WaerSysems水系統(tǒng)知識專題講座

2023年1月18日

WaterSystems

水系統(tǒng)知識講座九新藥業(yè)國際認證部經(jīng)理高級工程師徐影Toexaminethebasictechnologyandrequirementsfor:檢查以下方面的基本技術(shù)和要求：

1)Watertreatmentsystems水處理系統(tǒng)

2)Storagerequirements

貯存要求

3)Samplingandtesting

取樣和檢測4)Differenttypesofwaterusedinpharmaceuticals制藥用水的不同類型

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

目的C&Q-V-ModelV

VURS用戶需求URS¤FDS¤DQ¤SAT¤IQ¤OQWatersystemdesign

水系統(tǒng)的設(shè)計

1)Pipesslopedsowaterdoesnotpoolandcandraineasily

管道要有斜度，以防止積水，易于排空2)Sanitaryfittings&connections潔凈配件和接口3)Constructedofsuitablematerialssuchasstainlesssteel建造材料適合，如不銹鋼4)Circulatethewater水要循環(huán)Furtherwatertreatmentpurificationstagesdownstreamofthepre-treatmentsystem預(yù)處理系統(tǒng)后水的進一步純化

1)Filtration

過濾

2)Disinfection

消毒3)Reverseosmosisorde-ionization反滲透或去離子

4)Distillationorultra-filtration

蒸餾或超濾Thereshouldbenodeadlegs不應(yīng)有死角WaterscoursdeadlegIfD=25mm&distanceXis

greaterthan75mm,wehaveadeadlegthatistoolong.如果D=25mm，X大于75mm，則有較長的死角Deadlegsection死角部分<3DFlowdirectionarrows

onpipesareimportant管道中的流向很重要SanitaryValve潔凈閥DXWatersystemdesign(1)

水系統(tǒng)設(shè)計（一）3.Thewateriscontaminatedasitpassesthroughthevalve當水通過閥門時，被污染

2.Bacteriacangrowwhenthevalveisclosed

當閥門關(guān)閉時，會生長細菌1.Ballvalvesareunacceptable不可使用球閥

Stagnantwaterinsidevalve閥門中的死水Watersystemdesign(2)

水系統(tǒng)設(shè)計（二）1)Sanitarypumps潔凈泵2)ClampsandOringsversusthreadedfittings卡箍和O環(huán)，不用螺紋配件3)Heatexchangers換熱器4)Sidearmlevelmeasuringdevicesareunacceptable不可使用邊側(cè)臂狀水位測量裝置Watersystemdesign(3)

水系統(tǒng)設(shè)計（三）rawwater原水Highpressure高壓Feed

water

Under

pressure加壓進水RejectWater不合格水Semi-permeableMembrane半滲透膜PermeateWater滲透水drainorrecycle排放或循環(huán)Lowpressure低壓Purifiedwater純化水Reverseosmosis(RO)theory反滲透（RO）原理CationiccolumnAnioniccolumnHygienicpump衛(wèi)生泵Outletsorstorage.OzonegeneratorUVlightHClNaOHEluatestoneutralizationplantAirbreaktosewer空氣斷開

