- ... Dli:PARTM.ENT OF HEAL"J'll AND HUMAN S.ERVl C ES

FOOD AND DR.UO ADMINISTRATION DIS!~JCT AOOr«::E.S Jo.Jo.ID P..IO'Hi:: MJMa5.R OA!E(S) OF INSt-t:CHCN

1431 Harbor Bay Parhvay 01/08/2013 - 02/28/2013* FEI NL'MSCR.Alameda, CA 94502 - 7070

(510) 337- 67 00 Fax: {510) 337-6702 3004182921 I ndustry Information.: www.fda . gov/oc/ i ndus t ry ~f AND riTLE OF INOMOUA1. TO WHOM REPCflT IS6UCO

TO: Chungchiang Hsu, President (y Chief Executive Office r F'IRMNA.IJ,JO'

Impax Laborato r .i.e s , I nc . en\'. S'fATE, ZIP COOE. COUN'J'IW

Hayward , CA 94544-BOS

Sl~f:T ADDRF.SS

31145 Sa r: Antonio S t reet r\'PE: ESTA6ti$HM£N, INSPECT EO

Drug t"lanufac·turer

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. lf y0\1have an objection regarding ao observation. or have implc:mented, or pl:m to implement, corrective action in response to an observation. you may discuss the ob;ect1on or action with the FDA representative(s} during the iusp<~ction or submit this infonnation to FDA at the address above. lfyou have any questions, please contact FDA at the phone number and address above.

-DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

OBSERVATION 1

The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established .

Specifically, Pertaining to NDA,(b){4)):,evod.opa/Carbid(m~JPX066 A. T he method val idation performed for NDA1(bf(4t:,(t?1(4 ) (lPX066) (Levodopa/Carbidopa Capsule) finished drug products a..o; specified in Test Method, T066RS.J 8: Quantitation ofDegradation Products in IPX066, is inadequate. For example:

l) The firm fai led to establisl1 ~eci fications (evaluate, identifY, monitor, and test) for the two known impurities and/or

dcgradantsJb) {4) 1and (b) 4 that are identified on the COA fo r API, levodopa,

manufactured by (b) (4)

2) The impurity profile does 1\0t include these two (2) known impurities in the finished stability produc1.

3) ·n1e speci fi city of the test method is not established because the force degradation studies were not performed t\nder

acid, base and oxidations cond itions.

4) The USP as.say fest method used for lot rel.ease and retesting of the carbidopa and levodopa API is not stability

indicat ing.

5) Water determination using(D) (4) titrator for components l, ll , Ill and. IV wa not validated.

6) The firm is not testing for the isomer d .. Dopa in tl1e levodopa API during release.

7) The ~1udy to determine the relative response factor (RRF) for impurity(b) (4 )wa inadequate. The firm's Relative

Respon:,;e Factor was not determined with a fully validated method because._.i~~r.~ed accuracy and linearity lo cover

the validation ranges. (6} (4)purity was based on ~t)) (4) ofLevodopa. (b 4} t:ilizing placebo samples (free of

the active) was not studied and no comparison of'u' ,.. 1 area response to a solution of(D) ( 4) standard.

!>APlOYEEIS)SlGN>.TU"~ !D.!>TE ISSUE)

Dani el J . Roberts , Inv~s t i gator ~~~ Walde n SEE REVERSE ~ · Lee , ,...Chemis·t . . ....::> . ~~OZ/28/20 13

OF THIS PAGE Ki.m L . <homas ·~ruse, Chem1st~ _

I

FORM FUA 48~ (09/0~) PRFVKHI.'i PDI T1.C>NONSO!k:tf INSI'ECTlONAL OBSRRVATlONS PAGE I OF 17. PAGES

- - --

DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINJSTRATJON

DISTRICT ADDRESS AND PdONE NUMBER DATE(S) Of INSPECTION

1431 Harbor Bay Parkway 01/08/2013 - 02/28/2013* FEI NUMBER Alameda, CA 94502-7070

(510) 337-6700 Fax: (510) 337-6702 3004182921 Industry Information: Hvvw. fda. gov / oc/ industry NAME AND TITLE OF INDIVIDUAL TO WHOM REPORT ISSUED

TO: Chungchiang Hsu, President & Chief Executive Officer F!RM NAME I STREET ADDRtcSS

Imp ax Laboratories, Inc. 31145 San Antonio Street CITY, STATE, z;p CODE, COUNTRY TYPE ESTABUSHMENT INSPECTED

~~ayward, C~. 94544-7905 IDrug Manufacturer

EMPLOYEE!S) SiGNATURE CATE ISSUED

Daniel J'. Roberts, Inves~.:.gator 'ls;:,~ Walden H. Lee, C1emistSEE REVERSE

02/28/2013Kim L. Thomas Cruse, Chemis~~OF THIS PAGE

FORM FDA 411) (09/fiS) FRf,VI0lT~ Rll!TIIlN i'lHSilLFTF INSPECTIONAL OBSERVATIONS PAliE20FJ2PAGES

Commercial Products B. Non~suitable test methods are used to release finished drug products.

