FDA QC实验室检查指南.docx
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FDA QC实验室检查指南.docx
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FDAQC实验室检查指南
GUIDETOINSPECTIONSOFPHARMACEUTICALQUALITYCONTROLLABORATORIES
Note:
ThisdocumentisreferencematerialforinvestigatorsandotherFDA
personnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,
privileges,benefits,orimmunitiesfororonanyperson(s).
1.INTRODUCTION
Thepharmaceuticalqualitycontrollaboratoryservesoneofthemost
importantfunctionsinpharmaceuticalproductionandcontrol.Asignificant
portionoftheCGMPregulations(21CFR211)pertaintothequalitycontrol
laboratoryandproducttesting.Similarconceptsapplytobulkdrugs.
Thisinspectionguidesupplementsotherinspectionalinformationcontained
inotheragencyinspectionalguidancedocuments.Forexample,Compliance
Program7346.832requiringpre-approvalNDA/ANDAinspectionscontains
generalinstructionstoconductproductspecificNDA/ANDAinspectionaudits
tomeasurecompliancewiththeapplicationsandCGMPrequirements.This
includespharmaceuticallaboratoriesusedforin-processandfinished
producttesting.
2.OBJECTIVE
Thespecificobjectivewillbespelledoutpriortotheinspection.The
laboratoryinspectionmaybelimitedtospecificissues,ortheinspection
mayencompassacomprehensiveevaluationofthelaboratory'scompliancewith
CGMP's.Asaminimum,eachpharmaceuticalqualitycontrollaboratoryshould
receiveacomprehensiveGMPevaluationeachtwoyearsaspartofthe
statutoryinspectionobligation.
Ingeneraltheseinspectionsmayinclude
--thespecificmethodologywhichwillbeusedtotestanewproduct
--acompleteassessmentoflaboratory'sconformancewithGMP's
--aspecificaspectoflaboratoryoperations
3.INSPECTIONPREPARATION
FDAInspectionGuidesarebasedontheteaminspectionapproachandour
inspectionofalaboratoryisconsistentwiththisconcept.Aspartofour
efforttoachieveuniformityandconsistencyinlaboratoryinspections,we
expectthatcomplex,highlytechnicalandspecializedtestingequipment,
proceduresanddatamanipulations,aswellasscientificlaboratory
operationswillbeevaluatedbyanexperiencedlaboratoryanalystwith
specializedknowledgeinsuchmatters.
Districtmanagementmakesthefinaldecisionregardingtheassignmentof
personneltoinspections.Nevertheless,weexpectinvestigators,analysts
andotherstoworkasteamsandtoadvisemanagementwhenadditional
expertiseisrequiredtocompleteameaningfulinspection.
Teammembersparticipatinginapre-approvalinspectionmustreadandbe
familiarwithComplianceProgram7346.832,Pre-Approval
Inspections/Investigations.RelevantsectionsoftheNDAorANDAshouldbe
reviewedpriortotheinspection;butiftheapplicationisnotavailable
fromanyothersource,thisreviewwillhavetobeconductedusingthe
company'scopyoftheapplication.
Teammembersshouldmeet,ifpossible,priortotheinspectiontodiscuss
theapproachtotheinspection,todefinetherolesoftheteammembers,and
toestablishgoalsforcompletionoftheassignment.Responsibilitiesfor
developmentofallreportsshouldalsobeestablishedpriortothe
inspection.ThisincludesthepreparationoftheFDA483.
TheCenterforDrugEvaluationandResearch(CDER)mayhaveissued
deficiencyletterslistingproblemsthatthesponsormustcorrectpriorto
theapprovalofNDA/ANDA'sandsupplements.Theinspectionteamisexpected
toreviewsuchlettersonfileatthedistrictoffice,andtheyareexpected
toasktheplantforaccesstosuchletters.Theteamshouldevaluatethe
repliestotheseletterstoassurethatthedataareaccurateandauthentic.
Completetheinspectioneventhoughtherehasbeennoresponsetothese
lettersorwhentheresponseisjudgedinadequate.
4.INSPECTIONAPPROACH
A.General
InadditiontothegeneralapproachutilizedinadrugCGMPinspection,the
inspectionofalaboratoryrequirestheuseofobservationsofthe
laboratoryinoperationandoftherawlaboratorydatatoevaluate
compliancewithCGMP'sandtospecificallycarryoutthecommitmentsinan
applicationorDMF.Whenconductingacomprehensiveinspectionofa
laboratory,allaspectsofthelaboratoryoperationswillbeevaluated.
Laboratoryrecordsandlogsrepresentavitalsourceofinformationthat
allowsacompleteoverviewofthetechnicalabilityofthestaffandof
overallqualitycontrolprocedures.SOPsshouldbecompleteandadequateand
theoperationsofthelaboratoriesshouldconformtothewrittenprocedures.
Specificationsandanalyticalproceduresshouldbesuitableand,as
applicable,inconformancewithapplicationcommitmentsandcompendial
requirements.
