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2012 > Celltex Therapeutics Corporation 9/24/12

Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions Warning Letters

Inspections,Compliance,Enforcement,andCriminalInvestigations
CelltexTherapeuticsCorporation9/24/12

DepartmentofHealthandHumanServices

PublicHealthService FoodandDrugAdministration CenterforBiologicsEvaluation andResearch 1401RockvillePike Rockville,MD208521448

WARNINGLETTER September24,2012 CBER1210 VIAFACSIMILEANDUPS DavidG.Eller ChiefExecutiveOfficerandPresident CellTexTherapeuticsCorporation 12621W.AirportBlvd.,Suite800 Sugarland,TX77478 DearMr.Eller: Duringaninspectionofyourfirm,CellTexTherapeuticsCorporation,locatedat12621W.AirportBlvd., Suite800,Sugarland,Texas77478,conductedbetweenApril16andApril27,2012,theFoodandDrug Administration(FDA)determinedthatyourfirmreceivesadiposetissue(akalipoaspirate)thathasbeen recoveredfromautologousdonors.Using(b)(4),yourfirmisolatescellsfromthelipoaspirate,and selectsandexpandsthroughcellculture,adiposederivedmesenchymalstemcells(AdMSC).The autologousproductisadministeredtopatientsby(b)(4)forawidevarietyofindications. Ourinvestigationofyourfirmfurtherdeterminedthatyourfirmpromotesyourprocessandtheuseof AdMSCtophysiciansbyencouragingphysicianstoenrollpatientsinoneofyourclinicaltrials.Your protocolsentitled,(b)(4)bothexplainthatpatientshaveanopportunitytobeenrolledintheseclinical trialsiftheyarepresentlydiagnosedwithan(b)(4)forwhichthereishypothesizedordemonstrated clinicalbenefitforthe(b)(4)oftheAdMSCproduct. CellTexsproductisahumancell,tissue,orcellularandtissuebasedproduct(HCT/P)asdefinedin21CFR 1271.3(d).However,thisproductdoesnotmeetallofthecriteriain21CFR1271.10(a)andthereforeis notregulatedsolelyundersection361ofthePublicHealthServiceAct(PHSAct)[42U.S.C.264]andthe regulationsin21CFRPart1271.Specifically,yourprocessingwith(b)(4)alterstheoriginalrelevant characteristicsoftheadiposetissuerelatingtothetissuesutilityforreconstruction,repair,or replacement.Therefore,yourprocessingdoesnotmeetthedefinitionofminimalmanipulationfor structuraltissuesuchasadiposetissueasdescribedin21CFR1271.3(f)(1).Furthermore,yourfirms processoftissueculture,expansionandpassagingalsofailstomeetthedefinitionofminimalmanipulation forstructuraltissuein21CFR1271.3(f)(1).Asaresult,theCellTexproductdoesnotmeetthecriterionin 21CFR1271.10(a).
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Additionally,theclinicalusesdetailedinyourprotocolsdonotmeetthedefinitionofhomologoususein21 CFR1271.3(c).AlsorecordscollectedduringinspectionindicateclinicalusesoftheAdMSCproduct involving(b)(4)Theseuseswouldlikelynotbeconsideredhomologoususeandasaresult,theCellTex productdoesnotmeetthecriterionin21CFR1271.10(a)forregulationsolelyundersection361ofthePHS Actand21CFRPart1271. YouarepromotingtheCellTexproductinamannerthatcausestheproducttobeadrugundersection 201(g)oftheFDCAct[21U.S.C.321(g)]andabiologicalproductasdefinedinsection351(i)ofthePHS Act[42U.S.C.262(i)].Pleasebeadvisedthatinordertolawfullymarketsuchabiologicaldrugproduct,a validbiologicslicensemustbeineffect[21U.S.C.355(a)42U.S.C.262(a)].Suchlicensesareissued onlyafterashowingofsafetyandefficacyfortheproductsintendeduse.Whileinthedevelopmentstage, forexample,whilebeingstudiedinaclinicalinvestigation,suchproductsmaybeusedinhumansonlyif thesponsorhasaninvestigationalnewdrug(IND)applicationineffectasspecifiedbyFDAregulations[21 U.S.C.355(i)21CFRPart312].TheCellTexAdMSCproductisnotthesubjectofanapprovedbiologics licenseapplication(BLA)noristhereanINDineffect.Basedonthisinformation,yourproductviolatesthe FDCActandthePHSAct. Additionally,duringtheinspection,FDAinvestigatorsdocumentedevidenceofsignificantdeviationsfrom