WHO961文件附件6无菌药品良好生产规范中英文.docx
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WHO961文件附件6无菌药品良好生产规范中英文
©WorldHealthOrganization
WHOTechnicalReportSeries,No.961,2011
WHO技术报告丛书961,2011
Annex6
WHOgoodmanufacturingpracticesforsterilepharmaceuticalproducts
附件6
无菌药品良好生产标准
Introduction
FollowingimplementationoftheseWHOgoodmanufacturingpractices(GMP)guidelines
(1)withinthecontextoftheWHOPrequalificationofMedicinesProgramme,clarifying,editorialmodificationshavebeenproposed.Thesechangeswereadoptedformaintenancepurposes.InordertoeasereadingthefullguidelinehasbeenreproducedagainasanAnnextothecurrentreportof
theWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.
引言
以下WHO药品质量管理标准〔GMP〕〔1〕指南在WHO预审药物设计、阐明、编辑修改中已经被提出。
这些变更的应用以维护的目的。
为了便于阅读,整篇指南已被重新编制并作为WHO药品标准专家委员会报告的一个附件。
WHOgoodmanufacturingpracticesforsterilepharmaceuticalproducts
WHO无菌药品良好生产标准
1.Generalconsiderations
1总则
1.1Theproductionofsterilepreparationsshouldbecarriedoutincleanareas,entrytowhichshouldbethroughairlocksforpersonneland/orforequipmentandmaterials.Cleanareasshouldbemaintainedtoanappropriatestandardofcleanlinessandsuppliedwithairthathaspassedthroughfiltersoftherequiredefficiency.
1.1无菌产品的生产应在洁净区进行,人员和/或设备和物料进入洁净区应通过气闸室进入。
洁净区应保持适当的洁净度标准并提供经过有效的过滤的空气。
1.2Thevariousoperationsofcomponentpreparation(suchasthoseinvolvingcontainersandclosures),productpreparation,fillingandsterilizationshouldbecarriedoutinseparateareaswithinthecleanarea.Theseareasareclassifiedintofourgrades(seesection4).
1.2组件的准备〔如相关的容器和密闭包装〕,产品的制备、灌装和灭菌操作应在洁净区内分区域进行。
这些洁净区分为四个等级〔见第4节〕。
1.3Manufacturingoperationsaredividedhereintotwocategories:
—first,thosewheretheproductisterminallysterilized;and
—second,thosewhichareconductedasepticallyatsomeorallstages.
1.3生产操作在此可以划分为两类:
—第一,仅在最后阶段灭菌的产品;
—第二,部分或全部工序采用无菌生产工艺的产品。
2.Qualitycontrol
2质量控制
2.1Thesterilitytestappliedtothefinishedproductshouldonlyberegardedasthelastinaseriesofcontrolmeasuresbywhichsterilityisassured.Thetestshouldbevalidatedfortheproduct(s)concerned.
2.1成品的无菌检测仅作为一系列确保无菌度的控制措施的最后一步。
相关产品的无菌度检测应进行验证。
2.2Samplestakenforsterilitytestingshouldberepresentativeofthewholeofthebatchbutshould,inparticular,includesamplestakenfrompartsofthebatchconsideredtobemostatriskofcontamination,forexample:
•forproductsthathavebeenfilledaseptically,samplesshouldincludecontainersfilledatthebeginningandendofthebatchandafteranysignificantinterruptionofwork;
•forproductsthathavebeenheatsterilizedintheirfinalcontainers,considerationshouldbegiventotakingsamplesfromthatpartoftheloadthatispotentiallythecoolest.
2.2无菌度检测取样的样品应能代表整个批次,并且应包括最容易受到污染风险的部位的样品。
●无菌灌装的产品,取样应包括灌装前、灌装后和有明显中断的时候。
●仅在在最后步骤进行高温灭菌的产品,应考虑从最凉处取样。
2.3Thesterilityofthefinishedproductisassuredbyvalidationofthesterilizationcycleinthecaseofterminallysterilizedproducts,andby“mediasimulation”or“mediafill”runsforasepticallyprocessedproducts.Batch-processingrecordsand,inthecaseofasepticprocessing,environmentalqualityrecords,shouldbeexaminedinconjunctionwiththeresultsofthesterilitytests.Thesterilitytestprocedureshouldbevalidatedforagivenproduct.Pharmacopoeialmethodsshouldbeusedforthevalidationandperformanceofthesterilitytest.Inthosecaseswhereparametricreleasehasbeenauthorizedinplaceofsterilitytestingspecialattentionshouldbepaidtothevalidationandthemonitoringoftheentiremanufacturingprocess.
