37 page fda-483 to tablet manufacturer

7/29/2019 37 Page FDA-483 to Tablet Manufacturer

1/37

DEPARTMENT OF HEALTH AND HUMAN SRRVlCESfOOD AND DRUG ADMINIS11tAnON0lSTR1CT ACXlRESS AHO PHONE ~ 11630 W. 80th s t r e e tLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111In d u s t ry Information: www.fda.gov/oc/ industryNAME ANO nTLE Of INOlVlOUAl TOWHOM REPORT ISSUEDTO: Mr. David A. Van Vliet , Interim Pres i d en t andOf f i ce rfIRM NAME SlREET AOCRSSSKV Pharmaceutical Co Westport 2280 SchuetzCITY, STAlE, ZIP CODE, 00lJIN1RY TYPE e S T ~ ttSF'EC'TIDSaint Louis, MO 63146-3411 Human Drug ManufacturerThis document lists observations made 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 anobservation, or have implemented. or plan to implement, corrective action in response to an observation, you may discuss the objection oraction with the FDA representative(s) during the inspection or submit this information to FDA at the address above. I f you have anyquestinns, please contact FDA at the phone number and address above.

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED:

Observations cover inspections at the following firms inspected from 15Dec2008 - 02F.eb2009-

KV Pharmaceuticals, Inc., 2503 South Hanley Road, SI. Louis, MO 63144-FEI#1940015 KV Pharmaceuticals, fuc., (Westport), 2303 Schuetz Road, SI. Lows, Mo 6 3 1 4 6 ~ F E I # 1937079 KV Pharmaceuticals, Inc., (R&D Lab Metro II), 10858 Metro Court, Maryland Heights, MO 63043FEI#3002946714 , KV Pharmaceuticals, Inc.,_(EarthCity I), 13622 Lake!i"om Dr., Earth'City, MO 63045-FEI#3003266206 KV Pharmaceuticals, Inc., (Earth City IV), -Dne Corporate Woods Dr., Bridgeton, MO 63044-FEI#3004839832 KV Pharmaceuticals , Inc., (Controlled Release), 8050 L-itzinger Road, SI. Louis, MO 63144-FEI#I922566 KV Pharmaceuticals, Inc.;' 2258 Schuetz Road, Maryland Heights, MO 63043-No FEI KV Pharmaceuticals, I n c ~ '2280 Schuetz Road, SI. Louis, MO 63146-FEI#3007259359 KV Pharmaceuticals, Inc., 10876 Metro Court, Maryland Heights, MO 63043-No FEI KV Pharmaceuticals, Inc.,"I3910/13912 SI. Charles Rock Road, Bridgeton,'MO 63044-FE1#1922566

-QUALITY SYSTEM .. -

OBSERVATION 1The responsibilities and procedures applicable to the quality control unit are not fully followed.Specifically, the Quality ControVQuality Assurance (QC/QA) functions have failed as evidenced by the following examplesn

EM?LOYEE{S} SlGNAlUR.E . - { ( J .b .Q,lyn G Dic::k1n"oll, Inves


2/37

(b)

(b) (4)

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

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

(b) (4)

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATIONOISTRK:T ADDRESS AND PHONE Nl..IMBER DATC(S) OF INSPECTlON11630 w. 80th S t r ee t 12/15/2008 - 02/02/2009

"'NUMBERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 1937G79 3007 d-. 'Sq 3 5 rIndus try Information: www.fda.gov/oc/industry ~ NAME AND TTTLE OF INDfVDUAL TO WHJM REPORT ISSlJWTO: Mr. David A. Van Vlie t , Interim Pres iden t an d Interim Chief ExecutiveOff ice r

STIl>ET -"""ESS,-KV Pharmaceutical Co westpor t 2280 Schuetz RoadcrTY. STATE. ZIPCOOE. COlIN'TRY T"tPl:: ESTASl..l$l-NENT HS?ECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturerand the remaining observations cited OD the FDA 483.For example,a. After dissolutioD failures occurred with Metoprolol Succinate 25 mg ER Tablets manufactured with ER pellet lots ",ithbelow target assay values, several lots ofthe ER pellets (#'s 96671, 96856, 96857, 96858, 96859, 96860), with assayvalues below the target were bleDded offwith ER pellet lots with assay values at or above the target value. There is DOformal documeDtatioD or justificatioD for ihe bleDd-offprocess. This bleDdiDg off of sub par product was cODducted iD

approximately. lots of

(b) (4)

bulk tablets from September until November 2008. This was performed at the iDstructioD ofupper managemeDt and acceptance by Quality Assurance.b. After dissolutioD problems were eDcountered with Metoprolol ER pellets due to high acetic acid values' .J iD

acetic acid value of approximately and was used with 101# 122572_ in at l eas t . lots ofER pellets(#'s 98950-98954 and 101203-101214) in November of2008...

c. The quality control unit has failed to implement adequate corrective and preventative action into the hundreds ofcomplaints ofl eaking capsules received on PrimaCare .One, Prenatal Multivitamin/Mineral Capsules. The firmcontinued distributioD of this product despite continued complaints ofleaking capsules as evidenced by the following.The iDvestigation is ODgOing and produj:! is currently being reformulated.

2007 complaint statistics; over 350 complaints ofleaking capsules for PrimaCare ODe, with 26 documentedadverse eveDt reports (ADEs); CorrespoDdence from the manufacturing firm dated 02Jan2008 in which an "improvemeDt plan" is addressedfor the PrimaCaie ODe manufacturing process; and by 2008 complaint statistics; over 630 complaints ofleaking capsules with 21 documented ADEs.

d. Rework by re-screening due to unacceptable particle size was performed in August 2007, without chaoge C O D t r o ~ QAapproval and validation, OD IR pellets 101# 87843 (G-664). This pellet lofwas.used duriDg the remainder of 2007 andearly 2008 in the manufacture 0 Metoprolol Succinate 100 mgl200 mg tablet batches which weresubsequeDtly released. The batches included lot #'s Further, a pre-approval supplemeDt was not pursued forthis rework process Dor was this rework process submitted in the Annual Report dated 05Ju12008. Notes from an uppermanagement meeting indicate the re-screened product cannot be used for commercial sale until the pre-approvalsupplemeDt is approved.

e. The quality unit did not effectively review the packagiDg batch record priOriO the release of Oxycodone 15mg TabletsEMPlOYEE(S) SlGNA.1URE "'TE 0SS


3/37

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISnATION

0lSTR1CT AOORESS NID PHOHE M.JMBER OATE(S) OF INSPE


4/37

(b) (4)

(b) (4)

- 02/02/2009

Inte r im Chief Execut ive

2280 Schuetz RoadHuman Drug Manufacturer

Metoprolol Manufacturing IssuesSince the FDA approval dates

l ! ~ ~ i ~ ~ I ~ ~ ~ ~ ~ ~ ~ ~

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATION

CtSlRICT AOORESS AND PH(,IE NUMSER11630 W. 80th s t r ee t 12/15/2008

Fe NUMBERLenexa, KS 66214(913) 752-2100 Fax; (913) 752-2111I ndus t r y Information: w w ~ . f d a . g o v / o c / i n d u s t r y NAME AND TITLE OF INClMOl.W.TO WHOM REPORT ISSUEDTO: Mr. David A. Van V l i e t , Inte r im Pres ident andOff ice rKV Pharmaceutical Co WestportCfTY. STAlE. ZP CODE, COlJNT'IiySain t Louis, MO 63146-3411

100/200 mg ER pellets50 mg ER pellets25 mg ER pellets

100/200 mg IR pellets50 mg IR pellets25 mg IR pellets

50 mg bulk25 mg bulk

200 mg bulk100 mg bulk50 mg tablet25 mg tablet

200 tab,etl00 mgg tablet(b) (4)

Percentage of Batches

Michele Perry W i l l i ~ . I n v . ~ t 1 9 a t o r Regina T. Brawn, I n v e ~ t i 9 a t o r Kara 1.. Roden, I n v e ~ t l q a t o r ~ .. L _ SEE REVERSEOF THIS PAGEEric C. Nielsen. Invest igator l _ ~ Pat r ick L. KIsor, Inve:!ltl,,;ator lrvWar:en J. Lopicka. I n V e $ t i g a t ~ r " -Jennifer Cahill , Investigator 02/02/2009Joseph R. Lamber t , Invea t iga t

M a t t h ~ ' J. M ~ r r i s o n , InvestigatorTere L. King, Investigator ~ FORM FDA 483 (04103) PRE:VlOUS EDITIID: OBSOLETE !NSPECTIONAL OBSERVAnONS PAGE 4 OF 37 PAGE


5/37

(b) (4)

(b) (4)

(b) (4)

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

(b) (4)

(b)

(b)

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

(b) (4)

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTR...8 . . . . .BERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 1 9 ~ 7 G 7 g -Industry Information: www.fda.gov/oc/ industry ~ ~ W 7 b < S '13;"9

NAME AHOTTnE OF INOIV'Dl.JAJ.. TOWHOM REPORT ISSUEOTO: Mr. David A. Van Vliet , Inter im President an d Inter im Chief ExecutiveOff icer " . .NAME s m E 8 ~ S S KV Pharmaceutical Co Westport 2280 Schuetz RoadOTY. STAlE, ZP CODE, COl..WTRY TYPE ESiASl...lSHMENT NSPECTEOSaint Louis, MO 63146-3411 Human Drug Manufacturer

Product OOS NCR Lots RejectedInitiated100 mg tablet I-200 mg tablet I-25 mg tablet ( I-50 m a tablet ( I-100 ma bulk t' f-200 mg bulkl I-25 mobulkr r f-50 mg bulk I25 ma IR oellets -. f - I-'50 mg IR pellets. f - 100/200 ma IR oelletsr I-'25 maER pellets ~ .50 mg ER oellets' I f - l-100/200 maERpelletsT

..

