美欧GMP药厂主要设施专项培训教材

Revisedasof23November2020Revisedasof23November2020美欧GMP药厂主要设施专项培训教材cGMPCompliantDesign,CommissioningandValidationofPharmaceuticalandBiotechnologyFacilities&UtilitySystems化学药厂与生物技术药厂厂房设施与辅助系统的cGMP符合性设计、调试和验证:NaderMoslemianDirector,EngineeringOperationsNaderMoslemian工程运行主任PharmEngTechnologyInc.加拿大制药工程公司.Instructor’sContactInformation授课专家联系信息NaderMoslemianNaderMoslemianthth1Introduction导言CourseObjectives课程目标Introductionto:DesignandValidationofPharmaceuticalandBiotechnologyUtilitySystems:–HVACSystems–PurifiedWaterandWFIWaterSystems–PureSteamSystem–CleanInPlace(CIP)/SanitizationInPlace(SIP)Systems–CompressedAirandMedicalGasSystems–WasteDisposalSystems–OtherUtilitySystems学习和了解化学药厂与生物技术药厂厂房设施与辅助系统的设计与验证–HVAC（加热、通风与空调）系统–纯化水与注射用水系统–纯蒸气系统–现场清洁(CIP)/现场消毒系统(SIP)–压缩空气与医用气体系统–废弃物处置系统–其它辅助设施系统2CourseOutlines课程梗概1.HVACSystemsDesignandValidation2.PurifiedandWFIWaterSystemsDesignandValidation3.PureSteamSystemDesignandValidation4.CIPandSIPSystemsDesignandValidation5.WasterWaterTreatmentSystemsDesignandValidation6.CompressedAirandMedicalGasesDesignandValidation7.IntroductiontoOtherProcessUtilitySystems1.HVAC系统设计与验证2.纯化水与注射用水系统设计与验证3.纯蒸气系统设计与验证4.CIP和SIP系统设施与验证5.废水处理系统设计与验证6.压缩空气和医用气体设计与验证7.其它工艺辅助设施系统介绍Resources参考资料ISPEBaselinePharmaceuticalEngineeringGuide–Volume1:BulkPharmaceuticalChemicals–Volume2:SolidDosageForm–Volume3:SterileManufacturingFacilities–Volume4:WaterandSteamSystems–Volume5:CommissioningandQualificationTheBuildingCommissioningHandbook,APPAASHRAEGuidelinesCurrentGoodManufacturingPracticeUnitedStatesPharmacopeia(USP)ISO14644-1&14644-2&14644-2ISPE制药工程基础指南–卷-1:化学原料药–卷-2:固体制剂–卷-3:无菌生产设施–卷-4:水和蒸气系统–卷-5:调试与确认APPA厂房调试手册ASHRAE指南cGMP美国药典(USP)ISO14644-1&14644-2&14644-23PharmaceuticalandBiotechnologyFacilityDesign&Compliance化学药厂与生物技术药厂厂房设计与GMP符合性Layout&ArchitecturalDesign布局与建筑设计DESIGNOFMATERIALFLOW物流设计–(SHIPPING,RECEIVING,MATERIALHANDLING,MATERIALTRACKING,AREASEGREGATION)DESIGNOFPERSONNELFLOW–(送货、收货、物料处置、物料跟踪、区域分隔)人流设计–分隔、产品。人员保护、隔离、单向–SEGREGATION,PRODUCT/PERSONNELPROTECTION,ISOLATION,UNIDIRECTIONDESIGNOFAIRFLOWDESIGNOFPRODUCTIONANDEQUIPMENTLAYOUTHEALTH&SAFETYCONSIDERATIONS气流设计生产与设备布局的设计健康与安全考量4Layout&ArchitecturalDesign(cont’d)

布局与建筑设计续)OVERALLFACILITYLAYOUT&AREADEFINITION厂房总体布局与区域规划ROOMLAYOUT操作室布局–DATASUMMARY,CLASSIFICATION&CONDITIONSOFALLUSEDAREA,UTILITY&PROCESSREQUIREMENT–数据归纳、所有使用区域的分类与条件、辅助设施与过程要求ARCHITCTURALFINISHOFFLOOR,WALL,CEILING&地板、墙、密封和门的建筑完工DOOR升降装置设计、形状、区段DESIGNOFELEVATIONS,SHAPE,SECTIONS建造和材料的功能规格FUNCTIONALSPECIFICATIONSOFCONSTRUCTION&MATERIALSNonSterileManufacturingFacilityLayout非无菌生产厂房布局5AsepticManufacturingFacilityPart-Plan灭菌生产厂房部分规划AirFlow气流AirPressurization空气增压CleanCorridorsandAirLocks洁净走道和气锁AirFlowDirection气流方向AirChanges空气置换AreaClassification(GMP,Electrical,Hazardous,etc.)CommitteeEvaluationofAirFlow区域分类(GMP,电力、有毒等)气流调试评估6Non-AsepticManufacturingAirFlow非灭菌生产气流AsepticManufacturingAirFlow灭菌生产气流7MaterialFlow物流Unidirectional单向DefinitionandSeparation规划与分离Receipt,Quarantined,Released,In-Process