05/06/20ll SEE REVERSE OF THIS PAGE Zache1·y

FOR~ I I'JJA 4~3iUWIIX)

(b) (4)

· HEALTH AND HUMAi\' SEI~\'JCES D DRUG ADMIN!STRATJON

- 05/06/2011

·vice Pre.sider'lt

Boul eva.rd

Broomfield CO 80020 ~1 632

This document lists observmions made by. the FDA repres~::ntative(sl during the inspection ofyom facility. They are inspcctional observations, and do Jloi represent a iinal Agency determination regai·ding your compliance. If yon have an ol~ject ion regarding an observation, or hnve implemented, or plan to implement. corn:ctive action in response to an observation, you may d i~cuss the oqjection or action with tht: FDA representntive(s) dlll'ing the inspection or submi l this information to FDA at the add ress above. If you have any questions, please contact FDA al the phone number and address above.

·

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1

Control procedures are not established which vaiidate the performance of those manufactnring processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. ·

Specifically, L (b) (4)(b) (4) I blenders, were used jnterchangeab1y for the production of Triamtererre and Hvdrochlorothiazide (50/25_LCapsules between 1998~2007 . (b) (4) (b) (4)

Blenders (b) (4) re identical in the- construction. Blende1 ~.,,as used for the (b) (4)

process validation of Triamterene and Hydrochlorothiazide (50/25) Capsules. BlenderO .'as equipped ·with a (b) (4) ~'~'hich was removed for the roduction of

, :

Triamterene and Hydrochlorothiazide (:50/25) Capsules, leaving . . -·---~_. ~~--(b) (4)~~~~-=~-----____. 'The average finished product dissolutio11 history documented a

downward trend for Triamterene and Hydrochloi·othiazide (50/25) Capsules JX~~· deviuti·un # 1 0-0065, . (b)

dated 02/11/2010, and was attributed by the firm as being "directly associated ·witb the use of blender (4)based on review of product history." "It is suspected that the blencting of i material is optimizec} with the use ofblendeJD(b) rhich does not have the (b) (4) . In 2007,

(4) (b) (4)blende1 (b) (4) was removed from service. Blender - were used interchangea 1998-2007 without any form of process validation for the productioi1 of Triamterene and Hydrochlorothiazide (50/25) Capsules with blender (b)

(4)

Currently manufactured products blended with blenders that ':vere not' validated for the product during process validation include:

SEE REVERSE a OF THIS PAGE

E~lPLOYEE!SJ SIGNATURE g~..__

E r ika V. But ler , Investigator , .,_ . I<:imbel-ley A. Hoefen , Investigator of}:> r-\ Zachery L. Mil ler, Investigat~~-- 0 5 /06/2011

DATEJSSU;:O

· JNSPeCTJO!\AL OBSER\ ATIONS __ .. _______ ._. _. - ·..:.· ·I',;,;AGE l ·OFY I'AGES --., ll:.f~- --~........--..-._

(b) (4)

J_:..:...:.:..:..::..:..!:.=::.:::.:..:.::....:_ _ _:_~==~=-··-··--;-C __ ,.,.. __ ... - ...,..._ =- --~- .. ... -- -

- -·---·-·-- - -----------

·• ---~---~-··&'«'' x·:.rr--··- ~-·--~~DEPART/I'IEIW OF HEALTB AND HUMAr\ SEHVi CE.S . ! FOOD AND DRUG ADJvi!NtSTRATIOl'

I OAE(SJ o.~ INSPECTION j · 5th r,, Kipling ·st . (P.O. Box 250 87 ) ~9/2011 - 0 5 / 06/2011

Denver, CO 8 0225 -00 87 j .dhUMBi:R li-

DJSTAI:;i AODP.ESS AND P!-ION~ NUMBER

( 3 b 3) 2 3 6- 3 0 0 0 Fax: ( 3 0 3) 2 3 6- 3 1 0 0 ' l 7l 7 7 59 : I ndust ::-y Information: www·.·£da. gov / oc/ i ndust ry ~NwAM~E~A~~~TM.lT~l"~~~-~~~~~OIV~IO~U~Al~T~O"W~HO~M~R~:ro~RT~IS~S~U:~D------~~--~------~~------~-----------------------------------

' TO : Gaspar . p._. Zunga .. Vice Pr esident: of TechnicEl.l Opel-a-ci on.s fiP.MNf\Mi:. STRE:T ADDRESS

Sandoz Inco~~p;,;o;::t=--a:.:.·-=c-=e-=d=--------------------+T<:2.;;,5,..:,5,5=W..,.e,;:,,;,s"'t.-;;;oM;-,ii,;d,.,\•,.·a""y'-· -B.:...o.:...u.:...'_l_e_-v_-a_J.:...~o.:...' ________________ -il CITY, STATE, Zl? CODE, COUNTRY · TYP::: ESTABliSHMENT ~NSPECTED

Broomfie l d, CO 80020-1632 Drug Manuf actu::er

)

This is a repeat observation from the 5/28/2010 FDA inspection.

