ATOTALSYSTEMSMELTDOWN WHATHAPPENSTOTHEPATIENTWHENQUALITYOVERSIGHTISDEFICIENTATMANYLEVELS byMichaelAnisfeld,SeniorConsultant,Globepharm,USA Asyoureadthis,thereareseveredrugshortagesofoncogenicandotherdrugsinmanycountries. AccordingtotheUnitedStatesGovernmentAccountabilityOffice1therewereshortagesof220finished drugproductsin2011.TheFDACoordinatoroftheAgency'sDrugShortageProgramhassaidthat54%of theshortageswereduetoqualityormanufacturingissues.IntheUSA,closureofBenVenue Laboratories(BVL)Bedford,OhiofacilityislikelytoexacerbateashortageofJohnsonandJohnsons Doxilthathaspersistedsincethesummerandhascutofftreatmentformanycancerpatients.About 2,700peopleareonaJ&Jwaitinglisttoreceivethedrug,whichisusedtotreatovariancancer,multiple myelomaandothercancers2. NationalRegulatoryAgency(NRA)inspectionsperformedatBVLsBedfordfacilitiesduring2011 resultedwiththeBritishandFrenchauthoritieswithdrawingProductLicenses(PL)fromseveral companiesthatusedBVLastheircontractmanufacturingsource.

.BVLhasbeeninbusinessforover70 yearsasaContractManufacturingOrganization(CMO)andspecializedatitsBedfordfacilityinthe asepticmanufactureofmanydrugs,especiallyoncogenicdrugs.BVLsclientsrangefromthelargest multinationalstothesmalleststartupsneedingsomeonetomakesmallbatchesofPhaseIIclinical trialssupplies.BVLproductwasdistributedandtrialed/marketedbyBVLclientsaroundtheworld. Atimelineof2011regulatoryinspectionsatBVLshowsthatcurrentcompanytroublesbeganwitha jointBritish(MHRA)andFrench(AFSSAPS)inspectioninJanuary/February2011whichfoundmany pointsofconcernwithbasicGMPcomplianceandseriousissuesinvolvedasepticproductmanufacture (EUGMPsAnnex13;adocumentequivalenttoFDAsGuidanceonAsepticProcessing).Theyadvised BVLoftheirconcernsandthroughtheFDAandMHRAMemorandumofUnderstandingtheirinspection findingsweresharedwithFDA.ThisgaveFDAqualmsaboutthequalityofproductmadeattheBedford facilityandbetweenMay2ndand25th,2011ateamofbetweenvariously6and14inspectorsinspected thefacilityperforminganindepthGMPcomplianceinvestigation.Thisinvestigationresultedina33 pageFD483listingofinspectionalobservations,containing46differentareasofconcernaboutBVLs asepticprocessoperationsissuedtothecompanysPresidentandCEO.4 AreasofconcerncitedduringthisMay2011inspectionincluded(paraphrasing): Failuretoidentifytherootcause,orimplementcorrectiveactions,involvingthepresenceof stainlesssteelparticles,inBVLproducts.FDAnotes8differentclientcomplaintsonthismatter covering17batchesofproducts;

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http://www.gao.gov/search?q=FDA

http://online.wsj.com/article/SB10001424052970203699404577048760847025768.html?KEYWORDS=Ben+Venue+Laboratories
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http://ec.europa.eu/health/documents/eudralex/vol4/index_en.htm.TheroleandresponsibilitiesoftheQPiscurrentlyunder reviewasdiscussedinanEMAConceptPaperissuedinOctober2011.
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Thefull,butpartiallyredacted,FD438canbedownloadedfromFDAsElectronicReadingRoomat http://www.fda.gov/RegulatoryInformation/foi/ElectronicReadingRoom/default.htm