,BulkProducts,PackagingComponents,Storage,DistributionCommitteeEvaluationofMaterialFlow收货,隔离（待验）,放心,中间工艺,半成品,包装组分,仓储,分发物流调试评估Non-AsepticManufacturingMaterialFlow非灭菌生产区物流8AsepticManufacturingMaterialFlow灭菌生产区物流PersonnelFlow人流MinimizePotentialforCrossContamination使交叉污染最小可能AirlockWhenAppropriate适当情况下采用气锁DedicatedUniform&Shoes专用制服与鞋CommitteeEvaluationofPersonnelFlow人流调试评估9Non-SterileManufacturingPersonnelFlow非无菌生产区人流AsepticManufacturingPersonnelFlow灭菌生产区人流10AreaClassifications区域分类LevelIGeneralAreaShipping,Warehouse,etc.LevelIIGMPArea/ProtectedAreaDispensingGranulationCompressionPackagingLevelIIICriticalAreaI-级普通区域送货、仓库等II-级GMP区域/保护区域分发制粒压片包装III-级控制区域AsepticSterileParentalToxic灭菌无菌注射有毒PharmaceuticalFacilityValidation制药设施验证REVIEWSYSTEMDESIGNUSINGPRINCIPLESOFGMP(GOODMANUFCTURINGPRACTICE)/GEP(GOODENGINEERINGPRACTICE)PREPAREVALIDAITONMASTERPLANDESIGNQUALIFCATIONPROTOCOLINSTALLATIONQUALIFICATIONOPERATIONALQUALIFICATIONPERFORMANCEVALIDATIONCHANGECONTROLMANAGEMENTSYSTEMDOCUMENTATIONMANAGEMENTSYSTEM使用GMP/GEP原则评价系统设计准备验证主计划设计确认方案安装确认运行确认性能验证变更控制管理系统文件管理系统11FacilityandUtilitiesDocumentation厂房设施与辅助设施文件FACILITYSYSTEMAS-BUILTDRAWINGSFINALAPPROVEDSHOPDRAWINGSP&IDWIRINGDIAGRAMSPRESSURETESTINGREPORTISOMETRICDRAWINGSBALANCINGREPORTSYSTEMDESIGNCALCULATIONWORKPERMITCOPYASMECERTIFICATIONPASSIVATIONREPORTBLOCKDIAGRAMSSYSTEMSCHEMATICSEQUIPMENTLISTCLEANINGREPORTCOMMISSIONINGREPORT厂房设施系统完成图纸最后批准的车间图纸P&ID线路图压力检测报告等比例图纸平衡报告系统设计计算工作许可证复印件ASME证书钝化报告结构图纸系统图表设备清单清洁报告调试报告Instrumentation&ControlDesign仪器与控制设计DEFINEINSTRUMENTATIONANDCONTROLPHILOSOPHYIDENTIFYAUTOMATION,CONTROLSANDMONITORINGSYSTEMREQUIREMENTBUILDINGMANAGEMENTSYSTEM(BMS)FACILITYMONITORINGSYSTEMFMS)IDENTIFYINPUT/OUTPUTCONFIGUREHARDWARE&SOFTWAREINTERFACEOPERATIONSCALIBRATIONREQUIREMENT21CFRPART11ASSESSMENT确定仪器与控制设计思路明确自动化、控制和检测系统要求建筑管理系统(BMS)厂房设施监测系统(FMS)明确输入/输出布局硬件和软件接口运行校验要求美国FDA计算机过程控制的21CFRPART11评价12EquipmentDesignForProcessOptimization过程优化的设备设计MINIMIZEEQUIPMENTINGMPAREAGMP区域设备最小化IMPLEMENTCLOSED-LOOPPRODUCTIONSYSTEM实现封闭生产系统设计现场清洁程序DESIGNCLEAN-IN-PLACEPROCEDURES

标准化工艺与设备STANDARDIZEPROCESSESANDEQUIPMENTEquipmentIntegration设备整合VENDORSELECTION供应商选择EQUIPMENTSELECTIONEQUIPMENTMANUFATURINGFACTORYACCEPTANCETEST(FAT)SYSTEMINSTALLATIONSITEACCEPTANCETEST(SAT)设备选择设备制造厂方接受测试(FAT)系统安装现场接受测试(SAT)COMMISSIONINGVALIDATION(IQ/OQ/PQ)调试验证(IQ/OQ/PQ)13UtilitySystems辅助设施系统WHATAREUTILITYSYSTEMS什么是辅助设施系统–UTILITYSYSTEMSARENECESSARYANDANCILIARYSYSTEMSREQUIREDTOSUPPORTPHARMACEUTICALPRODUCTIONSYSTEMSCRITICALUTILITYSYSTEMSMUSTBEVALIDATEDNON-CRITICALUTILITYSYSTEMSONLYREQUIRECOMMISSIONINGANDQUALIFICATION–辅助设施系统是支持制药生产系统必需的协助系统关键辅助设施须验证非关键辅助设施仅需要调试与确认Critical/Non-CriticalSystems关键/非关键系统CRITICALSYSTEMSNON-CRITICALSYSTEMS关键系统非关键系统SYSTEMSWHICHHANDLEAND/ORCONTAINSUBSTANCESWHICHWILLCOMEINTOPRODUCTCONTACTTHESESYSTEMSMUSTBEVALIDATEDSYSTEMSWHICHHANDLEAND/ORCONTAINSUBSTANCESWHICHWILLNOTCOMEINTOCONTACTWITHPRODUCT.THESESYSTEMSMUSTBEQUALIFIED.处置和或包含将与产品接触的物质的系统这些系统必须要验证处置和或包含不与产品接触的物质的系统这些系统必须要确认14CommonUtilitySystems常见辅助设施HVACSYSTEMNITROGEN(N2)-INERTINGOFVESSELSHYDROGEN(H2)-HYDROGENATIONREACTIONSOXYGEN(O2)-AEROBICFERMENTATIONCARBONDIOXIDE(CO2)-ANAEROBICFERMENTATIONCOMPRESSEDAIR-PRESSURETRANSFER,LINEBLOWING,INSTRUMENTATIONCONTROLSTEAMSYSTEMS-SIPSTEAMPLACESANITIZATION,HEATSOURCE,HUMIDIFICATION空调系统氮气(N)–反应容器的惰性化保护氢气(H)-加氢反应氧气(O)-有氧发酵二氧化碳(CO)-无氧（厌）氧发酵压缩空气–压力传输、管道吹风、仪器控制蒸气系统-现场蒸气消毒（SIP）、热源、湿度化CommonUtilitySystems(cont’d)常见辅助设施续)PURIFIEDWATERSYSTEMS(RINSINGANDNONSTERILECOMPOUNDING)WFIWATERSYSTEMS(FINALRINSINGANDSTERILECOMPOUNDING)THERMALHEATTRANSFERSYSTEMS(HEATINGANDCOOLINGOFPROCESSESFROM–to350deg.C)CLEAN-IN-PLACE(CIP)SYSTEMS纯化水系统(清洗和非无菌化合反应)注射用水（WFI）系统(最后清洗用水和无菌化合反应)热能传输系统(工艺的加热和冷却从到350deg.C)现场清洗(CIP)系统15MiscellaneousSystems其它系统AUTOCLAVES高压灭菌设施

LYOPHYLIZATIONSYSTEMS冷冻干燥系统

WASTETREATMENTSYSTEMS三废处理系统––气––液––固SOLVENTRECOVERYSYSTEMS溶剂回收系统–DISTILLATIONTOWERS–蒸馏塔

–LOWTEMPERATURECONDENSERS–低温冷凝器SafetySystems安全系统PESSURERELIEFSYSTEMS(RELIEFVALVES,RUPTUREDISCS)VENTINGSYSTEMSGASSCRUBBINGSYSTEMSSPILLCONTAINMENTSYSTEMSOPERATORPROTECTIVESYSTEMSFIREPROTECTIONSYSTEMSEXPLOSIONPROTECTION(BUILDINGS,EQUIPMENT)压力泄放系统(泄放阀、破裂片)通风系统气体清洁系统溅洒污染系统操作者防护系统火灾防护系统防爆(建筑、设备)16PrimaryAuthorities主要药监机构HEALTHCANADA,HPFBI(HEALTHPOTECTION,FOODBRANCHINSPECTORATE)USFDA(UNITEDSTATESFOODANDDRUGADMINISTRATION)HPFBI(加拿大卫生部医保与食品检查署）FDA(美国食品药品监管局)USP(UNITEDSTATESPHARMACOPIA)BP(BRITISHPHARMACOPIA)CFR21(CODEOFFEDERALREGULATIONScGMP)USP(美国药典)BP(英国药典)TPP(THERAPUTICPRODUCTSPROGRAMGMP2002)CFR21(美国联邦法规cGMP)TPP(加拿大药品管理规范GMP2002)DesignAuthorities设计监管机构HPFBI&USFDABOTHSTIPULATETHATNOGOVERNINGAUTHORITYISALLOWEDTOBECIRCUMVENTEDINTHEDESIGNOFPHARMACEUTICALFACILITIES.cGMPSMUSTBEACHIEVEDWHILEABIDINGBYTHECODESANDREGULATIONSOFALLGOVERNINGAUTHORITIES.加拿大和美国药监机构（HPFBI&USFDA）都规定在药厂厂房设计方面必须接受各监管机构监管。在遵守所有监管部门法规的同时还必须达到cGMP符合性要求。17AuthoritiestoComplyWith需要遵从的监管机构MINISTRYOFTHEENVIRONMENTOHSA(OCCUPATIONALHEALTH&SAFETYACT)EPA(ENVIRONMENTALPROTECTIONAGENCY)UL(UNDERWRITERSLABORATORIES)NIST(NATIONALINSTITUTEOFSTANDARDS)ASHRAE(AMERICANSOCIETYOFHEATING,REFRIGERATIONANDAIRCONDITIONINGENGINEERS)ISPE(INTERNATIONALSOCIETYOFPHARMACEUTICALENGINEERS)NBC(NATIONALBUILDINGCODE)OBC(ONTARIOBUILDINGCODE)NFC(NATIONALFIRECODE)NFPA(NATIONALFIREPROTECTIONASSOCIATION)MINISTRYOFTHEENVIRONMENT(环境部)OHSA(职业健康与安全法)EPA(环境保护署)UL保险实验室)NIST(国家计量标准所)ASHRAE美国加热、冷冻和空调工程协会)ISPE(国际制药工程协会)NBC(国家建筑法)OBC安大略建筑法)NFC国家防火法)NFPA国家防火协会)AuthoritiestoComplyWith(cont’d)

需要遵从的监管机构续)TSSA(TECHNICALSTANDARDSANDSAFETYAUTHORITY)ESA(ELECTRICALSAFETYAUTHORITY)CSA(CANADIANSTANDARDSASSOCIATION)ASME(AMERICANSOCIETYOFMECHANICALENGINEERS)ASTM(AMERICANSOCIETYFORTESTINGMATERIALS)ANSI(AMERICANNATIONALSTANDARDSINSTITUTE)HPFBI&USFDABOTHSTIPULATETHATNOGOVERNINGAUTHORITYISALLOWEDTOBECIRCUMVENTEDINTHEDESIGNOFPHARMACEUTICALFACILITIES.cGMPSMUSTBEACHIEVEDWHILEABIDINGBYTHECODESANDREGULATIONSOFALLGOVERNINGAUTHORITIES.TSSA(技术标准与安全机构)ESA(电力安全机构)CSA(加拿大标准协会)ASME(美国机械工程协会)ASTM(美国材料检测协会)ANSI(美国国家标准所)加拿大和美国药监机构（HPFBI&USFDA）都规定在药厂厂房设计方面必须接受各监管机构监管。在遵守所有监管部门法规的同时还必须达到cGMP符合性要求。