processes and re-cer tifying existing aseptic filling processes".

Media Fill Date of Vial size Vials Number Assignable cause forIncubated ofrejects rejectsill

Study

- •Unknown / unclear

Unknown / unclear

- Unknown /lmdear•- • Unknown / undear

- - Unknown /lmdear

(b) (4)(b) (4)

(b) (4)

(b) (4)

8. The procedure entitled: Certification and Re-certification of the Aseptic Filling Processes at Allston Landing, VP-026-15,

requires operators be involved in a successful media fill to be qualified. Operators are to be re-qualified in a media fill e v e r

_ Operators are to be qualified before they are allowed perform any aseptic filling operations.~ i the fill suite during the fillingofCerezyme lot A7034 on 5/15/07 and forCerezyme lot A7030 on

4/30/07. Ope r a t o . was in the fill suite during the filling of Cerezyme lot A7030 on 4/30107. Operators••••were last qualified during the 1118/06 media fill.

• Operators were in the fill suite during the filling of Thyrogen lot A9053 on 9/9/09 and Thyrogen lot A9054 on

9/15/09. Neither operator has been qualified thru a successful media fill.

EMPLOYEE{S) NAME AND TITLE (Print orType) DATE ISSUEDEE

REVERSE Debra M. Emerson, Investigator 1l/13/09OF THIS

Thomas 1. Arista, InvestigatorPAGE

PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS



(b) (4)

(b



OISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

1 Montvale Ave Stoneham, ~ 02180 781-596-7700 10/8/09 - 11/13/09

FEI NUMBER

1000305672


TO: Henri A. Termeer, Chairman, President , an d CEOFIRM NAME

Genzyme Corporat ion


Alls ton , MA 02134

STREET ADDRESS



Drug Manufacturer




OBJECTION OR ACTION WITH THE FDA REPRESENTATlVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF


DURING AN INSPECTION OF YOUR FIRM%(WE)OBSERVED:

9. Th e ~ A s e p t i c Qual i f ica t ion fo r Personnel t o Pa r t i c ipa t e i n Fil l ing Operat ions", document

#MF-101-07 es t ab l i shes a s tandard prac t ice an d "aprocedure fo r the qua l i f i ca t ion of personnel to ente r the F i l l Finish Core Area during a

f i l l i ng operat ion in l ieu of i n i t i a l

(b) (4)

par t i c ipa t ion in a "due to

the t iming of these media f i l l s an d the hi r ing of new opera to rs

(b) (4)

media fill opera t ion," And,

an a l t e r n a t e , more rigorous

approach wa s developed which would serve to qua l i f y operators to par t i c ipa te in

(b) (4)

s t e r i l e

thepera t ions (non product contact steps) u n t i l th e next scheduled media fill." Despi te

asep t ic fill processing commitments submitted in the NDAs and

(b) (4)

a "more

BLAs, the ~ m o r e r igorous

approach" to asep t i c media fill qua l i f i ca t ion o f personnel i s r igorous scenario than

par t i c ipa t ing in a media f i l l " in support of the asept ic f i l l i n g process has not

submit ted to the Agency fo r p r i o r or post approval change to the app l i ca t ions .

a. Th e Microbiology Manager confirms there i s no document tha t describes the ~ m o r e r igorous

approach" to qual i fy opera to rs to par t i c ipa te in s t e r i l e operat ions .

b. There i s no record to document or describe how the "more r igorous approach" i s comparable

or equiva lent to , and ~ m o r e r igorous" than , asep t ic media fill opera t ions .

10. There i s no record (e .g . , batch product ion an d con t ro l records) to document the actual

number v i a l s t h a t a re asep t ica l ly f i l l ed with microbia l growth medium p r i o r to the

lyoph i l i za t ion process . In add i t ion ,

• Th e lyoph i l i za t ion process t ime fo r rou t ine product ion, dependent on the f in ished product,

can ranges f r o m " o r up to . . 11IIII The l yoph i l i z a t ion process s imulat ion performed

during the media fill i s approximately The Valida t ion Manager confirms there i s

no r a t iona le to suppor t the process simulation when compared to a rout ine

lyoph i l i za t ion process t ime of up to . . 11IIII(b) (4)

been

In addi t ion,

(' .

~ P L O Y E E ( S ) SIGNATl!.RE EMPLOYEE(S) NAME AND TITLE (Print or Trpej DATE ISSUEDEE ,_

REVERSE _ ~ " ~ . . , ~ ~ \ \ ' : \ . ~ , . . , . . , ~ ~ ' i ' \l'\VOF THIS '-.-.::sDebra Emerson, nves t iga tor 11/13/2009

PAGE L,.;... i. . . . . . . . ' ~ . . r > . FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS



(b) (4) (b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)



DISTRICT OFFiCE ADDRESS AND PHONE NUMBER

1 Montvale Ave Stoneham, MA 02180 781-596-7700

DATE(S) OF INSPECTION

10/8/09 - 11/13/09

FEI NUMBER

1000305672


TO: Henri

FIRM NAME

A. Termeer, Chairman/ President , and CEO

STREET ADDRESS

(b) (4)

Genzyme corporation 50 0 Soldie r s Fie ld Road

TYPE OF ESTABLISHMENT INSPECTEDITY. STATE AND ZIP CODE

Drug Manufacturerl l s ton, MA 02134

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE{S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAl

OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATlON REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN

OBSERVATION, OR HAVE IMPLEMENTED, OR PlAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS THE

OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDAATTHE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR F I R ~ y f f ( W E ) OBSERVED:

11. The Thyrogen@ NDA 20-898 commits t h a t the media f i l l ed v ia l s

fo r a minimum o ollowed b' P? pEpp fo r a minimum of

contrary t o ' t h e ~ f i l l i n c u b a t i o ~ commitments the

Alls ton H document #PR-093-44 1 estab l i shes an d provides s pec i f i c ins truct ion to "Transfer

storage cages to the appropriate Quarantine ) Areal/. The storage cages

conta in the media f i l led v ia l s an d the performed pr io r to the requis i te

t ime an d temperature incubation requirements submitted in the NDA. The NDA does not provide

any provis ion for thellllllllllllll' of media f i l l ed v i a l s prior to i n c u b ~ t i o n , The.....

, was p e 00 8 and the Apr i l 1, 2009 media f i l l re F

c e r 1ca 10ns. (Note: the ob jec t ionab le condit ion i s app l icab le fo r media f i l l s used to

suppor t the asept ic f i l l i n g process of the Cerezyme (NDA # 020367), Fabrazyme, (BLA #103979)

and Myozyme (BLA # 125141) f inished products manufactured a t the Alls ton f ac i l i t y ) .

12. Th e "Cert i f ica t ion & Re-cer t i f icat ion of the Asept ic Fi l l ing Processes at Alls ton

Landing" document #VP-026 -15 1 l i s t s rout ine and non-routine interventions for media fill

which l "must be incorporated into i n i t i a l media fill cer t i f i ca t i ons an d performed on an

_ bases for media fill re-cert i . f icat ions Non-routine intervent ions occurring during

product ion fills shal l be incorporated into the next schedule media fill. I The \ \Process

Val ida t ion for Therapeutic Products ll document #VP-026-84 1 estab l i sh \\Some types o f process

val idat ion ut i l i z e a worst case val idat ion strategy to properly demonstrate process

cons i s tency an d robustness at commercial scale . During the crea t ion of the process

val idat ion protocol , an a s s ~ s s m e n t of operat ing ranges an d worst case condit ions i s

performed when def ining the process val idat ion s t r a t e g y . ~ "The in tent ion of te s t ing at

worst c a s ~ condit ions i s to ensure the process operates e f fec t i ve l y within th e allowable

batch record range,lI Despite the aforementioned procedures I the Validat ion Manager

confirmed there i s no record to ~ o e u m e n t the kat ionale that es tab l i shed the routine and non

routine media f i l l intervent ions an d the frequency of the interventions .

