关于淋洗取样

STERISRinsesamplingforCleaningValidationStudies清洁验证中淋洗取样法的研究DestinA.LeBlancRinse-samplingproceduresthatdrawfromthefinalrinsesolutioncanprovideupper-limitestimatesofpotentialcontaminationinsubsequentlymanufacturedproducts.Theprocesscanbeimprovedbyseparatingtheprocessrinsefromthesamplingrinse.Thismayresultinmoreaccurateactualestimates,moreflexibilityinselectinganalyticalprocedures,andmoreflexibilityinchoosingasamplingrinsesolutionthatisdifferentfromtheprocessrinsesolution.Proceduresforsuchdeterminationsdependonadequaterinserecoverystudies.Thisarticledescribesthesestudies.从最终淋洗溶液取样的淋洗液取样程序可以提供后续生产产品中潜在污染物的上限评估。该程序中也可将淋洗工艺和取样工艺分开。选择不同的更加灵活分析规程、选择与淋洗工艺不同的取样淋洗溶剂，均可以得到更准确的结果评估。这些检测程序均基于充分的淋洗回收率研究。本文即描述这些研究ValidationofcleaningprocessesusedforproductcontactsurfacesinpharmaceuticalmanufacturingisrequiredbyFDA.The1993decisionofUSv.BarrLaboratoriesgaveFDAtherighttomandatethatcleaningisacriticalprocessthatmustbevalidated(1).Althoughthisdecisionfocusedmainlyonissuesrelatedtoretestingafterout-of-specificationresults,italsoheldthatFDAhadtherightinthiscasetomandatevalidationofcleaningprocesses.InJuly1992,whilethiscasewasbeinglitigated,theagency’sMid-AtlanticRegionstaffdevelopedaninternalinspectionguidelineforcleaningvalidation(2).InJuly1993,themoreofficialandstillcurrent“GuidetoInspectionsofValidationofCleaningProcesses”wasissued(3)FDA要求药品生产中对于产品直接接触的表面清洁工艺必须进行验证。1993年美国BarrLaboratories案例（注1）的判决结果中赋予了FDA将清洁规定为关键工艺且必须经过验证的权利。尽管这次决议主要关注的是OOS后的复测相关问题，但仍可认为FDA在这次案例中获得了清洁工艺验证的授权。1992年7月，这场官司还在诉讼期时，中大西洋地区部门开发了清洁验证内部检查指南（注2）。1993年7月，更官方的并且现在仍通行的《清洁验证检查指南》发布了（注3）。The1992Mid-Atlanticguidediscussesthreetypesofsampling:directsurface,rinse,andplacebo.Directsurfaceisratedmostdesirable,rinseisconsideredlessdesirable,andplaceboisconsideredgenerallyunacceptable.Inthe1993guide,althoughnotexplicitlystated,therelativerankingofthesemethodsisassumedtohold—withdirectsurfacebeingmostdesirableandplacebobeingacceptableonlyifdirectsurfaceorrinsesamplingisalsodone.Tworeasonssupporttheless-desirabledesignationforrinsesampling.Thefirstissueiswhethertheresidueofconcernissolubleintherinsesolution.Oneanalogyisthatofadirtypot.Iftheconcerniswhetherornotawashedpotisclean,doesoneexaminetherinsewaterorthepotitself?Thesecondconcernistheanalyticalstrategyused.SomepharmaceuticalcompaniespreviouslyanalyzedtherinsewaterandtesteditmerelyforUSPcompendialspecificationsforpurifiedwaterorforwaterforinjection.FDAargued(quiterightly)thatmanufacturersshouldhaveatargetresidueandmeasurethattargetresidue.ItispossiblethattherinsewatermeetsUSPspecificationsandyetmaynotreasonablyindicatecontaminantsintherinsewaterbecausethetargetresidueispresenteitheratalevelorasachemicalspeciesthatcannotbeadequatelydetectedbyUSPwaterspecifications.1992年的中大西洋指南谈到了3种取样方法：表面直接取样、淋洗取样和安慰剂取样。表面直接取样被认为最优先考虑的，其次为淋洗取样，而安慰剂取样一般认为是不可接受的。在1993年的指南中，尽管没有明确的规定，但三种方法的优先级可以这样认为：表面直接取样为最合适的，安慰剂取样只有在结合直接取样或淋洗取样进行的情况下可以考虑。淋洗取样被认为次级可取的方法有两条原因。第一个问题是，残留是否会溶于淋洗液中。类似的问题如：“脏点”。如果清洗点是干净的，是否只检查淋洗水或者清洗点本身？第二个问题是使用的分析策略。一些公司以前只检测淋洗水是否符合USP关于纯化水或注射用水法定标准。FDA主张（非常肯定）生产商必须确定测试的目标残留物。淋洗水有可能符合USP水的标准但不能表示其中的污染物符合要求，因为目标残留有可能在USP检测标准水平以下或未经充分检测的化学种类。The1993documentdoesoffersomeguidanceonacceptableresiduelevelsbycitingapaperfromscientistsatEliLillyabouttheirproceduresforsettingresiduelimits(4).Theseresiduelimitsarebasedonthepossiblecontaminationofproductsubsequentlymanufacturedinthesameequipment.TheEliLillyscientistsproposedlimitsinthesubsequentproductthatwouldproduce0.001ofaminimumdailydoseofthedrugresidueinamaximumdailydoseofthenextdrugproduct.Theyalsoproposedthatifthecalculatedvaluebasedonthe0.001dailydoseismorethan10ppm,thenadefaultvalueof10ppmresidueinthesubsequentproductshouldbeused.1993年的文件中引用了一些残留物限度可接受标准，这些标准来自礼来科学家在生产中残留限度设定的文献（注4）。这些残留限度基于使用同一台设备生产可能带入后续生产的污染物。礼来的科学家建议，后一批产品最多日治疗量中允许带入的前一批产品量不得超过前一批产品的日最低治疗量的1/1000，以此作为确定残留的限度。他们同时建议，如果按0.001日治疗量的计算值超过10个ppm，则应使用10ppm作为标准。Basedonpossiblecontaminationofthesubsequentproduct,itisthenpossibletocalculate—usingparameterssuchasbatchsize,surfacearea,andsamplingtechnique—itemssuchasallowablecontaminationpersurfaceareaorperswabsample.Althoughswab-samplingresiduelimitshavebeendiscussedinnumerouspapers(5,6,7),rinsesamplinghasnotbeencoveredasrigorously.基于后续产品中可能的污染物，建立残留限度时可以考虑批量、表面积、取样手法、单位面积污染物量或每擦拭量。尽管擦拭取样残留限度在很多文献（注5,6,7）中都被论述过，但淋洗取样仍未被严格的讨论过。Basedontheauthor’sexperience,manufacturershaveoftenmadeassumptionsaboutacceptablerinsewaterlimitswithoutadequateconsiderationofthepotentialforcontaminationofthesubsequentlymanufacturedproduct.Inmanycases,arinsewaterlimitof10ppmhasbeenautomaticallyselectedandassumedtorepresentanacceptableresiduelimitintherinsesolution.Therestofthisarticlefocusesonthecriticalrelationshipbetweenrinse-samplingresultsandpotentialcontaminationofthesubsequentproduct.Issuescoveredincluderinsesamplingasitiscurrentlydone(i.e.,grabsampleattheendoftherinsingprocess),rinse-samplingprocessesthatmayprovidemorescientificallyjustifiedresiduelimits,andmethodsthatmayadequatelydeterminerinse-samplingrecovery.根据笔者的经验来看，一些生产商经常在设定淋洗水限度可接受标准时，未充分考虑到对后续生产带来的潜在污染。在很多案例中，10ppm通常被作为淋洗水残留物限度可接