Annex 2QC 世界卫生组织药品微生物实验室管理规范

WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理 规范 编程规范下载gsp规范下载钢格栅规范下载警徽规范下载建设厅规范下载 1of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。©WorldHealthOrganization世界卫生组织WHOTechnicalReportSeries,No.961,2011世界卫生组织技术报告系列，编号961，2011年Annex2附录2WHOgoodpracticesforpharmaceuticalmicrobiologylaboratories世界卫生组织药品微生物实验室管理规范 目录 工贸企业有限空间作业目录特种设备作业人员作业种类与目录特种设备作业人员目录1类医疗器械目录高值医用耗材参考目录 Background背景.............................................................................................................................2Introductionandscopeofdocument文件介绍和范围...................................................................2Glossary术语表...............................................................................................................................31.Personnel人员............................................................................................................................52.Environment环境........................................................................................................................62.1Premises房屋...........................................................................................................................62.3Cleaning,disinfectionandhygiene清洁、消毒和卫生...............................................................82.4Sterilitytestfacilities无菌试验设施............................................................................................83.Validationoftestmethods检验方法的验证..............................................................................104.Equipment设备.........................................................................................................................104.1Maintenanceofequipment设备维护.......................................................................................114.2Qualification验证....................................................................................................................114.3Calibration,performanceverificationandmonitoringofuse校准、性能确认和使用的监控......114.3.3Temperaturemeasurementdevices温度测量装置.....................................................................114.3.4Incubators,water-bathsandovens培养箱、水浴和烘箱..........................................................114.3.5Autoclaves,includingmediapreparators高压灭菌锅，包括培养基制备器............................124.3.6Weightsandbalances砝码和天平..................................................................................................134.3.7Volumetricequipment测定体积的设备..........................................................................................134.3.8Otherequipment其他设备................................................................................................................135.Reagentsandculturemedia试剂和培养基..............................................................................145.1Reagents试剂.........................................................................................................................145.2Media培养基...........................................................................................................................145.3Labelling贴签..........................................................................................................................165.4Organismresuscitation微生物复苏.........................................................................................166.Referencematerialsandreferencecultures标准物质和标准菌株..........................................166.1Internationalstandardsandpharmacopoeialreferencesubstances国际标准和药典标准品....166.2Referencecultures标准菌株...................................................................................................177.Sampling取样............................................................................................................................188.Samplehandlingandidentification样品处理和鉴定...............................................................189.Disposalofcontaminatedwaste污染废物的处理.....................................................................