1) During the establishment inspection, we reviewed test methods for eighteen ( 18) products and found that 100% of

the reviewed methods were not properly validated. For example, accuracy, sensitivity, linearity, LOD, LOQ,

and/or specificity were not assessed in the method validations. There is no assurance of the reliability of the data

and results generated with the use of the following test methods:

s Test I TeSI

Product Orvin Loss on

1 Substances Purity/Related '

Dissolution fi:Jrmity. Uni Content

Assay

Acarbose Tablets NV IV IV IV IV

Bethanechol Cl Tablets IV IV IV IV

Bupropion HCl! ER (XL) Tablets NV IV IV IV IV

Carbidopal Levodopa ER Tablets NV IV IV IV IV

Fenofibrate Tablets IV IV IV IV

Nadolol/ Bendroflumethiaz

.J9e 'fablets NV IV IV IV IV

Colestipol Tablets IV IV IV

Carprofen Tablets NV IV IV IV IV

Tamsulosin Hydrochlmide Capsules IV I IV IV

IV IV IV IV

Terbutaline Sulfate Tablets NV

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

' '

I

I

I

DEPARTMENT OF HEALTH AND HliMAN SERVICES FOOD AND DRUG ADMrNISTRATION

DISTRICl ADDRESS AND PHONE NUMBER DATE(S) OF INSPECTION

01/08/2013 - 02/28/2013*1431 Harbor Bay Parkway FEI NUMBERAlameda, CA 94502-7070

(510) 337-6700 Fax: (5 0) 337-6702 3004182921 Industry Information: www. fda. gov/oc/industry______L__ -----------------1 NAME AND Tl";i_E OF INDIVIDUAL TO WKOivl REPORT ISSUED

TO: Chungchiang Hsu, President & Chief Executive Officer STREET ADDRESSFIRM NAME

31145 San Antonio StreetIrnpax Laboratories, Tnc. CITY. STATE ZIP CODE, COUNTRY TYPE ESTABLISHMENT INSPECTED

Hayward, CA 9 4 54 4-7 9~.csc____.__________jc_::Dc:rc'u-_·g:L~Manu facture r

SEE REVERSE OF THIS PAGE

FORM FDA 41!J (09/0Rl

DAPLOYEE(S) SIGNA 11JRE DATE ISS:JooD

PHEVJOil' FllJTI(IN OBSfllYTF rl\SPECTIONAL OBSERVATIONS PAfiE10Fl2l'A()ES

'Test i Test

Produc! Loss on Drving

Chromatographic Puri!y/Rclated Substances Dissolution Uniformitv A~say

Phosphate Chloroquin I

Tablets NV

Dipyridamole Tablets NV

Loratadine Tablets NV

Primidone Tablets NV

Orphenadrine Citrate Tablets NV

Oxybutynin HCI Tablets NV

Oxymorphone HCJ Tablets NV

IV- Inadequate Validation Data NV- No Validation Data

2) The firm's consultant completed an assessment of one hundred and twenty seven (127) test methods for stability

and product release and found them inadequate. The analytical methods include, but arc not limited to,

identification; assay; content uniformity; dissolution and related substance. As of2/8/20l3, QC and/or QA

approved and concurred with eighteen of these assessments. The firm continues to analyze and release products

with these methods regardless of the known deficiencies.

Lots i with

Product !)osage Lot#

Acarbose Tablets 25, 50, 100 mg

H0030371, 10000593, 10004381,10002860, 10002859,10004380, 10000595, 10001534, H9071531

Bethanechol Cl Tablets 15,10, 25,50 mg H0091541, 10003129, 10001683, 10001801

DEPARTMENT Oli JIEAL'fH AND !-lUMAN SlmVJCES FOOD AND DRUGADMINISlRATION

6iS1RICT AOc;tF-SS ANCPHON!i NUMBER 1 OA.Tf(S) or tNS PECn ON

1' ~1 Ha r bor Bay Park1vay-.~k

Al ameda , CA 94502 - 7070 (510 ) 337-6700 Fax : (510) 337- 6702 Industry I nfo rmation : www . fda . gov/oc/industry NAME AND 71n.C:. OF !NCnfiOUAL I OWI.fOM REPORT I$$UEO

01/08/201 3 - 02/28 /2013 * f CIIIIJMSER

3004182921

TO: Ch ungch iang Hsu , ?residen t & Chte f Executive Officer FIRMNAil.IE

Impax Laborato r-ies , I nc . arv. sr-.rE~ ZIPCOOf. covtn 'tv

Hayward, CA 94 544 - 7905

STRer,·, NJORESS

31145 San Antonio St reet TY"': ESTASUSI<:JEHT IHS0 EC1ED

Dru2 Manufacturer

CMP~OYEE(SI SIGNA"fVRE OA'ff. ISSV£0

Dan.ie l J . Robe r ts, Investigator~~~~ Walden H. Lee , Chemist SEE REVERSE 02/28/2013OF THIS PAGE Kim L. Thoma s Cruse , Ch emist ~41..~ -....A­

~

I'ORM FDA OJl' (D9M8) PJt t.:\•loJ •~ l'!l"'rTinNn"~ol.em

! Lots l{eieii:<Oed wirb Defic-il,nt Test Methods i r--·-·----·-·-·--····-----------~=,-;;; ·--·--··----·-- r:-:--··-·---..-·--··--------,

l'roduct Dosa~e

100, 1_50, 200 ml!;Bupropioll HCI ER Tablet

25/ 100, 50/200 mgCarbidopa/Levodopa ER Tablets

54, 160 mg~!?Ea..te Capsules

Nadolo l/Bendroflumethiazide Tablet 40/5, 80/5 mg

Lot # 1

10000516, 10005195, 10003829 I10000700, 10000803, 10000804, H9 10! 291, H9 10!551 , H910 134 l , H9 10135l 10001036, 10001037, 10001294, 10001223 , 1000 1293, 10002865 10005261 , 10003033, 10001642

c--·--·---·-······-····--····--·······--······---··--······-....- -·-······--·---···-······:······--·-······-····--·····-·····--··,

