2022年12月9日

WaterSystems

水系統知識講座九新藥業國際認證部經理高級工程師徐影2022年12月8日WaterSystems1Toexaminethebasictechnologyandrequirementsfor:檢查以下方面的基本技術和要求：

1)Watertreatmentsystems水處理系統

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Toexaminethebasictechnolog2C&Q-V-ModelV

VC&Q-V-ModelV

V3URS用戶需求URS¤FDS¤DQ¤SAT¤IQ¤OQURSURS¤FDS¤DQ¤SAT¤IQ¤OQ4Watersystemdesign

水系統的設計

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Watersystemdesign5Furtherwatertreatmentpurificationstagesdownstreamofthepre-treatmentsystem預處理系統后水的進一步純化

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Furtherwatertreatmentpurifi6Thereshouldbenodeadlegs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)

水系統設計（一）ThereshouldbenodeadlegsWa73.Thewateriscontaminatedasitpassesthroughthevalve當水通過閥門時，被污染

2.Bacteriacangrowwhenthevalveisclosed

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

Stagnantwaterinsidevalve閥門中的死水Watersystemdesign(2)

水系統設計（二）3.Thewateriscontaminateda81)Sanitarypumps潔凈泵2)ClampsandOringsversusthreadedfittings卡箍和O環，不用螺紋配件3)Heatexchangers換熱器4)Sidearmlevelmeasuringdevicesareunacceptable不可使用邊側臂狀水位測量裝置Watersystemdesign(3)

水系統設計（三）1)SanitarypumpsWatersystem9rawwater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Lowpressure低壓Purifiedwater純化水Reverseosmosis(RO)theory反滲透（RO）原理rawwaterHighpressureFeedwat10CationiccolumnAnioniccolumnHygienicpump衛生泵Outletsorstorage.OzonegeneratorUVlightHClNaOHEluatestoneutralizationplantAirbreaktosewer空氣斷開

Drainlinefromwatersoftener軟水機WatermustbekeptcirculatingTypicalde-ionizerschematic典型的去離子示意圖123456123456Returntode-ioniserCartridgefilter5μmCartridgefilter1μmCationiccolumnAnioniccolumnH11BranchBranchCartridgefilter1μmSecondstageROcartridge

FirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewer

Secondstagerejectwatergoesbacktofirststagebuffertank

SecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertank

Waterfromsoftenerorde-ioniser

Typical2-stageROschematic典型二級反滲透示意圖HygienicpumpFirststageROcartridgeHighpressurepumpBranchBranchCartridgeSecondst12Advantages優點Disadvantages缺點Manyuses應用領域purifiedwater純化水feedingofdistillationunitsorultra-filtrationunits蒸餾器或超濾器的進水WaterforFinalRinse最終沖洗用水WaterforInjections(ifpermissible)注射用水（如許可）Useofreverseosmosis反滲透的應用

AdvantagesUseofreverseosmo13CanbeusedforWFIorforWaterForFinalRinsingfor

parenteralmanufacturing(ifpermitted)可用作注射用水或生產注射劑的最終沖洗用水（如許可）Removesorganiccontaminants,suchas

endotoxins去除有機污染物，如內毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下運行，在121°C進行滅菌Ultra-filtration超濾

CanbeusedforWFIorforWat14Single-effectdistillation

單效蒸餾simpledistillation,singleeffect簡單蒸餾，單效vapourcompression,thermocompression蒸汽壓縮，熱壓縮Multieffectdistillation

多效蒸餾multipleeffectstills多效蒸餾機Distillation蒸餾Single-effectdistillationDist15Typicalwaterstorageanddistributionschematic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Typicalwaterstorageanddist16StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpBallvalv17StillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorStillStoragetankPumpsTCTOCDia18Watersystemsdesign水系統設計Check檢查Why?HowFeedWaterQuality進水質量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的處理階段無法處置未受限制的微生物和內毒素負荷Connections連接Sampling取樣Minimalcrevices最小裂縫Inspection檢查Watersystemsdesign水系統設計Check19Watersystemsdesign水系統設計Check檢查Why?HowFinishes拋光Reducebacterialadhesion減少細菌粘著Pipeslopes管道傾斜度Certification證書Drain

