MHRA-OOS-OOT-Oct17+中英

OutofSpecification&OutofTrendInvestigations超标&偏离趋势调查October2017/2017年10月2HowtousetheInvestigationFlowchart/如何使用调查流程图Navigation导航:ClickingonthoseProcessStepboxeswithaheavyborderinaprocessflowwilltakeyoutoanewpagewithfurtherdetailaboutthatinvestigationstep.点击流程图中深色框图标，将跳转至详细解释调查步骤的新一页幻灯OneachpagetherealinktoreturntotheOverviewpage回到主流程页Thismovesbackupwardswithasectionoftheinvestigationstep回到上一调查步骤Thismovesdownwardstothenextpage跳转至下页3LaboratoryAnalysisSatisfactoryOOS(OOT)ResultPhaseIbInvestigationPhaseIIInvestigationManufacturingInvestigationProductImpactAssessmentPhaseIIIInvestigationBatchDispositionPhaselaInvestigationSatisfactoryOverview4化验室分析SatisfactoryOOS(OOT)结果Ib阶段调查II阶段调查生产调查产品影响性评估III阶段调查批处置La阶段调查满意结果概览5LaboratoryAnalysisInvestigationsofOutofSpecification(OOS)/OutofTrend(OOT)/Atypicalresultshavetobedoneincasesof:•Batchreleasetestingandtestingofstartingmaterials.•In-ProcessControltesting:ifdataisusedforbatchcalculations/decisionsandifinadossierandonCertificatesofAnalysis.•Stabilitystudiesonmarketedbatchesoffinishedproductsandoractivepharmaceuticalingredients,on-going/followupstability(nostresstests)•PreviousreleasedbatchusedasreferencesampleinanOOSinvestigationshowingOOSorsuspectresults.•Batchesforclinicaltrials.Allsolutionsandreagentsshouldberetaineduntilalldatahasbeensecondpersonverifiedasbeingwithinthedefinedacceptancecriteria.Pharmacopoeiahavespecificcriteriaforadditionalanalysesofspecifictests(i.e.dissolutionlevelspecificationforS1,S2&S3testing;Uniformityofdosageunitsspecificationfortestingof20additionalunits;SterilityTesting).Howeverifthesampletestcriteriaisusuallythefirstleveloftestingandasamplehastobetestedtothenextlevelthisshouldbeinvestigatedasitisnotfollowingthenormaltrend.TheOOSprocessisnotapplicableforIn-processtestingwhiletryingtoachieveamanufacturingprocessend-pointi.e.adjustmentofthemanufacturingprocess.(e.g.pH,viscosity),andforstudiesconductedatvariableparameterstochecktheimpactofdrift(e.g.processvalidationatvariableparameters).6化验室分析如果OOS/OOT/异常结果发生在以下情形，则必须进行调查：•批放行检测和起始物料检测•中控检测：数据用于进行批产品质量的计算/决策，数据将包括在申报资料中，数据将包括在COA上•制剂或原料药上市批次的稳定性试验、持续稳定性试验、稳定性追踪（没有强降解试验时）•之前放行的批次用于OOS调查中作为对照样品时发现其结果为OOS或可疑结果•临床试验批产品所有溶液和试剂必须保持原状，直到所有数据由第二人进行核查并认可其在既定的可接受标准内药典对有些测试项目有附加分析标准（即，溶出度在S1、S2和S3检测标准的水平，剂量均匀性标准中有加测20个制剂单位的描述，无菌测试）但是如果样品测试标准在正常情况下是测试的第一个阶段，一个样品必须进行测试到下一个阶段，则应进行调查，因为它通常不会满足正常趋势OOS过程不适用于生产过程终点控制的中控检测，即，生产工艺的调节（例如PH、粘度），不适用于研究变量参数以检查漂移的影响（例如，对可变参数进行工艺验证）7OOS/OOTResultOut-of-Specification(OOS)Result–•Testresultthatdoesnotcomplywiththepre-determinedacceptancecriteria(i.e.forexample,filedapplications,drugmasterfiles,approvedmarketingsubmissions,orofficialcompendiaorinternalacceptancecriteria).