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

Letters 2012
Inspections,Compliance,Enforcement,andCriminalInvestigations

AlereSanDiego,Inc.10/22/12

PublicHealthService
DepartmentofHealthandHumanServices
FoodandDrugAdministration
LosAngelesDistrict
19701Fairchild
Irvine,California926122506
Telephone(949)6082900
Fax(949)6084415
WARNINGLETTER

VIAUNITEDPARCELSERVICE
SIGNATUREREQUIRED

October22,2012WL0113

Mr.RonaldZwanziger
ChairmanandCEO
Alere,Inc.
51SawyerRoad,Suite200
Waltham,MA02453

DearMr.Zwanziger:

DuringaninspectionofyourfirmlocatedinSanDiego,California,onMarch12throughJune27,2012,
investigatorsfromtheUnitedStatesFoodandDrugAdministration(FDA)determinedthatyourfirmmanufactures
Triagebrandcardiacmarkerdevices,specificallytheTriageCardioProfilerPanel,TriageCardiacPanel,Triage
ProfilerSOB,TriageBNP,TriageDDimerproducts,aswellastheTriagebrandTOXDrugScreenproduct.Under
section201(h)oftheFederalFood,Drug,andCosmeticAct(theAct),21U.S.C.321(h),theseproductsare
devicesbecausetheyareintendedforuseinthediagnosisofdiseaseorotherconditionsorinthecure,
mitigation,treatment,orpreventionofdisease,ortoaffectthestructureoranyfunctionofthebody.

Thisinspectionrevealedthatthesedevicesareadulteratedwithinthemeaningofsection501(h)oftheAct,21
U.S.C.351(h),inthatthemethodsusedin,orthefacilitiesorcontrolsusedfor,theirmanufacture,packing,
storage,orinstallationarenotinconformitywiththecurrentgoodmanufacturingpracticerequirementsofthe
QualitySystemregulationfoundatTitle21,CodeofFederalRegulations(CFR),Part820.Wereceiveda
responsefromMarkGladwell,PresidentandGeneralManager,datedJuly17,2012,concerningourinvestigators
observationsnotedontheFormFDA483(FDA483),ListofInspectionalObservations,thatwasissuedtoyour
firm.Weaddressthisresponsebelow,inrelationtoeachofthenotedviolations.Theseviolationsinclude,butare
notlimitedto,thefollowing:

1.Failuretoadequatelyensure,whentheresultsofaprocesscannotbefullyverifiedbysubsequentinspection
andtest,thattheprocessshallbevalidatedwithahighdegreeofassuranceandapprovedaccordingto
establishedprocedure,asrequiredby21CFR820.75(a).Forexample:

a.PerProcedureNo.MSOP214(b)(4)ApplicationSolution,SetupOperationsandMaintenance,RevisionR,
yourfirmviaan(b)(4)processappliesa(b)(4)solutiontoitsTriagequantitative(b)(4)(thesearethe(b)(4)
fortheTriageCardiacMarkertests;thesetestshavea(b)(4)component).PerProcedureNo.MSOP214,the
(b)(4)applicationprocessrequiresanovensetpointtemperatureof(b)(4)degreesCelsiusandadryingtime
of(b)(4).However,theearliestvalidationdocumentation(VP9804ProcessQualificationReportCardiac
Assembly,dated4/23/1998)doesnotprovideobjectiveevidenceofhowyourfirmestablishedtheoven
specifications.Instead,reportNo.VP9804onlyindicates,Afterdispensing,the(b)(4)arecuredinacalibrated
ovenforasetduration.

Wereviewedyourfirmsresponseandconcludethatitisnotadequatebecauseyourfirmhasnotcompletedan
engineeringstudythatdeterminestheoptimalsettingsfortheovensetpointandthedurationofthedrying
process.Yourfirmalsowillneedtocompletearevalidationofthe(b)(4)dryingprocessaftertheengineering
studyiscompleted.Inaddition,yourfirmmustreviewand,asneeded,reviseitsproductdevelopmentand
processvalidationprocedurestorequirethatobjectiveevidencebegeneratedtojustifyhowprocessparameters
areset.