3) The firm fai led to determine the acceptabil ity of test methods prior to using them in the QC laboratory through formal method transfer procedures . The test methods are currently used by the QC laboratory ro release raw and in-process materials, fi nished drug products, and siability samples. SOP 2ALY-01 2.07, "Transfer of Analytical Test Method", effective on 8!15/1 2, states in Section 2.2: This procedure applies to 1he tranrfer ofvalidaled. non-compendia/, analytical test methods from the Origirwting Lttborawry (OL} to the Receiving lAboratory (RL) (including transfers to andfrom an lmpax laboratory r.o a conJracf laborarory). Examples includes:

..........................................,,,_,H•.•• - .....- - •·•--.............,.,..,__,...,....__~,o-.---·- ······--··----­---· ---······-- ·--·___fu~!.t~matc M'~:_!:~o.~.I.!:!~f£!:.. __ _______.._ Product -- · Test Method ·Loratadinc/Pseudoephedrine ER Assay, Dissolution, Relat~d---Tablets Substances

Assay, Content Unifom1ity, ~~ HCITablets Dissolution, Related Substances

Assay, Content Uniformity, Terbutatine Sulfate Tablets Dissolution, Related Substances

4) lmpax use.~ test methods that are not stabili ty indicating to re-teSt and release active pharmaceutical ingredients (API) used in the production of finished drug products. Examples include:

a. The linn uses USP assay test method (T itrat ion Method) for Pyrid.ostigmine Bromide API. for raw material retest. Titration is not a stabil ity indicating method and cannot detect unknown de1aradants. For example, Pyridostigmine Bromide purchased from the API manufactur&{D) (4)ot( D) (4) vith retest dales (re­

evaluation) ofNovember 24, 2009, were retested by the finn using the USP iitration method. This API lots were use.d in the manufa~t~re ofPyridostigmine Bromide 60 mg tablets lot\(~) (4 )""l pproved .Tune 23, 2010.

­

INSJ'ECTIONAL ORSERVAl'IONS PAGF. 4 OI'IHAGF.S

OI::PARTI\IENT Of REALTH AND HUMAN SERVICES FOOD ,\ND DRU<} ADMJNISTRATION

OISl R.iCT li.P\JI<t:a::! AIID f'~N£ NUMOER

l<J 31 Harbor Bay Parkway Al~nnecla , CA 94 502-707 0 /510) 337 - 6700 Fax : (510} 337-670 2 I ndust ry In format i on : WWvJ . fda. gov/oc / industry MAU:! ANCmLEOF lt«;;iV10UAl TOWHCMRE~r :ssut.o

OAT£.(S)Of. INSPECliON

01/08 / 2013 - 02 /28/2013* FEINIJM81!.R

300418 2 921

TO: Chungchiang Hsu , President £ Chief Execut ive ot:: i cer FIRJdiH_A\~

Impax Laborato r ies , I n.c . CITY, STATE. liP CCDE. COUNT~Y

~9yward , CP.. 945 44-7 905 ...-...

STP;t:El. A<'JCRESS

3114 5 San An tonio Street fYPF. F:SiABL!S!i~JtJ( l l+$f't:C'1ED

Drug Hanu f actur.er

£1:M"LCYE-ZISJ SICiUATURE OAl'C: 1SSUF;P

Daniel J . Robe:rts, ~nvestigator ~~ . SEE REVERSE ~Jalden H. Le e , Chemlst _ ~

02/28 /2013I<im L. Thoma 8 Cr u s e , Chemi st ~ · ~.....-A'~.~-OF THIS PAGE

mRM PDA 483 109/uSl f'JI I•Yil'lSN Fnrrlf')NOfi~!!-<Tf; INSI'fCTlONA I, ORS F:RV A TJONS ?AGt l OF 1l PAC.ES

b. T he firm uses USP assay test method for Bendroflumetbiazide API (a titration method) for raw materia} retest

T itration method is not a stabil ity indicating method and crumot detect unknown degradants. For example, Bendroflumethiazide I>Urchased from the API manufacturer( b } (4) Jot (o (4) with retest date (re­

e valuation) of September 4, 2012, and wa.~ retested by the fi nn using the USP titration method. Tnis APT lot

was used in the mrum facture ofNadoloi/Bcndroflumeth iazide 40/5 mg tablets lo b } (4} jiPProved November 30, 2012.

c. The firm uses USP assay test method for Pseudoephedrine Sulfate API (a titralion method) for raw mater ial

retest Titration i ~ uot a stability indicating method and cannot detect \mk.Jlown degradants. For example,

Pseudoephedrine Sulfate purchased from the API vendor(b ) (4 ) Jot1Dl.!~1 with retest date (re­

evaluation) of September l , 2009, was retested by the firm using the USP titration method. This API lot was

used in the manufacmre of Lora tadine/Pseudoephedrine Sulfate 5/ 120 mg tablets lot ( b ) (4 approved November 18,2009.

REPEAT O BSERVATION

OBSERVATION 2

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

Specifi cally ,

Pertajning to NDA(b) (4) Levodo~a/Carbidona ! PX066

. A. The fi rm's bulk hold studies dala for the drug @Oduct and intermediate component lots(b ) (4) (6)(4)

b ) (4) _;how a tai ling and/or co-eluting on the Levodopa peak in the chromatogram. There is no assurance t·hat the results generated from these Studies are accurate and precise.