18FDAWarningletterFDA警告信FDAWarningletterFDA警告信19FDAWarningletterFDA警告信FDAWarningletterFDA警告信20FDAWarningletterFDA警告信FDAWarningletterFDA警告信21CoffeeBreak茶休…………HVACSystemDesignandValidationHVAC系统的设计与验证22TypicalHVACSystemComponents典型HVAC系统的组成部分–AirHandlingUnit(s)–空气处理装置–CoolingandRefrigerationSystem(s)–冷却与冷冻系统–HeatingSystem(s)–加热系统–HVACPipingSystem–HVAC泵系统–DuctworkandAirDistributionSystem–管道系统和空气分散系统–ControlandMonitoringSystem(s)–控制与检测系统TypicalHVACSystemComponents(cont’d)AirHandlingUnit(s)典型HVAC系统的组成部分(续)空气处理单元),)))23TypicalHVACSystemComponents(cont’d)典型HVAC系统的组成部分(续)CoolingandRefrigerationSystem(s)zz冷却与制冷系统)z)zzzzzzz圈)zzzzzzzzzzTypicalHVACSystemComponents(cont’d)典型HVAC系统的组成部分(续)HeatingSystem(s)加热系统)zzzzzz/zzzzzzzz)zzzzzzzzzzzz24TypicalHVACSystemComponents(cont’d)典型HVAC系统的组成部分(续)HVACPipingSystemHVAC管道系统zzzzzzzzzzzzz)zzz)zzzzzzzzTypicalHVACSystemComponents(cont’d)DuctworkandAirDistributionSystemzz/z/z/zzzzzzzzz/典型HVAC系统的组成部分(续)管道系统和空气分散系统zz/箱zzzzzzzz/器zzz25TypicalHVACSystemComponents(cont’d)典型HVAC系统的组成部分(续)ControlandMonitoringSystem(s)控制与监测系统zzzzzzzzzz)HVACSystemsDesignConsiderationsHVAC系统设计考量1.ClassofCleanroom/“LevelofCleanliness”1.洁净区类别/“洁净程度”2.Pressurization(RoomsPressureDifferentials)3.AirFlowDirection2.增压(房间压力差)3.气流方向4.Containment5.Cross-contaminationPrevention6.FreshAir/Make-upAirRequirement4.控制区5.交叉污染预防6.新鲜空气/补充空气要求7.TemperatureandHumidityRequirement(Insidevs.OutsidedesignConditions)7.温度与湿度要求(内部相对外部设计条件)26HVACSystemsDesignConsiderations(cont’d)HVAC系统设计考量（续）8.Amountofrequiredexhaustfromthe.Fumehoods,ExhaustArms,DustCollectors,GeneralExhaustsfromServices,etc.)9.AvailabilityofSupportUtilitySystems.Electricity,PrimaryCoolingSources[ChilledWater],PrimaryHeatingSource[HotWater,Steam],CompressedAiretc.)10.ArchitecturalLayout,SpacesandforMechanicalServices/Plenum/Ductworks/Pipework,RequiredClearanceforMaintenance8.来自通风橱、废气区、粉尘收集器、服务区普通废气等的废气量9.辅助设施支持系统的可得性，例如，电力、首要冷却源（冷却水）、首要热源（热水、蒸气）、压缩空气等。10.机械服务压力区管道系统管道工程的建筑布局、空间和所需要的保养性清洁。HVACSystemsDesignConsiderations(cont’d)HVAC系统设计考量（续）11.BuildingStructure11.建筑构造12.CarefulReviewofInsulationRequirements13.AnalysisofFanPerformanceCurvesvs.SystemPerformanceCurves14.NeedforBack-upEquipment15.CarefulanalysisofDuctPressureDrops(EqualFrictionMethodvs.StaticRegainMethod)12.绝缘要求的仔细审阅13.风扇性能曲线和系统性能曲线的分析14.备用设备需求15.管道压力下降的细致分析(均等摩擦法相对于静压恢复法)27VariousTypesofPharmaceuticalandBiotechnologyFacilities各类化学制药与生物制药厂房设施BulkPharmaceuticalChemicals.APIs)OralSolidDosageForms.Tablets,Capsules)SterileManufacturingFacilities.Vaccines,Injectables,SterileAPIs)化学半成品药例如原料药)口服固体制剂例如片剂、胶囊)无菌生产设施例如疫苗、注射液、无菌原料药)外用(例如药膏、霜剂)Topical.ointments,creams,etc.)生物研究实验室

