WaerSysems水系统知识专题讲座

2023年1月18日

WaterSystems

水系统知识讲座九新药业国际认证部经理高级工程师徐影Toexaminethebasictechnologyandrequirementsfor:检查以下方面的基本技术和要求：

1)Watertreatmentsystems水处理系统

2)Storagerequirements

贮存要求

3)Samplingandtesting

取样和检测4)Differenttypesofwaterusedinpharmaceuticals制药用水的不同类型

5)Microbiallimits,disinfection微生物限度、消毒Objectives

目的C&Q-V-ModelV

VURS用户需求URS¤FDS¤DQ¤SAT¤IQ¤OQWatersystemdesign

水系统的设计

1)Pipesslopedsowaterdoesnotpoolandcandraineasily

管道要有斜度，以防止积水，易于排空2)Sanitaryfittings&connections洁净配件和接口3)Constructedofsuitablematerialssuchasstainlesssteel建造材料适合，如不锈钢4)Circulatethewater水要循环Furtherwatertreatmentpurificationstagesdownstreamofthepre-treatmentsystem预处理系统后水的进一步纯化

1)Filtration

过滤

2)Disinfection

消毒3)Reverseosmosisorde-ionization反渗透或去离子

4)Distillationorultra-filtration

蒸馏或超滤Thereshouldbenodeadlegs不应有死角WaterscoursdeadlegIfD=25mm&distanceXis

greaterthan75mm,wehaveadeadlegthatistoolong.如果D=25mm，X大于75mm，则有较长的死角Deadlegsection死角部分<3DFlowdirectionarrows

onpipesareimportant管道中的流向很重要SanitaryValve洁净阀DXWatersystemdesign(1)

水系统设计（一）3.Thewateriscontaminatedasitpassesthroughthevalve当水通过阀门时，被污染

2.Bacteriacangrowwhenthevalveisclosed

当阀门关闭时，会生长细菌1.Ballvalvesareunacceptable不可使用球阀

Stagnantwaterinsidevalve阀门中的死水Watersystemdesign(2)

水系统设计（二）1)Sanitarypumps洁净泵2)ClampsandOringsversusthreadedfittings卡箍和O环，不用螺纹配件3)Heatexchangers换热器4)Sidearmlevelmeasuringdevicesareunacceptable不可使用边侧臂状水位测量装置Watersystemdesign(3)

水系统设计（三）rawwater原水Highpressure高压Feed

water

Under

pressure加压进水RejectWater不合格水Semi-permeableMembrane半渗透膜PermeateWater渗透水drainorrecycle排放或循环Lowpressure低压Purifiedwater纯化水Reverseosmosis(RO)theory反渗透（RO）原理CationiccolumnAnioniccolumnHygienicpump卫生泵Outletsorstorage.OzonegeneratorUVlightHClNaOHEluatestoneutralizationplantAirbreaktosewer空气断开

