Revisedasof23November2020Revisedasof23November2020美歐GMP藥廠主要設(shè)施專項(xiàng)培訓(xùn)教材cGMPCompliantDesign,CommissioningandValidationofPharmaceuticalandBiotechnologyFacilities&UtilitySystems化學(xué)藥廠與生物技術(shù)藥廠廠房設(shè)施與輔助系統(tǒng)的cGMP符合性設(shè)計(jì)、調(diào)試和驗(yàn)證:NaderMoslemianDirector,EngineeringOperationsNaderMoslemian工程運(yùn)行主任PharmEngTechnologyInc.加拿大制藥工程公司.Instructor’sContactInformation授課專家聯(lián)系信息NaderMoslemianNaderMoslemianthth1Introduction導(dǎo)言CourseObjectives課程目標(biāo)Introductionto:DesignandValidationofPharmaceuticalandBiotechnologyUtilitySystems:–HVACSystems–PurifiedWaterandWFIWaterSystems–PureSteamSystem–CleanInPlace(CIP)/SanitizationInPlace(SIP)Systems–CompressedAirandMedicalGasSystems–WasteDisposalSystems–OtherUtilitySystems學(xué)習(xí)和了解化學(xué)藥廠與生物技術(shù)藥廠廠房設(shè)施與輔助系統(tǒng)的設(shè)計(jì)與驗(yàn)證–HVAC（加熱、通風(fēng)與空調(diào)）系統(tǒng)–純化水與注射用水系統(tǒng)–純蒸氣系統(tǒng)–現(xiàn)場(chǎng)清潔(CIP)/現(xiàn)場(chǎng)消毒系統(tǒng)(SIP)–壓縮空氣與醫(yī)用氣體系統(tǒng)–廢棄物處置系統(tǒng)–其它輔助設(shè)施系統(tǒng)2CourseOutlines課程梗概1.HVACSystemsDesignandValidation2.PurifiedandWFIWaterSystemsDesignandValidation3.PureSteamSystemDesignandValidation4.CIPandSIPSystemsDesignandValidation5.WasterWaterTreatmentSystemsDesignandValidation6.CompressedAirandMedicalGasesDesignandValidation7.IntroductiontoOtherProcessUtilitySystems1.HVAC系統(tǒng)設(shè)計(jì)與驗(yàn)證2.純化水與注射用水系統(tǒng)設(shè)計(jì)與驗(yàn)證3.純蒸氣系統(tǒng)設(shè)計(jì)與驗(yàn)證4.CIP和SIP系統(tǒng)設(shè)施與驗(yàn)證5.廢水處理系統(tǒng)設(shè)計(jì)與驗(yàn)證6.壓縮空氣和醫(yī)用氣體設(shè)計(jì)與驗(yàn)證7.其它工藝輔助設(shè)施系統(tǒng)介紹Resources參考資料ISPEBaselinePharmaceuticalEngineeringGuide–Volume1:BulkPharmaceuticalChemicals–Volume2:SolidDosageForm–Volume3:SterileManufacturingFacilities–Volume4:WaterandSteamSystems–Volume5:CommissioningandQualificationTheBuildingCommissioningHandbook,APPAASHRAEGuidelinesCurrentGoodManufacturingPracticeUnitedStatesPharmacopeia(USP)ISO14644-1&14644-2&14644-2ISPE制藥工程基礎(chǔ)指南–卷-1:化學(xué)原料藥–卷-2:固體制劑–卷-3:無菌生產(chǎn)設(shè)施–卷-4:水和蒸氣系統(tǒng)–卷-5:調(diào)試與確認(rèn)APPA廠房調(diào)試手冊(cè)ASHRAE指南cGMP美國(guó)藥典(USP)ISO14644-1&14644-2&14644-23PharmaceuticalandBiotechnologyFacilityDesign&Compliance化學(xué)藥廠與生物技術(shù)藥廠廠房設(shè)計(jì)與GMP符合性Layout&ArchitecturalDesign布局與建筑設(shè)計(jì)DESIGNOFMATERIALFLOW物流設(shè)計(jì)–(SHIPPING,RECEIVING,MATERIALHANDLING,MATERIALTRACKING,AREASEGREGATION)DESIGNOFPERSONNELFLOW–(送貨、收貨、物料處置、物料跟蹤、區(qū)域分隔)人流設(shè)計(jì)–分隔、產(chǎn)品。人員保護(hù)、隔離、單向–SEGREGATION,PRODUCT/PERSONNELPROTECTION,ISOLATION,UNIDIRECTIONDESIGNOFAIRFLOWDESIGNOFPRODUCTIONANDEQUIPMENTLAYOUTHEALTH&SAFETYCONSIDERATIONS氣流設(shè)計(jì)生產(chǎn)與設(shè)備布局的設(shè)計(jì)健康與安全考量4Layout&ArchitecturalDesign(cont’d)

布局與建筑設(shè)計(jì)續(xù))OVERALLFACILITYLAYOUT&AREADEFINITION廠房總體布局與區(qū)域規(guī)劃ROOMLAYOUT操作室布局–DATASUMMARY,CLASSIFICATION&CONDITIONSOFALLUSEDAREA,UTILITY&PROCESSREQUIREMENT–數(shù)據(jù)歸納、所有使用區(qū)域的分類與條件、輔助設(shè)施與過程要求ARCHITCTURALFINISHOFFLOOR,WALL,CEILING&地板、墻、密封和門的建筑完工DOOR升降裝置設(shè)計(jì)、形狀、區(qū)段DESIGNOFELEVATIONS,SHAPE,SECTIONS建造和材料的功能規(guī)格FUNCTIONALSPECIFICATIONSOFCONSTRUCTION&MATERIALSNonSterileManufacturingFacilityLayout非無菌生產(chǎn)廠房布局5AsepticManufacturingFacilityPart-Plan滅菌生產(chǎn)廠房部分規(guī)劃AirFlow氣流AirPressurization空氣增壓CleanCorridorsandAirLocks潔凈走道和氣鎖AirFlowDirection氣流方向AirChanges空氣置換AreaClassification(GMP,Electrical,Hazardous,etc.)CommitteeEvaluationofAirFlow區(qū)域分類(GMP,電力、有毒等)氣流調(diào)試評(píng)估6Non-AsepticManufacturingAirFlow非滅菌生產(chǎn)氣流AsepticManufacturingAirFlow滅菌生產(chǎn)氣流7MaterialFlow物流Unidirectional