 RepeatedfailurestomeetBVLsownasepticmediafill(processsimulation)criteria.Onefailure includesaBVLdeviationreportnotingthatthemediafillbatchsizeislessthanthebatchsizenoted inthevalidationprotocol,butdespitethisnotationthemediafillwaspassedanddeemed acceptable; BVLsvalidationmasterplanspecifiedthefrequencyofperformingmediafills,butthisfrequency wasnotadheredto; Cleanroomqualificationsdidnotincludeassessmentofairflowpatternsunderconditionsofroom usage; ThesitesofenvironmentalmonitoringusedbyBVLdidnotreflectBVLsownproceduresandfailed toreflectactualoperationalconditionsofcleanroomusage; Somesterilitytestfailureswereattributedtocontaminationbyanaerobes,buttheenvironmental monitoringprogramdidnotincludetestingforanaerobiccontaminants; Overa15monthperiodBVLhadrecoveredatleast1,171microbialcontaminants,ofwhich1,047 organismsweregrampositive.BVLfailedtoidentifytherootcause,orimplementcorrectiveactions toaddressthecontaminations; Notrendingofmicrobialcontaminationshadbeenperformed,norhadcontaminantsbeen identifiedtospeciesandgenuslevels. Despitethecompanyhavinglimitsfornonviablecontaminationincleanrooms,thesewere exceeded112timesduringa5monthperiod.EventhoughBVLrequiredfillingactivitiestohaltifthe automatedsystemdetectedanOOSnonviableparticlecounttheremediationprocedureemployed didnotincludesanitizingthefillinglines; BVLdidnotkeeprecordsofpressuredifferentialsofcleanroomsandsurroundingareas; Temperatureandhumidityofthesterilestoragewasnotmonitored,includingduringtheoccasions whenrainwaterleakedfromtheroofthroughtheHEPAplenumandintothesterilestoragearea; Visualobservationofcleanroomactivitiesfromtheoutsideareawasdifficultinthatdoorwindows didnotprovideafullviewofcleanroomoperations; Thecomputercontrolledstopperwasheranddepyrogenationtunnelisdeficientinthatthereisno documentationofwhichindividualshaveaccesstowhichlevelsofpasswordcontrol.Additionally alarmreportsforvariousoutoflimitstunneloperationsarenotreviewedortrended; andon,andon.

ItseemsthattheauthoritiesgaveBVLtimetocleanuptheiract,literally,butinNovember2011athree weekjointinspectionbytheFDA(4inspectorsincludingMr.ThomasArista,FDAsnationalexperton sterileproductmanufacture)andinspectorsfromAFSSAPSandMHRAreturnedtoreviewremediation progressaftertheearlierinspections.TheinspectorswereinaquandaryBVLwastheonly manufacturerformanytheanticancerproducts;iftheystoppedthecompanymanufacturingthese productspatienttherapyandsafetywasatrisk.Whattodoallowproductontothemarketwith potentiallylethalqualityproblems,orshutthefacilityanddeprivepatientsofdesperatelyneededanti cancertherapy?

TheFD483,issuedtoBVLsnewPresidentandCEOfollowingtheNovember2011inspectionrunsto11 pagesandcites10areasofconcernwitheachareahavingmultiplesubitemsofconcernmanyof themissuesthathadnotbeencorrectedfromthe6monthpreviousMayinspection. InmidNovembertheBritishandFrenchwithdrewtheProductLicensesfromseveralBVLmanufactured productswitharecommendationtotheEuropeanMedicinesAgencythatthisbeaEurowideban.