currentgoodmanufacturingpractice(CGMP)andcurrentgoodtissuepractice(CGTP)inthemanufactureof (b)(4)batchesofyourAdMSCproductfromJuly2011throughApril2012.ThesedeviationsfromCGMP andCGTPincludetheapplicablerequirementsofSection501(a)(2)(B)oftheFDCAct,Sections351(a)and 361ofthePHSAct,andTitle21,CodeofFederalRegulations,(21CFR)Parts210,211,and1271. Atthecloseoftheinspection,ourinvestigatorsissuedaFormFDA483,InspectionalObservations,which describedanumberofsignificantobjectionableconditionsrelatingtoyourfacility'scompliancewithCGMP andCGTP.Theseinclude,butarenotlimitedtothefollowing: 1.Failuretoestablishandfollowwrittenproceduresdesignedtopreventmicrobiological contaminationofdrugproductspurportingtobesterile.Suchproceduresshallincludevalidationof allasepticandsterilizationprocesses[21CFR211.113(b)].Forexample: a.TheasepticmanufacturingprocessatyourSugarland,Texasfacilityhasnotbeenvalidated. b.Youhavenotvalidatedyourasepticgowningprocessandroutinepersonnelmonitoringisnot performed. c.Youhavenotvalidatedyourautoclavesterilizationcycle.Theautoclaveisusedtosterilize equipmentusedinasepticprocessing. 2.Failuretoestablishandfollowwrittenproductionandprocesscontrolproceduresdesignedto assurethatthedrugproductshavetheidentity,strength,quality,andpuritytheypurportorare representedtopossessandtoassuresuchproceduresaredrafted,reviewedandapprovedbythe appropriateorganizationalunits[21CFR211.100(a)].Forexample,youhavefailedtovalidateyour manufacturingprocessatyourSugarland,Texasfacility. 3.Failuretomaintainlaboratorycontrolsthatincludetheestablishmentofscientificallysoundand appropriatespecifications,standards,samplingplans,andtestproceduresdesignedtoassurethat components,drugproductcontainers,closures,inprocessmaterials,labeling,anddrugproducts conformtoappropriatestandardsofidentity,strength,quality,andpurity[21CFR 211.160(b)].Specifically,youdonotperformtestingofthefinalAdMSCproduct,includingtestsfor identity,safety,purityandpotency. 4.FailuretotesttheAdMSCproduct,a(b)(4)drugproduct,forthepresenceof(b)(4)althougha reasonablepossibilityexiststhatthe(b)(4)drugproducthasbeenexposedtocrosscontamination with(b)(4)Yourfirmused(b)(4)duringculturingofyourAdMSCproduct.Specifically,(b)(4)was usedduringmanufacturingofthe(b)(4)batchesofyourAdMSCproductreviewed.The(b)(4)drug productmustnotbemarketedifdetectablelevelsof(b)(4)arefound. 5.Failuretothoroughlyinvestigateanyunexplaineddiscrepancyorthefailureofabatchoranyof itscomponentstomeetanyofitsspecifications,whetherornotthebatchhasalreadybeen distributed[21CFR211.192].Forexample,therewerenoinvestigationsperformedforthefollowing: a.TherewerenumerousinprocesssterilityfailuresforAdMSCbatches.
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b.BacterialandfungallimitshavebeenexceededfortheBiologicalSafetyCabinets(BSCs) usedinmanufacturing,andinthegowningandgeneralareas. 6.Failuretoassurealldrugproductproductionandcontrolrecords,includingthoseforpackaging andlabeling,arereviewedandapprovedbythequalitycontrolunittodeterminecompliancewithall established,approvedwrittenproceduresbeforethebatchisreleasedordistributed[21CFR 211.192].Therewasnoevidenceofreviewandapprovalbythequalitycontrolunitpriortorelease ofanyofthe(b)(4)batchesofyourAdMSCproduct. 7.Youfailedtoassurebatchproductionandcontrolrecordsarepreparedforeachbatchofdrug productproducedandthatyoudocumentthateachsignificantstepinthemanufacture,processing, packing,orholdingofthebatchwasaccomplished[21CFR211.188(b)].Forexample: a.Thereisnodocumentationoftheadditionof(b)(4)toyourfinalAdMSCproduct. b.ThereisnodocumentationofthepersonnelinvolvedinpackagingofthefinalAdMSC product.