1910.Qualityassuranceofresultsandqualitycontrolofperformance结果的质量保证和性能的质量控制..............................................................................................................................................1910.1Internalqualitycontrol内部质量控制......................................................................................1911.Testingprocedures检验程序...................................................................................................2012.Testreports检验报告...............................................................................................................20References参考文件......................................................................................................................20Furtherreading补充书目..............................................................................................................21Appendix1附件1..........................................................................................................................22WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范2of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。Examplesofzonesinwhichoperationscouldbecarriedout可进行操作的区域的例子............22Appendix2附件2..........................................................................................................................23Examplesofmaintenanceofequipment设备维护的例子............................................................23Appendix3附件3..........................................................................................................................24Examplesofcalibrationchecksandintervalsfordifferentlaboratoryequipment不同实验室设备校准检查和间隔的例子.................................................................................................................24Appendix4附件4..........................................................................................................................25Examplesofequipmentqualificationandmonitoring设备验证和监控的例子............................25Appendix5附件5..........................................................................................................................27Generaluseofreferencecultures标准菌株的一般用途...............................................................27Background背景TheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationsadoptedin2009arevisedversionoftheGoodpracticesforpharmaceuticalqualitycontrollaboratories(1).世界卫生组织制剂产品的质量标准专家委员会在2009年通过了药品质量控制实验室管理规范的修订版本(1)。Duringtheinspectionscarriedoutwhenprequalifyinglaboratories,theinspectorshadnoticedthatsomeofthetextsoftheseguidelinesmightbenefitfromadditionalguidance,withaspecialfocusonmicrobiology.在预验证实验室时所进行的检查过程中，检查官注意到这些指导原则的部分内容可能受益于附加的特别关注微生物的指导原则。Inlightoftheabove,theExpertCommitteerecommendedthattheWHOSecretariatinitiatetheprocessofdevelopinganewtextongoodpracticesforpharmaceuticalmicrobiologylaboratories.鉴于以上，专家委员会建议世界卫生组织秘书处启动撰写新的药品微生物实验室管理规范的程序。Thefollowingtextisproposedtocoverthisspecifictypeoflaboratory.提出下文以包含这种特殊类型的实验室。Introductionandscopeofdocument文件介绍和范围Pharmaceuticalmicrobiologylaboratoriesmaybeinvolvedin:药品微生物实验室可涉及到：—sterilitytesting;无菌试验；—detection,isolation,enumerationandidentificationofmicroorganisms(bacteria,yeastandmoulds)andtestingforbacterialendotoxinsindifferentmaterials(e.g.startingmaterials,water),products,surfaces,garmentsandtheenvironment;and—在不同物料（如原辅料、水）、产品、表面、外衣和环境中的微生物（细菌、酵母菌和霉菌）的 检测 工程第三方检测合同工程防雷检测合同植筋拉拔检测方案传感器技术课后答案检测机构通用要求培训 、分离、计数和鉴别，以及细菌内毒素的检验；—assayusingmicroorganismsaspartofthetestsystem.—使用微生物作为检验系统的一部分进行含量测定。Theseguidelinesrelatetoallmicrobiologylaboratoriesinvolvedintheabove-mentionedtestingactivities,whethertheyareindependentoradepartmentorunitofapharmaceuticalmanufacturingWHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范3of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。facility.这些指导原则有关于所有在上述检验活动中涉及的微生物实验室，无论它们是独立的或是药品生产厂的一个部门或单位。