FDA QC实验室检查指南Word下载.docx

1、Thespecificobjectivewillbespelledoutpriortotheinspection.Thelaboratoryinspectionmaybelimitedtospecificissues,ortheinspectionmayencompassacomprehensiveevaluationofthelaboratoryscompliancewithCGMPs.Asaminimum,eachpharmaceuticalqualitycontrollaboratoryshouldreceiveacomprehensiveGMPevaluationeachtwoyear

2、saspartofthestatutoryinspectionobligation.Ingeneraltheseinspectionsmayinclude-thespecificmethodologywhichwillbeusedtotestanewproduct-acompleteassessmentoflaboratorysconformancewithGMPs-aspecificaspectoflaboratoryoperations3.INSPECTIONPREPARATIONFDAInspectionGuidesarebasedontheteaminspectionapproacha

3、ndourinspectionofalaboratoryisconsistentwiththisconcept.Aspartofourefforttoachieveuniformityandconsistencyinlaboratoryinspections,weexpectthatcomplex,highlytechnicalandspecializedtestingequipment,proceduresanddatamanipulations,aswellasscientificlaboratoryoperationswillbeevaluatedbyanexperiencedlabor

4、atoryanalystwithspecializedknowledgeinsuchmatters.Districtmanagementmakesthefinaldecisionregardingtheassignmentofpersonneltoinspections.Nevertheless,weexpectinvestigators,analystsandotherstoworkasteamsandtoadvisemanagementwhenadditionalexpertiseisrequiredtocompleteameaningfulinspection.Teammemberspa

5、rticipatinginapre-approvalinspectionmustreadandbefamiliarwithComplianceProgram7346.832,Pre-ApprovalInspections/Investigations.RelevantsectionsoftheNDAorANDAshouldbereviewedpriortotheinspection;butiftheapplicationisnotavailablefromanyothersource,thisreviewwillhavetobeconductedusingthecompanyscopyofth

6、eapplication.Teammembersshouldmeet,ifpossible,priortotheinspectiontodiscusstheapproachtotheinspection,todefinetherolesoftheteammembers,andtoestablishgoalsforcompletionoftheassignment.Responsibilitiesfordevelopmentofallreportsshouldalsobeestablishedpriortotheinspection.Thisincludesthepreparationofthe

7、FDA483.TheCenterforDrugEvaluationandResearch（CDER）mayhaveissueddeficiencyletterslistingproblemsthatthesponsormustcorrectpriortotheapprovalofNDA/ANDAsandsupplements.Theinspectionteamisexpectedtoreviewsuchlettersonfileatthedistrictoffice,andtheyareexpectedtoasktheplantforaccesstosuchletters.Theteamsho

8、uldevaluatetherepliestotheseletterstoassurethatthedataareaccurateandauthentic.Completetheinspectioneventhoughtherehasbeennoresponsetotheselettersorwhentheresponseisjudgedinadequate.4.INSPECTIONAPPROACHA.GeneralInadditiontothegeneralapproachutilizedinadrugCGMPinspection,theinspectionofalaboratoryrequ

9、irestheuseofobservationsofthelaboratoryinoperationandoftherawlaboratorydatatoevaluatecompliancewithCGMPsandtospecificallycarryoutthecommitmentsinanapplicationorDMF.Whenconductingacomprehensiveinspectionofalaboratory,allaspectsofthelaboratoryoperationswillbeevaluated.Laboratoryrecordsandlogsrepresent

10、avitalsourceofinformationthatallowsacompleteoverviewofthetechnicalabilityofthestaffandofoverallqualitycontrolprocedures.SOPsshouldbecompleteandadequateandtheoperationsofthelaboratoriesshouldconformtothewrittenprocedures.Specificationsandanalyticalproceduresshouldbesuitableand,asapplicable,inconforma

11、ncewithapplicationcommitmentsandcompendialrequirements.Evaluaterawlaboratorydata,laboratoryproceduresandmethods,laboratoryequipment,includingmaintenanceandcalibration,andmethodsvalidationdatatodeterminetheoverallqualityofthelaboratoryoperationandtheabilitytocomplywithCGMPregulations.Examinechromatog

12、ramsandspectraforevidenceofimpurities,poortechnique,orlackofinstrumentcalibration.susesystemsthatprovidefortheinvestigationoflaboratorytestfailures.Thesearegenerallyrecordedinsometypeoflog.Asktoseeresultsofanalysesforlotsofproductthathavefailedtomeetspecificationsandreviewtheanalysisoflotsthathavebe

13、enretested,rejected,orreworked.Evaluatethedecisiontoreleaselotsofproductwhenthelaboratoryresultsindicatethatthelotfailedtomeetspecificationsanddeterminewhoreleasedthem.B.Pre-ApprovalDocumentsrelatingtotheformulationoftheproduct,synthesisofthebulkdrugsubstance,productspecifications,analysisoftheprodu

14、ct,andothersareexaminedduringthereviewprocessinheadquarters.However,thesereviewsandevaluationsdependonaccurateandauthenticdatathattrulyrepresentstheproduct.Pre-approvalinspectionsaredesignedtodetermineifthedatasubmittedinanapplicationareauthenticandaccurateandiftheprocedureslistedintheapplicationwer