單向DefinitionandSeparation規(guī)劃與分離Receipt,Quarantined,Released,In-Process,BulkProducts,PackagingComponents,Storage,DistributionCommitteeEvaluationofMaterialFlow收貨,隔離（待驗(yàn)）,放心,中間工藝,半成品,包裝組分,倉(cāng)儲(chǔ),分發(fā)物流調(diào)試評(píng)估Non-AsepticManufacturingMaterialFlow非滅菌生產(chǎn)區(qū)物流8AsepticManufacturingMaterialFlow滅菌生產(chǎn)區(qū)物流PersonnelFlow人流MinimizePotentialforCrossContamination使交叉污染最小可能AirlockWhenAppropriate適當(dāng)情況下采用氣鎖DedicatedUniform&Shoes專用制服與鞋CommitteeEvaluationofPersonnelFlow人流調(diào)試評(píng)估9Non-SterileManufacturingPersonnelFlow非無菌生產(chǎn)區(qū)人流AsepticManufacturingPersonnelFlow滅菌生產(chǎn)區(qū)人流10AreaClassifications區(qū)域分類LevelIGeneralAreaShipping,Warehouse,etc.LevelIIGMPArea/ProtectedAreaDispensingGranulationCompressionPackagingLevelIIICriticalAreaI-級(jí)普通區(qū)域送貨、倉(cāng)庫(kù)等II-級(jí)GMP區(qū)域/保護(hù)區(qū)域分發(fā)制粒壓片包裝III-級(jí)控制區(qū)域AsepticSterileParentalToxic滅菌無菌注射有毒PharmaceuticalFacilityValidation制藥設(shè)施驗(yàn)證REVIEWSYSTEMDESIGNUSINGPRINCIPLESOFGMP(GOODMANUFCTURINGPRACTICE)/GEP(GOODENGINEERINGPRACTICE)PREPAREVALIDAITONMASTERPLANDESIGNQUALIFCATIONPROTOCOLINSTALLATIONQUALIFICATIONOPERATIONALQUALIFICATIONPERFORMANCEVALIDATIONCHANGECONTROLMANAGEMENTSYSTEMDOCUMENTATIONMANAGEMENTSYSTEM使用GMP/GEP原則評(píng)價(jià)系統(tǒng)設(shè)計(jì)準(zhǔn)備驗(yàn)證主計(jì)劃設(shè)計(jì)確認(rèn)方案安裝確認(rèn)運(yùn)行確認(rèn)性能驗(yàn)證變更控制管理系統(tǒng)文件管理系統(tǒng)11FacilityandUtilitiesDocumentation廠房設(shè)施與輔助設(shè)施文件FACILITYSYSTEMAS-BUILTDRAWINGSFINALAPPROVEDSHOPDRAWINGSP&IDWIRINGDIAGRAMSPRESSURETESTINGREPORTISOMETRICDRAWINGSBALANCINGREPORTSYSTEMDESIGNCALCULATIONWORKPERMITCOPYASMECERTIFICATIONPASSIVATIONREPORTBLOCKDIAGRAMSSYSTEMSCHEMATICSEQUIPMENTLISTCLEANINGREPORTCOMMISSIONINGREPORT廠房設(shè)施系統(tǒng)完成圖紙最后批準(zhǔn)的車間圖紙P&ID線路圖壓力檢測(cè)報(bào)告等比例圖紙平衡報(bào)告系統(tǒng)設(shè)計(jì)計(jì)算工作許可證復(fù)印件ASME證書鈍化報(bào)告結(jié)構(gòu)圖紙系統(tǒng)圖表設(shè)備清單清潔報(bào)告調(diào)試報(bào)告Instrumentation&ControlDesign儀器與控制設(shè)計(jì)DEFINEINSTRUMENTATIONANDCONTROLPHILOSOPHYIDENTIFYAUTOMATION,CONTROLSANDMONITORINGSYSTEMREQUIREMENTBUILDINGMANAGEMENTSYSTEM(BMS)FACILITYMONITORINGSYSTEMFMS)IDENTIFYINPUT/OUTPUTCONFIGUREHARDWARE&SOFTWAREINTERFACEOPERATIONSCALIBRATIONREQUIREMENT21CFRPART11ASSESSMENT確定儀器與控制設(shè)計(jì)思路明確自動(dòng)化、控制和檢測(cè)系統(tǒng)要求建筑管理系統(tǒng)(BMS)廠房設(shè)施監(jiān)測(cè)系統(tǒng)(FMS)明確輸入/輸出布局硬件和軟件接口運(yùn)行校驗(yàn)要求美國(guó)FDA計(jì)算機(jī)過程控制的21CFRPART11評(píng)價(jià)12EquipmentDesignForProcessOptimization過程優(yōu)化的設(shè)備設(shè)計(jì)MINIMIZEEQUIPMENTINGMPAREAGMP區(qū)域設(shè)備最小化IMPLEMENTCLOSED-LOOPPRODUCTIONSYSTEM實(shí)現(xiàn)封閉生產(chǎn)系統(tǒng)設(shè)計(jì)現(xiàn)場(chǎng)清潔程序DESIGNCLEAN-IN-PLACEPROCEDURES

標(biāo)準(zhǔn)化工藝與設(shè)備STANDARDIZEPROCESSESANDEQUIPMENTEquipmentIntegration設(shè)備整合VENDORSELECTION供應(yīng)商選擇EQUIPMENTSELECTIONEQUIPMENTMANUFATURINGFACTORYACCEPTANCETEST(FAT)SYSTEMINSTALLATIONSITEACCEPTANCETEST(SAT)設(shè)備選擇設(shè)備制造廠方接受測(cè)試(FAT)系統(tǒng)安裝現(xiàn)場(chǎng)接受測(cè)試(SAT)COMMISSIONINGVALIDATION(IQ/OQ/PQ)調(diào)試驗(yàn)證(IQ/OQ/PQ)13UtilitySystems輔助設(shè)施系統(tǒng)WHATAREUTILITYSYSTEMS什么是輔助設(shè)施系統(tǒng)–UTILITYSYSTEMSARENECESSARYANDANCILIARYSYSTEMSREQUIREDTOSUPPORTPHARMACEUTICALPRODUCTIONSYSTEMSCRITICALUTILITYSYSTEMSMUSTBEVALIDATEDNON-CRITICALUTILITYSYSTEMSONLYREQUIRECOMMISSIONINGANDQUALIFICATION–輔助設(shè)施系統(tǒng)是支持制藥生產(chǎn)系統(tǒng)必需的協(xié)助系統(tǒng)關(guān)鍵輔助設(shè)施須驗(yàn)證非關(guān)鍵輔助設(shè)施僅需要調(diào)試與確認(rèn)Critical/Non-CriticalSystems關(guān)鍵/非關(guān)鍵系統(tǒng)CRITICALSYSTEMSNON-CRITICALSYSTEMS關(guān)鍵系統(tǒng)非關(guān)鍵系統(tǒng)SYSTEMSWHICHHANDLEAND/ORCONTAINSUBSTANCESWHICHWILLCOMEINTOPRODUCTCONTACTTHESESYSTEMSMUSTBEVALIDATEDSYSTEMSWHICHHANDLEAND/ORCONTAINSUBSTANCESWHICHWILLNOTCOMEINTOCONTACTWITHPRODUCT.THESESYSTEMSMUSTBEQUALIFIED.