TheseguidelinesarebasedonandsupplementtherequirementsdescribedinGoodpracticesforpharmaceuticalqualitycontrollaboratories(1);Generalguidelinesfortheestablishment,maintenanceanddistributionofchemicalreferencesubstances.Revision(2);TheInternationalPharmacopoeia,FourthEdition(3);FirstSupplementtoTheInternationalPharmacopoeia,FourthEdition(4);andISO/IEC17025(5).这些指导原则是建立在以下规定的要求的基础上的，并对其进行补充：药品质量控制实验室管理规范(1)；建立、维护和分发化学标准品的通用指导原则(2)；国际药典，第四版(3)；国际药典的第一附录，第四版(4)；和ISO/IEC17025(5)。Glossary术语表calibration校准Thesetofoperationsthatestablish,underspecifiedconditions,therelationshipbetweenvaluesindicatedbyaninstrumentorsystemformeasuring(especiallyweighing),recordingandcontrolling,orthevaluesrepresentedbyamaterialmeasure,andthecorrespondingknownvaluesofareferencestandard.Limitsforacceptanceoftheresultsofmeasuringshouldbeestablished.在规定条件下建立一台测量（特别是称量）、记录和控制的设备或系统所显示的值，或一个实物量具所代表的值和相应的标准品的值之间关系的一套操作。应建立测量结果的可接受限度。certifiedreferencematerial检定合格的标准物质Referencematerial,characterizedbyametrologicallyvalidprocedureforoneormorespecifiedproperties,accompaniedbyacertificatethatprovidesthevalueofthespecifiedproperty,itsassociateduncertaintyandastatementofmetrologicaltraceability.标准物质，通过度量衡有效的程序对一个或多个指定属性进行性质确证，具有提供指定属性的值、其相关不确定度和对度量衡可追溯性的说明的证书。limitofdetection检测限Thelowestnumberofmicroorganismsthatcanbedetected,butinnumbersthatcannotbeestimatedaccurately.可被检测出、但在数量上不能被准确估算的微生物的最低数量。precision精密度Thedegreeofagreementamongindividualresults.单个结果之间一致的程度。quantitationlimit(limitofquantitation)定量限Appliedtoquantitativemicrobiologicaltests.Thelowestnumberofmicroorganismswithinadefinedvariabilitythatmaybecountedundertheexperimentalconditionsofthemethodunderevaluation.适用于定量微生物试验。在被评估的方法的试验条件下，在规定的变异性之内，可被计数的微生物的WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范4of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。最低数量。referencecultures标准菌株Collectivetermforreferencestrainandreferencestocks.参考菌株和参考原株的总称。referencematerial标准物质Materialsufficientlyhomogeneousandstablewithrespecttooneormorespecifiedproperties,whichhasbeenestablishedtobefitforitsintendeduseinameasurementprocess.具有足够均一和稳定的一个或多个指定属性的物质，建立该物质以适合于其在测量过程中的预期用途。referencemethod参考方法Amethodwhichhasbeenvalidatedasbeingfitforpurpose,withwhichanalternativemethodmaybecompared.经过验证证明适合于目的的方法，将替代性的方法与之相比较。referencestocks参考原株Asetofseparateidenticalculturesobtainedbyasinglesubculturefromthereferencestrain(6).从参考菌株进行一次继代培养所获得的一套独立的完全相同的培养物(6)。referencestrains参考菌株Microorganismsdefinedatleasttothegenusandspecieslevel,cataloguedanddescribedaccordingtoitscharacteristicsandpreferablystatingitsorigin(6).Normallyobtainedfromarecognizednationalorinternationalcollection.根据其性质至少规定到种属级别的分类和描述的微生物，最好说明其来源(6)。通常从认可的国家或国际保藏处获得。repeatability重复性Closenessoftheagreementbetweentheresultsofsuccessivemeasurementsofthesamemeasureandunderthesameconditionsofmeasurement(adaptedfromISO).同一被测物在相同的测量条件下连续多次测量结果之间相一致的紧密程度。reproducibility重现性Reproducibilityexpressesprecisionbetweenlaboratories.重现性表示不同实验室之间的精密度。robustness(orruggedness)耐用性WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范5of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。Theabilityoftheproceduretoprovideanalyticalresultsofacceptableaccuracyandprecisionunderavarietyofconditions.程序在不同条件下提供具有可接受的准确度和精密度的分析结果的能力。sensitivity灵敏度Thefractionofthetotalnumberofpositiveculturesorcoloniescorrectlyassignedinthepresumptiveinspection(7).在假定检验中正确指定的阳性培养物或菌落的总数中的部分(7)。specificity(selectivity)专属性（选择性）Theabilityofthemethodtodetecttherequiredrangeofmicroorganismsthatmightbepresentinthetestsample.方法能够检测出可能存在于被检样品中的微生物的必需范围的能力。validation验证Actionofproving,inaccordancewiththeprinciplesofgoodpracticequalityguidelinesandregulations(GxP),thatanyprocedure,process,equipment(includingthesoftwareorhardwareused),material,activityorsystemactuallyandconsistentlyleadstotheexpectedresults.根据质量管理规范指导原则和法规（GxP）的原则，证明任何程序、工艺、设备（包括所用的软件或硬件）、物料、行为或系统真正能够始终产生预期结果的行动。verification确认Theapplicationofmethods,procedures,testsandotherevaluations,inadditiontomonitoring,todeterminecompliancewithGxPprinciples.除了监控之外，应用方法、程序、检验和其他评估来确定符合GxP原则。workingculture工作菌株Aprimarysubculturefromareferencestock(6).从参考原株处得到的主要继代培养物(6)。