WaerSysems水系統(tǒng)知識專題講座

2023年1月11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典型二二級反反滲透透示意意圖HygienicpumpFirststageROcartridgeHighpressurepumpAdvantages優(yōu)點Disadvantages缺點Manyuses應用領領域purifiedwater純化水水feedingofdistillationunitsorultra-filtrationunits蒸餾器器或超超濾器器的進進水WaterforFinalRinse最終沖沖洗用用水WaterforInjections(ifpermissible)注射用用水（（如許許可））Useofreverseosmosis反滲透透的應應用CanbeusedforWFIorforWaterForFinalRinsingforparenteralmanufacturing(ifpermitted)可用作作注射射用水水或生生產(chǎn)注注射劑劑的最最終沖沖洗用用水（（如許許可））Removesorganiccontaminants,suchasendotoxins去除有有機污污染物物，如如內(nèi)毒毒素Operationat65-80°°C,andsterilizationat121°°C在65-80°C下運行行，在在121°C進行滅滅菌Ultra-filtration超濾Single-effectdistillation單效蒸蒸餾simpledistillation,singleeffect簡單蒸蒸餾，，單效效vapourcompression,thermocompression蒸汽汽壓壓縮縮，，熱熱壓壓縮縮Multieffectdistillation多效效蒸蒸餾餾multipleeffectstills多效效蒸蒸餾餾機機Distillation蒸餾餾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水系系統(tǒng)統(tǒng)設設計計Check檢查查Why?HowFeedWaterQuality進水水質(zhì)質(zhì)量量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后后的的處處理理階階段段無無法法處處置置未未受受限限制制的的微微生生物物和和內(nèi)內(nèi)毒毒素素負負荷荷Connections連接接Sampling取樣樣Minimalcrevices最小小裂裂縫縫Inspection檢查查Watersystemsdesign水系系統(tǒng)統(tǒng)設設計計Check檢查查Why?HowFinishes拋光光Reducebacterialadhesion減少少細細菌菌粘粘著著Pipeslopes管道道傾傾斜斜度度Certification證書書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檢查查spiritlevel水平平儀儀Isometrics等容容法法Watersystemsdesign水系系統(tǒng)統(tǒng)設設計計Check檢查查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造造不不利利于于微微生生物物生生長長和和附附著著的的條件件Sanitisation消毒毒Flowmeter流速速計計Records記錄錄Velocityinloop回路路中中流流速速Forcontrolofmicrobialproliferationandinresponsetoproblems控制制微微生生物物繁繁殖殖,解解決決問問題題Watersystemsdesign水系系統(tǒng)統(tǒng)設設計計CheckWhy?HowNot““reactive,additiveorabsorptive””不"產(chǎn)產(chǎn)生生反反應應,添添加加或或吸吸附附"Instruments儀器器Certificates證書書Certificates證書書Inspection檢查查Materialsofconstruction材質(zhì)質(zhì)Calibrated已校校正正Sanitary清潔潔Watersystemsdesign水系系統(tǒng)統(tǒng)設設計計CheckWhy?HowMinimalcrevices最小小裂裂縫縫Passivation鈍化化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件件(焊焊接接工工資資質(zhì)質(zhì)確確認認,焊焊接接日日志志)焊接接取取樣樣,焊焊接接檢檢查查Documentation(Procedures,Passivationlog)文件件(規(guī)規(guī)程程,鈍鈍化化日日志志)Welding焊接接Maximumcorrosionresistance最大大耐受受腐腐蝕蝕性WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality證實實有有持持續(xù)續(xù)產(chǎn)產(chǎn)生生高高品品質(zhì)質(zhì)水水的的能能力力MasterPlan,驗證證主主計計劃劃Protocols,驗證證方方案案summaryreports總結(jié)結(jié)報報告告Validation驗證證Heat熱-Oneofthemostreliablemethodsofdisinfectionofwatersystems最可可靠靠的的消消毒毒水水系系統(tǒng)統(tǒng)的的方方法法之之一一Ozone臭氧氧-Producedeasily容易易制制備備-Leavesnoresidue沒有有殘殘留留Disinfection(1)消毒毒（（一一））UV紫外外-UVdoesnot““sterilize””紫外外不不可可滅滅菌菌-Flowratecritical流速速很很關(guān)關(guān)鍵鍵-Post-irradiationrecontaminationmaybeanissue后放射再再污染可可能是個個問題- Lampshavefinitelife燈的壽命命有限Otherchemicals其他化學學法-XO2-Halogen鹵素- Formaldehyde甲醛Disinfection(2)消毒（二二）Theremustbeasamplingprocedure必須有取取樣規(guī)程程Sampleintegritymustbeassured必須保證證樣品的的完整性性Samplertraining取樣人培培訓Samplepoint取樣點Samplesize取樣多少少Sampling(1)取樣（一一）Samplecontainer取樣容器器Samplelabel樣品標簽簽Samplestorageandtransport樣品儲存存和轉(zhuǎn)移移Arrivalatthelaboratory到達實驗驗室Startoftest開始測試試Sampling(2)取樣（二二）Testing-settingspecificationsforpurifiedwaterorWFI測試–規(guī)定純化化水或注注射用水水標準PurifiedWater純化水Ph.Eur.中國藥典典（2005）USPNitrates硝酸鹽≤0.2ppm≤0.06ppm-Conductivity電導率≤5.1μS/cm@25oC-≤1.3μS/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)定純化化水或注注射用水水標準WFI注射用水水Ph.Eur.中國藥典典（2005）USPNitrates硝酸鹽≤0.2ppm≤≤0.06ppm-Conductivity電導率≤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)建議的微微生物限限度純純化水（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.如果沒有有給出指指導值，，可采用用EU指南的限限度(前面提到到的）做做為行動動限。如如果有歷歷史數(shù)據(jù)據(jù)，可以以將行動動限定為為3倍的平均均值的標標準偏差差，警戒戒限定為為2倍的平均均值的標標準偏差差ActionandAlertLimits行動限和和警戒限限Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring微生物監(jiān)監(jiān)測31十十二月202234Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系統(tǒng)微微生物監(jiān)監(jiān)測的推推薦方法法:PurifiedWater純化水PourPlateMethod平皿法Minimumsample1.0ml.最小取樣量1.0毫升Platecountagar48to72hoursincubation培養(yǎng)基培養(yǎng)48-72小時WaterforInjection注射用水MembraneFiltrationMethod薄膜過濾法Minimumsample100ml.最小取樣量100毫升Platecountagar48to72hoursincubation培養(yǎng)基培養(yǎng)養(yǎng)48-72小時Methodverification方法確認Chemicaltesting化學測試Microbiologicaltesting微生物測試testmethod測試方法typesofmediaused使用的培養(yǎng)基基類型incubationtimeandtemperature培養(yǎng)時間和溫溫度objectionableandindicatororganisms異議和指示有有機體don’tunderstandmanufacturermustsetspecifications生產(chǎn)商必須制制定標準Testing檢測InternationalpharmacopoeiarequirementsforWFIarethoseforpurifiedwaterplusitmustbefreefrompyrogens國際藥典對注注射用水的要要求除了那些些對純化水的的要求外，還還要求必須不不含有熱源Usuallypreparedbydistillation通常由蒸餾器器制得Storagetimeshouldbelessthan24hours儲存時間應少少于24小時Microbiallimitsmustbespecified必須制定微生生物限度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31十二二月202242OperationandRoutineMonitoring運行和日常常監(jiān)控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系統(tǒng)描述（（制備系統(tǒng)統(tǒng)組件，循循環(huán)的數(shù)量量，物料，，控制系統(tǒng)統(tǒng)）Listusers列明使用點點Listrequirementsforsysteme.g.:列明系統(tǒng)要要求，例如如：Generatingcapacity制備能力Storagecapacity儲存容量Diversity(howmanypointsofusecanbeopenedsimultaneously)差異性（（可以同時時開啟幾個個使用點））Flowrate流速Temperature溫度Specificationsforwaterqualityateachstage每個階段的的水質(zhì)標準準31十二二月202243OperationandRoutineMonitoring運行和日常常監(jiān)控Describesystemoperationincluding:系統(tǒng)統(tǒng)的的運運行行描描述述包包括括Systemstartup系統(tǒng)統(tǒng)啟啟動動Systemshutdown關(guān)機機Emergencyshutdown緊急急停停機機Normaloperations正常常運運行行Monitoringduringroutineoperation日常常運運行行的的監(jiān)監(jiān)控控Describesamplingactivities描述述取取樣樣活活動動Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每每一一步步純純化化階階段段（（監(jiān)監(jiān)測測類類型型，，頻頻次次，，接接受受標標準準））pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS應對對31十十二二月月202245MaintenanceandCalibration維護護和和校校正正Routineinspectionandmaintenanceactivitiescarriedout:進行行的的日日常常檢檢查查及及維維護護活活動動Daily每日日Weekly每周周Monthly每月月Annually每年年Triggerevents(e.g.afterobservationofaspecificcondition)““觸發(fā)”事件（（例如，觀觀察到特殊狀狀況）Includeprocedure,acceptancecriteria,forms包括規(guī)程，接接受限度，表表格31十二月月202246MaintenanceandCalibration維護和校正PeriodicCalibrationactivitiescarriedout:應進行定期校校正，包括Listinstruments–make,model儀器清單-廠家，型號Range范圍Tolerance限度Criticality重要性Timeintervalbetweencalibration頻次Ifcarriedoutbycontractor,refertoSOPforcontrolofthirdparties如果由合同商商校正，應參參照第三方管管理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果內(nèi)部校正正，確保每個個校正規(guī)程有有單獨的SOP31十二月月202247Cleaningandsanitization清潔和消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每個組件件的清潔和消消毒活動Methods方法Chemicalsused使用的化學物物質(zhì)Frequency頻次Duration持續(xù)時間Chemicalconcentration/temperature化學濃度/溫度31十十二二月202248Cleaningandsanitization清潔和和消毒毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系系統(tǒng)停停機后后需要要的清清潔和和消毒毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定義系系統(tǒng)停停機后后最長長多久久需要要消毒毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定義使使用前前，哪哪些情情況需需要消消毒（（例例如，，敞開開的循循環(huán)，，污染染等））Definedurationofmonitoringaftershutdownorunusualevents定義關(guān)關(guān)閉或或非正正常情情況下下需要要監(jiān)控控的時時間31十十二二月202249Validation驗證Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方方針和水系系統(tǒng)驗證活活動Durationofmonitoring監(jiān)控時間Samplinglocations取樣位置Typesoftesting監(jiān)測類型Requirementsforrevalidation再驗證要求求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不會描述述具體的系系統(tǒng)或活動動，而應是是每個項目目的驗證主主計劃和方方案中的內(nèi)內(nèi)容。SOP為編寫具體體項目驗證證文件提供供指導31十二二月202250Validation驗證Initialphase初始階段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此階段,會制訂操操作參數(shù)和和清潔/消消毒規(guī)程和和頻率。2-4周內(nèi)內(nèi)，在純化化過程的每每一步，以以及在每一