SEE EMPLOYEE(S) SIGNATURE EMP OYEE(S) NAME ANlATmEtPrint or ltpe) DATE ISSUED

ReVERSE ~ Q'\rY'-0- '? ' ~ t \ \ ~ " ~ f u ~ INJ ,F THIS . - - \ " ' Debra Emerson, Invest igator 11/13/2009

PAGE ~ ' " " < i : : . . . , , •FORM FDA 463 (4/03) PREVIOUS EDITION 0: - : : ' B S " ' 0 " L ' : : E ~ T E : " - - - - - - - ~ I N : : S ~ P ~ E ~ C ~ T ; : ; I - ; : : O " " N " A 7 L - ' O ; : ' B = S = E = R : C V 7 A = T : : I O ~ N 7 S = - - - - · - P A - G - ' E L . - r - - 0 - F - J J . - ; - . - - P A - G - E - S - '



(b) (4)(b) (4)

(b) (4)

(b) (4)


DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S} OF INSPECTION


FEI NUMBER

1000305672

NAME AND TITlE OF INDIVIDUAL TO IM-IOM REPORT IS ISSUED

TO: Henri A. Termeer, Chairman, Pres iden t , an d CEOFIRM NAME

(b) (4)

Genzyme Corporation


Alls ton , MA 02134

STREET ADDRESS

50 0 Soldie r s Fie ld Road


Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL

OBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGAR01NG YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN



YOU HAVE ANY QU ESTIONS, PLEASE CONTACT FDA AT TH E PHONE NUMBER AND ADDRESS ABOVE_

DURING AN INSPECTION OF YOUR FIRd'WE) OBSERVED:

13. There are asept ic manual connect ions o f th e s t e r i l e f i l t e r e d formula ted bulk so lu t ion

t r a n s f e r hoses from the bulk so lu t ion s t a i n l e s s s t e e l vesse l to the IIIIIIII f i l l ingequipment (room FF2-016, 180-5 I Class 100) . Th e asep t ic manual connect ions are performed

under a mezzanine floor-'lllllllllllll loca ted in F i l t r a t i o n Room FF2-09 [180-7 / Class

10,000 . . Th e asep t ic manual connect ions performed on the formulated bulk

so lu t ion s ta in les s s t e e l vesse l a re not made with in HEPA f i l t r a t i o n to con t ro l and p r ev en t

th e ingress of objec t ionab le microorganisms and non-viable par t i c l es . (Note: The

objec t ionab le condi t ion i s appl icable fo r th e Cerezyme (NDA # 020367), Fabrazyme, (BLA

#103979) and Myozyme (BLA # 125141) f in i shed products manufactured a t the Alls ton f a c i l i t y ) .

14. Visual inspect ion i s performed to accept o r r e j ec t lyoph i l i zed f in i shed products fo r a

var ie ty of qual i ty a t t r i b u t e s (e .g . cracks , defec t ive c losure , improper fill volume,

di sco lo r a t ion , cake f laws, and fo re ign mat ter on cake, v i a l , or s topper ) . The t r a in ing o f

opera to rs for the visua l inspec t ion process i s i n su f f i c i en t in tha t :

~ u a l i f i e d fo r lyoph i l i zed product us ing v ia l s f i l l e d with

. . . . . . . . . . . . . . . , which i s not the same cons is tency o r has the same phys ica l

c h a r a c t e r i s t i c s o f the l yoph i l i z ed mater ia l . Opera to rs a re not qual i f ied using ac t u a l

lyophi l i zed drug product .

• Operators a re not qua l i f i ed on vi sua l inspec t ion fo r 5 cc v ia l s . Fabrazyme 5mg an d

Thyrogen are f i l l e d in to 5cc v i a l s .

• Th e visua l inspec t ion accep tance an d r e j ec t ion o f l yoph i l i z ed f in ished product v i a l s i s

performed by the product ion depar tment and not by the Qual i ty Unit .

SEE

REVERSE!

OF THIS

PAGE

EMPLOYEE(S} NAME AN9.TITLE ( -nl or T y ~ ! \ DATE ISSUED

2;) ,n,,-".l / \\'\.J

Debra Emerson, Inves t iga tor 11/13/2009

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS P A G E f - 0 ~ P A G E S



(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)


DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S}OF INSPECTION


FEI NUMBER

1000305672

NAME AND TITLE OF INDIVIDUAL TO INHOM REPORT IS ISSUED

TO: Henr i A. Termeer, Chairman, President , and CEQFIRM NAME

Genzyrne Corpora t ion


Alls ton , MA 02134

STREET ADDRESS

500 Sold iers Fie ld Road


Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAl





DURING AN INSPECTION OF YOUR FIRM)t(WE) OBSERVED:

15. Inves t iga t ions reviewed were not complete in documentat ion, i nves t iga t ion , or cor rec t ive

ac t ion . Examples of in su f f ic ien t inves t iga t ions a re l i s ted below:

• Inves t iga t ion AIR 1484 dated 4/30/07 which wa s opened because of a pos i t ive r e su l t which

wa s obta ined from an opera to r who was sampled per s tandard procedures from h is gloves.

The o p e ra t o r was l eav ing th e fill su i t e a f t e r th e completion o f the f i l l i ng o f Cerezyme

A7030. Th e organism wa s i d e n t i f i e d as Baci l lus megaterium. Th e i nves t iga t ion did not

confi rm th e source of the Baci l lus megaterium i ns ide the fill su i te . Th e of

th e fill su i te \'las performed on 6/15/07. There were. add i t ional l o t s o f drug product

f i l l e d in th i s su i te between 4/30/07 an d 6/12/07 wi th no product impact assessment mentioned

in the i nves t iga t ion . Th e inves t iga t ion d id no t inc lude confi rmat ion t h a t th e ; J

removed the Baci l lus megaterium from the fill s u i t e .

• I nves t iga t ion AIR 1517 dated 6/21/07 was opened because i HEPA f i l t e r s in the f i l l i n g

su i t e f a i l ed rou t ine r ece r t i f i ca t ion . The i nves t iga t ion found metal p a r t i c l e s embedded in

s ev e ra l o f the HEPA f i l t e r s . However, no rou te cause was determined fo r th e source o f themeta l contaminat ion found in these f i l t e r s .

• There were mult iple i nves t iga t ions opened to document rouging £ound i n s i d e of columns (ex.

Pur i f i ca t ion Columns) . The inves t iga t ions conducted by the f i rm i n to the column rouging

did not include any ana ly t i ca l t e s t ing or assessment as to whether any component of the i ron

oxide wa s re leased in to the e lua te during process ing .

DATE ISSUEDa E 1 0 ~ E ( S } NAME A N ~ T b l f \ ( f ' L i ~ T y p e ) .,SEEREVERSE I \ -v---f<.--";> "d ;\f1XlN. \ { \ .VOF THIS Debra Emerson, Inves t iga to r 11/13/2009PAGE

FORM FDA 483 (4f03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS

I



(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4) (b) (4)





FEI NUMBER

1000305672


TO: Henr iA.

Termeer, Chairman, Pres iden tI

and CEOFIRM NAME



Al l s ton , MA 02134

STREET ADDRESS



Drug Manufacturer



yOU

than (not exceed in ) . "(b) (4)

HAVE ANY QUESTIONS. PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR F I R M ~ ( W E ) OBSERVED:

(b) (4)

16. Th e documentation recorded by opera to rs in the ba tch records i s i n s u f f i c i e n t .

Speci f i ca l lYIA. For f i l l i n g opera t ions :

• Operator s do not IIIIIIIIIIII i s used during each fill. Th e f i rm h a s "ecord which

d i f f e r en t

• o p e ra t o r s do not record the ac tua l knob s e t t i n g s from thellllllll f i l l e r which inc ludes

th e speed o f the 1111111111111 an d th e se t t ing for the . . .. . . .. . .- < U s e d t o se t th e l ine

the ac tua l number o f v i a l s f i l l e d during a run. Opera tors do

not document

(b) (4)

the ac tua l number of v i a l s t h a t are p laced in to th e l yoph i l i z e r .