OBSERVATION 2

Investigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific fai lure or d iscrepancy.

Specifically, 14 out of 79 (18%) laboratory investigations (LBINV) lacked documentation of an investigation into other batches or products or the estabiishment of a corrective action:

a) In-process specification for blend uniformity was not met for validated processes, including: wu; /f./.

Kipling St. (P.O. Box 25087) 80225-0087

Fax: (303) 236-3100 ViV.,TW. fda.

Vice Presi

ted

co 80020-1632

04

1717759

of rations

Boulevard

l\1anufacturer

011

SEE REVERSE OF THIS [>AGE

Erika V. Butler, Investigator Kimberley A. Hoe:Een, Investigator Zacl1ery L. Miller, Investigator

~~~-~-i.'

05/06/2011

----~--~-- ~~~~

SEE REVERSE . OF THIS PAGE

EMPLOYi:C:(SJ SIGNATUR;

Erika V. Butle~ , Investigator Kimber l ey A . Hoefen, Investigate~

Zacher y L. Mi l ler, Investigator

l'it!:Vidus Euni0i{01JSOLUT£. I .. -ololat.WI .

DATCtSSVEO

05/06/2011

(b) (4) (b) (4)APl identity out of specifications for

( ==-=t-:-::-~~1on (

03/ 15/201 1 and finished product related compound __ J on 12/07/2011 '"'ere rerun without the establishment of root cause 0._1 __ -co- I-.1.e- -ct...,i_v_e_a_c_tl.,...o_.ns.

t _.....,_ -- --~·D'£P'A'Rn·!E~;T OF HEALTH AND HU~'lr\.1\" SERV!CEsu -i FOOD AND DRU(i ADMINlSTRATIU!'\ ' O ISTRlCT ADDRESS AND Pt-K>N: I\1JMB€R

6th & Kipling St. (P.O. Box 25087 ) ·Denver, CO 80 225-0087

(303) 23 6 -3 0 00 Fax: {30 3) 236 -3100

DATE(SI 0" INSPECTION

04/19/2011 - 05 /06/2011 FC:INUMB EP.

1717759 · ::!::1dustry I rtforma'.: ion : www. fda. gov f oe/industry i N AM!:. AND TITL:: OF INOfVIOUAl. 10 WtiOM REPOP.T I~ SUED

· TO: Gaspa r "P.. Zunga , Vice ?residen:. of Technical Operations

Sandoz Incorporated CITY. STATE. ZIP CODE. COUNTRY

Broomf·ield , CO 8002.0 - 1 632

I STREET AOOr<ESS

i 2535 vJest Midw;:..y Boulevard ., . TYPE E:STA13LtGI-tM::NT 1NSPEG1ED

Drug l'1anufacturer =

-,

c) The purified water in the laboratory failed specification for microbiology testing on 02/07/201 1 (b) (4) (b) (4)for \Vater sampling point on 02/14/201 1 for water sampllng pointc=J Q.u_Q2/22/20 11

(b) (4)(b) (4)for water sampling point and on 03/07/201 1 fo r water sampling point! JTb.e laboratory investigation stated that "the assignable cause is biological contamination due to stagnation of water in a DOn-circulating branch of the water system." "Laboratory water is not a product ingredient and does not affect product quality." Each time the problem was fixed with flushing of the system and retesting. Investigations were not performed on any impact the purified water might have had on the laboratory tests performed between the previous check and the one that was out of specification.

This is a repeat obsen·ati~n from the 5/28/2010 FDA inspection.

OBSERVATION 3

The quality control unit lacks authority to fu lly investigate errors that have occurred.

Specifically, a) On 6/30/2010, a report was received from your contract packager that black specks were

observed on tablets while blister packaging Loratadine 10 mg batches j 95524, 195525 and 195529. Yom· investigation found an 11excess amount of the active" present in the extracted dark particles. The Quality Assurance evaluation concluded the dark spots are characteristic of the material and closed the investigation on 7/9/201 0. There '"'as no investigation as to the potency or purity of the speckled tablets or if they would pose harm to the consumer. The finished product lots were released and distributed.