1.Personnel人员1.1Microbiologicaltestingshouldbeperformedandsupervisedbyanexperiencedperson,qualifiedinmicrobiologyorequivalent.Staffshouldhavebasictraininginmicrobiologyandrelevantpracticalexperiencebeforebeingallowedtoperformworkcoveredbythescopeoftesting.应由有经验的、具备微生物或相等资质的人员进行和指导微生物检验。在被允许进行检验范围所包含的工作之前，员工应接受基本的微生物和相关实践经验的培训。1.2Currentjobdescriptionsforallpersonnelinvolvedintestsand/orcalibrations,validationsandverificationsshouldbemaintained.ThelaboratoryshouldalsomaintainrecordsofalltechnicalWHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范6of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。personnel,describingtheirqualifications,trainingandexperience.应保存在检验和/或校准、验证和确认中涉及的所有人员的现行职务说明书。实验室还应保存所有技术人员的记录，描述他们的资质、培训和经验。1.3Ifthelaboratoryincludesopinionsandinterpretationsoftestresultsinreports,thisshouldbedonebyauthorizedpersonnelwithsuitableexperienceandrelevantknowledgeofthespecificapplicationincluding,forexample,regulatoryandtechnologicalrequirementsandacceptabilitycriteria.若实验室包括对报告中检验结果的 意见 文理分科指导河道管理范围浙江建筑工程概算定额教材专家评审意见党员教师互相批评意见 和解释，应由具备具体应用的合适经验和相关知识的获得授权的人员来进行，具体应用包括，例如法规和技术要求和可接受标准。1.4Thelaboratorymanagementshouldensurethatallpersonnelhavereceivedadequatetrainingforthecompetentperformanceoftestsandoperationofequipment.Thisshouldincludetraininginbasictechniques,e.g.platepouring,countingofcolonies,aseptictechnique,mediapreparation,serialdilutions,andbasictechniquesinidentification,withacceptabilitydeterminedusingobjectivecriteriawhererelevant.Personnelmayonlyperformtestsonsamplesiftheyareeitherrecognizedascompetenttodoso,oriftheydosounderadequatesupervision.Competenceshouldbemonitoredcontinuouslywithprovisionforretrainingwherenecessary.Whereamethodortechniqueisnotinregularuse,thecompetencyofthepersonneltoperformthetestshouldbeverifiedbeforetestingisundertaken.Insomecasesitisacceptabletorelatecompetencetoageneraltechniqueorinstrumentbeingusedratherthantoparticularmethods.实验室管理层应保证所有人员受到了充分的培训，以胜任检验和设备操作。这将包括基本技术的培训，例如平皿倾灌、菌落计数、无菌技术、培养基制备、连续稀释和鉴别的基本技术，以及使用相关的客观标准决定可接受性。人员仅在被认可能够胜任，或在充分监督下才能进行样品检验。应不断监控其能力，必要时进行再培训。若不定时使用某方法或技术，应在承担检验之前确认进行检验的人员的能力。在有些情况下，将能力与普通技术或在用仪器而非特殊方法关联起来，是可以接受的。1.5Personnelshouldbetrainedinnecessaryproceduresforcontainmentofmicroorganismswithinthelaboratoryfacility.人员应接受实验室设施内微生物防范的必要程序的培训。1.6Personnelshouldbetrainedinsafehandlingofmicroorganisms.人员应接受安全处理微生物的培训。2.Environment环境2.1Premises房屋2.1.1Microbiologylaboratoriesandcertainsupportequipment(e.g.autoclavesandglassware)shouldbededicatedandseparatedfromotherareas,especiallyfromproductionareas.微生物实验室和支持性设备（如高压灭菌器和玻璃器皿）应是专用的，并独立于其他区域，特别是独立于生产区域。2.1.2Microbiologylaboratoriesshouldbedesignedtosuittheoperationstobecarriedoutinthem.Thereshouldbesufficientspaceforallactivitiestoavoidmixups,contaminationandcross-contamination.Thereshouldbeadequatesuitablespaceforsamples,referenceorganisms,media(ifnecessary,withcooling),testingandrecords.Duetothenatureofsomematerials(e.g.sterilemediaversusreferenceorganismsorincubatedcultures),separatestoragelocationsmaybenecessary.WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范7of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。微生物实验室的设计应与在其中所进行的操作相称。应有充足的所有活动的空间，以避免混淆、污染和交叉污染。应有样品、参考有机体、培养基（必要时进行冷却）、检验和记录的足够的合适空间。鉴于一些物料（如无菌培养基和参考有机体或培养菌株）的性质，单独的储存位置可能是必要的。2.1.3Laboratoriesshouldbeappropriatelydesignedandshouldtakeintoaccountthesuitabilityofconstructionmaterialstoenableappropriatecleaning,disinfectionandminimizetherisksofcontamination.实验室应有合适的设计，并应考虑到建筑材料的适宜性，能够进行合适的清洁、消毒，尽量降低污染的风险。2.1.4Thereshouldbeseparateairsupplytolaboratoriesandproductionareas.Separateair-handlingunitsandotherprovisions,includingtemperatureandhumiditycontrolswhererequired,shouldbeinplaceformicrobiologicallaboratories.Theairsuppliedtothelaboratoryshouldbeofappropriatequalityandshouldnotbeasourceofcontamination.实验室和生产区域应有独立的供风。应有微生物实验室的独立的空气处理机组和其他供应装备，包括所需的温湿度控制。供给给实验室的空气应有适宜的质量，不得成为污染源。2.1.5Accesstothemicrobiologicallaboratoryshouldberestrictedtoauthorizedpersonnel.Personnelshouldbemadeawareof:仅限获得授权的人员进入微生物实验室。