Evaluaterawlaboratorydata,laboratoryproceduresandmethods,laboratory
equipment,includingmaintenanceandcalibration,andmethodsvalidationdata
todeterminetheoverallqualityofthelaboratoryoperationandtheability
tocomplywithCGMPregulations.
Examinechromatogramsandspectraforevidenceofimpurities,poor
technique,orlackofinstrumentcalibration.
susesystemsthatprovidefortheinvestigationof
laboratorytestfailures.Thesearegenerallyrecordedinsometypeoflog.
Asktoseeresultsofanalysesforlotsofproductthathavefailedtomeet
specificationsandreviewtheanalysisoflotsthathavebeenretested,
rejected,orreworked.Evaluatethedecisiontoreleaselotsofproductwhen
thelaboratoryresultsindicatethatthelotfailedtomeetspecifications
anddeterminewhoreleasedthem.
B.Pre-Approval
Documentsrelatingtotheformulationoftheproduct,synthesisofthebulk
drugsubstance,productspecifications,analysisoftheproduct,andothers
areexaminedduringthereviewprocessinheadquarters.However,these
reviewsandevaluationsdependonaccurateandauthenticdatathattruly
representstheproduct.
Pre-approvalinspectionsaredesignedtodetermineifthedatasubmittedin
anapplicationareauthenticandaccurateandiftheprocedureslistedin
theapplicationwereactuallyusedtoproducethedatacontainedinthe
application.Additionally,theyaredesignedtoconfirmthatplants
(includingthequalitycontrollaboratory)areincompliancewithCGMP
regulations.
Theanalyticalsectionsofdrugapplicationsusuallycontainonlytest
resultsandthemethodsusedtoobtainthem.Sponsorsarenotrequiredto
fileallthetestdatabecausesuchactionwouldrequirevoluminous
submissionsandwouldoftenresultinfilingredundantinformation.Sponsors
maydeliberatelyorunintentionallyselectandreportdatashowingthata
drugissafeandeffectiveanddeservestobeapproved.Theinspectionteam
mustdecideifthereisvalidandscientificjustificationforthefailure
toreportdatawhichdemonstratestheproductfailedtomeetits
predeterminedspecifications.
Coordinationbetweenheadquartersandthefieldisessentialforacomplete
reviewoftheapplicationandtheplant.Experiencedinvestigatorsand
analystsmaycontactthereviewchemist(withappropriatesupervisory
concurrence)whenquestionsconcerningspecificationsandstandardsarise.
Inspectionsshouldcomparetheresultsofanalysessubmittedwithresultsof
analysisofotherbatchesthatmayhavebeenproduced.Evaluatethemethods
andnoteanyexceptionstotheproceduresorequipmentactuallyusedfrom
thoselistedintheapplicationandconfirmthatitisthesamemethod
listedintheapplication.Theanalystisexpectedtoevaluateraw
laboratorydatafortestsperformedonthetestbatches(biobatchesand
clinicalbatches)andtocomparethisrawdatatothedatafiledinthe
application.
5.FAILURE(OUT-OF-SPECIFICATION)LABORATORYRESULTS
Evaluatethecompany'ssystemtoinvestigatelaboratorytestfailures.These
investigationsrepresentakeyissueindecidingwhetheraproductmaybe
releasedorrejectedandformthebasisforretesting,andresampling.
Inarecentcourtdecisionthejudgeusedtheterm"out-of-specification"
(OOS)laboratoryresultratherthantheterm"productfailure"whichismore
commontoFDAinvestigatorsandanalysts.HeruledthatanOOSresult
identifiedasalaboratoryerrorbyafailureinvestigationoranoutlier
test.Thecourtprovidedexplicitlimitationsontheuseofoutliertests
andthesearediscussedinalatersegmentofthisdocument.,orovercomeby
retesting.Thecourtruledontheuseofretestingwhichiscoveredina
latersegmentofthisdocument.isnotaproductfailure.OOSresultsfall
intothreecategories:
--laboratoryerror
--non-processrelatedoroperatorerror
--processrelatedormanufacturingprocesserror
A.LABORATORYERRORS
Laboratoryerrorsoccurwhenanalystsmakemistakesinfollowingthemethod
ofanalysis,useincorrectstandards,and/orsimplymiscalculatethedata.
Laboratoryerrorsmustbedeterminedthroughafailureinvestigationto
identifythecauseoftheOOS.OncethenatureoftheOOSresulthasbeen
identifieditcanbeclassifiedintooneofthethreecategoriesabove.The
inquirymayvarywiththeobjectunderinvestigation.
B.LABORATORYINVESTIGATIONS
Theexactcauseofanalysterrorormistakecanbedifficulttodetermine
specificallyanditisunrealistictoexpectthatanalysterrorwillalways
bedeterminedanddocumented.Nevertheless,alaboratoryinvestigation
consistsofmorethanaretest.Theinabilitytoidentifyanerror'scause
withconfidenceaffectsretestingprocedures,nottheinvestigationinquiry
requiredfortheinitialOOSresult.
Thefirm'sanalystshouldfollowawrittenprocedur
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