• When an in -process weight check f a i l s during f i l l i n g , opera tor s are r equ i red to not i fy a

s u p e rv i s o r or designee . Page 28 of th e Thyrogen f i l l i ng record prov ides a place fo r

o p e ra t o r s to document t h i s n o t i f i c a t i o n . During th e f i l l i n g opera t ions fo r Thyrogen lo t

A9054 t he r e was a weight check f a i lu re . There wa s no documentation in the batch record tha t

th e opera to r not i f ied t h e i r superv i sor . There i s a l so no documentat ion t ha t qual i ty was

made molare o f the f a i l ed \-Ieigh t check.

B. For inspect ion operat ions:

• The procedure en t i t l ed : Inspect ion o f Lyophi l ized Product Using th e ..1111......1111.(b) (4)


OBJECTION OR ACTION WITH THE FDA REPRESENTATlVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE" ADDRESS ABOVE. IF

(b) (4)

speed) .

• Operators do not document

requi res opera tor s "must inspec t fo r no longer

Inspec to rs do not document th e ac t u a l t ime

t h a t they s t a r t or s top t h e i r vi sua l inspec t ion o f v i a l s . Inspector s record the hour in

m i l i t a r y t ime and ins tead of recording the minutes from th e clock, they record a calcu la ted

percen tage .

• The procedure e n t i t l e d : Inspect ion of F inal Product (unlabeled) Using th e 11111111111111..... 7;,,)' a t Alls ton Landing, QA-006-05, requ i res opera to rs can spend a maximum

o f . . consecut ive minutes inspec t ing v i a l s using the Th e AQL inspect ion of

v i a l s i s performed by the qua l i t y s t a f f , there i s no documentat ion by these inspector s to

r eco rd th e t ime t ha t they s t a r t or s top t h e i r inspec t ion of these v i a l s .

C. For qua l i t y i nves t iga t ions :

• In th e event t ha t a qua l i t y i s sue de tec ted dur ing f i l l i n g , the qua l i ty depar tment wil l

make th e decis ion t h a t ind iv idual t r ays are to be segregated as they a re removed t ray by

t r ay from the l yoph i l i z e r . This decis ion made by qua l i ty to segregate v i a l s i s not

documented.

APLOYEE(S) SIGNATURE ~ / ? 0 J ~ - ( \ < - . - ' \ ) I

DATE ISSUEDM PLOYEE(S) NAME At-{g,TITL lint or T y p e ~SEE

REVERSE \ \ ~ , ~ . ~ n \ "-.\1OF THIS Debra EmerS6n, Inves t iga tor 11/13/2009PAGE

FORM FDA 483 (4103) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS



(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)



DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE{S) OF INSPECTION


FEI NUMBER

1000305672

NAME AND TITLE OF INDIVIDUAL TO 'M-lOM REPORT IS ISSUED

TO:Henri A. Termeer, Chairman, Pres iden t , and

CEO

FIRM NAME



A l l s to n , MA 02134

STREET ADDRESS

50 0 Sold iers Fie ld Road


Drug Manufacturer




OBJECTION OR ACTION INITH THE FDA REPRESENTATIVE{S) DURING THE INSPECTION OR SUBMIT THIS INFORMATiON TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDAAT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM . .nWEj OBSERVED;

17. Th e "Decontaminat ion and Res t a r t Plan r e l a t ed to AIR 1871-Rapid C e l l Decline r e l a t ed in

Cerezyme Bioreac tor 5A (Lot #11808406) a t th e A l l s to n Landing Fac i l i t y" dated 06/20/09response to the Vesiv i rus 2117 contaminat ion, descr ibes t h a t "a more comprehensive and

aggress ive decontaminat ion s t r a t egy needs to be implemented to provide assurance t ha t t h i s

v i r a l contaminant has been e f f e c t i v e l y el irninated.H For example,

• Th e scope of work by fo r Genzyme, Amendments dated 07/02/09 and 07/07/09 r equ i res

1II I I I I I s tud ies were conducted in on June 29, 2009 to i d e n t i f y any remediate any

p o t e n t i a l adverse a i r f lows i n to o r out o f th e H However, the Associa te

D ir ec to r o f Quali ty Cont ro l Microbiology, Senior Direc to r of Bulk Manufactur ing and the

Contractor/Vendor confirm that there are no records to document the s tudies " to

(b) (4)

i den t i f y and rernediate any p o t e n t i a l adverse a i r f lows i n t o or out o f th e

area.H (Note: th e a i r ve loc i ty and flow of a i r a s s i s t s to convey th e VHP to the hard to

reach work sur faces and equipment . )

'IIIIIIIII w i l l

(b) (4)

c a l c u l a t e opt ima l i n j ec t ion dura t ion and placement

(b) (4)

uni t s andf th e VHP

fans to achieve opt ima l VHP concen t ra t ion and disbursement th roughout th e t a r ge t 2one.H

However, there i s no r ecord to document the ca lcu la t ions to suppor t th e optimal i n j ec t ion

dura t ion or a document t h a t descr ibes th e r a t iona le t o support the placement and l oca t ions

of th e VHP uni t s and f an s .

18. The June 23, 2009 VHP Decontamina t ion o f Al l s ton Cel l Cul ture , d es c r ib es

t h a t "The loca t ions o f the B ls a re also determined by r i sk -based approach and a revievl o f

th e manufactur ing p r o ces s in th e area . H However, t h e re i s no record to document th e " r i sk

based approach and review of th e manufactur ing p r o ces s " , In addi t ion ,

• There i s no r ecord to document th e loca t ions o r placement o f the

Bi o l o g i ca l In d i ca t o r s (Bls) t h a t a re used to suppor t th e decontaminat iono f th e A l l s to n Ce l l Cul tu re and the bulk manufactur ing f a c i l i t y .

• Th e Bio-decontamina t ion of Alls ton Landing Fac i l i ty Bulk Manufac tur ing Areas

in Response to AIR 1871", document #09TRA0165, dated 07/23/09 descr ibes t h a t , "The

bio log ica l i nd ica to r s (Bls) were d i s t r i b u t e d around th e t a r ge t areas in worst case

loca t ions H• However, t h e re i s no record to document th e evaluat ion performed to determine

th e "wors t case l oca t ions H•

DATE ISSUEDMPlOYEE(S) NAME Atj.Q!IT {Print qf T ~ EEREVERSE . \ \ ","",A', """,,-,, " / \(\..'OF THIS·

Debra Emerson, In v es t i g a t o r 11/13/2009PAGE

FORM FDA 483 (4103) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONSPAGE-7r-0Fj :b PAGES



(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)(b) (4)

1

(b) (4)


DISTRICT OFFICE ADDRE

Montvale Ave Stoneham,

SS AND PHONE

MANUMBER

02180 781-596-7700


10/8/09

FEI NUMBER

- 11/13/09

THIS DOCUMENT LISTS OBSERVATIONS MAOE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL


(b) (4)

OBSERVATION. OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU

OBJECTION OR ACTION 'MTH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR

(b) (4)

SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE.

MAY DISCUSS THE

IF


DURING AN INSPECTION OF YOUR FIRM%(WE)OBSERVED;

19.

forthe various bulk manufactur ing areas t ha t include fo r example the pur i f i ca t ion process

areas , c e l l

(b) (4)

cul ture rooms, media prepara t ion and buf f e r preparat ion rooms, are ca lcula ted

with considerat ions of the overa l l room dimensions of the respec t ive t a rge t zones with

product ion equipment. However, there i s no record to document the manner ~ I i t h which the VHP

decontaminat ion cycle parameters were developed. As confirmed by the Contrac tor /Vendor

illIlIlIlIlIlI, the VHP Process was developed via liliiii

20. The July 13, 2009 ac t ion no t i f i ca t ion at tachment form documents, ~ loca l ized number of

BI ' s are pos i t i ve a f t e r th e complet ion of the VHP of Pro te in Pur i f ica t ion" , which wa s

a t t r ibu ted to the B ls being covered with adhesive tape during the VHP decontaminat ion.