2.3最终产品的无菌度检测,如果是仅在最后步骤灭菌的产品,应确保整个灭菌周期的验证,如果是无菌工艺生产的产品,应确保进行了“培养基模拟”和“培养基灌装”。
批生产记录和环境质量记录〔无菌生产过程中的〕应结合无菌度检测结果进行检查。
对给出的产品应进行无菌度检测验证。
验证和无菌度检测应使用药典的方法。
如果授权使用参数放行取代无菌度检测,应注意特别关注验证和整个生产过程的监测。
2.4Forinjectableproductsthewaterforinjectionandtheintermediate,ifappropriate,andfinishedproductsshouldbemonitoredforendotoxins,usinganestablishedpharmacopoeialmethodthathasbeenvalidatedforeachtypeofproduct.Forlarge-volumeinfusionsolutions,suchmonitoringofwaterorintermediatesshouldalwaysbedone,inadditiontoanytestsrequiredbyanapprovedmonographforthefinishedproduct.Whenasamplefailsatest,thecauseofthefailureshouldbeinvestigatedandnecessaryactionshouldbetaken.Alternativemethodstothoseinthepharmacopoeiasmaybeusediftheyarevalidated,justifiedandauthorized.
2.4关于注射产品,对注射用水和中间体,如果适用,还有成品,应采用已建立的经过验证药典方法进行内毒素监测。
对于大容量输液剂,除了符合专论要求的成品检测外,还应对水和中间体进行监测。
当样品检测不合格时,应进行调查并采取必要的措施。
也可采用经验证、合理并授权的方法取代药典中的方法。
2.5Theuseofrapidmicrobiologicalmethodstoreplacethetraditionalmicrobiologicalmethods,andtoobtainearlierresultsonthemicrobiologicalqualityof,forexample,water,theenvironmentorbioburden,couldbeconsideredifappropriatelyvalidatedandifacomparativeassessmentoftheproposedrapidmethodisperformedagainstthepharmacopoeialmethod.
2.5使用快速微生物学方法取代传统的微生物学方法,如果微生物质量可靠,并可早点获得检测结果,如:
水、环境或生物负荷,是可以考虑的,但是提议的快速方法应进行了验证,并与药典方法进行比对评估。
3.Sanitation
3卫生
3.1Thesanitationofcleanareasisparticularlyimportant.Theyshouldbecleanedfrequentlyandthoroughlyinaccordancewithanapprovedwrittenprogramme.Wheredisinfectantsareused,morethanonetypeshouldbeemployed.Monitoringshouldberegularlyundertakentodetectcontaminationorthepresenceofanorganismagainstwhichthecleaningprocedureisineffective.Interactionsbetweendifferentcleaningmaterialsshouldbevalidated.Appropriatecleaningvalidationshouldbecarriedouttoensuredisinfectantresidualscanbedetectedandareremovedbythecleaningprocess.
3.1洁净区的环境卫生极为重要。
应根据批准的书面规程定期并彻底地清洁。
使用清洁剂时,应不止一种。
应定期进行监测以检测污染或清洁程序对之无效的生物体。
应确定不同清洁材料之间的相互作用。
应进行适当的清洁验证,确保能检测到清洁剂残留并能通过清洁程序去除。
3.2Disinfectantsanddetergentsshouldbemonitoredformicrobialcontamination;dilutionsshouldbekeptinpreviouslycleanedcontainersandshouldonlybestoredfordefinedperiodsunlesssterilized.DisinfectantsanddetergentsusedinGradeAandBareasshouldbesterilebeforeuse.
3.2消毒剂和清洁剂应进行微生物污染监测;稀释剂应保存在预先清洁的容器中并按规定的期限储存,除非被消毒灭菌。
在A级和B级洁净区使用的消毒剂和清洁剂应在使用前应进行灭菌。
3.3Adisinfectantprogrammeshouldalsoincludeasporicidalagentsincemanycommondisinfectantsareineffectiveagainstspores.Theeffectivenessofcleaninganddisinfectantproceduresshouldbedemonstrated.
3.3消毒程序还应包括杀孢子剂,因为通常的消毒剂对孢子是无效的。
应证明清洁和消毒程序是有效的。
3.4Fumigationofcleanareasmaybeusefulforreducingmicrobialcontaminationininaccessibleplaces.
3.4洁净区熏蒸法对于减少死角的微生物污染有效。
4.Manufactureofsterilepreparations
4无菌产品的生产
4.1Cleanareasforthemanufactureofsterileproductsareclassifiedaccordingtotherequiredcharacteristicsoftheenvironment.Eachcleanlinessintheoperationalstatetominimizetherisksofparticulateormicrobialcontaminationoftheproductormaterialsbeinghandled.manufacturingoperationrequiresanappropriatelevelofenvironmental
4.1生产无菌产品的洁净区根据所需环境特点划分。
操作阶段每个生产操作都需要相适应的洁净水平以减少产品或物料处理时微粒或微生物污染的风险。
4.2Detailedinformationonmethodsfordeterminingthemicrobiologicalandparticulatecleanlinessofair,surfaces,etc.,isnotgivenintheseguidelines.
ISO14644-1
(2)shouldbeusedforclassificationofcleanlinessaccordingtoconcentrationofairborneparticles(determinationofnumberofsamplelocations,calculationofsamplesizeandevaluationofclassificationfromthedataobtained).Table1shouldalsobeusedtodefinethelevelstobeusedasthebasisformonitoringcleanareasforairborneparticles.
4.2本指南没有给出空气或外表等的微生物和微粒洁净度的详细检测方法。
依据空气中悬浮粒子的浓度〔确定样品监测位置数目、计算取样量和根据活的的数据进行几倍划分评估〕,参考ISO14644-1〔2〕划分洁净等级。
表1也应用于定义监测洁净区空气中悬浮粒子的依据。
〕
4.3Forthemanufactureofsterilepharmaceuticalpreparations,fourgradesofcleanareasaredistinguishedasfollows:
•GradeA:
Thelocalzoneforhigh-riskoperations,e.g.fillingandmakingasepticconnections.Normallysuchconditionsareachievedbyusingaunidirectionalairflowworkstation.Unidirectionalairflowsystemsshouldprovideahomogeneousairspeedof0.36–0.54m/s(guidancevalue)atadefinedtestposition15–30cmbelowtheterminalfilterorairdistributorsystem.Thevelocityatworkinglevelshouldnotbelessthan0.36m/s.Theuniformityandeffectivenessoftheunidirectionalairflowshouldbedemonstratedbyundertakingairflowvisualizationtests.
•GradeB:
Inasepticpreparationandfilling,thisisthebackgroundenvironmentfortheGradeAzone.
•GradesCandD:
Cleanareasforcarryingoutlesscriticalstagesinthemanufactureofsterileproductsorcarryingoutactivitiesduringwhichtheproductisnotdirectlyexposed(i.e.asepticconnectionwithasepticconnectorsandoperationsinaclosedsystem).
Aunidirectionalairflowandlowervelocitiesmaybeusedinclosedisolatorsandgloveboxes.
4.3对无菌产品的生产,洁净区可以分为以下四个等级:
A级:
高风险操作的局部区域,如:
灌装和无菌操作连接。
通常这些情况是通过单向气流工作站实现的。
单向气流系统应在规定的终端过滤器或空气分配器系统下方15-30cm的位置提供一个速度为0.36~0.54m/s〔指导值〕的均匀气流。
工作时的速度应不小于0.36m/s。
单向气流的均一性和有效性应在气流可视化试验下证明。
B级:
在无菌配制和灌装中作为A级区域的背景环境。
C级和D级:
较少的关键阶段或生产中产品没有直接暴露的生产活动〔如:
无菌连接器的无菌连接和密闭系统的操作〕在此洁净区进行。
封闭的隔离器或手套箱可采用单向气流和较低的速度。
4.4InordertoreachtheB,CandDairgradesthenumberofairchangesshouldbeappropriateforthesizeoftheroomandtheequipmentandpersonnelpresentinit.
4.4为了到达B、C和D的空气等级,换气次数应符合房间大小和里面的设备和人员要求。
4.5High-efficiencyparticulateair(HEPA)filtersshouldbesubjectedtoaninstalledfilterleakagetestinaccordancewithISO14644-3(3)atarecommendedintervalofevery6months,butnotexceeding12months.Thepurposeofperformingregularleaktestsistoensurethefiltermedia,filterframeandfiltersealarefreefromleaks.TheaerosolselectedforHEPAleaktestingshouldnotsupportmicrobialgrowthandshouldbecomposedofasufficientnumberormassofparticles.HEPAfilterpatchingisallowedatthefiltermanufacturerandinsituoperationprovidedt