abilityespeciallyofcondensateaftersteamsanitising排水性,尤其是蒸汽消毒后的冷凝水Inspection檢查spiritlevel水平儀Isometrics等容法Watersystemsdesign水系統設計Check20Watersystemsdesign水系統設計Check檢查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利于微生物生長和附著的條件Sanitisation消毒Flowmeter流速計Records記錄Velocityinloop回路中流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生物繁殖,解決問題Watersystemsdesign水系統設計Check21Watersystemsdesign水系統設計CheckWhy?HowNot“reactive,additiveorabsorptive”不"產生反應,添加或吸附"Instruments儀器Certificates證書Certificates證書Inspection檢查Materialsofconstruction材質Calibrated已校正Sanitary清潔Watersystemsdesign水系統設計Check22Watersystemsdesign水系統設計CheckWhy?HowMinimalcrevices最小裂縫Passivation鈍化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工資質確認,焊接日志)焊接取樣,焊接檢查Documentation(Procedures,Passivationlog)文件(規程,鈍化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蝕性Watersystemsdesign水系統設計Check23WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality證實有持續產生高品質水的能力MasterPlan,驗證主計劃Protocols,驗證方案

summaryreports總結報告Validation驗證WaterSystemsdesignCheckWhy?H24Heat

熱

- Oneofthemostreliablemethodsofdisinfectionofwater systems

最可靠的消毒水系統的方法之一Ozone

臭氧

- Producedeasily

容易制備

- Leavesnoresidue

沒有殘留Disinfection(1)消毒（一）

HeatDisinfection(1)25UV

紫外

- UVdoesnot“sterilize”

紫外不可滅菌

- Flowratecritical

流速很關鍵

- Post-irradiationrecontaminationmaybeanissue

后放射再污染可能是個問題

- Lampshavefinitelife

燈的壽命有限Otherchemicals

其他化學法

- XO2

- Halogen

鹵素

- Formaldehyde

甲醛Disinfection(2)消毒（二）

UVDisinfection(2)26Theremustbeasamplingprocedure

必須有取樣規程Sampleintegritymustbeassured

必須保證樣品的完整性Samplertraining

取樣人培訓Samplepoint

取樣點Samplesize

取樣多少Sampling(1)取樣（一）

Theremustbeasamplingproce27Samplecontainer

取樣容器Samplelabel

樣品標簽Samplestorageandtransport

樣品儲存和轉移Arrivalatthelaboratory

到達實驗室Startoftest

開始測試Sampling(2)取樣（二）

SamplecontainerSampling(2)28Testing-settingspecificationsforpurifiedwaterorWFI

測試–規定純化水或注射用水標準

PurifiedWater純化水

Ph.Eur.中國藥典（2005）

USP

Nitrates硝酸鹽

≤

0.2ppm

≤0.06ppm

- Conductivity電導率

≤5.1μS/cm@25oC

-

≤1.3μS/cm@25oC TOC

≤0.5mg/l

-

≤0.5mg/l

Heavymetals重金屬≤

0.1ppm

≤0.5ppm

- Microbia微生物

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

測試–規定純化水或注射用水標準

WFI注射用水

Ph.Eur.

中國藥典（2005）USP Nitrates硝酸鹽

≤

0.2ppm≤

0.06ppm - Conductivity電導率

≤1.3μS/cm@25oC -

≤1.3μS/cm@25oCTOC

≤0.5mg/l -

≤0.5mg/l Microbial微生物

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

/mL)建議的微生物限度純化水（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10100Suggestedbacteriallimitsfor31TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果沒有給出指導值，可采用EU指南的限度(前面提到的）做為行動限。如果有歷史數據，可以將行動限定為3倍的平均值的標準偏差，警戒限定為2倍的平均值的標準偏差ActionandAlertLimits行動限和警戒限TheactionlimitistheEUgui32Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=52.45Standarddeviationis7.732SD=15.463SD=23.19Alertlimit(meanplus2SD)=68Actionlimit(meanplus3SD)=76Actionlimit(regulatoryguidance)=100MicrobiologicalMonitoring

微生物監測Example(PurifiedWaterUserP3309十二月202234Methodologiesthatcanberecommendedasgenerallysatisfactoryformicrobiologicalmonitoringpharmaceuticalwatersystemareasfollows水系統微生物監測的推薦方法:PurifiedWater純化水PourPlateMethod平皿法Minimumsample1.0ml.最小取樣量1.0毫升