處置和或包含將與產(chǎn)品接觸的物質(zhì)的系統(tǒng)這些系統(tǒng)必須要驗(yàn)證處置和或包含不與產(chǎn)品接觸的物質(zhì)的系統(tǒng)這些系統(tǒng)必須要確認(rèn)14CommonUtilitySystems常見輔助設(shè)施HVACSYSTEMNITROGEN(N2)-INERTINGOFVESSELSHYDROGEN(H2)-HYDROGENATIONREACTIONSOXYGEN(O2)-AEROBICFERMENTATIONCARBONDIOXIDE(CO2)-ANAEROBICFERMENTATIONCOMPRESSEDAIR-PRESSURETRANSFER,LINEBLOWING,INSTRUMENTATIONCONTROLSTEAMSYSTEMS-SIPSTEAMPLACESANITIZATION,HEATSOURCE,HUMIDIFICATION空調(diào)系統(tǒng)氮?dú)?N)–反應(yīng)容器的惰性化保護(hù)氫氣(H)-加氫反應(yīng)氧氣(O)-有氧發(fā)酵二氧化碳(CO)-無氧（厭）氧發(fā)酵壓縮空氣–壓力傳輸、管道吹風(fēng)、儀器控制蒸氣系統(tǒng)-現(xiàn)場(chǎng)蒸氣消毒（SIP）、熱源、濕度化CommonUtilitySystems(cont’d)常見輔助設(shè)施續(xù))PURIFIEDWATERSYSTEMS(RINSINGANDNONSTERILECOMPOUNDING)WFIWATERSYSTEMS(FINALRINSINGANDSTERILECOMPOUNDING)THERMALHEATTRANSFERSYSTEMS(HEATINGANDCOOLINGOFPROCESSESFROM–to350deg.C)CLEAN-IN-PLACE(CIP)SYSTEMS純化水系統(tǒng)(清洗和非無菌化合反應(yīng))注射用水（WFI）系統(tǒng)(最后清洗用水和無菌化合反應(yīng))熱能傳輸系統(tǒng)(工藝的加熱和冷卻從到350deg.C)現(xiàn)場(chǎng)清洗(CIP)系統(tǒng)15MiscellaneousSystems其它系統(tǒng)AUTOCLAVES高壓滅菌設(shè)施

LYOPHYLIZATIONSYSTEMS冷凍干燥系統(tǒng)

WASTETREATMENTSYSTEMS三廢處理系統(tǒng)––氣––液––固SOLVENTRECOVERYSYSTEMS溶劑回收系統(tǒng)–DISTILLATIONTOWERS–蒸餾塔

–LOWTEMPERATURECONDENSERS–低溫冷凝器SafetySystems安全系統(tǒng)PESSURERELIEFSYSTEMS(RELIEFVALVES,RUPTUREDISCS)VENTINGSYSTEMSGASSCRUBBINGSYSTEMSSPILLCONTAINMENTSYSTEMSOPERATORPROTECTIVESYSTEMSFIREPROTECTIONSYSTEMSEXPLOSIONPROTECTION(BUILDINGS,EQUIPMENT)壓力泄放系統(tǒng)(泄放閥、破裂片)通風(fēng)系統(tǒng)氣體清潔系統(tǒng)濺灑污染系統(tǒng)操作者防護(hù)系統(tǒng)火災(zāi)防護(hù)系統(tǒng)防爆(建筑、設(shè)備)16PrimaryAuthorities主要藥監(jiān)機(jī)構(gòu)HEALTHCANADA,HPFBI(HEALTHPOTECTION,FOODBRANCHINSPECTORATE)USFDA(UNITEDSTATESFOODANDDRUGADMINISTRATION)HPFBI(加拿大衛(wèi)生部醫(yī)保與食品檢查署）FDA(美國(guó)食品藥品監(jiān)管局)USP(UNITEDSTATESPHARMACOPIA)BP(BRITISHPHARMACOPIA)CFR21(CODEOFFEDERALREGULATIONScGMP)USP(美國(guó)藥典)BP(英國(guó)藥典)TPP(THERAPUTICPRODUCTSPROGRAMGMP2002)CFR21(美國(guó)聯(lián)邦法規(guī)cGMP)TPP(加拿大藥品管理規(guī)范GMP2002)DesignAuthorities設(shè)計(jì)監(jiān)管機(jī)構(gòu)HPFBI&USFDABOTHSTIPULATETHATNOGOVERNINGAUTHORITYISALLOWEDTOBECIRCUMVENTEDINTHEDESIGNOFPHARMACEUTICALFACILITIES.cGMPSMUSTBEACHIEVEDWHILEABIDINGBYTHECODESANDREGULATIONSOFALLGOVERNINGAUTHORITIES.加拿大和美國(guó)藥監(jiān)機(jī)構(gòu)（HPFBI&USFDA）都規(guī)定在藥廠廠房設(shè)計(jì)方面必須接受各監(jiān)管機(jī)構(gòu)監(jiān)管。在遵守所有監(jiān)管部門法規(guī)的同時(shí)還必須達(dá)到cGMP符合性要求。17AuthoritiestoComplyWith需要遵從的監(jiān)管機(jī)構(gòu)MINISTRYOFTHEENVIRONMENTOHSA(OCCUPATIONALHEALTH&SAFETYACT)EPA(ENVIRONMENTALPROTECTIONAGENCY)UL(UNDERWRITERSLABORATORIES)NIST(NATIONALINSTITUTEOFSTANDARDS)ASHRAE(AMERICANSOCIETYOFHEATING,REFRIGERATIONANDAIRCONDITIONINGENGINEERS)ISPE(INTERNATIONALSOCIETYOFPHARMACEUTICALENGINEERS)NBC(NATIONALBUILDINGCODE)OBC(ONTARIOBUILDINGCODE)NFC(NATIONALFIRECODE)NFPA(NATIONALFIREPROTECTIONASSOCIATION)MINISTRYOFTHEENVIRONMENT(環(huán)境部)OHSA(職業(yè)健康與安全法)EPA(環(huán)境保護(hù)署)UL保險(xiǎn)實(shí)驗(yàn)室)NIST(國(guó)家計(jì)量標(biāo)準(zhǔn)所)ASHRAE美國(guó)加熱、冷凍和空調(diào)工程協(xié)會(huì))ISPE(國(guó)際制藥工程協(xié)會(huì))NBC(國(guó)家建筑法)OBC安大略建筑法)NFC國(guó)家防火法)NFPA國(guó)家防火協(xié)會(huì))AuthoritiestoComplyWith(cont’d)

