1Scope范围
Themanufactureofsterilemedicinalproductscoversawiderangeofproducttypes,(sterileactivesubstancethroughtofinisheddosageform),batchsizes(singleunittomultipleunits),processes(fromhighlyautomatedsystemstomanualprocesses),primarypackagingmaterialsandtechnologies(e.g.biotechnology,classicalsmallmoleculemanufacturingandclosedsystems).ThisAnnexprovidesgeneralguidancethatshouldbeusedforallsterilemedicinalproductsandsterileactivesubstances,viaadaption,usingtheprinciplesofQualityRiskManagement(QRM),toensurethatmicrobial,particulateandpyrogencontaminationassociatedwithmicrobesispreventedinthefinalproduct.
无菌药品的生产涵盖多种产品类型，（从无菌活性成分至最终的制剂成品），批量（从单个单位到多个单位），工艺（从高度自动化系统到人工操作），内包装材料及技术（例如，生物技术，小分子生产以及密闭系统）。本附录提供了适用于所有无菌药品和无菌活性成分的通用指南，使用质量风险管理（QRM）的原则适当调整，以确保能够防止最终产品中的微生物、颗粒和与微生物有关的热原污染。
TheintentoftheAnnexistoprovideguidanceforsterilemedicinalproducts.Howeversomeoftheprinciplesandguidance,suchascontaminationcontrolstrategy,roomqualification,classification,monitoringandgowning,maybeusedtosupportthemanufactureofotherproductsthatarenotintendedtobesterile(suchascertainliquids,creams,ointmentsandlowbioburdenbiologicalintermediates)butwherethecontrolofmicrobial,particulateandpyrogencontamination,toreduceitasfaraspossible,isconsideredimportant.
本附录的目的是为无菌药品提供指导。然而，有些原则和指导，例如污染控制策略，房间确认，洁净级别，监测和更衣，也可被用于支持其他不需要无菌，但其微生物、颗粒和热原污染的控制被认为很重要的产品的生产，以尽可能减少它们的污染（例如某些液体制剂，膏剂，软膏剂以及低微生物负荷的生物中间体）。
2Principle原则
Themanufactureofsterileproductsissubjecttospecialrequirementsinordertominimizerisksofmicrobiological,particulateandpyrogencontamination.Thefollowingkeyareasshouldbeconsidered:
无菌药品的生产需符合特殊的要求以降低微生物，颗粒及热原的污染风险。应考虑以下关键区域：
a.Facility,equipmentandprocessdesignmustbeoptimizedqualifiedandvalidatedaccordingtoAnnex11andAnnex15ofEUGMP.Theuseofappropriatecurrenttechnologiesshouldbeimplementedtoensureprotectionandcontroloftheproductfrompotentialextraneoussourcesofparticulateandmicrobialcontaminationsuchaspersonnel,materialsandthesurroundingenvironment.
设施，设备及工艺的设计须按照EUGMP附录11和附录15中的要求进行最有效的确认和验证。应适当应用最新的技术以确保保护和控制产品中潜在的外来颗粒和微生物的污染，例如人员，物料及周边环境。
b.Personnelmusthaveappropriateskills,trainingandattitudeswithaspecificfocusontheprinciplesinvolvedintheprotectionofsterileproductduringthemanufacturing,packaginganddistributionprocesses.
人员须具备在生产、包装及发运过程中与保护无菌药品的原则相适应的技能，培训及态度。
c.Processesandmonitoringsystemsforsterileproductmanufacturemustbedesigned,commissioned,qualifiedandmonitoredbypersonnelwithappropriateprocess,engineeringandmicrobiologicalknowledge.
无菌药品的生产和监控系统须由具有适当工艺、工程以及微生物知识的人员进行设计、使用、确认和监控。
Processes,equipment,facilitiesandmanufacturingactivitiesshouldbemanagedinaccordancewithQRMprinciplesthatprovideaproactivemeansofidentifying,scientificallyevaluatingandcontrollingpotentialriskstoquality.RiskassessmentsshouldbeusedtojustifyalternativeapproachestothosespecifiedinthisAnnexonlyifthesealternativeapproachesmeetorsurpasstheintentofthisAnnex.
工艺、设备、设施及生产活动应基于QRM的原则进行管理，该原则提出了一个前瞻性的方法用于识别、科学评估及控制潜在的质量风险。只有当这些可选择的方法满足或优于本附录的目的时，风险评估方可被用于判断本附录中所明确的那些可选择的方法。
QualityAssuranceisparticularlyimportant,andmanufactureofsterileproductsmuststrictlyfollowcarefullyestablishedandvalidatedmethodsofmanufactureandcontrol.Acontaminationcontrolstrategyshouldbeimplementedacrossthefacilityinordertoassesstheeffectivenessofallthecontrolandmonitoringmeasuresemployed.Thisassessmentshouldleadtocorrectiveandpreventativeactionsbeingtakenasnecessary.
质量保证尤其重要，无菌药品的生产必须严格遵循仔细建立的以及经过验证的生产和控制方法。一个污染控制策略应在整个设施内被实施以便评估所有采用的控制以及监测方法的有效性。该评估应能在必要时引入纠正和预防措施。
Thestrategyshouldconsiderallaspectsofcontaminationcontrolanditslifecyclewithongoingandperiodicreviewandupdateofthestrategyasappropriate.
该策略应考虑所有污染控制的因素，在其生命周期内应具有持续性和周期性的审核，并在必要时更新该策略。
Contaminationcontrolandstepstakentominimisetheriskofcontaminationfrommicrobialandparticulatesourcesareaseriesofsuccessivelylinkedeventsormeasures.Thesearetypicallyassessed,controlledandmonitoredindividuallybutthesemanysourcesshouldbeconsideredholistically.
所采取的用于降低来自微生物和微粒来源的污染风险的污染控制和步骤是一系列连续关联的事件或措施。这些事件或措施应被单独地进行评估、控制和监测，但有些来源可进行整体考虑。
Thedevelopmentofsuchstrategiesrequiresthoroughtechnicalandprocessknowledge.Potentialsourcesofcontaminationareattributabletomicrobiologicalandcellulardebris(e.g.pyrogens/endotoxins)aswellasparticulatematter(glassandothervisibleandsub-visibleparticles).
该策略的开发需要通过技术和工艺知识。潜在的污染源被归结于微生物及细胞残骸（例如热原/内毒素）以及微粒（玻璃及其他可见和不可见微粒）。
Elementstobeconsideredwithinsuchadocumentedcontaminationcontrolstrategyshouldinclude(butnotbelimitedto):
文件中需记录的污染控制策略应考虑的要素有（但不限于）：
a.Designofboththeplantandprocess.工厂及工艺的设计。
b.Equipmentandfacilities.设备和设施。
c.Personnel.人员。
d.Utilities.公用系统。
e.RawMaterialsControl–includingin-processcontrols.原料控制-包括过程控制。
f.Productcontainersandclosures.产品容器及密闭。
g.Vendorapproval–suchaskeycomponentsuppliers,sterilizationofcomponentsandsingleusesystems,andservices.供应商的批准-例如关键成分的供应商、组分的灭菌及一次性系统和服务。
h.Foroutsourcedservices,suchassterilization,sufficientevidenceshouldbeprovidedtothecontractgivertoensuretheprocessisoperatingcorrectly.对于外部提供的服务，例如灭菌，应将充分的证据提供给合同的委托方，以确保工艺被正确地操作。
i.Processriskassessment.工艺风险评估。
j.Processvalidation.工艺验证。
k.Preventativemaintenance–maintainingequipmentandpremises(plannedandunplannedmaintenance)toastandardthatwillnotaddsignificantriskofcontamination.预防性维护保养-设备及设施的维护保养（计划性及非计划性维护保养）应有一个标准，使之不会带来重大的污染风险。
l.Cleaninganddisinfection.清洁和消毒。
m.Monitoringsystems-includinganassessmentofthefeasibilityoftheintroductionofscientificallysound,modernmethodsthatoptimizethedetectionofenvironmentalcontamination.监测系统-包括对引入科学合理、现代方法的可行性评估，该方法用于优化环境污染的检测。
n.Prevention–Trending,investigations,correctiveandpreventiveactions(CAPA),rootcausedeterminationandtheneedformorerobustinvestigationaltools.预防-趋势化、调查、纠正和预防措施、根本原因的确定以及对更有利的调查工具的需要。
o.Continuousimprovementbasedoninformationfromtheabovesystems.基于来自上述系统信息的持续改进。
Themanufacturershouldtakeallstepsandprecautionsnecessarytoassurethesterilityoftheproductsmanufacturedwithinitsfacilities.Solerelianceforsterilityorotherqualityaspectsmustnotbeplacedonanyterminalprocessorfinishedproducttest.
生产者应采取所有必要的步骤及防范措施以确保在其设施内所生产产品的无菌性。无菌性或其他质量因素不能仅仅依靠任何一个最终工艺步骤或成品检测。
Note1:Thisguidancedoesnotlaydowndetailedmethodsfordeterminingthemicrobiologicalandparticulatecleanlinessofair,surfacesetc.ReferenceshouldbemadetootherdocumentssuchastheEN/ISOStandardsandPharmacopoeialmonographsformoredetailedguidance.
注释1：不建议用本指导方法来确定空气、表面等的微生物及微粒洁净度。更具体的指导应参照其他标准，例如EN/ISO标准以及药典中各论的相关要求。
Note2:Wherenationallegislationpermits,additionalguidanceregardingthepreparationofunlicensedsterilemedicinalproductsnormallyperformedbyhealthcareestablishmentsfordirectsupplytopatients,referencemaybemadetotheAnnex1:“Guidelinesonthestandardsrequiredforthesterilepreparationofmedicinalproducts”ofthePIC/Sguidetogoodpracticesforthepreparationofmedicinalproductsinhealthcareestablishments,PE010.
注释2：如国家立法许可，由医疗机构建立的用于直接供患者使用的非上市的无菌药品的制备其他指导标准可参见PIC/S《良好的医疗机构药品制备管理规范》，PE010附录1：《药品无菌制备标准指南》.
3PharmaceuticalQualitySystem(PQS)
制药质量体系（PQS）
3.1Themanufactureofsterilemedicinalproductsisacomplexactivitythatrequiresadditionalcontrolsandmeasurestoensurethequalityofproductsmanufactured.Accordingly,themanufacturer’sPharmaceuticalQualitySystem(PQS)shouldencompassandaddressthespecificrequirementsofsterileproductmanufactureandensurethatallactivitiesareeffectivelycontrolledsothatallfinalproductsarefreefrommicrobialandothercontamination.InadditiontothePQSrequirementsdetailedinchapter1oftheEUGMPs,thePQSforsterileproductmanufacturersshouldalsoensurethat:
无菌药品的生产是一个复杂的活动，该活动需要额外的控制和措施以确保所生产的产品质量。通常，生产者的制药质量体系（PQS）应包括或强调无菌药品生产的具体要求以确保所有的活动均得到了有效地控制，以便使所有的最终产品没有微生物或其他的污染。此外，在EUGMP第一章关于PQS的描述中，无菌产品生产者的PQS应能确保：
a.Thereisaneffectiveriskmanagementsystemintegratedintotheproductlifecycletominimisemicrobialcontaminationtoensurethesafety,qualityandefficacyofsterilemanufacturedproduct,includingassuranceofsterility.
应有一个有效的风险管理系统与产品的生命周期相结合以降低微生物污染，确保无菌生产的药品的安全、质量及效力，包括无菌保证。
b.Themanufacturerhassufficientknowledgeandexpertiseinrelationtotheproductsmanufacturedandthemanufacturingmethodsemployed.
生产者应具有足够的与产品生产及所开发的生产方法相关的知识和经验。
c.Rootcauseanalysisofprocedural,processorequipmentfailureiskeytoensurethattherisktoproductiscorrectlyunderstoodandsuitablecorrectiveandpreventativeactionsareimplemented.
程序上的、工艺或设备失败的根本原因的分析是保证正确地理解产品风险，实施恰当的纠正和预防措施的关键。
d.Riskassessmentisperformedtoidentify,assess,eliminate(whereapplicable)andcontrolcontaminationriskstopreventcontamination,tomonitoranddetectcontamination,andtoestablishprocessrequirementsandacceptancecriteriaforallelementsofasterilemanufacturingprocess.Theriskassessmentshouldbedocumentedandshouldincludetherationalefordecisionstakeninrelationtomitigatingrisks,discountingofpotentialrisksandresidualrisk.Theriskassessmentshouldbereviewedregularlyaspartofongoingqualitymanagement,duringchangecontrolandduringtheperiodicproductqualityreview.
实施风险评估是为了识别、评价、排除（如适用）及控制污染风险以防止污染，监测和检测污染，并为所有无菌生产工艺要素建立工艺要求和接受标准。风险评估应被记录并包括所采取的用于减轻风险、降低潜在风险和剩余风险的合理决定。风险评估应被作为持续质量管理的一部分在变更控制以及产品周期质量回顾时进行定期审核。
e.Processesassociatedwiththefinishingandtransportofsterileproductsshouldnotcompromisethefinishedsterileproductintermsofcontainerintegrityorposeariskofcontaminationandensurethatmedicinalproductsarestoredandmaintainedinaccordancewithregisteredstorageconditions.
与无菌产品的结束和运输相关的过程不应对无菌产品的容器密闭性造成危害或形成一个污染风险以确保药品按照其注册的储存条件被储存和维护。
f.Personsresponsiblethequalityreleaseofsterilemedicinesshouldhaveappropriateaccesstomanufacturingandqualityinformationandpossessadequateknowledgeandexperienceinthemanufactureofsteriledosageformsandtheircriticalqualityattributesinordertobeabletoascertainthatthemedicineshavebeenmanufacturedinaccordancewiththeregisteredspecificationandareoftherequiredsafety,qualityandefficacy.
负责无菌产品质量放行的人员应能获得足够的生产及质量信息，并具备足够的无菌剂型生产和关键质量属性的知识和经验以便能够确定药品是按照注册的质量标准被生产出来并符合所要求的安全、质量及效力。
3.2Investigationsshouldbeperformedintonon-conformities,suchassterilitytestfailuresorenvironmentalmonitoringexcursionsordeviationsfromestablishedprocedures,withaspecificfocusregardingthepotentialimpacttosterility,tonotonlythespecificbatchconcernedbutalsoanyotherpotentiallyimpactedbatch.Thereasonsforincludingorexcludingproductfromthescopeoftheinvestigationshouldbeclearlyrecordedandjustifiedwithintheinvestigation.
应对不符合项进行调查，例如无菌性检验失败或环境监控超标或与已建立的程序存在偏差。调查可通过对无菌性的潜在影响进行具体关注，不仅涉及到某一具体批次，还涉及到其他存在潜在影响的批次。对于在调查范围内涵盖或排除产品的原因，应在调查时被明确地记录并证明。
4Personnel人员
4.1Themanufacturershouldensurethattherearesufficientappropriatepersonnel,suitablyqualifiedandexperiencedinthemanufactureandtestingofsterilemedicinesandanyofthespecificmanufacturingtechnologiesusedinthesite’smanufacturingoperations,toensurecompliancewithGoodManufacturingPracticeapplicabletothemanufactureofsterilemedicinalproducts.
生产商应确保有足够的符合条件的人员，这些人员有对无菌药品生产和检测的资质和经验，以及在生产现场所使用的任何一种具体生产技术，以确保无菌药品的生产符合良好药品生产质量管理规范的要求。
4.2Onlytheminimumnumberofpersonnelrequiredshouldbepresentincleanrooms.ThemaximumnumberofoperatorsincriticalareasshouldbedeterminedbasedonQRMprinciples,documentedinthecontaminationcontrolstrategy,andvalidatedduringactivitiessuchasinitialqualificationandasepticprocesssimulations,soasnottocompromisesterilityassurance.Thisisparticularlyimportantduringasepticprocessing.Inspectionsandcontrolsshouldbeconductedoutsidethecleanareasasfaraspossible.
洁净室内人员数量应尽量少。关键区域内允许进入的操作人员的最大数量的确定应基于QRM原则，并记录在污染控制策略中，然后在生产活动时进行验证，例如首次确认和无菌工艺模拟，以确保不会对无菌保证带来危害。这对于无菌工艺过程尤其重要。检查和控制应尽可能的在洁净区域外进行。
4.3Allpersonnel(includingthoseperformingcleaningandmaintenance)employedinsuchareasshouldreceiveregulartraining,qualification(includingsamplingoftheoperatorsbioburden,usingmethodssuchascontactplates,atkeylocationse.g.handsarmsandchest)andassessmentindisciplinesrelevanttothecorrectmanufactureofsterileproducts.Thistrainingshouldincludereferencetohygiene,cleanroompractices,contaminationcontrol,aseptictechniques,andpotentialsafetyimplicationstothepatientofalossofproductsterilityandinthebasicelementsofmicrobiology.
工作在这一区域的所有人员（包括那些从事清洁和维护保养的人员）应经常接受培训，确认（包括操作人员微生物负荷的取样；使用方法，例如接触碟；关键位置，例如手部，手臂及胸部）以及与无菌药品正确生产相关的纪律的评估。该培训应包括关于卫生，洁净室实践，污染控制，无菌技术以及由于产品无菌性及微生物基本要素的缺失而对患者造成的的潜在安全影响。
4.4ThepersonnelworkinginagradeA/Bcleanroomshouldbetrainedforasepticgowningandasepticpractices.Compliancewithasepticgowningproceduresshouldbeassessedandconfirmedandthisshouldbeperiodicallyreassessedatleastannuallyandshouldinvolvebothvisualandmicrobiologicalassessment(usingadditionallocationssuchasarmsandchest).Onlytrainedpersonnelwhohavepassedthegowningassessmentandhaveparticipatedinasuccessfulasepticprocesssimulation(APS)test,duringwhichtheyperformedtheirnormalduties,shouldbeauthorizedtoenteranygradeA/Barea,inwhichasepticoperationswillbeconducted,orarebeingconducted,whilstunsupervised.ThemicrobialmonitoringofpersonnelinthegradeA/Bareashouldbeperformedtoassesstheirasepticbehaviour.Thismonitoringshouldtakeplaceimmediatelyaftercompletionofacriticalinterventionanduponeachexitfromthecleanroom.Itshouldbenotedthatthereshouldalsobeanongoingcontinuousmonitoringprogramforpersonnelincludingsomeconsiderationofperiodicmonitoringunderthesupervisionofthequalityunit.