8.Failuretoassurethatdistributionrecordscontainthenameandstrengthoftheproductandthe descriptionofthedosageform,andthenameandaddressoftheconsignee[21CFR 211.196].Specifically,ofthe(b)(4)batchesreviewed,allwerelackingaproductname,dosage form,andthenameandaddressoftheconsignee. 9.Failuretoestablishandfollowwrittenproceduresdescribinginsufficientdetailthereceipt, identification,storage,handling,sampling,testing,andapprovalorrejectionofcomponentsanddrug productcontainersandclosures[21CFR211.80(a)].Specifically,therearenowrittenproceduresin placeforthesuppliesandreagentsyouusetomanufactureyourAdMSCproductatyourSugarland, Texasfacility. 10.Failuretoassurethateachlotofcomponents,drugproductcontainers,andclosuresshallbe withheldfromuseuntilthelothasbeensampled,tested,orexamined,asappropriate,andreleased forusebythequalitycontrolunit[21CFR211.84(a)].Forexample,thefollowingcomponentsand containersarenottestedorexaminedbeforerelease: a.The(b)(4)usedtorinsethecellsandformulatethefinaldrugproduct.Moreimportantly, theCertificateofAnalysisforthe(b)(4)states:Forinvitrodiagnosticuse.CAUTION:Notfor humanoranimaltherapeuticuse.Usesotherthanthelabeledintendedusemaybeaviolation oflocallaw. b.The(b)(4)thatcontainthefinalproduct. 11.Failuretoestablishawrittenrecordofmajorequipmentcleaning,maintenanceanduseto includeinthatrecordthedate,time,productandlotnumberofeachbatchprocessed[21CFR 211.182].Forexample,therearenowrittenrecordsofcleaning,maintenanceanduseforthe(b)(4) andBSCsusedforasepticprocessingortherefrigeratorsandfreezersusedtostore(b)(4)and reagentsusedtomanufacturetheAdMSCproduct. 12.Failuretoassurethatautomatic,mechanicalandelectronicequipmentusedinthemanufacture, processing,packingandholdingofadrugproductisroutinelycalibrated,inspectedorchecked accordingtoawrittenprogramdesignedtoassureproperperformance,andthatwrittenrecordsof thosecalibrationchecksandinspectionsaremaintained[21CFR211.68(a)].Specifically,thereisno evidencethatoperationalorperformancequalificationhasbeenperformedforyourBSCstoassure theirproperfunction. 13.Failuretoassureanadequatecontrolsystemfortemperatureandhumidityisinplacetoprevent contaminationduringasepticprocessing[21CFR211.42(c)(10)(ii)].Specifically,thereisnosystem forthemonitoringoftemperatureorhumidityoftheprocessingroomsatyourSugarland,Texas facility,whereyoumanufacturetheAdMSCproduct.Themanufacturer'smanualforyour(b)(4) BSCsstatesthattheyshouldbeoperatedinenvironmentalconditionsofamaximumrelative humidityof(b)(4) 14.Failuretoassureanairsupplyfilteredthroughhighefficiencyparticulateairfiltersunder
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positivepressureforasepticprocessingoperationsisinplacetopreventcontaminationduring asepticprocessing[21CFR211.42(c)(10)(iii)].Specifically,yourSugarland,Texasfacilitydoesnot filtertheairsupplythroughhighefficiencyparticulateairfiltersunderpositivepressurebetweenthe cleanroomsandtheexteriorroomstoassurethatnoncontrolledairdoesnotflowintotheclean rooms. 15.Failuretoassureasystemformonitoringenvironmentalconditionsisinplacetoprevent contaminationduringasepticprocessing[21CFR211.42(c)(10)(iv)].Specifically,yourSugarland, Texasfacilitydoesnothaveanestablishedenvironmentalmonitoringprogram. 16.Failuretoestablishandfollowwrittenproceduresdescribingthehandlingofallwrittenandoral complaintsregardingadrugproduct[21CFR211.198(a)].Specifically,duringtheinspectionyou couldnotprovideevidenceoftheexistenceofwrittenproceduresdescribingthehandlingofwritten andoralcomplaintsrelatedtoyourAdMSCproduct. 17.Failuretoestablishaqualitycontrolunitthatshallhave: a.Theresponsibilityandauthoritytoapproveorrejectallcomponents,drugproduct containers,closures,inprocessmaterials,packagingmaterial,labeling,anddrugproducts, andtheauthoritytoreviewproductionrecordstoassurethatnoerrorshaveoccurredor,if errorshaveoccurred,thattheyhavebeenfullyinvestigated[21CFR211.22(a)] b.Theresponsibilityforapprovingorrejectingallproceduresorspecificationsimpactingonthe identity,strength,quality,andpurityoftheproduct[21CFR211.22(c)] c.Theresponsibilitiesandproceduresapplicabletothequalitycontrolunitinwriting[21CFR 211.22(d)].

