WaerSysems水系统知识专题讲座

2023年1月11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典型二二级反反渗透透示意意图HygienicpumpFirststageROcartridgeHighpressurepumpAdvantages优点Disadvantages缺点Manyuses应用领领域purifiedwater纯化水水feedingofdistillationunitsorultra-filtrationunits蒸馏器器或超超滤器器的进进水WaterforFinalRinse最终冲冲洗用用水WaterforInjections(ifpermissible)注射用用水（（如许许可））Useofreverseosmosis反渗透透的应应用CanbeusedforWFIorforWaterForFinalRinsingforparenteralmanufacturing(ifpermitted)可用作作注射射用水水或生生产注注射剂剂的最最终冲冲洗用用水（（如许许可））Removesorganiccontaminants,suchasendotoxins去除有有机污污染物物，如如内毒毒素Operationat65-80°°C,andsterilizationat121°°C在65-80°C下运行行，在在121°C进行灭灭菌Ultra-filtration超滤Single-effectdistillation单效蒸蒸馏simpledistillation,singleeffect简单蒸蒸馏，，单效效vapourcompression,thermocompression蒸汽汽压压缩缩，，热热压压缩缩Multieffectdistillation多效效蒸蒸馏馏multipleeffectstills多效效蒸蒸馏馏机机Distillation蒸馏馏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水系系统统设设计计Check检查查Why?HowFeedWaterQuality进水水质质量量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后后的的处处理理阶阶段段无无法法处处置置未未受受限限制制的的微微生生物物和和内内毒毒素素负负荷荷Connections连接接Sampling取样样Minimalcrevices最小小裂裂缝缝Inspection检查查Watersystemsdesign水系系统统设设计计Check检查查Why?HowFinishes抛光光Reducebacterialadhesion减少少细细菌菌粘粘着着Pipeslopes管道道倾倾斜斜度度Certification证书书Drainabilityespeciallyofcondensateaftersteamsanitising排水水性性,尤尤其其是是蒸蒸汽汽消消毒毒后后的的冷冷凝凝水水Inspection检查查spiritlevel水平平仪仪Isometrics等容容法法Watersystemsdesign水系系统统设设计计Check检查查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造造不不利利于于微微生生物物生生长长和和附附着着的的条件件Sanitisation消毒毒Flowmeter流速速计计Records记录录Velocityinloop回路路中中流流速速Forcontrolofmicrobialproliferationandinresponsetoproblems控制制微微生生物物繁繁殖殖,解解决决问问题题Watersystemsdesign水系系统统设设计计CheckWhy?HowNot““reactive,additiveorabsorptive””不"产产生生反反应应,添添加加或或吸吸附附"Instruments仪器器Certificates证书书Certificates证书书Inspection检查查Materialsofconstruction材质质Calibrated已校校正正Sanitary清洁洁Watersystemsdesign水系系统统设设计计CheckWhy?HowMinimalcrevices最小小裂裂缝缝Passivation钝化化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件件(焊焊接接工工资资质质确确认认,焊焊接接日日志志)焊接接取取样样,焊焊接接检检查查Documentation(Procedures,Passivationlog)文件件(规规程程,钝钝化化日日志志)Welding焊接接Maximumcorrosionresistance最大大耐受受腐腐蚀蚀性WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality证实实有有持持续续产产生生高高品品质质水水的的能能力力MasterPlan,验证证主主计计划划Protocols,验证证方方案案summaryreports总结结报报告告Validation验证证Heat热-Oneofthemostreliablemethodsofdisinfectionofwatersystems最可可靠靠的的消消毒毒水水系系统统的的方方法法之之一一Ozone臭氧氧-Producedeasily容易易制制备备-Leavesnoresidue没有有残残留留Disinfection(1)消毒毒（（一一））UV紫外外-UVdoesnot““sterilize””紫外外不不可可灭灭菌菌-Flowratecritical流速速很很关关键键-Post-irradiationrecontaminationmaybeanissue后放射再再污染可可能是个个问题- Lampshavefinitelife灯的寿命命有限Otherchemicals其他化学学法-XO2-Halogen卤素- Formaldehyde甲醛Disinfection(2)消毒（二二）Theremustbeasamplingprocedure必须有取取样规程程Sampleintegritymustbeassured必须保证证样品的的完整性性Samplertraining取样人培培训Samplepoint取样点Samplesize取样多少少Sampling(1)取样（一一）Samplecontainer取样容器器Samplelabel样品标签签Samplestorageandtransport样品储存存和转移移Arrivalatthelaboratory到达实验验室Startoftest开始测试试Sampling(2)取样（二二）Testing-settingspecificationsforpurifiedwaterorWFI测试–规定纯化化水或注注射用水水标准PurifiedWater纯化水Ph.Eur.中国药典典（2005）USPNitrates硝酸盐≤0.2ppm≤0.06ppm-Conductivity电导率≤5.1µS/cm@25oC-≤1.3µS/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–规定纯化化水或注注射用水水标准WFI注射用水水Ph.Eur.中国药典典（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)建议的微微生物限限度纯纯化水（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.如果没有有给出指指导值，，可采用用EU指南的限限度(前面提到到的）做做为行动动限。如如果有历历史数据据，可以以将行动动限定为为3倍的平均均值的标标准偏差差，警戒戒限定为为2倍的平均均值的标标准偏差差ActionandAlertLimits行动限和和警戒限限Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring微生物监监测31十十二月202234Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系统微微生物监监测的推推荐方法法:PurifiedWater纯化水PourPlateMethod平皿法Minimumsample1.0ml.最小取样量1.0毫升Platecountagar48to72hoursincubation培养基培养48-72小时WaterforInjection注射用水MembraneFiltrationMethod薄膜过滤法Minimumsample100ml.最小取样量100毫升Platecountagar48to72hoursincubation培养基培养养48-72小时Methodverification方法确认Chemicaltesting化学测试Microbiologicaltesting微生物测试testmethod测试方法typesofmediaused使用的培养基基类型incubationtimeandtemperature培养时间和温温度objectionableandindicatororganisms异议和指示有有机体don’tunderstandmanufacturermustsetspecifications生产商必须制制定标准Testing检测InternationalpharmacopoeiarequirementsforWFIarethoseforpurifiedwaterplusitmustbefreefrompyrogens国际药典对注注射用水的要要求除了那些些对纯化水的的要求外，还还要求必须不不含有热源Usuallypreparedbydistillation通常由蒸馏器器制得Storagetimeshouldbelessthan24hours储存时间应少少于24小时Microbiallimitsmustbespecified必须制定微生生物限度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31十二二月202242OperationandRoutineMonitoring运行和日常常监控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系统描述（（制备系统统组件，循循环的数量量，物料，，控制系统统）Listusers列明使用点点Listrequirementsforsysteme.g.:列明系统要要求，例如如：Generatingcapacity制备能力Storagecapacity储存容量Diversity(howmanypointsofusecanbeopenedsimultaneously)差异性（（可以同时时开启几个个使用点））Flowrate流速Temperature温度Specificationsforwaterqualityateachstage每个阶段的的水质标准准31十二二月202243OperationandRoutineMonitoring运行和日常常监控Describesystemoperationincluding:系统统的的运运行行描描述述包包括括Systemstartup系统统启启动动Systemshutdown关机机Emergencyshutdown紧急急停停机机Normaloperations正常常运运行行Monitoringduringroutineoperation日常常运运行行的的监监控控Describesamplingactivities描述述取取样样活活动动Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每每一一步步纯纯化化阶阶段段（（监监测测类类型型，，频频次次，，接接受受标标准准））pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS应对对31十十二二月月202245MaintenanceandCalibration维护护和和校校正正Routineinspectionandmaintenanceactivitiescarriedout:进行行的的日日常常检检查查及及维维护护活活动动Daily每日日Weekly每周周Monthly每月月Annually每年年Triggerevents(e.g.afterobservationofaspecificcondition)““触发”事件（（例如，观观察到特殊状状况）Includeprocedure,acceptancecriteria,forms包括规程，接接受限度，表表格31十二月月202246MaintenanceandCalibration维护和校正PeriodicCalibrationactivitiescarriedout:应进行定期校校正，包括Listinstruments–make,model仪器清单-厂家，型号Range范围Tolerance限度Criticality重要性Timeintervalbetweencalibration频次Ifcarriedoutbycontractor,refertoSOPforcontrolofthirdparties如果由合同商商校正，应参参照第三方管管理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果内部校正正，确保每个个校正规程有有单独的SOP31十二月月202247Cleaningandsanitization清洁和消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每个组件件的清洁和消消毒活动Methods方法Chemicalsused使用的化学物物质Frequency频次Duration持续时间Chemicalconcentration/temperature化学浓度/温度31十十二二月202248Cleaningandsanitization清洁和和消毒毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系系统停停机后后需要要的清清洁和和消毒毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定义系系统停停机后后最长长多久久需要要消毒毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定义使使用前前，哪哪些情情况需需要消消毒（（例例如，，敞开开的循循环，，污染染等））Definedurationofmonitoringaftershutdownorunusualevents定义关关闭或或非正正常情情况下下需要要监控控的时时间31十十二二月202249Validation验证Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方方针和水系系统验证活活动Durationofmonitoring监控时间Samplinglocations取样位置Typesoftesting监测类型Requirementsforrevalidation再验证要求求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不会描述述具体的系系统或活动动，而应是是每个项目目的验证主主计划和方方案中的内内容。SOP为编写具体体项目验证证文件提供供指导31十二二月202250Validation验证Initialphase初始阶段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此阶段,会制订操操作参数和和清洁/消消毒规程和和频率。2-4周内内，在纯化化过程的每每一步，以以及在每一