Drainlinefromwatersoftener軟水機WatermustbekeptcirculatingTypicalde-ionizerschematic典型的去離子示意圖123456123456Returntode-ioniserCartridgefilter5μmCartridgefilter1μmBranchBranchCartridgefilter1μμmSecondstageROcartridgeFirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewerSecondstagerejectwatergoesbacktofirststagebuffertankSecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertankWaterfromsoftenerorde-ioniserTypical2-stageROschematic典型二級級反滲透透示意圖圖HygienicpumpFirststageROcartridgeHighpressurepumpAdvantages優(yōu)點Disadvantages缺點Manyuses應(yīng)用領(lǐng)域域purifiedwater純化水feedingofdistillationunitsorultra-filtrationunits蒸餾器或或超濾器器的進水水WaterforFinalRinse最終沖洗洗用水WaterforInjections(ifpermissible)注射用水水（如許許可）Useofreverseosmosis反滲透的的應(yīng)用CanbeusedforWFIorforWaterForFinalRinsingforparenteralmanufacturing(ifpermitted)可用作注注射用水水或生產(chǎn)產(chǎn)注射劑劑的最終終沖洗用用水（如如許可））Removesorganiccontaminants,suchasendotoxins去除有機機污染物物，如內(nèi)內(nèi)毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下運行，，在121°°C進行滅菌菌Ultra-filtration超濾Single-effectdistillation單效蒸餾餾simpledistillation,singleeffect簡單蒸餾餾，單效效vapourcompression,thermocompression蒸汽壓縮縮，熱壓壓縮Multieffectdistillation多效蒸餾餾multipleeffectstills多效蒸餾餾機Distillation蒸餾Typicalwaterstorageanddistributionschematic典型的水貯存和分配示意圖WatermustbekeptcirculatingSprayballCartridgefilter1μmAirbreaktodrainOutletsHygienicpumpOptionalin-linefilter0,2μmUVlightFeedWaterfromDIorROHeatExchangerOzoneGeneratorHydrophobicairfilter&burstdisc疏水性呼吸過濾器&安全隔膜StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorWatersystemsdesign水系統(tǒng)設(shè)設(shè)計Check檢查Why?HowFeedWaterQuality進水質(zhì)量量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的處處理階段段無法處處置未受受限制的的微生物物和內(nèi)毒毒素負荷荷Connections連接Sampling取樣Minimalcrevices最小裂縫縫Inspection檢查Watersystemsdesign水系統(tǒng)設(shè)設(shè)計Check檢查Why?HowFinishes拋光Reducebacterialadhesion減少細菌菌粘著Pipeslopes管道傾斜斜度Certification證書Drainabilityespeciallyofcondensateaftersteamsanitising排水性,尤其是是蒸汽消消毒后的的冷凝水水Inspection檢查spiritlevel水平儀Isometrics等容法Watersystemsdesign水系統(tǒng)設(shè)設(shè)計Check檢查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利利于微生生物生長長和附著著的條件Sanitisation消毒Flowmeter流速計Records記錄Velocityinloop回路中流流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生生物繁殖殖,解決決問題Watersystemsdesign水系統(tǒng)設(shè)設(shè)計CheckWhy?HowNot““reactive,additiveorabsorptive”不"產(chǎn)生生反應(yīng),添加或或吸附"Instruments儀器Certificates證書Certificates證書Inspection檢查Materialsofconstruction材質(zhì)Calibrated已校正Sanitary清潔Watersystemsdesign水系統(tǒng)設(shè)計CheckWhy?HowMinimalcrevices最小裂縫Passivation鈍化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工資質(zhì)質(zhì)確認,焊接接日志)焊接取樣,焊焊接檢查Documentation(Procedures,Passivationlog)文件(規(guī)程,鈍化化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蝕性WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality證實有持續(xù)產(chǎn)產(chǎn)生高品質(zhì)水水的能力MasterPlan,驗證主計劃Protocols,驗證方案summaryreports總結(jié)報告Validation驗證Heat熱-Oneofthemostreliablemethodsofdisinfectionofwater systems最可靠的消毒毒水系統(tǒng)的方方法之一Ozone臭氧-Producedeasily容易制備- Leavesnoresidue沒有殘留Disinfection(1)消毒（一）UV紫外-UVdoesnot“sterilize”紫外不可滅菌菌- Flowratecritical流速很關(guān)鍵- Post-irradiationrecontaminationmaybeanissue后放射再污染染可能是個問問題- Lampshavefinitelife燈的壽命有限限Otherchemicals其他化學(xué)法-XO2-Halogen鹵素- Formaldehyde甲醛Disinfection(2)消毒（二）Theremustbeasamplingprocedure必須有取樣規(guī)規(guī)程Sampleintegritymustbeassured必須保證樣品品的完整性Samplertraining取樣人培訓(xùn)Samplepoint取樣點Samplesize取樣多少Sampling(1)取樣（一）Samplecontainer取樣容器Samplelabel樣品標簽Samplestorageandtransport樣品儲存和轉(zhuǎn)轉(zhuǎn)移Arrivalatthelaboratory到達實驗室Startoftest開始測試Sampling(2)取樣（二）Testing-settingspecificationsforpurifiedwaterorWFI測試–規(guī)定純化水或或注射用水標標準PurifiedWater純化水Ph.Eur.中國藥典（2005））USPNitrates硝酸鹽≤0.2ppm≤0.06ppm-Conductivity電導(dǎo)率≤5.1μμS/cm@25oC-≤1.3μμS/cm@25oCTOC≤0.5mg/l-≤0.5mg/lHeavymetals重金屬≤0.1ppm≤0.5ppm-Microbia微生物<100cfu/ml<100cfu/ml<100cfu/mlTesting-settingspecificationsforpurifiedwaterorWFI測試–規(guī)定純化水或或注射用水標標準WFI注射用水Ph.Eur.中國藥典（2005））USPNitrates硝酸鹽≤0.2ppm≤≤0.06ppm-Conductivity電導(dǎo)率≤1.3μS/cm@25oC-≤1.3μS/cm@25oCTOC≤0.5mg/l-≤0.5mg/lMicrobial微生物<10cfu/100ml<10cfu/100ml<10cfu/100mlEndotoxin內(nèi)毒素<0.25IU/ml<0.25EU/ml<0.25EU/mlSuggestedbacteriallimitsforPurifiedWater(CFU/mL)建議的微生物物限度純化化水（CFU/ml）Samplinglocation取樣位置Alert報警限Action行動限Rawwater原水300500Postmultimediafilter多介質(zhì)過濾器后300500Postsoftener軟化劑后300500Postactivatedcarbonfilter活性炭后300500FeedtoRO回水至RO200500ROpermeate