Furthermore. the SL'\. (6) month hold time data s ubmitted for intermediate components{bl (ll)~nd the IPX066 ~) ~} and (b ) (4} fini shed bulk drug product was not complete at the time of filing this application.

B. Two (2) deviations occurred during the execution ofthe air and ocean shipping studies for the finished bulk drug product. These deviations included the following:

l. T he refrigerated truck cooling system was not turned on.

2. A plastic strap was noted on the fi11ished bulk container shipment in lieu of the metal strap specified in tbe protocol during the ocean shipping study.

·- Vtt' !I'. 4AI P -.oMMJi . ijWi i . J_ .,......

J)EPARTMENT OF Hli:AI.Til AND HUMAN SERVICES POOD AND DRUG ADM!NlSTRATJON

0 1/08/2013 - 02/28/2013*1431 Harbor Bay Parkway FEI NUMBERAlameda , CA 94502-7070

(S lO ) 337-670 0 Fax : (510) 337-6702 30041829 21 I nd•.;stry I nforma t ion: www.fda.gov/oc/ i nd us try

~«~~~~MOl~1:1~Y•t~tO< I IOOM~T~O ~ ~~~~~~~~~~~~~~~-------L--------------------·------------~£~~ &~~~~ lW~I~O~~R~E~~~T

TO: Ch~.mgchiang Hsu, P-resi dent & Chie f Executive Officer

I mp ax Labo r atories , I nc . 311 45 San Anton i o St .reet TY~ IP""CO:;D;.;.E,:;CO;;;~;;,.TR;;,.Y=...::c:c.!............::.;.:.;:...'------ i ;;.;~;;;,;t-;C:;;:I . ~Sl;;AT,<,""Z"" ,N~ ------+mpt,:;£~S1;.:<AB;.,l;iSH ii F.?.il\lfmsPECTED ---------------~

Hayward , CA 94544 - HC S 1 Drug Hanufacturer

04iE ISS.•J::OffAPWVfE(SjS~AT\oiRt;

Daniel ~ . Robe rt.s, ~nvesti gat.or ')"'<'::~~ SEE REVERSE ~va lden h. Lee , Ch em1st ~ ;T .0; 02 /28/20 13Kim L. Thomas Cruse , Chemi st ~~OF THIS PAGE

TNSPECTIONAL OBSF.RVATJONS

These deviations were never discussed or evaluated in t.~e air and ocean shipping validation report.

Commercial P1·oduct.s

Established manufacturing process parameters are not always validated.

C. The established sampling plans during process validations,are not statistically representative of the batch size. Fo,!~ example, the finn uses the generic sampling plan to collec(b) (4l:amples from tl1e blender fo;: blend unifonnitv and(b) (4

samples for dissolution during compression/encapl.-ulation irrespecti ve of the batcJ1 size o~(b) (4) nits Ol(b} (4} (b 4 units.

D. The inlet air temperatureuseddurin~oating to accelerat~ the,drying process ofhygroscopic Colesfipol tablets has an established proce<;s parameter oJ\(6) (4~C and a tan~et of b)(

41·c in the batch productioll record. The validation data only supports a process parameter range o (b) (4) tc.

1411. in 201 2, 33 of the!bl Colestipol 1000 mg tablets batches manufactured were outside the validated process

parameter rAnge 01 b) (4) JCduring the coating process. The finn has received five (5) complaints of!>'WOllen Colestipol tablets in 2012.

E. The compression force feeder speed that is used to maintain uniform die fill and compressibility during tablet compression for D 4 ) abletshas an established process parameter of(b} <4~M in the batch production record. 1l1e validation data only supports a process parameter o(6J (4}lPM.

4F. On 118/2013 during a tom ofBuildinr < J\Iarehouse, we observed several in-process materials being stored at the

compounding, blending, and compres ion stage of the manufacturing process. SOP #2QUA-036.06:Tracking Bulk Holding Date oflntennediateand Fir.ished Product in SAP states that in-process hold-times in the warehouse are

(b) (4) n;e fum has no scientific data through valid.-'ltion to support the assignecfbl 1411ays.

REPEAT OBSERVATION

OBSERVATION 3

There is a fail ure to thoroughly review any unexplained discrepancy and the failure ofa batch or any of its components to meet any of its specificat ions whether or not the batch has been already distributed.

Specifically, There is a failure to thoroughly review and document unexplained discrepancics. Examples include:

1A. The d eaning solution rinse water from the Samp)jng Thief. D (4) was tested on 07/25/20 12 and unknown peaks were identified on the HPLC chromatogram. There is no deviation report, investigation, or root cause assessment [or the unidentified peak observed in the HPLC chromatogram from this test. Tht: sample was re­injected(b ) <4~1d re-vialed without documentation.

