品研究实验原始记录审核技术要求.ppt

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1、品研究实验原始记录审核技术要求 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望新药研发过程新药研发过程2新药研发过程质量规范新药研发过程质量规范GLP历史沿革历史沿革遵从遵从GLP的意义的意义GLP规范基本要求规范基本要求原始数据核查要点原始数据核查要点非临床实验室常见错误非临床实验室常见错误法规对法规对GLP或非或非GLP的要求的要求案例分析案例分析内容提要内容提要4GLP历史历史美国美国WhatpromptedUSFDAtoissueGLPregulation

2、s?Inthe1960sand1970s,inadditiontothe“Thalidomide”story,FDAfound:SelectivelysubmittedfindingsFabricateddataFalsifieddataDiscrepanciesinreporting(e.g.,betweenindividualandsummarydata)Poorlaboratoryrecordkeeping(resultingininabilitytoreconstructstudyperformance)GLP历史历史美国美国In the 1960s and 1970s,FDA als

3、o found:Noprotocols,protocolswrittenafterstudyperformance,studynotperformedaccordingtoprotocolNooneinchargeofstudiesSloppylaboratorypracticesUSFDAGLP法规法规1976CongressionalhearingsGLPsproposed1978GLPsfinalized1979GLPsbecomeeffectiveUSFDAGLP法规法规 21CFR:CodeofFederalRegulations,Food&DrugAdministration.21

4、CFRPart58:GoodLaboratoryPracticesforNonclinicalLaboratoryStudies21CFRPart11:ElectronicRecords;ElectronicSignaturesUSFDAGLPPart58要求要求Describes requirements for conducting and reporting nonclinical laboratory studiesIntent:provides a framework for conducting well-controlled studiesassures quality and

5、integrity of the datafacilitates study reconstructionprovides overall accountability Nonclinical studies that evaluate safety must be GLP compliantUSFDAGLP检查检查FDAGLP检查过的美国国内实验室检查过的美国国内实验室200余家余家,CRO,药厂药厂USFDAGLP检查检查FDAGLP检查过的美国境外实验室检查过的美国境外实验室40余家余家,CRO,药厂药厂USFDAGLP检查：检查：MOU8个国家个国家日本日本法国法国德国德国加拿大加拿大

6、意大利意大利瑞典瑞典瑞士瑞士荷兰荷兰USFDAGLP检查：中国检查：中国GLP实验室实验室2009年年7月月检查了三家了三家GLP实验室室国家安国家安评中心中心(NCSED)昭衍（昭衍（JOINN)Bridge(康康龙化成化成)昭衍提交的昭衍提交的试验报告告获得美国得美国FDA认可可,用于支持美国的用于支持美国的临床床试验。OECDGLP规范规范Developedin1978USFDAGLPprovidedthebasisforOECDRevisedOECDprinciplesadoptedin1997PrimaryobjectivesimilartoUSFDAToensurethegener

7、ationofhighqualityandreliabletestdatarelatedtothesafetyofindustrialchemicalsubstancesandpreparationsintheframeworkofharmonisingtestingproceduresforthemutualacceptanceofdata(MAD)OECDMAD（数据互认）（数据互认）DatageneratedinthetestingofchemicalsinanOECDmembercountryinaccordancewithOECDTestGuidelinesandOECDPrinci

8、plesofGLPshallbeacceptedinotherMembercountriesforpurposesofassessmentandotherusesrelatingtotheprotectionofmanandtheenvironmentOECDMemberCountriesAustralia,Austria,Belgium,Canada,CzechRepublic,Denmark,Finland,France,Germany,Greece,Hungary,Iceland,Ireland,Italy,Japan,Korea,Luxembourg,Mexico,Netherland

9、s,NewZealand,Norway,Poland,Portugal,SlovakRepublic,Spain,Sweden,Switzerland,Turkey,UnitedKingdom,UnitedStates中国中国GLP发展历史发展历史1993年年12月，国家科委发布了月，国家科委发布了GLP（试行）（试行）1999年年10月，月，SDA发布发布GLP（试行）（试行）2001年中国修订年中国修订中华人民共和国药品管理法中华人民共和国药品管理法、药品法实施条例药品法实施条例，将，将GLP明确为法定要求明确为法定要求2003年年9月月,SFDA颁布实施颁布实施GLP（二号令）（二号令）

10、280条条,开展开展GLP认证检查认证检查2007年年1月月法规毒理实验强制要求法规毒理实验强制要求GLP2009年年7月月3家在中国的家在中国的GLP实验室接受美国实验室接受美国FDA检查检查中国中国GLP管理规范管理规范药物非临床研究质量管理规范（局令第药物非临床研究质量管理规范（局令第2号）号）2003年年9自自2003年年9月月1日起施行日起施行共九章共九章45条条非临床研究质量管理规范认证标准非临床研究质量管理规范认证标准280条条药品注册现场核查管理规定药品注册现场核查管理规定7章、章、59条、条、5个附件个附件遵从遵从GLP的意义的意义Assuresqualitydataandd

11、ataintegrityProtectsthewell-beingofsubjectsinclinicaltrialsmanyofwhomarehealthyvolunteers(humansafety)Ensuresthatastudycanbecompletelyreconstructedfromarchivedrecords对中国对中国CRO来说，研究报告可以得到国际来说，研究报告可以得到国际认可。认可。GLP规范要素规范要素Whatisanonclinicallaboratory?IntheSFDAorUSFDAregulatoryworld,alaboratoriesthatcond

12、uctnonclinicalstudiesinvolvingtestarticlestodevelopdatathatwillbesubmittedtotheagencyinsupportofanapplicationandmarketingapprovalGLP规范要素规范要素TestArticlestheSFDA-/USFDA-regulatedproductbeingtestedGLP规范要素规范要素TestSystemsMouse/Rat,GuineaPig,Rabbit,Dog(Beagle),Pig,Monkey,Primate,(Chimpanzee)TheABCofGLPReg

13、ulationsDefinitionsPersonIndividualPartnershipGovernmentagencyOrganizationalunitCorporationScientificoracademicestablishmentGLP规范要素规范要素RawDataLaboratoryworksheetsRecords&documentMemorandaNotesComputerprint-outsAllcommunications(internal/external/sponsors)GLP规范要素规范要素OrganizationandPersonnelEducationT

14、rainingExperienceJobdescriptionPersonnelRecordPersonnelManagementStudyDirectorQAUFollowprotocolDocumentdeviationsArchiveGLP规范要素规范要素OrganizationandPersonnelReviewQAUPersonnelStudyDirectorMasterschedulesheetProtocolsInspectionrecordsSOPsManagementStatusreportFinalstudyreportGLP规范要素规范要素FacilitiesNoncli

15、nicallaboratoryReceiptandstorageMixingGLP现场核查现场核查Process-orientedqualitydataasaresultofproperutilizationofandcontroloverfacilities,personnelandproceduresAllowsflexibilityinlaboratoryoperationanduseofscientificjudgmentstudydirectorsmustexertthisjudgmentoverallresponsibilityfortechnicalconduct,interpr

16、etationandreporting现场核查要点现场核查要点Step1:InventoryDocuments文件清单文件清单MakesurenecessarydocumentswereincludedinthestudyreportProtocolProtocolamendments方案修改方案修改Protocoldeviations方案偏离方案偏离(withexplanationsonpossibleimpacttostudyinterpretationandvalidity)Report(withsufficientlydetailedsummaryandindividualanimal

17、data)现场核查要点现场核查要点Step2:Identifytestarticle供试品供试品testarticlecodeornamesaltformformulationpurityUniformity均一性均一性Stability稳定性稳定性lotorbatch#现场核查要点现场核查要点Step3:Theexperimentaldesign试验设计试验设计Studiesarefluid;whatisinaprotocolfrequentlychangesduringthecourseofastudyNoteimportantdates(experimentaldesignlandmar

18、ks)experimentalordosingstartdate(REPORT)studyinitiationdate(REPORT)protocolamendmentdate(s)(AMENDMENTS)experimentalcompletiondate/necropsydate(REPORT)现场核查要点现场核查要点Step3:Theexperimentaldesign试验设计试验设计Notehowexperimentaldesign/methodschangedlookatprotocolamendmentsanddeviationsconsiderifthechangesinvali

19、datedthestudysobjectivesconsiderifthechangescausedstudytobeinconsistentwithstatedguidelines/methods(andevaluatesignificance)Makesureyouunderstandexperimentaldesign(as performed)andchronologyperamendmentsanddocumenteddeviations现场核查要点现场核查要点Step4:Comparedocumentsforconsistency 一致性一致性Doreportscomplywith

20、GLPrequirementsonreportingfortestarticlecharacteristicstestingofdosingformulationsforpuritystabilityuniformity现场核查要点现场核查要点Step4:Comparedocumentsforconsistency Makesurethatdataandtheirassociateddocumentsareconsistentwithoneanother.现场核查要点现场核查要点Step4:Comparedocumentsforconsistency Areprotocol-specified

21、evaluationsofdataapplied?statisticaltestscriteriaforacceptablestudy,positivefinding(e.g.,genotoxicitytests)Doesselectionofhighestdosecomplywithprotocol?Withreferencedguideline?现场核查要点现场核查要点Step4:ComparedocumentsforconsistencyArefindingsforallprotocol-specifiedevaluationsreportedbodyweightclinicalchem

22、istryhistopathologyforallprotocol-specifieddosegroupstoxicokinetics现场核查要点现场核查要点Step5:Dodataseemcredible?ReportRawdata/Reality现场核查要点现场核查要点Step6:Evaluationofsignificanceoflapses失误的评估失误的评估ThebigquestionsDidproblemsinstudydocumentsresultinyourinabilitytodrawmeaningfulconclusionsfromthestudy(withrespectt

23、ostudysstatedobjective)?Didinconsistenciesinthispartofthesubmission,relativetootherpartsofthesubmission,makeyouhavelessfaithintheintegrityofotherportionsofthesubmission?Intheconclusionsofotherstudies?现场核查要点现场核查要点Notalllapsesprecludedrawingconclusionsfromastudymistakescanhappeninperformingastudyindes

24、cribingfactsometimesfactisnotconvenientTheevaluationofmistakesrequiresanevalutionoftheirmagnitudeandnature.Areerrorswidespread?Limited?Doerrorsoccurinreportingofendpointsthatarecriticaltoscientificinterpretation?Doerrorsspeakforareport-specificproblemorsomethingthatisasystemicproblem?现场核查要点：职责现场核查要点

25、：职责TESTINGFACILITYMANAGEMENT:Overall laboratory management and administrative functionsdesignatesstudydirectorbeforestudyisinitiatedreplacesstudydirector(promptly),ifnecessaryassuresthereisaqualityassuranceunit(QAU)assurestestandcontrolarticleshavebeenappropriatelyevaluatedforidentity,strength,purit

26、y,stabilityanduniformity(asapplicable)现场核查要点：职责现场核查要点：职责TESTINGFACILITYMANAGEMENT:(contd)assuresappropriatestaffing,facilities,equipmentandmaterialsareavailableforscheduledtestsassuresthatstaffunderstandsthefunctionstheyaretoperformassuresdeviationsreportedbyQAUarepromptlyreportedtostudydirector现场核查

27、要点：职责现场核查要点：职责STUDYDIRECTORSingle point of study controlhasoverallresponsibilityfor:ProtocolpreparationtechnicalconductofstudyinterpretationofresultsanalysisofresultsdocumentationofresultsreportingofresultsArchiving现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)Protocolpreparation现场核查要点：职责现场核查要点：职责STUDYDIRE

28、CTOR:(contd)ContributorsOphthalmologyCardiologyImmunologyAnalyticalFormulationanalysisBioanalyticalStatisticalanalysisSpecialists/ConsultantsAntibodiesBonemarrowdifferentialcountsSpecializedclinicalpathologySpermAnalysis现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)SpecialProceduresConsiderationsArethereSO

29、Psinplace?Arethestaffappropriatelytrained?Isthistrainingdocumented?Areliteraturesearchesnecessary?IACUCimplications?Doyouneedtouseaconsultant/PIforthework?现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)Multi-SiteStudies*Work(i.e.phaseofaGLPstudy)performedatageographicallydistinctsite(NotaFDAGLPterm)AssignaP

30、ItoensurecompliancewithGLPsWillsignanAcceptanceofResponsibilitiesformWillsignastatementtothisfactuponcompletionoftheworkStudydirectorremainsthesinglepointofcontrolandmaintainsresponsibilityforoverallconductQualityassuranceofthetestsite*OECDrequirement现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)StudySched

31、ulingConsiderationsTestarticleavailabilityAnimalavailability/orderingHousingTrainedstaffAnalyticalchemistryClinicalpathologyNecropsyReports现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)TestArticleCalculations-Howmuchwillyouneed?Whenisitavailable?Finaldoses?AnalyticalConfirmationStorage/handlingconditionsCe

32、rtificateofAnalysis(COA),MSDS,purity,stabilityIsthereadoseformulation?现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)ProtocolReview&ApprovalManagementSDSponsor(ifdonebyCRO)ScientificcontributorsandlaboratorystaffReportpreparationstaffQAUIACUC现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)OvetsightofStudyConductObse

33、rveanimalsandproceduresReviewdataCommunicatewithscientificcontributorsandtechnicalstaffQAauditsinternalandexternalInteractionswithcontributors/PIsSubmissionofsamplesReceipt/reviewofreportRespondtounexpectedevents现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)OversightofStudyConductProtocolamendments-aplanne

34、dchangeProtocoldeviationsnotplanned;impactonstudymustbedeterminedSOPdeviations现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)ExampleofDocumentationProtocol/protocolamendmentProtocol/SOPdeviationsAnimalorderTestarticlereceipt/informationTestarticlepreparationprocedureDoseaccountability(outofrange?)Studyfilen

35、otesVeterinaryrequests/approvaloftreatmentEnvironmentaldeviations(e.g.light/darkcycleandhumidity)observationsofanimals/proceduresDatareviewCorrespondenceemail,fax,letter,telephonecallsReports现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)ReportPreparation现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)ArchivingProto

36、col/amendmentsRawdataDocumentationSpecimensFinalreport现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)SDResponsibilitiesforaFinalReportDatainterpretationPreliminarydraftaudited?unaudited?Integrationoftoxicology,pathology,TKandothersupportivedataContributingScientist/PIreportsStopped/suspendedprogramsGLPcompl

37、ianceDeviationsandimpactondata现场核查要点：职责现场核查要点：职责STUDYDIRECTOR:(contd)assuresthat:protocol,includinganychanges,isapprovedasspecifiedinGLPs,andisfollowedallexperimentaldata,includingobservationsofunanticipatedresponsesofthetestsystem,areaccuratelyrecordedandverifiedunforeseencircumstances,thatmayaffec

38、tthequalityandintegrityofthestudy,arenotedwhentheyoccur,andthatcorrectiveactionistakenanddocumented现场核查要点：职责现场核查要点：职责QUALITYASSURANCEUNIT(QAU):Oversees GLPCompliance in laboratoryresponsibleformonitoringeachstudyforGLPcomplianceorganizationally,QAUreportstotestfacilitymanagementindependentoftheperso

39、nnelengagedinthedirectionandconductofindividualstudiesassuresthatfacilities,equipment,personnel,methods,practices,records,andcontrolsareinconformancewiththeGLPs现场核查要点：职责现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(contd)Oversees GLP compliance in laboratorykeepsup-to-daterecordsofallstudiesscheduled/performe

40、dwithmasterscheduleatlabmaintainscopiesofallstudyprotocols现场核查要点：职责现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(contd)Inspectsstudiesatintervalsadequatetoassuretheintegrityofthestudymaintainswrittenandproperlysignedrecordsateachinspectionidentifyingdateofinspectionthestudyinspectedphaseorsegmentofstudyinspec

41、tedpersonperforminginspection现场核查要点：职责现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(contd)maintainswrittenandproperlysignedrecordsateachinspectionidentifyingfindingsandproblemsobservedduringinspectionscheduleddateforreinspection,ifapplicableproblemsmustimmediatelybebroughttoattentionofstudydirectorandmanageme

42、nt现场核查要点：职责现场核查要点：职责QUALITYASSURANCEUNIT(QAU):(contd)submitsperiodicstatusreportsoneachstudytomanagementandstudydirectornotesproblemsnotescorrectiveactionstakendeterminesthatnodeviationfromapprovedprotocolsorstandardsoperatingproceduresweremadewithoutproperauthorizationanddocumentation现场核查要点：职责现场核查要

43、点：职责QUALITYASSURANCEUNIT(QAU):(contd)Reviewsfinalstudyreporttoassurethat:reportaccuratelydescribesmethodsandstandardoperatingproceduresreportedresultsaccuratelyreflectthestudysrawdataPreparesandsignsstatementstobeincludedwiththefinalreportspecifyingdetailsoninspections现场核查要点：职责现场核查要点：职责FacilityOpera

44、tionsStandardoperatingprocedures(SOP)CompleteandcomprehensiveUptodateSoundscienceandpracticalReagentsandsolutionsIdentity,titer/concentration,storagerequirements,andexpirationdateAnimalcareandIACUCMajorissuesofdataauditWhatdowelookforwhileauditingaGLPlabStudyDirectorFacilityManagementQualityAssuranc

45、eChemistryPathology(Clinicalandanatomical)TechnicalStaffReportwritingSponsorAccountingSubcontractors非临床实验室常见错误非临床实验室常见错误StudydirectorFailuretofollowprotocolMostcommonbecauseeverythingisdrivenbyprotocol.Examples:TAStabilitydeterminationEnvironmentalconditionsExposuretotestarticle(dosing)非临床实验室常见错误非临床

46、实验室常见错误Studydirector(contd)FinalReportCommonlyseefailurestoaddressissuesthatoccurredduringstudythatcouldaffectoutcomes非临床实验室常见错误非临床实验室常见错误Studydirector(contd)FailuretorecordalldataandverifyFormulationDosing非临床实验室常见错误非临床实验室常见错误Studydirector(contd)DocumentationissuesBestway,protocolamendment.Mustbedon

47、ebeforeaction(signedbySDandalsoQA,managementandsponsor).Secondbest,deviationreport(deviationfromprotocolorSOP).Completedafter-the-factbypersonmakingtheobservation(signedbySDandalsoQAandmanagement).Deviationisnotedinstudyreportalongwithdescriptionoftheimpactthedeviationhasonstudyintegrity.非临床实验室常见错误非

48、临床实验室常见错误InconsistencieswithinaprotocolorbetweenprotocolandSOPOmissionofnecessaryinformationfromprotocolLateentriesinstudybooksNonGLPcorrectionsFailuretosignanddateentriesExpiredreagents非临床实验室常见错误非临床实验室常见错误FailuretoissuetimelyprotocolamendmentsanddeviationreportsPaperworkmissingfromstudybookInconsis

49、tenciesbetweenprotocolandreportorrawdataandreport.非临床实验室常见错误非临床实验室常见错误QAUfailstoauthorizedeviationDeviationsnotdetectedbytheQAU,butshouldhavebeen非临床实验室常见错误非临床实验室常见错误Transferofdata,specimens,recordstoarchivesAtcompletionofstudyNotallrecordstransferred非临床实验室常见错误非临床实验室常见错误DidnotfollowSOPsforrequiredaud

50、itingInappropriatetrainingrecordkeepingEquipmentcalibrationissuesSanitationcage/roomdisinfectantsWatersystemattachedtocagerackGLPornotGLPSafetyPharmacologystudies,Core/GLP,followupstudiesdependingonthedesign/nonGLPPrimaryPharmacodynamic/non-GLP,SecondaryPD/nonGLPunlesscontributetothesafetyevaluation