在A/B级洁净室工作的人员应接受无菌更衣以及无菌实践的培训。应对无菌更衣程序的符合性进行评估和确认，并且应当至少每年进行周期性再评价，包括目测及微生物的评估（使用额外的位置，例如手臂及胸不）。只有经过培训并通过更衣的评估，并且成功地参与了一次按照其日常任务执行的无菌工艺模拟试验（APS）的人员方可被授权进入A/B级区域，该区域将要从事无菌操作或正在进行，即使没有监督。应通过对A/B级区域的人员的微生物监测来评估其无菌行为。该监测应在关键干扰结束后以及每次退出洁净室前立即进行。值得注意的是，应有一个对人员的持续的监测计划，包括考虑在质量部门监督下的一些周期性监测。
4.5Thereshouldbesystemsinplacefordisqualificationofpersonnelfromentryintocleanrooms,basedonaspectsincludingongoingassessmentand/ortheidentificationofanadversetrendfromthepersonnelmonitoringprogram.Oncedisqualified,retrainingandrequalificationisrequiredbeforepermittingtheoperatortohaveanyfurtherinvolvementinasepticpractices.ThisshouldincludeconsiderationofparticipationinasuccessfulAsepticProcessSimulation(APS).
现场应有取消人员进入洁净室资质的体系，该体系基于来自人员监测计划的负面趋势的持续评估和/或的识别。一旦取消资质，需要在允许该操作人员重新获得任何再次参与无菌实践之前被再次培训并重新获得资质。这应当包括其成功参与一次无菌工艺模拟（APS）的考虑。
4.6Manufacturersshouldestablishwrittenproceduresoutliningtheprocessbywhichoutsidestaffwhohavenotreceivedsuchtraining(e.g.buildingormaintenancecontractors)needtobebroughtintogradeA/Bareas.Accessbythesepersonsshouldonlybegiveninexceptionalcircumstances,evaluatedandrecordedinaccordancewiththePQS.
生产者应建立书面程序来规定没有接受过相应培训（例如建筑物或维护保养的合同商）的外部员工需要进入A/B级区域的流程。这些人员的进入只能被指定在特定的环境下，并根据PQS进行评估和记录。
4.7Highstandardsofpersonalhygieneandcleanlinessareessential.Personnelinvolvedinthemanufactureofsterilepreparationsshouldbeinstructedtoreportanyspecifichealthconditionsorailmentswhichmaycausethesheddingofabnormalnumbersortypesofcontaminantsandthereforeprecludecleanroomaccess;periodichealthchecksforsuchconditionsshouldbeperformed.Actionstobetakenwithregardtopersonnelwhocouldbeintroducinganunduemicrobiologicalhazardshouldbedescribedinproceduresdecidedbyadesignatedcompetentperson.
人员卫生和洁净度的高标准是非常重要的。参与无菌制备生产的人员应被指导报告任何可能引起非正常的污染数量或污染类型的具体健康状况或不适，并禁止进入洁净区；对该种状况的周期性体检应被执行。应在程序中描述由指定负责人所确定的对可能引入一个不合适的微生物危害的人员所采取的措施。
4.8Staffwhohavebeenengagedintheprocessingofhumanoranimaltissuematerialsorofculturesofmicro-organisms,otherthanthoseusedinthecurrentmanufacturingprocess,oranyactivitiesthatmayhaveanegativeimpacttoquality,e.g.microbialcontamination,shouldnotentersterileproductareasunlessrigorous,clearlydefinedandeffectiveentryprocedureshavebeenfollowed.
从事人体或动物的组织材料加工或微生物培养的员工，除用于当前生产工艺的，或任何可能对质量产生负面影响的活动，例如微生物污染，不应进入无菌产品区域，除非按照严格、清晰定义的和有效的进入程序执行。
4.9Wristwatches,make-upandjewelleryandotherpersonalitemssuchasmobilephonesshouldnotbeallowedincleanareas.
手表，化妆和首饰及其他个人物品，如手机，不得被带入洁净区。
4.10Changingandhandwashingshouldfollowawrittenproceduredesignedtominimizecontaminationofcleanareaclothingorcarry-throughofcontaminantstothecleanareas.Garmentsshouldbevisuallycheckedforcleanlinessandintegritypriortoentrytothecleanroom.Forsterilizedgarments,particularattentionshouldbetakentoensurethatgarmentsandeyecoveringshavebeensterilizedandthattheirpackagingisintegralbeforeuse.Re¬usablegarmentsshouldbereplacedbasedatasetfrequencydeterminedbyqualificationorifdamageisidentified.
更衣和洗手应按照书面程序执行，该程序的设计用于降低洁净区的更衣污染或带入洁净区的污染。进入洁净区前，应通过目测的方式检查洁净服的洁净度和完整性。对于无菌洁净服，应特别注意使用前的检查，以确保洁净服及放护目镜已经过灭菌，且包装是完整的。可重复使用的洁净服的更换应基于确认或可被识别的破损所确定的一组频率。
4.11Theclothinganditsqualityshouldbeappropriatefortheprocessandthegradeoftheworkingarea.Itshouldbeworninsuchawayastoprotecttheproductfromcontamination.
工服及其质量应适用于工艺及所处工作区域的级别。其穿戴方式应能保护产品不被污染。
4.12Thedescriptionofclothingrequiredforeachgradeisgivenbelow:
下面给出了每个洁净级别更衣要求的描述
a.GradeD:Hair,beardsandmoustachesshouldbecovered.Ageneralprotectivesuitandappropriatelydisinfectedshoesorovershoesshouldbeworn.Appropriatemeasuresshouldbetakentoavoidanycontaminationcomingfromoutsidethecleanarea.
应当将头发、胡须等相关部位遮盖。应当穿合适的工作服和鞋子或鞋套。应当采取适当措施，以避免带入洁净区外的污染物。
b.GradeC:Hair,beardsandmoustachesshouldbecovered.Asingleortwo-piecetrousersuitgatheredatthewristsandwithhighneckandappropriatelydisinfectedorsterilizedshoesorovershoesshouldbeworn.Theyshouldshedvirtuallynofibresorparticulatematter.
C级洁净区：应当将头发、胡须等相关部位遮盖，应当戴口罩。应当穿手腕处可收紧的连体服或衣裤分开的工作服，并穿适当的鞋子或鞋套。工作服应当不脱落纤维或微粒。
c.GradeA/B:Sterileheadgearshouldtotallyenclosehairandfacialhair;itshouldbetuckedintotheneckofthesterilesuit;asterilefacemaskandsterileeyecoveringsshouldbeworntocoverallfacialskinandpreventthesheddingofdropletsandparticles.Appropriatesterilized,non-powderedrubberorplasticglovesandsterilizedfootwearshouldbeworn.Trouser-legsshouldbetuckedinsidethefootwearandgarmentsleevesintothegloves.Theprotectiveclothingshouldshedvirtuallynofibresorparticulatematterandretainparticlesshedbythebody.Garmentsshouldbepackedandfoldedinsuchawayastoallowoperatorstochangeintothegarmentswithcontacttotheoutersurfacesofthegarmentreducedtoaminimum.
A/B级洁净区：应当用头罩将所有头发以及胡须等相关部位全部遮盖，头罩应当塞进衣领内，应当戴口罩以防散发飞沫，必要时戴防护目镜。应当戴经灭菌且无颗粒物（如滑石粉）散发的橡胶或塑料手套，穿经灭菌或消毒的脚套，裤腿应当塞进脚套内，袖口应当塞进手套内。工作服应为灭菌的连体工作服，不脱落纤维或微粒，并能滞留身体散发的微粒。工服的包装和折叠应便于操作人员在更换时尽可能地接触工服的外表面。
Note:Thisisminimumguidanceandhigherstandardsofclothingmayberequireddependentontheprocessesperformedinthespecificarea.
注意：这只是一个最低指导原则，更高标准的更衣要求可能会取决于所处的具体区域的具体步骤。
4.13OutdoorclothingshouldnotbebroughtintochangingroomsleadingtogradeBandCrooms.Itisrecommendedthatfacilitysuits,includingdedicatedsocksbewornbeforeentrytochangeroomsforgradeCandB.Whereclothingisreusedthisshouldbeconsideredaspartofthequalification.
个人外衣不得带入通向B级或C级洁净区的更衣室。建议在进入C级和B级区的更衣室前应穿戴好包括有专用的袜子在内的厂区工作服。应考虑将工作服的再次使用应作为确认的一部分。
4.14ForeveryworkerinagradeA/Barea,cleansterilizedprotectivegarments(includingeyecoveringsandmasks)ofanappropriatesizeshouldbeprovidedateachworksession.Glovesshouldberegularlydisinfectedduringoperations.Garmentsandglovesshouldbechangedatleastforeveryworkingsession.
每位员工每次进入A/B级洁净区，每班应当更换合适尺寸无菌防护服（包括放护目镜和口罩）。手套在操作过程中应经常被消毒。每班应至少更换一次工服及手套。但应当用监测结果证明这种方法的可行性。操作期间应当经常消毒手套，并在必要时更换口罩和手套。
4.15Cleanareaclothingshouldbecleaned,handledandworninsuchawaythatitdoesnotgatheradditionalcontaminantswhichcanlaterbeshed.Theseoperationsshouldfollowwrittenprocedures.Separatelaundryfacilitiesforsuchclothingaredesirable.Inappropriatetreatmentofclothingwilldamagefibresandmayincreasetheriskofsheddingofparticles.Afterwashingandbeforesterilization,garmentsshouldbecheckedforintegrity.
洁净区所用工作服的清洗，处理和穿戴方式应当能够保证其不携带有污染物，该污染物随后可能会脱落。操作应按照书面程序执行。洗衣间最好单独设置。对工服处理不当会损坏纤维物并可能增加颗粒脱落的风险。清洗后和灭菌前，应对工服的完整性进行检查。
4.16Activitiesincleanareas,especiallywhenasepticoperationsareinprogress,shouldbekepttoaminimumandmovementofpersonnelshouldbecontrolledandmethodicaltoavoidexcessivesheddingofparticlesandorganismsduetoover-vigorousactivity.Operatorsperformingasepticoperationsshouldadheretostrictaseptictechniqueatalltimes.Topreventchangesinaircurrentsthatintroducelowerqualityair,movementadjacenttothecriticalareashouldberestrictedandtheobstructionofthepathoftheunidirectionalairflowmustbeavoided.Theambienttemperatureandhumidityshouldbesettopreventsheddingduetooperatorsbecomingtoocold(leadingtoexcessivemovement)ortoohot.
在洁净区内的活动应尽量减少，尤其是当无菌操作正在进行时。人员的移动应当是受控的并有方法的，以避免由于过分的活动而导致的额外的微粒和微生物的脱落。操作人员无论在任何时候进行无菌操作时均应执行严格的无菌技术。为防止因气流的变化而导致的空气质量下降，应严格限制其流至与之相邻的关键区域，并防止单向流的路径被阻碍。应设置周围环境的温湿度以防止操作人员因过冷（导致过多的活动）或过热而带来的脱落。
5Premises
设施
5.1Themanufactureofsterileproductsshouldbecarriedoutincleanareas,entrytowhichshouldbethroughairlocksforpersonneland/orforequipmentandmaterials.Cleanareasshouldbemaintainedtoanappropriatecleanlinessstandardandsuppliedwithairwhichhaspassedthroughfiltersofanappropriateefficiency.
无菌产品的生产要在洁净区域内进行，进入这些区域内的人员和/或设备、物料，必须通过气闸室。洁净区必须保持一定的洁净级别，空气必须通过规定的过滤器。
5.2Thevariousoperationsofcomponentpreparation,productpreparationandfillingshouldbecarriedoutwithappropriatetechnicalandoperationalseparationmeasureswithinthecleanarea.
各种原料的准备、产品的准备和灌装，必须使用适当的技术和操作隔离的方式在洁净区进行。
5.3Forthemanufactureofsterilemedicinalproducts4gradesofcleanroomcanbe
distinguished.
对于无菌药品的生产，应确定以下4个级别的洁净室：
GradeA:Thelocalzoneforhighriskoperations,e.g.fillingzone,stopperbowls,openampoulesandvials,makingasepticconnections.Normally,suchconditionsareprovidedbyalocalisedairflowprotection,suchaslaminarairflowworkstationsorisolators.Unidirectionalairflowsystemsshouldprovideahomogeneousairspeedinarangeof0.36–0.54m/s(guidancevalue),thepointatwhichtheairspeedmeasurementistakenshouldbeclearlyjustifiedintheprotocol.Duringinitialqualificationandrequalificationairspeedsmaybemeasuredeitherclosetotheterminalairfilterfaceorattheworkingheight,Whereeverthemeasurementistakenitisimportanttonotethatthekeyobjectiveistoensurethatairvisualizationstudiesshouldcorrelatewiththeairspeedmeasurementtodemonstrateairmovementthatsupportsprotectionoftheproductandopencomponentswithunidirectionalairattheworkingheight,wherehighriskoperationsandproductandcomponentsareexposed.ThemaintenanceofunidirectionalairflowshouldbedemonstratedandvalidatedacrossthewholeofthegradeAarea.EntryintothegradeAareabyoperatorsshouldbeminimizedbyfacility,processandproceduraldesign.
A级：用于高风险的生产操作，如灌装区、压塞区、容器开口区、和进行无菌连接的地方。通常这种情况是带有局部气流保护的，例如层流工作站或隔离器。单向流系统应提供0.36-0.54m/s（指导值）的均匀气流速度，气流速度的测试点应被明确定义在方案中。在首次确认和再确认时，气流速度可以在靠近终端空气过滤器或工作面高度的位置测试，不管以何种方式测试，需要重点注意的是关键目的是确保气流流型测试需要与气流流速测试相关联，从而证实在高风险操作和产品、原料暴露区域，气流流动可以工作高度对产品和暴露的原料提供单向流的保护。应证实和验证整个A级区域单向流的保持。应通过设施、工艺和程序化设计最大程度减少操作人员进入A级区域。
GradeB:Forasepticpreparationandfilling,thisisthebackgroundenvironmentforthegradeAzone.Ingeneral,onlygradeCcleanroomsshouldinterfacewiththegradeBasepticprocessingarea.Lowergradescanbeconsideredwhereisolatortechnologyisused(refertoclause5.19-5.20).
B级：对于无菌制备和灌装，B级区域是A级区域的背景环境。通常情况下，只有C级洁净区才能与B级无菌生产区域对接。当使用隔离技术时，可以考虑低级别（见5.19-5.20）。
GradeCandD:Cleanareasforcarryingoutlesscriticalstagesinthemanufactureofsterileproducts.
C级和D级：执行无菌产品非关键生产步骤的洁净区。
5.4Incleanareas,allexposedsurfacesshouldbesmooth,imperviousandunbrokeninordertominimizethesheddingoraccumulationofparticlesormicro-organismsandtopermittherepeatedapplicationofcleaningagents,anddisinfectants,whereused.
在洁净区，所有暴露的表面应光滑、不透水的和不破裂，以减少粉尘和微生物的脱落和累积，允许重复使用清洁剂和消毒剂。
5.5Toreduceaccumulationofdustandtofacilitatecleaningthereshouldbenouncleanablerecessesandaminimumofprojectingledges,shelves,cupboardsandequipment.Doorsshouldbedesignedtoavoiduncleanablerecesses.
为减少粉尘的累积并且易于清洁，不能有清洁不到的角落，保持最少量的突出物、支架、柜子和设备。门的设计要避免难清洁角落。
5.6Materialsliabletogeneratefibresshouldnotbepermittedincleanareas
该区域不得使用易生产纤维的物料。
5.7Falseceilingsshouldbedesignedandsealedtopreventcontaminationfromthespaceabovethem.
吊顶应密封，防止来自夹层的污染。
5.8SinksanddrainsshouldbeprohibitedingradeA/Bareas.Inotherareasairbreaksshouldbefittedbetweenthemachineorsinkandthedrains.Floordrainsinlowergraderoomsshouldbefittedwithtrapsorwatersealstopreventbackflowandshouldberegularlycleanedanddisinfected.
A/B级区域不得设水池和地漏。其他区域的设备或水槽与排水系统间要设置空气断路。低洁净级别区域的房间的地漏要有水弯或水封防止倒流，并应定期清洁和消毒。
5.9Airlocksshouldbedesignedandusedtoprovidephysicalseparationandtominimizemicrobialandparticulatecontaminationofthedifferentareas,andshouldbepresentformaterialandpersonnelmovingfromdifferentgrades,typicallyairlocksusedforpersonnelmovementareseparatetothoseusedformaterialmovement.Theyshouldbeflushedeffectivelywithfilteredair.Thefinalstageoftheairlockshould,intheat-reststate,bethe
samegradeastheareaintowhichitleads.Theuseofseparatechangingroomsforenteringandleavingcleanareasisgenerallydesirable.
应设计和使用气闸以对不同区域提供物理隔离并减少微生物和颗粒污染。物料和人员在穿越不同级别应设置气闸，通常，用于人员穿越的气闸应独立于物料传递的。它们应经过过滤空气的有效冲洗。气闸室的最终状态应是，在静态条件下，与其进入区域的级别相同。通常进入和离开洁净室分别使用独立更衣室是令人满意。
a)Personnelairlocks.Acascadeconceptshouldbefollowedforpersonnel(e.g.fromgradeDtogradeCtogradeB).Ingeneralhandwashingfacilitiesshouldbeprovidedonlyinthefirststageofthechangingrooms.
人员气闸室，应遵循瀑布原理（例如从D级到C级到B级）。通常洗手设施只能在第一阶段更衣室使用。
b)Materialairlocks(usedformaterialsandequipment).
物料气闸（用于物料和设备）
i.Passthroughhatcheswithoutactivefilteredairsupplyshouldbeavoided.Ifnecessary,provisionsandproceduresshouldbeinplacetoavoidanyriskofcontamination(e.g.bytheincomingmaterialorbyenteringair).
应避免使用非空气过滤的传递窗。必要时，应有规定和规程以避免任何污染的风险（例如传入物料或进入空气的污染）
ii.ForairlocksleadingtogradeAandBareas,onlymaterialsandequipmentthathavebeenincludedaspartofthequalificationlistshouldbeallowedtobetransferredintothegradeA/Bareaviatheairlockorpassthrough;thecontinuityofgradeAshouldbemaintainedintheasepticcorewhenthematerialshavetobetransferredfromgradeBtogradeAareas,considerationshouldbegiventolistingtheseitemsonanauthorizedlist.Anyunapproveditemsthatrequiretransfershouldbeanexception.Appropriateriskevaluationandmitigationstrategiesshouldbeappliedandrecordedasperthemanufacturer’scontaminationcontrolstrategyandshouldincludeaspecificsanitisationandmonitoringregimeapprovedbyqualityassurance.
对于进入A级和B级的气闸室，只有已经列入作为确认清单部分的物料和设备才可以被允许通过气闸或传递窗传入A/B级区域；当物料从B级传入A级时，无菌核心区域A级应能够连续保持，应考虑罗列允许传入的清单。任何未被允许的物品在需要传递时，均被视为异常。应根据生产商的污染控制策略使用适当的风险评估和减轻的措施并进行记录，风险评估和措施应包括特殊的清洁消毒和监测机制，并经QA批准。
iii.Themovementofmaterialfromcleannotclassified(CNC)togradeCshouldbebasedonQRMprinciples,withcleaninganddisinfectioncommensuratewiththerisk.
物料从洁净未定级区域（CNC）到C级应基于质量风险管理原则，通过与风险相当的清洁和消毒。
5.10Bothairlockdoorsshouldnotbeopenedsimultaneously.Theopeningofmorethanonedooratatimeshouldbeprevented,forairlocksleadingtogradeAandBaninterlockingsystemshouldusuallybeused;forairlocksleadingtogradeCandDatleastavisualand/oraudiblewarningsystemshouldbeoperated.Whererequiredtomaintainzonesegregation,atimedelaybetweentheclosingandopeningofinterlockeddoorsshouldbeestablished.
气闸室的门不能同时打开。应避免在同一时间打开超过一道门，对于进入A级和B级的气闸室，通常应使用互锁系统；对于进入C级和D级的气闸室，应至少使用声和/或光报警系统。必要时，为了保持区域隔离，互锁的门关闭后开启应设置一段延迟时间。
5.11AHEPAorULPAfilteredairsupplyshouldmaintainapositivepressureandanairflowrelativetosurroundingareasofalowergradeunderalloperationalconditionsandshouldflushtheareaeffectively.Adjacentroomsofdifferentgradesshouldhaveapressuredifferentialof10-15Pascals(guidancevalues).Particularattentionshouldbepaidtotheprotectionofthezoneofgreatestrisk,thatis,theimmediateenvironmenttowhichaproductandcleanedcomponentswhichcontacttheproductareexposed.Therecommendationsregardingairsuppliesandpressuredifferentialsmayneedtobemodifiedwhereitbecomesnecessarytocontainsomematerials,e.g.pathogenic,highlytoxic,radioactiveorliveviralorbacterialmaterialsorproducts.Decontaminationoffacilities,e.g.thecleanroomsandHVAC,andthetreatmentofairleavingacleanareamaybenecessaryforsomeoperations.
在所有运行条件下，HEPA或ULPA过滤空气送风（A级送风）应对周围低级别区域保持正向压力和气流。并应能有效冲洗该区域。不同级别相邻房间压差范围10-15Pa（指导值）。应特别关注对高风险区域的保护，高风险区域即产品和原料直接暴露的环境。当该区域包含一些物料如致病性、剧毒性、放射性、病毒性或微生物物料或产品时，送风和压差的建议可能需要调整。对一些操作，可能需要设施，如洁净室和HVAC的文件记录和排风的处理。
5.12Itshouldbedemonstratedthatair-flowpatternsdonotpresentacontaminationrisk,e.g.careshouldbetakentoensurethatairflowsdonotdistributeparticlesfromaparticle-generatingperson,operationormachinetoazoneofhigherproductrisk.AirflowpatternsshouldbevisualisedingradeA/Bareastoevaluateifairflowisunidirectional.Whereunidirectionalairflowisnotdemonstrated,correctiveactions,suchasdesignimprovements,shouldbeimplemented.Intheotherareas,theneedtodemonstratetheairflowpatternsshouldbebasedonariskassessment.Airflowpatternstudiesshouldbeperformedunderdynamicconditions.Videorecordingsoftheairflowpatternsarerecommended.Theoutcomeoftheairvisualisationstudiesshouldbeconsideredwhenestablishingthefacility'senvironmentalmonitoringprogram.
应证实气流组织不存在污染的风险，例如，应小心确保气流不会将颗粒从产尘的人员、操作或设备上带入高风险区域。A/B级区域应拍摄气流流型以评价气流是否单向。当无法证实单向时，应采取纠正措施，例如设计方面的改善。在其他区域，应基于风险评估确定哪些区域需要进行气流流型测试。气流流型测试应在动态条件下进行。建议拍摄视频记录。建立厂房的环境监测程序应考虑气流流型测试的结果。
5.13Awarningsystemshouldbeprovidedtoindicatefailureintheairsupplyandreductionofpressuredifferentialsbelowsetlimits.Indicatorsofpressuredifferencesshouldbefittedbetweenareas,basedonQRMprinciples.Thesepressuredifferencesshouldberecordedregularlyorotherwisedocumented.
应有一个报警系统来识别空气供应故障和压差降低至设定限度以下的情况。应基于风险管理原则在不同区域之间安装压差计。这些压差要定期进行记录或用文件证明。
5.14Considerationshouldbegiventodesigningfacilitiesthatpermitobservationofactivitiesfromoutsidethecleanareas,e.g.throughtheprovisionofwindowsorremotecameraaccesswithacompleteviewoftheareaandprocessestoallowobservationandsupervisionwithoutentry.
应考虑设计设施以允许可以在洁净区外观察活动，例如通过视窗或监控录像提供区域和生产全视图以允许不需进入即可观察和监管。
BarrierTechnologies
隔离技术
5.15IsolatororRestrictedAccessBarrierSystem(RABS)technologies,andtheassociatedprocesses,shouldbedesignedsoastoprovidemaximumprotectionofthegradeAenvironment.ThetransferofmaterialsintoandoutoftheRABSorisolatorisoneofthegreatestpotentialsourcesofcontaminationandthereforetheentryofadditionalmaterialsfollowingsterilisationshouldbeminimized.Anyactivitiesthatpotentiallycompromisethe
sterilityassuranceofthecriticalzoneshouldbeassessedandcontrolsappliediftheycannotbeeliminated.
隔离器和RABS技术及其相关工艺应设计以对A级环境提供最大保护。物料传入和传出RABS或隔离器是最大的污染潜在来源，应减少多余物料的传递。任何可能对关键区域的无菌保证造成破坏的活动均应被评估，如无法消除，应采取控制。
5.16ThedesignoftheRABSorisolatorshalltakeintoaccountallcriticalfactorsassociatedwiththesetechnologies,includingthequalityoftheairinsideandthesurroundingarea,thematerialsandcomponenttransfer,thedecontamination,disinfectionorsterilizationprocessesandtheriskfactorsassociatedwiththemanufacturingoperationsandmaterials,andtheoperationsconductedwithinthecriticalzone.
RABS或隔离器的设计应考虑与包括内部和外部空气质量、物料和部件传递，净化，消毒或灭菌程序技术相关的关键因素，以及与生产操作和物料、关键区域内操作相关的风险因素。
5.17ThecriticalzoneoftheRABSorisolatorusedforasepticprocessesshouldmeetgradeAwithunidirectionalairflow.Undercertaincircumstancesturbulentairflowmaybejustifiedinaclosedisolatorwhenproventohavenonegativeimpactontheproduct.ThedesignoftheRABSandopenisolatorsshouldensureapositiveairflowfromthecriticalzonestothesurroundingareas;negativepressureisolatorsshouldonlybeusedwhencontainmentofthe
productisconsideredessential.
用于无菌生产的RABS或隔离器关键区域应符合A级，提供单向流。在特定条件下，当证实对产品没有不良影响时，密闭隔离器也可以是湍流。RABS的设计和开放式隔离器应确保从关键区域到周围区域维持正向气流；负压隔离器仅可以在当产品的限制被认为很必要时。
5.18ForRABS,thebackgroundenvironmentshouldmeetgradeB.ForopenRABS,orwheredoorsmaybeveryrarelyopenedduringprocessing,andstudiesshouldbeperformedtodemonstratetheabsenceofairingress.
对于RABS，背景环境应符合B级。对于开放式RABS或生产过程中存在开门情况的，应进行测试证明没有空气进入。
5.19Foropen,positivepressureisolatorsorclosedisolatorswithdecontaminationbyasporicidalagent,thesurroundingareashouldcorrespondtoaminimumofgradeD.Thedisinfectionregimeshouldbeincludedasakeyconsiderationwhenperformingtheriskassessmenttodesignthecontaminationcontrolstrategyforanisolator.
对于带杀孢子剂进化的开放式正压隔离器或密闭式隔离器，周围环境应至少达到D级。当进行风险评估确定污染控制策略时，应包括对消毒机制的考虑。
5.20Forisolators,therequiredbackgroundenvironmentcanvarydependingonthedesignoftheisolator,itsapplicationandthemethodsusedtoachievebio-decontamination.Thedecisionastothesupportingbackgroundenvironmentshouldbedocumentedinariskassessmentwhereadditionalrisksareidentified,suchasfornegativepressureisolators.Whereitemsareintroducedtotheisolatorafterdisinfectionthenahighergradeofbackgroundshouldbeconsidered
对于隔离器，所需的背景环境取决于该隔离器的设计，使用，以及用以实现生物净化的方法。当识别了额外的风险，对于背景环境的决定应记录于风险评估中，例如对于负压隔离器。当物品是在消毒后传入隔离器的，则需要考虑更高级别的背景。
5.21Glovesystems,aswellasotherpartsofanisolator,areconstructedofvariousmaterialsthatcanbepronetopunctureandleakage.Thematerialsusedshallbedemonstratedtohavegoodmechanicalandchemicalresistance.Integritytestingofthebarriersystemsandleaktestingoftheisolatorandtheglovesystemshouldbeperformedusingvisual,mechanicalandphysicalmethods.Theyshouldbeperformedatdefinedperiods,ataminimumofthebeginningandendofeachbatch,andfollowinganyinterventionthatmayaffecttheintegrityoftheunit.
手套系统，以及隔离器的其他部件，由不同材料组成，容易刺穿和泄漏。所用的材料应被证实拥有良好的机械和化学稳定性。应进行屏障系统的完整性测试以及隔离器和手套系统的泄漏测试，使用目测的、机械的和物理的方法。应定期进行，测试频率至少应是每批的开始和结束，以及在任何可能影响该系统完整性的干预之后。
5.22DecontaminationprocessesofanisolatororRABSshouldbevalidatedandcontrolledinaccordancewithdefinedparameters.EvidenceshouldalsobeavailabletodemonstratethattheagentdoesnotaffectanyprocessperformedintheisolatororRABS,suchashavinganadverseimpactonproductorsterilitytesting.
隔离器或RABS的净化程序应被验证并控制以符合规定参数。应有证据证实试剂不会影响在隔离器或RABS里面的任何操作，例如不会对产品或无菌检查造成不良影响。
Cleanroomandcleanairdevicequalification
洁净室和洁净空气设备确认
5.23Cleanroomsandcleanairdevices(cleanareas)forthemanufactureofproductsshouldbequalifiedaccordingtotherequiredcharacteristicsoftheenvironment.Eachmanufacturingoperationrequiresanappropriateenvironmentalcleanlinesslevelintheoperationalstateinordertominimizetherisksofparticulateormicrobialcontaminationoftheproductormaterialsbeinghandled.
无菌产品生产的洁净室和洁净空气设备（洁净区）应根据所需求的环境特性进行确认。每个生产操作都需要一个适当的操作状态下的环境洁净度以减少被处理产品或物料颗粒或微生物污染的风险。
Note:Classificationisamethodofassessingthelevelofaircleanlinessagainstaspecificationforacleanroomorcleanareadevicebymeasuringtheairborneparticleconcentration.Theclassificationispartofthequalificationofacleanarea.
注释：分级是一种评估空气洁净度水平的方法，通过监测空气悬浮粒子符合洁净室或洁净区设备的标准。分级是洁净区确认的一部分。
5.24CleanroomsandcleanairdevicesshouldbequalifiedinaccordancewithAnnex15ofEUGMP.ReferencefortheclassificationofthecleanroomsandcleanairdevicescanbefoundintheISO14644seriesofstandards.
洁净室和洁净空气设备应根据EUGMP附录15进行确认。洁净室和洁净空气设备的分级参考ISO14644系列标准。
5.25Forclassification,theairborneparticlesequaltoorgreaterthan0.5µmshouldbemeasured.Thismeasurementshouldbeperformedbothatrestandinoperation.Themaximumpermittedairborneparticleconcentrationforeachgradeisgivenintable1.
对于分级，应监测大于等于0.5µm空气悬浮粒子。静态和动态条件下都要进行测试。各级别的最大允许悬浮粒子浓度检表1：
Table1:Maximumpermittedairborneparticleconcentrationduringclassification
表1：分级时的最大允许悬浮粒子浓度
Maximumpermittednumberofparticlesequaltoorgreaterthan0.5µm大于等于0。5µm悬浮粒子最大允许数量
(a)ForgradeD,no“inoperation”limitsaredefined;thecompanyshouldestablishinoperationlimitsbasedonariskassessmentandonhistoricaldata,whereapplicable.
对于D级，没有定义动态的标准；必要时，企业应基于风险评估和历史数据建立动态标准。
5.26ForinitialclassificationtheminimumnumberofsamplinglocationscanbefoundinISO14644Part1.
对于首次确认，采样点的数量见ISP14644-1。
However,ahighernumberofsamplesandsamplevolumeistypicallyrequiredfortheasepticprocessingroomandtheimmediatelyadjacentenvironment(gradeA/B)toincludeconsiderationofallcriticalprocessinglocationssuchaspointoffillstopperbowls.Withtheexceptionoftheasepticprocessingroom,thesamplinglocationsshouldbedistributedevenlythroughouttheareaofthecleanroom.Forlaterstagesofqualificationandclassification,suchasperformancequalification,locationsshouldbebasedonadocumentedriskassessmentandknowledgeoftheprocessandoperationstobeperformedinthearea
但是，对于无菌生产房间和与直接相邻的环境（A/B级），则通常需要更多的采样点数量和采样体积，考虑所有关键生产位置，如分装加塞区。除了无菌生产房间之外，采样点位置应该均匀分布覆盖整个房间。在确认和分级的后续阶段，例如性能确认，应基于书面的风险评估和该房间所进行的工艺、操作的知识确定采样点位置。
a)The“inoperation”and“atrest”statesshouldbedefinedforeachcleanroomorsuiteofcleanrooms.
应定义每个或每套洁净室的动态和静态状态。
b)Thedefinitionof“atrest”istheroomcompletewithallHVACsystems,utilitiesfunctioningandwithmanufacturingequipmentinstalledasspecifiedbutwithoutpersonnelinthefacilityandthemanufacturingequipmentisstatic.
“静态”是指房间HVAC系统、公用设施具备其功能，生产设备已经按要求安装但是没有操作人员在场并且生产设备不运行。
c)The“inoperation”stateistheconditionwheretheinstallationisfunctioninginthedefinedoperatingmodewiththespecifiednumberofpersonnelworking.
“动态”是指在规定运行条件下和有规定数量的人员在场操作。
d)“Inoperation”classification,qualificationandrequalificationmaybeperformedduringnormaloperations,simulatedoperationsorduringasepticprocesssimulations(whereworstcasesimulationisrequired).
动态的分级、确认和再确认可以在正常操作、模拟操作条件下或在无菌工艺模拟期间进行（需要考察最差条件）。
e)TheparticlelimitsgiveninTable1aboveforthe“atrest”stateshouldbeachievedaftera“cleanup”periodoncompletionofoperations.The"cleanup"periodshouldbedeterminedduringtheinitialclassificationoftherooms.
在操作完成后通过一段自净时间应达到表1给出的静态条件粒子限度，房间的首次分级应确定自净时间。
f)Inordertomeet“inoperation”conditionstheseareasshouldbedesignedtoreachcertainspecifiedair-cleanlinesslevelsinthe“atrest”occupancystate.
为了符合动态条件，这些区域应被设计以达到规定的静态空气洁净水平。
5.27Themicrobialloadofthecleanroomsshouldbedeterminedaspartofthecleanroomqualification.Therecommendedmaximumlimitsformicrobialcontaminationduringqualificationforeachgradearegivenintable2.
应确定洁净室的微生物负荷作为洁净室确认的一部分，各级别推荐的微生物污染最大限度见表2.
Table2:Recommendedlimitsformicrobialcontaminationinoperation
表2：推荐的动态条件下微生物污染限度
Grade级别airsamplecfu/m3浮游菌settleplates(diameter90mm)cfu/4hours(a)沉降菌（直径90mm）contactplates(diameter55mm)cfu/plate接触皿（直径55mm）
(a)Individualsettleplatesmaybeexposedforlessthan4hours.Wheresettleplatesareexposedforlessthan4hoursthelimitsinthetableshouldstillbeused,norecalculationisnecessary.Settleplatesshouldbeexposedforthedurationofcriticaloperationsandchangedasrequiredafter4hours.
单个沉降碟可以放置少于4小时。这种情况下，仍然使用表中的限度，不需要换算。应在关键操作期间放置沉降碟，必要时，超过4小时需要更换。
(b)ItshouldbenotedthatforgradeAtheexpectedresultshouldbe0cfurecovered;anyrecoveryof1cfuorgreatershouldresultinaninvestigation.
需要注意的是，对于A级，期望的结果应是0cfu；任何大于或等于1cfu的结果均应调查。
Note:Forqualificationofpersonnel,thelimitsgivenforcontactplatesandgloveprintsintable6shouldbeapplied.
注释：对于人员的确认，应使用表6中给出的接触碟和衣服限度标准。
5.28Cleanroomqualification(includingclassification)shouldbeclearlydifferentiatedfromoperationalprocessenvironmentalmonitoring.
洁净室确认（包括分级）应与日常工艺环境监测区分开来。
5.29Cleanroomsshouldberequalifiedperiodicallyandafterchangestoequipment,facilityorprocessesbasedontheprinciplesofQRM.ForgradeAandBzones,themaximumtimeintervalforrequalificationis6months.ForgradesCandD,themaximumtimeintervalforrequalificationis12months.
洁净室应定期再确认，并在设备、设施、工艺变更后基于风险管理原则进行再确认。对于A级和B级，再确认的最大间隔是6个月，对于C、D级，再确认的最大间隔是12个月。
5.30Othercharacteristics,suchastemperatureandrelativehumidity,dependontheproductandnatureoftheoperationscarriedout.Theseparametersshouldnotinterferewiththedefinedcleanlinessstandard.
其他特性，例如温度和相对湿度，应基于产品和所进行的操作的特点。这些参数不应影响既定的洁净标准。
Disinfection
消毒
5.31Thedisinfectionofcleanareasisparticularlyimportant.Theyshouldbecleanedanddisinfectedthoroughlyinaccordancewithawrittenprogramme(fordisinfectiontobeeffective,cleaningtoremovesurfacecontaminationmustbeperformedfirst).,Morethanonetypeofdisinfectingagentshouldbeemployed,andshouldincludetheperiodicuseofasporicidalagent.Disinfectantsshouldbeshowntobeeffectiveforthedurationoftheirinuseshelf-lifetakingintoconsiderationappropriatecontacttimeandthemannerinandsurfacesonwhichtheyareutilized.Monitoringshouldbeundertakenregularlyinordertoshowtheeffectivenessofthedisinfectionprogramandtodetectthedevelopmentofresistantand/orsporeformingstrains.Cleaningprogramsshouldbeeffectiveintheremovalofdisinfectantresidues.
洁净室的消毒是非常重要的。应根据书面规程全面清洁和消毒（为了使消毒有效，应先进行清洁以清除表面的污染）。应使用至少一种消毒剂，包括定期使用杀孢子剂。应证实消毒剂在其使用期限内有效，考虑适当的接触时间、使用方式及其接触的表面。应定期进行监测以证实消毒程序的有效性并发现耐药菌株或芽孢生长。清洁程序应有效清除消毒残留。
5.32Disinfectantsanddetergentsshouldbemonitoredformicrobialcontamination;dilutionsshouldbekeptinpreviouslycleanedcontainersandshouldonlybestoredfordefinedperiods.DisinfectantsanddetergentsusedingradeAandBareasshouldbesterilepriortouse.
应监测消毒剂和清洗剂的微生物污染；稀释应在预先清洗的容器中进行并只能在规定期限内存放。用于A级和B级的消毒剂和清洗剂在使用前应是无菌的。
5.33Disinfectantsshouldbeshowntobeeffectivewhenusedonthespecificfacilities,equipmentandprocessesthattheyareusedin.
应证实消毒剂对其使用的具体设施、设备和工艺有效。
5.34FumigationorvapourdisinfectionofcleanareassuchasVapourHydrogenPeroxide(VHP)maybeusefulforreducingmicrobiologicalcontaminationininaccessibleplaces.
洁净区的熏蒸或汽化消毒，如汽化过氧化氢（VHP）可以有效降低难以达到的角落的微生物污染。
6Equipment
设备
6.1Awritten,detaileddescriptionoftheequipmentdesignshouldbeproduced(including
diagramsasappropriate)andkeptuptodate.Itshoulddescribetheproductandothercritical
gasandfluidpathwaysandcontrolsinplace.
应有详细描述设备设计（包括适当的图纸）的书面文件，并保持持续更新。应描述产品及关键气体、液体的路径，及其控制。
6.2Equipmentmonitoringrequirementsshouldbedeterminedduringqualification.Process
alarmeventsshouldbereviewedandapprovedandevaluatedfortrends.
应在设备确认期间确定设备监测要求。应对工艺报警事件进行审核批准并趋势分析。
6.3Asfaraspracticableequipment,fittingsandservicesshouldbedesignedandinstalledsothatoperations,maintenance,andrepairscanbecarriedoutoutsidethecleanarea,ifmaintenancehastobeperformedinthecleanareathenprecautionssuchasadditionaldisinfectionandadditionalenvironmentalmonitoringshouldbeconsidered.Ifsterilizationisrequired,itshouldbecarriedout,whereverpossible,aftercompletereassembly.
设备、配件及服务器的设计或安装应尽可能确保其操作、维护及维修可在洁净区外进行。如果不得不在洁净区内进行维护，则应该考虑相应的措施如额外的消毒和环境监测。如需灭菌，尽可能在完成重新组装后再进行。
6.4Whenequipmentmaintenancehasbeencarriedoutwithinthecleanarea,theareashouldbecleaned,disinfectedand/orsterilizedwhereappropriate,beforeprocessingrecommencesiftherequiredstandardsofcleanlinessand/orasepsishavenotbeenmaintainedduringthework.
若在洁净区内进行设备保养，并且保养过程中无法维持洁净区的洁净和/或无菌要求，则在重新生产前，应对该区域进行清洁消毒和/或灭菌（如适用）。
6.5Thecleaningprocessshouldbevalidatedsothatitcanbedemonstratedthatit:
清洁工艺应经过验证，应证明如下方面：
a)Canremoveanyresiduesthatwouldotherwisecreateabarrierbetweenthesterilizingagentandtheequipmentsurfaces.
能去除任何在灭菌试剂和设备表面间形成屏障的残留物。
b)Preventschemicalandparticulatecontaminationoftheproductduringtheprocessandpriortodisinfection.
防止产品在生产过程中和消毒前受化学和微粒污染。
6.6Allcriticalsurfacesthatcomeintodirectcontactwithsterilematerialsshouldbesterile.
所有与无菌物料直接接触的关键表面均应无菌。
6.7Allequipmentsuchassterilizers,airhandlingandfiltrationsystems,watertreatment,generation,storageanddistributionsystemsshouldbesubjecttoqualificion,monitoringandplannedmaintenance;theirreturntouseshouldbeapproved.
所有设备如灭菌柜、空调系统、水系统（处理、制备、存储及分配）都应进行确认，监控以及计划性维修。恢复使用需经过批准。
6.8AconveyorbeltshouldnotpassthroughapartitionbetweenagradeAorBareaandaprocessingareaofloweraircleanliness,unlessthebeltitselfiscontinuallysterilized(e.g.inasterilizingtunnel).
传送带不得从A/B级洁净区跨越到低级别生产区，除非传送带不断灭菌（例如在灭菌隧道内）。
6.9Particlecountersshouldbequalified(includingsamplingtubing).Portableparticlecounterswithashortlengthofsampletubingshouldbeusedforqualificationpurposes.Isokineticsampleheadsshallbeusedinunidirectionalairflowsystems.
粒子计数器（包括采样管）需经过确认。应当用较短采样管的手持式粒子计数器来进行确认。在单向气流系统内应使用等动力采样头。
6.10Whereunplannedmaintenanceofequipmentcriticaltothesterilityoftheproductistobecarriedout,anassessmentofthepotentialimpacttothesterilityoftheproductshouldbeperformedandrecorded.
对产品无菌性能有重大影响的设备进行非计划性维修时，应对给产品无菌性带来的潜在影响进行评估并记录。
7Utilities
公用系统
7.1Thenatureandamountofcontrolsassociatedwithutilitiesshouldbecommensuratewiththeriskassociatedwiththeutilitydeterminedviariskassessment.
应通过风险评估确定与公用系统风险相对应的控制措施的程度和数量。
7.2Ingeneralhigherriskutilitiesarethosethat:
一般而言，高风险的公用系统主要包括如下：
a)Directlycontactproducte.g.compressedgases.
与药品直接接触的，如压缩空气
b)Contactmaterialsthatultimatelywillbecomepartoftheproduct.
与物料接触并最终成为药品的一部分的
c)Controlcontaminationofsurfacesthatcontacttheproduct.
用以控制药品接触表面污染的
d)Orotherwisedirectlyimpacttheproduct.
或者直接影响药品的
7.3Utilitiesshouldbeinstalled,operatedandmaintainedinamannertoensuretheutilityfunctionsasexpected.
应该以适当方法对公用系统进行安装、运行及维护以保证其功能符合预期。
7.4Resultsforcriticalparametersofthehighriskutilityshouldbesubjecttoregulartrendnalysistoensurethatsystemcapabilitiesremainappropriate.
应对高风险公用系统关键参数结果进行定期的趋势分析，以保证系统性能保持良好。
7.5Currentdrawingsshouldbeavailablethatidentifycriticalsystemattributessuchas:pipelineflow,pipelineslopes,pipelinediameterandlength,tanks,valves,filters,drainsandsamplingpoints.
应具备现行版图纸并能识别关键系统属性，如管道流向、管道倾斜度、管道直接和长度、储罐、阀门、过滤器、排放口、取样点。
7.6Pipesandductsandotherutilitiesshouldbeinstalledsothattheydonotcreateecesses,unsealedopeningsandsurfaceswhicharedifficulttoclean.
所有管道或其他公用系统应当正确安装以防止凹槽、缺口或难于清洁的表面。
Watersystems
水系统
7.7Watertreatmentplantsanddistributionsystemsshouldbedesigned,constructedandmaintainedtominimizetheriskofmicrobialcontaminationandproliferationsoastoensureareliablesourceofwaterofanappropriatequality.WaterproducedshouldcomplywiththecurrentmonographoftherelevantPharmacopeia.
水处理车间及分配系统应经过设计、建造和维护以降低微生物污染及扩散的风险，从而保证一个合格水质的可靠来源。所制备的水应符合现行版药典标准。
7.8Waterforinjections(WFI)shouldbeproducedfrompurifiedwater,storedanddistributedinamannerwhichpreventsmicrobialgrowth,forexamplebyconstantcirculationatatemperatureabove70°C.WheretheWFIisproducedbymethodsotherthandistillationfurthertechniquespostReverseosmosis(RO)membraneshouldbeconsideredsuchasnanofiltration,andultra-filtration.
注射用水应从纯化水制备而来，并应以适当方法进行存储和分配以防止微生物生长，如70℃上不断循环。当采用非蒸馏法制备注射用水，则应在RO膜采取进一步控制，如纳米过滤，超滤。
7.9Watersystemsshouldbevalidatedtomaintaintheappropriatelevelsofphysical,hemicalandmicrobialcontrol,takingseasonalvariationintoaccount.
水系统应经过验证以证明其物理化学微生物控制处于适当的水平，并考虑季节变化。
7.10Waterflowshouldremainturbulentthroughthepipestopreventmicrobialadhesion.
管道内流水应保持湍流以防止细菌黏附。
7.11Thewatersystemshouldbeconfiguredtopreventtheproliferationofmicroorganisms,e.g.slopingofpipingtoprovidecompletedrainageandtheavoidanceofdeadlegs.Wherefiltersareincludedinthesystem,specialattentionshouldbetakenwithregardstothemonitoringandmaintenanceofthesefilters.
水系统应设计以防止微生物扩散，例如管道倾斜保证排水充分，防止死角。对于水系统的过滤器，应特别关注其监测及维护。
7.12WhereWFIstoragetanksareequippedwithhydrophobicbacteriaretentiveventfiltershefiltersshouldbesterilized,andtheintegrityofthefiltertestedbeforeandafteruse.
当注射用水储罐安装有疏水性细菌截留过滤器时，应对过滤器进行灭菌，并在使用前后进行完整性测试。
7.13Topreventtheformationofbiofilms,sterilizationordisinfectionorregenerationofwatersystemsshouldbecarriedoutaccordingtoapredeterminedscheduleandalsowhenmicrobialcountsexceedactionandalertlimits.Disinfectionofawatersystemwithchemicalsshouldbefollowedbyavalidatedrinsingprocedure.Watershouldbeanalyzedafterdisinfection/regeneration;resultsshouldbeapprovedbeforethestartofuseofthewatersystem.
为防止生物膜的形成，应根据既定计划或当微生物计数超过行动限和警告限时，对水系统进行灭菌或消毒或重新制备。对水系统的化学消毒应按照经过验证的冲洗程序。应对消毒/重新制备后的水进行检测分析，其结果经过批准后方可重新开始用水。
7.14Asuitablesamplingscheduleshouldbeinplacetoensurethatrepresentativewateramplesareobtainedforanalysisonaregularbasis.
应具备适当的取样计划以保证可定期取得代表性的水样用于检测。
7.15Regularongoingchemicalandmicrobialmonitoringofwatersystemsshouldbeperformedwithalertlimitsbasedonthequalificationthatwillidentifyanadversetrendintheperformanceofthesystems.Samplingshouldincludealloutletsanduserpointsataspecifiedinterval.Asamplefromtheworstcasesamplepoint,e.g.theendofthedistributionloopreturn,shouldbeincludedeachtimethewaterisusedformanufacturingandmanufacturingprocesses.Abreachofanalertlimitshouldtriggerreviewandfollow-up,whichmightincludeinvestigationandcorrectiveaction.Anybreachofanactionlimitshouldleadtoarootcauseinvestigationandriskassessment.
应对水系统进行化学微生物的持续监测，警戒限应确保能够识别系统性能的不良趋势。取样应在一定时间间隔内覆盖所有出水口及使用点。针对最差点的水样，例如分配管道末端回水点，每次生产均应进行取样。超出警戒限应进行审查和跟踪，其中可能包括调查和纠正措施。超出行动限应进行根本原因调查及风险评估。
7.16WFIsystemsshouldincludecontinuousmonitoringsystemssuchasTotalOrganicarbon(TOC)andconductivity.
注射用水系统应具备连续监测系统如TOC和电导率。
Steamusedforsterilization
灭菌用蒸汽
7.17Purifiedwater,withalowlevelofendotoxin,shouldbeusedastheminimumqualityeedwaterforthepuresteamgenerator.
纯蒸汽发生器源水至少应当是具有较低内毒素水平的纯化水。
7.18Steamusedforsterilizationprocessesshouldbeofsuitablequalityandshouldnotcontainadditivesatalevelwhichcouldcausecontaminationofproductorequipment.ThequalityofsteamusedforsterilizationofporousloadsandforSteam-In-Place(SIP)shouldbeassessedperiodicallyagainstvalidatedparameters.Theseparametersshouldincludeconsiderationofthefollowingexamples:non-condensablegases,drynessvalue(drynessfraction),superheatandsteamcondensatequality.
灭菌用蒸汽应具有合适的质量，不能含有在一定程度上可导致产品或设备污染的添加剂。对于多孔装载灭菌和SIP的蒸汽质量应对验证参数进行定期评估。这些参数包括考虑以下几种：不凝性气体、干度、过热和冷凝水质量。
Compressedgasesandvacuumsystems
压缩气体及真空系统
7.19Compressedgasesthatcomeindirectcontactwiththeproduct/containerprimarysurfacesshouldbeofappropriatechemical,particulateandmicrobiologicalpurity,freefromoilwiththecorrectdewpointspecificationand,whereapplicable,complywithappropriatepharmacopoeialmonographs.Compressedgasesmustbefilteredthroughasterilizingfilter(withanominalporesizeofamaximumof0.22µm)atthepointofuse.Whereusedforasepticmanufacturing,confirmationoftheintegrityofthefinalsterilizationgasfiltershouldbeconsideredaspartofthebatchreleaseprocess.
7.19与产品/容器内表面直接接触的压缩气体应有具备合适的化学，微粒和微生物纯度，在相应露点标准下应无油，在适当情况下，应符合相应的药典各论。压缩气体在使用时须通过除菌过滤器过滤（最大孔径为0.22µm）。如使用于无菌工艺中，终端除菌气体过滤器完整性的确认应作为批放行审核的一部分。
7.20Thereshouldbepreventionofbackflowwhenanyvacuumorpressuresystemisshutoff.
当真空或压力系统关闭时应有防止倒流的措施。
Coolingsystems
冷却系统
7.21Majoritemsofequipmentassociatedwithhydraulicandcoolingsystemsshould,wherepossible,belocatedoutsidethefillingroom.Wheretheyarelocatedinsidethefillingroomthereshouldbeappropriatecontrolstocontainanyspillageand/orcrosscontaminationassociatedwiththehydraulicsofcoolingsystemfluids.
与液压和冷却系统相关设备的主要部件应尽可能安装在分装间外部。当其安装在分装间内部时，应当有适当的措施以控制冷却系统冷凝液相关的泄漏和/或污染。
7.22Anyleaksfromthecoolingsystemmustbedetectable(i.e.anindicationsystemforleakage).Inaddition,theremustbeadequatecoolingflowwithinthesystem.
冷却系统的所有泄漏应当是可检测的（如有泄漏指示系统）。另外，系统内应当有足够的冷却流。
7.23Thecoolingcircuitshouldbesubjecttoleaktestingbothperiodicallyandfollowinganymaintenance.
冷却循环系统应定期进行泄漏检测，并跟踪维护。
7.24Thereshouldbeperiodiccleaning/disinfectionofboththevacuumsystemandcoolingsystems.
真空系统和冷却系统应进行定期清洁和消毒。
8ProductionandSpecificTechnologies
产品和特定技术
Terminallysterilizedproducts
最终灭菌产品
8.1PreparationofcomponentsandmostproductsshouldbedoneinatleastagradeDenvironmentinordertogivealowriskofmicrobial,pyrogenandparticulatecontamination,sothattheproductissuitableforfiltrationandsterilization.Wheretheproductisatahighorunusualriskofmicrobialcontamination,(forexample,becausetheproductactivelysupportsmicrobialgrowthand/ormustbeheldforalongperiodsbeforesterilisationand/orisnotprocessedmainlyinclosedvessels),thenpreparationshouldbecarriedoutinagradeCenvironment.
原料和大多数产品的准备在不低于D级的环境下进行，以尽可能降低微生物、热原和微粒污染的风险，使产品对适用于过滤和最终灭菌。产品本身具有高的或特殊的微生物染污风险的（例如产品容易长菌、配制后需要等待较长时间方可灭菌或不在密闭系统中配制），应在C级环境下进行制备。
8.2FillingofproductsforterminalsterilizationshouldbecarriedoutinatleastagradeCenvironment.
最终灭菌产品的灌装应该在至少C级环境下进行。
8.3Wheretheproductisatanunusualriskofcontaminationfromtheenvironmentbecause,forexample,thefillingoperationisslow,thecontainersarewideneckedorarenecessarilyexposedformorethanafewsecondsbeforeclosing,ortheproductisheldforextendedperiodspriortoterminalsterilization,thentheproductshouldbefilledinagradeAzonewithatleastagradeCbackground.Preparationandfillingofointments,creams,suspensionsandemulsionsshouldgenerallybecarriedoutinagradeCenvironmentbeforeterminalsterilization.
8.3当产品存在特殊的环境污染风险，如，灌装操作慢，广口容器或是容器需要暴露数秒方可进行密封，或是产品需要在最终灭菌前需要存放较长时间，则产品灌装至少需要C级背景下的A级环境进行。在最终灭菌前，软膏，霜剂，混悬液和乳剂的配制和灌装通常应在C级环境下进行。
8.4Processingofthebulksolutionshouldincludeafiltrationsteptoreducebioburdenlevelsandparticulatespriortofillingintothefinalproductcontainers.
灌装到最终产品容器之前，溶液的处理应包含过滤步骤以降低生物负载水平和微粒。
8.5Examplesofoperationstobecarriedoutinthevariousgradesaregivenintable3.
最终灭菌产品不同级别环境生产操作举例见表3。
Table3:Examplesofoperationsandgradestheyshouldbeperformedinforterminallysterilizedproducts
表3：最终灭菌产品生产操作及其对应洁净级别示例
AFillingofproducts,whenunusuallyatrisk.高污染风险产品的灌装
Asepticpreparation
无菌工艺
8.6Asepticprocessingisthehandlingofsterileproduct,containersand/ordevicesinacontrolledenvironment,inwhichtheairsupply,materialsandpersonnelareregulatedtopreventmicrobialcontamination.AdditionalrequirementsapplytoRestrictedAccessBarrierSystems(RABS)andisolators(referclauses5.15-5.22).