BiologicalResearchLaboratoriesDesignConsiderationforHVACSystemsHVAC系统的设计考量LevelofProtection(basedonexposurelevel)–LevelI,General:normalhousekeepingandmaintenanceisrequired.closedreactorssamplingwithoutexposure)–LevelII,Protected:Stepsaretakentoprotectexposeddrugsubstance.closedfiltration,crystallizerhandhole,dividingwallsbetweenreactors)–LevelIII,Controlled:specificenvironmentalconditionsaredefined,controlledandmonitoredtopreventcontaminationofexposeddrugsubstance.controlledroompressurizationandtemperatureindryingarea,useonlyonematerialatatime,controlledgloveboxforfilters,processenclosures)防护级别(根据暴露程度)–I-级,普通级:要求常规的空气清洁与维护(例如无暴露封闭式反应罐取样)–II-级,防护级:要求采取步骤来保护暴露的药物质(例如封闭式过滤、结晶罐手孔、反应罐之间的隔离墙)–III-级,控制级:建立、控制和监测专门的环境条件以防止暴露的药物质的污染(例如干燥区中受控的房间增压和温度、每次只使用一种材料、用于过滤的受控手套箱、工艺围栏)28DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)LevelofProtection(basedonexposurelevel)防护级别(根据暴露程度)–III-级,控制级:–LevelIII,Controlled:III(a)-级,非无菌:没有微生物控制要求LevelIII(a),Non-aseptic:nomicrobialcontrolrequirementIII(b)-级,无菌:有微生物控制要求LevelIII(b),Aseptic:microbialcontrolrequiredDesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)TypesofOperation:运行类型:–ExposedorOpen:drugsubstanceisexposedtotheenvironmentduringaprocess–暴露或敞开式:工艺过程中药物质暴露于环境–NotExposedorClosed:drugsubstanceisnotexposedtotheenvironmentduringaprocess–非暴露或封闭式:工艺过程中药物质不暴露于环境29DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)Compliancewithallapplicablebuilding,safety,hygiene,andenvironmentalregulationsFutureprocessexpansionandprocessflexibilityPossibilityofemployingIsolator/BarrierTechnologyExtremeoutdoorconditions符合所有的关于建筑、安全、卫生和环境法规未来工艺扩展和工艺变更灵活性采用隔离屏障技术的可能性极端室外条件吸入和排放位置IntakeandexhaustlocationsWinddirectionRoomParametersaffectingtheProductquality风向房间参数影响产品质量DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)CostFactor–UseofIsolator/BarrierTechnology–Workersprotectiondevices–Cross-contaminationpreventionbymeansofusingonce-throughHVACsystemsanduseofairfilters,dedicatedAHUs–Useofsafetydevicessuchassensors,firedampers,isolatingdampers–Productprotection,useofgloveboxesandlaminarflowhoods–FreeCoolingSystem(inmildweatherconditions)–UseofEnergyRecoverySystems成本因素–使用隔离/屏障技术–员工防护装置–使用贯流式HVAC系统使用空气过滤器、专用空气处置装置（AHUs）防止交叉污染–使用类似于传感器、火闸、隔离闸等安全装置–使用手套箱和层流罩–自由冷却系统(在温和的气候条件下)–使用能量回收系统30DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)CriticalCost关键成本OperatingCost运行成本DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)PotentialSourceforRoomContamination–OutdoorAir–HVACsystemcomponents–ProcessEquipment/Operation–Infiltration–FailureofHVACSystemresultingreversalflow–RoomConstructionMaterial–Personnel–MultipleProductandMaterialinafacility–FloorDrains房间污染的可能来源–室外空气–HVAC系统组件–工艺设备/运行–渗透–HVAC系统失效导致逆流–房间建筑材料–人员–设施中有多个产品和材料–地漏31DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)–Dispersalofproductaroundmanufacturingfacilitiesthroughinadequatelydesigned(nonGMP)airhandlingsystemzoning,airlocks,androompressuredifferentials–Spreadofproductaroundmanufacturingfacilitiesviaenvironmentalandprocessairhandlingsystems–Dispersalofproductduringthecleaningandmaintenanceofenvironmentalandprocessairhandlingplantandequipment–通过设计不当的空气处置系统分区（非GMP）、气锁和房间压差造成产品在生产设施内散布–通过环境和工艺空气处置系统产品在生产设施内扩散–在清洁和维护生产环境和工艺空气处置车间和设备时造成产品散布DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)–Maximizethepracticeofcontainmentofproductwithinthemanufacturingprocesssystemtominimizethepotentialsourcesofproductcross-contamination.–Whereverproductormaterialisexposed,useadequatelydesignedlocalizedcontainment,forexample,localexhaustventilationandcontainmentbooths,etc.–在生产工艺系统中实现使产品控制区最大化以使产品交叉污染的可能来源最小化–任何产品或物料暴露的地方，采用设计恰当的局部化的控制区，例如局部排废通风和控制台等32DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)RoomAirDistribution房间空气分布–Thekeyfunctionofanairhandlingsystemistofacilitateenvironmentalconditionsoftemperatureandhumidity.–Provisionsforreducingroomparticlecountduringmanufactureoperationsshouldbeprovidedthroughcarefuldilutionofparticle-contaminatedroomairwithparticlefreesupply.–一个空气处置系统的关键功能是调节环境的温度与湿度条件.–应通过采用无颗粒送气来逐步稀释含颗粒污染房间的空气的方式为生产运行期间降低颗粒数提供保障DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)ZoningofAirHandlingSystems–handlingforspecificmanufacturingdepartments,example,dry,liquid,andsterileproductmanufacture–Separatehandlingformanufacturingandmanufacturingoperations,example,manufacturingandprimarypacking,secondarypacking,laboratoriesasin-processandadministrationfacilities,–handlingunitsforproductscontainingspecificactiveingredientswherepossible–Once-throughairhandlingplants.,norecirculation)recirculationsystemsAirlocksbetweenairhandlingzones空气处置系统的分区––QC––(33DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)AirLocks气锁–Negativepressureairlocks:Accountshallbetakenoftheriskofbringingproduct-contaminatedairstreamsfromtwoairhandlingzonesclosertogetherwhenusingnegativeairlocks.–Positivepressureairlocks:Carefulconsiderationshouldbegiventoensuringthatairisnotsuppliedtopositivepressureairlocksfromaproduct-contaminatedsource.–负压气锁:使用负压气锁时需要注意把来自两个空气处置区的产品污染气流带得更为接近的风险–正压气锁:需要仔细考虑确保来自一个产品污染源的空气不向正压气锁方向流动DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)RoomPressureDifferentials房间压差–Roompressuredifferentialsshouldbeadequatetominimizethedispersalofproductbyensuringairmovementinacontrolledandpredetermineddirection.–房间压差应该通过使气流运动按照控制的和预先确定的方向流动来足以把产品扩散最小化。34DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)PressurizationControl––––––––增压控制––––––––VariousTypesofHVACSystems各种类型HVAC系统ConstantAirVolumevs.VariableAirVolume恒定气流体积相对于可变气流体积Once-Throughvs.Re-circulated贯流式相对于再循环式Ordinaryvs.CleanRoom非洁净区相对于洁净区Dilutionvs.Displacement稀释式相对于置换式Horizontalflowvs.VerticalFlow平行流式相对于垂直流式TurbulentFlowvs.UnidirectionalFlow乱流式相对于单向流式ExplosionProofvs.Non-ExplosionProof防爆式相对于非防爆式35VariousTypesofHVACSystems(cont’d)各种类型HVAC系统续)ConstantAirVolumevs.VariableAirVolume恒定气流体积相对于可变气流体积–ConstantAirVolumeSystem:–恒定气流体积系统:SimpletoBalanceandHighlyStable易于平衡和高度稳定Generallynoneedforcontinuousadjustmentandairbalancingduringnormaloperations在常规操作情况下一般不需要连续调节和平衡气流VeryreliableandwidelyusedinPharmaceuticalandBiohazardContainmentLaboratories非常可靠并广泛应用在制药和生物毒性封闭式实验室中LessInitialCostofInstallation较少的初始成本