18.FailuretolabeleachHCT/Pinaccordancewiththerequirementsin21CFR1271.370.Forexample: a.ThefollowinginformationdoesnotappearontheAdMSCproductlabel:adistinctidentification numberaffixedtotheHCT/Pcontainer,andassignedinaccordancewith21CFR1271.290(c)a descriptionofthetypeofHCT/Panexpirationdate,ifany. b.TheAdMSCproduct,whichisforautologoususe,wasnotprominentlylabeledasbeingFor autologoususeonly.Thiswarningisrequiredunder21CFR1271.90(b).

Additionally,significantdeviationsinthemanufactureofyourAdMSCintermediateswereobservedduring theinspection.ThesedeviationsviolateSection501(a)(2)(B)oftheFDCActandSection351(a)ofthePHS Act.Specificareasofconcerninclude,butarenotlimitedto: EQUIPMENT 19.Youhavenotqualifiedanyoftheequipmentusedinmanufacture,processing,packagingand holdingofyourAdMSCintermediatesatyourSugarland,Texasfacility. 20.Therearenoproceduresdesignedtoassureproperperformanceofequipmentusedinthe culture/expansionofyourAdMSCintermediates.Forexample: a.Youdidnotcalibrateyour(b)(4)fortemperatureand(b)(4)toassurethattheirdisplays areaccurate.Yourmanufacturingrecordspecifiesthatcultureistobeperformedat(b)(4) degreesCelsiusand(b)(4) b.Thereisnoindicationthatthetemperatureoftherefrigeratorsandfreezersusedtostore culturemedia,(b)(4),andreagentsusedtomanufacturetheAdMSCproductisconsistently monitored. 21.The(b)(4)and(b)(4)usedinproductionareplaceddirectlyonthefloorratherthanelevated ontables.Discarded(b)(4)andmediabottleswereobservednexttothisequipmentduringuse. PRODUCTIONANDPROCESSCONTROLS 22.Youhavenotvalidatedyourcellcultureprocessandtheasepticprocessinginvolvedinculturing
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ofthecells.TherewerenumerousinprocesssterilityfailuresforAdMSCbatchesindicatingalackof controlofyourasepticprocess. 23.Youdonotdocumentthedailychecksofyourculture(b)(4)forevidenceofcontamination. 24.Youdonotdocumentchecksof(b)(4)forcontamination,ortheroutinechangingofthe(b)(4) inthe(b)(4) 25.Youdonotdocumentthetemperatureofyour(b)(4)usedduringtheadiposetissue(b)(4)step forisolatingstemcells.YourBatchProductionRecordspecifiesthatthetemperatureofthe(b)(4)be (b)(4)degreesCelsiusforthe(b)(4)step. 26.Thecomponentsusedinproductionwerenotalwayslabeledcorrectly,whichcouldresultinmix ups.Forexample: a.Abottlelabeled(b)(4)ononesidewaslabeled(b)(4)ontheother. b.Abottlecontainingtheculturemedium(b)(4)(mesenchymalstemcellattachmentculture mediumsupplementedwith(b)(4)waslabeled(b)(4)onthelid,but(b)(4)ontheside.

RECORDSANDREPORTS 27.Onnumerousoccasionsyoufailedtoconductinvestigationsonsterility,(b)(4)and(b)(4) failuresorIndeterminateresults.Additionally,youdidnotinvestigateenvironmentalexcursionsof TooNumeroustoCount(TNTC)inthe(b)(4)usedformanufactureofyourAdMSCintermediates. CONTROLOFCOMPONENTS 28.Therearenoproceduresforreceipt,identification,storage,handling,sampling,testing,and approvalorrejectionofthefollowingsuppliesandcomponentsusedtocultureandexpandthe AdMSCintermediates. a.The(b)(4)usedtopreventbacterialandfungalgrowthintheculturemedia. b.The(b)(4)and(b)(4)usedforcellexpansion. c.The(b)(4)usedtoharvesttheAdMSCintermediates. d.The(b)(4)and(b)(4)conical(b)(4)tubes. e.The(b)(4),and(b)(4)serologicalpipettes. f.The(b)(4)addedtothecellsasa(b)(4). 29.(b)(4)frozenvialsofisolatedAdMSCs,whichhadnotbeenexpandedinculture,werereceived fromtheRNLlocationsinGermantown,MD,andSeoul,Koreaforuseinmanufacturing.Youhadno recordsassociatedwiththesecomponents.