人员应了解：—theappropriateentryandexitproceduresincludinggowning;—适当的进出规程，包括更衣；—theintendeduseofaparticulararea;特殊区域的预期用途；—therestrictionsimposedonworkingwithinsuchareas;—在这些区域内工作的限制条件；—thereasonsforimposingsuchrestrictions;and这些限制条件的原因；—theappropriatecontainmentlevels.适当的防范等级。2.1.6Laboratoryactivities,suchassamplepreparation,mediaandequipmentpreparationandenumerationofmicroorganisms,shouldbesegregatedbyspaceoratleastintime,soastominimizerisksofcross-contamination,false-positiveresultsandfalse-negativeresults.Wherenon-dedicatedareasareused,riskmanagementprinciplesshouldbeapplied.Sterilitytestingshouldalwaysbeperformedinadedicatedarea.实验室活动，例如样品制备、培养基和设备准备、微生物计数，应通过空间或至少通过时间进行隔离，以尽量降低交叉污染、假阳性结果和假阴性结果的风险。若使用非专用区域，应使用风险管理原则。在专用区域内应始终进行无菌试验。2.1.7Considerationshouldbegiventodesigningappropriateclassifiedareasfortheoperationstobeperformedwithinthemicrobiologylaboratory.Theclassificationshouldbebasedonthecriticalityoftheproductandtheoperationbeingcarriedoutinthearea.Sterilitytestingshouldbeperformedunderthesameclassasusedforsterile/asepticmanufacturingoperations.Appendix1showsrecommendationsforzoneclassifications.应为微生物实验室内所进行的操作考虑设计适当分类的区域。应根据产品和区域内所进行的操作的危急程度来划分类别。进行无菌试验的级别应与用于无菌洁净生产操作的级别相同。附件1为区域分类的建议。2.1.8Ingeneral,laboratoryequipmentshouldnotroutinelybemovedbetweenareasofdifferentcleanlinessclass,toavoidaccidentalcross-contamination.LaboratoryequipmentusedintheWHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范8of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。microbiologylaboratoryshouldnotbeusedoutsidethemicrobiologyarea,unlesstherearespecificprecautionsinplacetopreventcross-contamination.总之，通常实验室设备不得在不同洁净级别的区域之间移动，以避免意外的交叉污染。微生物实验室内使用的实验室设备不得在微生物区域外使用，除非有具体的防范措施防止交叉污染。2.2Environmentalmonitoringinthelaboratory实验室内的环境监控2.2.1Wherenecessaryandappropriate(e.g.inareasforsterilitytesting)anenvironmentalmonitoringprogrammeshouldbeinplacewhichcovers,forexample,useofactiveairmonitoring,airsettlingorcontactplates,temperatureandpressuredifferentials.Alertandactionlimitsshouldbedefined.Trendingofenvironmentalmonitoringresultsshouldbecarriedout.必要和适当时（如在无菌试验区域内），应有环境监控 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包括，例如，使用活性空气监控、空气沉降或接触平皿、温度和压差。应规定警报限和行动限。应进行环境监控结果的趋势分析。2.3Cleaning,disinfectionandhygiene清洁、消毒和卫生2.3.1Thereshouldbeadocumentedcleaninganddisinfectionprogramme.Resultsofenvironmentalmonitoringshouldbeconsideredwhererelevant.应有书面清洁和消毒计划。应在相关时考虑环境监控结果。2.3.2Thereshouldbeaprocedurefordealingwithspillages.应有处理泄漏的规程。2.3.3Adequatehand-washingandhand-disinfectionfacilitiesshouldbeavailable.应有足够的手部清洗和消毒的设施。2.4Sterilitytestfacilities无菌试验设施2.4.1Sterilitytestfacilitieshavespecificenvironmentalrequirementstoensuretheintegrityoftestscarriedout.WHOgoodmanufacturingpractices(GMP)forsterilepharmaceuticalproducts(8)requiresthatsterilitytestingshouldbecarriedoutandspecifiesrequirementsforsterilitytesting.Thissectiondetailstheclean-roomrequirementsforasterilitytestfacility.无菌试验设施有专门的环境要求，以保证所进行的试验的完整性。世界卫生组织无菌药品的生产质量管理规范(GMP)(8)要求应进行无菌试验，并规定了无菌试验的要求。这一章节详细规定了无菌试验设施的洁净室要求。2.4.2Sterilitytestingshouldbeperformedunderasepticconditions,whichshouldbeequivalenttoairqualitystandardsrequiredfortheasepticmanufactureofpharmaceuticalproducts.Thepremises,servicesandequipmentshouldbesubjecttotheappropriatequalificationprocess.应在无菌条件下进行无菌试验，该条件应与无菌生产制剂产品所要求的空气质量标准相等。应有适当的确认程序来管理厂房、服务和设备。2.4.3ThesterilitytestingshouldbecarriedoutwithinaGradeAunidirectionalairflowprotectedzoneorabiosafetycabinet(ifwarranted),whichshouldbelocatedwithinacleanroomwithaGradeBbackground.Alternatively,thetestingcanbecarriedoutwithinabarrierisolator.Careshouldbetakenwiththedesignofthefacilitylayoutandroomairflowpatterns,toensurethattheunidirectionalairflowpatternsarenotdisrupted.无菌试验应在位于B级背景下的洁净室内的A级单向气流保护的区域或生物安全柜（若获得批准）内进行。或者在屏障隔离器中进行该实验。应小心设计设施布局和房间气流模式，以保证不破坏单向气流WHO技术指南报告No.961,2011,annex2WHO药品微生物实验室管理规范9of27ThisDocumentcanonlybeusedinHECR&DCenter.Anyunauthorizeduseandcopyisforbidden.仅限东阳光研究院内部使用。未经授权，不得使用或拷贝。模式。2.4.4Theclean-roomclassificationandair-han