Despi te the s t r a t egy descr ibed in the June 19, 2009 Decontamination an d Res t a r t plan re la ted

to the Rapid Cel l Decl ine in Cerezyme Reactor SA ( lo t 11808406) a t the Alls ton Landing

Fac i l i ty , VHP decontaminat ion wa s not performed fo r the af fec ted areas . In addi t ion,

• Par t of the cor rec t ive ac t ion o f the Ju ly 13, 2009 ac t ion n o t i f i c a t i o n l " ~ : : : : : : : : : : : : ~ I I . was performed. However, the August 2005 Evaluat ion of I

,-iiiiiiiiiiiistudies document tha t the ~ w a s unable to e f f e c t i v e l y

i nac t iva t e the Staphylococcus aureus , Micrococcus l u t eus an d Candida a lb icans or

Baci l lus sub t i lus pores and s ign i f ican t ly reduce Baci l lus cereus spores" .


1000305672

NAME AND TITLE OF INDIVIDUAL TO VVI-IOM REPORT IS ISSUE 0

TO: Henri A. Termeer, Chairman, President , an d CEO

(b) (4) used in the Cell Cul ture was not included in the WHP The

decontaminat ion.

21. There i s no record to document tha t the var ious pieces of equipment used during the

asep t i c f i l l i ng process a re cleaned an d san i t i z ed pr io r to use (e .g . , mobile c a r t s , chai rs ,

s tep s too l ) an d there i s no record to document the c lean ing of the product ion equipment used

in bulk manufacturing. In add i t ion ,

• There i s a metal too l box containing hand t oo l s ( e .g . , ad jus tab le & hex-head wrenches,

p l i e r s , cu t te r s ) tha t a re used during the se t up of th e fill equipment and during rout ine

manufactur ing operat ions fo r the ~ a s e p t i c core" and in the asept ic fill room #FF2-016.

However, th e Product ion Manager confirms there i s no record to document t h a t the too l s area

SEE ' MPLOYEE(S) SIGNATURE EMPLOYEE(S) NAME AND T (PfVt or Type) DATE ISSUED

REVERSE!'-. . ~ , AJ ~ . ...~ ~ ~ ~ \'{\JFTH/S v Debra Emerson, Inves t iga tor 11/13/2009PAGE I

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS P A G E ~ O F P P A G E S

FIRM NAME



Alls ton, MA 02134

STREET ADDRESS

50 0 Soldie r s Fie ld Road

TYPE OF E S T ~ B L I S H M E N T INSPECTED

Drug Manufacturer



(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)



DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE{S} OF INSPECTION


FEI NUMBER

1000305672


TO:

HenriA.

Termeer, Chairman,Pres iden t ,

andCEO

FIRM NAME



Alls ton , MA 02134

STREET ADDRESS

50 0 Soldiers Field Road


Drug Manufacturer


OBSERVATIONS; AND 00 NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN

OBSERVATION, OR HAVE IMPLEMENTED. OR PlAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THE

OBJECTION OR ACTION 'vVITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF


DURING AN INSPECTION OF YOUR FIRM%(VoIE} OBSERVED:

22 . The uEvaluat ion o f 2 and Maximum Hold Time to

Control Microbia l Populat ions on Hard Surfaces" , document #05TRNI02 dated 09/07/05 concludest h a t the was shown to be an p a r t i a l l y e f f e c t i v e dis infec tant by

s ign i f i can e v ia b i l i t y o f most gram pos i t i ve & gram negat ive

vegeta t ive bac te r i a , yeas t mold spores . However, it was unable to e f f e c t i v e l y inac t iva te

the Staphylococcus aureus , Micrococcus l u t eus and Candida a lb icans or Baci l lus

(b) (4)

sub t i l us pores and s i g n i f i c a n t l y reduce Bac i l lus cereus spores ." In add i t ion ,

• The ~ S a n i t i z a t i o n of the Asept ic Area of th e F i l l / F i n i s h Department a t Alls ton" document

#MF-082-S0 es t ab l i shes the frequency fo r san i t i za t ion , which includes a of the

F i l l / F i n i s h asep t i c a reas {e.g" FF2-09 & FF2-016} and ~ s s o c i a t e d a i r locks with

However, as previously descr ibed the i s ~ u n a b l e to

ef fec t ive ly inac t iva te th e Staphylococcus aureus , Micrococcus lu teus and Candida albicans

or Baci l lus sub t i lus pores and s ign i f i can t ly reduce Baci l lus cereus spores ."

23. Th e ~ A u d i t o f Asept ic Technique During F i l l i n g Operations a t A l l s t o n " , document

#QA-100-09" i s ~ u s e d to evaluate the asep t i c t echn ique of personnel in fill room FF2-16 fo r

a l l f i l l i n g opera t ions inc lud ing media f i l l s , c l i n i c a l product f i l l s , and commercial product

f i l l s . " Qual i ty Assurance personnel observe and evaluate the media fill se t -up , asep t i c

f i l l i n g and capping opera t ions fo r compliance to the es tab l i shed procedures . However, a

s imi l a r l eve l o f r espons ib i l i ty , review and approval are not performed fo r rout ine

product ion (Ucommercial product f i l l s " ) , i.e., rout ine se t -up o f th e fill room equipment,

asept ic f i l l i n g opera t ions and capping of f in i shed products . In add i t ion ,

• A s imi l a r

(b) (4

l eve l of evaluat ion i s · n o t performed fo r the f i l t r a t i o n s t eps , . . . . 1performed in room #FF2-09.

24. Th e design o f th e asep t i c f i l l i n g room #FF2-016

th e 130-5 areas (Class IOO) do not preven t th e i ngr e s s of ob jec t ionab le microorganisms an d

non-viable p a r t i c l e s . In add i t ion ,

• Due to the des ign o f th e asept ic fill room and th e f i l l i n g equipment there are up

to .. product ion personnel t h a t a re needed fo r the asept ic f i l l i n g opera t ions , which promotes

th e ingress of objec t ionab le microorganisms and non-viable par t i c l es within the 130-5 areas .t ]

MPLOYEE{S} S I G N A T ~ R E _......\' EMPLOYEE{S) NAME AND 'hQlE ( ·nt or Type! J DATE ISSUEDSEEREVERSE \ \ ~ A - ' 7 ~ i " " ; n ' . ,\RV

' - ! - -n ' J ' . ~ . - ? :S ""'"('\""'"F THISDebra Emerson, I nves t iga to r 11/13/2009

PAGE

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOlETE INSPECTIONAL OBSERVATIONSPAGE-e-0F f f -PAGES



(b) (4)

(b) (4)

(b) (4)

(b) (4)



DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE{S) OF INSPECTION

10/8/09 - 11/13/091 Montvale Ave Stoneham, MA 02180 781-596-7700

FEI NUMBER

1000305672

NAME AND TiTlE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

TO: Henri A. Termeer, Chairman, Pres iden t , and CEO

FIRM NAME STREET AODRESS

Genzyme Corpora t ion 50 0 Sold ier s F ie ld Road

CITY. STATE AND ZIP CODE TYPE OF ESTABLISHMENT INSPECTED

Alls ton , MA 02134 Drug Manufacturer

THIS DOCUMENT liSTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAl


OBSERVATION. OR HAVE IMPLEMENTED. OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THE

OBJECTiON OR ACTION VY'ITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF


DURING AN INSPECTION OF YOUR F I R ~ (\'\'E) OBSERVED:

25. Due to the design of th e bui ld ing , i n i t i a l personne l

f low o f product ion personnel I

and the

) \..

i t h in

room

the f a c i l i t y promote the ingress o f ob jec t ionab le microorganisms and non-viable p a r t i c l e s

in to th e c l a s s i f i e d and unclass i f ied manufactur ing areas . In add i t ion ,

• Product ion personnel work on or corne i n d i r e c t contac t with th e l a r ge wooden ( r ecep t ion

l i ke ) desk t ha t i s loca ted in the common personnel corr idor , which i s not a smooth and

c l ean ab le s u r f ace . Th e Assoc ia t e Direc to r o f Qual i ty Control Microbiology and Senior

Manager o f F i l l Fin ish Operat ions confi rm t h e re i s no record to document t ha t the wooden

desk i s sea led . Th e Assoc ia t e Direc to r o f Qual i ty Control Microbio logy confirms t ha t the

wooden desk i s not pa r t of EM Program o r sampled fo r the presence o r absence of

objec t ionab le microorganisms.

26. There i s an observat ion \'t'indm..., a p p r o x i m a t e l ~ • I . . . . t h a t i s used to observe the asep t i c f i l l i ng opera t ions . Th e window sea l s and the sec t ions

where th e \'t'indow s t a i n l e s s s t e e l frame meets , as conf irmed by the Direc to r of Qual i ty ,

Produc t ion S u p ~ r v i s o r , and Val idat ion Manager, a re not sea led such t h a t ~ 3 v e r i f i e d l eak" around th e window s t a i n l e s s s t e e l molding . Th e Senior Di rec tor F a c i l i t i e s

confi rms t h a t t h e re i s no record to document t h a t the i n t e r i o r s u r f aces of the wall are

sea led . In add i t ion ,

• Th e Q u al i t y Assurance personne l obse rve th e media fill se t -up , a s e p t i c media f i l l s and the

capping opera t ions v ia th e observat ion window in the personnel c o r r i d o r . However, not a l l

o f the p roduct ion a c t i v i t i e s can be observed in t h a t the area where the ~ r e v e r s e weight

check" i s performed i s not v i s i b l e from th e observat ion window.

27. Product ion personnel are r equ i red to remove t h e i r s t r e e t a t t i r e and shoes and don the

p l a n t uniform (blue co lor scrubs and ded ica ted fac to ry shoes) p r i o r to proceeding to t h e i r

r e s p ec t i v e work a reas . Dependent on t h e i r work area , ' e .g . , f i l t r a t i on room, component

p rep a ra t i o n , and asep t i c f i l l i n g , product ion per sonnel a re a l so requ i red to don add i t ional

gowning a t t i r e , e . g . , l ab coat , bea rd and bouf fan t h a i r cover , pr o tec t ive eye \'lear.

However, th e product ion personne l in t h e i r blue scrubs p l an t uniform come in di r ec t con tac t ,

v ia th e common personnel co r r i d o r s and s t a i r w e l l s , with non-product ion personnel ( i . e . ,

personnel wear ing t h e i r s t r e e t a t t i r e ) . Th e produc t ion personne l f low and t h e i r d i rec t

co n t ac t with non-product ion personnel promote cross contaminat ion o f microb ia l and non

viab le p a r t i c l e s .

S E E . MPLOYEE{S) SIGNA . __ EMPL YEE{S) NAME AND TIT (Print or Typt) DATE ISSUED

REVERSE - - l - ' ' I > V ' ~ ~ _ . ' \ >;:\.--?"""" , ~ ~ , < : ; ) \.\\vOF THIS '_ Debra Emerson, I nves t iga to r 11/13/2009PAGE

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONSPAGE-tbf-0F -!:9=-PAGES



(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4) (b) (4)

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(b) (4)(b) (4)

(b) (4)

(b) (4)


the f i l l ed v ia l s from the t ray loader

from th e s t a in less s tee

This i s not in tended to be


DISTRICT OFFICE ADDRESS AND PHONE NUMBER DATE(S} OF INSPECTION

10/8/09 - 11/13/091 Montvale Ave Stoneham, MA 02180 781-596-7700

FEI NUMBER

1000305672

NAME AND TITLE OF INDIVIDUAL TO IM-lOM REPORT IS ISSUED

TO: Henri A. Termeer, Chairman, Pres iden t , an d CEO

THIS DOCUMENT LISTS OBSERVATIONS MADE BY

(b) (4)

THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAl



OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF

YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND AODRESS ABOVE.

DURING AN INSPECTION OF YOUR F I R ~ { ' N E ) OBSERVED;

28. The ~ G u i d e l i n e s fo r the Performance of Airf low Pat te rn Tes t ing fo r Clean Rooms and

Laminar Flow Hoods", document #VP-009-33 ~ p r o v i d e s minimum guide l ines fo r performing a i r f low

pa t te rn tes t ing ( used to assess un id i rec t iona l a i r flow condi t ions in

asep t ic processing areas , support cGMP operat ions a t Genzyme's Alls ton Landing and

Framingham f ac i l i t i e s . " The Senior

(b

Direc tor of Qual i ty Opera t ions confi rms t ha t the a i r f low

pa t te rn t es t ing an d requirements es tabl i shed in th e document are a ~ m u s t " . The January 2009

(b) (4)

....... evaluat ion video does not completely an d adequately demonstrate unid i r ec t iona l a i r

flow within the ISO-5 (Class 100) asep t ic fill zones and within the various ISO-5 areas in

FF-2-016 e .g . , personnel en ter ing and ex i t i ng out o f the , personnel

(Note: an a l l inc lus ive list of events) . In addi t ion!

• There are mult iple HEPA f i l t e r s in the 150-5 (Class 100) area i . e . , above the . . . . . equipment tha t provides a ver t i ca l flow of a i r and a HEPA f i l t e r t ha t provides hor izonta l

a i r f lml beneath the _ equipment an d the loca t ion Ylhere the depyrogenated and

s i l i con ized s toppers are o f f loaded from the in to the 1IIIIIIII s topper t r ans fe r

ves se l . Th e Apri l 2006 II1II s tudy documents the airf low benea th the moving in an

upward di r ec t ion r a ther than in a downward and outward d i rec t ion . No evaluat ion has been

performed to determine cause o r impact to th e s t e r i l i z e d and depyrogenated s toppers of the

upward movement of th e HEPA f i l t e red a i r .

(b) (4)

• There i s an a i r exhaust vent immediately beneath a HEPA f i l t e r tha t i s loca ted on the l e f t

hand upper s ide of th e 1S0-5 area above The documents HEPA f i l t e r ed a i r

ex i t ing ou t of th e HEPA f i l t e r an d d i r ec t ly in to the a i r exhaust vent. The ~ t u d y does

not completely o r adequately demonstrate unid i r ec t iona l a i r f low on the l e f t hand s ide o f the~ m e n t and when personnel a re p e r f o r m i n ~ during the

IIIIIIIIIII ... from the I11III i n to the

• The ~ C e r t i f i c a t i o n o f HEPA F i l t e r s , Biological Safety Cabinets and Chemical Fume Hoods",

document #GN-OI0-36 es tab l i shes tha t ~ Metrology r epr e sen ta t ive wil l a lso witness II1IIPat te rn Analysis / Test ing for c r i t i c a l Class 10 0 Bio Safe ty Cabinets an d Laminar Flow

Hoods / dev ices ." HOViever, the Metrology Manager confirmed there i s no data ( i . e . , ......pa t t e rn video) to suppor t the Pat te rn Analysis" .