Drainlinefromwatersoftener软水机WatermustbekeptcirculatingTypicalde-ionizerschematic典型的去离子示意图123456123456Returntode-ioniserCartridgefilter5µmCartridgefilter1µmBranchBranchCartridgefilter1µµmSecondstageROcartridgeFirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewerSecondstagerejectwatergoesbacktofirststagebuffertankSecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertankWaterfromsoftenerorde-ioniserTypical2-stageROschematic典型二级级反渗透透示意图图HygienicpumpFirststageROcartridgeHighpressurepumpAdvantages优点Disadvantages缺点Manyuses应用领域域purifiedwater纯化水feedingofdistillationunitsorultra-filtrationunits蒸馏器或或超滤器器的进水水WaterforFinalRinse最终冲洗洗用水WaterforInjections(ifpermissible)注射用水水（如许许可）Useofreverseosmosis反渗透的的应用CanbeusedforWFIorforWaterForFinalRinsingforparenteralmanufacturing(ifpermitted)可用作注注射用水水或生产产注射剂剂的最终终冲洗用用水（如如许可））Removesorganiccontaminants,suchasendotoxins去除有机机污染物物，如内内毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下运行，，在121°°C进行灭菌菌Ultra-filtration超滤Single-effectdistillation单效蒸馏馏simpledistillation,singleeffect简单蒸馏馏，单效效vapourcompression,thermocompression蒸汽压缩缩，热压压缩Multieffectdistillation多效蒸馏馏multipleeffectstills多效蒸馏馏机Distillation蒸馏Typicalwaterstorageanddistributionschematic典型的水贮存和分配示意图WatermustbekeptcirculatingSprayballCartridgefilter1µmAirbreaktodrainOutletsHygienicpumpOptionalin-linefilter0,2µmUVlightFeedWaterfromDIorROHeatExchangerOzoneGeneratorHydrophobicairfilter&burstdisc疏水性呼吸过滤器&安全隔膜StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorWatersystemsdesign水系统设设计Check检查Why?HowFeedWaterQuality进水质量量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的处处理阶段段无法处处置未受受限制的的微生物物和内毒毒素负荷荷Connections连接Sampling取样Minimalcrevices最小裂缝缝Inspection检查Watersystemsdesign水系统设设计Check检查Why?HowFinishes抛光Reducebacterialadhesion减少细菌菌粘着Pipeslopes管道倾斜斜度Certification证书Drainabilityespeciallyofcondensateaftersteamsanitising排水性,尤其是是蒸汽消消毒后的的冷凝水水Inspection检查spiritlevel水平仪Isometrics等容法Watersystemsdesign水系统设设计Check检查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利利于微生生物生长长和附着着的条件Sanitisation消毒Flowmeter流速计Records记录Velocityinloop回路中流流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生生物繁殖殖,解决决问题Watersystemsdesign水系统设设计CheckWhy?HowNot““reactive,additiveorabsorptive”不"产生生反应,添加或或吸附"Instruments仪器Certificates证书Certificates证书Inspection检查Materialsofconstruction材质Calibrated已校正Sanitary清洁Watersystemsdesign水系统设计CheckWhy?HowMinimalcrevices最小裂缝Passivation钝化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工资质质确认,焊接接日志)焊接取样,焊焊接检查Documentation(Procedures,Passivationlog)文件(规程,钝化化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蚀性WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality证实有持续产产生高品质水水的能力MasterPlan,验证主计划Protocols,验证方案summaryreports总结报告Validation验证Heat热-Oneofthemostreliablemethodsofdisinfectionofwater systems最可靠的消毒毒水系统的方方法之一Ozone臭氧-Producedeasily容易制备- Leavesnoresidue没有残留Disinfection(1)消毒（一）UV紫外-UVdoesnot“sterilize”紫外不可灭菌菌- Flowratecritical流速很关键- Post-irradiationrecontaminationmaybeanissue后放射再污染染可能是个问问题- Lampshavefinitelife灯的寿命有限限Otherchemicals其他化学法-XO2-Halogen卤素- Formaldehyde甲醛Disinfection(2)消毒（二）Theremustbeasamplingprocedure必须有取样规规程Sampleintegritymustbeassured必须保证样品品的完整性Samplertraining取样人培训Samplepoint取样点Samplesize取样多少Sampling(1)取样（一）Samplecontainer取样容器Samplelabel样品标签Samplestorageandtransport样品储存和转转移Arrivalatthelaboratory到达实验室Startoftest开始测试Sampling(2)取样（二）Testing-settingspecificationsforpurifiedwaterorWFI测试–规定纯化水或或注射用水标标准PurifiedWater纯化水Ph.Eur.中国药典（2005））USPNitrates硝酸盐≤0.2ppm≤0.06ppm-Conductivity电导率≤5.1µµS/cm@25oC-≤1.3µµS/cm@25oCTOC≤0.5mg/l-≤0.5mg/lHeavymetals重金属≤0.1ppm≤0.5ppm-Microbia微生物<100cfu/ml<100cfu/ml<100cfu/mlTesting-settingspecificationsforpurifiedwaterorWFI测试–规定纯化水或或注射用水标标准WFI注射用水Ph.Eur.中国药典（2005））USPNitrates硝酸盐≤0.2ppm≤≤0.06ppm-Conductivity电导率≤1.3µS/cm@25oC-≤1.3µS/cm@25oCTOC≤0.5mg/l-≤0.5mg/lMicrobial微生物<10cfu/100ml<10cfu/100ml<10cfu/100mlEndotoxin内毒素<0.25IU/ml<0.25EU/ml<0.25EU/mlSuggestedbacteriallimitsforPurifiedWater(CFU/mL)建议的微生物物限度纯化化水（CFU/ml）Samplinglocation取样位置Alert报警限Action行动限Rawwater原水300500Postmultimediafilter多介质过滤器后300500Postsoftener软化剂后300500Postactivatedcarbonfilter活性炭后300500FeedtoRO回水至RO200500ROpermeate

RO渗透50100PointsofUse使用点10100TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果没有给出出指导值，可可采用EU指南的限度(前面提到的））做为行动限限。如果有历历史数据，可可以将行动限限定为3倍的平均值的的标准偏差，，警戒限定为为2倍的平均值的的标准偏差ActionandAlertLimits行动限和警戒戒限Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring微生物监测04一月月202334Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系统微生生物监测的的推荐方法法:PurifiedWater纯化水PourPlateMethod平皿法Minimumsample1.0ml.最小取样量量1.0毫毫升Platecountagar48to72hoursincubation培养基培养48-72小时时WaterforInjection注射用水水MembraneFiltrationMethod薄膜过滤法法Minimumsample100ml.最小取样量量100毫毫升Platecountagar48to72hoursincubation培养基培培养48-72小时时Methodverification方法确认Chemicaltesting化学测试Microbiologicaltesting微生物测试试testmethod测试方法typesofmediaused使用的培养养基类型incubationtimeandtemperature培养时间和和温度objectionableandindicatororganisms异议和指示示有机体don’tunderstandmanufacturermustsetspecifications生产商必须须制定标准准Testing检测InternationalpharmacopoeiarequirementsforWFIarethoseforpurifiedwaterplusitmustbefreefrompyrogens国际药典对对注射用水水的要求除除了那些对对纯化水的的要求外，，还要求必必须不含有有热源Usuallypreparedbydistillation通常由蒸馏馏器制得Storagetimeshouldbelessthan24hours储存时间应应少于24小时Microbiallimitsmustbespecified必须制定微微生物限度度WaterforInjections注射用水Waterforfinalrinsemustbeofthesamequalityasthewaterrequiredforpharmaceuticalpreparation最终冲洗用用水的质量量必须与药药品制备所所要求的水水的质量相相同WaterforFinalRinse最终冲洗用用水Anycompoundinjectedintomammalswhichgivesrisetofeverisa“Pyrogen”任何注入哺哺乳动物体体内可引起起发烧的物物质称为““热源”Endotoxinsarepyrogenic,comefromGramnegativebacterialcellwallfragments内毒素具有有热源性，，来源于革革兰阴性菌菌细胞壁Detectendotoxinsusingatestforlipopolysaccharides(LPS)检测内毒素素使用脂多多糖的测试试rabbittestdetectspyrogens兔子试验检检测热源LALtestdetectsendotoxins鲎试剂检测测内毒素Ultrafiltration,distillation,&ROmayremovepyrogens超滤、蒸馏馏和反渗透透可能会去去除热源Pyrogensandendotoxins热源和内毒毒素Trending趋势分析DescribethemicrobiologicalproblemsofthisWFIsystem.描述注射用用水系统的的微生物问问题CountsaretotalnumberofColonyFormingUnitsper100mlActionAlertSOPsSOPsshouldaddressSOPs中应包括以以下内容:Operationandroutinemonitoring操作和日常常监控Maintenanceandcalibration维护和校正正Cleaningandsanitization清洁和消毒毒Validation验证04一一月月202342OperationandRoutineMonitoring运行行和和日日常常监监控控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系统统描描述述（（制制备备系系统统组组件件，，循循环环的的数数量量，，物物料料，，控控制制系系统统））Listusers列明明使使用用点点Listrequirementsforsysteme.g.:列明明系系统统要要求求，，例例如如：：Generatingcapacity制备备能能力力Storagecapacity储存存容容量量Diversity(howmanypointsofusecanbeopenedsimultaneously)差异异性性（（可可以以同同时时开开启启几几个个使使用用点点））Flowrate流速速Temperature温度Specificationsforwaterqualityateachstage每个阶段段的水质质标准04一一月202343OperationandRoutineMonitoring运行和日日常监控控Describesystemoperationincluding:系统的运运行描述述包括Systemstartup系统启动动Systemshutdown关机Emergencyshutdown紧急停机机Normaloperations正常运行行Monitoringduringroutineoperation日常运行行的监控控Describesamplingactivities描述取样样活动Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每一一步纯纯化阶阶段（（监测测类型型，频频次，，接受受标准准）pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS应对04一一月月202345MaintenanceandCalibration维护和和校正正Routineinspectionandmaintenanceactivitiescarriedout:进行的的日常常检查查及维维护活活动Daily每日Weekly每周Monthly每月Annually每年Triggerevents(e.g.afterobservationofaspecificcondition)““触发””事件件（（例如如，观观察到到特殊殊状况况）Includeprocedure,acceptancecriteria,forms包括规规程，，接受受限度度，表表格04一月月202346MaintenanceandCalibration维护和校正正PeriodicCalibrationactivitiescarriedout:应进行定期期校正，包包括Listinstruments––make,model仪器清单-厂家，型号号Range范围Tolerance限度Criticality重要性Timeintervalbetweencalibration频次Ifcarriedoutbycontractor,refertoSOPforcontrolofthirdparties如果由合同同商校正，，应参照第第三方管理理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果内部校校正，确保保每个校正正规程有单单独的SOP04一一月202347Cleaningandsanitization清洁和消消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每个个组件的的清洁和和消毒活活动Methods方法Chemicalsused使用的化化学物质质Frequency频次Duration持续时间间Chemicalconcentration/temperature化学浓度度/温度04一一月202348Cleaningandsanitization清洁和消消毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系统统停机后后需要的的清洁和和消毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定义系统统停机后后最长多多久需要要消毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定义使用用前，哪哪些情况况需要消消毒（（例如，，敞开的的循环，，污染等等）Definedurationofmonitoringaftershutdownorunusualevents定义关闭闭或非正正常情况况下需要要监控的的时间04一月202349Validation验证Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方针针和水系统验验证活动Durationofmonitoring监控时间Samplinglocations取样位置Typesoftesting监测类型Requirementsforrevalidation再验证要求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不会描述具具体的系统或或活动，而应应是每个项目目的验证主计计划和方案中中的内容。SOP为编写具体项项目验证文件件提供指导04一月202350Validation验证Initialphase初始阶段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此阶段,会会制订操作参参数和清洁/消毒规程和和频率。2-4周内，在在纯化过程的的每一步，以以及在每一个个使用点，应应每日取样。。取样点的取取样规程应反反映水的质量量。2-4周周结束时，公公司应制订出出水系统操作作的SOP。04一一月月202351Validation验证证第二二阶阶段段--ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqu