行业指南：药品检测结果OOS调查指南

GuidanceforIndustry，InvestigatingOutofSpecification(OOS)TestResultsforPharmaceuticalProduction行业指南：药品检验结果OOS的调查DRAFTGUIDANCE指南草案U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)September1998CP#TABLEOFCONTENTS目录I.INTRODUCTION序言...........................................................1II.BACKGROUND.背景...........................................................1III.IDENTIFYINGANDASSESSINGOOSTESTRESULTSOOS检验结果的判断和评估....2A.ResponsibilityoftheAnalyst检验员的责任.........................................2B.ResponsibilitiesoftheSupervisor主管的责任...........................................3IV.INVESTIGATINGOOSTESTRESULTSOOS检验结果的调查.....................5A.GeneralInvestigationalPrinciples..一般调查原则..................................5B.LaboratoryPhaseofanInvestigation.实验室的调查阶段................................6V.CONCLUDINGTHEINVESTIGATION..调查结论...................................10A.InterpretationofInvestigationResults.调查结果的解释................................10B.Reporting...报告................................................................11ThisguidancehasbeenpreparedbytheOfficeofCompliance/DivisionofManufacturingandProductQuality,CenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration.ThisguidancedocumentrepresentstheAgency’scurrentthinkingonevaluatingOOStestresults.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Analternativeapproachmaybeusedifsuchapproachsatisfiestherequirementsoftheapplicablestatute,regulations,orboth.本指南由FDA的CDER的达标办公室/制造、产品、质量分部起草，本指南阐明了机构关于评估OOS检验结果的现行的想法。它不会创造或赠与任何人任何权力，也不会约束FDA或公众。如果其他可选择的相接近的指南能满足适用的法令和法规的要求，也可以使用。GUIDANCEFORINDUSTRY1InvestigatingOutofSpecification(OOS)TestResultsforPharmaceuticalProduction行业指南：药品检验结果OOS的调查I.INTRODUCTION序言ThisguidanceforindustryprovidestheAgency’scurrentthinkingonhowtoevaluatesuspect,oroutofspecification(OOS),testresults.Forpurposesofthisdocument,thetermOOSresultsincludesallsuspectresultsthatfalloutsidethespecificationsoracceptancecriteriaestablishedinnewdrugapplications,officialcompendia,orbythemanufacturer.本行业指南反应了FDA关于如何评估怀疑的或OOS检验结果的现行想法，本指南的目的，OOS结果包括超出了新药申请材料、法定标准、生产商建立的可接受标准或规格的所有可疑的结果。Thisguidanceappliestolaboratorytestingduringthemanufactureofactivepharmaceuticalingredients,excipients,andothercomponentsandthetestingoffinishedproductstotheextentthatcurrentgoodmanufacturingpractices(CGMP)regulationsapply(21CFRparts210and211).Specifically,theguidancediscusseshowtoinvestigatesuspect,orOOStestresults,includingtheresponsibilitiesoflaboratorypersonnel,thelaboratoryphaseoftheinvestigation,additionaltestingthatmaybenecessary,whentoexpandtheinvestigationoutsidethelaboratory,andthefinalevaluationofalltestresults.本指南适用于API、赋形剂和其它组分生产的实验室检验和CGMP法规应用的成品检验。特别的，指南讨论了如何调查可疑的或OOS检验结果，包括了实验室人员的责任、实验室阶段调查、必须的额外试验，何时进行实验室范围外的调查和对所有检验结果的最终评估。II.BACKGROUND背景FDAconsiderstheintegrityoflaboratorytestinganddocumentationrecordstobeoffundamentalimportanceduringdrugmanufacturing.Laboratorytesting,whichisrequiredbytheCGMPregulations(§211.165),isnecessarytoconfirmthatcomponents,containersandclosures,inprocessmaterials,andfinishedproductsconformtospecifications,includingstability.TestingSpecificationsmustbescientificallysoundandappropriate(21CFR211.160(b)),andtestproceduresmustbevalidatedastotheiraccuracy,reliability,andsuitabilityunderactualconditionsofuse(21CFR211.194(a)(2)).ForproductsthatarethesubjectsofNDAs,ANDAs,orINDs,specificationsarecontainedintheapplication.Specificationsfornon-applicationproductsmaybefoundinofficialcompendia,orestablishedbythemanufacturer.FDA认为在药品生产中实验室检验和文件记录的完整性是基本重要的。CGMP要求的实验室检验，必须确定成分、容器和封口材料、生产用辅料、成品符合标准要求，包括稳定性。检验标准必须是科学正确和适当的（1CFR211.160(b)，检验方法必须验证现行使用条件下的正确性、线性和适应性(21CFR211.194(a)(2))，如果是用于NDAs,ANDAs,或INDs申请的产品，申请材料中应包括标准。如果是非申请产品的质量标准，可以在法定标准中找到或由企业自已建立。AlthoughthesubjectofthisdocumentisOOSresults,muchoftheguidancemaybeusefulforexaminingresultsthatareoutoftrend.alsosupportsanalyticalandprocessvalidationefforts.GeneralCGMPregulationscoveringlaboratoryoperationscanbefoundinpart211,subpartsI(LaboratoryControls)andJ(RecordsandReports).Theseregulationsprovidefortheestablishmentofscientificallysoundandappropriatespecifications,standards,andtestproceduresthataredesignedtoensurethatcomponentsandcontainersofdrugproductsconformtotheestablishedstandards.Section211.165(f)oftheCGMPregulationsspecifiesthatproductsthatfailtomeetestablishedstandardsandotherrelevantqualitycontrolcriteriawillberejected.尽管本指南的目的是OOS结果，其中许多部分对于调查超出趋势以外的结果也是有用的，对分析和工艺验证也有用。有关实验室操作一般性CGMP法规可以在211部分，分目I(实验室控制)和分目J(报告和记录)找到。这些法规规定了科学正确和适当的用于保证制剂的成分和容器符合建立标准的规格、标准和检验方法的建立。CGMP的211.165(f)章节规定不符合既定标准和其它相关质量控制标准的产品不得放行。III.IDENTIFYINGANDASSESSINGOOSTESTRESULTSOOS检验结果的判断和评估FDAregulationsrequirethataninvestigationbeconductedwheneveranOOStestresultisobtained.ThepurposeoftheinvestigationistodeterminethecauseoftheOOS.EvenifabatchisrejectedbasedonanOOSresult,theinvestigationisnecessarytodetermineiftheresultisassociatedwithotherbatchesofthesamedrugproductorotherproducts.Batchrejectiondoesnotnegatetheneedtope