•Testresultsthatfalloutsideofestablishedacceptancecriteriawhichhavebeenestablishedinofficialcompendiaand/orbycompanydocumentation(i.e.,RawMaterialSpecifications,In-Process/FinalProductTesting,etc.).OutofTrend(OOT)Result–•Isgenerallyastabilityresultthatdoesnotfollowtheexpectedtrend,eitherincomparisonwithotherstabilitybatchesorwithrespecttopreviousresultscollectedduringastabilitystudy.Howeverthetrendsofstartingmaterialsandin-processsamplesmayalsoyieldoutoftrenddata.•TheresultisnotnecessarilyOOSbutdoesnotlooklikeatypicaldatapoint.•Shouldbeconsideredforenvironmentaltrendanalysissuchasforviableandnonviabledata(actionlimitorwarninglimittrends)Atypical/Aberrant/AnomalousResult–•Resultsthatarestillwithinspecificationbutareunexpected,questionable,irregular,deviantorabnormal.Exampleswouldbechromatogramsthatshowunexpectedpeaks,unexpectedresultsforstabilitytestpoint,etc.8OOS/OOT结果OOS结果–•检查结果不符合预定的可接受标准（即，例如，提交的申报资料、药物主文件、批准的上市申报资料，或官方药典或内部可接受标准）•落在官方药典和/或公司文件既定的可接受标准以外的检测结果（即，原料质量标准、中控/最终产品检测等）OOT结果–•通常是不落在预期的趋势内的稳定性试验结果，或者相比于其它稳定性试验批次，或相比于之前的稳定性试验中收集析结果。当然，起始物料和中控样品的趋势分析也可能会发现超出趋势的数据。•结果不一定是OOS，但看似一个异常的数据点•应考虑环境趋势分析，例如悬浮粒子和微生物的数据（行动限或警戒限趋势）非典型、反常、异常结果–•结果仍然在质量标准范围内，但不是期望值，值得质疑，不同寻常、偏离正常数据，或表现异常。例如色谱图显示非预期峰，在稳定性试验检测时间点结果并非预期结果等。9NoErrorfoundPhaselaInvestigationNoFurtherInvestigationRequiredObviousErrorDocumentandCorrectInvalidResultInitiatePhaseIbLaboratoryInvestigation10未发现错误Ia阶段调查不需要进一步调查明显错误记录和纠正无效结果启动Ib阶段化验室调查11PhaselaInvestigationDefinition:PhaselainvestigationistodeterminewhethertherehasbeenaclearobviouserrorsduetoexternalcircumstancessuchaspowerfailureorthosethattheanalysthasdetectedpriortogeneratingdatasuchasspillingsamplethatwillnegatetherequirementofaPhaseIbinvestigation.Formicrobiologicalanalysisthismaybeaftertheanalysishasbeencompletedandreviewedduringreadingofthesamples.Itisexpectedthattheseissuesaretrendedevenifalaboratoryinvestigationlborllwasnotraised.12第Ia阶段调查定义：第IA阶段调查如发现是否有来自于外部环境的明显错误，例如供电问题，分析员在数据产生前即已察觉的问题，如样品泼洒，发现这些原因则不需要进入IB阶段调查。对于微生物分析，则可能是在检验完成之后，在对样品进行读取数据的时候。即使没有进行IB阶段或第二阶段化验室调查，也要求对这些问题进行趋势分析。13PhaselaInvestigation-ObviousErrorExamplesCalculationerror–analystandsupervisortoreview,bothinitialanddatecorrection.Poweroutage–analystandsupervisordocumenttheevent,annotate“powerfailure;analysistoberepeated”onallassociatedanalyticaldocumentation.Equipmentfailure–analystandsupervisordocumenttheevent