-.z.GUIDETOINSPECTIONSOFHIGHPURITYWATERSYSTEMSNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).Thisguidediscusses,primarilyfromamicrobiologicalaspect,thereviewandevaluationofhighpuritywatersystemsthatareusedforthemanufactureofdrugproductsanddrugsubstances.Italsoincludesareviewofthedesignofthevarioustypesofsystemsandsomeoftheproblemsthathavebeenassociatedwiththesesystems.Aswithotherguides,itisnotall-inclusive,butprovidesbackgroundandguidanceforthereviewandevaluationofhighpuritywatersystems.TheGuideToInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories(May,1993)providesadditionalguidance.I.SYSTEMDESIGNOneofthebasicconsiderationsinthedesignofasystemisthetypeofproductthatistobemanufactured.Forparenteralproductswherethereisaconcernforpyrogens,itise*pectedthatWaterforInjectionwillbeused.Thisappliestotheformulationofproducts,aswellastothefinalwashingofponentsandequipmentusedintheirmanufacture.DistillationandReverseOsmosis(RO)filtrationaretheonlyacceptablemethodslistedintheUSPforproducingWaterforInjection.However,inthebulkPharmaceuticalandBiotechnologyindustriesandsomeforeignpanies,UltraFiltration(UF)isemployedtominimizeendoto*insinthosedrugsubstancesthatareadministeredparenterally.Forsomeophthalmicproducts,suchastheophthalmicirrigatingsolution,andsomeinhalationproducts,suchasSterileWaterforInhalation,wheretherearepyrogenspecifications,itise*pectedthatWaterforInjectionbeusedintheirformulation.However,formostinhalationandophthalmicproducts,purifiedwaterisusedintheirformulation.Thisalsoappliestotopicals,cosmeticsandoralproducts.Anotherdesignconsiderationisthetemperatureofthesystem.Itisrecognizedthathot(65–80℃)systemsareselfsanitizing.Whilethecostofothersystemsmaybelesse*pensiveforapany,thecostofmaintenance,testingandpotentialproblemsmaybegreaterthanthecostofenergysaved.Whetherasystemiscirculatingorone-wayisalsoanimportantdesignconsideration.Obviously,waterinconstantmotionislessliabletohavehighlevelsofcontaminant.Aone-waywatersystemisbasicallya"dead-leg".Finally,andpossiblythemostimportantconsideration,istheriskassessmentorlevelofqualitythatisdesired.Itshouldberecognizedthatdifferentproductsrequiredifferentqualitywaters.Parenteralsrequireverypurewaterwithnoendoto*ins.Topicalandoralproductsrequirelesspurewateranddonothavearequirementforendoto*ins.Evenwithtopicalandoralproductstherearefactorsthatdictatedifferentqualitiesforwater.Fore*ample,preservativesinantacidsaremarginallyeffective,somorestringentmicrobiallimitshavetobeset.Thequalitycontroldepartmentshouldassesseachproductmanufacturedwiththewaterfromtheirsystemanddeterminethemicrobialactionlimitsbasedonthemostmicrobialsensitiveproduct.Inlieuofstringentwateractionlimitsinthesystemthemanufacturercanaddamicrobialreductionstepinthemanufacturingprocessforthesensitivedrugproduct(s).II.SYSTEMVALIDATIONAbasicreferenceusedforthevalidationofhighpuritywatersystemsistheParenteralDrugAssociationTechnicalReportNo.4titled,"DesignConceptsfortheValidationofaWaterforInjectionSystem."Theintroductionprovidesguidanceandstatesthat,"Validationofteninvolvestheuseofanappropriatechallenge.Inthissituation,itwouldbeundesirabletointroducemicroorganismsintoanon-linesystem;therefore,relianceisplacedonperiodictestingformicrobiologicalqualityandontheinstallationofmonitoringequipmentatspecificcheckpointstoensurethatthetotalsystemisoperatingproperlyandcontinuouslyfulfillingitsintendedfunction."Inthereviewofavalidationreport,orinthevalidationofahighpuritywatersystem,thereareseveralaspectsthatshouldbeconsidered.Documentationshouldincludeadescriptionofthesystemalongwithaprint.Thedrawingneedstoshowallequipmentinthesystemfromthewaterfeedtopointsofuse.Itshouldalsoshowallsamplingpointsandtheirdesignations.Ifasystemhasnoprint,itisusuallyconsideredanobjectionablecondition.Thethinkingisifthereisnoprint,thenhowcanthesystembevalidated"Howcanaqualitycontrolmanagerormicrobiologistknowwheretosample"Inthosefacilitiesobservedwithoutupdatedprints,seriousproblemswereidentifiedinthesesystems.Theprintshouldbeparedtotheactualsystemannuallytoinsureitsaccuracy,todetectunreportedchangesandconfirmreportedchangestothesystem.Afteralltheequipmentandpipinghasbeenverifiedasinstalledcorrectlyandworkingasspecified,theinitialphaseofthewatersystemvalidationcanbegin.Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobedrawne.g.ifahoseisusuallyattachedthesampleshouldbetakenattheendofthehose.IftheSOPcallsforthelinetobeflushedbeforeuseofthewaterfromthatpoint,thenthesampleistakenaftertheflush.