b.Yourfirmhasnotadequatelyestablishedtheprocessvalidationassociatedwiththecardiacmarkerassembly
process,whichincludesthe(b)(4)applicationsolution,(b)(4)addition,(b)(4)dispensing,(b)(4),and
packaging(allcriticalsteps)forthefollowingTriageCardiacmarkerdevices:CardioProfiler(devicePN:80192/kit
PN:97100CP),ProfilerSOB(devicePN:80176/kitPN:97300),andDDimer(devicePN:98100/kitPN:
80221).Forexample,thequalificationofthecardiacmarkerassemblyprocessviathereleaseofreports(VP98
04,VP9840,VP9840R,VP9924,andVP9924R),dated4/1998thru2/2000wasconductedutilizingthe
firmsTriageCardiacBNPandTriageCardiacPaneltestsonly.Noadditionalcardiacassemblyprocess
qualificationswereconductedutilizingtheCardioProfiler,ProfilerSOB,orDDimerdevices.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmhasprovidedanoverviewofa
plantoensurethatallprocesseshavebeenadequatelyvalidatedtocurrentindustrystandards.Yourfirmstates
thatitwillundertakeacomprehensivevalidationreviewandrevalidationprogram.Yourfirmalsostatesthatit
will:1)developavalidationmasterplan;2)performavalidationassessment;and3)performprocessre
validationorvalidation.Yourfirmhasalsoprovidedtimelinesfortheseactivities.Theresponseisnotadequate
becauseyourfirmhasnotcompletedthedocumentation,whichincludesadescriptionandevidenceof
implementationofthecorrectiveactionfortheCardioProfiler,ProfilerSOB,orDDimerdevices.

c.TheInstallationandOperationalQualification(IQ/OQ)/ItemSeriesNo.1081forthefirms(b)(4)brand(b)
(4)machine(ModelNo.(b)(4)whichisusedto(b)(4)theTriageproductpackagedkitboxeswasconductedon
5/16/2006through5/24/2006.However,reviewofthesubjectIQ/OQrevealedthatthesetpointtemperatures
forthe(b)(4)andthe(b)(4)are(b)(4)and(b)(4)Fahrenheit,respectively.Inaddition,intheeventthatthe
(b)(4)isnotuniformandsealsarenotintactandlargeholesarevisible,productcanbererun(anunlimited
amountoftimes)throughthe(b)(4).ReviewofIQ/OQNo.1081revealednotestchallengeforthenumberof
timestheproductcanbererunthroughthe(b)(4)inanattempttodetermineanyadverseimpacttothefirms
Triageproducts,whicharelabeledforstorageat28Celsius(35.646.4Fahrenheit).

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmperformedastudytodefinethe
maximumnumberofpassesthataproductcanberunthroughthe(b)(4).Yourfirmalsoimplementedaprocess
toensurethatmultiplepassesthroughthe(b)(4)arerecorded.Theresponseisnotadequatebecause,afterthe
engineeringstudywasperformed,thereisnoevidencethattheproductthatwasrunthroughthe(b)(4)
numeroustimeswastestedtoensurethatitstillmetreleasespecifications.

d.TheVerificationTestfortheProgramming/Verificationofcodechips(nodocumentcontrolnumber)dated4/21
22/2005isinadequateinthat:

i.Thereisnodocumentcontrolnumber.
ii.Step6oftheverificationtestrequiresarepeatofthestep(b)(4)times,(b)(4)foratotalofsample
sizeof(b)(4).Instead,theprotocol/rawdataindicatesonly(b)(4)blankcodechipswereutilizedto
conducttheprogramming/codechipdownloadchallenge(i.e.,(b)(4)chipsforeachofthe(b)(4)code
chiptypes).
iii.Upondownloadofthecodechipinformation,therewasnoverificationactivitytoensurethatthe
integrityoftheperformancedata,whichisuniquetoeachlotcode,wasnotcompromised.
iv.Therawdataassociatedwiththedownloadchallenge/programmingofthe(b)(4)chipismissingfrom
theProgramming/VerificationofCodeChipsdocuments.

Inaddition,yourfirmhasonfile37complaintsfrom10/2009thru3/12/2012,whichareassociatedwithcode
chipissues.Twentythree(62%)ofthe37complaintsinvolvecodechipissuessuchaschecksumerrors,code
chipinvalidmessage,cannotreadcodechip,kitcodechiprequiresreloading,andcodechipdidnotwork.The
codechipsareusedwiththeTriagemeter,whichisanautomatedelectronicinstrumentforusetomeasurethe
resultsofyourfirmscardiacmarkerdevices.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Youhavestatedthatyourfirmwillre
verifythecodechipprogrammingprocessandgenerateanewverificationreport.Yourfirmhasalsostatedthatit
willreviewtheprocessforprogrammingcodechipstodetermineifanyadditionalprocesscontrolsarenecessary
toreducethepossibilityofprogrammingerrorsandthepotentialforcustomercomplaints.Yourfirmhasstated
thatitwilltraintheappropriatepersonnelonallaspectsofprocessvalidation.Theresponseisnotadequate
becauseyourfirmhasnotsubmitteddocumentationthatincludesadescriptionandevidenceofthe
implementationofthecorrectionandthecorrectiveaction.