, The OOS test reports included but were not limited to the following: Assay; Loss on Drying; Dissoilition; ContentUniformity, andParticle Size.' ..The NCRs included but were'not limited to the following: Foreign Tablet; unapproved deviation; Speed Study; Fail edAQL-broken tablet; Omission oflR Pellets; ExpiredER pellets, Conte;1I Uniformity; Metal shavingfound onPress; IR pellet Particle Size; SamplePrep error; andER pell etparticle size.b. There is insufficient evidence to support the release ofMetoprolol Succinate 100 mg ER Tablets processed with activephannaceutical ingredient (API), Metoprolol Succinate USP, which was different from that used in the designed procesSince your 05Aug2007 IR pellet validation study (07CRC-664 (R7] PE-I4-08) using the Mexican Intermediate ofMetoprolol Succinate in the production of loomg and 200mg tablets, you have had approximately.NCRs relating toparticle size. The particle size of post-validation lots of this API, are smaller than the particle size of the API used in th2007 validation study.You continued to manufacture and distribute approximately _ l o t s of these tablets until 170ct2008, when you ceasedproduction. The IR and ER pellet batches used in the tablet batches have sporadically failed particle size tests since tha

EMPlOYEE{S) SlGNAnJRE ~ ""'" SSUSJGWyn G Dicki.Dson, Inves t iga to rMichele Per.=y W i . l l i . ~ , Inves t iga toRe;ina t . Brown, Inves t iga to rK.Ilra L. Roden, Inv ." t ige to r ~ J\../Eric C. Nielsen, Investiqatoc ~SEE REVERSE ' . " ie ' L . Wi,eo, , " " e n i ' ' ' ~ Warren J . LopieJ:a, Inves t i q" to r ' I- 02/02/200OF THIS PAGE J e n n ~ f e r C ahi l l , Inves t iga to r JO""'ph R. Lambert, InvliI"tigaMatthew J . Morrison, Inves t iga to r Tare L. King, I n v e s t i 9 " t o c ~ ~

FORM FDA 483 (04IOJ) PREVIOUS EDmON 08SOLETE INSPECfIONAL OBSERVATIONS PAGE 5 OF 37 PAG


6/37

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

(b) (4)

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

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

(b) (4)

DEPARTMENT OF HEALTH AND HUlIIAN SERVICESFOOD AND DRUG AOMIN1STRATION

OATE{S) OF IN.SPECTlCli11630 W. 80th S t r e e tLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111Indust ry Information: www.fda.gov/oc/ industryNAA'EANDnn.E OF IHOiVD..IAl TOWHOM REPORT ISSUED

12/15/2008 - 02/02/2009FE NUMBER~ 300 71). s "135'7

TO: Mr. David A. Van V l i e t , Inte r im Pres ident and Inter im Chief Execut iveOff icer

KV Pharmaceu t ica l Co 2280 Schuetz RoadTYPE: ESTABUSHMEN'T INSPECTIDITY, STATE. ZIP COOE. CCllJNTR,(Human Drug Manufacturer

time. In fact, since 03Ju12008, 23 lR Pellet batches were rejected for particle size problems. You have also releasedSa in t Louis , MO

(b) (4)

Westport63146-3411

(b) (4)

several batches ofMetoprolol Succinate 100 mg ER Tablets manufactured using the API lots received with a changed,smaller article size that had been received prior to 03Ju12008. These include batch #'sufactured in July of2oo8 to mid October 2008, using Pellet lots that had included API lot #' s

c. You failed to take appropriate corrective actions after investigational findings identified the root cause for dissolutionfailures ofMetoprolol Succinate ER Tablets, 50 mg. During the 06Aug2008 investigation ofNCR #'s 14969 and 14181you identified excessive press speed to be the root cause of the dissolution failures for lot #'s 93394 and 93862This data brings the validation study, (08WP70369 00 [RI] PV-07-01), under suspect, in which the press s range is_ In addition, you continued to operate at press speeds 0 and released approximate lots ofMetoprolol Succinate Tablets SOmg from 06Aug2008 to the time of this mspection.

d. Rework by re-screening due to unacceptable particle size, was perfonned in August 2007, without change control, QAapproval and validation, on lR pellets.lot# 87843 .(C-664) used in the manufacture, release and distribution of thefollowing MetoprolollOO mg/200 mg tablet batches, lot #'s: Further, a pre-approval supplement was not

(b)

(4)

pursued for this rework process nor was this rework process submitted in the Annual Report dated 05Ju12oo8. Notesfrom an upper management meeting indicate the re-screened product cannot be used for commercial sale until the preapproval supplement is approved.

HydromorphoneHel Tabletse. 111 batches ofHydromorphone HCIlR 4mg Tablets on the market within their expiry, were manufacturedutilizing an un-validated, auto-fill process. The batches are lot #'s

Validation batches manufactured Dec2oo5 and Jan2006, failed to demonstrate control and reproducibility; blendunifonnity and potency failures occurred. Modifications were made to the compression stage of the manufacturingprocess and a new validation study was perfonned in Jun2006 with acceptable results. The modifications includeddecreasing the press speed during compression t and using a manual hand fill process for transferring theblend to the press hopper. The Auto-Fill powder transfer system which is a vacuum system used to transfer the powderblend to the tablet press hopper was previously used. The master batch record was not revised to require the blend to behand fed to the tablet press resulting in a l l . batches manufactured from Jun2006 to Aug2008 being manufactured usingthe Auto-Fill transfer system instead of hand filling.

MPlOYEE(S) SIGNATURE 0 ...TE ISSlJEDGwyn G Dickin.son, I:westiqator ~

ich91e Perry Will iams, I n Y e s t i ~ a ~ o r ~ R e q i n ~ T. Brown. I n v e ~ t l q a t o ~ Kare L. Roden. Investi ;ator K~ r i e C. Nielsen. InVEstigator 1.4;JSEE REVERSE Patrick nisor. Investigator ~ Karre:l J. L c p i c t ~ . In\e.5tigato .. "ftlIf}- 02/02/2009OF THIS PAGE JerJlifer Cahil l , !:lvestiQ8torblot!,...Jon'ph R. Lalllbert. r n v . l l ~ i q a . t 8 l r

~ ~ t t h e w J. Morrison. Investigatorlare 1.. Kinq. InVEstigator ~ FORM FDA 483 (04/03) PREVlOUS E D I T I ~ O B S O L n E INSPECTIONAL OBSERVATIONS PAGE 6 OF3' PAGE

(b) (4)


7/37

(b) (4)

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

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

b 4(b) (4)

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

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

(b)

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATIONDISTRICT ADDRESS AND F't-IONC: NUMaR DATE(S) OF INSPECllClN11630 W. 80th St ree t 12/15/2008 - 02/02/2009

FEl ....BERLenexa, KS 66214'J 3007 : ; l 5 9 3S?~ (913) 752-2100 Fax: (913) 752-2111Indust ry Information: www.fda.gov/oc/ industry

NAME AND nn.e Of N>lVlOUAL TOWHQM REPORT ISSUEDTO: Mr. David A. Van Vliet , Interim Pres iden t an d Interim Chief E x e c u ~ i v e Off i ce rfIRM NAME STREET ADDRESSKV Pharmaceut ical Co Westport 2280 Schuetz RoadCITY, 51 ....lE. ZIP COOE, COUNlRY 1YPE ESTA6lJSHMENT INSPECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturer

The validation study was also flawed:0 There is no documentation of the times the samples were collected to ensure adequacy of compression acrossthe batch.0 Discrepancies were noted in the data for tablet hardness samples collected at various hardness levels. Thevalidation protocol required collecting samples at[ I for dissolution, weightvariation, hardness, thickness and friability testing.

o The samnles at tar:let hardness of collected from lot #' s 72722 and 73523 ranged from.I r e s p ~ o The samples coIJected for from lot # 73523 ranged from _

0 Samples were not collected at the due to "the faCt that no tablets compressedat level exhibited proper physical characteristics for weight and thickness specificationsstated in the MBR-" However, the master batch record was not revised to change the hardness range which.is currently .0 During compression

(b) (4)

of one the validation batches, lot # 73523, to evaluate tablets at a.speed ~ _ the press was run at a speed or. which equates to about tablets. There is nodocumentation of this in the validation report, data or batch record or of the disposition of these tablets.