OIJ:I'ARTM.~NTOF HEAL'l'H ANl> HUMAN SERVICES fOOD A.l-10 DRliG ADM!NfSTRA TION

QIS";RJCT A!JbRC: 5S .&.NO Pi-tONE 1\VMSER

1 431 Har bor aay Pa rkwa y Alame d a , CA 945 02 - 7070 ( 51 0) 337-6700 Fax: (510) 337 -6702 I ndustry I nformat ion : www . f da . gov/oc/ i ndust ry ~~E ANO TtH.E Of I'NOIV\OUN.. TOWHOI:A RSPORT ISSVt:O

bATE{S) Of= tN&~CTION

01 /08/2013 - 02/28/2 0 1.3 * .::-a NUMBER

3004182921

-TO: Chur.gch.:. ang Hsu, Pr es iden t & Chief ~xecutive Officer

F<AM N>ME 51REEl AOORESS

311 45 San Antonio St r ee tl :mpax Labora t or i es , I nc . 1'VP£ ES1 ..\6U SHMENT 11-l$Pf:C'TEC CITY. STA Tf , ZIP COOE, COUI-ln\Y

Ha ywar.d , CA 9~5 4 4 -7905 1 Drug Manufacturer

-

B. Eight (8) complaints from ~even (7) different lots were received for broken tablets ofCarprofen 75mg and Carprofen JOOmg between September and November 2012. Dur.ing the investigation of these complaints, broken tablets were confim1ed in I wo of the seven complaint lots. In addition, nine (9) broken tablets were also observed in the Carprofen IOOtng Io\{b) ~wing 104 week !>tab:ility sarnple testing. The investigations failed io identify the root cause and stated that broken Carprofen tablets are a known occun·ence.

c. Deviation PR lD #: 1301 wa.s initiated to investi?ate condensation and clumping in,(~)_(4)_ drums of(b) ( 4) Pyridostigmine Bromide, USP, lot t>) ( 4) This API is hygroscopic, thus sensitive to temperature I humidity. The deficiencies in this inve::rtigation repo11 are as follows:

1. It fai ls to address the impact of the warehouse storage conditions especia lly since the firm does not monitor humidity in the warehouse.

2. This deviation report fails to explain why assay for PyridostigmineBromide, USP, l oL~ tl) (4) 1vas not perfonned prior to ·use to manufacture finished dmg product: Pyridostigmine Bromide 60 rng tablets lots

(b){4) anct (b} (4)

OBSERVATION 4

Appropriate controls are nm exercised over computers or related systems to assure that changes i11 master production and control records or other records are instituted only by authorized personneL

Specifica lly,

Pertainiug to NDA. (b) (4) Levodopa/.Carbidopa IPX06_2 A. The software that controls the b 4) spectrophotometer, ,(6)l4hnd,{b)_{1 )_p anicle size analyzer used

for NDA (b) t4JOCb) (~(lPX066) were not validatt:d. These instruments/equjpment were used to analyze the NDA product The firm did not valjdate the instrllments data integrity acquisition system to ensure that analyst cannot re­write or delete analytical data during analyses. Data audit t.rails are not maintained and instrument audit logs are not saved. These instrumenU; generated data for the NDA submission.

Comme.rcial Products B. (b) (4) ~isture analyzer and UV spectrophotometer are used for~4} -.J

testing. The finn did not validate the instruments data integri ty acquismon system to ensure that analysts cannot re­write or delete analytical data during analyses. Data audit trails are not maintained and instmment audit logs are JJO!

saved. These instruments are used in the quality control and research and development laboratories. c. The in-process weight checks performe.d during tbe compression and encapsulation process are performed on

equipment scales that allow all production personnel to alter dates and time when performing these in-process weight checks. In addition, thelE>J!/ test machine,(t)} (4} 11lows for printing oftablet

Ef'PI OY'££(S j SIC..,\I'.'T...,R,ir OJo.TE ISSUED

Dan ie l J . Roberts , I nve s tiga tor :Js)~ SEE REVERSE Walden H . Lee, Chemist ~~ 02/28/201 3OF THIS PAGE Kim L . Thorr.as Cruse , Chemist ·

FORM FI>A 4H' i O"OR) 'f'REVIf) lJS J:nn f()'N Dll~OlETEW'S'Mll:la fNSI'I':C:1lONA I . OriSEUVA TIONS PI\Gf'iOF 1 2 1',\GI~S

~---

-DlcPARTMENT OF HEALTH AND HUMAN SERVlCES FOOD AND DRUGADMIN!STRATION

OISTR!Cf AIJOReiS.S AND fHONE M.JM:rif:l:l

14.31 Harbor Bay Parkwa y Alamed a, CA 94 502-7070 ( 510) 3 37-670 0 Fax: 1510) 337-6702 Industr y Information: www .fda.gov/oc /indus t r y

NA.\IE ANO m~~ 0 ' I •"<OIVlOV~~ TO WHQI,I OtPOR~ ISQJ[O

{lATE{SI C# 1!11SP£C'rlCN

01 /CS/2 0 13 - 02/28 / 2013* rEI IIA)NSt~

3 004182921

TO: Chu ngch.i..;ng Hsu , President & Ch ief Execut i ve Of f i cer FIRM NAIIJE

Imp ax Labora t o ries , I nc . c;TY, STJ..T'fi',""il COOE, COUNTRY

Hayward , CA 94544 - 190 5

S r.tE:t:T ADORES.&

31145 San Antonio Street \' 'I! ESTABUS~!V\t.NT INSPECl [ D

D::u.g Manu fa c t ur er

hardness raw data results durin.g in-process testing. However, the finn has never enabled this function, hence does not have or store raw data of this operation during production or process validations. --- ·

OBSERVATION 5

Written procedures for cleaning and maintenance fail to include description in sufficient detail ofmethods, equipment and materials used, description in sufficient detail of the methods of disassembling and reassernbling equipment as neces~ary to assure proper cleaning and maintenance, and pa1·arneters relevant to tbe operation.