需要遵從的監(jiān)管機(jī)構(gòu)續(xù))TSSA(TECHNICALSTANDARDSANDSAFETYAUTHORITY)ESA(ELECTRICALSAFETYAUTHORITY)CSA(CANADIANSTANDARDSASSOCIATION)ASME(AMERICANSOCIETYOFMECHANICALENGINEERS)ASTM(AMERICANSOCIETYFORTESTINGMATERIALS)ANSI(AMERICANNATIONALSTANDARDSINSTITUTE)HPFBI&USFDABOTHSTIPULATETHATNOGOVERNINGAUTHORITYISALLOWEDTOBECIRCUMVENTEDINTHEDESIGNOFPHARMACEUTICALFACILITIES.cGMPSMUSTBEACHIEVEDWHILEABIDINGBYTHECODESANDREGULATIONSOFALLGOVERNINGAUTHORITIES.TSSA(技術(shù)標(biāo)準(zhǔn)與安全機(jī)構(gòu))ESA(電力安全機(jī)構(gòu))CSA(加拿大標(biāo)準(zhǔn)協(xié)會(huì))ASME(美國(guó)機(jī)械工程協(xié)會(huì))ASTM(美國(guó)材料檢測(cè)協(xié)會(huì))ANSI(美國(guó)國(guó)家標(biāo)準(zhǔn)所)加拿大和美國(guó)藥監(jiān)機(jī)構(gòu)（HPFBI&USFDA）都規(guī)定在藥廠廠房設(shè)計(jì)方面必須接受各監(jiān)管機(jī)構(gòu)監(jiān)管。在遵守所有監(jiān)管部門法規(guī)的同時(shí)還必須達(dá)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系統(tǒng)的設(shè)計(jì)與驗(yàn)證22TypicalHVACSystemComponents典型HVAC系統(tǒng)的組成部分–AirHandlingUnit(s)–空氣處理裝置–CoolingandRefrigerationSystem(s)–冷卻與冷凍系統(tǒng)–HeatingSystem(s)–加熱系統(tǒng)–HVACPipingSystem–HVAC泵系統(tǒng)–DuctworkandAirDistributionSystem–管道系統(tǒng)和空氣分散系統(tǒng)–ControlandMonitoringSystem(s)–控制與檢測(cè)系統(tǒng)TypicalHVACSystemComponents(cont’d)AirHandlingUnit(s)典型HVAC系統(tǒng)的組成部分(續(xù))空氣處理單元),)))23TypicalHVACSystemComponents(cont’d)典型HVAC系統(tǒng)的組成部分(續(xù))CoolingandRefrigerationSystem(s)zz冷卻與制冷系統(tǒng))z)zzzzzzz圈)zzzzzzzzzzTypicalHVACSystemComponents(cont’d)典型HVAC系統(tǒng)的組成部分(續(xù))HeatingSystem(s)加熱系統(tǒng))zzzzzz/zzzzzzzz)zzzzzzzzzzzz24TypicalHVACSystemComponents(cont’d)典型HVAC系統(tǒng)的組成部分(續(xù))HVACPipingSystemHVAC管道系統(tǒng)zzzzzzzzzzzzz)zzz)zzzzzzzzTypicalHVACSystemComponents(cont’d)DuctworkandAirDistributionSystemzz/z/z/zzzzzzzzz/典型HVAC系統(tǒng)的組成部分(續(xù))管道系統(tǒng)和空氣分散系統(tǒng)zz/箱zzzzzzzz/器zzz25TypicalHVACSystemComponents(cont’d)典型HVAC系統(tǒng)的組成部分(續(xù))ControlandMonitoringSystem(s)控制與監(jiān)測(cè)系統(tǒng)zzzzzzzzzz)HVACSystemsDesignConsiderationsHVAC系統(tǒng)設(shè)計(jì)考量1.ClassofCleanroom/“LevelofCleanliness”1.潔凈區(qū)類別/“潔凈程度”2.Pressurization(RoomsPressureDifferentials)3.AirFlowDirection2.增壓(房間壓力差)3.氣流方向4.Containment5.Cross-contaminationPrevention6.FreshAir/Make-upAirRequirement4.控制區(qū)5.交叉污染預(yù)防6.新鮮空氣/補(bǔ)充空氣要求7.TemperatureandHumidityRequirement(Insidevs.OutsidedesignConditions)7.溫度與濕度要求(內(nèi)部相對(duì)外部設(shè)計(jì)條件)26HVACSystemsDesignConsiderations(cont’d)HVAC系統(tǒng)設(shè)計(jì)考量（續(xù)）8.Amountofrequiredexhaustfromthe.Fumehoods,ExhaustArms,DustCollectors,GeneralExhaustsfromServices,etc.)9.AvailabilityofSupportUtilitySystems.Electricity,PrimaryCoolingSources[ChilledWater],PrimaryHeatingSource[HotWater,Steam],CompressedAiretc.)10.ArchitecturalLayout,SpacesandforMechanicalServices/Plenum/Ductworks/Pipework,RequiredClearanceforMaintenance8.來自通風(fēng)櫥、廢氣區(qū)、粉塵收集器、服務(wù)區(qū)普通廢氣等的廢氣量9.輔助設(shè)施支持系統(tǒng)的可得性，例如，電力、首要冷卻源（冷卻水）、首要熱源（熱水、蒸氣）、壓縮空氣等。10.機(jī)械服務(wù)壓力區(qū)管道系統(tǒng)管道工程的建筑布局、空間和所需要的保養(yǎng)性清潔。HVACSystemsDesignConsiderations(cont’d)HVAC系統(tǒng)設(shè)計(jì)考量（續(xù)）11.BuildingStructure11.建筑構(gòu)造12.CarefulReviewofInsulationRequirements13.AnalysisofFanPerformanceCurvesvs.SystemPerformanceCurves14.NeedforBack-upEquipment15.CarefulanalysisofDuctPressureDrops(EqualFrictionMethodvs.StaticRegainMethod)12.絕緣要求的仔細(xì)審閱13.風(fēng)扇性能曲線和系統(tǒng)性能曲線的分析14.備用設(shè)備需求15.管道壓力下降的細(xì)致分析(均等摩擦法相對(duì)于靜壓恢復(fù)法)27VariousTypesofPharmaceuticalandBiotechnologyFacilities各類化學(xué)制藥與生物制藥廠房設(shè)施BulkPharmaceuticalChemicals.APIs)OralSolidDosageForms.Tablets,Capsules)SterileManufacturingFacilities.Vaccines,Injectables,SterileAPIs)化學(xué)半成品藥例如原料藥)口服固體制劑例如片劑、膠囊)無菌生產(chǎn)設(shè)施例如疫苗、注射液、無菌原料藥)外用(例如藥膏、霜?jiǎng)?Topical.ointments,creams,etc.)生物研究實(shí)驗(yàn)室