Platecountagar48to72hoursincubation

培養基

培養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

培養基培養48-72小時08十二月20223434Methodverification

方法確認Chemicaltesting

化學測試Microbiologicaltesting

微生物測試testmethod

測試方法typesofmediaused

使用的培養基類型incubationtimeandtemperature

培養時間和溫度objectionableandindicatororganisms

異議和指示有機體don’tunderstandmanufacturermustsetspecifications

生產商必須制定標準Testing

檢測MethodverificationTesting

檢測35InternationalpharmacopoeiarequirementsforWFI

arethoseforpurifiedwaterplusitmustbefreefrompyrogens

國際藥典對注射用水的要求除了那些對純化水的要求外，還要求必須不含有熱源Usuallypreparedbydistillation

通常由蒸餾器制得Storagetimeshouldbelessthan24hours

儲存時間應少于24小時Microbiallimitsmustbespecified

必須制定微生物限度WaterforInjections

注射用水Internationalpharmacopoeiare36Waterforfinalrinsemustbeofthe

samequalityasthewaterrequired

forpharmaceuticalpreparation

最終沖洗用水的質量必須與藥品制備所要求的水的質量相同WaterforFinalRinse最終沖洗用水Waterforfinalrinsemustbe37Anycompoundinjectedintomammalswhichgivesrisetofeverisa“Pyrogen”

任何注入哺乳動物體內可引起發燒的物質稱為“熱源”Endotoxinsarepyrogenic,comefromGramnegativebacterialcellwallfragments

內毒素具有熱源性，來源于革蘭陰性菌細胞壁Detect

endotoxinsusingatestforlipopolysaccharides(LPS)

檢測內毒素使用脂多糖的測試rabbittestdetectspyrogens

兔子試驗檢測熱源LALtestdetectsendotoxins

鱟試劑檢測內毒素Ultrafiltration,distillation,&

RO

mayremovepyrogens

超濾、蒸餾和反滲透可能會去除熱源Pyrogensandendotoxins熱源和內毒素Anycompoundinjectedintomam38Trending趨勢分析DescribethemicrobiologicalproblemsofthisWFIsystem.描述注射用水系統的微生物問題Trending趨勢分析Describethemicro39CountsaretotalnumberofColonyFormingUnitsper100mlCountsaretotalnumberofCol40ActionAlertActionAlert41SOPsSOPsshouldaddressSOPs中應包括以下內容:Operationandroutinemonitoring操作和日常監控Maintenanceandcalibration維護和校正Cleaningandsanitization清潔和消毒Validation驗證09十二月202242SOPsSOPsshouldaddressSOPs中應42OperationandRoutineMonitoring

運行和日常監控Describesystem(generatingcomponents,numberofloops,materials,controlsystem)系統描述（制備系統組件，循環的數量，物料，控制系統）Listusers列明使用點Listrequirementsforsysteme.g.:列明系統要求，例如：Generatingcapacity制備能力Storagecapacity儲存容量Diversity(howmanypointsofusecanbeopenedsimultaneously)差異性（可以同時開啟幾個使用點）Flowrate流速Temperature溫度Specificationsforwaterqualityateachstage每個階段的水質標準09十二月202243OperationandRoutineMonitori43WaterSystems水系統知識專題講座課件44OperationandRoutineMonitoring

運行和日常監控Describesystemoperationincluding:系統的運行描述包括Systemstartup系統啟動Systemshutdown關機Emergencyshutdown緊急停機Normaloperations正常運行Monitoringduringroutineoperation日常運行的監控Describesamplingactivities描述取樣活動Ateachpurificationstage(typeoftests,frequencyacceptancecriteria)在每一步純化階段（監測類型，頻次，接受標準）pH,Conductivity,TOC,Chlorine,Microbial,EndotoxinetcResponsetoOOSOOS應對09十二月202245OperationandRoutineMonitori45MaintenanceandCalibration

維護和校正Routineinspectionandmaintenanceactivitiescarriedout:進行的日常檢查及維護活動Daily每日Weekly每周Monthly每月Annually每年Triggerevents(e.g.afterobservationofaspecificcondition)“觸發”事件（例如，觀察到特殊狀況）Includeprocedure,acceptancecriteria,forms包括規程，接受限度，表格09十二月202246MaintenanceandCalibration

維護46MaintenanceandCalibration

維護和校正PeriodicCalibrationactivitiescarriedout:應進行定期校正，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如果由合同商校正，應參照第三方管理SOPIfcarriedoutinhouse,ensurethereareindividualSOPsforcalibrationprocedures如果內部校正，確保每個校正規程有單獨的SOP09十二月202247MaintenanceandCalibration