·

, (b) (4) (b) (4)b) On 04/19/2011 the ocated in suite was "On Hold" as noted in the

E ~pment/Room Use and Cleaning Log for 11 011 hold for rust and paint bubble. Previously

"-:------~--=----:----"""":"-~___.(b) (4) An investigation was not performed to evaluate any impact on previously run drug products.

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

DEPARTMENT OF F()OLJ AN

(P.O. Box 25087)

o::: / indust

, . Vic?. President o£

Broomfield, CO 80020 - 1632 .

- 05 / 06/2011

Boulevard

SEE REVERSE OF THIS PAGE

Erika V. Butler, I nvestigator Kimberley P,_. Hoe:Een, I nv e stigator Zachery L. rhl ler, Investigator 05/06/2011

OBSERVATION 4

Equipm~nt and utensils are not cleaned and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity, strength, qLtality or purity of the drug product.

Specifically, Equipment was observed not clean and in sanitary condition. Below is a list of the unclean equipment observed:

'

(b) (4) Complete Clean accompiished and verified, equipment is on hold status.

Complete Clean accomplished and verified, ready to use. Diclofenac 75 mg Tablets_ Batch

(b) (4)- was c;ated pri;r to the complete clean.

Observed a thick (approximate l inch) build-up of pink Complete Clean accomplished and coating material adhering to the exhaust bypass vaives. Exhaust valve is located within the confines of the

verified, ready to use. Diclofenac 75 (b) (4)mgT ablets, Batch

porous coating pan. coated prior to the

(b) (4)Observed Kettle a parts cart had incorrect Room labeled "Complete Clean," on status labeling, indicating "in:.process" instead ofthe 4/25/11. "comp lete clean" performed status.

Observed a cleaned processing hose return line stored on the floor after "complete clean" had been performed. Hose transfers coating material from mixer into the tablet coater · Observed a dirty cloth wipe underneath the tablet coater after the room had been labeled, "complete clean."

DE!'ARTJ\·IE!'\T OF HEALT H AND HUMAl\' SERV ICES I FOOD AND DIWG ADMINISTRATION 1

CIS 1 RICT ADDRESS'AI\!D PHONE NUM!ER l OATE.(SJ Of= 11\!SP i:. CTION

6th 0: Kipl i ng St . (P.O . Box 2 5 0 8 7) i 04/19 / 20 l l - 05/06 / 2 0 11 Denver, co 80 225- 0087 . I FEI N'JI.iiEP. I

(303) 236 -3 00 0 F a ): : ( 3 03) 236 - 31 00 1 71775 9 I ndustry Information: wwv1. fda . g ov /oc/industr:y

, ~~~.kE AND TIT~E OF INDIVIDUAL TO WHOM Rc::~ORT ISSUED

TO : G.p.spar _.h.. Zunga , Vi ce Pr esident of Technical Operat ions FIRM NAJ<.E I sr?.=Er ;.oo~ess )

Sando z I ncorporated ·2555 West l11idway Boulevard (

CITY. S1 ATE, ZIP coo=. COUN TRI' I T:PE ESTABLISKM!O~Jl'~I<SPECT:OD' '

Broomfield , co 8 0020- 1 6 3 2 Drug f\1anur ac~urer

l

i

OBSERVATION 5 l

An NDA-Field Alert Report was not submitted within three working days of receipt of information concerning significant chemical , physical, or other change or deterioration in a distributed drug product.

:

Specifically, On 12/29/201 0, your firm received a complaint from a pharmacist who reported finding a · Methazolamide 50 mg tablet (batch number 191103 2 that appeared to look "twice as large as the others. 1'

(b) (4)Your investigation found the tab~et weigl:edl . "' . . . lher(b) (4)~t (b) (4)

ilirn the targeted tablet weight ofl jrl11S exceeaed your upper specmcCl.t10n lnmt of grams. The FDA Denver District was not notified of this out of specification.

!

E

OBSERVATiON 6 l

Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information.

Speciftcally, - - . -Since 1 0/2008 until 04/1512010, there were 6082 Serious and Unlisted Adverse Drug Experience Ale1i Reports submitted to FDA by your firm, of which 116 were not submitted in a timely manner. For example the following is a list of ADE reports submitted past the 15 day time frame:

I

'

Case Number Product Day Submitted to Manufacture Number of days FDA Receipt date of Late to FDA

ADE

GXKR2009GB 12154 Citalopram/Lamotringine I 1/ 11/2010 11/4/2009 53 CHNY2008GBOI J 14 Ibuprofen 3/1 9/2010 3/3/2008 731 GXKR2009GB07550 Omeprazole 3/30/20 I 0 7/1 /2009 257 I GXKR201 0USI 0030 Carisoprodol 10/25/2010 9/3/201 0 37

This is a repeat obsen'ation from the 10/08/2008 FDA inspection.

EtA~OYEE(SJ SIGfo/A7URf g t--.(;{_t"-- OAT!: ISSUED

Erika. v. But le:::-, Investiga tor SEE REVERSE Kimberley 1' • . Hoef en, Inves tigator \!);, \J,

O(THIS PAGE Zac hery L . Mi l l er , Investigator -...._.~ 05 / 06/ 2011 ' '

~ ----- I /

.. .. ·Fort~ r mx 4~3 <o9TORJ .. · · rP.ovu;,us r.orntr.< o~w~arE · · INSPECf!O!':A L OBSER VATIO!I:S- _,, • M > ' ' .. . PACiE 6-Qf.O. J'AGES~ -... .

w ""//.

DEPAHTi'I'IENT OF HEALTH AN FOOD AND DRUG /\Divil

( P . 0 _ Box. 2 5 0 8 7 )

Vice President of

05 /06 201 1

Boulevard

Broomfield co 80020- 1632

O~SERVA TION 7

Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to fac ilitate operations for its cleaning and inaintenance.

Specifically, observed. the following equipment not maintained.

.. ,· •: , ...

(b) (4) Observed too numerous to count Complete Clean accomplished and verified, ready for use.

m~~·rvl'n metal lters in disrepair, j agged stl'ands protruding from filtering surface.

Complete Clean accomplished and verified. Previous! ' run procluct was Orphenadrine, lot# (b) (4)

This is a r(;! eat observation from the 5/28/2010 FDA ins ou.

OBSERVATION 8

Buildings used in the manufacture, processing, packing or holding of drug products are not maintained in a clean and sanitary condition.

Specifically, Multiple production rooms were observed not clean and in sanitary condition after a "Complete Clean" was accomplished and verified, including:

! 0

•. '·

(b) (4) Observed a used pipe seal, and piece a paper approximately 2 X 2 inches located underneath a vertical "Complete Clean," on mixer after coinplete clean. 4/2511 1.

Observed a pool of standing water on the fioor, directly under mixer and below mixer outlet contained within an ~Ipproximate 2 X 2 foot floor stain.

(b) (4) Observed a nest of packaging (b) (4)debris undemeath

SEE REVERSE OF THIS PAGE

Erika V. Butler, Investigator Kimberley A. Hoefen , Investigator Zachery L. Mil ler , Investigat

' i'fii::VIOU3 EfJITIO:o: OUSOl=lE ·· ·

05 /06 / 2011

!'AGE 7..0f

- ---------

6t- & l'.~p ~ng ..... . . Box ::> I} 4 i l _ - 5/06 2011 Denver, co 80225-0087 I FEINUMilER I (303) 236 - 3000 Fax: (303) 236 -3100 1 71 775 9 Industry I nformation: vJWV.•. fda. gov / oc / industry-. . '

NAM:. AND TITLE 0~ INDIVIDUA!. TO WliOM REPORT ISSV::C.

'

' TO: · Gaspar A. Zunga, Vice Pres ident of 'l'echni cel Ope!·a t: ior"s

FlRMNAN.:. I ~T;=;•SApO;:: t Sandoz Incorporated rHdv1ay Bouleve.rd CITY, STA E. Z.IP COO;, COUNTRY ' ' ' ! f)'PE E~TAe!..1SHM€:NT I NSP~CTEP

I

:Sroomfield , co 80020 - 1632 j Drug !'1anu:Eacturer • '

