FDA QC实验室检查指南Word下载.docx

FDA QC实验室检查指南Word下载.docx

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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'

sanalystshouldfollowawrittenprocedure,checkingoffeachstep

asitiscompletedduringtheanalyticalprocedure.Weexpectlaboratory

testdatatoberecordeddirectlyinnotebooks;

useofscrappaperandloose

papermustbeavoided.Thesecommonsensemeasuresenhancetheaccuracyand

integrityofdata.

ReviewandevaluatethelaboratorySOPforproductfailureinvestigations.

SpecificproceduresmustbefollowedwhensingleandmultipleOOSresults

areinvestigated.ForthesingleOOSresulttheinvestigationshouldinclude

thefollowingstepsandtheseinquiriesmustbeconductedbeforethereisa

retestofthesample:

otheanalystconductingthetestshouldreporttheOOSresulttothe

supervisor

otheanalystandthesupervisorshouldconductaninformallaboratory

investigationwhichaddressesthefollowingareas:

1.discussthetestingprocedure

2.discussthecalculation

3.examinetheinstruments

4.reviewthenotebookscontainingtheOOSresult

AnalternativemeanstoinvalidateaninitialOOSresult,providedthe

failureinvestigationprovesinconclusive,isthe"

outlier"

test.However,

specificrestrictionsmustbeplacedontheuseofthistest.

1.Firmscannotfrequentlyrejectresultsonthisbasis.

2.TheUSPstandardsgovernitsuseinspecificcasesonly.

3.Thetestcannotbeusedforchemicaltestingresults.Aninitialcontent

uniformitytestwasOOSfollowedbyapassingretest.TheinitialOOSresult

wasclaimedtheresultofanalysterrorbasedonastatisticalevaluationof

thedata.Thecourtruledthattheuseofanoutliertestisinappropriate

inthiscase..

4.Itisneverappropriatetoutilizeoutliertestsforastatistically

basedtest,i.e.,contentuniformityanddissolution.

Determineifthefirmusesanoutliertestandevaluateth