BiologicalResearchLaboratoriesDesignConsiderationforHVACSystemsHVAC系統(tǒng)的設(shè)計(jì)考量LevelofProtection(basedonexposurelevel)–LevelI,General:normalhousekeepingandmaintenanceisrequired.closedreactorssamplingwithoutexposure)–LevelII,Protected:Stepsaretakentoprotectexposeddrugsubstance.closedfiltration,crystallizerhandhole,dividingwallsbetweenreactors)–LevelIII,Controlled:specificenvironmentalconditionsaredefined,controlledandmonitoredtopreventcontaminationofexposeddrugsubstance.controlledroompressurizationandtemperatureindryingarea,useonlyonematerialatatime,controlledgloveboxforfilters,processenclosures)防護(hù)級(jí)別(根據(jù)暴露程度)–I-級(jí),普通級(jí):要求常規(guī)的空氣清潔與維護(hù)(例如無暴露封閉式反應(yīng)罐取樣)–II-級(jí),防護(hù)級(jí):要求采取步驟來保護(hù)暴露的藥物質(zhì)(例如封閉式過濾、結(jié)晶罐手孔、反應(yīng)罐之間的隔離墻)–III-級(jí),控制級(jí):建立、控制和監(jiān)測(cè)專門的環(huán)境條件以防止暴露的藥物質(zhì)的污染(例如干燥區(qū)中受控的房間增壓和溫度、每次只使用一種材料、用于過濾的受控手套箱、工藝圍欄)28DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))LevelofProtection(basedonexposurelevel)防護(hù)級(jí)別(根據(jù)暴露程度)–III-級(jí),控制級(jí):–LevelIII,Controlled:III(a)-級(jí),非無菌:沒有微生物控制要求LevelIII(a),Non-aseptic:nomicrobialcontrolrequirementIII(b)-級(jí),無菌:有微生物控制要求LevelIII(b),Aseptic:microbialcontrolrequiredDesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))TypesofOperation:運(yùn)行類型:–ExposedorOpen:drugsubstanceisexposedtotheenvironmentduringaprocess–暴露或敞開式:工藝過程中藥物質(zhì)暴露于環(huán)境–NotExposedorClosed:drugsubstanceisnotexposedtotheenvironmentduringaprocess–非暴露或封閉式:工藝過程中藥物質(zhì)不暴露于環(huán)境29DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))Compliancewithallapplicablebuilding,safety,hygiene,andenvironmentalregulationsFutureprocessexpansionandprocessflexibilityPossibilityofemployingIsolator/BarrierTechnologyExtremeoutdoorconditions符合所有的關(guān)于建筑、安全、衛(wèi)生和環(huán)境法規(guī)未來工藝擴(kuò)展和工藝變更靈活性采用隔離屏障技術(shù)的可能性極端室外條件吸入和排放位置IntakeandexhaustlocationsWinddirectionRoomParametersaffectingtheProductquality風(fēng)向房間參數(shù)影響產(chǎn)品質(zhì)量DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))CostFactor–UseofIsolator/BarrierTechnology–Workersprotectiondevices–Cross-contaminationpreventionbymeansofusingonce-throughHVACsystemsanduseofairfilters,dedicatedAHUs–Useofsafetydevicessuchassensors,firedampers,isolatingdampers–Productprotection,useofgloveboxesandlaminarflowhoods–FreeCoolingSystem(inmildweatherconditions)–UseofEnergyRecoverySystems成本因素–使用隔離/屏障技術(shù)–員工防護(hù)裝置–使用貫流式HVAC系統(tǒng)使用空氣過濾器、專用空氣處置裝置（AHUs）防止交叉污染–使用類似于傳感器、火閘、隔離閘等安全裝置–使用手套箱和層流罩–自由冷卻系統(tǒng)(在溫和的氣候條件下)–使用能量回收系統(tǒng)30DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))CriticalCost關(guān)鍵成本OperatingCost運(yùn)行成本DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))PotentialSourceforRoomContamination–OutdoorAir–HVACsystemcomponents–ProcessEquipment/Operation–Infiltration–FailureofHVACSystemresultingreversalflow–RoomConstructionMaterial–Personnel–MultipleProductandMaterialinafacility–FloorDrains房間污染的可能來源–室外空氣–HVAC系統(tǒng)組件–工藝設(shè)備/運(yùn)行–滲透–HVAC系統(tǒng)失效導(dǎo)致逆流–房間建筑材料–人員–設(shè)施中有多個(gè)產(chǎn)品和材料–地漏31DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))–Dispersalofproductaroundmanufacturingfacilitiesthroughinadequatelydesigned(nonGMP)airhandlingsystemzoning,airlocks,androompressuredifferentials–Spreadofproductaroundmanufacturingfacilitiesviaenvironmentalandprocessairhandlingsystems–Dispersalofproductduringthecleaningandmaintenanceofenvironmentalandprocessairhandlingplantandequipment–通過設(shè)計(jì)不當(dāng)?shù)目諝馓幹孟到y(tǒng)分區(qū)（非GMP）、氣鎖和房間壓差造成產(chǎn)品在生產(chǎn)設(shè)施內(nèi)散布–通過環(huán)境和工藝空氣處置系統(tǒng)產(chǎn)品在生產(chǎn)設(shè)施內(nèi)擴(kuò)散–在清潔和維護(hù)生產(chǎn)環(huán)境和工藝空氣處置車間和設(shè)備時(shí)造成產(chǎn)品散布DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))–Maximizethepracticeofcontainmentofproductwithinthemanufacturingprocesssystemtominimizethepotentialsourcesofproductcross-contamination.