Specifically,

Cleaning procedures and operations are deficient. Examples include:

A. The cleaning validation protocol tailed to address the swab location and the swabbing technique on manuf-acturing equipment during cleaning validatio11.

B. Swab studies have not been performed to determine the best swab for maximum recovery of active ingredient and other chemical residues after the cleaning operation of non-dedicated manufacturing equipment.

c. There's a failure to establish scientific rationale for tllc use of(b) {4) as a cleaning agent on product.ion equipment used to manufacture finished drug products.

D. During the cleaning val idation ofTerbuta line Sulfate, two (2) lots (lot#~) fai.led ma.ximum Terbutaline Sulfate chemical product carryover after the initial cleaning process from the(b) (4) spray gun. TI1e equipment was re-cleaned and the incident was never d iscussed in the cleaning validation summary report.

E. Equipment swab locations performed during the(b) (4) outine cleaning moni toring do not always include the most difficult to clean equipment parts specified in SOP 2VAL-001: Cleaning Verification and Validation Program.

1) For example, not all difficult to clean equipment parts included in this e()cedure are tested during (b) (4) ·outine cleam monitoring. The ( b ) (4) and:(t>) (4) parts specified for routine sampl ing on the (b) (4) Blender are not per l~mned . Additionally, SOP 2VAL-OO I: Cleaning Verification and Validation Program does not include the cleaning verification of non-dedicated sampling thief used for sampling multiple raw materials and APls.

F. On 1/1 1/2013, during a tour ofproduction area in Buildinewe observed the storage of loose~}]~wabs u.sed for swabbing clealled manufacturing equipment for the evaluation of APl and chemical res1 ue in a glass beaker. Thes~(b) (4) wabs expire within seven (7) days fi·om the date they are removed from the vendor packaged plastic v1rap andt fie "finn does not document the traceabili ty ofthese swabs through documentation of vendor expiration dates.

G. SOP# 2MFG~~02 . I 7: Cie'<~~lingProcedures for Processing Equipment that describes the preparation of in-house cleaning agents (diluted b ) (4). is inadequate because the preparation ofthis cleaning agent is not documented. A batch record w1th manutacturing instructious, lot numbers and expiration date have not bee!l established for this process.

UM'I.OYEE{S j SIGNA.1~ CAl£ !SSUI'dl

Danie l J . Rooerts,. I nvestiga t or ~~~ SEE REVERSE Walde n H. Lee , Chemi s ;: . .,::>' ~ o2; 2S/20 l 3 OF THIS PAGE Kim L . ThoMas Cruse , Cnenust ~ "'-- ­

! FORM PI"IA 4RJ W~!V&) P~EVfnt1.~ P))r)'JON 01\SfllF ff. fNSPECfTONAL OR:rifo:R"VATIONS PAfiiH OF 12 I'AGES

....._,., &llll*lll:lltl AII!Mi!IOIIraiRl" • ... IU .-~~....... -~f~---·- DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRt\TlON

D\STI<ICl AOORESSAN:l ?HONE N\J\18E~ OA~{S) r:::JF I~JsPECfiON

Oi/08/2013 - 02/28/2013*143i Harbor Bay Pa rkway Fl:fNUMSE~JUameda , CA 94502-7070

!510) 337-6700 Fax : / 5J O) 337- 6702 3()04 182921 Indus tr y Inform.atton : www. fda. gov/oc /industry -TO: Chungchiang Hsu , President & Ch:te f Executl.ve Officer

N.<r.IE ANO mle oF INDIVIOU•L 70 WWa'< I'<EI'd<T ISSUED

fiR!I.iNAMf

Imp ax Laboratories , I nc . CITY, STAl~. tiP COOE, COUNTRY

Haywa rd , CA 94544 - 7905

STR'EET AOORCSS

311 45 San Antonio Street '(Yt'E ESTASUSHMENT 1NSPECTEO

D!:ug Manufactur.:;r

.

OBSERVATION 6

Batch production and control record!i do not include complete iofonnation re lating to the production and control of each batch.

Specifically, A. Start and .stop times for critical procel>S parameters (CPP) are not recorded in the batch record during production

operation. For example, the start and stop time is not documented for Pyridostigmine Br CPP during pre-blending and final blending that affectblendwJifonnity.

B. AJ>I Assay results are not always used 1.0 calculate the amount of active ingredient needed to manufacture a given batch of drug products. For example, during the manufacture of Pyridostigmine, TamsuJosin, Cnlestipol, Carprofen, Fludroconisone, Primidone, Promethazine, Fenofibrafe, Dipyridamole, Galantamine, Terbutaline, and Oxybutynin; the amotull ofactive ingred ient to add during manufacturing is dete rmined by a theoretical val'ue of 100% and not the act-ual potency value.

c. There is a failure to maintain raw data during in-proces parameter checks for tablet hardness and thickness. F'or

exampie, all batch records <md process validations reviewed during the EJ do not have raw data printouts for hardness and thickness.

OBSERVATION 7

Reports of analysis from component suppliers are accepted in lieu of testing each component for confonnity 'Nith all appropriate written specifications, without establishing the reliability cfthe supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

Specifically,

The firm does not perform tes1ing ofraw materials for confonnity with all written specifications reported on the vendot's Certificate ofAnalysis (COA). They only perform limited testing and have not established the reliability of the supplier's test results. The finn has no documented justification for not perfonning all tests listed on the certificate. For example:

Pertaining to NDA(b) (It} _,e, •odopa/Car bidopa lPX066

A. For Carbidopa lots(D) (4} (IS) (4)

used to manufacture NDA lot~(b) {4} I "f the finn has not performed bulk and tap density.

