WaterSystems水系统知识专题讲座课件

2022年12月9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2022年12月8日WaterSystems1Toexaminethebasictechnologyandrequirementsfor: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Toexaminethebasictechnolog2C&Q-V-ModelV

VC&Q-V-ModelV

V3URS用户需求URS¤FDS¤DQ¤SAT¤IQ¤OQURSURS¤FDS¤DQ¤SAT¤IQ¤OQ4Watersystemdesign

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Watersystemdesign5Furtherwatertreatmentpurificationstagesdownstreamofthepre-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Furtherwatertreatmentpurifi6Thereshouldbenodeadlegs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）ThereshouldbenodeadlegsWa73.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）3.Thewateriscontaminateda81)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）1)SanitarypumpsWatersystem9rawwater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rawwaterHighpressureFeedwat10CationiccolumnAnioniccolumnHygienicpump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-ioniserCartridgefilter5µmCartridgefilter1µmCationiccolumnAnioniccolumnH11BranchBranchCartridgefilter1µmSecondstageROcartridge

FirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewer

Secondstagerejectwatergoesbacktofirststagebuffertank

SecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertank

Waterfromsoftenerorde-ioniser

Typical2-stageROschematic典型二级反渗透示意图HygienicpumpFirststageROcartridgeHighpressurepumpBranchBranchCartridgeSecondst12Advantages优点Disadvantages缺点Manyuses应用领域purifiedwater纯化水feedingofdistillationunitsorultra-filtrationunits蒸馏器或超滤器的进水WaterforFinalRinse最终冲洗用水WaterforInjections(ifpermissible)注射用水（如许可）Useofreverseosmosis反渗透的应用

AdvantagesUseofreverseosmo13CanbeusedforWFIorforWaterForFinalRinsingfor

parenteralmanufacturing(ifpermitted)可用作注射用水或生产注射剂的最终冲洗用水（如许可）Removesorganiccontaminants,suchas

endotoxins去除有机污染物，如内毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下运行，在121°C进行灭菌Ultra-filtration超滤

CanbeusedforWFIorforWat14Single-effectdistillation

单效蒸馏simpledistillation,singleeffect简单蒸馏，单效vapourcompression,thermocompression蒸汽压缩，热压缩Multieffectdistillation

多效蒸馏multipleeffectstills多效蒸馏机Distillation蒸馏Single-effectdistillationDist15Typicalwaterstorageanddistributionschematic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Typicalwaterstorageanddist16StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpBallvalv17StillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorStillStoragetankPumpsTCTOCDia18Watersystemsdesign水系统设计Check检查Why?HowFeedWaterQuality进水质量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的处理阶段无法处置未受限制的微生物和内毒素负荷Connections连接Sampling取样Minimalcrevices最小裂缝Inspection检查Watersystemsdesign水系统设计Check19Watersystemsdesign水系统设计Check检查Why?HowFinishes抛光Reducebacterialadhesion减少细菌粘着Pipeslopes管道倾斜度Certification证书Drain

abilityespeciallyofcondensateaftersteamsanitising排水性,尤其是蒸汽消毒后的冷凝水Inspection检查spiritlevel水平仪Isometrics等容法Watersystemsdesign水系统设计Check20Watersystemsdesign水系统设计Check检查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利于微生物生长和附着的条件Sanitisation消毒Flowmeter流速计Records记录Velocityinloop回路中流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生物繁殖,解决问题Watersystemsdesign水系统设计Check21Watersystemsdesign水系统设计CheckWhy?HowNot“reactive,additiveorabsorptive”不"产生反应,添加或吸附"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Check22Watersystemsdesign水系统设计CheckWhy?HowMinimalcrevices最小裂缝Passivation钝化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工资质确认,焊接日志)焊接取样,焊接检查Documentation(Procedures,Passivationlog)文件(规程,钝化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蚀性Watersystemsdesign水系统设计Check23WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality证实有持续产生高品质水的能力MasterPlan,验证主计划Protocols,验证方案

summaryreports总结报告Validation验证WaterSystemsdesignCheckWhy?H24Heat

热

- Oneofthemostreliablemethodsofdisinfectionofwater systems

最可靠的消毒水系统的方法之一Ozone

臭氧

- Producedeasily

容易制备

- Leavesnoresidue

没有残留Disinfection(1)消毒（一）

HeatDisinfection(1)25UV

紫外

- UVdoesnot“sterilize”