(b) (4)

.

(b)

(4)

AQL Failuresfor Tablet Products. - ,f. You have failed to adequately study causes for the acceptable quality limit (AQL) fitilures which occur across product

(b)

(4)

lines and include among atners, nutritional, Metoprolol Succinate and Morphine family products. The AQL encompassestatistical sampling to evaluate aesthetic fablet defects, setting limits on the amount of statisticalJy acceptable defects perbatch. Despite changes to manufacturing equipmeJit in tablet coating, product failures continue. This brings into doubtthe validation of this process step for all coated products and the quality of products on the market. Investigations existwhich occasionally list upstream manufacturing of core tablet issues as possible causes to coaled tablet failures. Some othese encompass, hardness, % loss on drying of the granulation, compression speeds and compression force. None ofthese issues is adequately investigated to determine theroot cause and instead coating is solely blamed with systemupgrades. .AQL failures are summarized as evidenced by1) bulk batches spanning a 4 y, month period from 18July2008through 7Nov2008 of the MorphineSulfate ER and IR families, failed to perform as validated during compression and coating due to AQL failures.

of those batches were re-inspected for AQL; on average about of al] re-inspected batches werediscarded; in one instance .ofthe batch was discarded. The acceptable portions were subsequently released forfurther processing, packaging or were sold total batches were sold, at close of the inspection several were still

EMPLOYEE\S) SIGNATURE DATE ISSUEDQ.yn G Dicki.nscn. I n \ e ~ t i ~ e t . o r ~

~ c h e l e Per:y W i l l l ~ . l o Y e ~ t i q a t o r R:ei;1.na 1. Br(lOo,"n. I o Y e . s t i ~ a t o r Kara L. Roden, Inve.st:igator K.1oolL. , i e C. Nielsen, I O V . " i . " O ~SEE REVERSE Pat:rick L. Wi:sor, lnvest:iqat:or v

~ a r r e n J. Lopicka, Invest:iii!!.t 02/02/2009OF THIS PAGE Jennifer Cahil l , Inve.stlqi!!.to_Joseph R. ~ r t . Investi'-Y ~ t t h e w J. Morrison, Investigator

T a r a ~ . King. I n v e s t i 9 a t C r ~

FORM FDA 483 (1I.w3) PItEVlOUS EDmON OBSOLETE INSPECTIONAL OBSERVATIONS PAGE 7 Of 37 PAGE

(b)(4)

..


8/37

DEPARTMENT OF REALm M'D HUMAN SERVICESFOOD AND DRUG ADMINISTRAnONDISTriCT ~ E S S A H O PHONE NIJtJBER OAT'ECS) OF WS?ECTION12/15/2008 - 02/02/20091630 W. 80th s t r e e t'6 NUhOBERlQn8 , :300 7 ;9.. 5" {35"1~ Lenexa, KS 66214Ind(913) 752-2100 Fax: (913) 752-2111ustry Information: www.fda.gov/oc/ industry

NAM AND Tlll..EOF INOIVI:IUAl. TOWHOM REPORT ISSlJEOTO: Mr . David A. Van Vlie t , In te r im Pres iden t and Interim Chief ExecutiveOff icer""''''''EKV Pharmaceut ical Co Westpor tCfTY. STA1'E, lIP CODE, (;()l..tlTRySa in t Louis, MO 63146-3411

STRET AOOflESS2280 Schuetz RoadTYPE ESTAa.lSIiMENTJiSPECTEOHuman Drug Manufacturer

awaiting a disposition). The investigation did not extend to complaints received for batches manufactured in thisperiod. Forty-eigbt complaints have been received concerning tablet defects. The size of the AQL sample forroutine batches has not been increased to evaluate and ensure the effectiveness of the corrective actions. Theprobable cause of the failure was identified as prohlems with the air handling unit for the coating pans and upgradesto the air handling system were completed in Dec 2008. Some batches whicb failed specifications during thecompression and coating process are (note: this table is not all inclusive):-

..

, :. . .0-

0

,- ...

.. , '. < .0 .''0

'. . .,. .-

SEE REVERSEOFTHIS PAGE

EMPLO'!'EE.lS) SIGNATURE DATE ISSUEDGo.yn G Dickinson, !n\"elltiq,H:O= ~

c h e l e Perry ~ 1 1 l i ~ 1 l . ! n v e l l ~ ! ~ a t c r Req!na r _ Broo..-n, In.estiliatorKart! L. Roden, Inv.el!ltiqato: Eric C. Nielsen. I n v e s t i ~ a t o r ~ i'atrick L. Wisor. Investi911torpJl .Warren J. Lopic:k:a. ! n Y e S ' : . i g a t ~ ~ 02/02/2009Jennifer cahi l l . InvestigaterJoseph R. La.mb4rt. InvllUtiqll.t. ...

~ ~ t t h ~ ~ J. H o r r i ~ o n . : n v e ~ t . i C l l . t o r ':'ara i. . K1nq. Investigat.or ~ FORM FDA 4B3 (04103) PRIVlOUS E!)I'TJ()N OBSOLTE INSPECI10NAL OBSERVATIONS PAGE 8 on7 PAGES


9/37

(b) (4)

(b) (4)

(b) (4)

(b)

(b)

(b) (4)

DEPARTMENT OF HEALTH AND HUMAJ'\' SI;RVICESFOOD AND DRUG ADMINISlRATIONDISTRICT AOORESS ANO ~ E NUMBER OATE(S) OF INSPECTlON11630 W. 80th s t r ee t 12/15/2008 - 02/02/2009

FElNUMBERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 .1-937879 300795 ' 1351Industry Information: www.fda.gov/oc/industry ~ NAME AND TJTl..E OF IND!VIE:lUAL TOlo'v'H:lM RCPORT ISSUEDTO: Mr. David A. Van Vliet , Inter im President and Interim Chief ExecutiveOfficer

ARM NAME STREET ADDRESSKV Pharmaceutical Co Westport 2280 Schuetz RoadCITY. STATE. 21? cooe. cx:un'Ry TYPE ESTA&.lSHNENT INSPECl'EDSaint Louis, MO 63146-3411 Human Drug Manufacturer

Date Morphine Batch NCR Percentage ReasonSulfate waste fromProduct re-insvection7/7/08 60mgER 91290 "15810 Inspecuoo data nota\'8.ilable; missing Fails sorted AQL for s m f a ~ spots andcode number illeglDlefmcompleu:from betch'records7/1 8/087/1 8/08 60m2ER60 nigER 9551295573 15360.. "15384 lRejected; DOlinsPected

Failed AQL for defectCode number illegible/incomplete; localerosion

7/27/08 30mgER 94421 15553 Inspection data no tavailable; Drisiing Failed sorted AQL; tablet Dot uniform incolor/color VariatiOll, from betch records812108 60mgER 95575 15682 Fails AQL for illegible code and brokentablets8/6/08 60m2'ER 97337 15729 Fails AQL for tablets Dot smooth8/22/08 30mgER 97332 15993 During cooling pan failed AQ L for table..not smooth, illeoible debossin.8/28/08 60 mgER " 97340 16i19 Rejected; Dol Fails AQL for illegible codeiDSDected9/4/08 6 0 m ~ ~ E R 98019 16220 Fails AQL-for incomplete code9/9/08 30 msER 97335 16339 - ( ~ " . . . .mspecbOD data Dot Failed AQ L fOT not smooth and illegible.tablets'

- available; missing9/ll/08 15mgER 98757 " '.' 16397 from batcb =ords)c:.J .. Failed AQLfornot smooth and illegibletablets9/]2/08 15mgER ~ 8 7 5 8 16400 Rejected; Dolinspected During coating pan failed AQL for tabletsnot smooth. 'illegible debossinglI/6/08 15mgER 99.751 17418 Inspection data notavailable; missing Failed AQL for not smooth and illegibletablets and nOl uniformly polishedfrom batcll records11/6/08 60mgER 99766 17433 Failed AQ L for not smooth tablets andilleoible codeslIn08 15mgER 100553 17464 Failed AQL for not smooth tablets andillescible codeslI/7/08 15 mgER 100554 17465 Failed AQL for not smooth tablets andillel#ble codes

EMPtOYEE{S) SlGHAl\.IRE ""TE OSSUEOGw).-n G Dickinson. I o v e " t i 9 ~ t o r ~ ichele Perry Williams, I o v e 5 t i 9 ~ t o .Re91na r. Brown. ! n v e 5 t i 9 ~ t o r ',


10/37

(b)

(b)

(b) (4)

(b)

(b) (4)

(b) (4)

(b)

(b)

DEPARTMENf OF IlEALTH AND BUMAN SERVICESFOOD AND DRUG ADMINISTRATlONQISlRICT AOOFIESS AND P HONE NlJM6ER DATE(S) Of INSPECTION11630 W. 80th S t r ee t 12/15/2008 - 02/02/2009

FE NUMBERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 ;937079 -:700 7 fil.. S Cf 357Indust ry Information: www.fda.gov/oc/ industry ~ NAME AND Tm.E OF INDIY1DUAI. TO WHOM REPORT ISSUEDTO: Mr. David A. Van Vl ie t , Interim Pres iden t and Inter im Chief ExecutiveOff i ce r FIRM ""'" ""'En AII:>l'


11/37

(b)

(b)(b) (4)

(b)(b)

(b) (4)(b)

(b) (4)

(b) (4)

(b)

(b) (4)

(b)

DEPARTMENT OF HEALTH AND HUMAN SERVlCESFOOD AND DRUG ADMINISTRAnONDlS'mlCT AODRSS AND PI-IOHE NlJMElER OA1E(SjOFINSPECtlON11630 W. 80th S t r e e t 12/15/2008 - 02/02/2009

FE! /lAJMSERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 i937e79 3a? 761.5'1351Indus t ry In format ion : www.fda .gov/oc/ indust ry ~ NAME AND TTTL OF I/IlDlVIOUAI.. TO WHOM REPORT ISSUEDTO : Mr. David A. Van Vlie t , Inter im President and Inter im Chief ExecutiveOf f i ce rFIRM NAME: STREET AOORESSKV Pharmaceut i ca l Co Westpor t 2280 Schuetz RoadaTY. STATE. ZIP CODE. COUH1'Ry T'l'?E ESTA8lJSHWHT INSPECTEDSa i n t Louis, 110 63146-3411 Human Drug Manufacturer

15456)9/23/08 95489 16601 Erosion, surface IL......JAll Changes in coatingblemishes & rejected no parameters under

illegible Code inspection olanned deviation,5120/08 95488/95276 14526 SUlface failedc:::J Product formulationblemishes, " p a n s ~ f and manufacturingbreaks, chips total batch process

and illegiblecodes

4/23-24/08 94192/95275 14036 Not fully L..,....Jpans Operating Pan Air. covered, breaks, r e j e c t e d ; _ Flow & Spray Ratenot smooth, oftotal batch " at the minimum

illegible code control limits of3/8-14/08 92360/91751 13271 Local erosion' L . . J o f

Ir ".mproper dedustingreinspectedportion

1127-28/08 91270/91752 12636 Local erosion & _o f Inadequate processsurface reinspected parameters (low

" . blerrushes'. Pornon ,-. pump rpm & sprayrate)1/26-27/08 91269/9J749 .,

"

12615 Tablets notsm"ooth and not

1t..,..,.J ofreinspected

Equipment Failureduring coatingfully"covered portion

1/2-5/08 88707/89081 12306 Local erosion, _o f 1midequatesurface reinspected temperature in theblemishes, chios oortion coating Dan

1211011/08 86593/91695 12034 Local e r o s i ~ n & : I lo f Inadequate heatingsurface reinspected ' . of tablets duringblemishes oortion coating

10/31 86594/87759 11622 Surface c::::.:.:of Inadequate heating1111/07 blemishes, reinspected of tablets duringchips, breaks & portion coatingtablets notsmooth

EMPLOYEE(S) SIGN....TURE D!oTE ISSUED G Dickinson, I n v e s ~ 1 9 ~ t o r ~ i e h e l e Pe=ry W i l l i ~ . lnvest19&torReqio{!. 'i'. Brown, In .. ~ t 1 9 ; ! ! t e r !(ere. L. Roden, l l l v e ~ t i l i e . t e r \ l v l U VEric C. Niel:len, Inve;:iltiqator 1\.:JSEE REVERSE Patrick L. Wi:lor, Inve: l t igater i;dJ'Warre:! J . LQpieka, I n > . e ! ! . : : i g l ! l ~ .... 02/02/2009OF THIS PAGE Jennifer Cahill , lnve:lt igatc ~ Joseph R. Lambert, Inves t iga 4

M a t t h ~ J J. Mer-risen, I n ~ e s ; ; ; i l i a t o r Tara King, : ~ v e ~ t i s ~ t e = ~

FORM FDA 483 (041(l3) PREVIOUS EDT1lO:'l"oBSOl.m INSPECTIONAL OBSERVATIONS PAGE 11 OF 31P,"GE


12/37

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

(b) (4)

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINlSTRAnON0lSTR1CT ADOAESS ANDPHONE NlN.BER DATE(S) OF NSF'ECllClN11630 W. 80th s t r e e t 12/15/2008 - 02/02/2009

Fe ..........Lenexa, 'KS 66214(913) 752-2100 Fax: (913) 752-2111 -937'619 30078-5> 93S ' 1Indus t ry Information: www.fda .gov/oc/ indust ry ~ AME AND Tm.E Of INDlVlOlJ.&J..TOWHOM REPORT ISSUEDTO: Mr . David A. Van Vl ie t , Interim Pres iden t and Inter im Chief ExecutiveOff i ce rARMNAME STREET AOORESSKV Pharmaceut ica l Co Westpor t 2280 Schuetz RoadOTY. STATE, ZIP CODE. COUNTRY TYPE eSTolISUSHMENT INSPECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturer

OBSERVATION 3Written records are not always made of investigations into unexplained discrepancies and the failure of a batch or any of itscomponents to meet specifications.Specifically, ..a. There was no investigation into conflicting assay results between the release bead uniformity potency results for

Metoprolol Succinate ER pellet batches, which were lower than target but within 'specification, and the results from asecond subsequent test on a composite (retain) sample, performed under special request by the production department.There is no raw data for the composite sample results collected under this special request. These comoosite results were~ g h e r than the orio;n.' bead uniformitv results fo r_ C-759 pellet batches (lot #'sl~ b a t c h e s ofMetoprolol SuccinateER Tablets 23.75 mg, were manufactured inJuly and August of2008, using the composite potency values from the pellet batches rather than the bead uniformity

potency results. No evaluation has been performed of validation data to ensure 23.75 mg tablets will meet specificationwhen blended with pellets with potency values below the target blend uniformity specification limit.b. No investigation to determine the root cause was performed for the following incidents:

Metoprolol Succinate ER pellet batch, lot # 98459 (47.5 mg tablets) which failed dissolution testing and wasconfirmed by DOS (# 00S-08-SEP-012). NCR # 17634 was initiated 17Nov2008. Potassium Chloride bead batch, lot # 99938 which was confirmed to be ODS (#OOS-Q8'SEP-005) for time releasedissolution. The results were outs ide 'of the proven acceptable range at hours NCR #16706 was initiated29Sep2008. Potassium Chloride (KCI) blend batches, lot #'s 99900 {00S-Q8-0CT-017) and 99910 (OOSOS-OCT-045) whichwere confirmed ODS for timed release dissolution on 300ct2008 and O4Nov2008, respectively. NCR #17397 wasinitiated for both lots on OSNov2008. . Complaints of "black spots" and "moldy looking areas" were received for PreCare Premier prenatal vitamins; batch#'s 76051, 91544, 90006, 79697, 91545, 95301. At least eight (8) complaints of this nature were listed for lot 90006alone, yet a le lter was sent to a complainant stating this was an "isolated incident."

EMPLOYEE(S) $IGNIITURE DATE ISSUEDW jn G 01ckln.son, In .... ~ t i q " t o e _ ./-45~ ~ c h e l e Feery W i l l i ~ , I n V e ~ t 1 q e : ; ; Reqlne T. Brow::!, ! n v e ~ t i g a . t o r K4ca L. Roden, I ~ v e . $ t i q e t o r )l...t..Jr.1Eric C. Nielsen, Investiq"tor ~ SEE REVERSE Petrick L. W i ~ o r , InvEstisetor loJOF THIS PAGE Werren J. Lopicke, I n V e ~ t i g e ~ _ ~ t - 02/02/2009Je:mi.fer Cahill , ! n \ ' e s t 1 q e t o ~ " '"Sos_ph R. Latnbert, Invest.is-a r rMBt.thew J. ~ ~ r r i s o n . I n v e . $ t i ~ " t o r I u e 1.. Ki:lg. In\e3tiget.or ~

FORM FDA 4&3 (04JU3) PREVlOUS EDmON OBSOLETE JNSPECTIONAL OBSERVA110NS PAGE 12 OF 37 PAGES


13/37

(b) (4)

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

(b

(b) (b)

DEPARTMEI''T OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATIONDISTRICT ADDRESS AND PHONENUMBER O A T E ( S ) O F I ~

11630 W. 80th St ree t 12/15/2008 - 02/02/2009FE"""""Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 1 ~ 3 7 0 ' 9 300 7 ;;>'5 q 35i

Indus t ry Information: www.fda .gov/oc/ indust ry ...4&G'NAME AND nn E OF INOIVlOOAl TOWHOM REPORT ISS UDTO : Mr. David A. Va n Vl ie t , Interim President and Inter im Chief ExecutiveOff i ce rARM NAME STREET '!XlRESSKV Pharmaceut ical Co Westpor t 2280 Schuetz RoadCITY, Sf ...TE. ZIP cooe. COUNlRY TYPE ESTAElUSHMEN'T INSPECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturer

(b) (4)

OBSERVATION 4Written records of investigations into unexplained discrepancies and the failure of a batch or any of its components to meetspecifications do not always include the conclusions and follow-up.Specifically,a. Corrective and preventive ilCtions have nbt been carried out regarding NCR 12156 when Hydromorphone HCl Tablets 2

mg, lot 82575 failed the acceptance criteria for content uniformity in Dec 2007. TheNC R determined the cause wassegregation due to the use of the Auto Filler to transfer the powder blend into the press hopper. The report states_~ T h e master record was not reviseO until July 2008 with the correctionbeing implemented inSeptember 2008. During that time numerous batches were manufactured using the Auto Fil ler; . of these remain withitheir expiry period. .b. Corrective actions were not taken to rectifY a systematic problem allowing compression prior to verification of

acceptable blend uniformity data for' products including Oxycodone HCI. QA approval of the blending process prior tocompression is required. For example, Oxycodone HCliot # 96621 was blended on 23Jim2008 and compressed on24Jun08. The batch failed bleild uniformity 00 08Ju12008. An investigation indicates the cause was sampling error yetno re-sample could betaken-io corifum or renlte the results because the batch had heen compressed..c. No corrective or preveotive action has been reconimeitded con=ning NCRs 14181 and 14969 which were initiated forlot #'s 93394 and 93862 ofMetoprolol Succinate ER'Tablets 47.5 ing which failed .$. I n v e ~ i g e t o : : . . . . 4 Regina T. Brown. !nvestiqa>;or Kart! L. Roden, Investiqator ~ ~ Eric C. Nielsen, InvestiqatorSEE REVERSE Patrick L. Wisor, InvestiglltorWarren J. Lopicka, Investigator't;.(JL- 02/02/2009OF THIS PAGE ~ . n n i ~ e r Cahill. ! n V e S : i ; a t o ~ Joseph R. L&cbert. I n v ~ s t i 9 a t

M a t t h ~ J. Morrison. In.est iqatorTara L. King. :nvestigator ~ FORM FDA 483 (04/03) PRIVTOUS EDmoN OBSOi..ITE INSPECI10NAL OBSERVATIONS PAGE 13 Of37PAGE


14/37

(b) (b) (4)

(b) (4)

(b)

DEPARTMEI\'T OF HEALTH AND HUMAN SERVICESFooD.AND DRUG ADMINISTRATION

0lS1RCf ADDRESS AND PHONE HlM3EI< Oo\TE{S)OF INSl"'ECR:lN11630 W. 80th St r ee t 12/15/2008 - 02/02/2009

F6NVPI!EiSRLenexa, KS 66214(9 l3) 752-2100 Fax: (913) 752-2111 =l9J'IB79 3 0 ~ 7P . S 13- .7I n d u s t r y In format ion : www. fda .gov/oc / indus t ry ~ NAME I\NlJ T1l.E OF N:lN'OJAl TO REPORT tSSUEDTO: Mr. David A. Va n V l i e t , Interim Pres i d en t and Inter im Chief ExecutiveO ff i ce r _NAME S1RElO" ADCRESSKV Pharmaceut ica l Co Westpor t 2280 Schuetz RoadaTY, 51A IE , ZIP COOE, COl.JHTl;:y TYPE ESTA8lJSHMENT INSPECTEDSaint Louis, MO 63146-3411 Human Drug Manufacturer

e. After compressing Prenatal Rx1 Tablets lot # 954S9 in May of2ooS, compression tooling was found damaged witb chipand broken keys. Tbe cause was attributed to exceeding tbe allowable compression force of the tooling. Tbe tooling israted for_ of compression force and lbe press was set at _ The compression force is a critical parameter but inot recorded in batch records. The maSler and batcb production records bave not been revised to specify lbe toolingrating and to require documenting the compression force. -

f. Corrective actions per CAPA 1703S, tn" -.I specification and to revise the MBR for inputadjustment of Prednisolone USP based on potenCy for Predni solone Syrup, USP, 5 mg/5mL were not implemented.Stability data showed potency results trended downward through product expiry.

g. No CAPA follow up or master batch record'(MBR) revision has been documented concerning, NC R 16469 opened on 1Sep 2008 for Morphine Sulfate ER 100 ing tablets. TheNCR Captures excursion outside written procedures where bulkbatcb # 97343 was not compressed within lbe _limit as stated in lbe batch record.. ".The NCR discussed that the limit was not establisbed according to stability data and a CAPA, #17728, 24 Nov 2008, waopened to revise lbe hold time in the MBR between blending and compression.

. ..b. No corrective and preventive action was initiated for OOS-OS-OCT-038 wben a supervisor and data auditor failed to no

the total recovery for the timed release dissolutionwas'out of range for Potassium Chloride bead lo t # 100098. Tbe dataauditor and supervisor 1ililed to realize the lot should have been retested due to tOtalTecovery of the potassium chloridebeing out of specification and retraining sbould bav,e been conducted for failure to recognize the need to retest.

..

"1. Tbere is a failure to implement'corrective and preventative actions or follownp on investigations concerning severalproducts whicb are not limited to Morphine Sulfate Tablets, Metoprolol Succinate ER Tablets and Prenatal Rx l TabletAQL coating failures (surface blemisbes, chips, breaks, erosion, rough surfaces, illegible code, etc.). Issues areidentified in non-conformance1'eportFTrending has identified repeated failures fortablet defects. Yet, AQL tabletcoating failures persist desp ite coating equipment upgrades;.and equipment qualification.-

Notably, When Prenatal Rxl bulk tablet batcb # 86594 (packaged l ot # 87759) failed lbe AQL in Nov2oo7, tbe cause wasattributed to inadequate beating of the tablets during lbe coating process; bowever, there is no evidence to support

this conclusion. Process parameters used to process the tablet pans whicb failed were similar to otber pans whichpassed and were released.

Wben Prenatal Rx1 bulk tablet batcb # 91270 (packaged l ot # 91752) failed lbe AQL in Jan 200S for local erosionEMPLOYEE(SJ SJGNAlURE ~ D"n:: ISSUEDGw)'n G Dickinson, !rwe,,::iqato

M i c : : h ~ l e Perry Wl11ia::l3, Investigator ~ Reg!:!'" 1'. B:own, In:Jest. igator vtKa.re 1.. Roden, Investlgi!!to: 1/..: tJtxlc C. Nielsen, InvestigatorSEE REVERSE "',ie' L. Wi,o,_ ' " " " i " ' ~ Warren J. Lcpic:ka, Investigat r . 02/02/2009OF THIS PAGE Jennifer Cahill. Investigato.JOSQ?J'l R. ~ r t . Invfo!st1'i1'" J!}'--Katthew J . Mortiso:::l, Ir,vestlJ;ator!arr . L. Kinq. I n v ~ t i ' i a t o r ~

FORM FDA 48.l (G4KlJ) PREVTOlJSED!'TIO!'lOBSOLETE INSPECJ10NAL OBSERVATIONS PAGE 14 OF37 PAGE


15/37

(b) (4)

(

(

(b)

(b) (4)

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

DEPARTMENf OF HEALTH AND HUMAN SERVICESfOOD AND DRUG ADMINISTRATION0tSlR1CT AND FM:lNENUUBER 0A1(S) OF INSFa:T'ICIN11630 W. 80th St ree t 12/15/2008 - 02/02/2009

m . . . . . . . Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 1 - 9 3 j O ' ~ 3 0 0 7 9 - 5q3 ' S ' I Indus t ry Information: www.fda .gov/oc/ indust ry .;:;

NAME AND mt.E OF INOIVlOlJAl TO WHOM REPORT ISSUEDTO: 112" David A. Van Vl ie t , Interim Pres iden t and Interim Chief ExecutiveOff i ce r FIRM NAME STREET A.DORESSKV Pharmaceutical Co Westpor t 2280 Schuetz RoadCITY, STATE,IP cooe. c::oumRY TYPE ESTA8l..lSiliMENT INSPECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturer

and surface blemishes, the cause was attributed to inadequate process parameters during tablet coating whichaffected tablet appearance (low pump rpm and spray rate). Hnwever, these are the batcb operating parametersspecified in the MPR (master production record).

Prenatal Rx1 bulk tablet lot #'s 86593 (packaged lot # 91695) and 8.8707 (packaged lot # 89091) failed the AQL on11-12Dec2007 and 03C05Jan2008, respectively. Root cause was determined to be inadequate temperature in thecoating pans. CAPA 12429 was initiated to replace the temperature probes and display for the coating pans yet theyhave not been replaced on coating pans 'hich were used fnr these batcbes. Prenatal Rxl, bulk tablet lot #'s 95491 (pkgd. lot 95280), 95492 (pkgd. lot 95279), 95493 (rejected) and 95495(pkgd. lot 97487), failed the AQL, 29May2008 - 09Ju02008. The cause was attributed to a combination of tooling,

(b) (4)

compression and coat ing parameters not optimal for this prodtict. CAPA # 15456 was initiated 23Ju12008 toevaluate and mOdiJY as appropriate the tooling, cOmpression and coating parameters. To date this CAPA has notoccurred. Prenatal Rx l bulk tablet lot # 94192 (pkgd. lot 95275) failed the AQL in April 2008. "The investigat ion indicated

there is an ongoing project to improve/replace coating equipment and to review and improve all coating recordparameters and instnictions. The coating equipment has since been upgraded and bas undergone qualification; yetthe product process parameters bave not been reevaluated nor revalidated with new coating parameters.

_c -

During packaging of Prenatal Rx l Tablets, bulk batch # 95488 (pkgd.10t 95276)fierators noted unacceptabletablets. A secnnd AQL sample was" colleCted in A p r i l 2 0 0 8 ~ d . product pans 0 flliled. Tablet weight andhardness checks perfonried during compression of p a n s ~ e r e low but were within the acceptable limits. Thecause of the defects was nOt di:termined; bowever, tbe product "[onnulation and manufacturing process wereidentified as "strong factors:" Follow up states the Research and Development lind Operations departments willdefine appropriate parilmeters to use in the coating process for this product. The coating equipment has beenupgraded and has undergone qualification; yet th" produetprocess parameters have riot been re-evaluated norrevalidated with new coating parameters. The CAPA is still open pending validation approval.

Metoprolol ER Tablets, 23.75mg, lot # 95931 flliled the AQL for broken tablets in July 2008. The ARN (AnalyticalRmeetsr due to Metoprolo] sensitivity to heat yet no corrective action was taken. The batch recordcurrently specifies a start exhaust temperature range ofesearcb and Development) department determined the coating process should begin when the exhaust temperature

NCR 15223 was initiated for Metoprolol Succinate ER Tablets, 47.5mg, lot # 93933 when the tablets failed thecoating AQL in July 2008. The investigation determined the most likely cause was due to reduced air flow duringthe coating process. The hatch was processed using a pan air flow o ~ T b e target is with0A1E ossueoEM"lOVEE


16/37

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

(b) (4)

(b) (4)

(b) (4) (b)

(b) (4)

DEPARTMENT OF HEALTH Mill HUMAN SERVlCESFOOD AND DRUG ADMINISTRATIONDISTRICT ADDRESS MID PHONE NUMBER OATE{S) OF 1NSF'ECT1ON11630 W. 80th St r ee t 12/15/2008 - 02/02/2009

FElNUMaERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 193'767g 30079 - 5 3 . 5 9 Industry Information: www.fda .gov/oc/ indust ry ~ AME AND1m.E OF INDIVOJAl O ~ REPORT ISSUEDTO: Mr . David A. Van Vliet , Interim Pres iden t and Inter im Chief ExecutiveOff icerFIRM NAME

(b)(4_ (con t ro l limitsof_. cbange initiation form (ClF) was


17/37

(b) (4)

(b) (4)

(

(

(

(b) (4)

(b)

(

(b)

(b) (4)

DEPARTMENT OF HEALTH AND HUMAN SERVICESFOOD AND DRUG ADMINISTRATIONlllSTR CT AND PHONE Nl..lMSR DATE(S) OF INSPECTlON11630 W. 80th St ree t 12115/2008 - 02/02/2009

FE""" ' "Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 i - 9 3 7 0 7 ~ 30079 SC(3S r Indus t ry Informat ion: www.fda .gov/oc/ indust ry .Jj-drNAME: AND Tm.E OF INOMOlJAl. TO WHOM REPORT ISSlJEOTO : Mr. David A. Van Vliet , In ter im Pres iden t and In terim Chie f ExecutiveOff i ce r""" 'NAME ST1lEETAllDRE5SKV Pharmaceut ica l Co Westpor t 2280 Schuetz RoadOTY. STATE, ZIPCOOE. COUNTRY TYPE ESi ...auSHMENT INSPCTEDSain t Louis, MO 63146-3411 Human Drug Manufacturer

sampling procedure was unable to assure that 100'10 of the distributed encapsulated products were within specifications.These additional products include: Pangestyme CN20, Pangestyme MT16, Pangestyme UL18, Pangestyme UL20,Disopyramide, Potassium Chloride 10 mEq, Micro-K 8 mEq, Micro-K 10 mEq and Potassium Chloride 8 mEq.

b. The investigation ofcomplaint # 17365 concerning an oversized tablet ofHydromorphoDe HCI USP, 2 mg, packaged lot# 90219, did not extend to other Hydromorphone HCI 2 mg batches to determine if Compression Events logs documentthe production of oversized tablets. During the investigation, the compression event log was reviewed and found theMain Compression Roll and Dosing allowed for the production of oversized tablets during set-up, which is believed tobe due to failure to accept the recipe settings prior to the addition of powder to the hopper.c. There was a failure to thoroughly investigate discrepancies in stage testing investigations in which the results wereinvalidated due to "injection error." Identified injection error did not prompt all other injections from the same lot andother lots run on the HPLC to be re-run to determine the extent of the error. 'Examples include invalidated data for thefollowing:

Metoprolol IR beads, C-735, 101# 95795, sublot G-blend uniformity samplesr 1blend uniformitysamples (Stage Testing (ST), ST-08-JUL-00l). MetoproloJ IR heads, C-664, 101# 95005EF-blend uniformity sampleI (ST"08-JUL-003). Metoprolol IR beads, C-735,101# 97059D-blend uniformity sample. (ST-08-JUL-006). ST-38-JUL-007 on Metoprolol IR beads, C-735, 101# 97059F-blend uniformity Sample. ST-08-SEP-005 on MetoprololER,'C.{;65, 10t#98454-bleno uniformity samples and 101# 98462 (on thesame HPLC run) bleOd uniformity samples - . ST-08-SEP-015 on Metoprolol iR e a d s , C-664, 101#-98478 AlB-blend uniformity sampl ST-08-0CT-004 on Oxycodone IR blend 101# 97443"blend uniformity sample. . ST-08-DEC-1 0 on Metonrolol ER beads, C-665, 101# 102834-blend uniformitYsamole

OBSERVATION 6There is a failure to thoroughlYTeView any unexplaioed discrepancy and the failUre ofa batch or any of its components tomeet any of its specifications whether or not the batch has been already distributed.Specifically,a. Investigations, 9209 and 9820, conducted 06Feb2007 and 0lMay2007 respectively and covering several batches of

Histinex HC Syrup packaged with an incorrect closure, were deficient. In Feb2007, Histinex batches were packaged, inpart, using closures which did not have the required foil liners. A partial shipment of faulty closures was received fromthe vendor. Pan of the shipment had an incorrect liner in the cap while the other portion of the shipment contained theEMPLOYEE($) SIGNATURE ""rE LSSVEDG:or,tn G DickinsOll, :nvellUljll.t:o: ~

~ e h e l e Perry W i l l l ~ . Investiqator~ i r . a t. Brown, !nvesriqll.tcr

K ~ r a L. Roden, Investigator ~ ~ ~ ric C. Nielsen, InvestiqaterSEE REVERSE Patrick L. Wisor. Invest igator ilIJWarren .J. Lopieka, I n V e s t i q a ' t ~ ) . . . 02/02/2009OF THIS PAGE Jennifer Cahill , Investigator r.JOll_ph R. Lambi!rt, lnvast iqat - t-~ ~ t t h e w J. Morrison, Investigator~ < l l r a L. Kin;, investigater d ~

FORM FDA 483 (04J03) PRn'lOlJS EDmON OBSOUTE INSPECTIONAL OBSERVATIONS PAGE 17 OF3' P.o\GES


18/37

(b) (4)

(b

(b) (b) (4)

(b) (4)

(b)

(b)

(b) (4)

DEPARTMENT OF HEALTH AM> HUMAl' SERVICESfOOD AND DRUG ADMINISTRATIONDISTRICT AlXlRESS AND PHONE NUMBER ~ T E { S ) Of lNSPECTlClJ,l11630 W. 80th St r ee t 12/15/2008 - 02/02/2009

FE! NI./MBERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 19378/:; 30 0 / ' 851357In d u s t ry In format ion : www. fda .gov/oc / indus t ry f t9ANDllTl..EO f INOlVO.JA!.. TOWriOM REPORT ISSUED

TO: Mr. David .... Van Vliet , In ter im President and Interim Chief ExecutiveOf f i ce rFIRM N"-ME STREET "'llRESSKV Pharmaceut i ca l Co Westpor t 2280 Schuetz RoadCITY, STATE, ZIP CODE. c:outml:Y TYPE ESTABUSHMEHT IHSPECT'EOSaint Louis, MO 63146-3411 Human Drug Manufacturer

(b)

(4)

specified cap liner. The lot of closures in question was vendor's lot # 200623449770. The investigation was closed on16May2007. _hatches ofHistinex were packaged using this lot of closures and were subsequently released baseEC1lON11630 W. 80th s t r ee t 12/15/2008 - 02/02/2009

FE! NUMBERLenexa, KS 66214 -913) 752-2100 Fax: (913) 752-2111 3oc7..:?S't3S'fIndus try Information: ~ ~ . f d a . g o v / o c / i n d u s t r y ~ NAME ANOTfTL OF INDlVlOl.lM. TOWl-iOt>I REPORT ISSUEDTO : Mr. David A. Van Vl ie t , In ter im President and Interim Chief ExecutiveOff ice r ARMNAME STREET AOO!


31/37

(b) (4)(b)

(b) (b) (4)

(b) (b)

(4)

(b) (b)

(4)

(b) (4)

(b)

(4)

(b)

(4)

DEPARTMENT OF HEALTH AND HUMAN SERVICESfOOD AND DRUG ADMINISTRATIONClSlRlCT ADORESS ANOPHONE.......mER OAT'E(S) OF lNSPECTlON11630 W. 80th s t ree t 12/15/2008 - 02/02/2009

FE NUMBERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 T . 7 . ; J ' V 3cC7:=1SQ3S'iIndustry Infor.nation: www.:da.gov/oc/industry

(b)

(4)

~ "'-:.E AND nnE OF INI:IVDJot... TOWrtOM R&ORT l S S l J3 )TO : Mr . David A. Van Vlie t , Interim President an d Interim Chief Execu-:iveOfficer

FIRhl NAME STREET ADORESSKV Pharmaceutical Co Westport 2280 Schuetz Road0'iY. STAlE. ZP CODE. CXlUNTRY 1 ' Y F ' E E S T ~ ~ Sa in t Louis , MO 63146-3411 Human Drug Manufacturer

ER Pellets Release Expiration As=.y Quantity BulkOate Used Packaged Lotilot# Oate Date (mg/g) Used (kg) Tablet96671 7/812008 12131/2008 -7/30/2008 96664 96919

(b) (4)

7/31/2008 98603 98871816/2008 98606 9692181412008 98609 Rejected

96866 71212008 12131/2008 - 8/612008 98606 Rejected/4/2008 98607 Rejected81412008 98608 Rejected11/16/2008 100769 9647496866 8111/2008 12131/2008 - 8/612008 98604 9887210/31/2008 98636 10168710/31/2008 99236 10169910/10/2008 100644 ECIV Inventory(b) (4)

96867 7/812008 12131/2008 9/10/2008 98623 9966310/8/2008 100640 96906- 10/8/2008 100641 96906101912008 100642 10092710/10/2008 100643 100928I

6868 7/6/2008 12131/2008 - 8/612008 98606 9692181412008 98610 Rejected1111/2008 100768 10169111/312008 100762 10169611/16/2008 100769 96474I6869 7/912008 12131/2008 10/28/2008 98633 10168810/27/2008 98634 101689- 10/10/2008 100546 10168110/13/2008 100646 10168210/14/2008 100647 101683&101686

96860 7/10/2008 12131/2008 - 10/30/2008 99242 96908

11/312008 100769 10169211/3/2008 100760 10169311/3/2008 100761 101694

' - ~ ~ N A ~ - 1 : ~ """IE "" '" ' "Q.yr: G Dickinson. I n v . s t 1 g e ~ o r Michele Perry w l 1 1 1 ~ s . Invest1getor~ i n e T. Brown, InvestigatorKata L. Roden, I n Y . s t l q a t o r ~ ~ E:rlc c. Hil!llsen. Invest lqator t..r"SEE REVERSE Patrick L. Wisor. Inv .s t iqa tc r (....IOFTHIS PAGE W4.rnm .:;. Lcpicka, InVe1fltiqatcrg:. 02/02/2009J'enni:1!UC cah i l l , I r : v e 1 f l t i q a t o ~ J01fleph tl.. LaMer t , Inv 'ut196 q.

H 4 t t h ~ J. ~ ~ r r i 1 f l o n , I n v . ~ t i ~ a t o r : a r a L. King, Inve1!ltiqator . ~ ~

FORM FDA 48J (04/03) PREVIOUS romo.lII OBSOLETE lNSPECTIONA L OBSERVATIONS rhOE310Y37P ....GES


32/37

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

(b) (4)

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

DEPARTMENT OF HEALTH AND HlJlItAN SERVICESFOOD AND DRUG ADMINISTRA llONDISTRICT AODRESS AND PI-iONE NUMBER OATE(S) OF INSPECTION

11630 W. 80th Stree t 12/15/2008 - 02/02/2009" , _ s a


33/37

(b) (b)

(4)

(b) (4)

(b)

(4)


O.-.TE(S) OF INSPECTION11630 W. 60th S t r ee t 12/15/2006 - 02/C2/2009Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 193787!lIndus t ry Information: www.fda.gov/oc/ industry NAME Nl.OTTTL OF INOIVIOUA!. TOWHOM REPORT ISSlJEOTO: Mr. David A. Van Vliet, Interim President and Interim Chief ExecutiveOff i ce rFIRM NAME STREEl ADORESSKV Pharmaceut ical Co Westport 2260 Schuetz RoadCITY, STATE, 2IPCOOE, CClt..lN1liYSa in t Louis , MO 63146-3411 Human Drug Manufacturer

(b)

(4)

Received Expiration Amount UsedAssay (ppm) ER Pellet lot # Dale UsedDate Date (kg)122572 8/20/2008 17000.0000 98950 1112612008

98951 1112412008- 98952 111241200898953 11126/200898954 11124/2008101203 1112'12006101204 11124/2008101205 1112512008101206 1112512008101207 1112512008101208 11125/2008101209 1112512008101210 1112512008101211 .1112512008101212 1112512008101213 1112512008101214 1112612008101215 1211912008101216 12/19/2008101217 12/19/2008101218 12/19/2008101219 11212009101220 11212009101221 11212009101222 11212009101223 11212009

121415 5n12008 17000.0000 98950 111261200898951 11124/200898952 11124/200998953 11126/200898954 11/24/2008101203 11124/2008101204 1112412008101205 1112512008101205 1112512008101207 1112512008101208 1112512008101209 1112512008101210 1112512008101211 1112512008101212 1112512008

EMPLOYEE{SJ SIGNA1URE I..

-DATE 1SSUE:l

1112612008G-yn G Dickinson, Investio;;,eto=..)J!1t> ~ 1 2 1 4 Miehele Perry W i l l l ~ . ...el!l:ti;a:o:.AJRegina ,. B r o - ~ . Invest igate:KII:lI 1.. Roden. Invest:igllt.or'lJ.Erie C. Nielsen. Investio;ator ~ SEE REVERSE Patrick L. Wisor, Investigator ty;JWarren J. Lopickll. I n v e s t i 9 a t o r y l ~ ~ 02/02/2009OF THIS PAGE Jennifer Cahill, I D v e ~ t ! 9 . t ~ ~ Joseph i'l.. Lam.bQt"t, I n v e s t i g a ~ t , . r-.atthew J. M o r r i ~ c : l , ::wes"tic;ator:ar& L. King, Investigater.;:;....-

FORM fD A 48J (04/UJ) PREVlQVS EDITlOtJ OflSOLETE INSPECfIONAL OBSERVATIONS PAGE)) 0F37 PIIGES


34/37

(b) (4)

(b) (4)

(b) (4)

(b) (4)

DEPARTMENT OF HEALTIlAND HlJMA1' SERVlCESFOOD AND DRUG ADMlNlSTRATJON

11630 W. 80th S t r e e t 12/15/2008 - 02/02/2009Lenexa, KS 66214 Fe " " " " " "(913) 752-2100 Fax: (913) 752-2111 \4.'J87f>'l-5r 3 0 C 7 d 59.3:5'1

(b) (4)

www.fda.gov/oc/ industry ~ g -ndus t r y In fo rmat ion :NAME AND TITLE Of INOMOUAI. TO Wl-lOM REPORT ISSUEDTO: Mr. David A. Van V l i e t , In te r im Pres iden t an d Inter im Chief ExecGtiveOf f i ce rFIRM NAME STREET ADDRESSKV Pharmaceu t ica l Co Westport 2280 Schuetz RoadCITY, STATE. ZIP CODE, COI.)t..'iRy

(b) (4)

S a i n t Louis , MO 63146-3411 Human Drug Manufacturer

c. ots of Hydromorphone APLlot number 00119768 and 00122132. Lot 0019768 was received prior to receipt oflot no. 00122132

(b) (4)

Bulk batch 98794 of HydromorphoDe was manufactured usingThe firm has in stock a total of_ofHydromorphone lot 00122132 received llJul2008 and

(b) (4)

0.455 kg ofHydromorphone lot 0119768 which was received IlDec2007. Instead of exhausting theentire first in lot of Hydromorphone lot 00119768 a decision was made to use 00122132 receivedllJul2008 first, without justification.

(b) (4)

OBSERVATION 32

(b) (4)

Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans designed toassure that components confonn to appropriate standards of identity, strength, quality and purity.Specifically, the manner in which the water samples are collected does not allow you to detennine the actual quality of thewater.

(b)

(4)

QAlQC sampling and testing of wate r from the closed loop, continuously circulated purified USP water system (SOP211.84.01 "Sampling, Testing, and Approval ofPuritied Water USP, Deionized Water, and Potable Water") is not perfonnedat a minimum 0 nor perfonned at a frequency to encompass worse case testing. Sampling is not perfonnedmore frequently on water ports which have a greater use rate, and sampling is not organized to ensure it is representative oftrue use scenarios when sampling occasionally occurs post sanitization. SOP 211.84.01 section 7.2.6.2.2 states

Port No sampling is documeoted in the point of use log from 30ct2008 through29Nov2008; nearly a two month time span. Port No sampling is documented in the point ofuse log encompassing the dates from

270ct2008 until 1Dec2008, which is outside tbe time 0 as specified in the SOP. Additionally, asample was collected after bose saoitization witb no production use documented betweeotbose points.

Po Sampling occurred on270c12008 as documented in the point ofuse log. Sampling failed to occur again until 8Dec2008 and was notdocumented again, showing s a m p l i n g . during a 2 month time span.

EMPLOYEE(S) SIGNAlURE DATE ISSUEDQ-yn G Dickinson. lnveztic;atorM[chele ?eery ~ i l l i a m 3 . I n v e z ~ i q a t o ~ Reqlna r . Brown, I ~ v e z t i 9 a t o r L. Roden, ! n v ~ . s t i < ; a t . o : - \t'"Ve1e C. Nielsen, InvestigatorSEE REVERSEOF THIS PAGE Patrick L. Wisor, Investigator ~ Warc'=Il J. Lcpicka . I n v e s t i 9 a t o ~ ' " 02/02/2009Jennifer C a h ~ l l . InvestiqatOrO


35/37

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

(b) (4)

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

(b)

(

(b)

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

DEPARTMENT OF HEALW AND HUMAN SERVICESFOOD AND DRUG ADM INISTRATIONClSTRICT ,c.OORESS AND PHONE NUM6ER' OATE(S) OF INSPECTION11630 W. 80th St ree t 12/15/2008 - 02/02/2009

FE NUMBER

(b) (4)

(b

)(4

)

(b) For example for Hydromorphone HCl Tablets, 2 mgis currently on versiocopies of the available for review.procedure.

(4)(b) (4)

Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111Indus try Information: ~ ~ . f d a . g o v / o c / i n d u s t r y NAM

PRODUCTION SYSTEMOBSERVATION 33

(b) (4)

Written production and process control procedures are not followed in the execution of production and process controlfunctions.

E ANDTfilE OF 1H0f\fll)(JAl TOWHOM"EF'ORT1SS UEOTO: Mr. David A. Van Vliet , Interim President and Interim Chief Execu:iveOff ice r

(b) (4)

FIRM NAME STREET -'OORESSKV Pharmaceutical Co Westport 2280 Schuetz RoadCTY. STATE, ZIP CODE. COI.INTRY TYPE ESTA6...lSHMEN'T INSPECTEDSa in t Louis, MO 63146-3411 Human Drug Manufacturer

(b) (4)

(b) (4)

Specifically,a. You failed to follow your procedure, 211.68.343, "Assignment and Control ofPasswords and Recipes Used forProduction Equipment," in which no change documentation was submitted for numerous updated recipe versions. This

procedure requires that a,C=======::=====::::=======:IThe procedure also requires the NCR #16175 was initiated 31 Aug2008 for lack oftraining and a formal program to ensure compliance with this procedure. CAPA #16J 75 was initiated 14Nov2008 toimplement a program to ensure compliance. However to date the ro am has nnt been fully implemented.

b. You failed to justify the deletion of testing in the master production record (MPR) for PotassiumChloride Extended-Release Granules (vpCL-2C wit t e proper change control documentation. Review of the MPRhistory for this product found the following description added to revision. This revision reads in an1!l!l1i. The reason for the revision listed in the MPR isHowever, during the review of the most recent revision toth: - e " M P ~ : ' : R : - : ' ( r - e - V J " s " i o - n - : : . =the required test wasn't present and hadn't been present since revisionI I The history does not indicate this test wasremoved, nor does it give a justification for its deletion.

c. You failed to follow your SOP 211.100.94-03 "Change Control" for Change Initiation Form CIF-0007492 fortherevision ofPotassium Chloride ER Capsule 750 mg method no. 5128.19. Review of the redline document for thismethod finds Proven Acceptable Range (PAR) s ecifications were added to the method for the timed release test andstates in part

EM?l..OYEE(S) SIGNAlUREGIo"ln G Dickinson, I n v e " t i ~ " ' t o r H 1 c h ~ l ~ P ~ r r y Williams, Inves t ige to rRe;ina 1 . Brown, Inves t iga to rKara Roden, Investigator Eric C. Niel"en , Inves t iga to r f\"JSEE REVERSE Patrick L. " i sar , InveniglltoI: W;';aI:len J. Lapie);a, I l w e s t i ~ a t Q ; ' " ~ 02/02/2009OF THIS PAGE J.nnife= Cahil l , I D v e . 5 t i c ; a , ; : o ~ } C - Joaepn R. Laaborto, Inveatic;attt"r.;,

~ ~ t t h e w J . Morri"on, :nve"tic;"'torTara L. King, In .e " t lqa to r ~ FOR\1 FDA 483 (1)411))) PREVIOUS EDmON OBSOLETE INSPECTIONAL OBSERVAnONS P....GE 35 OF 37 PAGES

(b) (4)

there is no log documenting these changes .orAdditionally, CME, Press Technician has not been trained regarding this


36/37

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

(b) (4)

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

(b)

(b) (4)

(b) (4)

(b) (4)

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

(b) (4)

(b) (4)

(b) (4)


DISTRICTADDRESS AfIIO PHONE Nl..lMEiER OATE(S} OF lNSPCTON

(b) (4)

11630 W. 80th St ree t 12/15/2008 - 02/02/2009F8NUMllERLenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111

Indust ry Information: www.fda.gov/oc/ industryNAME AND TITlE OF l N o r v l O l J ~ TOWHQMREPQRTlSSUEDTO: Mr. David A. Van Vl i e t , Inter im Pres iden t and Inter im Chief Execut iveOff ice rKV Pharmaceutical Co Westport 2280 Schuetz RoadCITY, STATE. ZP CODE, COlMTRY "TYPE ESTABl..JSHMENT WSPECTEDSain t Louis, MO 63146-3411 Human Drug Manufacturer

specifications are listed in the method and are outside the specifications in LIMS.The Change Control procedure was not followed in that the ClF document under L.,.."... . .""".....,...-,does not describe the and the justl Icahon forspecification by the analysts.

d. You failed to follow procedure l300.05..()4 which in section 7:6.2 states;

(

b

)(

4

)

(b)

(4)

...."""....._ ...._ ...._ ........__ ............. The drum will beUpon inspection of the controlled substance vault,,numerous'containers werefound unsealed and in some cases polyplastic bags were the onlycontainment of controlled substances such as Morphine and Oxycodone drug products. In this same procedure in section7.7.2.1 it states . It was observed that w,aste.had spilled out of unsealedplastic bags and were not contained in the typical fiber drums.

e. Master Production Records (MPRs) for bulk .Morphine Sulfate 30 & 60 mg ER Tablets are deficient in that; There are no in-process time limits for the time between date ofmanufacture and the end oftbe processing ofthe tablets There are two different The 60 m MPR ineorrecil

OBSERVATION 34All processing lines used during the production of a batcb ofdrug product is not properly identified at all times to indicate thephase ofprocessing of the batch. .Specifically, the cleaning and use Jog for bay numher. and did not agree with the in-process batchnumber listed on the placard at the entrance toB a y . According to the cleaning and use logs, Oxycodone 30 mg, lot #98705 was to be manufactured and approved on l6Oec2008. However, the placard indicated Oxycodone 30 mg, lot # 98706bad been approved for use on 16Oec2008.

EMPlOYEE(S) SlGN ....TURE ~ OATE ISSU'EOQ..yn G Dickinl!lon. I n v e ~ t i q a : : Q . r _

~ ~ c h . l e Perry W i l l i ~ s . I n v e s ~ q B t c r R.egina T_ Srown. Investigator!(a=a L. Roden. Inve:!tiqatcr JSEE REVERSEOF THIS PAGE

Eric c . N l e l ~ e n , Investiqator P ~ t : i c k L. W i ~ o : , I n v e s t l q a t o : ~ ~ 6 0 Warren J. Lopic:ka, Investiqator "" V vJennifer Cahil l , I n v e ~ t l q a t o ~ ~ 02/02/2009

,Joll-ph R. Lambert, Inv


37/37

(b) (4)

DEPARTMEI ,T OYHEALTH AND HUlIfAN SERVICESFOOD AND DRUG ADMINISTRAllONDiSTRICT AlX)RESS AN ) PHONE NULtaER OATE(S}OF NSPECT ION

11630 W. 80th Stree t 12/15/2008 - 02/02/2009Fe........,.Lenexa, KS 66214(913) 752-2100 Fax: (913) 752-2111 300'7..:

37 page fda-483 to tablet manufacturer

Documents