T11e firm has not established the reliability of the vendor's analyses for th is test.

'f'WJ-t.OYEE(Sj S.GNATUR.E DAl E ISGIJtcO

Dani el J. Roberts, Investigator -'Is~ Wa lde n H. I,ee , ChemistSEE REVERSE I02/28/2013K.im L. Thomas Cruse , Chemist ~~~~~OF THIS PAGE

F'ORM FilA 483 ((IW081 l'F.F\IY.Ifi!\ i~01l'JONOaS~'H ,f>il : lNSrRCTTONAL OBSERV A TJONS rAGF:9 ()p 12 PAC.F..~

-- --

DRPAH:l'MENT OF HEALTH AND UUMAN SERVIC ES 1'000 AND DRliG ADMINISTRATION

C!STRICTAOORESS AND PHONE NUMBeR OA'tE(S~ OF lNS~ECT!OI"\

14.31 Harbo r Ba y Pa rkway 01/08/20 13 - 02/28 /2013* f EI...,.lllol<Alameda , CA 9 4 ~02 - 7 070

(51 0) 337- 6 700 Fax : !510) 337- 6702 I 3 004 ! 82921 I ndust .ry I n f e r mat ion : www. fda . gov/ oc /_indus t r ;x: I

t\IAME AND TITlE Of INO!V~DUAL l O WHOM REPOO f ISSUED

TO: Ch u ng c b i a ng Hsu , Pr es.tctent IX Ch i e f Execu ti ve Off.ice .r FIRM NAIJ"

! mpax Labor a tor i.es, I nc . a Y, .ST:.TE..ZIPCOOE.CCI'JN 1r(1

Ha yward , CA 9454 4- 7905

s ·t• EET AOCAF.ss

311 45 Sa n Anton i o St r eet lYPE E$fASVSH>"E!fi IIISY;:clfO

Drug Ma::u£actu r e r

B. For Levodopa lots(D) r:J) d used to manufacture NDA lots(o (4 ) (o) (4) ____.md(b) (4) e firm has not evaluated the presence of the enantiomeric impurity, d-Dopa. The firm bas not established the reliabil ity of the vendor's analyses for tlli~ test .

c. For "Hard Gelatin Ca~ule Shells, Size 00,(b}(~}(6) (4) Body and@ (4) Cap", manufacrurcr lot (b ) (4 ) and (b) (4 ) used in the submission, NDAJb) 4} the firm did not perform tests such as identjficat ion of Ti0 2, acetic acid content and loss on d ty ing. The firm bas not e-stablished the re liability of the vendor's ana lyses reported on the COA for these tests.

D. For (b ) (4 ) manufacturer's lot(D) (4 ) used in the submission lots, NDA (b) @) the finn did not perform tests such as sieve, apparent den ity, rapped density and an acid value as reported on the manufacturer's COA. The !irm has not established the reliability of the vendor's analyses reported on the COA for these tests.

E. For(b) (4 ) manufacturer's lots (0 (4) ):l nd 0 (4) respectively, the firm did not perform the residue on evaporation tests and did not report an acid value. The fi nn has not established the rel iability ofthe vendor's analyses reported on the COA for these tests.

OBSERVATION 8

Drug products are not stored under appropriate condi tions of humidi ty so that their identity, strength, quality, a11d purity are not affected.

TI1e fitm stores hygrosw pic drug products, such as Pyridostigmine and Colestipol, in warebousellifl4\ nd warehouse 14yithout ~tab l ish il]Lcontro l limits and monitoring procedures to prevent product degradation from moisture.

OBSERVATION 9

An annual report did not include a fu ll description of the manufacturing and control changes not requiring a supplemental application, listed by date in the order in which they were implemented.

Specifically,

A. SOP bas not been ~iablishcd describing or referencing the criteria for fil ing changes being effected (CBE) or prior approval supplement submissions.

B. Change in humidi ty specification from~5) (4)lH to(b) <4JR.H during production for Pyridostigmine was not addressed in a Changes Being Effected (CBE) su mission or in the 2004 Annual Report .submission to the Agency. Pyr idostigmine is a hygroscopic dru.g product.

c. Change in final blending time froml"114lminute- tc(bl <4J:nimates during production of Pyridostigmine was not addressed in a Changes Being Effected (CBE) submission or in the 2004 Annua l Report submission to the Agency. The increase in blend time was changed to improve blend uniformity .

- EJ!lPLCYEE(S: $1GNA1UR.E DATE ISSU~O..

Dani e l J . Robe r t s , I ~ve s t i ga tor ~~~ Walden H. Lee , Chemis tSEE REVERSE

02 / 28/2013OF THIS PAGE K.im L . Th omas Cr u s e , Chemist ~-----~ I

... I H Ul M J'I)A 4~) (0910&) VRFVIOI$ flr\rFION f)llSl~l .}lo'! ~ !NSPF:CTIONAL OBSl>:RVATfONS PAGE IQOf 12 PAGf.~-

HEPARTMlW I' OF HEI\l.Tli AND HUMAN SJmVICES FOOlJ AND DRUG 1\0MINISTRA'!'ION

OtSfRI{.T AOOr~EGS "-.NO ~~IE N\H\.WE.R

14 31 Har bor Bay Par kway Alameda , CA 9450 2- 7070 ( 510) 337-6700 Fax : (510) 337-67 02 Indus t r y Informa t ion : www.fda.gov/oc/indus try

l'liAAI:S: ANP rrn E OF INDIVIDUAl T0Wt-t0M REPORT : SSUi,O

OATE(S) ~ INSPECTI()t(

01/08/2013 - 02 /2 8 /2013~ F'I:IN:.IIJ>BEA

3004 18292 1

TO: Chungchiang Hsu, President & Chi e f Executive Office r FIF\11! ~4AMt'

I mpax Laborato r ies , I nc. CITY. STA'1e. ZIP CODE. COUNTI\Y

Hay~<Tard , CA 945<: 4-7905

6TR!!fT ADDRE.SS

3 1145 San Anton i o St reet TVPf ESTABLISHMG.N l INSPECTfO

Drug Manufac turer

--

-

OBSERVATION 10

Procedures describing the warehousing of drug products are not followed.

Specifically,

SOP 2WHC-004.14: Staging & Allocating :Manufacturing Materials in Section 4.3 states that the electronic enterprise resource planning system is used to document the location, transfer and movement of materials in the warehouse.

On lll0~~013"{4} )equested printout~ n·om the electronic enterprise resource planning management system. TI1e status and location o (b) 4 dnuns of raw material Co povidone lot(b ( 4 ) that were stored in the warehouse were unaccounted for in the electronic enterprise resource plruming management system.

REPEA1' OBSERV A UON ... ·­

OBSERVATION 11

Written procedures are not followed for evaJuations done at least rumually and including provisions for a review of complaints, recalls .. retumed or salvaged drug products, and investigations conducted for each drug product.

Specifically, SOP 2QUA-040.06: Annual Product Reviav that describes the review and approval ofAPR ~1ates in Section 5.!.5 that (b} (4)

[l@.[f4) ___:Jrhis procedure is not followed . For example on 1/22/2013, the most recent annual product review (APR) for Bupropion Hydrochloride Extended Relca e JOOmg between 1/28/2011-l/27/2012 was not complete (approximate ly 12 months after the due date).

OBSERVATION 12

Employees engaged in the manufacture and processing of a drug product lack the training and expe~iencc required to perfonn their assigned functions.

Employees involved. in all aspects of production and analytical testing ofdrug products are not adequately trained to perform their duties, see OBS 1- 11.

* DATES Oft INSPECTION: Ol/08/2013(Tue), Ol /09/20 l3(Wed), 01/l0/20 13(Thu), Ol/ll/2013(Fri), 0 !/ 1212013(Sat), OI/J4/2013(Mon), 0!11 5/20!3(Tue), Ol / l6/2013(Wed). Ol/ 17/20 J3(Thu), 0 1/ 18120 l3(Fri ), 01119120l3(Sat), Ol/2l/201 3(Mon), 0 1/22/201 J(fue), OJ/23/20l3(Wed),

£f>'Pi.0'<EElSJ SIG!\1A.lUf.fo Dl<TE t&w:O

Daniel J . Robe r ts , l nvestigator. ~~·~~ Walden H . Lee , Chemi st ~· 'SEE REVERSE _0 2/28/ 201 3

OF THIS PAGE Ki m L . Thomas Cruse , Chemist~-~-

FORM r<OA 4R~ (09108) f'RF..V~OUS f..UT(JIIN (l0S01£'[J:: TNSl'f:CTIONA L 01\SI?.l<VATfONS PM;E 11M 12 PAGES *'1111121< RS m ___,. • ........-== ....._ UOtt""t::er:::!:

--

--- --

DEPARTMENT OF HEALTH AND HVMAN SEH.VICES FOOD AND DRUG ADMINISTRATION

DISTRICT ADDRESS AND PHONE NUMBER

1431 Harbor Bay Parkway Alameda, CA 94502-7070 I510 I 337-6700 Fax: (510) 337-6702 Indust:ry Information: www.fda.gov/oc/industry NAME AND TITLE OF 'NDIV'DUAL TO WHOM REPORT ISSUED

DATE(S) OF INSPECTION

01/08/2013 - 02/28/2013* Ff'l NUMBER

300418292]

TO: Chungch.iang Hsu, President & Chief Executive Officer F;RM NAME 1 STREET A~DRESS

Irr.pax Laboratories, Inc. 31]4~ San Antonio Street: C!TY, STATE ZIP CODE. COUNTRY bTABLI~I:E~T ~N:P~CTED ·r

Hayward, CA 94544-7905 g Ma,,~fncture_,_ --

Ol/24/20 ll(Thu), 0 l/25/20 ll(Fri), 0 l/28/20!3(Mon), 0 l/29/2013(Tue), Ol/30/2013(Wed), 0 Ill l/20 l J(Thu), 02/0l/2013(Fn), 02/04/20 !3(Mon), 02/05/20 ll(Tue), 02/08/20!3(Fri), 02!12/20 ll(Tue), 02/26/20!3(Tue), 02/28/201 J(Thu)

fMPLOYEE(S) SIGNATURE DATE ISSUED

Daniel ~. ~oberts, ~nvestiqator ~·~~.:'" SEE REVERSE \riJaJ..den H.. Lee, Chem.lst ~ ) 02/28/2013OF THIS PAGE Kim L, Thomas Cr-use, Chemist ~~-=-=

FORM fl)A 41!~ (09/lll!) PRFVlOliS F!Jlll(IN ClfiSI1i.l'lT fNSPECTIONAI, OBSERVATIONS PMiE 12 Of 12 PAGES