以高效质量方式生产的无菌产品-顺应新版GMP的要求--吴旭2011.10上海ISPE

ISPE-CCPIECHINACONFERENCE2011October25-282011Shanghai1SterileproductsinaQualityefficientway-incompliancewiththenewGMP以高效质量方式生产的无菌产品-顺应新版GMP的要求ProcessDesignwithRABsandIsolatorTechnology使用RABs和隔离器技术的工艺设计吴旭ISPE-CCPIECHINACONFERENCE20112Topic话题•NewSFDAGMPrequirementsforsterilemanufacturingareaSFDA新版GMP对无菌生产区域的要求•Riskassessmentfortheasepticprocess无菌工艺的风险评估•KeypointsinprocessdesignwithIsolator/RABsTechnology隔离装置/RABs技术工艺设计的关键点ISPE-CCPIECHINACONFERENCE2011GMPrequirement/GMP要求•ClearlydefineGradeAarea明确定义A级区域GradeA:Thelocalzoneforhighriskoperations,e.g.fillingzone,stopperbowls,opencontainersthatareindirectcontactwithsterilepreparations,makingasepticconnections.Normallysuchconditionsareprovidedbyauni-directionalairflowworkstation.GradeB:Forasepticpreparationandfilling,thisisthebackgroundenvironmentforthegradeAzone.A级：高风险操作区，如灌装区、放置胶塞桶和与无菌制剂直接接触的敞口包装容器的区域及无菌装配或连接操作的区域，应当用单向流操作台（罩）维持该区的环境状态。B级：指无菌配制和灌装等高风险操作A级洁净区所处的背景区域。•Clearlydefinetheatrestandinoperationrequirement明确定义静态和动态的要求particleandmicrobiological粒子和微生物seetable1andtable2参见表1和表2Clearlygivethemonitoringrequirement明确监控要求ForGradeAzones,particlemonitoringshouldbeundertakenforthefulldurationofcriticalprocessing,includingequipmentassembly,exceptwherejustifiedbycontaminantsintheprocessthatwoulddamagetheparticlecounterorpresentahazard对于A级区域，对关键工艺操作要进行全程粒子监控，包括部件设置的时候，但是需要评估过程中的污染物会损坏粒子计数器或存在危险。ISPE-CCPIECHINACONFERENCE2011CleanlinessClassificationandmaximumpermittedairborneparticleconcentration洁净分级和悬浮粒子浓度上限Grade级别Atrest静态Inoperation动态Maximumpermittednumberofparticlesperm3equaltoorgreaterthanthetabulatedsize直径等于或大于表内大小的粒子每立方米允许最大数量≥0.5μm≥5μm≥0.5μm≥5μmA352020352020B3520293520002900C3520002900352000029000D352000029000Notdefined不作规定NotDefined不作规定Table1表1ISPE-CCPIECHINACONFERENCE2011Limitsformicrobiologicalmonitoringofcleanareasduringoperation动态洁净区微生物监控上限Grade级别airsamplebacteriacfu/m3浮游菌/立方米settleplatesbacteria(90mm)cfu/4hours沉降菌/4小时Surfacemicrobiological表面微生物contactplates(55mm)cfu/platecfu/接触碟Gloveprint5fingerscfu/glovecfu/5指手套A1111B10555C1005025－D20010050－Table2表2ISPE-CCPIECHINACONFERENCE2011Responsetothenewrequirement应对新要求Annex1SterileMedicinalProductsareclosertoEUGMPannex1.Itisnotsochallengeforinternationalcompany附件1对无菌制剂要求接近欧盟GMP附件1的要求，这对跨国公司来说挑战不大。Forlocalpharmaceuticalplant,somerequirementsinAnnex1arenewandchallenge对国内药厂来说，附件1的某些要求是新的并且有难度SuchasChapter3CleanlinessClassificationandItsMonitoring,especiallygradeAandBrequirement,seetable1andtable2比如第三章洁净分级和监控，特别是A级和B级要求，参见表1和表2Chapter4Isolatortechnology第四章隔离技术Partoflocalcompanydon‟tunderstandsterileoperationrisk.