紫外不可灭菌

- Flowratecritical

流速很关键

- Post-irradiationrecontaminationmaybeanissue

后放射再污染可能是个问题

- Lampshavefinitelife

灯的寿命有限Otherchemicals

其他化学法

- XO2

- Halogen

卤素

- Formaldehyde

甲醛Disinfection(2)消毒（二）

UVDisinfection(2)26Theremustbeasamplingprocedure

必须有取样规程Sampleintegritymustbeassured

必须保证样品的完整性Samplertraining

取样人培训Samplepoint

取样点Samplesize

取样多少Sampling(1)取样（一）

Theremustbeasamplingproce27Samplecontainer

取样容器Samplelabel

样品标签Samplestorageandtransport

样品储存和转移Arrivalatthelaboratory

到达实验室Startoftest

开始测试Sampling(2)取样（二）

SamplecontainerSampling(2)28Testing-settingspecificationsforpurifiedwaterorWFI

测试–规定纯化水或注射用水标准

PurifiedWater纯化水

Ph.Eur.中国药典（2005）

USP

Nitrates硝酸盐

≤

0.2ppm

≤0.06ppm

- Conductivity电导率

≤5.1µS/cm@25oC

-

≤1.3µS/cm@25oC TOC

≤0.5mg/l

-

≤0.5mg/l

Heavymetals重金属≤

0.1ppm

≤0.5ppm

- Microbia微生物

<100cfu/ml <100cfu/ml <100cfu/mlTesting-settingspecificatio29Testing-settingspecificationsforpurifiedwaterorWFI

测试–规定纯化水或注射用水标准

WFI注射用水

Ph.Eur.

中国药典（2005）USP Nitrates硝酸盐

≤

0.2ppm≤

0.06ppm - Conductivity电导率

≤1.3µS/cm@25oC -

≤1.3µS/cm@25oCTOC

≤0.5mg/l -

≤0.5mg/l Microbial微生物

<10cfu/100ml <10cfu/100ml <10cfu/100mlEndotoxin内毒素 <0.25IU/ml <0.25EU/ml <0.25EU/mlTesting-settingspecificatio30SuggestedbacteriallimitsforPurifiedWater(CFU

/mL)建议的微生物限度纯化水（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10100Suggestedbacteriallimitsfor31TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果没有给出指导值，可采用EU指南的限度(前面提到的）做为行动限。如果有历史数据，可以将行动限定为3倍的平均值的标准偏差，警戒限定为2倍的平均值的标准偏差ActionandAlertLimits行动限和警戒限TheactionlimitistheEUgui32Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring

微生物监测Example(PurifiedWaterUserP3309十二月202234Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系统微生物监测的推荐方法: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48-72小时08十二月20223434Methodverification

方法确认Chemicaltesting

化学测试Microbiologicaltesting

微生物测试testmethod

测试方法typesofmediaused

使用的培养基类型incubationtimeandtemperature

培养时间和温度objectionableandindicatororganisms

异议和指示有机体don’tunderstandmanufacturermustsetspecifications

生产商必须制定标准Testing

检测MethodverificationTesting

检测35InternationalpharmacopoeiarequirementsforWFI

arethoseforpurifiedwaterplusitmustbefreefrompyrogens

国际药典对注射用水的要求除了那些对纯化水的要求外，还要求必须不含有热源Usuallypreparedbydistillation

通常由蒸馏器制得Storagetimeshouldbelessthan24hours

储存时间应少于24小时Microbiallimitsmustbespecified

必须制定微生物限度WaterforInjections

注射用水Internationalpharmacopoeiare36Waterforfinalrinsemustbeofthe

samequalityasthewaterrequired

forpharmaceuticalpreparation

最终冲洗用水的质量必须与药品制备所要求的水的质量相同WaterforFinalRinse最终冲洗用水Waterforfinalrinsemustbe37Anycompoundinjectedintomammalswhichgivesrisetofeverisa“Pyrogen”

任何注入哺乳动物体内可引起发烧的物质称为“热源”Endotoxinsarepyrogenic,comefromGramnegativebacterialcellwallfragments

内毒素具有热源性，来源于革兰阴性菌细胞壁Detect

endotoxinsusingatestforlipopolysaccharides(LPS)

检测内毒素使用脂多糖的测试rabbittestdetectspyrogens

兔子试验检测热源LALtestdetectsendotoxins

鲎试剂检测内毒素Ultrafiltration,distillation,&

RO

mayremovepyrogens

超滤、蒸馏和反渗透可能会去除热源Pyrogensandendotoxins热源和内毒素Anycompoundinjectedintomam38Trending趋势分析DescribethemicrobiologicalproblemsofthisWFIsystem.描述注射用水系统的微生物问题Trending趋势分析Describethemicro39CountsaretotalnumberofColonyFormingUnitsper100mlCountsaretotalnumberofCol40ActionAlertActionAlert41SOPsSOPsshouldaddressSOPs中应包括以下内容:Operationandroutinemonitoring操作和日常监控Maintenanceandcalibration维护和校正Cleaningandsanitization清洁和消毒Validation验证09十二月202242SOPsSOPsshouldaddressSOPs中应42OperationandRoutineMonitoring

运行和日常监控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系统描述（制备系统组件，循环的数量，物料，控制系统）Listusers列明使用点Listrequirementsforsysteme.g.:列明系统要求，例如：Generatingcapacity制备能力Storagecapacity储存容量Diversity(howmanypointsofusecanbeopenedsimultaneously)差异性（可以同时开启几个使用点）Flowrate流速Temperature温度Specificationsforwaterqualityateachstage每个阶段的水质标准09十二月202243OperationandRoutineMonitori43WaterSystems水系统知识专题讲座课件44OperationandRoutineMonitoring

运行和日常监控Describesystemoperationincluding:系统的运行描述包括Systemstartup系统启动Systemshutdown关机Emergencyshutdown紧急停机Normaloperations正常运行Monitoringduringroutineoperation日常运行的监控Describesamplingactivities描述取样活动Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每一步纯化阶段（监测类型，频次，接受标准）pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS应对09十二月202245OperationandRoutineMonitori45MaintenanceandCalibration

维护和校正Routineinspectionandmaintenanceactivitiescarriedout:进行的日常检查及维护活动Daily每日Weekly每周Monthly每月Annually每年Triggerevents(e.g.afterobservationofaspecificcondition)“触发”事件（例如，观察到特殊状况）Includeprocedure,acceptancecriteria,forms包括规程，接受限度，表格09十二月202246MaintenanceandCalibration

维护46MaintenanceandCalibration

维护和校正PeriodicCalibrationactivitiescarriedout:应进行定期校正，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如果由合同商校正，应参照第三方管理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果内部校正，确保每个校正规程有单独的SOP09十二月202247MaintenanceandCalibration

维47Cleaningandsanitization

清洁和消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每个组件的清洁和消毒活动Methods方法Chemicalsused使用的化学物质Frequency频次Duration持续时间Chemicalconcentration/temperature化学浓度/温度09十二月202248Cleaningandsanitization

清洁和消48Cleaningandsanitization

清洁和消毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系统停机后需要的清洁和消毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定义系统停机后最长多久需要消毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定义使用前，哪些情况需要消毒（例如，敞开的循环，污染等）Definedurationofmonitoringaftershutdownorunusualevents定义关闭或非正常情况下需要监控的时间09十二月202249Cleaningandsanitization

清洁和49Validation验证Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方针和水系统验证活动Durationofmonitoring监控时间Samplinglocations取样位置Typesoftesting监测类型Requirementsforrevalidation再验证要求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不会描述具体的系统或活动，而应是每个项目的验证主计划和方案中的内容。SOP为编写具体项目验证文件提供指导09十二月202250Validation验证Describecompany50Validation验证Initialphase初始阶段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.

AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此阶段,会制订操作参数和清洁/消毒规程和频率。2-4周内，在纯化过程的每一步，以及在每一个使用点，应每日取样。取样点的取样规程应反映水的质量。2-4周结束时，公司应制订出水系统操作的SOP。09十二月202251Validation验证Initialphase初始阶段51Validation验证第二阶段--ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqualityofwater.系统验证的第二阶段应证明，在符合SOP下运行，能持续产生高品质水。取样的频次（每日）和时间（2-4周）应和初始阶段相同。在此阶段结束时，应有数据显示系统能持续产生高品质水。52Validation验证第二阶段5252Validation验证第三阶段ThethirdphaseofvalidationisdesignedtodemonstratethatwhenthewatersystemisoperatedinaccordancewiththeSOPsoveralongperiodoftimeitwillconsistentlyproducewaterofthedesiredquality.Anyvariationsinthequalityofthefeed

waterthatcouldaffecttheoperationandultimatelythewaterqualitywillbepickedupduringthisphaseofthevalidation.Samplingisperformedaccordingtoroutineproceduresandfrequencies.验证的第三阶段应证明当系统在符合SOP下运行较长时间，能持续产生高品质水。任何会影响系统运行并会影响最终水质的进水质量的变异，都会在此验证阶段进行考察。应按照日常的规程和频次进取样。53Validation验证第三阶段5353Validation验证ForWaterforInjectionsystemsthesamplesshouldbetakendailyfromaminimumofonepointofuse,withallpointsofusetestedweekly.Thevalidationofthewatersystemiscompletedwhenthefirmhasafullyearsworthofdata.对于注射用水系统取样应每日至少一个使用点，所有点每周轮检。当公司收集一整年有效数据后，水系统验证完成。54Validation验证ForWaterforInje5455ThankYou谢谢Questions?问题？55ThankYou552022年12月9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2022年12月8日WaterSystems56Toexaminethebasictechnologyandrequirementsfor: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Toexaminethebasictechnolog57C&Q-V-ModelV

VC&Q-V-ModelV

V58URS用户需求URS¤FDS¤DQ¤SAT¤IQ¤OQURSURS¤FDS¤DQ¤SAT¤IQ¤OQ59Watersystemdesign

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Watersystemdesign60Furtherwatertreatmentpurificationstagesdownstreamofthepre-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Furtherwatertreatmentpurifi61Thereshouldbenodeadlegs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）ThereshouldbenodeadlegsWa623.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）3.Thewateriscontaminateda631)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）1)SanitarypumpsWatersystem64rawwater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rawwaterHighpressureFeedwat65CationiccolumnAnioniccolumnHygienicpump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-ioniserCartridgefilter5µmCartridgefilter1µmCationiccolumnAnioniccolumnH66BranchBranchCartridgefilter1µmSecondstageROcartridge

FirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewer

Secondstagerejectwatergoesbacktofirststagebuffertank

SecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertank

Waterfromsoftenerorde-ioniser

Typical2-stageROschematic典型二级反渗透示意图HygienicpumpFirststageROcartridgeHighpressurepumpBranchBranchCartridgeSecondst67Advantages优点Disadvantages缺点Manyuses应用领域purifiedwater纯化水feedingofdistillationunitsorultra-filtrationunits蒸馏器或超滤器的进水WaterforFinalRinse最终冲洗用水WaterforInjections(ifpermissible)注射用水（如许可）Useofreverseosmosis反渗透的应用

AdvantagesUseofreverseosmo68CanbeusedforWFIorforWaterForFinalRinsingfor

parenteralmanufacturing(ifpermitted)可用作注射用水或生产注射剂的最终冲洗用水（如许可）Removesorganiccontaminants,suchas

endotoxins去除有机污染物，如内毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下运行，在121°C进行灭菌Ultra-filtration超滤

CanbeusedforWFIorforWat69Single-effectdistillation

单效蒸馏simpledistillation,singleeffect简单蒸馏，单效vapourcompression,thermocompression蒸汽压缩，热压缩Multieffectdistillation

