粒度方法验证.docx
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粒度方法验证
1.通则
1.General
Physicaltestsperformedforreleasepurposesneedtobevalidated.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.purpose
2.1Todefinethetypicalanalyticalparametersthatshouldbeconsideredwhenavalidationofananalyticalmethodisperformed.
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。
2.2Todescribethewayinwhichamethodisvalidatedaccordingtotheseparameters
2.2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.Range
4.责任
4.Responsibility
4.1PhysicalR&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
DEFINITIONOFANALYTICALPARAMETERS
Inordertoprovetheanalyticalcapabilityofamethodthatassessesphysicalpropertiesofpowderorothersolidmaterials,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
5.1Precision
Theprecisionexpressestheclosenessofagreementbetweenaseriesofmeasurementsobtainedfrommultiplesamplingofahomogeneoussample.
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
5.3Accuracy
Theaccuracyoftheparticlesizemethodisdefinedastheclosenessoftestresultsobtainedbytheanalyticalproceduretothetruevalue.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
5.5Robustness
Therobustnessexpressesthesensitivityofthemethodtosmall,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.Validationprotocol
6.1AnydeviationfromtheSOPshouldbespecifiedinavalidationprotocol.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
7Generanprocedureforvalidationofamethod
ValidationofPSDmethodsisperformedonthreerepresentativesamples.
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(from"crude"step)shouldbeevaluatedbyphysicalR&Difmayaffectthephysicalpropertiesofthematerial(suchas:
solubility,PSDetc.).Afullvalidationmayberequiredifthechangewasevaluatedassignificant.Ifthesameanalyticalmethodisconsideredappropriatetouseafterthechange,andthechangeinparticlesizedistributionisconcludednotsignificant,onlyverificationofthemethodisrequired(repeatabilityandaccuracyshouldbecheckedononebatch).IncasethatthechangeisevaluatedtobenotrelevanttothePSDresults,noadditionalvalidationactivityisrequiredandthecurrentvalidatedmethodisapplied.
8方法验证程序
8Detailedprocedureforvalidationofamethod
8.1Methodrepeatability
8.1方法重复性
Analyst#1willanalyzesample1insixreplicatemeasurementsaccordingtotable.
RSDwillbecalculated.
分析员1将分析样品1,该样品应进行6次重复的分析,RSD应符合下表规定。
d(0.1),d(0.5)andd(0.9)的可接受标准:
结果
RSD
d(0.1)和d(0.9)>10um
NMT15%
d(0.1)和d(0.9)≤10um
NMT30%
d(0.5)>10um
NMT10%
d(0.5)≤10um
NMT20%
Note:
Ifthemeasuredvalueissmallerthan1.0microntheSD(Standarddeviation)shouldbeNMT0.5micronforacceptancecriteria.
注意—如果结果小于1.0um,SD应NMT0.5um。
Acceptancecriteriaforundersizeoversizepercent:
尺寸过小或过大比例的可接受标准:
结果
RSD
过大/过小尺寸≥70%
NMT15%
30%<过小尺寸/过大尺寸<70%
NMT20%
5%<过小尺寸/过大尺寸≤30%
NMT30%
过大/过小尺寸≤5%
NMT1%(SD)
Acceptancecriteriaforothervaluesthand(0.1),d(0.5),d(0.9):
d(0.1),d(0.5)andd(0.9)为其它结果的可接受标准:
结果
测试值
RSD
d(X)≤d(0.3)或≥d(0.7)
>10um
NMT15%
d(X)≤d(0.3)或≥d(0.7)
≤10um
NMT30%
d(0.3)<d(X)<d(0.7)
>10um
NMT10%
d(0.3)<d(X)<d(0.7)
≤10um
NMT20%
Note:
Ifthemeasuredvalueissmallerthan1.0microntheSD(Standarddeviation)shouldbeNMT0.5micronforacceptancecriteria
注意—如果测试结果小于1.0um,SD应NMT0.5um。
8.2中间精密度测试
IntermediatePrecisionTest
Analyst#2willanalysethesampleaccordingtomethodorAnalyst#1willanalyzethesamesampleonanotherdayaccordingtotable.
分析员2应根据方法分析样品或分析员1在另外一天分析样品。
Thedifferencebetweentheaverageresultandtheaveragerepeatabilityresult(orduplicateresultincaseofamendementtovalidation)willbecalculatedaccordingtoformula:
平均结果的偏差以及平均重复性结果(或修正案中的重复结果)按下式计算:
Totalaverage=(averagefromfirstmeasurement+averagefromthesecondmeasurement)/2
总平均值=(第一次分析的平均值+第二次分析的平均值)/2
%Difference=(averagefromfirstmeasurement–averagefromthesecondmeasurement)*100/totalaverage;
偏差=(第一次分析的平均值-第二次分析的平均值)*100/总平均值
d(0.1),d(0.5)andd(0.9)的可接受标准:
Acceptancecriteriaford(0.1),d(0.5)andd(0.9)values:
结果
RSD
d(0.1)和d(0.9)>10um
NMT30%
d(0.1)和d(0.9)≤10um
NMT60%
d(0.5)>10um
NMT20%
d(0.5)≤10um
NMT40%
Note:
Ifthemeasuredvalueissmallerthan1.0microntheabsolutedifferenceforacceptancecriteriashouldbeNMT1micron.
注意—如果测试结果小于1.0um,绝对偏差不得大于1um。
Acceptancecriteriaforundersizeoversizepercent:
尺寸过小或过大比例的可接受标准:
结果
RSD
过大/过小尺寸≥70%
NMT25%
30%<过小尺寸/过大尺寸<70%
NMT40%
5%<过小尺寸/过大尺寸≤30%
NMT60%
过大/过小尺寸≤5%
NMT2%(绝对偏差)
Acceptancecriteriaforothervaluesthand(0.1),d(0.5),d(0.9):
d(0.1),d(0.5)andd(0.9)为其它结果的可接受标准:
结果
测试值
RSD
d(X)≤d(0.3)或≥d(0.7)
>10um
NMT30%
d(X)≤d(0.3)或≥d(0.7)
≤10um
NMT60%
d(0.3)<d(X)<d(0.7)
>10um
NMT20%
d(0.3)<d(X)<d(0.7)
≤10um
NMT40%
Note:
Ifthemeasuredvalueissmallerthan1.0microntheabsolutedifferenceforacceptancecriteriashouldbeNMT1micron.
注意—如果测试结果小于1.0um,绝对偏差不得大于1um。
Incasetheresultsfallbetweentwolevelscategories,takethelowerlevelasacceptancecriteria(seetable).
如果结果介于两个限度,选择低的限度作为可接受标准。
8.3重现性
8.3InterlaboratoryStudy
Thesamplewillbetestedaccordingtomethodinanotherlaboratory(generallyQC)accordingtotable.
样品应在另外的实验室用同一方法进行测试。
Thedifferencebetweentheaverageresultandtheaveragerepeatabilityresult(orduplicateresultincaseofamendementtovalidation)willbecalculatedaccordingtoformula:
平均结果的偏差以及平均重复性结果(或修正案中的重复结果)按下式计算:
Totalaverage=(averagefromfirstlaboratory+averagefromsecondlaboratory)/2
%Difference=(averagefromfirstlaboratory–averagefromthesecondlaboratory)*100/totalaverage;
总平均值=(实验室一的平均值+实验室二的平均值)/2
%Difference=(averagefromfirstlaboratory–averagefromthesecondlaboratory)*100/totalaverage;
偏差=(实验室一的平均值-实验室二的平均值)*100/总平均值