8 生产和过程控制

8.3工序间的取样和控制8.30应当制定书面程序来监测会造成中间体和原料药质量特性变异的工艺步骤的进程，并控制其生产情况。工序间控制及其接受标准应当根据项目开发阶段或者以往的生产数据来确定。8.31综合考虑所生产中间体和原料药的特性，反应类型，该工序对产品质量影响的程度大小等因素来确定可接受的标准，检测类型和范围。前期生产的中间体控制标准可以松一些，越接近成品，中间控制的标准越严（如分离，纯化）。8.3工序间的取样和控制8.30应当制定书面程序来监测会造成中间体和原料药质量特性变异的工艺步骤的进程，并控制其生产情况。工序间控制及其接受标准应当根据项目开发阶段或者以往的生产数据来确定。8.31综合考虑所生产中间体和原料药的特性，反应类型，该工序对产品质量影响的程度大小等因素来确定可接受的标准，检测类型和范围。前期生产的中间体控制标准可以松一些，越接近成品，中间控制的标准越严（如分离，纯化）。8.32关键的中间控制（和工艺监测），包括控制点和方法，应当书面规定，并经质量部门批准。8.33中间控制可以由合格的生产部门的人员来进行，而调节的工艺可以事先未经质量部门批准，只要该调节在由质量部门批准的预先规定的限度以内。所有测试及结果都应当作为批记录的一部分全部归档。8.34应当制定书面程序，说明中间物料、中间体和原料药的取样方法。取样方案和程序应当基于科学合理的取样实践。8.35工序间取样应当按能防止污染所取的样品、其它中间体或原料药的程序进行。应当制定保证样品收集后的完整性的程序。8.3In-processSamplingandControlsWrittenproceduresshouldbeestablishedtomonitortheprogressandcontroltheperformanceofprocessingstepsthatcausevariabilityinthequalitycharacteristicsofintermediatesandAPIs.In-processcontrolsandtheiracceptancecriteriashouldbedefinedbasedontheinformationgainedduringthedevelopmentalstageorfromhistoricaldata.TheacceptancecriteriaandtypeandextentoftestingcandependonthenatureoftheintermediateorAPIbeingmanufactured,thereactionorprocessstepbeingconducted,andthedegreetowhichtheprocessintroducesvariabilityintheproduct’squality.Lessstringentin-processcontrolsmaybeappropriateinearlyprocessingsteps,whereastightercontrolsmaybeappropriateforlaterprocessingsteps(e.g.,isolationandpurificationsteps).Criticalin-processcontrols(andcriticalprocessmonitoring),includingcontrolpointsandmethods,shouldbestatedinwritingandapprovedbythequalityunit(s).In-processcontrolscanbeperformedbyqualifiedproductiondepartmentpersonnelandtheprocessadjustedwithoutpriorqualityunit(s)approvaliftheadjustmentsaremadewithinpre-establishedlimitsapprovedbythequalityunit(s).Alltestandresultsshouldbefullydocumentedaspartofthebatchrecord.Writtenproceduresshoulddescribethesamplingmethodsforin-processmaterials,intermediates,andAPIs.Samplingplansandproceduresshouldbebasedonscientificallysoundsamplingpractices.In-processsamplingshouldbeconductedusingproceduresdesignedtopreventcontaminationofthesampledmaterialandotherintermediatesorAPIs.Proceduresshouldbeestablishedtoensuretheintegrityofsamplesaftercollection.Out-of-specification(OOS)investigationsarenotnormallyneededforin-processteststhatareperformedforthepurposeofmonitoringand/oradjustingtheprocess.8.4BlendingBatchesofIntermediatesorAPIsForthepurposeofthisdocument,blendingisdefinedastheprocessofcombiningmaterialswithinthesamespecificationtoproduceahomogeneousintermediateorAPI.In-processmixingoffractionsfromsinglebatches(e.g.,collectingseveralcentrifugeloadsfromasinglecrystallizationbatch)orcombiningfractionsfromseveralbatchesforfurtherprocessingisconsideredtobepartoftheproductionprocessandisnotconsideredtobeblending.Out-of-specificationbatchesshouldnotbeblendedwithotherbatchesforthepurposeofmeetingspecifications.Eachbatchincorporatedintotheblendshouldhavebeenmanufacturedusinganestablishedprocessandshouldhavebeenindividuallytestedandfoundtomeetappropriatespecificationspriortoblending.Acceptableblendingoperationsinclude,butarenotlimitedto:BlendingofsmallbatchestoincreasebatchsizeBlendingoftailings(i.e.,relativelysmallquantitiesofisolatedmaterial)frombatchesofthesameintermediateorAPItoformasinglebatchBlendingprocessesshouldbeadequatelycontrolledanddocumented,andtheblendedbatchshouldbetestedforconformancetoestablishedspecifications,whereappropriate.8.36生产操作中的正常监控过程和工艺调节过程中出现的超出标准的偏差（OOS），通常情况不需要调查。8.4中间体或原料药的混批8.40根据本文件的目的，混合的定义是为了生产出均匀的中间体或原料药而将同一质量标准的物料混在一起的过程。同一批号几部分（例如，收集一个结晶批号出来的几次离心机装的料）的工艺间的混合，或者混合从几个批号来的部分作进一步加工，看作是生产工艺的一部分，而不是混合。8.41不合格的批号不能与其他批号混合在一起来达到符合质量标准的目的。混合的每一个批号都应该是用规定的生产工艺生产的，混合前应当单独检测，并符合相应的质量标准。8.42可接受的混合操作包括但不限于：•将小批混合，增大批量；•将多批同一中间体或原料药的尾料（例如，分离出的相对较少的量）混合成为-个批号。8.43混合过程应当充分控制并记录，混合后的批号应当根据情况进行测试，以确认是否达到质量标准。Thebatchrecordoftheblendingprocessshouldallowtraceabilitybacktotheindividualbatchesthatmakeuptheblend.WherephysicalattributesoftheAPIarecritical(e.g.,APIsintendedforuseinsolidoraldosageformsorsuspensions),blendingoperationsshouldbevalidatedtoshowhomogeneityofthecombinedbatch.Validationshouldincludetestingofcriticalattributes(e.g.,particlesizedistribution,bulkdensity,andtapdensity)thatmaybeaffectedbytheblendingprocess.Iftheblendingcouldadverselyaffectstability,stabilitytestingofthefinalblendedbatchesshouldbeperformed.Theexpiryorretestdateoftheblendedbatchshouldbebasedonthemanufacturingdateofthe