无菌处理是指无菌产品、容器和/或设备在受控环境中进行处理，该环境对送风、物料和人员进行管理以防止微生物污染。其它要求适用于RABS系统和无菌隔离系统（参照条款5.15-5.22）。
8.7Theasepticprocessshouldbeclearlydefined.Therisksassociatedwiththeasepticprocess,andanyassociatedrequirements,shouldbeidentified,assessedandappropriatelycontrolled.Thesite’scontaminationcontrolstrategyshouldclearlydefinetheacceptancecriteriaforthesecontrols,requirementsformonitoringandthereviewoftheireffectiveness.Methodsandprocedurestocontroltheserisksshouldbedescribedandimplemented.Residualrisksshouldbejustified.
无菌工艺应有明确定义。与无菌工艺相关的风险，以及其他相关要求，都应被确定、评估和适当地控制。工厂的污染控制策略应明确规定这些控制的可接受标准和监测要求，并回顾其有效性。应描述并执行控制这些风险的方法和程序。遗留风险应被论证。
8.8Precautionstominimisemicrobiological,pyrogenandparticulatecontaminationshouldbetaken,asperthesite’scontaminationcontrolstrategy,duringthepreparationoftheasepticenvironment,duringallprocessingstages,includingthestagesbeforeandafterfiltersterilization,anduntiltheproductissealedinitsfinalcontainer.Materialsliabletogeneratefibresshouldnotbepermittedincleanareas.
在无菌环境准备过程、生产操作过程包括无菌过滤前后，直到产品被密封入最终容器的整个过程中，应根据工厂污染控制策略采取预防措施最大程度降低微生物、热原和微粒的污染。易产生纤维的物料不得进入洁净区。
8.9Wherepossible,theuseofequipmentsuchasRABS,isolatorsorclosedsystems,shouldbeconsideredinordertoreducetheneedforinterventionsintothegradeAenvironmentandminimizetheriskofcontamination.Automationofprocessesshouldalsobeconsideredtoemovetheriskofcontaminationbyinterventions(e.g.dryheattunnel,automatedlyophilizerloading,SIP).
应尽可能考虑使用如RABS、隔离器或密闭系统等设备以减少对A级环境的干扰，将污染风险降到最低；也应考虑自动化工艺以排除干扰导致污染的风险（例如：灭菌燧道、自动装载冻干机、SIP）。
8.10Examplesofoperationstobecarriedoutinthevariousenvironmentalgradesaregiveninthetable4.
无菌工艺不同级别环境生产操作举例见表3。
Table4:Examplesofoperationsandwhichgradestheyshouldbeperformedin
表4：无菌工艺生产操作及其对应洁净级别示例
ACriticalprocessingzone.关键生产区域；Asepticassemblyoffillingequipment.灌装设备的无菌组装；Asepticconnections(shouldbesterilizedbysteam-in-placewheneverfeasible).无菌连接（应尽可能使用流通蒸汽灭菌）；Asepticcompoundingandmixing.无菌配制和混合；Replenishmentofsterileproduct,containersandclosures.生产过程中添加无菌产品、容器和密封部件Removalandcoolingofitemsfromheatsterilizers.热力灭菌器中物品的转移和冷却Stagingandconveyingofsterileprimarypackagingcomponents.无菌内包材的分装和转运；Asepticfilling,sealing,transferofopenorpartiallystopperedvials,includinginterventions.开口或半压塞瓶子的无菌灌装、密封、转移，包括干扰过程；Loadingandunloadingofalyophilizer冻干机的装载和卸载。
Note:IfIsolatorsareusedthenariskassessmentshoulddeterminethenecessarybackgroundenvironmentgrade;atleastaminimumofgradeDshouldbeused.Referclauses5.19-5.20.
备注：如果使用隔离器，应通过风险评估确定必要的背景环境等级；至少应为D级。参考5.19-5.20节。
8.11Wheretheproductisnotsubsequentlysterilefiltered,thepreparationofequipment,componentsandancillaryitemsandproductsshouldbedoneinagradeAenvironmentwithagradeBbackground.
如果产品不再进行除菌过滤，设备、部件和辅助用品的准备和产品的制备均应在B级背景下的A级环境中进行。
8.12Preparationandfillingofsterileproductssuchasointments,creams,suspensionsandemulsionsshouldbeperformedinagradeAenvironment,withagradeBbackground,whentheproductandcomponentsareexposedandtheproductisnotsubsequentlyfilteredorsterilized.
在产品和组分暴露并不再进行过滤或灭菌的情况下，无菌产品（如软膏，乳膏，混悬剂和乳剂）的制备和充填应在B级背景下的A级环境中进行。
8.13Unlesssubsequentlysterilizedbysteam-in-placeorconductedwithvalidatedintrinsicsterileconnectiondevices,asepticconnectionsshouldbeperformedinagradeAenvironmentwithagradeBbackground(orinanisolatorwithasuitablebackground),inawaythatminimizesthepotentialcontaminationfromtheimmediateenvironment,e.g.fromoperatorsorboundarieswithlowergrades.Asepticconnections,includingthoseperformedtoreplaceequipment,shouldbeappropriatelyassessedandtheireffectivenessverifiedasacceptablebyprocesssimulationtests.(Forrequirementsregardingintrinsicsterileconnectiondevices(referclause8.115).
除非后续采取流通蒸汽灭菌或在经验证的内部无菌的连接装置内进行，无菌连接应在B级背景下的A级环境中（或在适当背景下的隔离器中）进行，以将相邻环境污染的风险降到最低（例如来自操作人员或相邻低级别区域边界的污染）。应适当评估无菌连接（包括更换设备操作），并通过工艺模拟试验确认其有效性。（对于内部无菌连接设备的要求请参见条款8.115）。
8.14Thetransferofpartiallyclosedcontainerstoalyophilizer,shouldbedoneundergradeAconditions(e.g.HEPAfilteredpositivepressure)atalltimesand,wherepossible,withoutoperatorintervention.Portabletransfersystems(e.g.transfercarts,portableLaminarFlowWorkStations,etc.)shouldensurethattheintegrityoftransfersystemismaintainedandtheprocessoftransfershouldminimizetheriskofcontamination.
将半压塞容器转移至冻干机应始终在A级条件下（例如经HEPA过滤的正压环境），并且尽可能减少人员干预。移动式转运系统（如转运车、移动式层流工作台等）应确保转运系统的完整性，应减少转移过程污染的风险。
8.15Asepticmanipulations(includingnon-intrinsicasepticconnections)shouldbeminimizedusingengineeringsolutionssuchastheuseofpreassembledandsterilizedequipment.Wheneverfeasible,productcontactpipingandequipmentshouldbepre-assembled,thencleanedandsterilizedinplace.Thefinalsterilefiltrationshouldbecarried849outascloseaspossibletothefillingpointanddownstreamofasepticconnectionswhereverpossible
应从工程的角度考虑尽可能减少无菌操作（包括非内部无菌连接）的解决方案（例如使用预先组装和灭菌的设备）。如可行，直接接触产品的管道和设备应先进行组装，再进行清洗和灭菌。终端除菌过滤尽可能靠近灌装点并在无菌连接下游处。
8.16Thedurationforeachaspectoftheasepticmanufacturingprocessshouldbelimitedtoadefinedandvalidatedmaximum,including:
无菌生产过程的各个环节的持续时间应限定在规定最大限度内，并经过验证，包括：
a)Timebetweenequipment,component,andcontainercleaning,dryingandsterilization.设备、部件和容器的清洁、干燥和灭菌之间的时间
b)Holdingtimeforsterilizedequipment,components,andcontainerspriortoandduringfilling/assembly.在灌装/组装之前和期间，已灭菌设备、组件和容器的保存时间。
c)Thetimebetweenthestartofthepreparationofasolutionanditssterilizationorfiltrationthroughamicro-organism-retainingfilter.Thereshouldbeasetmaximumpermissibletimeforeachproductthattakesintoaccountitscompositionandtheprescribedmethodofstorage.溶液配制开始与其灭菌或除菌过滤之间的时间。每种产品的最长允许保存时间应根据其成分和规定的贮存方法确定。
c)Asepticassembly.装机时间。
d)Holdingsterileproductpriortofilling.无菌产品灌装前的保存时间。
e)Filling.灌装时长
f)Maximumexposuretimeofsterilizedcontainersandclosuresinthecriticalprocessingzone(includingfilling)priortoclosure.密封前已灭菌容器和封闭部件在关键操作区（包括灌装区）的最长暴露时间。
Finishingofsterileproducts
无菌产品最终处理
8.17PartiallystopperedvialsorprefilledsyringesshouldbemaintainedundergradeAconditions(e.g.useofisolatortechnology,gradeAwithBbackground,withphysicalsegregationfromoperators)orgradeALAFcarts(withsuitablegradeBbackgroundenvironmentandphysicalsegregationfromoperators)atalltimesuntilthestopperisfullyinserted.
半压塞的瓶子或预充式注射器在塞子完全插入之前应始终保持在A级条件下（如使用隔离技术、B级背景下的A级，及操作人员的物理隔离）或具有A级环境的LAF推车（在B级背景下，并将操作员物理隔离）。
8.18Containersshouldbeclosedbyappropriatelyvalidatedmethods.Containersclosedbyfusion,e.g.Form-Fill-SealSmallVolumeParenteral(SVP)&LargeVolumeParenteral(LVP)bags,glassorplasticampoules,shouldbesubjectto100%integritytesting.Samplesofothercontainersshouldbecheckedforintegrityutilisingvalidated887methodsandinaccordancewithQRM,thefrequencyoftestingshouldbebasedonthe888knowledgeandexperienceofthecontainerandclosuresystemsbeingused.Astatistically889validsamplingplanshouldbeutilized.Itshouldbenotedthatvisualinspectionaloneis890notconsideredasanacceptableintegritytestmethod.
应使用经验证的适当的方法密封容器。熔封容器，例如塑-灌-封小容量注射剂（SVP）和大容量注射剂（LVP）的袋、玻璃或塑料安瓿瓶，应进行100％的完整性测试。其他容器样品的完整性测试应选择经验证的方法并符合QRM要求，测试的频率应根据所使用的容器和封闭系统的知识和经验来确定。应该使用统计有效的抽样计划。应该注意仅仅使用目视检查进行完整性测试是不被接受的。
8.19Containerssealedundervacuumshouldbetestedformaintenanceofvacuumafteranappropriate,pre-determinedperiodandduringshelflife.
密封在真空条件下的容器应在既定时间后和货架期内测试其真空度的维持水平。
8.20Thecontainerclosureintegrityvalidationshouldtakeintoconsiderationanytransportationorshippingrequirements.
容器密封完整性验证应考虑运输的要求。
8.21Astheequipmentusedtocrimpvialcapscangeneratelargequantitiesofnon-viableparticulates,theequipmentshouldbelocatedataphysicallyseparatestationequippedwithadequateairextraction.
由于轧盖设备会产生大量的非活性粒子，此类设备应安装在物理隔离的位置并配置适当的抽风装置。
8.22Vialcappingcanbeundertakenasanasepticprocessusingsterilizedcapsorasacleanprocessoutsidetheasepticcore.Wherethislatterapproachisadopted,vialsshouldbeprotectedbygradeAconditionsuptothepointofleavingtheasepticprocessingarea,andthereafterstopperedvialsshouldbeprotectedwithagradeAairsupplyuntilthecaphasbeencrimped.WherecappingisamanualprocessitmustbeperformedingradeAconditionswithagradeBbackground.
瓶子的轧盖可以使用无菌铝盖进行无菌操作，也可以在无菌核心区域外进行洁净操作。在采用后一种方法时，瓶子在离开无菌操作区前应处于A级环境下。然后已加塞的瓶子在完成轧盖前应处于A级送风保护下。如果是手动轧盖，则必须在B级背景下的A级环境进行。
8.23InthecasewherecappingisconductedasacleanprocesswithgradeAairsupplyprotection,vialswithmissingordisplacedstoppersshouldberejectedpriortocapping.Appropriatelyvalidated,automatedmethodsforstopperheightdetectionshouldbeinplace.Microbialingressstudies(oralternativemethods)shouldbeutilizedtodeterminethe913acceptablestopperheightdisplacement.
在A级送风保护下进行轧盖操作的，在轧盖之前，应无塞或翘塞的样品剔除。应采用经过适当验证的胶塞高度自动检测方法。应使用微生物侵入试验（或替代方法）来确定可接受的塞子翘起高度。
8.24Wherehumaninterventionisrequiredatthecappingstation,appropriatetechnologyshouldbeusedtopreventdirectcontactwiththevialsandtominimizemicrobialcontamination.
轧盖过程需要人工干预时，应采取适当的措施防止直接接触玻璃瓶，最大限度减少微生物污染。
8.25RABSandisolatorsmaybebeneficialinassuringtherequiredconditionsandminimisingdirecthumaninterventionsintothecappingoperation.
RABS和隔离器有助于实现所要求的条件并减少人员直接干预轧盖操作。
8.26Allfilledcontainersofparenteralproductsshouldbeinspectedindividuallyforextraneouscontaminationorotherdefects.QRMprinciplesshouldbeusedfordeterminationofdefectclassificationandcriticality.Factorstoconsiderinclude,butarenotlimited,tothepotentialimpacttothepatientofthedefectandtherouteofadministration.Differentdefecttypesshouldbecategorizedandbatchperformanceanalyzed.Batcheswithunusuallevelsofdefects,whencomparedtoroutinedefectlevelsfortheprocess,shouldleadtoinvestigationandconsiderationofpartialorthewholerejectionofthebatchconcerned.Adefectlibraryshouldbegeneratedandmaintainedwhichcapturesallknowndefects.Thedefectlibrarycanbeusedasatrainingtoolforproductionandqualityassurancepersonnel.Criticaldefectsshouldnotbeidentifiedduringanysubsequentsamplingofacceptablecontainersasitindicatesafailureoftheoriginalinspectionprocess.
所有已灌装的注射用产品都应分别检查外部污染或其他缺陷。应根据QRM原则确定缺陷分类和严重性。考虑的因素包括但不限于缺陷对患者潜在影响以及给药途径。应对不同缺陷类型进行分类并对批产品性能进行分析。与日常工艺缺陷水平相比，出现异常的批次应进行调查，并考虑部分或全部报废。应建立和维护包括所有已知缺陷的缺陷库，该库可以作为生产和质量保证人员的培训工具。已检查合格的产品，任何取样过程中都不得检出关键缺陷，因为这表明最开始的检查过程是失败的。
8.27Wheninspectionisdonemanually,itshouldbedoneundersuitableandcontrolledconditionsofilluminationandbackground.Inspectionratesshouldbeappropriatelyvalidated.Operatorsperformingtheinspectionshouldundergorobustvisualinspectionqualification(whilstwearingcorrectivelenses,ifthesearenormallyworn)atleastannually.Thequalificationshouldbeundertakenusingappropriatesamplesetsandtakingintoconsiderationworstcasescenarios(e.g.inspectiontime,linespeed(wheretheproductistransferredtotheoperatorbyaconveyorsystem),componentsizeorfatigueattheendofshift)andshouldincludeconsiderationofeyesightchecks.Operatordistractionsshouldberemovedandfrequentbreaksofappropriatedurationfrominspectionshouldbetaken.
如果使用人工灯检，应在受控的合适的照度和背景条件下进行。检查速度应经过适当验证。灯检人员应至少每年接受一次灯检确认（戴眼镜的，应配备矫正镜片）。使用合适的一系列样品进行确认，并考虑最差情况（例如检查时间、传送速度（产品通过传送系统输送给操作人员）、部件尺寸或班次结束时的疲劳度）且应该包含视力检查。应避免检查人员分心，并应在合适的检查时间后给予休息。
8.28Whereautomatedmethodsofinspectionareused,theprocessshouldbevalidatedto945detectknowndefectswithsensitivityequaltoorbetterthanmanualinspectionmethodsand946theperformanceoftheequipmentcheckedpriortostartupandatregularintervals.
使用自动灯检方法前应验证该方法对已知缺项的灵敏度等于或优于人工灯检方法。启用前应检查设备的性能并定期进行。
8.29Resultsoftheinspectionshouldberecordedanddefecttypesandlevelstrended.Rejectratesforthevariousdefecttypesshouldalsobetrended.Investigationsshouldbeperformedasappropriatetoaddressadversetrendsordiscoveryofnewdefecttypes.Impacttoproductonthemarketshouldbeassessedaspartofthisinvestigation.
应记录灯检结果，缺陷类型和等级应进行趋势分析。各类缺陷的不合格品率也应进行趋势分析。当发现不良趋势或发现新的缺陷类型，应酌情进行调查。对已上市产品的影响也应作为调查的一部分进行评估。
Sterilization
消毒
8.30Wherepossible,finishedproductshouldbeterminallysterilizedusingavalidatedandcontrolledsterilizationprocessasthisprovidesagreaterassuranceofsterilitythanavalidatedandcontrolledsterilizingfiltrationprocessand/orasepticprocessing.Whereitisnotpossibleforaproducttoundergoasterilisation,considerationshouldbegiventousingterminalbioburdenreductionsteps,suchasheattreatments(pasteurization),combinedwithasepticprocessingtogiveimprovedsterilityassurance.
最终产品应尽可能采用经过验证和受控的灭菌工艺进行最终灭菌，它能提供比经过验证和受控的除菌过滤和/或无菌工艺更高的无菌保证。产品不能经受灭菌时，应考虑使用如热处理（巴氏消毒）等降低终端生物负载的步骤，并结合无菌工艺以提高无菌性保证。
8.31Theselection,designandlocationoftheequipmentandcycle/programmeusedforsterilizationshouldbedecidedusingQRMprinciples.Criticalparametersshouldbedefined,controlled,monitoredandrecorded.
应根据QRM原则确定设备和灭菌循环/程序的选择、设计和位置。应定义关键参数、并进行控制、监测和记录。
8.32Thereshouldbemechanismsinplacetodetectacyclethatdoesnotconformtothevalidatedparameters.Anyfailedoratypicalsterilizationcyclesmustbeformallyinvestigated.
应采取适当的方法监测不符合已验证参数的循环。任何失败或异常的灭菌周期均必须进行正式的调查。
8.33Allsterilizationprocessesshouldbevalidated.ParticularattentionshouldbegivenwhentheadoptedsterilizationmethodisnotdescribedinthecurrenteditionofthePharmacopoeia,orwhenitisusedforaproductwhichisnotasimpleaqueoussolution.Wherepossible,heatsterilizationisthemethodofchoice.Regardless,thesterilizationprocessmustbeinaccordancewiththeregisteredmarketingandmanufacturingspecifications.