e.ThePerformanceQualificationProtocol(documentNo.VAL1216PQ)dated4/29/11for(b)(4)Cleaning((b)
(4))wasnotfollowedorisinadequateinthat:

i.Section8.2ofVAL1216PQrequiresafinalreporttobewritten;nofinalreportwaswritten;
ii.Therewasnodiscrepancyreport,asrequiredperSection8.3;
iii.TherewasnodocumentedverificationofemployeetrainingperAttachment3;
iv.TherewasnodocumentedTestInstrumentCalibrationperAttachment4;
v.TherewasnodocumentedMaterialListperAttachment5;
vi.TherewasnodocumentedperformancetestingresultsperAttachment6;
viiTherundatesassociatedwithLogBookNo.(b)(4)theexecutionofVAL1216Qindicaterundates
4/15/20114/25/2011toincludepgs.2930and3351.However,VAL1216PQwasnotapproveduntil
4/29/2011;and
viii.ProtocolVAL1216PQdoesnotaddresschallengetestingforconductingmaximumnumberofruns
usingthe(b)(4)beforeacleaningprocessisnecessary.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmhassupplieda(b)(4)Cleaning
validationreportforthe(b)(4)mentionedintheobservation.Thisreportcoversalltheitemsmentionedinthe
observation.Yourfirmhasalsoaddressedthisissuesystemicallybyundertakingacomprehensiverevalidation
program.Theresponseisnotadequatebecauseyourfirmhasnotgivenanexplanationofwhythelogbook,
whichcoversrundatesof4/1525/2011,statesthattherawdatawithinthelogbooksupportsVAL1216PQ,
PerformanceQualificationProtocol,(b)(4)Cleaning,whichwasnotsignedoffuntil4/29/2011.

2.Failuretoestablishandmaintainadequateproceduresfordefininganddocumentingdesignoutputinterms
thatallowanadequateevaluationofconformancetodesigninputrequirements,asrequiredby21CFR
820.30(a).Forexample:

a.YourcurrentprocedureQTP169414TriageFamilyFinalReleaseSpecifications,RevisionE,whichisutilized
byyourfirmforthefinalreleasespecificationsassociatedwithyourcardiacmarkerproductlines,isnotin
alignmentwiththepackageinsertswithrespectto%CV.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.OnOctober1,2012,FDAandyourfirm
reachedanagreementonthefinalreleasespecifications.However,theresponseisnotadequatebecause:1)
yourfirmhasnotprovideddocumentationorevidencetodemonstratethatfinalreleasespecificationshavebeen
implemented;and2)productdevelopmentandchangecontrolproceduresthatrequirereleasetestspecifications
tobereviewedagainsttheapplicablepackageinserthavenotbeenwrittenandimplementedandtraininghasnot
beencompleted.

b.ProcedureQTP169414TriageFamilyFinalReleaseSpecifications,RevisionE,providesproducttoproduct
variation(P2P)rangingupto(b)(4)differencefortheTriagecardiacmarkersbetweenthemeanoftwolots
whentestedwiththesamesample.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.YourfirmhasrevisedtheP2P
specificationtoreducetheamountofvariationthatisallowed.Theresponseisnotadequatebecauseyourfirm
hasnotyetcompletedaprogrammeanttoreduceanalyticalvariationfortheTriageproductline.Inaddition,
yourfirmisstillworkingonfurthertighteningoftheP2PspecificationsfortheTriageCardiacproducts.

c.YourcurrentProcedureQTP18275TOX+MTDFinalReleaseSpecifications,RevisionF,whichisutilizedfor
thefinalreleasespecificationsassociatedwithyourdrugsofabuse/TOX+MTDproductline,isnotinalignment
withtheproductinsertwithrespecttothenumberoffalsepositiveandfalsenegative(b)(4)calibratorrecovery
testresultsallowedforthelotreleaseacceptancecriteriaversustheclaimednumberoffalsepositiveand
negativeresults,asdepictedwithintheproductinsert.

Wehavereviewedyourfirmsresponseandconcludethatitisnotadequate.YourfirmhaschangedtheTriage
TOXFinalReleaseSpecificationstorejectanylotwithoneormorefailuresat(b)(4).Yourfirmhasalsovalidated
thatthesoftware(b)(4)usedfordataanalysishascorrectlyimplementedthespecificationchanges.Yourfirm
hasprovidedtrainingrecordsfortheQCanalystswhousethesespecifications.Theresponseisnotadequate
becauseyourfirmhasnotcompletedtherevisionoftheproductdevelopmentandchangecontrolproceduresto
requirethatreleasetestspecificationsarereviewedagainsttheapplicablepackageinsert.

d.Yourfirmsreleasespecifications(perQTP18275TOX+MTDFinalReleaseSpecifications,RevisionF)for
yourdrugsofabusetestinclude(b)(4)calibratorrecoverytesting.However,yourfirmstestingregarding(b)
(4)leveltestingisconductedforinformationpurposesonly(FIO)andnotusedintheevaluationforproduct
release.Inaddition,thepackageinsert(Document/PN:26171enTriageTOXDrugScreenProductInsert)
RevisionA,providesthresholdperformancecharacteristicsforthefollowinglevelsofcalibratorrecoverytesting:
(b)(4).

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.YourfirmhaseliminatedFIOtestingfor
theTOXproducts.OnOctober1,2012,FDAandyourfirmreachedanagreementonthefinalrelease
specifications.However,theresponseisnotadequatebecauseyourfirmhasnotprovideddocumentationor
evidencetodemonstratethatfinalreleasespecificationshavebeenimplemented.Inaddition,yourfirmhasnot
completedtherevisionoftheproductdevelopmentandchangecontrolprocedurestorequirethatreleasetest
specificationsarereviewedagainsttheapplicablepackageinsert.

e.ProcedureNo.QTP18275TOX+MTDFinalReleaseSpecifications,RevisionF,providesaspecificationof
(b)(4)totaldevicedefectsforalotsizeof(b)(4)and(b)(4)totaldevicedefectsforalotsizeof(b)(4).In
addition,ProcedureNo.QTP18265TOX+MTDCalibrationSpecifications,RevisionB,providesaspecification
of(b)(4)errorcodesforalotsizeof(b)(4).However,thereisnodocumentedjustificationofhowthesedevice
defectsorerrorcodespecificationswereestablished.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmstatesthatthedevicedefects
anderrorcodesaddressedinthisobservationoccurwhenthedevicedoesnotprovideanyanalyticaldata.The
responseisnotadequatebecauseyourfirmhasnotcompletedtherevisionofthespecificationforthenumberof
allowabledefectsthatitstateswillbebasedontheanalysisofdata.Yourfirmhasalsonotcompletedtherevision
ofproductdevelopmentprocedurestorequirethatspecificationshaveajustificationatthetimethattheyare
developed.

3.Failuretoestablishandmaintainadequateprocedurestocontrolproductthatdoesnotconformtospecified
requirements,asrequiredby21CFR820.90(a).Forexample,on3/14/2012,duringawalkthroughofthe
facility,itwasobservedthattwocardiacmarkerproducts,PartNo.(b)(4)(BNP/LN:(b)(4))andPartNo.(b)(4)
(Cardiac/LN:(b)(4)),werefoundinconvectionovenNo.(b)(4)withasetpointtemperaturereadingof(b)(4)
degreesCelsius.However,reviewofProcedureNo.PN:(b)(4)DeviceBases,(b)(4),BNP,RevisionOand
ProcedureNo.PN:(b)(4)Cardiac,RevisionC,revealedsetpointtemperaturespecificationsof(b)(4)degrees
Celsius.Yourfirmsinitialresponsewastoimmediatelyresetthetemperaturetoitsspecificationsof(b)(4)
degreesCelsiusandnootherqualitysystemactionswereperformed.Afteradiscussionwithmanagement,Non
ConformanceReport(NCR)No.NC12114wasgeneratedinresponsetotheoutofspecification
condition.However,NCRNo.114isinadequateinthatitdoesnotaddressthefollowing:

a.Theoperatorwhoresetthesetpointtemperaturefrom(b)(4)to(b)(4)wasnotnotifiedofthe
nonconformance;and
b.Aninvestigationintohowlongthesetpointtemperaturehadbeenoutsidethespecificationof(b)(4).

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmhasprovidedproofthatthe
operatorwhoresetthesetpointhasbeencounseledregardinghisaction.YoualsorespondedthataNCRshould
havebeengeneratedwhenthesetpointtemperaturewasreset.Aninvestigationofhowthesetpointwas
changedwasconductedandyourfirmhassuppliedthatinformation.Theresponseisnotadequatebecauseyou
havenotcompletedthenonconformancecompliancetrainingrecordsforallmanufacturingandQApersonnel
whoareinvolvedintheprocessingofnonconformances.

4.Failuretoestablishandmaintainproceduresthatdefinetheresponsibilityforreviewandtheauthorityforthe
dispositionofnonconformingproduct,asrequiredby21CFR820.90(b).Forexample,on3/14/2012,duringa
walkthroughofthefacility,itwasobservedthattwocardiacmarkerproducts,PartNo.(b)(4)(BNP/LN:(b)(4))
andPartNo.(b)(4)(Cardiac/LN:(b)(4))werefoundinconvectionovenNo.(b)(4)withasetpoint
temperaturereadingof(b)(4)degreesCelsius.However,NCRNo.114doesnotaddresstheevaluationor
dispositionofthesecondlot(i.e.,CardiacPN:(b)(4)/LN:(b)(4)),whichwasalsointheovenatthetimeofthe
outofspecificationovencondition/temperature.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.AlthoughyourfirmhasprovidedtwoNon
ConformanceReportsforthetwoproductsthatwereaffectedandyouhavealsoprovidedscrapreportsforthese
twoproducts,yourfirmhasnotcompletedthenonconformancecompliancetrainingrecordsforall
manufacturingandQApersonnelwhoareinvolvedintheprocessingofnonconformances.

5.Failuretoestablishandmaintainadequateprocedurestocontrolenvironmentalconditionsthatcould
reasonablybeexpectedtohaveanadverseeffectonproductqualityandfailuretoperiodicallyinspect
environmentalcontrolsystemstoverifythatthesystemisadequateandfunctioningproperly,asrequiredby21
CFR820.70(c).Forexample:

a.ProcedureNo.MSOP240(b)(4)Manufacture,RevisionH,dated3/22/2012,providesinstructionswithin
Section7toUsestaticelectricityreductionmatsduring(b)(4)burninprocess.However,ProcedureNo.MSOP
240doesnotprovideinstructiontoconductperiodicmonitoringofthetwoElectrostaticDischarge/ESDmats
(EquipmentIDNo.:(b)(4)and(b)(4))locatedwithinthe(b)(4)areatoensurecommonpointground
connections.Inaddition,thesubjectprocedureisnotdefinedinthatitprovidesnoinstructionsfor
operators/personneltobegrounded(e.g.,viatheuseofwriststraps,conductiveflooring,conductiveshoes/foot
straps,ESDclothingoracombinationthereof)andthemethodologiesusedtogroundpersonnelmustbe
monitored.Finally,thetwosubjectESDmatswerenotincludedonyourfirmsperiodicmonitoringscheduleanda
commonpointgroundchallengewasnotconductedonthematsuntil3/12/2012,whichisninedaysafterthe
startofthecurrentinspection.

Wehavereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmhaschangedprocedure
MSOP240,(b)(4)Manufacture,torequirepersonneltowearawriststrapduring(b)(4).Yourfirmhasplaced
theESDstationsunderthecalibrationprogram.Theresponseisnotadequatebecauseyourfirmhasnot
completedacomprehensiveprogramtoenhancethecurrentESDcontrolswhichincludes:1)implementingan
ESDmonitoringprocessthatwillallowforperiodicmonitoringoftheESDcontrols;2)changingthegowning
proceduretodefineappropriateESDgowningandtesting;3)requiringESDsmockstobewornbyemployees
handling(b)(4);and4)providetrainingonESDandESDcontrolsforallemployeesthathandlethe(b)(4).

b.Thequalityofwaterforusewithinthecardiacmarkeranddrugsofabusemanufacturingis(b)(4).However,
theproceduresassociatedwiththe(b)(4)systemareinadequateasfollows:

i.Thewaterportsutilizedfordailytestingwithin(b)(4)associatedwithProcedureNo.MSOP0206
DeionizedWaterHardness&ChlorineLogSheet,RevisionAO,whichareusedonadailybasis,aremapped
incorrectly.Forexample,location(b)(4)ismapped(b)(4),location(b)(4)ismapped(b)(4),and
location(b)(4)ismapped(b)(4).
ii.Thepackagelabelingforthe(b)(4)brandfree(b)(4)testindicatesastorageconditionof(b)
(4).However,theareainwhichthe(b)(4)testwasfound,the(b)(4)systemwithin(b)(4),providesno
temperaturemonitoring.
iii.Thepackagelabelingforthe(b)(4)brandTotalHardnessTestKit(Model(b)(4))wasfoundwithan
illegiblelabel(i.e.,thelabelareawaswornortornaway)forlotnumberandexpirationdateidentification.
iv.ProcedureMSOP0203(b)(4)WaterLogSheet(b)(4),RevisionAO,providesaspecificationfor
(b)(4)wasnotlabeledforidentification.
v.ProcedureMSOP0206(b)(4)WaterHardness&(b)(4)LogSheet,RevisionAO,providesawater
qualityhardnessspecificationinPPM(partpermillion).However,thepackageinsert/procedurespecification
associatedwiththe(b)(4)brandTotalHardnessTestKitprovidesaspecificationinmg/L.Neitherofthese
proceduresprovidesadefinitionofthecorrelationbetweenPPMandmg/L.

Yourfirmsresponsetothisobservationappearstobeadequate.Yourfirmhascorrectedalltagnumbersthatare
listedinMSOP0201,(b)(4)WaterHardness&(b)(4)LogSheet.Thiscoversthe(b)(4)Watersystemsin(b)
(4).ThesetagnumbershavebeenphysicallyauditedandverifiedbyQualityAssurance.The(b)(4)brandfree
(b)(4)testkitisnowstoredinatemperaturecontrolledareathatmeetstherequirementofthe(b)(4)
recommendedstoragetemperature.The(b)(4)brandTotalHardnessTestKitModel(b)(4)withtheillegible
labelhasbeenreplacedwithanewkitwithlegiblelabels.MSOP020hasbeenrevisedtoinformoperatorstotake
actionifalabelisillegible.(b)(4)tankBT102hasbeenlabeledandall(b)(4)watersystemtagnumbershave
beenreviewed.MSOP0206,(b)(4)WaterHardness&(b)(4)LogSheet,hasbeenchangedsotheunits
betweenthetestkitandthelogsheetmatch.Allunitshavebeenmodifiedfromppmtomg/LforHardness,(b)
(4).

6.Failuretoestablishandmaintainadequateproceduresforidentifyingvalidstatisticaltechniquesrequiredfor
establishing,controlling,andverifyingtheacceptabilityofprocesscapabilityandproductcharacteristicsas
requiredby21CFR820.250(a).Forexample:

a.On4/15/2009thru5/20/2009,viaTriageFinalReleaseProcedureQTP1694RevisionI,andindividualTriage
CardiacFamilyReleaseProcedurestoincludeBNP/QTP16945,RevisionD,Cardiacpanel/QTP16946,Revision
F,ProfilerSOB/QTP16948,RevisionF,CardioProfiler/QTP16947,RevisionF,andDDimer/QTP16949,
RevisionEyourfirmimplementedatrimmedmeanmethodologyforthefinalreleasecriteria,whichwas
appliedtoallmanufacturedlots.Thetrimmedmeantechniqueallowedtheremovalofthe(b)(4)and(b)(4)ofn
samplemeasurementspriortocalculatingthearithmeticmean.Forexample,if(b)(4).If(b)(4).Assuch,the
datausedforfinalrelease/determinationofwithinrunprecision,whichisexpressedas%CV,didnotincludethe
removedtrimmedmeandata.Thismayallowlots,whichwereoriginallyoutofspecification,tobereleased.An
exampleofalotthatwasacceptableafterapplyingthetrimmedmeanmethodologyis(b)(4),whereinitiallythe
%CVforTnIwascalculatedas(b)(4).After(b)(4)testresultswereremoved/trimmed,thenew%CVwas
calculatedas(b)(4).

Wereviewedyourresponseandconcludethatitisnotadequate.Yourfirmhasremovedthetrimmedmean
methodfromtheanalysisofproductreleasetestdatafortheTriagecardiacfamilyofproducts.Thedocuments
thatgovernthereleasetestprocessandspecificationsfortheseproductshavebeenrevisedandyourfirmhas
provideddocumentationoftrainingontheseprocedures.Alllotsreleasedafterthesedocumentswereinstituted
usedataanalysisthatdoesnotusethetrimmedmeanmethod.Yourfirmhasalsorevisedthesoftware(b)(4)
thatisusedtoanalyzeproductionreleasedatatoensurethatthetrimmedmeanmethodologyisnotusedin
analyzingreleasedata.Yourfirmhasprovidedacopyofthevalidationprocedureusedtovalidatethesoftwareto
confirmthatthesoftwareusedthecorrectanalysistoreleaseproduct.Theresponseisnotadequatebecause
yourfirmhasnotcompletedareviewofyourproceduresandrevisedprocedurestoensurethatchangestothe
releasetestprocesses,includingstatisticalmethods,beapprovedbycertaindesignatedindividuals.Yourfirmhas
alsonotcompletedthereviewofreleasetestprocessesatthesitetoensurethattheappropriateanalytical
methodsareused.