Largermake-upair较大的补充空气Higheroperatingcost,ifnoenergyrecoveryused较高的运行成本,如果不采用能量回收的话VariousTypesofHVACSystems(cont’d)各种类型HVAC系统续)–VariableAirVolumeSystem–可变气流体积系统Mostlyusedforlaboratories大部分用于实验室LimitedtothefacilitiesthatallowUsageDiversityFactorNeedformorefrequentcheckingandbalancingduringnormaloperationHigherInitialInstallationCostHigherMaintenanceCost限制于允许UDF的设施在常规运行条件下需要更经常的检查与平衡较高的初始安装成本较高的维护成本36VariousTypesofHVACSystems(cont’d)各种类型HVAC系统续)Recirculationvs.Once-ThroughAirHandlingSystems再循环式相对于贯流式系统–回流到空气处置车间的气流将不是产品污染的–Returnairtoairhandlingplantshallnotbeproductcontaminated.–空气处置系统中的高效过滤器为防止产品交叉污染提供足够保护。选择正确的HEPA过滤器.–HEPAfiltersinairhandlingsystemgiveadequateprotectionagainstproductcross-contamination.SelectcorrectHEPAfilter.–Isairhandlingsystemservingothercriticalproductmanufacturingareas–空气处置系统服务于其它关键产品生产区域吗Once-ThroughAirHandlingSystems贯流式空气处理系统37Re-circulatingAirHandlingSystems再循环式空气处理系统DedicatedAHUsForMultipleProductFacility多产品设施专用空气处理装置38DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)AirHandlingPlants空气处置车间–Thelocationofdustcollectionsystemairhandlingplantsexternaltomanufacturingbuilding–Theuseofsafe-changefilterswherelocatedinproductcontaminatedairstreams–Segregationofairhandlingsystemplants–粉尘收集系统空气处置车间外接生产厂房的–在位于产品污染气流的地方使用安全更换过滤器–空气处置系统的分块DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)FreshAirIntakesandExhausts新鲜空气吸入和废气排出–Thelocationandsignoffreshairintakesanddischargeairexhauststotheatmospherefromairhandlingplantsshouldbedesignedtoeliminatetheriskofproductcross-contaminationbyshortcircuitingofairstreams.–新鲜空气吸入和把废气排放到来自空气处置车间的大气中的位置和标志应该通过短程气流循环来设计以排除产品交叉污染的风险39DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)EquipmentFailureMode设备故障模式–MechanicalFailureofSupply/Return/ExhaustFans–供气/回气/排气扇的机械故障–FailureofallfansduetoElectricalInterruption–因停电造成的所有风扇停转–SpecialSequenceofOperation–运行的特殊顺序–InterlocksandAlarms–互锁与警报–Room/ZoneFailSafeMode(Isolators)–房间/区域故障安全模式(隔离室)DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)CriticalParameters–Temperature–RelativeHumidity–AirBorneParticulates–RoomPressureandPressureDifferentials–AirChanges(ACH)–Monitoring–SpecialProcess–AirSupplyandDistributionMethod–Process,PersonnelandMaterialFlow–ActivityLevel关键参数–温度–相对湿度–空气粉尘颗粒–房间压力和压差–空气交换–监测–特殊工艺–供气与分布方法–工艺、人流与物流–作业级别40DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)TemperatureControl:温度控制:–Requiredforstableconditionfortheprocessmaterial,instrumentationaswellaspersonnelcomfort–工艺物料、仪器稳定条件以及人员舒适度的要求–放热工艺设备的考量–ConsiderationforHeat-GeneratingProcessEquipment–大厂房设施采用多个温度控制区–UseofMultipleTemperatureControlZonesforLargeFacilitiesDesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)HumidityControl:湿度控制:–Requiredfor:–以下要求:Preventing:corrosionand/oroxidation,condensation防止:腐蚀或氧化、工作区表面凝集、产品污染ontheworksurfaces,productcontamination减小静电ReducingStaticElectricity提供人员舒适度ProvidingPersonnelComfort控制微生物生长ControllingMicrobialGrowth41DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)UseofHEPAFilters–AreterminalHEPAfiltersonroomairsuppliesnecessarytopreventriskproductmigrationfromonemanufacturingareatoanotherthroughductworkdistributionsystemswhenairhandlingplantisinoperative–AreterminalHEPAfiltersonroomairreturnsnecessarytopreventproductcontaminationofairhandlingplantcomponentsandduct-workdistributionsystemorriskofproductmigrationfromonemanufacturingareatoanotherthroughductworkdistributionsystems–AreHEPAfiltersonmainreturnstoairhandlingplantsnecessarytopreventproductcontaminationofairhandlingplantcomponents–Willproductionarea,andhencereturnductworkandairhandlingplant,beproductcontaminatedIsthisacceptable使用HEPA过滤器–需要在房间空气供应终端安装HEAP过滤器以便防止产品在空气处置车间不在运转状态时通过管道分布系统从一个生产区域流动到另一个生产区域吗–需要在房间回气终端安装HEAP过滤器以便防止空气处置车间单元的产品污染或产品通过管道分布系统从一个生产区域流向另一个生产区域–需要在通向空气处置车间的主回气口安装HEPA过滤器以便防止空气处置车间单元的产品污染吗–生产区域及其回气管道系统和空气处置车间将会受到产品污染吗这可以接受吗DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)Non-GMPConsideration非GMP考量–WorkersComfort–人员舒适–OutdoorAirQuality.Odor)–室外空气质量（例如气味)–WorkplaceNoiseLevel–工作现场噪音程度–VentilationforHazardousEnvironment–有毒环境的通风42DesignConsiderationforHVACSystems(cont’d)HVAC系统的设计考量续)EnvironmentalStandards环境标准–ISO14644-1andISO14644-2–ISO14644-1和ISO14644-2–FS209E–FS209E–EuropeanStandards–欧洲标准–FDA–FDA–USP–USPClassifiedandControlledEnvironmentsinBiopharmaceuticalManufacturing生物制药厂房的分级和控制环境CriticalSurfaces关键工作面CriticalAreas(Class100orbetter)关键区域(100级或更高)–Wherecriticaltransfersareperformed–执行关键作业的地方AsepticProcessingAreas(Class10,000orbetter–Areasusedforchromatographyandotherfinalpurificationsteps无菌工艺区域(10,000级或更高）–用于色谱和其它最后纯化步骤的区域43ClassifiedandControlledEnvironmentsinBiopharmaceuticalManufacturing(cont’d)生物制药厂房的分级和控制环境(续)SupportAreastoAsepticProcessing(Class100,000orbetter)无菌工艺支持区域(100,000级或更高)–为更高级别区域准备物品的地方–WhereitemsarepreparedforuseintheareasofhigherclassificationNon-AsepticControlledAreas(FromClass100toClass100,000)Unclassifiedareas非无菌控制区域从100级到100,000级)无分级区域ClassificationsforanAsepticFacility一个无菌设施的分级44CleanRoomClassification洁净房间分级PointstoConsider考虑要点Eachareaunderstaticconditionsshouldnotexceed25%ofthedesignroomclassificationinuse.NMT25particles≥micronspercubicfootinaClass100zone)Thismayprovidegreaterconfidencethattheroomwillnotexceeditsdesignparticulatelevelunderdynamicconditions每个区域在静态条件下不应超过设计房间级别使用时的25%即在100级区域每平方英尺不超过25个尘粒大于微米)这将可以更加保证在动态条件下房间不会超过其设计尘粒水平。45ExampleforaClass10,000&Class100,000Cleanrooms10,000级和100,000级洁净室例子ExampleforaClass100Cleanroom100级洁净室例子46ExampleforaClass100Cleanroom100级洁净室例子Theprimaryairisprovidedbyaprimaryairhandlingunit,whichconsistsofamixingbox,80-95%filters,coolingcoil,heatingcoilandacontrollablepitchaxialflowfanwithbuiltinsoundattenuator.Thesupplyairisdistributedthroughmediumpressureductwork.TheprimaryairissuppliedtotheroomsbyindividuallyductedHEPAfilterunitsthatfilltheentirecleanroomT-gridceiling.Thesecondaryairhandlingunit(orMake-upairunitinthiscase)isprovidingpre-coolingandheatingandfreshair.Thereturnairfromthecleanroomsistransferredthroughfloor-mountedregistersintoanairtightreturnairplenum.Thenthereturnairpassesthroughtheceilingreturnairplenumandfinallyductedbacktotheprimaryairhandlingunit.Sincethereturnairplenumandchasesareusedforprocessequipmentservices,thereturnairshouldfiltered.新风由一个新风处置单元提供，该单元包括一个混合箱，8