components- cleaned weekly. 4/26/ ll . (b) (4) Observed plastic packaging debris throughout. Room labeled,

"Complete Clean," on ; Observed clumped debris (approximate Y:, inch in size) 4/26/11.

along NE corner of room.

i Observed a dirt/rust rype substance, covering a 2 inch sg_uare surface on the floor, in the NE corner ofrocnn. I I

.I

OBSERVATION 9

Deviations from ·written laboratory mechanisms are not recorded.

Specifically,

(b) (4)Standards requiring storage at - emperature were not documented to be returned on the day of analysis between 20 10-201 0.

~~$'£*~flff~tl.~'i;&~i~Y!Kil~~~!illi(f~~~ru?~'M1~~~\~ ~~~~~ir~~~zy;~~i$~itl~lfi~~~~tU:kte.f!~!;ii~}.~jl (b) (4) 09/30/2010 I Not listed

I I

10/07/20 10 I0/22i201 0 11 /29/2010

Not listed

I Not listed Not listed

I 1/2912010 Not listed 11 /29/20 10 I Not listed I

l 12/01/20 l 0 Not listed I

12/01/20 10 Not listed

12/16/2010 Not listed 12/ 16/20 10 Not listed 0 Ill 1/2011 Not listed Ol/20/2011 Not listed 02/15/201 1 Not listed 02/15/201 1 · Not listed 02/24/201 J Not listed 02/21/2011 04/18/2011

···--·--~---·--------------···-········ .. ·--·-···

~

·- --

I

E.MPLOYE€(Si S~GNATURE 'V~ --1/. g~~ DATE ISSUED

Eri ka v . Butler, Investigator SEE REVERSE Kimber l ey A. Hoe fen, Investigator \ !.\~, i-\

05/0 6/2 011 OF THIS PAGE zache:ry L. Miller, Investigat~

I I I

l..!s?R~I"J'n,\ ~83' IU'J!Q~I . . -. ~ . ' JIH!:VIOCS f!t>ll'IOP: Ol1-50tETI~ · ' . INSJ'CCTIONAI.. OBSERVATIONS · ·· ·· · ··- ,. .. . · ··-· !'AGE t .OF ~ !'.•\G!!S . --

(b) (4) 02/24/20 I I Not listed 03/03/20 J J Not listed 0 3/1 4/20 I J Not listed 04/07/201 I 04/J 3/20 I I

No! listed I 04/1 4/2011

DEPARTivlENT OF HEALTH AND m JMAN SEHVIC£S FOOD AND DR U(i ADMINiSTRATION

OtSTRICT AOORESS AND PHON~ NUMBER Dl,TE<SJ o~ INS>ECTION

6th &: Kipling ·st. (P.O; Box 25 087) 04 / 19/ 2011 - 05/06/2011 Denver , co 80225-0087 i=CI NUJABER

(303) 236 - 3000 Fa):: ( 3 03) 236 - 3100 11717759

' Indus try I n forma t ion: www. fda.gov/oc/ indus try

1 NAV.E AND TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

TO : Gaspar _1.>,. _ Zun ga, Vice President of Teclu1ical Operc.ti01~s FIRMNAM~ ! STREC:T ADDRESS

I , Sa11doz Incorpo ra. t ed I 2555 West ~1i dway Boulevard

· CtTl'. STAT~; ZIP Coo:. COUNTR\'· I TVPE'EST.~ELISHMEI~T INSPECTED . ;

. Br oomfield, co 80020 - 1632 Drug Manufacturer

OBSERVATION "i O

. Established laboratory control mechanisms are not followed .

S pecifi call y, SOP MATA008 "Laboratory Reference Stru1dards", revision 09, validity date 08/30/2010, was not foll()wed in that there ,;o,,as no documentation for:

(b) (4)

OBSERVATiON 'I 1 - .. _ ... - .. . --· - ...

There is a lack of rotation so that the oldest approved stock of components is used first.

Specifically, l (b) (4)For at least two productions of metformin tablets 1. multiple older lots of

metformin API (b) (4) lwere available for use and a newer lot of APl l (b) (4) I was selected by warehouse personnel to send to production.

EMptOYEE(S) SIGNATURE

0---~ v: [Jdffi___ Dlo.I: ISSUEO

Erika v. But ler, Investigator ,t" Cl·.,l.).~.~; t·: ;~ \' ~ \• \ \ tJ {; .; (./(\ SEE REVERSE Ki mberley Jo •. Hoe fen , Invest igator

05/06/ 2 0ll OF THIS PAGE Zachery L . Miller , Investigator

I

/ ~ - -I

' FOR~ ! FlM ·IS)'(U,/OS) r·ru::v10t.'S I:!Dinm·: oosou;:rc- - .. ... !NSl'ECTIOI'\AL OBSERVAT IONS . . .... . . . . ... ... . P'/\.Gr:. .~~ OF ~.l P .:\G!!S i

J I

'