–Whereverproductormaterialisexposed,useadequatelydesignedlocalizedcontainment,forexample,localexhaustventilationandcontainmentbooths,etc.–在生產(chǎn)工藝系統(tǒng)中實(shí)現(xiàn)使產(chǎn)品控制區(qū)最大化以使產(chǎn)品交叉污染的可能來源最小化–任何產(chǎn)品或物料暴露的地方，采用設(shè)計(jì)恰當(dāng)?shù)木植炕目刂茀^(qū)，例如局部排廢通風(fēng)和控制臺(tái)等32DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))RoomAirDistribution房間空氣分布–Thekeyfunctionofanairhandlingsystemistofacilitateenvironmentalconditionsoftemperatureandhumidity.–Provisionsforreducingroomparticlecountduringmanufactureoperationsshouldbeprovidedthroughcarefuldilutionofparticle-contaminatedroomairwithparticlefreesupply.–一個(gè)空氣處置系統(tǒng)的關(guān)鍵功能是調(diào)節(jié)環(huán)境的溫度與濕度條件.–應(yīng)通過采用無顆粒送氣來逐步稀釋含顆粒污染房間的空氣的方式為生產(chǎn)運(yùn)行期間降低顆粒數(shù)提供保障DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))ZoningofAirHandlingSystems–handlingforspecificmanufacturingdepartments,example,dry,liquid,andsterileproductmanufacture–Separatehandlingformanufacturingandmanufacturingoperations,example,manufacturingandprimarypacking,secondarypacking,laboratoriesasin-processandadministrationfacilities,–handlingunitsforproductscontainingspecificactiveingredientswherepossible–Once-throughairhandlingplants.,norecirculation)recirculationsystemsAirlocksbetweenairhandlingzones空氣處置系統(tǒng)的分區(qū)––QC––(33DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))AirLocks氣鎖–Negativepressureairlocks:Accountshallbetakenoftheriskofbringingproduct-contaminatedairstreamsfromtwoairhandlingzonesclosertogetherwhenusingnegativeairlocks.–Positivepressureairlocks:Carefulconsiderationshouldbegiventoensuringthatairisnotsuppliedtopositivepressureairlocksfromaproduct-contaminatedsource.–負(fù)壓氣鎖:使用負(fù)壓氣鎖時(shí)需要注意把來自兩個(gè)空氣處置區(qū)的產(chǎn)品污染氣流帶得更為接近的風(fēng)險(xiǎn)–正壓氣鎖:需要仔細(xì)考慮確保來自一個(gè)產(chǎn)品污染源的空氣不向正壓氣鎖方向流動(dòng)DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))RoomPressureDifferentials房間壓差–Roompressuredifferentialsshouldbeadequatetominimizethedispersalofproductbyensuringairmovementinacontrolledandpredetermineddirection.–房間壓差應(yīng)該通過使氣流運(yùn)動(dòng)按照控制的和預(yù)先確定的方向流動(dòng)來足以把產(chǎn)品擴(kuò)散最小化。34DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))PressurizationControl––––––––增壓控制––––––––VariousTypesofHVACSystems各種類型HVAC系統(tǒng)ConstantAirVolumevs.VariableAirVolume恒定氣流體積相對(duì)于可變氣流體積Once-Throughvs.Re-circulated貫流式相對(duì)于再循環(huán)式Ordinaryvs.CleanRoom非潔凈區(qū)相對(duì)于潔凈區(qū)Dilutionvs.Displacement稀釋式相對(duì)于置換式Horizontalflowvs.VerticalFlow平行流式相對(duì)于垂直流式TurbulentFlowvs.UnidirectionalFlow亂流式相對(duì)于單向流式ExplosionProofvs.Non-ExplosionProof防爆式相對(duì)于非防爆式35VariousTypesofHVACSystems(cont’d)各種類型HVAC系統(tǒng)續(xù))ConstantAirVolumevs.VariableAirVolume恒定氣流體積相對(duì)于可變氣流體積–ConstantAirVolumeSystem:–恒定氣流體積系統(tǒng):SimpletoBalanceandHighlyStable易于平衡和高度穩(wěn)定Generallynoneedforcontinuousadjustmentandairbalancingduringnormaloperations在常規(guī)操作情況下一般不需要連續(xù)調(diào)節(jié)和平衡氣流VeryreliableandwidelyusedinPharmaceuticalandBiohazardContainmentLaboratories非常可靠并廣泛應(yīng)用在制藥和生物毒性封閉式實(shí)驗(yàn)室中LessInitialCostofInstallation較少的初始成本

Largermake-upair較大的補(bǔ)充空氣Higheroperatingcost,ifnoenergyrecoveryused較高的運(yùn)行成本,如果不采用能量回收的話VariousTypesofHVACSystems(cont’d)各種類型HVAC系統(tǒng)續(xù))–VariableAirVolumeSystem–可變氣流體積系統(tǒng)Mostlyusedforlaboratories大部分用于實(shí)驗(yàn)室LimitedtothefacilitiesthatallowUsageDiversityFactorNeedformorefrequentcheckingandbalancingduringnormaloperationHigherInitialInstallationCostHigherMaintenanceCost限制于允許UDF的設(shè)施在常規(guī)運(yùn)行條件下需要更經(jīng)常的檢查與平衡較高的初始安裝成本較高的維護(hù)成本36VariousTypesofHVACSystems(cont’d)各種類型HVAC系統(tǒng)續(xù))Recirculationvs.Once-ThroughAirHandlingSystems再循環(huán)式相對(duì)于貫流式系統(tǒng)–回流到空氣處置車間的氣流將不是產(chǎn)品污染的–Returnairtoairhandlingplantshallnotbeproductcontaminated.–空氣處置系統(tǒng)中的高效過濾器為防止產(chǎn)品交叉污染提供足夠保護(hù)。選擇正確的HEPA過濾器.–HEPAfiltersinairhandlingsystemgiveadequateprotectionagainstproductcross-contamination.SelectcorrectHEPAfilter.–Isairhandlingsystemservingothercriticalproductmanufacturingareas–空氣處置系統(tǒng)服務(wù)于其它關(guān)鍵產(chǎn)品生產(chǎn)區(qū)域嗎Once-ThroughAirHandlingSystems貫流式空氣處理系統(tǒng)37Re-circulatingAirHandlingSystems再循環(huán)式空氣處理系統(tǒng)DedicatedAHUsForMultipleProductFacility多產(chǎn)品設(shè)施專用空氣處理裝置38DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))AirHandlingPlants空氣處置車間–Thelocationofdustcollectionsystemairhandlingplantsexternaltomanufacturingbuilding–Theuseofsafe-changefilterswherelocatedinproductcontaminatedairstreams–Segregationofairhandlingsystemplants–粉塵收集系統(tǒng)空氣處置車間外接生產(chǎn)廠房的–在位于產(chǎn)品污染氣流的地方使用安全更換過濾器–空氣處置系統(tǒng)的分塊DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))FreshAirIntakesandExhausts新鮮空氣吸入和廢氣排出–Thelocationandsignoffreshairintakesanddischargeairexhauststotheatmospherefromairhandlingplantsshouldbedesignedtoeliminatetheriskofproductcross-contaminationbyshortcircuitingofairstreams.–新鮮空氣吸入和把廢氣排放到來自空氣處置車間的大氣中的位置和標(biāo)志應(yīng)該通過短程氣流循環(huán)來設(shè)計(jì)以排除產(chǎn)品交叉污染的風(fēng)險(xiǎn)39DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))EquipmentFailureMode設(shè)備故障模式–MechanicalFailureofSupply/Return/ExhaustFans–供氣/回氣/排氣扇的機(jī)械故障–FailureofallfansduetoElectricalInterruption–因停電造成的所有風(fēng)扇停轉(zhuǎn)–SpecialSequenceofOperation–運(yùn)行的特殊順序–InterlocksandAlarms–互鎖與警報(bào)–Room/ZoneFailSafeMode(Isolators)–房間/區(qū)域故障安全模式(隔離室)DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))CriticalParameters–Temperature–RelativeHumidity–AirBorneParticulates–RoomPressureandPressureDifferentials–AirChanges(ACH)–Monitoring–SpecialProcess–AirSupplyandDistributionMethod–Process,PersonnelandMaterialFlow–ActivityLevel關(guān)鍵參數(shù)–溫度–相對(duì)濕度–空氣粉塵顆粒–房間壓力和壓差–空氣交換–監(jiān)測(cè)–特殊工藝–供氣與分布方法–工藝、人流與物流–作業(yè)級(jí)別40DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))TemperatureControl:溫度控制:–Requiredforstableconditionfortheprocessmaterial,instrumentationaswellaspersonnelcomfort–工藝物料、儀器穩(wěn)定條件以及人員舒適度的要求–放熱工藝設(shè)備的考量–ConsiderationforHeat-GeneratingProcessEquipment–大廠房設(shè)施采用多個(gè)溫度控制區(qū)–UseofMultipleTemperatureControlZonesforLargeFacilitiesDesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))HumidityControl:濕度控制:–Requiredfor:–以下要求:Preventing:corrosionand/oroxidation,condensation防止:腐蝕或氧化、工作區(qū)表面凝集、產(chǎn)品污染ontheworksurfaces,productcontamination減小靜電ReducingStaticElectricity提供人員舒適度ProvidingPersonnelComfort控制微生物生長(zhǎng)ControllingMicrobialGrowth41DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))UseofHEPAFilters–AreterminalHEPAfiltersonroomairsuppliesnecessarytopreventriskproductmigrationfromonemanufacturingareatoanotherthroughductworkdistributionsystemswhenairhandlingplantisinoperative–AreterminalHEPAfiltersonroomairreturnsnecessarytopreventproductcontaminationofairhandlingplantcomponentsandduct-workdistributionsystemorriskofproductmigrationfromonemanufacturingareatoanotherthroughductworkdistributionsystems–AreHEPAfiltersonmainreturnstoairhandlingplantsnecessarytopreventproductcontaminationofairhandlingplantcomponents–Willproductionarea,andhencereturnductworkandairhandlingplant,beproductcontaminatedIsthisacceptable使用HEPA過濾器–需要在房間空氣供應(yīng)終端安裝HEAP過濾器以便防止產(chǎn)品在空氣處置車間不在運(yùn)轉(zhuǎn)狀態(tài)時(shí)通過管道分布系統(tǒng)從一個(gè)生產(chǎn)區(qū)域流動(dòng)到另一個(gè)生產(chǎn)區(qū)域嗎–需要在房間回氣終端安裝HEAP過濾器以便防止空氣處置車間單元的產(chǎn)品污染或產(chǎn)品通過管道分布系統(tǒng)從一個(gè)生產(chǎn)區(qū)域流向另一個(gè)生產(chǎn)區(qū)域–需要在通向空氣處置車間的主回氣口安裝HEPA過濾器以便防止空氣處置車間單元的產(chǎn)品污染嗎–生產(chǎn)區(qū)域及其回氣管道系統(tǒng)和空氣處置車間將會(huì)受到產(chǎn)品污染嗎這可以接受嗎DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))Non-GMPConsideration非GMP考量–WorkersComfort–人員舒適–OutdoorAirQuality.Odor)–室外空氣質(zhì)量（例如氣味)–WorkplaceNoiseLevel–工作現(xiàn)場(chǎng)噪音程度–VentilationforHazardousEnvironment–有毒環(huán)境的通風(fēng)42DesignConsiderationforHVACSystems(cont’d)HVAC系統(tǒng)的設(shè)計(jì)考量續(xù))EnvironmentalStandards環(huán)境標(biāo)準(zhǔn)–ISO14644-1andISO14644-2–ISO14644-1和ISO14644-2–FS209E–FS209E–EuropeanStandards–歐洲標(biāo)準(zhǔn)–FDA–FDA–USP–USPClassifiedandControlledEnvironmentsinBiopharmaceuticalManufacturing生物制藥廠房的分級(jí)和控制環(huán)境CriticalSurfaces關(guān)鍵工作面CriticalAreas(Class100orbetter)關(guān)鍵區(qū)域(100級(jí)或更高)–Wherecriticaltransfersareperformed–執(zhí)行關(guān)鍵作業(yè)的地方AsepticProcessingAreas(Class10,000orbetter–Areasusedforchromatographyandotherfinalpurificationsteps無菌工藝區(qū)域(10,000級(jí)或更高）–用于色譜和其它最后純化步驟的區(qū)域43ClassifiedandControlledEnvironmentsinBiopharmaceuticalManufacturing(cont’d)生物制藥廠房的分級(jí)和控制環(huán)境(續(xù))SupportAreastoAsepticProcessing(Class100,000orbetter)無菌工藝支持區(qū)域(100,000級(jí)或更高)–為更高級(jí)別區(qū)域準(zhǔn)備物品的地方–WhereitemsarepreparedforuseintheareasofhigherclassificationNon-AsepticControlledAreas(FromClass100toClass100,000)Unclassifiedareas非無菌控制區(qū)域從100級(jí)到100,000級(jí))無分級(jí)區(qū)域ClassificationsforanAsepticFacility一個(gè)無菌設(shè)施的分級(jí)44CleanRoomClassification潔凈房間分級(jí)PointstoConsider考慮要點(diǎn)Eachareaunderstaticconditionsshouldnotexceed25%ofthedesignroomclassificationinuse.NMT25particles≥micronspercubicfootinaClass100zone)Thismayprovidegreaterconfidencethattheroomwillnotexceeditsdesignparticulatelevelunderdynamicconditions每個(gè)區(qū)域在靜態(tài)條件下不應(yīng)超過設(shè)計(jì)房間級(jí)別使用時(shí)的25%即在100級(jí)區(qū)域每平方英尺不超過25個(gè)塵粒大于微米)這將可以更加保證在動(dòng)態(tài)條件下房間不會(huì)超過其設(shè)計(jì)塵粒水平。45ExampleforaClass10,000&Class100,000Cleanrooms10,000級(jí)和100,000級(jí)潔凈室例子ExampleforaClass100Cleanroom100級(jí)潔凈室例子46ExampleforaClass100Cleanroom100級(jí)潔凈室例子Theprimaryairisprovidedbyaprimaryairhandlingunit,whichconsistsofamixingbox,80-95%filters,coolingcoil,heatingcoilandacontrollablepitchaxialflowfanwithbuiltinsoundattenuator.Thesupplyairisdistributedthroughmediumpressureductwork.TheprimaryairissuppliedtotheroomsbyindividuallyductedHEPAfilterunitsthatfilltheentirecleanroomT-gridceiling.Thesecondaryairhandlingunit(orMake-upairunitinthiscase)isprovidingpre-coolingandheatingandfreshair.Thereturnairfromthecleanroomsistransferredthroughfloor-mountedregistersintoanairtightreturnairplenum.Thenthereturnairpassesthroughtheceilingreturnairplenumandfinallyductedbacktotheprimaryairhandlingunit.Sincethereturnairplenumandchasesareusedforprocessequipmentservices,thereturnairshouldfiltered.新風(fēng)由一個(gè)新風(fēng)處置單元提供，該單元包括一個(gè)混合箱，8