RO滲透50100PointsofUse使用點10100TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果沒有給出出指導(dǎo)值，可可采用EU指南的限度(前面提到的））做為行動限限。如果有歷歷史數(shù)據(jù)，可可以將行動限限定為3倍的平均值的的標準偏差，，警戒限定為為2倍的平均值的的標準偏差A(yù)ctionandAlertLimits行動限和警戒戒限Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring微生物監(jiān)測04一月月202334Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系統(tǒng)微生生物監(jiān)測的的推薦方法法:PurifiedWater純化水PourPlateMethod平皿法Minimumsample1.0ml.最小取樣量量1.0毫毫升Platecountagar48to72hoursincubation培養(yǎng)基培養(yǎng)48-72小時時WaterforInjection注射用水水MembraneFiltrationMethod薄膜過濾法法Minimumsample100ml.最小取樣量量100毫毫升Platecountagar48to72hoursincubation培養(yǎng)基培培養(yǎng)48-72小時時Methodverification方法確認Chemicaltesting化學(xué)測試Microbiologicaltesting微生物測試試testmethod測試方法typesofmediaused使用的培養(yǎng)養(yǎng)基類型incubationtimeandtemperature培養(yǎng)時間和和溫度objectionableandindicatororganisms異議和指示示有機體don’tunderstandmanufacturermustsetspecifications生產(chǎn)商必須須制定標準準Testing檢測InternationalpharmacopoeiarequirementsforWFIarethoseforpurifiedwaterplusitmustbefreefrompyrogens國際藥典對對注射用水水的要求除除了那些對對純化水的的要求外，，還要求必必須不含有有熱源Usuallypreparedbydistillation通常由蒸餾餾器制得Storagetimeshouldbelessthan24hours儲存時間應(yīng)應(yīng)少于24小時Microbiallimitsmustbespecified必須制定微微生物限度度WaterforInjections注射用水Waterforfinalrinsemustbeofthesamequalityasthewaterrequiredforpharmaceuticalpreparation最終沖洗用用水的質(zhì)量量必須與藥藥品制備所所要求的水水的質(zhì)量相相同WaterforFinalRinse最終沖洗用用水Anycompoundinjectedintomammalswhichgivesrisetofeverisa“Pyrogen”任何注入哺哺乳動物體體內(nèi)可引起起發(fā)燒的物物質(zhì)稱為““熱源”Endotoxinsarepyrogenic,comefromGramnegativebacterialcellwallfragments內(nèi)毒素具有有熱源性，，來源于革革蘭陰性菌菌細胞壁Detectendotoxinsusingatestforlipopolysaccharides(LPS)檢測內(nèi)毒素素使用脂多多糖的測試試rabbittestdetectspyrogens兔子試驗檢檢測熱源LALtestdetectsendotoxins鱟試劑檢測測內(nèi)毒素Ultrafiltration,distillation,&ROmayremovepyrogens超濾、蒸餾餾和反滲透透可能會去去除熱源Pyrogensandendotoxins熱源和內(nèi)毒毒素Trending趨勢分析DescribethemicrobiologicalproblemsofthisWFIsystem.描述注射用用水系統(tǒng)的的微生物問問題CountsaretotalnumberofColonyFormingUnitsper100mlActionAlertSOPsSOPsshouldaddressSOPs中應(yīng)包括以以下內(nèi)容:Operationandroutinemonitoring操作和日常常監(jiān)控Maintenanceandcalibration維護和校正正Cleaningandsanitization清潔和消毒毒Validation驗證04一一月月202342OperationandRoutineMonitoring運行行和和日日常常監(jiān)監(jiān)控控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系統(tǒng)統(tǒng)描描述述（（制制備備系系統(tǒng)統(tǒng)組組件件，，循循環(huán)環(huán)的的數(shù)數(shù)量量，，物物料料，，控控制制系系統(tǒng)統(tǒng)））Listusers列明明使使用用點點Listrequirementsforsysteme.g.:列明明系系統(tǒng)統(tǒng)要要求求，，例例如如：：Generatingcapacity制備備能能力力Storagecapacity儲存存容容量量Diversity(howmanypointsofusecanbeopenedsimultaneously)差異異性性（（可可以以同同時時開開啟啟幾幾個個使使用用點點））Flowrate流速速Temperature溫度Specificationsforwaterqualityateachstage每個階段段的水質(zhì)質(zhì)標準04一一月202343OperationandRoutineMonitoring運行和日日常監(jiān)控控Describesystemoperationincluding:系統(tǒng)的運運行描述述包括Systemstartup系統(tǒng)啟動動Systemshutdown關(guān)機Emergencyshutdown緊急停機機Normaloperations正常運行行Monitoringduringroutineoperation日常運行行的監(jiān)控控Describesamplingactivities描述取樣樣活動Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每一一步純純化階階段（（監(jiān)測測類型型，頻頻次，，接受受標準準）pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS應(yīng)對04一一月月202345MaintenanceandCalibration維護和和校正正Routineinspectionandmaintenanceactivitiescarriedout:進行的的日常常檢查查及維維護活活動Daily每日Weekly每周Monthly每月Annually每年Triggerevents(e.g.afterobservationofaspecificcondition)““觸發(fā)””事件件（（例如如，觀觀察到到特殊殊狀況況）Includeprocedure,acceptancecriteria,forms包括規(guī)規(guī)程，，接受受限度度，表表格04一月月202346MaintenanceandCalibration維護和校正正PeriodicCalibrationactivitiescarriedout:應(yīng)進行定期期校正，包包括Listinstruments––make,model儀器清單-廠家，型號號Range范圍Tolerance限度Criticality重要性Timeintervalbetweencalibration頻次Ifcarriedoutbycontractor,refertoSOPforcontrolofthirdparties如果由合同同商校正，，應(yīng)參照第第三方管理理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果內(nèi)部校校正，確保保每個校正正規(guī)程有單單獨的SOP04一一月202347Cleaningandsanitization清潔和消消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每個個組件的的清潔和和消毒活活動Methods方法Chemicalsused使用的化化學(xué)物質(zhì)質(zhì)Frequency頻次Duration持續(xù)時間間Chemicalconcentration/temperature化學(xué)濃度度/溫度04一一月202348Cleaningandsanitization清潔和消消毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系統(tǒng)統(tǒng)停機后后需要的的清潔和和消毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定義系統(tǒng)統(tǒng)停機后后最長多多久需要要消毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定義使用用前，哪哪些情況況需要消消毒（（例如，，敞開的的循環(huán)，，污染等等）Definedurationofmonitoringaftershutdownorunusualevents定義關(guān)閉閉或非正正常情況況下需要要監(jiān)控的的時間04一月202349Validation驗證Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方針針和水系統(tǒng)驗驗證活動Durationofmonitoring監(jiān)控時間Samplinglocations取樣位置Typesoftesting監(jiān)測類型Requirementsforrevalidation再驗證要求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不會描述具具體的系統(tǒng)或或活動，而應(yīng)應(yīng)是每個項目目的驗證主計計劃和方案中中的內(nèi)容。SOP為編寫具體項項目驗證文件件提供指導(dǎo)04一月202350Validation驗證Initialphase初始階段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此階段,會會制訂操作參參數(shù)和清潔/消毒規(guī)程和和頻率。2-4周內(nèi)，在在純化過程的的每一步，以以及在每一個個使用點，應(yīng)應(yīng)每日取樣。。取樣點的取取樣規(guī)程應(yīng)反反映水的質(zhì)量量。2-4周周結(jié)束時，公公司應(yīng)制訂出出水系統(tǒng)操作作的SOP。04一一月月202351Validation驗證證第二二階階段段--ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqu