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16/22/20111生物样品分析方法验证工业指南的解读杨永胜博士声明:本讲座只代表个人意见,不代表官方立场。26/22/20112GuidanceforIndustryBioanalyticalMethodValidationU.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforVeterinaryMedicine(CVM)May2001BP36/22/20113提纲绪言指南覆盖的范畴分析方法验证的定义和种类药品非临床研究质量管理规范(GLP)标准对照品生物样本分析方法验证的主要参数与合格标准选择性线性范围准确度精密度提取回收率稳定性报告的主要内容小结绪言指南覆盖的范畴人用药品试验用新药申请(INDs),新药上市申请(NDAs)以及仿制药上市申请(ANDAs)的BA/BE研究临床前安全评价的PK/TK研究生物样品:全血、血浆、血清、尿样及皮肤和其他组织分析方法化学方法:GC,HPLC,GC-MS,GC-MS-MS,LC-MS,LC-MS-MS免疫学方法微生物学方法动物用药品BA,BE和PK研究只适用于血样和尿样绪言分析方法验证的定义和种类定义生物样品分析方法验证是一个有计划系统性收集验证资料的综合过程,以确保某一特定分析方法可靠,重现性好,适用于其所指定的生物样品定量分析。种类全面验证部分验证交叉验证绪言分析方法验证的种类--全面验证ForthefirsttimewhendevelopingandimplementingabioanalyticalmethodForanewdrugentityIfmetabolitesareaddedtoanexistingassayforquantification绪言分析方法验证的种类—部分验证Partialvalidationsaremodificationsofalreadyvalidatedbioanalyticalmethods.BioanalyticalmethodtransfersbetweenlaboratoriesoranalystsChangeinanalyticalmethodology(e.g.,changeindetectionsystems)ChangeinanticoagulantinharvestingbiologicalfluidChangeinmatrixwithinspecies(e.g.,humanplasmatohumanurine)ChangeinsampleprocessingproceduresChangeinspecieswithinmatrix(e.g.,ratplasmatomouseplasma)ChangeinrelevantconcentrationrangeChangesininstrumentsand/orsoftwareplatformsLimitedsamplevolume(e.g.,pediatricstudy)RarematricesSelectivitydemonstrationofananalyteinthepresenceofconcomitantmedicationsSelectivitydemonstrationofananalyteinthepresenceofspecificmetabolites绪言分析方法验证的种类—交叉验证ComparisonvalidationparametersoftwobioanalyticalmethodsTwoormorebioanalyticalmethodsforthesamestudyoracrossdifferentstudies:anoriginalvalidatedbioanalyticalmethodandtherevisedbioanalyticalmethod.Samplefromasinglestudy,butanalysisatmorethanonesiteormorethanonelaboratory,cross-validationwithspikedmatrixstandardsandsubjectsamplesshouldbeconductedateachsiteorlaboratorytoestablishinterlaboratoryreliability.Datageneratedusingdifferentanalyticaltechniques(e.g.,LC-MS-MSvs.ELISA)indifferentstudiesareincludedinaregulatorysubmission.Allmodificationsshouldbeassessedtodeterminetherecommendeddegreeofvalidation.绪言药品非临床研究质量管理规范(GLP)Theanalyticallaboratoryconductingpharmacology/toxicologyandotherpreclinicalstudiesforregulatorysubmissionsshouldadheretoFDAGoodLaboratoryPractices(GLPs)(21CFR58).ThebioanalyticalmethodforhumanBA,BE,PK,anddruginteractionstudiesmustmeetthecriteriain21CFR320.29.绪言GLP/GCP/GMP绪言:美国《联邦法规典集》(CodeofFederalRegulations,CFR)美国《联邦规章典集》第21篇“食品与药品”(Title21―FoodandDrugs)9卷(Volume)3章(Chapter)1499部(Parts)其中:第1―8卷第1章第1―1299部,为健康与人类服务部食品与药品管理局(DHHS/FDA)的规章GLPs(21CFR58)11Subparts(2reserved)A=GeneralProvisionsB=Organization&PersonnelC=FacilitiesD=EquipmentE=TestingFacilitiesOperationsF=TestandControlArticlesG=ProtocolforandConductofaNon-clinicalLaboratoryStudyH&I=[Reserved]J=RecordsandReportsK=Disqualification机构和人员ThreeKeyResponsibilities:TestingFacilityManagementStudyDirectorQualityAssuranceUnit机构和人员58.29Personnel(a)―Eachindividualengagedintheconductoforresponsibleforthesupervisionofanonclinicallaboratorystudyshallhaveeducation,training,andexperience,orcombinationthereof,toenablethatindividualtoperformtheassignedfunctions.‖(b)―Eachtestingfacilityshallmaintainacurrentsummaryoftrainingandexperienceandjobdescriptionforeachindividualengagedinorsupervisingtheconductofanonclinicallaboratorystudy.‖机构和人员58.33StudyDirector―Foreachnonclinicallaboratorystudy,ascientistorotherprofessionalofappropriateeducation,training,andexperience,orcombinationthereof,shallbeidentifiedasthestudydirector.Thestudydirectorhasoverallresponsibilityforthetechnicalconductofthestudy,aswellasfortheinterpretation,analysis,documentation,andreportingofresults,andrepresentsthesinglepointofstudycontrol.‖机构和人员58.35QualityAssuranceUnit―Atestingfacilityshallhaveaqualityassuranceunitwhichshallberesponsibleformonitoringeachstudytoassuremanagementthatthefacilities,equipment,personnel,methods,practices,records,andcontrolsareinconformancewiththeregulationsinthispart.Foranygivenstudy,thequalityassuranceunitshallbeentirelyseparatefromandindependentofthepersonnelengagedinthedirectionandconductofthatstudy.‖设施58.41General―Eachtestingfacilityshallbeofsuitablesizeandconstructiontofacilitatetheproperconductofnonclinicallaboratorystudies.Itshallbedesignedsothatthereisadegreeofseparationthatwillpreventanyfunctionoractivityfromhavinganadverseeffectonthestudy.‖AnimalcarefacilitiesAnimalsupplyfacilitiesFacilitiesforhandlingtestandcontrolarticlesLaboratoryoperationareasSpecimenanddatastoragefacilities仪器设备58.61EquipmentDesign―Equipmentusedin...shallbeofappropriatedesignandadequatecapacity...‖58.63MaintenanceandCalibration(b)―Thewrittenstandardoperatingprocedures...‖(c)―Writtenrecordsshallbemaintained...‖SOP―Atestingfacilityshallhavestandardoperatingproceduresinwritingsettingforth...toinsurethequalityandintegrityofthedatagenerated...‖TheSOPsshouldcoverallaspectsofanalysisfromthetimethesampleiscollectedandreachesthelaboratoryuntiltheresultsoftheanaly
本文标题:生物样品分析方法验证-工业指南的解读
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