多效蒸馏multipleeffectstills多效蒸馏机Distillation蒸馏Single-effectdistillationDist70Typicalwaterstorageanddistributionschematic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Typicalwaterstorageanddist71StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpBallvalv72StillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorStillStoragetankPumpsTCTOCDia73Watersystemsdesign水系统设计Check检查Why?HowFeedWaterQuality进水质量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的处理阶段无法处置未受限制的微生物和内毒素负荷Connections连接Sampling取样Minimalcrevices最小裂缝Inspection检查Watersystemsdesign水系统设计Check74Watersystemsdesign水系统设计Check检查Why?HowFinishes抛光Reducebacterialadhesion减少细菌粘着Pipeslopes管道倾斜度Certification证书Drain

abilityespeciallyofcondensateaftersteamsanitising排水性,尤其是蒸汽消毒后的冷凝水Inspection检查spiritlevel水平仪Isometrics等容法Watersystemsdesign水系统设计Check75Watersystemsdesign水系统设计Check检查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利于微生物生长和附着的条件Sanitisation消毒Flowmeter流速计Records记录Velocityinloop回路中流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生物繁殖,解决问题Watersystemsdesign水系统设计Check76Watersystemsdesign水系统设计CheckWhy?HowNot“reactive,additiveorabsorptive”不"产生反应,添加或吸附"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Check77Watersystemsdesign水系统设计CheckWhy?HowMinimalcrevices最小裂缝Passivation钝化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工资质确认,焊接日志)焊接取样,焊接检查Documentation(Procedures,Passivationlog)文件(规程,钝化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蚀性Watersystemsdesign水系统设计Check78WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality证实有持续产生高品质水的能力MasterPlan,验证主计划Protocols,验证方案

summaryreports总结报告Validation验证WaterSystemsdesignCheckWhy?H79Heat

热

- Oneofthemostreliablemethodsofdisinfectionofwater systems

最可靠的消毒水系统的方法之一Ozone

臭氧

- Producedeasily

容易制备

- Leavesnoresidue

没有残留Disinfection(1)消毒（一）

HeatDisinfection(1)80UV

紫外

- UVdoesnot“sterilize”

紫外不可灭菌

- Flowratecritical

流速很关键

- Post-irradiationrecontaminationmaybeanissue

后放射再污染可能是个问题

- Lampshavefinitelife

灯的寿命有限Otherchemicals

其他化学法

- XO2

- Halogen

卤素

- Formaldehyde

甲醛Disinfection(2)消毒（二）

UVDisinfection(2)81Theremustbeasamplingprocedure

必须有取样规程Sampleintegritymustbeassured

必须保证样品的完整性Samplertraining

取样人培训Samplepoint

取样点Samplesize

取样多少Sampling(1)取样（一）

Theremustbeasamplingproce82Samplecontainer

取样容器Samplelabel

样品标签Samplestorageandtransport

样品储存和转移Arrivalatthelaboratory

到达实验室Startoftest

开始测试Sampling(2)取样（二）

SamplecontainerSampling(2)83Testing-settingspecificationsforpurifiedwaterorWFI

测试–规定纯化水或注射用水标准

PurifiedWater纯化水

Ph.Eur.中国药典（2005）

USP

Nitrates硝酸盐

≤

0.2ppm

≤0.06ppm

- Conductivity电导率

≤5.1µS/cm@25oC

-

≤1.3µS/cm@25oC TOC

≤0.5mg/l

-

≤0.5mg/l

Heavymetals重金属≤

0.1ppm

≤0.5ppm

- Microbia微生物

<100cfu/ml <100cfu/ml <100cfu/mlTesting-settingspecificatio84Testing-settingspecificationsforpurifiedwaterorWFI

测试–规定纯化水或注射用水标准

WFI注射用水

Ph.Eur.

中国药典（2005）USP Nitrates硝酸盐

≤

0.2ppm≤

0.06ppm - Conductivity电导率

≤1.3µS/cm@25oC -

≤1.3µS/cm@25oCTOC

≤0.5mg/l -

≤0.5mg/l Microbial微生物

<10cfu/100ml <10cfu/100ml <10cfu/100mlEndotoxin内毒素 <0.25IU/ml <0.25EU/ml <0.25EU/mlTesting-settingspecificatio85SuggestedbacteriallimitsforPurifiedWater(CFU

/mL)建议的微生物限度纯化水（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10100Suggestedbacteriallimitsfor86TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果没有给出指导值，可采用EU指南的限度(前面提到的）做为行动限。如果有历史数据，可以将行动限定为3倍的平均值的标准偏差，警戒限定为2倍的平均值的标准偏差ActionandAlertLimits行动限和警戒限TheactionlimitistheEUgui87Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=