所有灭菌工艺都应该被验证。尤其注意采用的灭菌方法没被当前版本的药典描述，或者被灭菌产品不是简单的水溶液的情况。如有可能，应尽量选择热力灭菌。灭菌工艺必须符合注册的上市和生产标准。
8.34Beforeanysterilizationprocessisadopted,itssuitabilityfortheproductandequipmentanditsefficacyinachievingthedesiredsterilizingconditionsinallpartsofeachtypeofloadtobeprocessedshouldbedemonstratedbyphysicalmeasurementsandbybiologicalindicatorswhereappropriate.
采用任何灭菌工艺前，应视情况采用物理测量手段和生物指示剂来证明灭菌工艺适用于被灭菌的产品和设备，并证明该灭菌工艺在每种装载模式下的所有部位均能有效的达到预期的灭菌效果。
8.35Thevalidityoftheprocessshouldbeverifiedatscheduledintervals,withaminimumofatleastannually.Revalidationofthesterilizationprocessshouldbeconductedwheneversignificantmodificationshavebeenmadetotheproduct,productpackaging,sterilizationloadconfiguration,sterilizingequipmentorsterilizationprocessparameters.
应按照预定的周期对工艺有效性进行确认，至少进行一次。当对产品、产品包装、灭菌装载方式、灭菌设备和灭菌工艺参数的重大变更，应对灭菌工艺进行再验证。
8.36Foreffectivesterilization,thewholeofthematerialandequipmentmustbesubjectedtotherequiredtreatmentandtheprocessshouldbedesignedtoensurethatthisisachieved.
为进行有效灭菌，所有物料和设备均必须进行必要的处理，且生产工艺的设计要能确保其是可以实现。
8.37Routineoperatingparametersshouldbeestablishedandadheredtoforallsterilizationprocesses,e.g.physicalparametersandloadingpatterns,etc.
所有灭菌工艺均应建立日常操作参数，并应遵循这些参数进行灭菌，如物理参数和装载方式等。
8.38Suitablebiologicalindicators(BIs)placedatappropriatelocationsmaybeconsideredasanadditionalmethodformonitoringthesterilization.BIsshouldbestoredandusedaccordingtothemanufacturer’sinstructions.Priortouseofanewbatch/lotofBIs,thequalityofthebatch/lotshouldbeverifiedbyconfirmingtheviablesporecountandidentity.WhereBIsareusedtovalidateand/ormonitorasterilizationprocess(e.g.forEthyleneOxide),positivecontrolsshouldbetestedforeachsterilizationcycle,withstrictprecautionsinplacetoavoidtransferringmicrobialcontaminationfromBIs,includingpreventingpositivecontrolBIsfromcontaminatingBIsexposedtothesterilizationcycle.Ifbiologicalindicatorsareused,strictprecautionsshouldbetakentoavoidtransferringmicrobialcontaminationtothemanufacturingorothertestingprocesses.
在适当位置放置合适的生物指示剂（BI）可作为监测灭菌过程的附加手段。BI应按生产商说明进行保存和使用。在启用一批新的BI前，应鉴别并确认其活芽孢数量以确认该批BI的质量。当用BI来验证和/或监测某种灭菌工艺（如，环氧乙烷）时，每个灭菌周期均进行阳性对照检查。应建立严格的预防措施以避免BI之间的微生物污染，包括防止阳性对照污染已暴露于灭菌程序的BI。如使用生物指示剂，应建立严格的预防措施来避免将微生物污染转移至生产或其他检查过程。
8.39Thereshouldbeaclearmeansofdifferentiatingproducts,equipmentandcomponents,whichhavenotbeensterilizedfromthosewhichhave.Eachbasket,trayorothercarrierofproducts,itemsofequipmentorcomponentsshouldbeclearlylabelledwiththematerialname,itsbatchnumberandanindicationofwhetherornotithasbeensterilized.Indicatorssuchasautoclavetape,orirradiationindicatorsmaybeused,whereappropriate,toindicatewhetherornotabatch(orsub-batch)haspassedthroughasterilizationprocess.However,theseindicatorsshowonlythatthesterilizationprocesshasoccurred;theydonotnecessarilyindicateproductsterilityorachievementoftherequiredsterilityassurancelevel.
应明确区分已灭菌和未灭菌产品、设备和部件的方法。每个筐、托盘或其他产品的载具、设备或组件应清楚标识有物料名称、批号并指示是否已灭菌。应视情况使用热压灭菌指示胶带或辐射指示卡来指示某批（或亚批）物料是否已进行了灭菌。不过，这些指示剂只能显示是否进行了灭菌操作，它们不一定能代表产品处于无菌状态或达到了要求的无菌保障水平。
8.40Sterilizationrecordsshouldbeavailableforeachsterilizationrun.Theyshouldbereviewedandapprovedaspartofthebatchreleaseprocedure.
每次灭菌操作都要有灭菌记录。这些记录的审核和批准应作为批放行的一部分。
8.41Wherepossible,materials,equipmentandcomponentsshouldbesterilizedbyvalidatedmethodsappropriatetothespecificmaterial.Suitableprotectionaftersterilizationshouldbeprovidedtopreventrecontamination.Ifitemssterilized“inhouse”arenotusedimmediatelyaftersterilization,theseshouldbestored,usingappropriatelysealedpackaging,inatleastagradeBenvironment,amaximumholdperiodshouldalsobeestablished.ComponentsthathavebeenpackagedwithmultiplesterilepackaginglayersneednotbestoredingradeB(wherejustified)iftheintegrityandconfiguration(e.g.multiplesterilecoveringsthatcanberemovedateachtransferfromlowertohighergrade)ofthesterilepackallowstheitemstobereadilydisinfectedduringtransferintothegradeAzone.Whereprotectionisachievedbycontainmentinsealedpackagingthisprocessshouldbeundertakenpriortosterilisation.
如可能，各物料、设备和组件的灭菌应采用适用于其特定材料并经验证的方法。灭菌后应采取适当的保护措施以防止再次污染。如果公司内部对灭菌后物品不是立即使用，应将其适当密封包装，并保存于至少B级环境，应建立最长保存时间。当某组件用多层无菌袋包装时，如果无菌袋包装的完整性和结构能够使其在传入A级区时易于消毒（如，多层无菌呼吸袋，且每转移到更高级别环境时可脱去一层），则其不需要保存在B级环境（需要论证）。当用密封袋包装来实现保护时，应在灭菌前就实施。
8.42Transferofmaterials,equipment,andcomponentsintoanasepticprocessingareashouldbeviaaunidirectionalprocess(e.g.throughadouble-doorautoclave,adepyrogenationoven,effectivetransferdisinfection,or,forgaseousorliquidmaterials,abacteria-retentivefilter).
物料、设备和组件转移入无菌生产区域，应通过单向的过程（如，采用双扉灭菌器，去热原烘箱，有效的转移消毒，或，对于气态或液态物料，采用细菌截留过滤器）。
8.43Wherematerials,equipment,componentsandancillaryitemsaresterilizedinsealedpackagingandthentransferredintothegradeA/Barea,thisshouldbedoneusingappropriate,validatedmethods(forexample,airlocksorpassthroughhatches)withaccompanyingdisinfectionoftheexteriorofthesealedpackaging.ThesemethodsshouldbedemonstratedtobeeffectiveinnotposinganunacceptableriskofcontaminationofthegradeA/Bareaand,likewise,thedisinfectionprocedureshouldbedemonstratedtobeeffectiveinreducinganycontaminationonthepackagingtoacceptablelevelsforentryoftheitemintothegradeA/Barea.Packagingmaybemulti-layeredtoallowremovalofasinglelayerateachinterfacetoahighergrade.
当将物料、设备、部件和辅助物品装于密封包装内灭菌后转移至A/B级区时，应采用适当的，经验证的方法（如气闸或传递窗）并对密封包装的外表面进行消毒。应证明这些方法能有效防止对A/B级区的环境造成的不可接受的污染。同样，应证明消毒方法能将包装上的任何污染有效降低至进入A/B级区的可接受水平。包装可为多层形式，以便每进入一个更高级别的洁净区都可脱去一层包装。
8.44Wherematerials,equipment,componentsandancillaryitemsaresterilizedinsealedpackagingorcontainers,theintegrityofthesterileprotectivebarriershouldbequalifiedforthemaximumholdtime,andtheprocessshouldincludeinspectionofeachsterileitempriortoitsusetoensurethatthesterileprotectivemeasureshaveremainedintegral.
当将物料、设备、组件和辅助物品置于密封包装或容器内灭菌时，应确认无菌保护屏障完整性的最长保持时间。每件无菌物品在使用前应进行检查，以确认无菌保护措施仍然保持完整。
8.45Formaterials,equipment,componentsandancillaryitemsthatarenecessaryforasepticprocessingbutcannotbesterilized,aneffectiveandvalidateddisinfectionandtransferprocessshouldbeinplace.Theseitemsoncedisinfectedshouldbeprotectedtopreventrecontamination.Theseitems,andothersrepresentingpotentialroutesofcontamination,shouldbeincludedintheenvironmentalmonitoringprogram.
对于必须用于无菌工艺但不能进行灭菌的物料、设备、组件和辅助物品，应建立有效并经验证的消毒和传递程序。这些物品一旦消毒完成，应保护以防止再污染。这些物品以及其他存在潜在污染途径的物品，应纳入环境监测程序中。
8.46Whenadepyrogenationprocessisusedforanycomponentsorproductcontactequipment,validationstudiesshouldbeperformedtodemonstratethattheprocesswillresultinaminimum3logreductioninendotoxin.Thereisnoadditionalrequirementtodemonstratesterilizationinthesecases.
当对任何组件或产品接触设备进行除热原处理时，应进行验证研究证明该工艺至少能降低3个对数值的内毒素。在此情况下，无需额外证明灭菌效果。
Sterilizationbyheat
热力灭菌
8.47Moistheatsterilizationutilisescleansteam,typicallyatlowertemperaturesandshorterdurationthandryheatprocesses,inordertosterilizeaproductorarticle.Moistheatsterilizationisprimarilyeffectedbylatentheatofcondensationandthequalityofsteamisthereforeimportanttoprovideconsistentresults.Thereducedlevelofmoistureindryheatsterilizationprocessreducesheatpenetrationwhichisprimarilyeffectedbyconduction.Dryheatprocessesmaybeutilizedtosterilizeorcontrolbioburdenofthermallystablematerialsandarticles.Dryheatsterilizationisofparticularuseintheremovalofthermallyrobustcontaminantssuchaspyrogensandisoftenutilizedinthepreparationofasepticfillingcomponents.Moistheatsterilizationprocessesmaybeutilizedtosterilizeorcontrolbioburden(fornon-sterileapplications)ofthermallystablematerials,articlesorproductsandisthepreferredmethodofsterilization,wherepossible.
湿热灭菌采用纯蒸汽对产品或物品进行灭菌，与干热灭菌工艺相比，其灭菌温度更低
且灭菌时间更短。湿热灭菌主要是通过冷凝释放潜热实现灭菌，因此蒸汽质量对于获得一致的灭菌结果而言是非常重要的。干热灭菌工艺因湿度较低导致热穿透性低，因此热穿透主要是通过热传导来实现的。干热灭菌可用于热稳定物料和器具的灭菌或生物负载控制。干热灭菌尤其适用于去除耐热污染物如热原，常用于无菌分装部件的准备。湿热灭菌可用于热稳定材料、器具和产品的灭菌或生物负载控制（非无菌用途），是首选的灭菌方法。
8.48Inthosecaseswhereparametricreleasehasbeenauthorized,arobustsystemshouldbeappliedtotheproductlifecyclevalidationandtheroutinemonitoringofthemanufacturingprocess.Thissystemshouldbeperiodicallyreviewed.
在允许进行参数放行的情况下，应采用稳健的系统来进行产品生命周期验证以及生产工艺的日常监控。该系统应定期审核。
8.49Eachheatsterilizationcycleshouldberecordedonatime/temperaturechartwithasufficientlylargescaleorbyotherappropriateequipmentwithsuitableaccuracyandprecision.Monitoringandrecordingsystemsshouldbeindependentofthecontrollingsystem.
每个热力灭菌循环都应记录在一个具有足够大比例的时间/温度图表上或其他适当的有合适的准确度和精度的设备上。监测和记录系统应独立于控制系统。
8.50Thepositionofthetemperatureprobesusedforcontrollingand/orrecordingshouldhavebeendeterminedduringthevalidation(whichshouldincludeheatdistributionandpenetrationstudies),and,whereapplicable,alsocheckedagainstasecondindependenttemperatureprobelocatedatthesameposition.
用于控制和/或记录的温度探头的位置应在验证过程中确定(验证应该包括热分布和热穿透试验)，如适用，应在同一位置用第二个独立的温度探头进行核对。
8.51Chemicalorbiologicalindicatorsmayalsobeused,butshouldnottaketheplaceofphysicalmeasurements.
可以使用化学或生物指示剂，但不的代替物理测试。
8.52Sufficienttimemustbeallowedforthewholeoftheloadtoreachtherequiredtemperaturebeforemeasurementofthesterilizingtime-periodiscommenced.Thistimemustbedeterminedforeachtypeofloadtobeprocessed.
在监测灭菌周期时长前，必须允许足够的升温时间使得整个装载达到所要求的温度。应确定每种装载方式的升温时间。
8.53Afterthehightemperaturephaseofaheatsterilizationcycle,precautionsshouldbetakenagainstcontaminationofasterilizedloadduringcooling.Anycoolingfluidorgasincontactwiththeproductshouldbesterilizedunlessitcanbeshownthatanyleakingcontainerwouldnotbeapprovedforuse.
在热力灭菌程序的高温阶段结束之后，应采取预防措施防止灭菌后装载物在冷却过程中被污染。任何与产品接触的冷却液或气体必须灭菌，除非能证明不会使用存在任何泄漏容器。
Moistheatsterilization
湿热灭菌
8.54Time,temperatureandpressureshouldbeusedtomonitortheprocess.Eachitemsterilizedshouldbeinspectedfordamage,sealandpackagingmaterialintegrityandmoistureonremovalfromtheautoclave.Sealandpackagingintegrityshouldalsobeinspectedimmediatelypriortouse.Anyitemsfoundnottobefitforpurposeshouldberemovedfromthemanufacturingareaandaninvestigationperformed.
应监测灭菌过程的时间、温度和压力。每个灭菌后的物品均需检查其破损、密封和包装物料完整性以及水分。在临使用前也需检查密封和包装物料完整性。发现任何不合预期的物品都应该将其移出生产区，并进行调查。
8.55Systemandcyclefaultsshouldberegisteredandrecordedbythecontrolandmonitoringsystemandappropriateactionstakenpriortoreleaseoftheprocess.
应使用控制和监测系统来登记并记录系统和运行故障。并在工艺放行前采取适当措施。
8.56Forsterilizersfittedwithadrainatthebottomofthechamber,itmayalsobenecessarytorecordthetemperatureatthispositionthroughoutthesterilizationperiod.ForSteam-In-Place(SIP)systems,itmayalsobenecessarytorecordthetemperatureatcondensatedrainlocationsthroughoutthesterilizationperiod.
对于在腔室底部安装有排水口的灭菌柜，需在整个灭菌期间记录该点的温度。对于在线灭菌系统，也需要整个灭菌期间记录冷凝水排水点的温度。
8.57Validationshouldincludeaconsiderationofequilibrationtime,exposuretime,correlationofpressureandtemperatureandmaximumtemperaturerangeduringexposureforporouscyclesandtemperature,timeandFoforfluidcycles.Thesecriticalparametersshouldbesubjecttodefinedlimits(includingappropriatetolerances)andbeconfirmedaspartofsterilizationvalidationandroutinecycleacceptancecriteria.Revalidationshouldbeperformedannually.
验证时，针对多孔装载需考虑平衡时间、曝热时间、压力与温度的关系、曝热期间的最大温度范围，针对液体装载需考虑温度、时间和F0值。应确定这些关键参数的限度（包括适当的容差），并作为验证及日常操作的可接受标准的一部分。应每年进行再验证。
8.58Thereshouldbefrequentleaktestsonthesystemtobesterilizedwhenavacuumphaseispartofthecycleorthesystemisreturned,post-sterilization,toapressureequivalenttoorlowerthantheenvironmentsurroundingthesterilizedsystem.ThefrequencyoftestingshouldbebasedontheprinciplesofQRM.
当灭菌周期的某个部分为真空阶段，或者系统在灭菌后恢复到或者低于周围环境压力时，应该经常对其进行泄漏测试。测试频率应基于风险管理原则。
8.59Whenthesterilizationprocessincludesairpurging(e.g.porousautoclaveloads,lyophilizerchambers)thereshouldbeadequateassuranceofairremovalpriortoandduringsterilization.Loadstobesterilizedshouldbedesignedtosupporteffectiveairremovalandbefreedrainingtopreventthebuild-upofcondensate.
当灭菌过程包含空气置换时（如多孔装载灭菌柜、冻干腔室），需要充分保证灭菌前及灭菌期间的排气。灭菌装载的设置应能确保有效排气，并利于排水以防止凝结水积聚。
8.60Theitemstobesterilized,otherthanproductsinsealedcontainers,shouldbedry,wrappedinamaterialwhichallowsremovalofairandpenetrationofsteambutwhichpreventsrecontaminationaftersterilization.Allloaditemsshouldbedryuponremovalfromthesterilizer.Loaddrynessshouldbeconfirmedasapartofsterilizationprocessacceptance.
除装于密封容器内的产品以外，其他待灭菌物品应干燥，并包裹于一种可去除空气和可穿透蒸汽的材料中以防止灭菌后再污染。所有装载物从灭菌柜移出时均应是干燥的。装载物干度应作为灭菌程序标准的一部分来确认。
8.61Distortionanddamageofflexiblecontainers,suchascontainersproducedbyBlow-Fill-SealandForm-Fill-Sealtechnologythatareterminallysterilized,shouldbepreventedbysettingcorrectcounterpressureandloadingpatterns.
应通过设定正确的内压和装载方式来防止对弹性容器（如通过吹-灌-封或成型-灌-封技术生产并最终灭菌的容器）的变形和破损。
8.62Careshouldbetakentoensurethatmaterialsorequipmentarenotcontaminatedafterthesterilizationexposurephaseofthecycleduetotheintroductionofnon-sterileairintothechamberduringsubsequentphases;typicallyonlysterilefilteredairwouldbeintroducedintothechamberduringthesephases.