b.Actualstabilitytestingresultsarenotalwaysevaluatedagainstthespecificationateachstabilitytime
point.ProcedureNo.QSOP1572RealTimeMonitoringofTriageQuantitativeProducts,RevisionF,provides
instructionswithinSections6.3through6.5.4tocalculatepercentrecoveryat(b)(4)(newproductandcurrent
product)upto(b)(4)intervalsonly.(b)(4),yourfirmutilizes(b)(4)analysis/slopetocalculatepercent
recoverywithaspecificationof(b)(4)foreachtimepoint.However,thismethodologydoesnotaccountforthe
actualtimepointpercentrecoverycalculation.Itaccountsonlyforthe(b)(4)analysis/slope,whichfitsintothe
(b)(4)recoveryrange.Forexample,theRealTimeStabilityDeviceSummaryforPN:(b)(4)(TOX+MTD)/LN:
(b)(4),atthe(b)(4)lowreagentcontrolconcentrationforthe(b)(4)timepointintervalof5/3/2011,indicates
aTHC%recoveryof(b)(4).Also,the(b)(4)timepointintervalof6/30/2011indicatesanOPI%recoveryof
(b)(4).Boththe(b)(4)and(b)(4)recoveryfailthe(b)(4)specification;however,yourfirmappliesthe(b)
(4)slopetothespecificationandnottheactualtimepointresults.Thisallowstheresultstopassspecification.

Wereviewedyourfirmsresponseandconcludethatitisnotadequatebecauseyourfirmhasnotcompletedyour
StabilityTestProceduretoaddresstheissuesintheobservation.Yourfirmhasalsonotevaluatedthestability
monitoringmethodsusedfortheotherproductstoensurethattheproperanalyticalmethodsareused.

c.Thespecification(perProcedureQSOP1572RealTimeStabilityMonitoringofTriageQuantitativeProducts,
RevisionsFandG)thatisusedfortheTriage(cardiacmarkersanddrugsofabuse)productlinesarebasedupon
BNPprecisiondatathatsetapercentrecoveryrangeof(b)(4).Thespecificationallowsforarangeof+/(b)
(4).YourfirmhasadaptedthisBNPspecificationtoconformtoallotherdevicesintheTriageproduct
line.However,thejustificationofhowthisspecificationwasadaptedforallotherTriagedevicesisinadequate.

Wereviewedyourfirmsresponseandconcludethatitisnotadequatebecauseyourfirmhasnotcompletedits
reviewofthestabilityspecificationfortheproductlines.Yourfirmhasalsonotcompletedtherevisionofits
productdevelopmentprocedurestorequirethatmanufacturingspecificationshaveajustificationatthetimethat
theyarecreated.

7.Failuretoestablishandmaintainadequateprocedurestocontrolalldocuments,asrequiredby21CFR
820.40.Forexample,unapproved/draftprocedureswerefoundbeingusedwithinthefirmswarehousearea,
includingthefollowingprocedures:ReceivingExpensedPurchaseOrders,ShippingMarketingClinicalResearch
Orders,InventoryControlMaterialTransferRequests,ShippingQCDReplacements,ShippingprocessforSales
Orders,ReceivingDocktoStockandABONInventory,InventoryControlCycleCount,ABONShipments,and
ReceivingPurchaseOrders.Theseprocedures,whichallareatversionlevel0.01,havebeeneffectiveandindraft
modesince7/22/2010.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmhasacknowledgedthatthe
documentscitedinthisobservationwerenottheofficialqualitysystemprocedures.Yourfirmhasnowremoved
alluncontrolleddocumentsfromtheareaandhasperformedanaudittoensurethattherearenootherinstances
inwhichuncontrolleddocumentsareinuse.Compliancetrainingisscheduledforallemployeeswhoare
associatedwiththeuseofcontrolleddocuments.Theresponseisnotadequatebecausethistraininghasnotbeen
completed.

8.Failuretoestablishandmaintainadequateprocedurestoensurethatdevicehistoryrecords(DHRs)foreach
batch,lot,orunitaremaintainedtodemonstratethatthedeviceismanufacturedinaccordancewiththeDevice
MasterRecord(DMR),asrequiredby21CFR820.184.Forexample,on,orabout2/20/2012,yourfirmconducted
additionalsampletestingassociatedwithTOX+MTDLotno(b)(4)duetoMTDandTHCresultsof30%and
50%,respectively,forfalsenegativeresults.Yourfirmdidnotmaintaintherecordsassociatedwiththeadditional
testing,andevenwiththeadditionaltestresultsof23%falsenegativesforMTDand14%falsenegativesfor
THC.LN:(b)(4)wassubsequentlyreleased.

Wereviewedyourfirmsresponseandconcludethatitisnotadequate.Yourfirmtookactiontoquarantineand
scrapLot(b)(4).YourfirmhasrevisedtheproceduresgoverningTOXFinalReleasetoaddtheadditionaltesting
andspecificationstotheprocedure.Althoughyourfirmindicatesthatitwillreviewalltestprocessestoensure
thatdatathatiscollectedandanalyzedtosupportthereleasedecisionispartofthebatchrecord,yourfirmhas
notshowndocumentationthatthishasbeencompleted.Yourfirmhasnotindicatedthatitwillreviewallrecords
toensurethatalltestingthatwasdoneisincludedinthebatchrecord.Yourfirmhasalsonotcompleted
compliancetrainingofallpersonnelinvolvedinthereleasetestprocess.

Yourfirmshouldtakepromptactiontocorrecttheviolationsaddressedinthisletter.Failuretopromptlycorrect
theseviolationsmayresultinregulatoryactionbeinginitiatedbytheFDAwithoutfurthernotice.Theseactions
include,butarenotlimitedto,seizure,injunction,andcivilmoneypenalties.Also,federalagenciesmaybe
advisedoftheissuanceofWarningLettersaboutdevicessothattheymaytakethisinformationintoaccount
whenconsideringtheawardofcontracts.Additionally,premarketapprovalapplicationsforClassIIIdevicesto
whichtheQualitySystemregulationviolationsarereasonablyrelatedwillnotbeapproveduntiltheviolations
havebeencorrected.RequestsforCertificatestoForeignGovernmentswillnotbegranteduntiltheviolations
relatedtothesubjectdeviceshavebeencorrected.

Pleasenotifythisofficeinwritingwithinfifteenbusinessdaysfromthedateyoureceivethisletterofthespecific
stepsyourfirmhastakentocorrectthenotedviolations,aswellasanexplanationofhowyourfirmplansto
preventtheseviolations,orsimilarviolations,fromoccurringagain.Includedocumentationofthecorrections
and/orcorrectiveactions(includinganysystemiccorrectiveactions)thatyourfirmhastaken.Ifyourfirms
plannedcorrectionsand/orcorrectiveactionswilloccurovertime,pleaseincludeatimetableforimplementation
ofthoseactivities.Ifcorrectionsand/orcorrectiveactionscannotbecompletedwithinfifteenbusinessdays,
statethereasonforthedelayandthetimewithinwhichtheseactivitieswillbecompleted.Yourfirmsresponse
shouldbecomprehensiveandaddressallviolationsincludedinthisWarningLetter.

Yourfirmsresponseshouldbesentto:Mr.BlakeBevill,Director,ComplianceBranch,FoodandDrug
Administration,19701Fairchild,Irvine,CA926122506.PleaserefertoCMS#332958whenreplying.Ifyou
haveanyquestionsaboutthecontentsofthisletter,pleasecontact:Dr.WilliamVitale,ComplianceOfficerat
9496082919.

Finally,youshouldknowthatthisletterisnotintendedtobeanallinclusivelistoftheviolationsatyourfirms
facility.Itisyourfirmsresponsibilitytoensurecompliancewithapplicablelawsandregulationsadministeredby
FDA.ThespecificviolationsnotedinthisletterandintheInspectionalObservations,FDA483,issuedattheclose
oftheinspectionmaybesymptomaticofseriousproblemsinyourfirmsmanufacturingandqualitymanagement
systems.Yourfirmshouldinvestigateanddeterminethecausesoftheviolations,andtakepromptactionsto
correcttheviolationsandbringtheproductsintocompliance.

Sincerely,
/S/
AlonzaE.Cruse,Director
LosAngelesDistrict

cc:
Ms.IngeborgSmall,Chief
CaliforniaDepartmentofPublicHealth
FoodandDrugBranch
1500CapitolAvenue,MS7602
P.O.Box997435
Sacramento,CA958997435


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