EM LOYEE{S) NAME A TITL fint or T Y P ~ ) , DATE ISSUEDSEE

REVERS"_,---L--. \ " ' - ~ A L ; . ~ . V 1\--;;:<1 I { \vOF THIS

Debra Emerson, I nves t iga to r 11/13/2009PAGE

FIRM NAME

Genzyme corporation


Alls ton, ~ f f i 02134

STREET ADDRESS

(b) (4)



Drug Manufacturer

FORM FD A 483 (4103) PREVIOUS EDITION OBSOlETE INSPECTIONAL OBSERVATIONSPAGEtT-OF ~ P A G E S



(b) (4)



DISTRICT OFFICE ADDRESS AND PHONE NUMBER OATE(S) OF INSPECTION

1 Montvale Av e Stoneham, MA 02180 781-596-7700 10/8 /09 - 11/13/09

FEI NUMBER

1000305672

NAME AND TITLE OF INDIVIDUAL TO VVHOM REPORT IS ISSUED

TO: Henri A. Terrneer, Chairman, Pres iden t , and CEO

FIRM NAME



Al l s ton , MA 02134

STREET ADDRESS

50 0 So l d i e r s Fie ld Road


Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECT/GNAl





DURING AN INSPECTION OF YOUR FIRM p1JWE) OBSERVEO;

• Th e ~ O p e r a t i o n a l Qual i f i ca t ion Protoco l fo r th e Airf low Pat te rn Test ing in the Class 100

(IS05) F i l l i n g Room FF2-16 Located a t th e A l l s to n Landing Fac i 1 i ty

H document #04-2534, da ted

December 22, 2008" provides the ~ o b j e c t i v e o f t h i s pro toco l i s to def ine the requirements

and acceptance c r i t e r i a fo r th e performance of the Operat ional Qual i f i ca t ion of the a i r f lov l

pat te rn t e s t ing in fill room FF2-16 a t Alls ton Landing. This pro toco l i s in response to

co r r ec t i v e ac t i o n s / p rev en t a t i v e act ion (CAPA) ~ 8 u c c e s s f u l complet ion o f t h i s

pro toco l wi l l a l so demonstra te t h a t a i r f low pa t t e r ns a re adequate ly t e s t ed for tu rbu lence

t h a t would i n t e r f e r e with the sweeping ac t ion of the a i r dur ing represen ta t ive manufactur ing

opera t ions ." Th e Assoc ia te Director o f Qual i ty Cont ro l Microbiology conf irms t ha t th e video

o f the a i r f low pa t t e r ns have been reviewed and approved by th e Qual i ty Control department .

However, there i s no r ecord to document the a i r f low pa t t e r n ev a lu a t io n performed by th e

Qual i ty Cont ro l depar tment to suppor t t h a t th e es t ab l i s h ed acceptance c r i t e r i a was achieved .

[Note: th e Microbiology Department i s r espons ib le fo r the Environmental Monitoring (EM)

Program o f th e en t i r e manufactur ing opera t ions a t th e Alls ton f a c i l i t y ) .

29, There a re laminar flow hoods [LAF ISO-5 (Class 100)J t h a t a re used dur ing var ious

asep t i c opera t ions in bulk manufactur ing. Airf low pa t t e r n s tud ie s have been performed as

prev ious ly descr ibed in the preceding observat ion . Si mi l a r to th e 180-5 manufactur ing areas

in the F i l l & Fin ish manufactur ing a reas , t h e ; ; do not complete ly o r adequate ly

demonstra te unid i r ec t iona l a i r f low dur ing th e var ious a s e p t i c process ing s t eps performed in

th e l aminar flow hoods. In add i t ion ,

• Th e Apr i l 27, 2009 Risk Assessment of the ISO Class 5 Laminar Flow Hoods or ISO 5 Areas to

determine those t h a t should be cons ide red as ~ c r i t i c a l " o p er a t i o n H i den t i f i ed high, medium

and lo w r i sk ca t eg o r i e s . Th e a i r f low p a t t e r n s tud ies fo r th e high r i sk 180-5 LAF and

bio log ica l sa f e ty cab inets (BSC) have been evaluated . HOvlever, the a i r f lm ' l p a t t e rn

evaluat ions have not been performed fo r the BSCs t h a t a re used fo r th e b ioreactor sample

process ing .

C / \DATE ISSUED~ P l O Y E E { S ) NAME A N D A " ~ t i n t or Type}SEE ~ ~ O Y E E ( S ) SIGNATURE, < c ~ \ J .

REVERSE ~ V , ~ ~ "''"''''-'1 Y c " ~ " " " ~ ' ~ : 3 , I . ~ ~FTHfSDebra Emerson, In v es t rg a t o r 11/13/2009

PAGE "t-... , . ''"<;..

FORM FDA 483 (4/03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONSPAGEttOF# PAGES

(b) (4)



(b) (4) (b) (4) (b) (4) (b) (4)

(b) (4) (b) (4) (b) (4) (b) (4)

-------- - - - - -(b) (4)



DISTRICT OFFICEADDRESSAND PHONE NUMBER

I Montvale Ave

Stoneham MA 02180

781-596-7700


TO: Henri A. Tenneer, Chainnan, President, and CEOFIRM NAME

Genzyme Corporation


Allston, MA 02134


STREET ADDRESS


10/8/09-I l I I 3/09

FEI NUMBER

l000305672



Drug Manufacturer

(b) (4)

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATlVE(S) DURING THE INSPECTION OF

(b) (4)(b) (4)

YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY OETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING

OBSERVATION. OR HAVE IMPLEMENTED. OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS TOBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE ADDRESS ABOV

IF YOU HAVE ANY QUESTI ONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND AODRESS ABOVE.

DURING AN I NSPECTION OF YOUR FIRMpYfWE) OBSERVED:

30. There is no record to document the rationale (e.g., evaluation perfonned to detennine and support the justification) for the EM

(b) (4) (b) (4)

microbial sampling locations, which is ultimately used to suppor t the presence or absence ofobjectionable microorganisms in

the Allston manufacturing facility that includes but is not limited to the IS0-7 (Class 10K) filtration room #FF 2-09 and ISO-S(Class 100) aseptic filling room #FF2-0I6 as well as the bulk manufacturing areas. In addition,

• The microbial alert and action levels, that is, the level ofmicrobial contamination that init iate or trigger whether an

evaluation is required to determine the cause for the microbial excursions, for the bulk manufacturing facility and the

FilllFinish manufacturing areas are not based on the historical EM sampling data.

31. The 2008 and 2009 EM Trend data document the percent of microbial identification for Gram Positive rods (i.e.,

spore former, non-spore former, and unknown spore formers) from the EM sampling for the Allston facility, for example;

-2008

•2008 2008 2008 2009 2009

Area • • • •Fill 1Finish r-.-r-. Bulk mfr.

The EM sampling identifies the locations where the microbial contaminants were recovered. However, the evaluation

fail to identify the source(s) of the microbial contaminants, for example the root cause for the recurrent presence of th

Bacillus species contamination. The root cause evaluation(s) in tum assist to address, and ultimately control, the

ingress of objectionable microorganisms.

EMPLOYEE(S) NAME AND TITLE (Print orType) DATE JSSUEDEE EMPLOYEE(S) SIGNATURE

REVERSE ' 1 : : : l e . ~ 1"<"-. ~ ~ ~ ~ ~ Debra M. Emerson, Investigator ll/l3/09OF THIS .1 .- • , , -- ' "PAGE /' / t \ ...... ....- _. " ' ~ . Thomas J. Arista, Investigator

FD A 483 (4/03) P R E V I O ~ S E D m 6 N OBSOLETE '" INSPECTIONAL OBSERVATIONS



(b) (4(b) (4)

(b) (4) (b) (4)

(b) (4)

(

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AN D DRUG ADMINISTRATION

DISTRICT OFFICE ADDRESS AND PHONE NUMBER

I Montvale Ave

Stoneham MA 02180

781-596-7700

NAME AND TiTlE OF INDIVIDUAL TO WHOM REPORT IS ISSUED

TO: Henri A. Tenneer, Chairman, President, and CEOFIRM NAME

Genzyme Corporation


Allston, MA 02134

DURING AN INSPECTION OF YOUR FIRM {I} (WE) OBSERVED:


10/8/09-11/13/09

FEINUMBER

1000305672

STREET ADDRESS



Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING A

OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTNE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THOBJECTION OR ACTION WITH THE FDA REPRESENTATNE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE AODRESS ABOVIF YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF

(b) (4)

YOUR F I R ~ E ) OBSERVED:

32. There is a June 16, 2005 ' , that describes the

Non-viable Particle (NVP) should be placed above the aseptic filling work surfaces. However, the NVP that isnearest the aseptic fill nozzles, measured by Production Staff, is above the work surface. In addition,

• There are. NVP monitoring probes located approximately 7 feet above the floor on the left hand side ofth

Lyophilizer and near the glass vial in-feed table in the aseptic filling room #FF2-0 16. There is no record to documen

the rationale for the NVPs located on the walls.