維47Cleaningandsanitization

清潔和消毒Describecleaningandsanitizationactivitiesforeachcomponent:描述每個組件的清潔和消毒活動Methods方法Chemicalsused使用的化學物質Frequency頻次Duration持續時間Chemicalconcentration/temperature化學濃度/溫度09十二月202248Cleaningandsanitization

清潔和消48Cleaningandsanitization

清潔和消毒Describecleaningandsanitizationactivitiesrequiredaftershutdown描述系統停機后需要的清潔和消毒Definemaximumdurationofshutdownpermittedbeforesanitizationisrequired定義系統停機后最長多久需要消毒Defineothereventsthatrequiresanitizationpriortouseofwater(e.g.openingloop,contaminationetc)定義使用前，哪些情況需要消毒（例如，敞開的循環，污染等）Definedurationofmonitoringaftershutdownorunusualevents定義關閉或非正常情況下需要監控的時間09十二月202249Cleaningandsanitization

清潔和49Validation驗證Describecompanypolicyandpracticesforvalidatingwatersystems描述公司方針和水系統驗證活動Durationofmonitoring監控時間Samplinglocations取樣位置Typesoftesting監測類型Requirementsforrevalidation再驗證要求SOPwillnotdescribesspecificsystemoractivities,thiswillbeinProjectspecificVMPandProtocols.SOPprovidesguidancetothosewritingtheprojectspecificdocumentsSOP中不會描述具體的系統或活動，而應是每個項目的驗證主計劃和方案中的內容。SOP為編寫具體項目驗證文件提供指導09十二月202250Validation驗證Describecompany50Validation驗證Initialphase初始階段Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobe.

AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.在此階段,會制訂操作參數和清潔/消毒規程和頻率。2-4周內，在純化過程的每一步，以及在每一個使用點，應每日取樣。取樣點的取樣規程應反映水的質量。2-4周結束時，公司應制訂出水系統操作的SOP。09十二月202251Validation驗證Initialphase初始階段51Validation驗證第二階段--ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqualityofwater.系統驗證的第二階段應證明，在符合SOP下運行，能持續產生高品質水。取樣的頻次（每日）和時間（2-4周）應和初始階段相同。在此階段結束時，應有數據顯示系統能持續產生高品質水。52Validation驗證第二階段5252Validation驗證第三階段ThethirdphaseofvalidationisdesignedtodemonstratethatwhenthewatersystemisoperatedinaccordancewiththeSOPsoveralongperiodoftimeitwillconsistentlyproducewaterofthedesiredquality.Anyvariationsinthequalityofthefeed

waterthatcouldaffecttheoperationandultimatelythewaterqualitywillbepickedupduringthisphaseofthevalidation.Samplingisperformedaccordingtoroutineproceduresandfrequencies.驗證的第三階段應證明當系統在符合SOP下運行較長時間，能持續產生高品質水。任何會影響系統運行并會影響最終水質的進水質量的變異，都會在此驗證階段進行考察。應按照日常的規程和頻次進取樣。53Validation驗證第三階段5353Validation驗證ForWaterforInjectionsystemsthesamplesshouldbetakendailyfromaminimumofonepointofuse,withallpointsofusetestedweekly.Thevalidationofthewatersystemiscompletedwhenthefirmhasafullyearsworthofdata.對于注射用水系統取樣應每日至少一個使用點，所有點每周輪檢。當公司收集一整年有效數據后，水系統驗證完成。54Validation驗證ForWaterforInje5455ThankYou謝謝Questions?問題？55ThankYou552022年12月9日

WaterSystems

水系統知識講座九新藥業國際認證部經理高級工程師徐影2022年12月8日WaterSystems56Toexaminethebasictechnologyandrequirementsfor:檢查以下方面的基本技術和要求：

1)Watertreatmentsystems水處理系統

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Toexaminethebasictechnolog57C&Q-V-ModelV

VC&Q-V-ModelV

V58URS用戶需求URS¤FDS¤DQ¤SAT¤IQ¤OQURSURS¤FDS¤DQ¤SAT¤IQ¤OQ59Watersystemdesign

水系統的設計

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Watersystemdesign60Furtherwatertreatmentpurificationstagesdownstreamofthepre-treatmentsystem預處理系統后水的進一步純化

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Furtherwatertreatmentpurifi61Thereshouldbenodeadlegs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)

水系統設計（一）ThereshouldbenodeadlegsWa623.Thewateriscontaminatedasitpassesthroughthevalve當水通過閥門時，被污染

2.Bacteriacangrowwhenthevalveisclosed

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

Stagnantwaterinsidevalve閥門中的死水Watersystemdesign(2)

水系統設計（二）3.Thewateriscontaminateda631)Sanitarypumps潔凈泵2)ClampsandOringsversusthreadedfittings卡箍和O環，不用螺紋配件3)Heatexchangers換熱器4)Sidearmlevelmeasuringdevicesareunacceptable不可使用邊側臂狀水位測量裝置Watersystemdesign(3)

水系統設計（三）1)SanitarypumpsWatersystem64rawwater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Lowpressure低壓Purifiedwater純化水Reverseosmosis(RO)theory反滲透（RO）原理rawwaterHighpressureFeedwat65CationiccolumnAnioniccolumnHygienicpump衛生泵Outletsorstorage.OzonegeneratorUVlightHClNaOHEluatestoneutralizationplantAirbreaktosewer空氣斷開

Drainlinefromwatersoftener軟水機WatermustbekeptcirculatingTypicalde-ionizerschematic典型的去離子示意圖123456123456Returntode-ioniserCartridgefilter5μmCartridgefilter1μmCationiccolumnAnioniccolumnH66BranchBranchCartridgefilter1μmSecondstageROcartridge

FirststagefiltratefeedssecondstageROwithexcessbackto1ststagebuffertank.1ststagerejectconcentrateAirbreaktosewer

Secondstagerejectwatergoesbacktofirststagebuffertank

SecondstageROwatermeetsPharmacopoeiastandards1ststagebuffertank

Waterfromsoftenerorde-ioniser

Typical2-stageROschematic典型二級反滲透示意圖HygienicpumpFirststageROcartridgeHighpressurepumpBranchBranchCartridgeSecondst67Advantages優點Disadvantages缺點Manyuses應用領域purifiedwater純化水feedingofdistillationunitsorultra-filtrationunits蒸餾器或超濾器的進水WaterforFinalRinse最終沖洗用水WaterforInjections(ifpermissible)注射用水（如許可）Useofreverseosmosis反滲透的應用

AdvantagesUseofreverseosmo68CanbeusedforWFIorforWaterForFinalRinsingfor

parenteralmanufacturing(ifpermitted)可用作注射用水或生產注射劑的最終沖洗用水（如許可）Removesorganiccontaminants,suchas

endotoxins去除有機污染物，如內毒素Operationat65-80°C,andsterilizationat121°C在65-80°C下運行，在121°C進行滅菌Ultra-filtration超濾

CanbeusedforWFIorforWat69Single-effectdistillation

單效蒸餾simpledistillation,singleeffect簡單蒸餾，單效vapourcompression,thermocompression蒸汽壓縮，熱壓縮Multieffectdistillation

多效蒸餾multipleeffectstills多效蒸餾機Distillation蒸餾Single-effectdistillationDist70Typicalwaterstorageanddistributionschematic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Typicalwaterstorageanddist71StillStoragetankPumpBallvalves0.22umfilterPlateheatexchangerKEYStillStoragetankPumpBallvalv72StillStoragetankPumpsTCTOCDiaphragmvalvesT-TempprobeC-ConductivityTOC-TotalOrganicCarbonDoubletubesheetheatexchangerKEYSprayballBackPressureRegulatorStillStoragetankPumpsTCTOCDia73Watersystemsdesign水系統設計Check檢查Why?HowFeedWaterQuality進水質量Subsequenttreatmentstagescannotcopewithunrestrictedmicrobialandendotoxinload其后的處理階段無法處置未受限制的微生物和內毒素負荷Connections連接Sampling取樣Minimalcrevices最小裂縫Inspection檢查Watersystemsdesign水系統設計Check74Watersystemsdesign水系統設計Check檢查Why?HowFinishes拋光Reducebacterialadhesion減少細菌粘著Pipeslopes管道傾斜度Certification證書Drain

abilityespeciallyofcondensateaftersteamsanitising排水性,尤其是蒸汽消毒后的冷凝水Inspection檢查spiritlevel水平儀Isometrics等容法Watersystemsdesign水系統設計Check75Watersystemsdesign水系統設計Check檢查Why?HowToproduceunfavourableconditionsformicrobialgrowthandattachment制造不利于微生物生長和附著的條件Sanitisation消毒Flowmeter流速計Records記錄Velocityinloop回路中流速Forcontrolofmicrobialproliferationandinresponsetoproblems控制微生物繁殖,解決問題Watersystemsdesign水系統設計Check76Watersystemsdesign水系統設計CheckWhy?HowNot“reactive,additiveorabsorptive”不"產生反應,添加或吸附"Instruments儀器Certificates證書Certificates證書Inspection檢查Materialsofconstruction材質Calibrated已校正Sanitary清潔Watersystemsdesign水系統設計Check77Watersystemsdesign水系統設計CheckWhy?HowMinimalcrevices最小裂縫Passivation鈍化Documentation(WeldersQualification,weldlogs)Samplewelds,Weldinspection文件(焊接工資質確認,焊接日志)焊接取樣,焊接檢查Documentation(Procedures,Passivationlog)文件(規程,鈍化日志)Welding焊接Maximumcorrosionresistance最大耐受腐蝕性Watersystemsdesign水系統設計Check78WaterSystemsdesignCheckWhy?HowDemonstrationofconsistentabilitytoproducewaterofrightquality證實有持續產生高品質水的能力MasterPlan,驗證主計劃Protocols,驗證方案

summaryreports總結報告Validation驗證WaterSystemsdesignCheckWhy?H79Heat

熱

- Oneofthemostreliablemethodsofdisinfectionofwater systems

最可靠的消毒水系統的方法之一Ozone

臭氧

- Producedeasily

容易制備

- Leavesnoresidue

沒有殘留Disinfection(1)消毒（一）

HeatDisinfection(1)80UV

紫外

- UVdoesnot“sterilize”

紫外不可滅菌

- Flowratecritical

流速很關鍵

- Post-irradiationrecontaminationmaybeanissue

后放射再污染可能是個問題

- Lampshavefinitelife

燈的壽命有限Otherchemicals

其他化學法

- XO2

- Halogen

鹵素

- Formaldehyde

甲醛Disinfection(2)消毒（二）

UVDisinfection(2)81Theremustbeasamplingprocedure

必須有取樣規程Sampleintegritymustbeassured

必須保證樣品的完整性Samplertraining

取樣人培訓Samplepoint

取樣點Samplesize

取樣多少Sampling(1)取樣（一）

Theremustbeasamplingproce82Samplecontainer

取樣容器Samplelabel

樣品標簽Samplestorageandtransport

樣品儲存和轉移Arrivalatthelaboratory

到達實驗室Startoftest

開始測試Sampling(2)取樣（二）

SamplecontainerSampling(2)83Testing-settingspecificationsforpurifiedwaterorWFI

測試–規定純化水或注射用水標準

PurifiedWater純化水

Ph.Eur.中國藥典（2005）

USP

Nitrates硝酸鹽

≤

0.2ppm

≤0.06ppm

- Conductivity電導率

≤5.1μS/cm@25oC

-

≤1.3μS/cm@25oC TOC

≤0.5mg/l

-

≤0.5mg/l

Heavymetals重金屬≤

0.1ppm

≤0.5ppm

- Microbia微生物

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

測試–規定純化水或注射用水標準

WFI注射用水

Ph.Eur.

中國藥典（2005）USP Nitrates硝酸鹽

≤

0.2ppm≤

0.06ppm - Conductivity電導率

≤1.3μS/cm@25oC -

≤1.3μS/cm@25oCTOC

≤0.5mg/l -

≤0.5mg/l Microbial微生物

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

/mL)建議的微生物限度純化水（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10100Suggestedbacteriallimitsfor86TheactionlimitistheEUguidancelimit(whereprovided)Ifnoguidanceisgiven,whenyouhavehistoricaldatayoucansetactionlimitat3Standarddeviationsfrommean.Thealertlimitissetat2SDfrommean.如果沒有給出指導值，可采用EU指南的限度(前面提到的）做為行動限。如果有歷史數據，可以將行動限定為3倍的平均值的標準偏差，警戒限定為2倍的平均值的標準偏差ActionandAlertLimits行動限和警戒限TheactionlimitistheEUgui87Example(PurifiedWaterUserPoints)5653445565453350565746555943564454595861Mean=