FDAQC实验室检查指南英文版.docx

FDAQC实验室检查指南英文版.docx

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FDAQC实验室检查指南英文版

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'sanalystshouldfollowawrittenproced