33. Non-viable particle measurements are not taken during the routine dynamic operations performed in the Filtration Room #FF-

09 (ISO-7). In addition,

a. The NVP measurements are not taken near or next to the area where the aseptic connections of the filtration apparatusare performed. Rather, the NVP are taken approximately in the middle of the room.

34. There is a small step stool used by production personnel when setting up the filling hoses, connections and filling nozzles to th~ l 1 i n g equipment. During the set up the personnel position the step stool next to the fill equipment and the shoe cover

come wlthin close proximity (approximately I Y2- 2' ) to the filling equipment and fill zones. However, the step stool is not

sampled during the EM to determine the presence or absence of objectionable microorganisms.

35. We observed visible particles inside the air return duct from the observation window in front of aseptic fill room #FF2-016.

The Quality Unit could not confmn whether the visible particles were from the personnel corridor or the ISO-5 (Class 100)

aseptic fill room #FF2-016.

~ P L O Y E E ( S ) SIGNATURE _ EMPLOYEE(S} NAME ANo TITLE (Print orType) DATE ISSUEDEE

REVERSE Debra M. Emerson, Investigator 11113/09. ~ ~ ' . ~ - (F THISThomas J. Arista, Investigator

FD A 483 (4/03) INSPECTIONAL OBSERVATIONS PAGE rg;f 2 PAG

PAGE

p ; ; c ~ ~ ) ~ n ' I M



(b) (4)

(b) (4)

(b) (4)

DEPARTME NT OF HEALTH AND HUMAN SERVICES



I Montvale Ave

Stoneham MA 02180

781-596-7700

NAME AND TITLE OF INDNIDUAL TO WHOM REPORT IS ISSUED

TO : Henri A. Tenneer, Chairman, President, and CEO

FIRM NAME

Genzyme Corporation


Allston, MA 02134



10/8/09-11/13/09

FEI NUMBER

1000305672

STREET ADDRESS500 Soldiers Field Road


Drug Manufacturer

THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING OBSERVATION. OR HAVE IMPLEMENTED. OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS TOBJECTION OR ACTION WITH THE FDA REPRESENTATNE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE ADDRESS ABOVIF YOU HAVE ANY QUESTIONS. PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM,,(lj (WE) OBSERVED:

36. There has been no airflow pattern evaluation perfonned for th:1!!!!l!!!Isolators, which are used for Sterility Tests of

various finished products. The evaluation of airflow assists to etennme arrflow dynamic and turbulence created by the tests

equipment and load configurations within the Isolator, which in turn assists todetennine

the appropriate placement (e.g., worstcase) ofthe Chemical Indicators (CIs) challenges. In addition,

• There is no data to support the placement of the CIs. The CIs determine the presence or absence of the vaporized

on the work surfaces and worst case locations within the Isolator to decontaminate.

• The place of the CIs also assists to detennine the worst case challenge locations for th

Biological Indicators (Bls). However, in the absence of the airflow patt ern evaluation to support t e p acement 0 t e

CIs, there is no data to support the validity ofthe worst case challenge locations for the Bls.

• There is no record to document the rationale for the worst case load configurations for the Sterility Tests Isolators.

• There is no record to document the CIs that were used in support ofthe October 2008 Isolator requalification. In

addition,

• There is no rationale for the placement of the thennocouples within the Isolators.

• There is no established written procedure that describes the manner with which the Bls and Cis are attached to the

thennocouples during the requalification.

37. The most recent vendor audits of the BI and CI manufachlfers did not include assistance from the microbiology depal1ments,

which would provide a scientific evaluation ofthe vendor's microbiology methods of analysis in support of the BIs and CIs.

EMPLOYEE(S) NAME AND TITLE (PdnlorType)EE DATE ISSUED~ I G N A T U R E REVERSE Debra M. Emerson, Investiga tor 11113/09:1:' ,....

FTHISC.<-- Thomas J. Arista, Investiga torAGE '. A"--" '"

4103) P R E V I ~ T I O N OBSOLETE PAGE 1NSPECTIONAL OBSERVATIONS 12 PAG

PSC Media ~ ( 3 0 1 ) ~ 4 J - I 0 lfrt



(b) (4)(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)



(b) (4)

batch record was r e c o r d l e e ' d ~ a = = = = = •••

(b) (4

THIS DOCUMENT liSTS

(b) (4)

OBSERVATIONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AOBSERVATION. OR HAVE IMPLEMENTED. OR PLAN TO IMPLEMENT CORRECTNE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS THOBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S} DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE ADDRESS ABOVEIF YOU HAVE ANY QUESTIONS. PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM..QYtWE} OBSERVED:

38. The Isolator ~ e c k e d for leaks and holes via a so-called_'. However, there is no written procedure todescribe the__

(b) (4)

39. Cerezyme manufacturing process has not been updated to reflect cGMP's.

• Current industry standard when manufacturing with animal derived ceIls calls for

steps. The Cerezyme process hatl• • • • • • • • • • • • • •

40. Process validation is incomplete:

(b) (4)

• Microfiltration skid membrane for Cerezyme manufacturing is not validated for its reuse.

• Insufficient biochemical testing to support eluate hold times during the Cerezyme purification process.

(b) (4)

41. Quality Assurance oversight of control processes is insufficient:

• Cerezyme release specifications for drug substance and drug product do not reflect manufacturing history and process

capability.

• There is no release or in-process testing onth_ state 0••••••••• As a corrective action to a previous FDA 483 issued in 2008, a teclmical re

4/24/09. This report provided additional specifications for

_. There is no procedureor process in £lace to evaluate or implement information derived from these technical reports.

In August 2009, the batch records for t h buffers were changed to inc!ude these additional specifications listed in the

technical report. On 5/8/09

was manufactured. This bu

ofthis particular buffer. Prior to this inspection, there was no evaluation by quality into the

conductivity result which was documented in this batch record.

EMPLOYEE(S} NAME AND TITLE (Pn"nt orType) DATE ISSUEDEE Et4.E!-0YEE(S) SIGNATlJRE REVERSE Debra M. Emerson, Investigator II/] 3/09· \ ~ ~ , ~ ' · r )OF THIS ~ . ------ Thomas J. Arista, InvestigatorAGE

FDA 483 (4f03) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS PAG of 2 PAG

~ ( ; o I I W ' H m


I Montvale Ave

Stoneham MA 02180

78] -596-7700


TO: Henri A. Termeer, Chairman, President, and CEOFIRM NAME

Genzyme Corporation


Allston, MA 02134

DURINGAN INSPECTION OF YOUR FIRM (J) (WE} OBSERVED:


10/8/09-1 I113/09

FEINUMBER

1000305672

STREET ADDRESS



Drug Manufacturer



(b) (

(b) (4)

(b) (4)(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4)


(b) (4)

(b) (4)

STREET ADDRESS·



1 Montvale Ave 10/8/09-11/13/09

Stoneham MA 02180

(b) (4)

FEINUMBER781-596-7700 1000305672

(b) (4)


TO: Hemi A. Tenneer, Chairman, President, and CEO

FIRM NAMEGenzyme Corporation 500 Soldiers Field Road

CITY. STATE AND ZIP CODE TYPE OF ESTABLISHMENT INSPECTED

Allston, MA 02134 Drug Manufacturer


THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDINGOBSERVATION. OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION. YOU MAY DISCUSS TOBJECTION OR ACTION WITH THE FDA REPRESENTATNE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE ADDRESS ABOVIF YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM%(WE) OBSERVED:

(b) (4)

42. For raw material:

• There is no tracking or trending of failed incoming raw materials.

• There is no notification outsideof

QC that a lotof

raw material has failed upon receipt. In addition, this information is noalways provided to the Genzyme inspection team for audits unless a SCAR is written.

• The fmn does not normally change the incoming requirements for inspection of raw material even if the material failed

during the last inspection.

• The personnel gowning worn in the filling suite is sterile. The finn has never tested their jumpsui ts, hoods, booties, or

goggles to confirm sterility.

43.

(b) (4)

Procedure for Raw Materials, Q C ~ 0 4 8 - 72, requires that i d e n t i ~ from each container of a given lot. On 2/8/08,

For incoming of they us or identity. The firm's procedure entitled: Sampling

_•••••••••••••were received. This lot 0__ was then assigned Genzyme part number

and Genzyme lot number 923945.

• One of the identity tests is••••Viscosity. In reviewing the data for lot 923945 it was noted that the firm conducted

th Viscosity testof f of

a composite sample. I t was explained that individualb o t t ~ e s

should have been tested.• Another identity test i The data reviewed for this lot included one sheet that

(b) (4)

documented only one analysis was run. I t was explained that individual bottles should have been tested.

44. Some procedures reviewed are not reflective of the firm's current practice. For example:

• The procedure entitled: Operation

(b) (4)

ofth• • • • • • • • • • • • • • •, , , , T 2U?? ffective 10/13/09, allows operators the option to of dru

product. The last lot of

(b) (4)

product, Cerezyme A8062, run using indirect filtration was on ] l/3/08.

• The procedure entitled: Preventative Maintenance Process Procedures Using the Computerized maintenance

Management System at Allston Landing, PM-023-70 was changed effective 2/ll!09 to remove the requirement that quality

needs to review preventative maintenance documents. The rocedure for "Maintenance ofth • • • • • • •1Lyophilizer and 'effective 10/6/09 requires quality to perfonn

final reviewof

all maintenance logs. Quality reviewofthe

lyophilizer maintenance documents was discontinued asof

January 2009 but the individual equipment procedure has not yet been updated.

• A cleaning-in-place procedure used a check to ensure that water was flooding the pipes. Th. check was not

incorporated into the SOP.

• After a assay was performed in the QC lab, the data was compared agains t historical data in the Allston

Landin . This practice of trending results was not incorporated into the SOP.

SEE EMPLOYEE(S) NAME AND TITLE (Print orType)~ O Y E E ( S ) SIGNATURE DATE ISSUEDREVERSE Debra M. Emerson, Inves tigator 11/13/09

V) '" '

~ n - . , ~ G\.F THIS

Thomas J. Arista, InvestigatorAGE . ,

(4103) PREVIOUS EDITION OBSOLETE INSPECTIONAL OBSERVATIONS



(b) (4) (b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)(b) (4) (b) (4)

(b) (4)

(b) (4) (b) (4)


FOOD AND ElRUG ADMINISTRATION


1 Montvale Ave

Stoneham MA 02180

781 ~ 5 9 6 ~ 7700

NAME AND TITLE OF INoN IDUAL TO WHOM REPORT IS ISSUED

TO: Hemi A. Termeer, Chainnan, President, and CEO

FIRM NAMEGenzyme Corporation


Allston, MA 02134

DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED;

DATE(S} OF INSPECTION

I 0 / 8 / 0 9 ~ 11/13/09

FEINUMBER

1000305672

STREET ADDRESS500 Soldiers Field Road


Drug Manufacturer

THiS DOCUMENT LISTS OBSERVATiONS MADE BY THE FDA REPRESENTATNE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONOBSERVATIONS; AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDINGOBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS TOBJECTION OR ACTION WITH THE FDA REPRESENTATNE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO TO FDA AT THE ADDRESS ABOIF YOU HAVE ANY QUESTIONS, PLEASE CONTACT F ¢K'"HE PHONE ~ ~ ~ ~ AND ADDRESS ABOVE,

DURING AN INSPECTION OF YOUR FIRMjl{(\ivE) E V E \:\\\11 \cy 45. The "Preliminary Manufactur' g I n v e s t i g ~ t t l m Procedure in response to Out-of-Specification (OOS) or Unexpected results at

Allston Landing" document 100-32, dated 9/30109 establishes that a "preliminary manufacturing investigation will be initiat

upon receipt of notification of ODS or atypical non-failing value via the respective attachment in QC-019-05." However, the

Fabrazyme intermediate lot number

___ collected Q.n 4/22/2009 \ : . . ; , ~ , 1'1: \5 9'7

46. According to the "Qualificat ion ofPTS Cartridges 1Analysts and Validation of Samples using t h ~ e s tSystem", validation document flQC-051-40, effective 04/25/08, establishes the acceptance

ssay is betweel The December 4th

and 8th

, 2008 samples fell outside of the______

(b) (4)

an respectively. Despite _ acceptance criteria established in the validation document, the tests we

still approved.

47. The firm uses wet lines for their sprinkler system. The firm has covers over all in house sprinklers. The system is deficient in

that:

• The firm has not inspected each individual sprinkler in house since the system was originally installed.

• The as built drawings for the location of the individual sprinklers were reviewed. The as-built drawings do not reflect the

placement and location of all sprinklers at current day.

• The finn had a stainless steel housing mounted around the sprinklers in the class 100 fill suite. The firm does not have a

drawing or diagram for these sprinkler housings.

48. Training of employees is insufficient in that:

• Personnel are performing routine job functions without being trained on the current approved procedures. For example, a

quality fill finish inspector performed AQL visual inspect ions on three lots of drug product (Fabrazyme A9007, Thyrogen

A9003, and Fabrazyme A9006) wi thout being trained on current version of the following procedure: Inspection of the

Finished Vial Product (unlabeled) Using tht ' ; Machine at Allston Landing, QA-006-05.; ,

49. The qualitygroup

hasno t

approved all as-built drawingsand

floor plans on site.• An error was identified on the current floor plan, the filtration room F-9 was drawn with no door to enter the room, QA ha

not reviewed this floor plan.

• On 10115/09, the diagram was corrected but the engineer did not correct the square footage in the room, This document w

not reviewed by QA.

• Prior to May 2009, when floor plans were changed, the older floor plan was discarded and it was replaced with the modifi

floor plan without any review or approval by quality.

SEE

REVERSEOF THIS

PAGE ,

EMPLOYEE(S) SIGNATU_RE , --- . . . . . \ ~ . ~ ~ - .._.f)_ ..( .

EMPLOYEE(S) NAME AND TITLE (Print orType)

Debra M. Emerson, Investigator

Thomas J. Arista, Investigator

DATE ISSUED

11!l3/09

FDA 483 (4/03) PREVlOUS EDITION OBSOLETE P A Gm A

~ ( J O I 41).



The observations of objectionable conditions and practices listed on the front of this form

are reported:

1. Pursuant to Section 704(b) of the Federal Food, Drug and Cosmetic Act, or

2. To assist firms inspected in complying with the Acts and regulations enforced by the

Food and Drug Administration.

Section 704(b) olthe Federal Food, Drug, and Cosmetic Act (21 USC 374(b)) provides:

"Upon completion of any such inspection of a factory, warehouse, consulting

laboratory, or other establishment, and prior to leaving the premises, the officer or

employee making the inspection shall give to the owner, operator, or agent in charge areport in writing selting forth any conditions or practices observed by him which, in his

judgement, indicate that any food, drug, device, or cosmetic in such establishment (1)

consists in whole or in part of any filthy, putrid, or decomposed substance, or (2) has been

prepared, packed, or held under insanitary conditions whereby it may have become

contaminated with filth, or whereby it may have been rendered injurious to health. A copy of

such report shall be sent promptly to the Secretary."

genzyme allston 483 11-20-09 purged(3)

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