粒度方法验证

1.通则1.GeneralPhysicaltestsperformedforreleasepurposesneedtobevalidated.ThephysicaltestthatiscomprisedinthisvalidationprocedureisParticleSizeDistributionbyLaserDiffractionInstruments.ThisSOPcanserveasthevalidationprotocolforvalidatingamethodforparticlesizedistribution.AseparatevalidationprotocolisnecessaryincaseofanexceptionfromthisSOP.当物理测试作为放行目的的时候应被验证。本验证程序中包含的物理测试是通过激光粒度仪测试样品的粒度分布。该SOP可以作为验证粒度分布方法的协议。若有异议，可以有一个单独的验证方案。2.目的2.purpose2.1Todefinethetypicalanalyticalparametersthatshouldbeconsideredwhenavalidationofananalyticalmethodisperformed.2.1当执行一个分析方法验证的时候，应考虑典型分析参数的定义。2.2Todescribethewayinwhichamethodisvalidatedaccordingtotheseparameters2.2描述按照这些参数进行方法验证的方法。2.3Toestablishacceptancecriteriaforacceptance/rejectionofdrugsubstances,finishedproductsorothermaterials.2.3建立原料药，成品或其它原料的放行/拒绝标准。3.范围3.Range4.责任4.Responsibility4.1PhysicalR&Dlaboratoryanalyst–performanceofalllaboratoriesstudiesrequiredformethodvalidationaccordingtothisSOP.4.2PhysicalR&DLaboratorymanager–4.2.1VerificationtocomplianceofthisPhysicalR&DlaboratorywithGMPregulationsandthisSOP.4.2.2Approvalofvalidationprotocol(whenapplicable)andvalidationreport.4.3QCLaboratorymanager(onlyifaninterlaboratorystudyisperformedintheQClaboratory):4.3.1VerificationofcomplianceoftheQClaboratory,withGMPregulationswiththisSOPandthevalidationprotocol.4.3.2ToperformtheInterlaboratorystudy.4.3.3Approvalofvalidationprotocol(whenapplicable)andvalidationreport.4.4QAmanager–approvalofvalidationprotocol(whenapplicable)andvalidationreport.5.分析参数的定义DEFINITIONOFANALYTICALPARAMETERSInordertoprovetheanalyticalcapabilityofamethodthatassessesphysicalpropertiesofpowderorothersolidmaterials,threemainanalyticalparametersarerelevant:为了证明分析方法的可行性，评估粉末或其它固体原料的物理性质，下面三个主要的分析参数是比较重要的：Precision精密度Accuracy准确度Robustness耐用性5.1精密度5.1PrecisionTheprecisionexpressestheclosenessofagreementbetweenaseriesofmeasurementsobtainedfrommultiplesamplingofahomogeneoussample.精密度是指同一样品进行多次取样测试后的一致程度。Themethodprecisionshouldbeassessedinthreelevels:方法精密度应评估下列三个方面Repeatabilityreferstotheuseofanalyticalprocedurewithinalaboratoryoverashortperiodoftimeusingthesameanalystwiththesameequipment.重复性指的是同一分析人员用同一台仪器在间隔很短的时间内使用同一分析方法分析样品。Intermediateprecision(ruggedness)expresswithinlaboratoryvariation,asondifferentdays,orwithdifferentanalystsorequipmentwithinthesamelaboratory.中间精密度是指在同一实验室内，不同天，不同分析人员使用不同仪器分析样品。Interlaboratorystudy(reproducibilityortechnicaltransfer)referstotheuseoftheanalyticalprocedureindifferentlaboratories重现性是指不同实验室之间的研究。5.2准确度5.3AccuracyTheaccuracyoftheparticlesizemethodisdefinedastheclosenessoftestresultsobtainedbytheanalyticalproceduretothetruevalue.Accuracyofsamplepreparationisachievedwhentheresultsincludesalltheparticlesastheyarepresentedbyanindependentmethod–microscope.粒度方法的准确度是指通过分析方法测得的粒度值与真实值的接近程度。5.4耐用性5.5RobustnessTherobustnessexpressesthesensitivityofthemethodtosmall,butdeliberatevariationsinthemethodparametersandprovidesanindicationofitsreliabilityduringnormaluseandstabilityofthesuspensionduringthemeasurement.耐用性是指分析参数故意发生微小变化时分析方法的灵敏度，为正常使用时的重复性和在测试阶段悬浮液的稳定性提供指示。6验证方案6.Validationprotocol6.1AnydeviationfromtheSOPshouldbespecifiedinavalidationprotocol.Iftherearenodeviations,thisSOPcanserveasthevalidationprotocol.6.1任何偏离本SOP的偏差应在方案中被指出。如果没有偏差，本SOP可以作为验证方案。6.2Anymajorchangeintheprotocol,duetodifficultiesencounteredinthemethoddevelopmentwork,shouldbereflectedinamendmenttotheprotocol.6.2由于在方法开发阶段遭遇的困难，方案中任何主要的变更应反映在方案的修正案中。7方法验证的一般程序7GeneranprocedureforvalidationofamethodValidationofPSDmethodsisperformedonthreerepresentativesamples.PSD的方法验证应选取三批样品。Itispossibletoperformvalidationononeortworepresentativesamplesincasethatadditionalrepresentativesample/swillnotbeavailable,thevalidationshouldbecompletedwhenadditionalrepresentativesample/swillbeavailable(asanamendmenttovalidation).如果没有附加的样品测试，可以测试一批或者两批样品，如果有附加的样品测试（作为验证修正案），验证应被完成。Thevalidationexperimentstobeperformedinthevalidationprocedurearesummarizedinthefollowingtable.在验证阶段，下列项目应涉及：a–IntermediateprecisiontestisnotrequiredwheninterlaboratorystudyperformedbyQC(orotherlab).A-当测试了重现性的时候，中间精密度可以不做b-Wheninterlaboratorystudyisnotperformed,intermediateprecisioncanbedoneinstead.Themethodcannotbetransferredtoanotherlaboratoryuntilthattechnicaltransferisperformed.Valuesliked(0.1),d(0.5),d(0.9),undersize/oversizepercentorotherrelevantvalueswillberecordedandwillbeevaluatedaccordingtothetablesineachsection.B-当没做重现性时，可以做中间精密度代替。方法不得转移给其他实验室直到完成了技术转移。类似d(0.1),d(0.5),d(0.9),尺寸过小/尺寸过大比例或其他相关的数值应被记录并且评估。Note:Incasetheresultsfallbetweentwolevelscategories,takethelowerlevelasacceptancecriteria.注意—如果结果介于两个限度，选择低的限度作为可接受标准。Note:Forspecialmethodsinwhichmorereplicatesarerequireduseappendix1.注意—对于专属性方法，用按照附录1做更多的重复性。注意--AnychangedoneintheprocessatthestepwheretheAPImoleculealreadyproduced(fromcrudestep)shouldbeevaluatedbyphysicalR&Difmayaffectthephysicalpropertiesofthematerial(suchas:solubility,PSDetc.).Afullvalidationmayberequiredifthechangewasevaluatedassignificant.Ifthesameanalyticalmethodisconsideredappropriatetouseafterthechange,andthechangeinparticlesizedistributi