 Canada5,HongKongandothercountrieshaveinstitutedsimilaraction.IntheUSA,FDAconvincedBen VenueLaboratoriestoengageinavoluntaryshutdown.Theripplesoftheseregulatoryproduct withdrawalshavehadworldwidereach. Thereseemstohavebeenachainofineptitudeinmanyspheressurroundingthisentireissueatlocal, nationalandinternationallevels,resultinginpotentialrisktopatients. Atthelocallevel,wherewasBVLsownQAgroup,andBoehringerIngelheimsCorporateQA(BIis/was BVLsparentcompany)?Didnttheirinternalauditsrevealthesedefects,andiftheydidwhywerethe deficienciesfoundbyFDAin2011allowedtoremainunresolved.Surelytheseauditorshadno constraintsastowhereinthefactorytheycouldaudititappearsthatcleanroomoperationscouldnot beviewedwithoutgowningandenteringtheworkareawhichBVLconsistentlyrefusedentrytoclient auditorsandNRAinspectors6. The2011qualityconcernsarenotanepiphanyregardingtheBVLsqualityandGMPcompliance concerns.BVLsproblemscanbetracedbackoverthreedecadessincethe1980swiththeMHRA(andits priorincarnationsDHSSandMCA)andtheEuropeanMedicines(Evaluation)Agencyhavingovera thirtyyearperiodpulledseveralProductLicenses(P/L)fromcompanieswhereBVLwastheCMO.Each timeBVL,theworldslargestmanufacturerofoncogenicinjectabledrugproducts,committedtomake improvementsandtheneedfortheseproductsresultedinarestorationoftheP/L.Inhindsight remediationwasalwaysveryslowandoftenincomplete,butpatientneedstrumpedGMPcompliance suchistherisk/benefitequation. HowdidBVLcometothisquagmire?InBVLsownwords7theyaretheoldestandmostexperienced manufactureroflyophilizedproductsintheUnitedStates.IfBVLhastheseproblems,whatisthe Quality/GMPprofileofotherlessexperiencedcompanies?IsitcoincidentalthatwhentheGMP complianceproblemscametolightduringtheseAFSSAPS,FDAandMHRAinspections,thatGerman parentcompanyBoehringerIngelheimwhohadownedBVLsince1997announcedthattheywould divestthemselvesofBVLtoquoteconcentrateontheircorebusinesswhichpraytelliswhatifitis notpharmaceuticalmanufacture? WhydidittakeanoverseasinspectionbyMHRA/AFSSAPSintheUnitedStatestoshedlightonthese severeGMPdeficiencies,beforeFDAwentstormingintothefacility?WhyhadFDAsmuchlaudedrisk managementapproachtoGMPinspectionsnotresultedinmorefrequentandtougherinspections? Seemsthattheregulatorsneedtoprovidesomeanswers. Attheendof2011theEMArecalledallbatchesof8Busilvex(PierreFabreMdicament),Ecalta(Pfizer Limited),Luminity(LantheusMIUKLtd),Velcade(JanssenCilagInternationalNV),Vidaza(Celgene
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HealthCanada(HPFBI)announcedonAugust17,2011animportbanon17productsmanufacturedatBVL.Detailsare availableat:http://www.hcsc.gc.ca/dhpmps/medeff/advisoriesavis/prof/_2011/ben_ven_nthaaheng.php

personalcommunicationfromexFDA/MHRAinspectors

http://www.benvenue.com/pages/history.html

ThedrugproductsrecalledareshownwiththenamesoftheirMarketAuthorisationHoldersinparentheses:EMAwebsite http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landing_page.jsp&mid=WC0b01ac05800 1ce7e