15、eactuallyusedtoproducethedatacontainedintheapplication.Additionally,theyaredesignedtoconfirmthatplants（includingthequalitycontrollaboratory）areincompliancewithCGMPregulations.Theanalyticalsectionsofdrugapplicationsusuallycontainonlytestresultsandthemethodsusedtoobtainthem.Sponsorsarenotrequiredtofil

16、eallthetestdatabecausesuchactionwouldrequirevoluminoussubmissionsandwouldoftenresultinfilingredundantinformation.Sponsorsmaydeliberatelyorunintentionallyselectandreportdatashowingthatadrugissafeandeffectiveanddeservestobeapproved.Theinspectionteammustdecideifthereisvalidandscientificjustificationfor

17、thefailuretoreportdatawhichdemonstratestheproductfailedtomeetitspredeterminedspecifications.Coordinationbetweenheadquartersandthefieldisessentialforacompletereviewoftheapplicationandtheplant.Experiencedinvestigatorsandanalystsmaycontactthereviewchemist（withappropriatesupervisoryconcurrence）whenquest

18、ionsconcerningspecificationsandstandardsarise.Inspectionsshouldcomparetheresultsofanalysessubmittedwithresultsofanalysisofotherbatchesthatmayhavebeenproduced.Evaluatethemethodsandnoteanyexceptionstotheproceduresorequipmentactuallyusedfromthoselistedintheapplicationandconfirmthatitisthesamemethodlist

19、edintheapplication.Theanalystisexpectedtoevaluaterawlaboratorydatafortestsperformedonthetestbatches（biobatchesandclinicalbatches）andtocomparethisrawdatatothedatafiledintheapplication.5.FAILURE（OUT-OF-SPECIFICATION）LABORATORYRESULTSEvaluatethecompanyssystemtoinvestigatelaboratorytestfailures.Theseinv

20、estigationsrepresentakeyissueindecidingwhetheraproductmaybereleasedorrejectedandformthebasisforretesting,andresampling.Inarecentcourtdecisionthejudgeusedthetermout-of-specification（OOS）laboratoryresultratherthanthetermproductfailurewhichismorecommontoFDAinvestigatorsandanalysts.HeruledthatanOOSresul

21、tidentifiedasalaboratoryerrorbyafailureinvestigationoranoutliertest.Thecourtprovidedexplicitlimitationsontheuseofoutliertestsandthesearediscussedinalatersegmentofthisdocument.,orovercomebyretesting.Thecourtruledontheuseofretestingwhichiscoveredinalatersegmentofthisdocument.isnotaproductfailure.OOSre

22、sultsfallintothreecategories:-laboratoryerror-non-processrelatedoroperatorerror-processrelatedormanufacturingprocesserrorA.LABORATORYERRORSLaboratoryerrorsoccurwhenanalystsmakemistakesinfollowingthemethodofanalysis,useincorrectstandards,and/orsimplymiscalculatethedata.Laboratoryerrorsmustbedetermine

23、dthroughafailureinvestigationtoidentifythecauseoftheOOS.OncethenatureoftheOOSresulthasbeenidentifieditcanbeclassifiedintooneofthethreecategoriesabove.Theinquirymayvarywiththeobjectunderinvestigation.B.LABORATORYINVESTIGATIONSTheexactcauseofanalysterrorormistakecanbedifficulttodeterminespecificallyan

24、ditisunrealistictoexpectthatanalysterrorwillalwaysbedeterminedanddocumented.Nevertheless,alaboratoryinvestigationconsistsofmorethanaretest.Theinabilitytoidentifyanerrorscausewithconfidenceaffectsretestingprocedures,nottheinvestigationinquiryrequiredfortheinitialOOSresult.Thefirmsanalystshouldfollowa

25、writtenprocedure,checkingoffeachstepasitiscompletedduringtheanalyticalprocedure.Weexpectlaboratorytestdatatoberecordeddirectlyinnotebooks;useofscrappaperandloosepapermustbeavoided.Thesecommonsensemeasuresenhancetheaccuracyandintegrityofdata.ReviewandevaluatethelaboratorySOPforproductfailureinvestiga

26、tions.SpecificproceduresmustbefollowedwhensingleandmultipleOOSresultsareinvestigated.ForthesingleOOSresulttheinvestigationshouldincludethefollowingstepsandtheseinquiriesmustbeconductedbeforethereisaretestofthesample:otheanalystconductingthetestshouldreporttheOOSresulttothesupervisorotheanalystandthe

27、supervisorshouldconductaninformallaboratoryinvestigationwhichaddressesthefollowingareas:1.discussthetestingprocedure2.discussthecalculation3.examinetheinstruments4.reviewthenotebookscontainingtheOOSresultAnalternativemeanstoinvalidateaninitialOOSresult,providedthefailureinvestigationprovesinconclusi

28、ve,istheoutliertest.However,specificrestrictionsmustbeplacedontheuseofthistest.1.Firmscannotfrequentlyrejectresultsonthisbasis.2.TheUSPstandardsgovernitsuseinspecificcasesonly.3.Thetestcannotbeusedforchemicaltestingresults.AninitialcontentuniformitytestwasOOSfollowedbyapassingretest.TheinitialOOSresultwasclaimedtheresultofanalysterrorbasedonastatisticalevaluationofthedata.Thecourtruledthattheuseofanoutliertestisinappropriateinthiscase.4.Itisneverappropriatetoutilizeoutliertestsforastatisticallybasedtest,i.e.,contentuniformityanddissolution.Determineifthefirmusesanoutliertestandevaluateth