實驗室檢查指南英文版

1、GUIDETOINSPECTIONSOFPHARMACEUTICALQUALITYCONTROLLABORATORIESNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).INTRODUCTIONThepharmaceuticalqualitycontrollaboratoryservesoneof

2、themostimportantfunctionsinpharmaceuticalproductionandcontrol.AsignificantportionoftheCGMPregulations(21CFR211)pertaintothequalitycontrollaboratoryandproducttesting.Similarconceptsapplytobulkdrugs.Thisinspectionguidesupplementsotherinspectionalinformationcontainedinotheragencyinspectionalguidancedoc

3、uments.Forexample,ComplianceProgram7346.832requiringpre-approvalNDA/ANDAinspectionscontainsgeneralinstructionstoconductproductspecificNDA/ANDAinspectionauditstomeasurecompliancewiththeapplicationsandCGMPrequirements.Thisincludespharmaceuticallaboratoriesusedforin-processandfinishedproducttesting.OBJ

4、ECTIVEThespecificobjectivewillbespelledoutpriortotheinspection.Thelaboratoryinspectionmaybelimitedtospecificissues,ortheinspectionmayencompassacomprehensiveevaluationofthelaboratory'scompliancewithCGMP's.Asaminimum,eachpharmaceuticalqualitycontrollaboratoryshouldreceiveacomprehensiveGMPevalu

5、ationeachtwoyearsaspartofthestatutoryinspectionobligation.Ingeneraltheseinspectionsmayinclude-thespecificmethodologywhichwillbeusedtotestanewproduct-acompleteassessmentoflaboratory'sconformancewithGMP's-aspecificaspectoflaboratoryoperationsINSPECTIONPREPARATIONFDAInspectionGuidesarebasedonth

6、eteaminspectionapproachandourinspectionofalaboratoryisconsistentwiththisconcept.Aspartofourefforttoachieveuniformityandconsistencyinlaboratoryinspections,weexpectthatcomplex,highlytechnicalandspecializedtestingequipment,proceduresanddatamanipulations,aswellasscientificlaboratoryoperationswillbeevalu

7、atedbyanexperiencedlaboratoryanalystwithspecializedknowledgeinsuchmatters.Districtmanagementmakesthefinaldecisionregardingtheassignmentofpersonneltoinspections.Nevertheless,weexpectinvestigators,analystsandotherstoworkasteamsandtoadvisemanagementwhenadditionalexpertiseisrequiredtocompleteameaningful

8、inspection.Teammembersparticipatinginapre-approvalinspectionmustreadandbefamiliarwithComplianceProgram7346.832,Pre-ApprovalInspections/Investigations.RelevantsectionsoftheNDAorANDAshouldbereviewedpriortotheinspection;butiftheapplicationisnotavailablefromanyothersource,thisreviewwillhavetobeconducted

9、usingthecompany'scopyoftheapplication.Teammembersshouldmeet,ifpossible,priortotheinspectiontodiscusstheapproachtotheinspection,todefinetherolesoftheteammembers,andtoestablishgoalsforcompletionoftheassignment.Responsibilitiesfordevelopmentofallreportsshouldalsobeestablishedpriortotheinspection.Th

10、isincludesthepreparationoftheFDA483.TheCenterforDrugEvaluationandResearch(CDER)mayhaveissueddeficiencyletterslistingproblemsthatthesponsormustcorrectpriortotheapprovalofNDA/ANDA'sandsupplements.Theinspectionteamisexpectedtoreviewsuchlettersonfileatthedistrictoffice,andtheyareexpectedtoasktheplan

11、tforaccesstosuchletters.Theteamshouldevaluatetherepliestotheseletterstoassurethatthedataareaccurateandauthentic.Completetheinspectioneventhoughtherehasbeennoresponsetotheselettersorwhentheresponseisjudgedinadequate.1. INSPECTIONAPPROACHGeneralInadditiontothegeneralapproachutilizedinadrugCGMPinspecti

12、on,theinspectionofalaboratoryrequirestheuseofobservationsofthelaboratoryinoperationandoftherawlaboratorydatatoevaluatecompliancewithCGMP'sandtospecificallycarryoutthecommitmentsinanapplicationorDMF.Whenconductingacomprehensiveinspectionofalaboratory,allaspectsofthelaboratoryoperationswillbeevalu

13、ated.Laboratoryrecordsandlogsrepresentavitalsourceofinformationthatallowsacompleteoverviewofthetechnicalabilityofthestaffandofoverallqualitycontrolprocedures.SOPsshouldbecompleteandadequateandtheoperationsofthelaboratoriesshouldconformtothewrittenprocedures.Specificationsandanalyticalproceduresshoul

14、dbesuitableand,asapplicable,inconformancewithapplicationcommitmentsandcompendialrequirements.Evaluaterawlaboratorydata,laboratoryproceduresandmethods,laboratoryequipment,includingmaintenanceandcalibration,andmethodsvalidationdatatodeterminetheoverallqualityofthelaboratoryoperationandtheabilitytocomp

15、lywithCGMPregulations.Examinechromatogramsandspectraforevidenceofimpurities,poortechnique,orlackofinstrumentcalibration.susesystemsthatprovidefortheinvestigationoflaboratorytestfailures.Thesearegenerallyrecordedinsometypeoflog.Asktoseeresultsofanalysesforlotsofproductthathavefailedtomeetspecificatio

16、nsandreviewtheanalysisoflotsthathavebeenretested,rejected,orreworked.Evaluatethedecisiontoreleaselotsofproductwhenthelaboratoryresultsindicatethatthelotfailedtomeetspecificationsanddeterminewhoreleasedthem.Pre-ApprovalDocumentsrelatingtotheformulationoftheproduct,synthesisofthebulkdrugsubstance,prod

17、uctspecifications,analysisoftheproduct,andothersareexaminedduringthereviewprocessinheadquarters.However,thesereviewsandevaluationsdependonaccurateandauthenticdatathattrulyrepresentstheproduct.Pre-approvalinspectionsaredesignedtodetermineifthedatasubmittedinanapplicationareauthenticandaccurateandifth

18、eprocedureslistedintheapplicationwereactuallyusedtoproducethedatacontainedintheapplication.Additionally,theyaredesignedtoconfirmthatplants(includingthequalitycontrollaboratory)areincompliancewithCGMPregulations.Theanalyticalsectionsofdrugapplicationsusuallycontainonlytestresultsandthemethodsusedtoob

19、tainthem.Sponsorsarenotrequiredtofileallthetestdatabecausesuchactionwouldrequirevoluminoussubmissionsandwouldoftenresultinfilingredundantinformation.Sponsorsmaydeliberatelyorunintentionallyselectandreportdatashowingthatadrugissafeandeffectiveanddeservestobeapproved.Theinspectionteammustdecideifthere

20、isvalidandscientificjustificationforthefailuretoreportdatawhichdemonstratestheproductfailedtomeetitspredeterminedspecifications.Coordinationbetweenheadquartersandthefieldisessentialforacompletereviewoftheapplicationandtheplant.Experiencedinvestigatorsandanalystsmaycontactthereviewchemist(withappropr

21、iatesupervisoryconcurrence)whenquestionsconcerningspecificationsandstandardsarise.Inspectionsshouldcomparetheresultsofanalysessubmittedwithresultsofanalysisofotherbatchesthatmayhavebeenproduced.Evaluatethemethodsandnoteanyexceptionstotheproceduresorequipmentactuallyusedfromthoselistedintheapplicatio

22、nandconfirmthatitisthesamemethodlistedintheapplication.Theanalystisexpectedtoevaluaterawlaboratorydatafortestsperformedonthetestbatches(biobatchesandclinicalbatches)andtocomparethisrawdatatothedatafiledintheapplication.2. FAILURE(OUT-OF-SPECIFICATION)LABORATORYRESULTSEvaluatethecompany'ssystemto

23、investigatelaboratorytestfailures.Theseinvestigationsrepresentakeyissueindecidingwhetheraproductmaybereleasedorrejectedandformthebasisforretesting,andresampling.Inarecentcourtdecisionthejudgeusedtheterm"out-of-specification"(OOS)laboratoryresultratherthantheterm"productfailure"wh

24、ichismorecommontoFDAinvestigatorsandanalysts.HeruledthatanOOSresultidentifiedasalaboratoryerrorbyafailureinvestigationoranoutliertest.Thecourtprovidedexplicitlimitationsontheuseofoutliertestsandthesearediscussedinalatersegmentofthisdocument.,orovercomebyretesting.Thecourtruledontheuseofretestingwhic

25、hiscoveredinalatersegmentofthisdocument.isnotaproductfailure.OOSresultsfallintothreecategories:-laboratoryerror-non-processrelatedoroperatorerror-processrelatedormanufacturingprocesserrorLABORATORYERRORSLaboratoryerrorsoccurwhenanalystsmakemistakesinfollowingthemethodofanalysis,useincorrectstandards

26、,and/orsimplymiscalculatethedata.LaboratoryerrorsmustbedeterminedthroughafailureinvestigationtoidentifythecauseoftheOOS.OncethenatureoftheOOSresulthasbeenidentifieditcanbeclassifiedintooneofthethreecategoriesabove.Theinquirymayvarywiththeobjectunderinvestigation.LABORATORYINVESTIGATIONSTheexactcause

27、ofanalysterrorormistakecanbedifficulttodeterminespecificallyanditisunrealistictoexpectthatanalysterrorwillalwaysbedeterminedanddocumented.Nevertheless,alaboratoryinvestigationconsistsofmorethanaretest.Theinabilitytoidentifyanerror'scausewithconfidenceaffectsretestingprocedures,nottheinvestigatio

28、ninquiryrequiredfortheinitialOOSresult.Thefirm'sanalystshouldfollowawrittenprocedure,checkingoffeachstepasitiscompletedduringtheanalyticalprocedure.Weexpectlaboratorytestdatatoberecordeddirectlyinnotebooks;useofscrappaperandloosepapermustbeavoided.Thesecommonsensemeasuresenhancetheaccuracyandint

29、egrityofdata.ReviewandevaluatethelaboratorySOPforproductfailureinvestigations.SpecificproceduresmustbefollowedwhensingleandmultipleOOSresultsareinvestigated.ForthesingleOOSresulttheinvestigationshouldincludethefollowingstepsandtheseinquiriesmustbeconductedbeforethereisaretestofthesample:otheanalystc

30、onductingthetestshouldreporttheOOSresulttothesupervisorotheanalystandthesupervisorshouldconductaninformallaboratoryinvestigationwhichaddressesthefollowingareas:discussthetestingprocedurediscussthecalculationexaminetheinstrumentsreviewthenotebookscontainingtheOOSresultAnalternativemeanstoinvalidatean

31、initialOOSresult,providedthefailureinvestigationprovesinconclusive,isthe"outlier"test.However,specificrestrictionsmustbeplacedontheuseofthistest.1. Firmscannotfrequentlyrejectresultsonthisbasis.2. TheUSPstandardsgovernitsuseinspecificcasesonly.Thetestcannotbeusedforchemicaltestingresults.A

32、ninitialcontentuniformitytestwasOOSfollowedbyapassingretest.TheinitialOOSresultwasclaimedtheresultofanalysterrorbasedonastatisticalevaluationofthedata.Thecourtruledthattheuseofanoutliertestisinappropriateinthiscase.3. Itisneverappropriatetoutilizeoutliertestsforastatisticallybasedtest,i.e.,contentun

33、iformityanddissolution.DetermineifthefirmusesanoutliertestandevaluatetheSOP.DeterminethatafullscaleinquiryhasbeenmadeformultipleOOSresults.Thisinquiryinvolvesqualitycontrolandqualityassurancepersonnelinadditiontolaboratoryworkerstoidentifyexactprocessornonprocessrelatederrors.Whenthelaboratoryinvest

34、igationisinconclusive(reasonfortheerrorisnotidentified)thefirm:Cannotconduct2retestsandbasereleaseonaverageofthreetestsCannotuseoutliertestinchemicaltestsCannotuseare-sampletoassumeasamplingorpreparationerrorCanconductaretestofdifferenttabletsfromthesamesamplewhenaretestisconsideredappropriate(seecr

35、iteriaelsewhere)FORMALINVESTIGATIONSFormalinvestigationsextendingbeyondthelaboratorymustfollowanoutlinewithparticularattentiontocorrectiveaction.Thecompanymust:1. StatethereasonfortheinvestigationProvidesummationoftheprocesssequencesthatmayhavecausedtheproblemOutlinecorrectiveactionsnecessarytosavet

36、hebatchandpreventsimilarrecurrenceListotherbatchesandproductspossiblyaffected,theresultsofinvestigationofthesebatchesandproducts,andanycorrectiveaction.Specifically:oexamineotherbatchesofproductmadebytheerrantemployeeormachineoexamineotherproductsproducedbytheerrantprocessoroperationPreservethecomme

37、ntsandsignaturesofallproductionandqualitycontrolpersonnelwhoconductedtheinvestigationandapprovedanyreprocessedmaterialafteradditionaltestingINVESTIGATIONDOCUMENTATIONAnalyst'smistakes,suchasundetectedcalculationerrors,shouldbespecifiedwithparticularityandsupportedbyevidence.Investigationsalongwi

38、thconclusionsreachedmustbepreservedwithwrittendocumentationthatenumerateseachstepoftheinvestigation.Theevaluation,conclusionandcorrectiveaction,ifany,shouldbepreservedinaninvestigationorfailurereportandplacedintoacentralfile.INVESTIGATIONTIMEFRAMESAllfailureinvestigationsshouldbeperformedwithin20bus

39、inessdaysoftheproblem'soccurrenceandrecordedandwrittenintoafailureorinvestigationreport.PRODUCTFAILURESAnOOSlaboratoryresultcanbeovercome(invalidated)whenlaboratoryerrorhasbeendocumented.However,non-processandprocessrelatederrorsresultingfromoperatorsmakingmistakes,equipment(otherthanlaboratorye

40、quipment)malfunctions,oramanufacturingprocessthatisfundamentallydeficient,suchasanimpropermixingtime,representproductfailures.Examinetheresultsofinvestigationsusingtheguidanceinsection5aboveandevaluatethedecisiontorelease,retest,orreworkproducts.RETESTINGEvaluatethecompany'sretestingSOPforcompli

41、ancewithscientificallysoundandappropriateprocedures.Averyimportantrulinginonerecentcourtdecisionsetsforthaproceduretogoverntheretestingprogram.Thisdistrictcourtrulingprovidesanexcellentguidetouseinevaluatingsomeaspectsofapharmaceuticallaboratory,butshouldnotbeconsideredaslaw,regulationorbindinglegal

42、precedent.Thecourtruledthatafirmshouldhaveapredeterminedtestingprocedureanditshouldconsiderapointatwhichtestingendsandtheproductisevaluated.Ifresultsarenotsatisfactory,theproductisrejected.Additionally,thecompanyshouldconsiderallretestresultsinthecontextoftheoverallrecordoftheproduct.Thisincludesthe

43、historyoftheproduct.Thecourtorderedarecallofonebatchofproductonthebasisofaninitialcontentuniformityfailureandnobasistoinvalidatethetestresultandonahistoryofcontentuniformityproblemswiththeproduct.,typeoftestperformed,andin-processtestresults.Failingassayresultscannotbedisregardedsimplyonthebasisofac

44、ceptablecontentuniformityresults.ThenumberofretestsperformedbeforeafirmconcludesthatanunexplainedOOSresultisinvalidorthataproductisunacceptableisamatterofscientificjudgment.ThegoalofretestingistoisolateOOSresultsbutretestingcannotcontinueadinfinitum.Inthecaseofnonprocessandprocess-relatederrors,rete

45、stingissuspect.Becausetheinitialtestsaregenuine,inthesecircumstances,additionaltestingalonecannotcontributetoproductquality.Thecourtacknowledgedthatsomeretestingmayprecedeafindingofnonprocessorprocess-basederrors.Oncethisdeterminationismade,however,additionalretestingforpurposesoftestingaproductinto

46、complianceisnotacceptable.Forexample,inthecaseofcontentuniformitytestingdesignedtodetectvariabilityintheblendortablets,failingandnon-failingresultsarenotinherentlyinconsistentandpassingresultsonlimitedretestingdonotruleoutthepossibilitythatthebatchisnotuniform.Aspartoftheinvestigationfirmsshouldcons

47、idertherecordofpreviousbatches,sincesimilarorrelatedfailuresondifferentbatcheswouldbeacauseofconcern.RetestingfollowinganOOSresultisruledappropriateonlyafterthefailureinvestigationisunderwayandthefailureinvestigationdeterminesinpartwhetherretestingisappropriate.Itisappropriatewhenanalysterrorisdocum

48、entedorthereviewofanalyst'sworkis"inconclusive",butitisnotappropriateforknownandundisputednon-processorprocessrelatederrors.Thecourtruledthatretesting:omustbedoneonthesame,notadifferentsampleomaybedoneonasecondaliquotfromthesameportionofthesamplethatwasthesourceofthefirstaliquotomaybed

49、oneonaportionofthesamelargersamplepreviouslycollectedforlaboratorypurposesRESAMPLINGFirmscannotrelyonresampling.ThecourtorderedtherecallofonebatchofproductafterhavingconcludedthatasuccessfulresampleresultalonecannotinvalidateaninitialOOSresult.toreleaseaproductthathasfailedtestingandretestingunlesst

50、hefailureinvestigationdisclosesevidencethattheoriginalsampleisnotrepresentativeorwasimproperlyprepared.Evaluateeachresamplingactivityforcompliancewiththisguidance.AVERAGINGRESULTSOFANALYSISAveragingcanbearationalandvalidapproachwhentheobjectunderconsiderationistotalproductassay,butasageneralrulethis

51、practiceshouldbeavoided.Thecourtruledthatthefirmmustrecallabatchthatwasreleasedforcontentuniformityonthebasisofaveragedtestresults.becauseaverageshidethevariabilityamongindividualtestresults.ThisphenomenonisparticularlytroublingiftestinggeneratesbothOOSandpassingindividualresultswhichwhenaveragedare

52、withinspecification.Here,relyingontheaveragefigurewithoutexaminingandexplainingtheindividualOOSresultsishighlymisleadingandunacceptable.Contentuniformityanddissolutionresultsnevershouldbeaveragedtoobtainapassingvalue.InthecaseofmicrobiologicalturbidimetricandplateassaysanaverageispreferredbytheUSP.I

53、nthiscase,itisgoodpracticetoincludeOOSresultsintheaverageunlessanoutliertest(microbiologicalassays)suggeststheOOSisananomaly.BLENDSAMPLINGANDTESTINGThelaboratoryservesavitalfunctioninblendtestingwhichisnecessarytoincreasethelikelihoodofdetectinginferiorbatches.Blenduniformitytestingcannotbewaivedinf

54、avoroftotalrelianceonfinishedproducttestingbecausefinishedproducttestingislimited.Onecourthasruledthatsamplesizeinfluencesultimateblendtestresultsandthatthesamplesizeshouldresemblethedosagesize.Anyotherpracticewouldblurdifferencesinportionsoftheblendanddefeattheobjectofthetest.Ifasamplelargerthanthe

55、unitmustbetakeninitially,aliquotswhichresemblethedosagesizeshouldbecarefullyremovedforthetest,retests,andreservesamples.Obviously,theinitiallargersampleshouldnotbesubjectedtoanyadditionalmixingormanipulationpriortoremovingtestaliquotsasthismayobscurenon-homogeneity.Multipleindividualblenduniformitys

56、amplestakenfromdifferentareascannotbecomposited.Howeverwhenvariationtestingisnottheobjectofassaytesting,compositingispermitted.Iffirmssampleproductfromsitesotherthantheblender,theymustdemonstratethroughvalidationthattheirsamplingtechniqueisrepresentativeofallportionsandconcentrationsoftheblend.Thism

57、eansthatthesamplesmustberepresentativeofthosesitesthatmightbeproblems;e.g.weakorhotspotsintheblend.MICROBIOLOGICALThereviewofmicrobiologicaldataonapplicabledosageformsisbestperformedbythemicrobiologist(analyst).Datathatshouldbereviewedincludepreservativeeffectivenesstesting,bioburdendata,andproducts

58、pecificmicrobiologicaltestingandmethods.Reviewbioburden(beforefiltrationand/orsterilization)frombothanendotoxinandsterilityperspective.Fordrugsubstancelabsevaluatemethodsvalidationandrawdataforsterility,endotoxintesting,environmentalmonitoring,andfilterandfiltrationvalidation.Also,evaluatethemethods

59、usedtotestandestablishbioburdens.RefertotheMicrobiologicalInspectionGuideforadditionalinformationconcerningtheinspectionofmicrobiologicallaboratories.SAMPLINGSampleswillbecollectedonpre-approvalinspections.FollowthesamplingguidelinesinCP7346.832,PartIII,pages5and6.LABORATORYRECORDSANDDOCUMENTATIONReviewpersonalanalyticalnotebookskeptbytheanalystsinthelaboratoryandcomparethemwiththeworksheetsandgenerallabnotebooksandrecords.Bepreparedtoexamineallrecordsandworksheetsforaccuracyandauthenticityandtoverifythatrawdataareretainedtosupporttheconclusionsfoundinlaboratoryresults.Reviewlaborat