应小心保证防止物料或设备在灭菌后的暴露阶段由于后续程序非无菌空气进入腔室所造成的污染，通常在这些阶段应当只有无菌过滤的空气才能进入腔室。
WhereSterilizationinplace(SIP)systemsareused,(forexample,forfixedpipework,vesselsandlyophilizerchambers),thesystemshouldbeappropriatelydesignedandvalidatedtoassureallpartsofthesystemaresubjectedtotherequiredtreatment.Thesystemshouldbemonitoredfortemperature,pressureandtimeatappropriatecriticallocationsduringroutineuse,thisistoensureallareasareeffectivelyandreproduciblysterilized;thesecriticallocationsshouldbedemonstratedasbeingrepresentative,andcorrelatedwith,theslowesttoheatlocationsduringinitialandroutinevalidation.OnceasystemhasbeensterilizedbySIPitshouldremainintegralpriortouse,themaximumdurationoftheholdtimeshouldbequalified.
8.63当使用在线灭菌系统时，（如固定的管道、容器和冻干室，）该系统应恰当设计并验证以保证系统的所有部件受到必要处理。在日常使用中该对系统的恰当的关键位置监测温度、压力及时间，以保证灭菌的有效性和可重复性。这些关键位置应该被证明是具有代表性的。并且与首次及常规验证过程中升温最慢的位置相关。一旦系统已经通过SIP进行了灭菌，应该在使用之前保持系统的完整，最大保持时间应通过确认。
Dryheatsterilization
干热灭菌
8.64Thecombinationoftimeandtemperaturetowhichproduct,componentsandequipmentareexposedshouldproduceanadequateandreproducibleleveloflethalityand/orpyrogen(endotoxin)inactivation/removalwhenoperatedroutinelywithintheestablishedtolerances.
在既定允许范围内进行日常操作时，产品、部件和设备暴露的时间和温度的组合应能产生充分且可重复的杀灭率和/或去热原(内毒素)水平。
8.65Dryheatsterilizationordepyrogenationtunnelsaretypicallyemployedtopreparecomponentsforasepticfillingoperationsbutmaybeusedforotherprocesses.Tunnelsshouldbeconfiguredtoensurethatairflowpatternsprotecttheintegrityandperformanceofthesterilizingzone,bymaintainingastablepressuredifferentialandairflowpatternthroughthetunnelfromthehighergradeareatothelowergradearea.AllairsuppliedtothetunnelshouldpassthroughaHEPAfilter;periodictestsshouldbeperformedtodemonstratefilterintegrity.Anytunnelpartsthatcomeintocontactwithsterilizedcomponentsshouldbeappropriatelysterilizedordisinfected.Criticalprocessparametersthatshouldbeconsideredduringvalidationand/orroutineprocessingshouldinclude,butmaynotbelimitedto:
干热灭菌或除热原隧道通常用于准备无菌灌装操作所需的部件，但也可用于其他工艺。应确保隧道的气流组织以保护灭菌区域的完整性和性能，通过维持隧道内高级别至低级别区域的稳定压差及气流流型来实现。所有提进入隧道的空气均应通过HEPA过滤器;应该定期进行测试来证明过滤器的完整性。任何与无菌后组件接触的隧道部件都应该经过适当灭菌或消毒。验证和/或日常操作过程中需考虑的关键参数包括但不限于：
a)Beltspeedordwelltimewithinsterilisingzone.网带速度或灭菌区停留时间
b)Temperature–Minimumandmaximumtemperatures.温度-最小和最大温度
c)Heatpenetrationofmaterial/article.物料/部件的热穿透
Heatdistribution/uniformity.
d)热分布/均匀性Airflows–correlatedwiththeheatdistributionandpenetrationstudies.
e)气流-与热分布和热穿透测试相关
8.66Whenusingendotoxinspikedcontainerstheseneedtobecarefullymanagedwithafullreconciliationperformed.Endotoxinquantificationandrecoveryefficiencyshouldalsobedemonstrated.
当使用已加入内毒素的容器时，需要小心管理并100%平衡。并且需证实内毒素数量及回收率。
8.67Dryheatovensaretypicallyemployedtosterilizeordepyrogenateprimarypackagingcomponents,finishedmaterialsorAPIsbutmaybeusedforotherprocesses.Theyshouldbemaintainedatapositivepressuretolowergradeareas.AllairenteringtheovenshouldpassthroughaHEPAfilter.Criticalprocessparametersthatshouldbeconsideredinvalidationqualificationand/orroutineprocessingshouldinclude,butmaynotbelimitedto:
干热灭菌柜通常用于成品或API内包材部件的灭菌或去热原，但可用于其他工艺。应该对较低级别保持正压。所有进入灭菌柜的空气需经过HEPA过滤器。验证过程和/或日常操作过程中需考虑的关键参数包括但不限于：
Temperature.a)温度
Exposureperiod/time.b)曝热周期/时间
Chamberpressure.c)腔室压力
Heatpenetrationofmaterial/article(slowtoheatspotsanddifferentloads).d)物料/部件的热穿透（冷点和不同装载）
Heatdistribution/uniformity.e)热分布/均匀性
8.68Fordryheatsterilizationofstartingmaterialsandintermediatesthesameprinciplesshouldbeapplied.Considerationshouldbegiventofactorsaffectingheatpenetrationsuchasthecontainertype,sizeandpackingmatrix.
对于起始材料和中间体的干热灭菌，应该采用同样的原则。应考虑影响热穿透的因素，如容器类型、尺寸和包装基质。
Sterilizationbyradiation
照灭菌
8.69GuidanceregardingionisingradiationsterilizationcanbefoundwithinAnnex12oftheEUGMP.
关于电离辐射灭菌的指南参见EUGMP附录12.
8.70Radiationsterilizationisusedmainlyforthesterilizationofheatsensitivematerialsandproducts.Manymedicinalproductsandsomepackagingmaterialsareradiation-sensitive,sothismethodispermissibleonlywhentheabsenceofdeleteriouseffectsontheproducthasbeenconfirmed.Ultravioletirradiationisnotnormallyanacceptablemethodofsterilization.
辐射灭菌主要用于热敏感材料和产品的灭菌。许多医药产品和包装材料是辐射敏感的，所以只有在确认对产品没有不良影响的情况下才允许这种方法。紫外线照射通常不是一种可接受的灭菌方法。
8.71Validationproceduresshouldensurethattheeffectsofvariationsindensityofthepackagesareconsidered.
验证程序应确保考虑到不同包材的密度影响。
Sterilizationwithethyleneoxide
环氧乙烷灭菌
8.72Thismethodshouldonlybeusedwhennoothermethodispracticable.Duringprocessvalidationitshouldbeshownthatthereisnodamagingeffectontheproductandthattheconditionsandtimeallowedfordegassingtoreduceanyresidualethyleneoxide(EO)gasandreactionproductstodefinedacceptablelimitsforthetypeofproductormaterial.
仅在其他方法不适用情况下采用此法。在工艺验证中应证实对产品无破坏性影响，以及可减少残留环氧乙烷气体和反应产物至规定的产品或物料接受限度的排气条件和时间。
8.73Directcontactbetweengasandmicrobialcellsisessential;precautionsshouldbetakentoavoidthepresenceoforganismslikelytobeenclosedinmaterialsuchascrystalsordriedprotein.Thenatureandquantityofpackagingmaterialscansignificantlyaffecttheprocess.
气体和微生物细胞之间的直接接触是至关重要的。应当注意避免包裹在诸如晶体或干的蛋白质内的生物体。包装材料的性质和数量严重影响此工艺的效果。
8.74Beforeexposuretothegas,materialsshouldbebroughtintoequilibriumwiththehumidityandtemperaturerequiredbytheprocess.Thetimerequiredforthisshouldbebalancedagainsttheopposingneedtominimizethetimebeforesterilization.
在暴露气体前,物料应达到工艺所要求的温度和湿度的平衡。应平衡该时间与待灭菌时间的之间的矛盾。
8.75Eachsterilizationcycleshouldbemonitoredwithsuitablebiologicalindicators,usingtheappropriatenumberoftestpiecesdistributedthroughouttheloadunlessparametricreleasehasbeenauthorizedbytheNationalCompetentAuthority.
每个灭菌周期都应使用适当的生物指示剂进行监测，将适当数量的生物指示剂分布于装载中，除非获得国家主管当局批准进行参数放行。
8.76Criticalprocessvariablesthatshouldbeconsideredaspartofsterilizationprocessvalidationandroutinemonitoringinclude,butarenotlimitedto:EOgasconcentration,relativehumidity,temperatureandEOgaspressureandexposuretime.
灭菌工艺验证和日常监测应考虑的关键工艺变量包括但不限于:EO气体浓度，相对湿度、温度和EO气体压力和曝露时间。
8.77Aftersterilization,theloadshouldbeaeratedtoallowEOgasand/oritsreactionproductstodesorbfromthepackagedproducttopredeterminedlevels.Aerationcanoccurwithinasterilizerchamberand/orinaseparateaerationchamberoraerationroom.TheaerationphaseshouldbevalidatedaspartoftheoverallEOsterilizationprocessvalidation.
在灭菌后，应对装载物通气，以使EO气体和/或其反应物从包装产品中释放并达到设定水平。通气可以在灭菌柜内或在单独的通气柜或通气室内。通气阶段应该作为整个EO灭菌工艺的一部分进行验证。
Filtrationofmedicinalproductswhichcannotbesterilizedintheirfinalcontainer
非最终灭菌药品的过滤
8.78Ifaliquidproductcannotbeterminallysterilizedbyamicrobiocidalprocess,itshouldbesterilizedbyfiltrationthroughasterile,sterilizinggradefilter(withnominalporesizeof0.22micron(orless)orwithatleastequivalentmicro-organismretainingproperties),andsubsequentlyasepticallyfilledintoapreviouslysterilizedcontainer,theselectionofthefilterusedshouldensurethatitiscompatiblewiththeproduct,see8.119..Suitablebioburdenreductionand/orsterilizinggradefiltersmaybeusedatmultiplepointsduringthemanufacturingprocesstoensurealowandcontrolledbioburdenoftheliquidpriortotheprimarysterilizinggradefilter.Duetothepotentialadditionalrisksofasterilizingfiltrationprocessascomparedtoothersterilizationprocesses,asecondfiltrationthroughasterile,sterilisinggradefilter(positionedasperclause8.15),immediatelypriortofilling,isadvisable
如果某液态产品无法通过灭菌工艺进行最终灭菌，应经过无菌的除菌级过滤器（孔径至少是0.22微米或至少具有等效截留性能）进行除菌过滤，随后通过无菌分装至已灭菌容器内，应选择与产品相容的过滤器，见8.119节。可在生产过程多个位置使用降低微生物负荷和/或无菌级的过滤器，以保证液体在经过前端过滤器前具有一个较低和受控的微生物水平。与其他灭菌工艺相比，除菌过滤工艺存在额外的潜在风险，建议在灌装前使用另一个无菌的除菌级别过滤器（见8.15节）进行二级过滤。
8.79Theselectionofcomponentsforthefiltrationsystem(includingair,gasandventfilters)andtheirinterconnectionandarrangementwithinthefiltrationsystem,includingpre-filters,shouldbebasedonthecriticalqualityattributesoftheproducts,documentedandjustified.Thefiltrationsystemshouldnotgeneratefibres,unacceptablelevelsofimpuritiesorotherwisealterthequalityandefficacyoftheproduct.Similarly,thefiltercharacteristicsshouldnotbeadverselyaffectedbytheproducttobefiltered.Adsorptionofproductcomponentsandextraction/leachingoffiltercomponentsshouldbeevaluated(seeSingle-Use-Systems,Clauses8.117-8.119).
过滤系统（包括空气、气体或空调过滤器）部件的选择，及其在过滤系统中的相互连接和排列，包括预过滤，应基于产品质量属性，并记录和论证。过滤系统不能产生纤维、或不可接受的杂质、或影响产品质量或药效。同样的，过滤器特性不应受待过滤产品影响。应对产品吸附、过滤器组分的浸出/析出进行评估（见一次性使用系统8.117-8.119节）。
8.80Thefiltrationsystemshouldbedesignedto:
过滤系统应被设计为：
Allowoperationwithinvalidatedprocessparameters.a)允许在经过验证的工艺参数中进行操作
Maintainthesterilityofthefiltrate.b)维持滤液的无菌性
Minimisethenumberofasepticconnectionsrequiredbetweenthesterilizingfilterandthefinalfillingoftheproduct.c)最大程度降低除菌级过滤器与产品最终灌装的之间的无菌连接的次数。
Allowcleaningprocedurestobeconductedasnecessary.d)允许在必要时进行清洁操作
Allowsterilizationprocedures,includingSIP,tobeconductedasnecessary.Thesterilizationproceduresshouldbevalidatedtoensureachievementofatargetsterilizationassurancelevel(SAL)of10-6orbetter(e.g.10-7).e)允许在必要时进行包括SIP在内的灭菌程序。灭菌程序应经验证以达到10-6的无菌保障水平（SAL）目标或更佳（如10-7）。
Permitin-placeintegritytesting,preferablyasaclosedsystem,priortofiltrationasnecessary.In-placeintegritytestingmethodsshouldbeselectedtoavoidanyadverseimpactonthequalityoftheproduct.
f)必要时，允许在过滤前进行在线完整性测试，最好是一个封闭的系统。应选择合适的在线完整性测试方法以避免对产品质量造成负面影响。
8.81Liquid-sterilizingfiltrationshouldbevalidatedduringinitialprocessvalidation.Validationcanbegroupedbydifferentstrengthsorvariationsofaproduct,butshouldbedoneunderworst-caseconditions.Therationalforgroupingfluidsshouldbejustifiedanddocumented.
在首次工艺验证时应对液体灭菌过滤器进行验证。验证可按不同规格或不同产品组合进行，但应在最差条件进行。应论证和记录分组的合理性。
8.82Whereverpossible,theproducttobefilteredshouldbeusedforbacterialretentiontesting.Wheretheproducttobefilteredisnotsuitableforuseinbacterialretentiontesting,asuitablesurrogateproductshouldbejustifiedforuseinthetest.Thechallengeorganismusedinthebacterialretentiontestshouldbejustified.
应尽可能使用待过滤产品进行微生物截留测试。当待过滤产品不适用于微生物截留测试时，应评估适当的代替产品用于该测试。微生物截留测试所用的挑战菌也应经过评估。
8.83Filtrationparametersthatshouldbeconsideredinvalidationandroutineprocessingshouldincludebutarenotlimitedto:
验证和日常操作过程中应考虑的过滤参数应包括但不限于：
a)Ifthesystemisflushedorintegritytestedin-situwithafluidotherthantheproduct,thenflushingwiththeproductshouldbepartoftheprocess.如用产品外的其他液体对系统进行冲洗或进行完整性测试，则之后应使用产品进行冲洗。
b)Thewettingfluidusedforfilterintegritytestingbasedonfiltermanufacturer’srecommendationorthefluidtobefiltered.Forthelatter,theappropriateintegritytestvaluespecificationshouldbeestablished.用于过滤器完整性测试的润湿液应基于生产商的建议或待过滤液体。对后者，应建立适当的完整性测试标准。
c)Filtrationprocessconditionsincluding:过滤工艺条件包括：
i.Fluidprefiltrationholdingtimeandeffectonbioburden.待过滤液体的保存时间和对生物负载的影响。
ii.Filterconditioning,withfluidifnecessary.如有必要，用液体对过滤器进行润湿。
iii.Maximumfiltrationtime/totaltimefilterisincontactwithfluid.最长过滤时间/过滤器接触液体的总时间
iv.Flowrate.流速
v.Filtrationvolume.过滤量
vi.Temperature.温度
vii.Thetimetakentofilteraknownvolumeofbulksolutionandthepressuredifferencetobeusedacrossthefilter.Anysignificantdifferencesfromthosevalidatedtothoseobservedduringroutinemanufacturingshouldbenotedandinvestigated.Resultsofthesechecksshouldbeincludedinthebatchrecord.
过滤已知量原液所用时间和过滤时过滤器两端的压差。应关注并调查任何在日常生产中观察到的数值与验证过的数值之间的明显差异。这些检查结果应包含在批记录中。
8.84Theintegrityofthesterilizedfilterassemblyshouldbeverifiedbytestingbeforeuse,incaseofdamageandlossofintegritycausedbyprocessing,andshouldbeverifiedbyonlinetestingimmediatelyafterusebyanappropriatemethodsuchasabubblepoint,diffusiveflow,waterintrusionorpressureholdtest.Itisrecognisedthatforsmallbatchsizes,thismaynotbepossible;inthesecasesanalternativeapproachmaybetakenaslongasaformalriskassessmenthasbeenperformedandcomplianceisachieved.Thereshouldbewrittenintegritytestmethods,includingacceptancecriteria,andfailureinvestigationproceduresandjustifiedconditionsunderwhichthefilterintegritytestcanberepeated.Resultsoftheintegritytests(includingfailedandrepeatedtests)shouldbeincludedinthebatchrecord.
应在使用前对灭菌后的过滤器的完整性进行测试，如果因操作而造成完整性遭到破坏或降低，则应在其使用后立即通过适当的方法进行在线完整性确认，例如起泡点法、扩散流法、水侵入法、或压力保持试验。批量较小时不宜采用这种方式。在这种情况下，应进行正式的风险评估并确保合规，可采用其他方法代替。应有书面的完整性测试方法，包括可接受标准和失败调查程序以及复测的条件。完整性测试的结果（包括失败的和复测的结果）应被包含在批记录中。
8.85Theintegrityofcriticalsterilegasandairventfiltersinthefilterassemblyshouldbeverifiedbytestingafteruse.Theintegrityofnon-criticalairorgasventfiltersshouldbeconfirmedandrecordedatappropriateintervals.
关键的无菌气体和空气呼吸过滤器的完整性应在使用后测试确认。非关键空气或气体呼吸过滤器的完整性应以适当的间隔进行确认并记录。
8.86Forgasfiltration,theavoidanceofunintendedmoisteningorwettingofthefilterorfilterequipmentisimportant.Thiscanbeachievedbytheuseofhydrophobicfilters.
对于气体过滤，应避免对滤器或过滤设备的意外润湿。这可以通过使用疏水性过滤器实现。
8.87Whereserialfiltration(onefiltrationisfollowedbyasubsequentfiltration)isaprocessrequirementthefiltertrainisconsideredtobeasterilizingunitandallsterilizing-gradefilterswithinitshouldsatisfactorilypassintegritytestingbothbeforeuse,incaseofdamageduringprocessing,andafteruse.
当工艺要求进行串联过滤（一次过滤后再次进行过滤）时，它们应被视为一个除菌单元，且其中所有除菌级过滤器在使用前以及使用后均应成功地通过完整性测试，以防止过滤器在使用过程中损坏。
8.88Wherearedundantsterilizingfilterisused,theadditionalfilterdoesnotrequirepost-integritytestingunlesstheprimarysterilizingfilterfails,inwhichcasetheredundantfiltermustthensatisfactorilypasspost-useintegritytesting.Bioburdensamplesshouldbetakenpriortothefirstfilterandthesterilizingfilter,systemsfortakingsamplesshouldbedesignedsoasnottointroducecontamination.
当使用了冗余除菌过滤器时，附加的过滤器不必进行使用后的完整性测试，除非主除菌过滤器不合格。在此情况下，冗余过滤器必须成功通过使用后的完整性测试。应在第一个过滤器以及除菌过滤器前分别取样测试生物负荷，取样系统的设计不得引入污染。
8.89Liquidsterilizingfiltersshouldbediscardedaftertheprocessingofasinglelot.Thesamefiltershouldnotbeusedformorethanoneworkingdayunlesssuchusehasbeenvalidated.
液体除菌过滤器在处理完一批产品后应废弃。同一个过滤器使用不能超过一个工作日，除非经过验证。
Form-Fill-Seal
成型-灌装-密封
8.90Form-Fill-Seal(FFS)unitsincludeblowmouldingfromthermoplasticgranulateandthermoformingfromthermoplasticfilmtypicallyknownasBlow-Fill-Seal(BFS)andVertical-Form-Fill-Seal(VFFS)respectively.VFFSprocessisanautomatedfillingprocess,typicallyforterminallysterilizedprocesses,thatmayutilizeasingleordualwebsystemwhichconstructstheprimarycontaineroutofaflatrollofthermoplasticfilmwhilesimultaneouslyfillingtheformedbagswithproductandsealingthefilledbagsinacontinuousprocess.Allsuchcontainersareconsideredtobesealedbyfusionand,assuch,fallundertherequirementtoperform100%integritytesting.
成型-灌装-密封FFS单元包括吹塑成型和热压成型，通常分别被称为吹-灌-封（BFS）和垂直-成型-灌装-密封VFFS。VFFS工艺是一种自动化的灌装工艺，通常用于最终灭菌工艺。该工艺可用单网或双网系统将成卷的热塑性薄膜制成内包装材料，并同时对成型的软袋产品进行灌装，然后对灌装好的软袋进行密封。该工艺是一个连续的工艺过程。所有这些容器均被视为熔封型容器，并因此需要进行100%的完整性检查。
8.91Processparametersrelatingtosealintegrityshouldbevalidatedandappropriatelycontrolled.Criticalparametersinclude,butarenotlimitedto:sealstrength,sealuniformity,sealingtemperatures,pressures,sealingtimesanddwelltimeforfilling.Sealstrengthanduniformityshouldbemonitoredroutinely.
与密封完整性有关的工艺参数应进行验证并进行适当的控制。这些关键参数包括，但不限于：密封强度、密封均匀度、密封温度、压力、密封时间、密封后待灌装时间。密封强度和均匀度应进行日常监控。
8.92Samplesoffilledcontainersshouldbetestedforgeneralperformancee.g.ease-of-opening,andsealuniformity.SamplesizeandfrequencyshouldbebasedontheprinciplesofQRM.
应对灌装后容器取样进行一般性能的检查，如易开启性和密封均匀度。取样量和频率应基于QRM原则制定。
Blow-Fill-Sealtechnology吹-灌-封技术
8.93Blow-Fill-Seal(BFS)unitsarepurposebuiltmachinesinwhich,inonecontinuousoperation,containersareformedfromathermoplasticgranulate,filledandthensealed,allbytheoneautomaticmachine,seeglossaryforfulldefinition.
吹灌封（BFS）单元是特制的设备，可连续操作，通过全自动一体化设备进行热塑成型、分装然后密封，详细定义见术语部分。
8.94Riskmanagementprinciplesshouldbeusedtojustifythemachine’sdesignandoperationalcontrols.Thesecontrolsshouldbeinalignmentwiththesite’scontaminationcontrolstrategy.Aspectstobeconsideredshouldinclude(butarenotlimitedto):
应使用风险管理原则论证设备设计和运行控制。这些控制应与工厂的污染控制策略相联系。考虑的方面包括（但不限于）如下：
a)Determinationofthe“criticalzone”thatshouldbeprotectedfromcontamination,anditscontrol.
“关键区域”的确定及其控制，应避免污染。
b)Environmentalcontrolandmonitoring,bothoftheBFSmachineandthebackgroundinwhichitisplaced.应对吹灌封设备及其所处的背景进行环境控制和环境监测。
c)IntegritytestingoftheBFSproductpathways.
吹灌封产品路径的完整性测试。
d)Durationofthebatchorfillingcampaign.
批生产或灌装的时长。
e)Controlofpolymerstartingmaterial.
高分子起始物料的控制。
f)Cleaning-in-placeandsterilization-in-placeofequipment,andairandproductpathways.
设备、气体和产品通道的在线清洁和在线灭菌。
8.95ShuttleandRotary-typeequipmentusedforasepticproductionwhichisfittedwithaneffectivegradeAairshowershouldbeinstalledinatleastagradeCenvironment,providedthatgradeA/Bclothingisused.
当装有A级风淋的往复式和旋转式吹灌封设备用于无菌生产时，应至少安装在C级的环境中，并穿戴A/B级工作服。
8.96ForShuttle–typeequipment,theenvironmentshouldcomplywiththeviableandnon-
viablelimitsatrestandtheviablelimitonlywheninoperation.TheshuttlezoneshouldmeetgradeAviablelimits.
对于往复式设备，其环境应符合静态条件下的微生物和悬浮粒子标准，动态条件下，仅微生物限度应达到标准。穿梭区域应符合A级微生物限度要求。
8.97ForRotary-typeequipmenttheenvironmentshouldcomplywiththeviableandnon-
viablelimits“atrest”.Itisnotnormallypossibletoperformenvironmentalmonitoringwithintheparisonduringoperation"Monitoringofthebackgroundenvironmentshouldbeperformedinaccordancewithriskmanagementprinciples
对于旋转式设备，其环境应符合静态条件下的微生物和悬浮粒子标准。动态条件下通常无法对吹气成型部位进行环境监测。背景环境的监测应根据风险管理原则进行。
8.98TheenvironmentalcontrolandmonitoringprogramshouldtakeintoconsiderationthecomplexgasflowpathsgeneratedbytheBFSprocessandtheeffectofthehighheatoutputsoftheprocess.
环境控制及监测程序应同时考虑BFS操作产生气流的复杂性及高温工艺的影响。
8.99Inaddition,forShuttle-typedesigns,theareabetweenparisoncuttingandmouldsealingshouldbecoveredbyaflowofHEPAfilteredorsterileairofappropriatequalitytoprovide
gradeAatthecriticalzone.
另外，对于往复式设计的设备，吹气成型切割和模具密封区域应覆盖HEPA过滤的空气或合适质量的无菌空气，以为关键区域提供A级环境。
8.100Blow-Fill-SealequipmentusedfortheproductionofproductswhichareterminallysterilizedshouldbeinstalledinatleastagradeDenvironment.
8.100对于最终灭菌产品生产所用的BFS设备应至少安装在D级环境。
8.101Externalparticleandmicrobialcontaminationofthepolymershouldbepreventedbyappropriatedesign,control,andmaintenanceofthepolymerstorageanddistributionsystems.
应通过对高分子聚合物存放和分发系统进行恰当的设计、控制和维护以防止其外部异物及微生物污染。
8.102Interventionsrequiringcessationoffillingand/orblowingandsealingand,whererequired,re-sterilizationofthefillingmachineshouldbeclearlydefinedandwelldescribedintheasepticfillingprocedure,andincludedintheasepticprocesssimulation(referclause9.36).
应在无菌分装规程中明确定义并描述需要停止分装和/或吹气密封的干扰，必要时，对分装设备重新灭菌，并包含在无菌工艺模拟中（参见9.36节）。
8.103Processvalidationshouldtakeintoconsiderationcriticaloperatingparametersandvariablesoftheequipmentthatimpactonthequalityoftheproduct,e.g.fillingspeed,extrusiontemperature,fillingtimes.
工艺验证中应考虑影响产品质量的关键操作参数和设备变量，如分装速度、挤压温度、灌装次数。
8.104Samplesoffilledcontainersshouldbetestedforgeneralperformancee.g.ease-of-
openingandwallthickness;samplesizeandfrequencyshouldbebasedontheprinciplesofQRM.
应对灌装后的容器取样测试其性能，如易打开性、壁厚。应根据风险管理确定取样数量及频次。
Lyophilization冻干法
8.105Lyophilizationisacriticalprocessstepandallactivitiesthatcanaffectthesterilityoftheproductormaterialneedtoberegardedasextensionsoftheasepticprocessingofthatsterilizedproductormaterial.Thelyophilizationequipmentanditsprocessesshouldbedesignedsoastoensureproductormaterialsterilityismaintainedduringlyophilizationbypreventingmicrobiologicalandparticulatecontaminationbetweenthefillingoperationandcompletionoflyophilizationprocess.Allcontrolmeasuresinplaceshouldbedeterminedbythesite’scontaminationcontrolstrategy.
冷冻干燥是一个非常关键的操作步骤，所有影响产品或物料无菌性的活动均应认为是对已灭菌产品或物料的无菌操作。冻干设备及其工艺均应当设计以保证产品或物料的无菌性，防止在灌装和冻干程序完成期间的微生物或微粒污染。。
8.106Thelyophilizershouldbesterilizedbeforeeachload.Thelyophilizershouldbeprotectedfromcontaminationaftersterilization.
每一次装载前冻干机均需经过灭菌。并在灭菌后防止污染。
8.107Wherethereisaclosingsystemforpartiallyclosedcontainers,thesurfacesofanyequipmentprotrudingintothechambertoeffectsealingshouldalsobesterilized.
对用于半密封容器的密闭式系统，任何通过伸入箱体来影响密封的设备表面也应进行灭菌。
8.108Lyophilizationtraysshouldbecheckedtoensurethattheyarenotmisshapenanddamaged.
冻干托盘应检查以确保无变形或损坏。
8.109Themaximumpermittedleakageofairintothelyophilizershouldbespecified.
应规定冻干机的最大允许空气泄漏。
8.110Theintegrityofthesystemshouldbemonitoredperiodicallyalongwithconsiderationoftheleakratetest.应定期监测系统完整性并考虑泄漏率测试。
8.111Withregardtoloadingandunloadingthelyophilizer:关于冻干机的装载和卸载：
a)Theloadingpatternwithinthelyophilizershouldbespecifiedanddocumented.
应规定并记录冻干机的装载方式。
b)Transporttothelyophilizerandloadingoffilledproduct,orotherequipmentintothelyophilizershouldtakeplaceunderagradeAenvironment.
产品或其他设备的转运至冻干机及装载过程，应在A级环境下。
c)Airflowpatternsshouldnotbeadverselyaffectedbytransportdevicesandventingoftheloadingzone.UnsealedcontainersshouldbemaintainedundergradeAenvironment.
气流流型应不受运输装置和装载区排气的影响。未密封的容器应保持在A级环境下。
d)Whereseatingofthestoppersisnotcompletedpriortoopeningthelyophilizerchamber,productremovedfromthelyophilizershouldremainunderagradeAenvironmentduringsubsequenthandling.
在冻干机打开前，产品处于不完全加塞状态的，产品移出冻干机进行下一步操作的过程中应维持在A级环境下。
e)Utensilsusedduringtransferto,loadingandunloadingof,thelyophilizer(suchastrays,bags,placingdevices,tweezers,etc.)shouldbesubjectedtoavalidatedsterilizationprocess.
转运、装载和卸载过程中用到的工具（例如托盘、袋子、定位装置、镊子等）应经过已验证的灭菌工艺灭菌。
Closedsystems密封系统
8.112Closedsystemscanbebothsingleusesystems(SUS)(i.e.disposable)andfixedsystems(suchasvesselswithfixedpipework).Guidanceinthissectionisequallyapplicabletobothsystems.
密封系统可以是一次性使用系统（SUS）（用完即丢）和固定系统（如有固定管理的容器）。本章节的指导意见同时适用于两个系统。
8.113Theuseofclosedsystemscanreducetheriskofbothmicrobialandchemicalcontaminationduetointerventions.
使用隔离系统可减少干扰产生的微生物和化学污染的风险。
8.114Itiscriticaltoensurethesterilityofproductcontactsurfacesofclosedsystemsusedforasepticprocessing.Thedesignandselectionofanyclosedsystemusedforasepticprocessingmustensuremaintenanceofsterility.Tubing/pipeworkthatisnotassembledpriortosterilizationshouldbedesignedtobeconnectedaseptically,e.g.byintrinsicasepticconnectorsorfusionsystems.
保证无菌工艺所用隔离系统的产品接触面的无菌性是非常关键的。无菌工艺所用的任何隔离系统的设计及选择必须确保无菌性维持。未在灭菌前组装的管道应设计为无菌连接，如通过无菌连接器或熔接系统。
8.115Appropriatesystemsshouldbeinplacetoassuretheintegrityofthosecomponentsused.ThemannerinwhichthisisconductedshouldbedeterminedbasedonQRMprinciples.Appropriatesystemintegritytestsshouldbeconsideredwhenthereisariskofcompromisingproductsterility.
应有适当的系统以确保这些组件的完整性。应根据QRM原则确定所使用的方式。当有破坏产品无菌性的风险时，应考虑适当的系统完整性测试。
8.116Thebackgroundinwhichclosedsystemsarelocatedwillvary.IfthereisahighriskthatthesystemwillnotremainintegralduringprocessingitshouldbelocatedinagradeAenvironment.Ifthesystemcanbeshowntoremainintegralateveryusagethenlowergrades,includinggradeD,canbeconsidered.
隔离系统所处的背景条件可能会有所不同。如果系统在生产过程中无法保持完整性的风险高，它应当处于A级环境。如果能证明在各使用环境均能保持其完整性，则可以考虑较低级别，包括D级。
Singleusesystems一次性使用系统
8.117Singleusesystems(SUS)arethosetechnologiesusedinmanufactureofsterilemedicinalproductswhicharedesignedtoreplacereusableequipment.SUSaretypicallydefinedsystemsmadeupofcomponentssuchasbags,filters,tubing,connectors,storagebottlesandsensors.
一次性使用系统（SUS）是指在无菌药品生产中运用到的设计以代替重复使用性设备的技术。SUS通常定义为由相关部件如袋子、过滤器、管道、连接器、储瓶及传感器组成的系统。
8.118TherearesomespecificrisksassociatedwithSUSwhichinclude,butarenotlimitedto:
SUS有一定风险，包括但不限于：
a)Interactionbetweentheproductandproductcontactsurface(adsorption,leachableandextractables).
产品与产品接触表面的相互作用（吸附、浸出物和溶出物）。
b)Morefragilethanfixedreusablesys与固定的重复使用系统相比更脆弱。
c)Inreaseinnumberandcomplexityofmanualoperationsandconnectionsmade人工操作和连接的数量和复杂性增加
d)Designoftheassembly.组装的设计
e)Performanceofthepre-useintegritytestingforsterilizinggradefilters.(Refertoclause8.84.)
无菌级过滤器使用前完整性测试的执行（参见8.84节）
f)Integritytesti完整性测试
g)Pin-holeandleakage.针孔和泄漏
h)Thepotentialforcompromisingthesystematthepointofopeningtheouterpackaging. 打开外包装时对系统的潜在影响。
i)Assessmentofsuppliersofdisposablesystems(includingsterilizationofthesedisposablesystems.一次性系统供应商的评估（包括这些一次性系统的灭菌）。
j)Riskofparticulatecontamination.微粒污染的风险。
8.119Thecompatibilityofmaterialsusedforproductcontactsurfaceswiththeproductsshouldbeensuredundertheprocessconditionsbyevaluatinge.g.adsorptionandreactivitytotheproduct.
8.119应评价工艺条件下产品接触面的材料和产品的相容性，如产品吸附、产品反应。
8.120ExtractableprofiledataobtainedfromthesupplierofthecomponentsofSUSmaybeusefultoensurethatextractablesandleachablesfromtheSUSdonotalterthequalityoftheproduct.Ariskassessmentshouldbeconductedforeachcomponenttoevaluatetheapplicabilityoftheextractableprofiledata.Forcomponentsconsideredtobeathighrisktoleachables,includingthosetakingupleachablesextensivelyorthosestoredforlongerperiods,anassessmentofleachableprofilestudies,includingsafetyconcerns,andshouldbetakenintoconsideration,asnecessary.Ifapplyingsimulatedprocessingconditionstheseshouldaccuratelyreflecttheactualprocessingconditionsandbebasedonascientificrationale.
从SUS组件供应商处获得的可提取物数据可用来证明其浸出和析出物对产品质量无影响。应进行风险评估以评价每一个组件的这些可提取物数据的适用性。对于认为是析出物高风险的组件，包括产生大量析出物或长期存放的组件，必要时，应对其析出物试验数据进行评估，包括安全性方面的考虑。如果模拟工艺条件，应能准确反映实际工艺条件并基于一个科学的原理。
8.121SUSshouldbedesignedsoastomaintainintegrityduringtheintendedoperationalconditionsandduration,especiallythestructuralintegrityofthesingleusecomponentsunderextremeprocessandtransportconditionssuchasduringfreezeandthawprocesses.Thisshouldincludeverificationthatintrinsicasepticconnections(bothheatandmechanical)remainintegralundertheseconditions.
SUS的设计应能在预期操作条件和持续时间内下保持完整性，特别是在极端工艺和运输条件下的一次性组件的结构完整性，例如冷冻和解冻过程。这应包括确认在这些条件下保持其固有无菌连接（包括热连接和机械连接）完整性的确认。
8.122AcceptanceproceduresshouldbeestablishedandimplementedforSUScorrespondingtotherisksorcriticalityoftheproductsanditsprocesses.Onreceipt,avisualinspectionofouterpackaging(e.g.appearanceofexteriorcarton,productpouches),labelprinting,andattacheddocuments(e.g.CertificateofAnalysis,radiationcertificate)shouldbecarriedout.Priortouse,eachpieceofSUSshouldbecheckedtoensurethattheyhavebeenmanufacturedanddeliveredinaccordancewiththeapprovedspecification.
应建立并实施与产品及其工艺的关键性或风险相关的验收程序。验收时，应检查其外包装（例如外箱、产品保护袋的外观）、标签打印和随货文件（例如检验报告单（COA）、辐照证书）。使用前应检查每个SUS以确保他们的生产和运输符合已批准的质量标准。
8.123CriticalmanualhandlingoperationofSUS,suchasassemblingandconnecting,shouldbesubjecttoappropriatecontrolsandverifiedduringtheasepticprocesssimulationtest.
SUS的关键人工处理操作，如装配和连接，应该采取适当的控制措施，并应在无菌工艺模拟试验中验证。