一些国内企业不理解无菌操作的风险。Theyjustliketoaddonemonitoringsystem.他们只是想增加一套监控系统。ISPE-CCPIECHINACONFERENCE2011FactorsimpactGradeAduringoperationwithcurrentcleanroomdesign:当前洁净室设计下影响A级区域动态指标的因素：Equipment设备-Mostofproductdirectlycontractpartswillbesterilized直接接触产品的部件要进行灭菌-Equipmentitselfcanonlybedisinfected设备自身只能消毒-Partinstrumentscanonlybedisinfected部分仪表只能消毒Material原料-Productionmaterialwillbesterilized生产原料灭菌-Somepackingmaterialcanonlybedisinfected一些包材只能消毒RiskAssessmentforasepticprocess无菌工艺的风险评估ISPE-CCPIECHINACONFERENCE2011RiskAssessmentforasepticprocess无菌工艺的风险评估GradeAareaiscriticalareainasepticprocess在无菌工艺中A级区是关键区域FactorsimpactGradeAduringoperationwithcurrentcleanroomdesign:当前洁净室设计下影响A级区域动态条件因素：Operator操作人员-OperatorcannotbesterilizedbeforeenteringgradeBarea操作人员在进入B级区域前无法被灭菌-Duringoperation,operatorwillgenerateparticlestotheenvironment操作过程中，操作人员会产生粒子-Duringthemanufacturing,operatorwillintervenetheoperationingradeA生产过程中，操作人员会干预A级区域的运行ISPE-CCPIECHINACONFERENCE2011RiskAssessmentforasepticprocess无菌工艺的风险评估CurrentControls当前控制FollowGowningprocedure执行更衣程序FollowpersonnelbehavioringradeBarea执行B级区域人员行为规范Proposedaction建议措施Tofindagoodbarriersystemtopreventoperator’sinterruptioninthesterileoperation寻找一个好的隔离系统来防止操作人员对无菌操作的干扰ISPE-CCPIECHINACONFERENCE2011RiskAssessmentforasepticprocess无菌工艺的风险评估RiskAssessmentResultmaybedifferentindifferentcompany不同公司风险评估的结果可能不同•e.g,Inmanylocalcompany,thereisnocorrectrequirementforoperator’sbehavioringradeBarea.AndaccordingtooldGMPrequirement,theyhaven’tdoneenvironmentmonitoringinoperation.Beforetheydon’ttreatpersonnelinterruptionashighrisk.Currentlytheystarttothinkaboutit.例如许多国内公司没有关于操作人员在B级区域行为的正确要求。根据老版GMP的要求，动态不做环境监控的。之前他们不会把人员干预作为高风险，而现在他们开始考虑了。•Inmostinternationalcompany,itisalwaysconsideredthatoperator’sbehaviorinGradeA/Bareaishighrisk.多数的跨国公司都认为A/B级区域的人员活动都是高风险的ItisveryimportanttofindagoodtechnologytominimizethepeopleinterventiontothegradeAarea.寻找一个尽量减少人员对A级区域的干预的技术显得尤为重要。ISPE-CCPIECHINACONFERENCE2011Casestudyofsterileoperation无菌操作个案研究-WhichareaisgradeA哪个区域为A级-WhatistheinterfacebetweengradeAandgradeBA级和B级之间的界面是什么-Ifitisacceptableinfillingprocesswiththedooropen开门状态下的灌装是否可接受-Ifitismusttomonitoringparticleduringsterilepowderfilling无菌粉末灌装是否必须监控粒子数ISPE-CCPIECHINACONFERENCE2011Definition定义IsolatorisabarrierorsystemthatisequippedwithGradeB(ISO5)orevenhighercleannessairhandlingunitsandcanisolatecompletelytheinternalenvironmentfromexternalenvironment(e.gcleanroomandoperators).指配备B级（ISO5级）或更高洁净度级别的空气净化装置，并能使其内部