 EuropeLtd)andVistide(GileadSciencesInternationalLtd.)manufacturedatBenVenue.TheEMAalso askedhealthcareprofessionalstotakemeasuressuchasvisuallyexaminingvialsofCaelyx(JanssenCilag International),Ceplene(EpiceptGmbH)andTorisel(PfizerLimited)forthepresenceofmetalparticles theselastthreeproductswerenotrecalled. Iftheregulatorshavenotbeenontheball,whatoftheBVL/BIsandBVLsclientcompaniesQualified Person(QP)inthesupplyofpotentiallylifethreateningproducttopatients.Eachofthese7European companiescitedbyEMAintheirpressreleasehasaQPwhohascertifiedinalegalregisterthatthe productsreleasedtomarketconformedtoGMPrequirements9whenobviouslytheNRAshave disagreedandrecalledproduct.HowisitthattheQPs(andtheirUScousinsinQAgroupswhohavean equallysimilarproblem)allowedovermanyyearsmultiplebatchesof9productstobeplacedonthe marketthattheBritishandFrenchinspectors,andthroughthemtheEMA,deemednottohavebeen manufacturedinaccordwithGMP?WilltheseQPsnowreceivecensurefromtheircertifyingbodies (e.g.,UKsRoyalPharmaceuticalSociety)suchashavingtheirQPregistrationwithdrawnfordereliction inperformanceoftheirduties?SuchcensurewouldimmediatelystrengthentheQPspositionwithinthe pharmaceuticalindustryanddramaticallyimprovetheQPsoversightfunction.Obviouslyaswellasthe NRAs,companiesQPsweredeficientintheirresponsibilitytosafeguardandprotectpatients. WhyisitthattheGMPinspectionsbytheseauthoritiesrevealedaplethoraofGMPfailingswhilethe routineaudits/inspectionsbymanycompanyQPs(andforUScompanies,theirQAgroups)obviouslydid notfindcompellingreasonstoceasesourcingtheirproductfromBenVenueLaboratories?Several potentialreasonsmightbeatplay: i. BVLdidnotallowQPsindepthaccesstodatathattheregulatoryauthoritieswereabletoaccess. ii. TheQPsinspectionwasnotsufficientlyrigoroustoevaluatethetruestateofthecontract manufacturesGMPcomplianceprofile.ComparehowdeepaGMPcomplianceassessmentby1 experiencedcontractgiverauditorfor2days,thetypicaltimeallottedtosuchaudits,comparesto whatcanbegleanedby14experiencedgovernmentinspectorsonsitefor3weeks! iii. ContractgiverGMPcomplianceassessmentsarebiasedinfavoroffindingnothingcriticalandlittle ofconsequenceduringanauditthuscontinuingthecontractgivercontractreceiverrelationship. Whenregisteringadrug,thedrugapplicantstatesthenameoftheCMO,andallsubmittedstability andprocessvalidationdataisbasedontheCMOsinvolvement.IfaQA/QPauditrevealssignificant GMPfailures,thenseveringthecontractgiver/contractreceiverrelationshiprequireseffectively beingoffthemarketforonetwoyearswhileanalternateCMOisfound,stabilityandvalidation datageneratedandsubmittedtotheauthorities,andwaitingforapprovalofthesitechangefrom theauthorities.Wearetalkingmajormoneyinmakingadecisiontoseverarelationshipwitha CMO.Manycolleagueshavetoldmeofsituationswheretheyhavebeenrequiredbytheircompany tosignificantlytonedowntheirreport.AQA/QPauditisinherentlybiasedtocontinuethecontract giver/receiverrelationshipsuchthatcontractgiverssalesandprofitsarenotjeopardized;rarelydo thoughtsofpatientsafetyenterthediscussion,letaloneappearinminutesofmeetingstodiscuss whethertocontinuetheCMOrelationship.
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Article51ofEUDirective2001/83/ECandArticle55ofEUDirective2001/82/andEUGuidetoGoodManufacturingPractice (July2001)

 AndifthisisaproblemwithgovernmentNRAswhohavelegalclouttobackuptheirinspections,and QA/QPsnotfaithfullyfulfillingtheirdutieswhenitcomestoaCMOrelationshipforfinisheddosage formswheretheNRAalsoperformsindependentinspections;howbadisitwithActivePharmaceutical Ingredient(API)wheretheEuropeanNRAshaveessentially,withafewexceptions,abrogatedtheir inspectionsresponsibilitiesentirelyinfavoroftrustingtheQPsauditsoftheirAPIsources?Muchbetter istheUSsystemwhere,despiteseriousproblemswithFDAinspectionsthathavebeenhighlighted severaltimesbyCongressGeneralAccountabilityOffice10,FDAperformsitsowninspectionsofAPI suppliersworldwide.AtypicalQPauditofanAPIsourceisonetwodaysbyoneauditor;atypicalFDA inspectionistwoinvestigatorsforfivedays. 2011hasbeenanannushorribilisinGMPcompliancefortheUSpharmaceuticalindustry.Whatwiththe JohnsonandJohnsonTylenol(acetaminophen/paracetamol)debacleandthealmostcompleteremoval ofallTylenolproductsfromtheUSmarket;theUS$650millionfinepaidbyGSKforGMPnon complianceissues;andnowtheBVLexperienceweshouldallbeverydeeplyconcerned.Isallthisa consequenceofglobalization,ortheworldwideeconomicmalaiseandtheneedtocutcompanyquality oversightprograms,oramovetoeverleanerlowerandmiddlemanagement? PerhapsliketheUSmeatprocessingindustrywhereforatleast50yearsaUSDepartmentofAgriculture (USDA)inspectorispermanentlybasedineachfactory,weareheadedforanagewhereanFDA inspectorispermanentlybasedinfactoriesmanufacturingcriticalpharmaceuticalproducts?Muchfood forthought.
Copyright2012,MichaelH.Anisfeldallrightsreserved

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http://www.gao.gov/search?q=FDA