REVIEWOFINSPECTIONALRESPONSES WeacknowledgereceiptofyourwrittenresponsesdatedApril27,May18,May31,July31,andAugust31, 2012,whichseektoaddresstheinspectionalobservationsontheFormFDA483issuedatthecloseofthe inspection,andwehavereviewedtheircontents.Wehaveconcludedthatyourresponsesdidnotprovide sufficientdetailtofullyassesstheadequacyofyourcorrectiveactions. OverallResponse Pleaseprovidedetailsastohowyouplantodealwiththebiologicaldrugsthathavealreadybeen manufacturedatyourSugarland,TexasfacilityinviolationoftheFDCActandPHSAct.Additionally,we notethatSOPsandrecordscollectedduringtheinspectionaswellastranslatedcopiesprovidedinyour correspondenceappeartorelatetoyourRNLBiofacilityinKoreaandnotyourSugarland,Texasfacility. Inyourresponse,pleaseaddresstheconcernsthatyourAdMSCproductisadrugasdefinedinsection 321(g)oftheFDCActandbiologicalproductasdefinedinsection351(i)ofthePHSAct. NeitherthisletternortheobservationsnotedontheformFDA483,whichwerediscussedwithyouatthe conclusionoftheinspection,areintendedtobeanallinclusivelistofdeficienciesthatmayexistatyour
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facility.Itisyourresponsibilityasmanagementtoassurethatyourestablishmentisincompliancewith theprovisionsoftheFDCAct,PHSAct,andallapplicableFederallawsandregulations. Youshouldtakepromptactiontocorrectthesedeviations.Failuretopromptlycorrectthesedeviations mayresultinregulatoryactionwithoutfurthernotice.Suchactionsincludeseizureand/orinjunction. ForfurtherinformationaboutINDrequirements,contactDr.PatrickRiggins,DirectorofRegulatory ManagementStaff,OfficeofCellular,Tissue,andGeneTherapies,at(301)8275366.Pleaseincludea copyofthisletterwithyourinitialsubmissiontoCBER. Pleasenotifythisofficeinwriting,within15workingdaysofreceiptofthisletter,ofanyadditionalsteps youhavetakenorwilltaketocorrectthenotedviolationsandtopreventtheirrecurrence.Includeany documentationnecessarytoshowthatcorrectionhasbeenachieved.Correctiveactionsaddressedinyour priorresponsesmaybereferencedinyoursubsequentresponse.Ifyoudonotbelieveyourproductisin violationoftheFDCActandPHSAct,includeyourreasoningandanysupportinginformationforour consideration.Ifcorrectiveactionscannotbecompletedwithin15workingdays,statethereasonforthe delayandthetimewithinwhichthecorrectionswillbecompleted. YourresponseshouldbesenttotheU.S.FoodandDrugAdministration,CenterforBiologicsEvaluationand Research,HFM600,1401RockvillePike,Rockville,Maryland208521448.Ifyouhaveanyquestions regardingthisletter,pleasecontacttheDivisionofCaseManagement,CBERat3018276201. Sincerely, /S/ MaryA.Malarkey Director OfficeofComplianceandBiologicsQuality CenterforBiologicsEvaluationandResearch PageLastUpdated:10/15/2012 Note:Ifyouneedhelpaccessinginformationindifferentfileformats,seeInstructionsforDownloading ViewersandPlayers. AccessibilityContactFDACareersFDABasicsFOIANoFearActSiteMapTransparencyWebsite Policies U.S.FoodandDrugAdministration 10903NewHampshireAvenue SilverSpring,MD20993 Ph.1888INFOFDA(18884636332) EmailFDA ForGovernmentForPress CombinationProductsAdvisoryCommitteesScience&ResearchRegulatoryInformationSafety EmergencyPreparednessInternationalProgramsNews&EventsTrainingandContinuingEducation Inspections/ComplianceState&LocalOfficialsConsumersIndustryHealthProfessionals

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