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqualityofwater.ThethirdphaseofvalidationisdesignedtodemonstratethatwhenthewatersystemisoperatedinaccordancewiththeSOPsoveralongperiodoftimeitwillconsistentlyproducewaterofthedesiredquality.Anyvariationsinthequalityofthefeedwaterthatcouldaffecttheoperationandultimatelythewaterqualitywillbepickedupduringthisphaseofthevalidation.Samplingisperformedaccordingtoroutineproceduresandfrequencies.ForWaterforInjectionsystemsthesamplesshouldbetakendailyfromaminimumofonepointofuse,withallpointsofusetestedweekly.Thevalidationofthewatersystemispletedwhenthefirmhasafullyearsworthofdata.Whiletheabovevalidationschemeisnottheonlywayasystemcanbevalidated,itcontainsthenecessaryelementsforvalidationofawatersystem.First,theremustbedatatosupporttheSOPs.Second,theremustbedatademonstratingthattheSOPsarevalidandthatthesystemiscapableofconsistentlyproducingwaterthatmeetsthedesiredspecifications.Finally,theremustbedatatodemonstratethatseasonalvariationsinthefeedwaterdonotadverselyaffecttheoperationofthesystemorthewaterquality.Thelastpartofthevalidationisthepilationofthedata,withanyconclusionsintothefinalreport.Thefinalvalidationreportmustbesignedbytheappropriatepeopleresponsibleforoperationandqualityassuranceofthewatersystem.Atypicalproblemthatoccursisthefailureofoperatingprocedurestoprecludecontaminationofthesystemwithnon-sterileairremaininginapipeafterdrainage.InasystemillustratedasinFigure1,(below)atypicalproblemoccurswhenawasherorhoseconnectionisflushedandthendrainedattheendoftheoperation.Afterdraining,thisvalve(thesecondoffofthesystem)isclosed.Ifonthene*tdayorstart-upoftheoperationtheprimaryvalveoffofthecirculatingsystemisopened,thenthenon-sterileairremaininginthepipeafterdrainagewouldcontaminatethesystem.Thesolutionistopro-videforoperationalproceduresthatprovideforopeningthesecondaryvalvebeforetheprimaryvalvetoflushthepipepriortouse.Anothermajorconsiderationinthevalidationofhighpuritywatersystemsistheacceptancecriteria.Consistentresultsthroughoutthesystemoveraperiodoftimeconstitutetheprimaryelement.III.MICROBIALLIMITS微生物限度WaterForInjectionSystems注射用水系統(tǒng)Regardingmicrobiologicalresults,forWaterForInjection,itise*pectedthattheybeessentiallysterile.Sincesamplingfrequentlyisperformedinnon-sterileareasandisnottrulyaseptic,occasionallowlevelcountsduetosamplingerrorsmayoccur.Agencypolicyisthatlessthan10CFU/100mlisanacceptableactionlimit.Noneofthelimitsforwaterarepass/faillimits.Alllimitsareactionlimits.Whenactionlimitsaree*ceededthefirmmustinvestigatethecauseoftheproblem,takeactiontocorrecttheproblemandassesstheimpactofthemicrobialcontaminationonproductsmanufacturedwiththewateranddocumenttheresultsoftheirinvestigation.Withregardtosamplesize,100-300mLispreferredwhensamplingWaterforInjectionsystems.Samplevolumeslessthan100mLareunacceptable.TherealconcerninWFIisendoto*ins.BecauseWFIcanpasstheLALendoto*intestandstillfailtheabovemicrobialactionlimit,itisimportanttomonitorWFIsystemsforbothendoto*insandmicroorganisms.PurifiedWaterSystems純化水系統(tǒng)Forpurifiedwatersystems,microbiologicalspecificationsarenotasclear.USP**IIspecifications,thatitplieswithfederalEnvironmentalProtectionAgencyregulationsfordrinkingwater,arerecognizedasbeingminimalspecifications.Therehavebeenattemptsbysometoestablishmeaningfulmicrobiologicalspecificationsforpurifiedwater.TheCFTAproposedaspecificationofnotmorethan500organismsperml.TheUSP**IIhasanactionguidelineofnotgreaterthan100organismsperml.Althoughmicrobiologicalspecificationshavebeendiscussed,none(otherthanEPAstandards)havebeenestablished.Agencypolicyisthatanyactionlimitover100CFU/mLforapurifiedwatersystemisunacceptable.Thepurposeofestablishinganyactionlimitorlevelistoassurethatthewatersystemisundercontrol.Anyactionlimitestablishedwilldependupontheoverallpurifiedwatersystemandfurtherprocessingofthefinishedproductanditsuse.Fore*ample,purifiedwaterusedtomanufacturedrugproductsbycoldprocessingshouldbefreeofobjectionableorganisms.Wehavedefined"objectionableorganisms"asanyorganismsthatcancauseinfectionswhenthedrugproductisusedasdirectedoranyorganismcapableofgrowthinthedrugproduct.AspointedoutintheGuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories,thespecificcontaminant,ratherthanthenumberisgenerallymoresignificant.Organismse*istinawatersystemeitherasfreefloatinginthewaterorattachedtothewallsofthepipesandtanks.Whentheyareattachedtothewallstheyareknownasbiofilm,whichcontinuouslysloughofforganisms.Thus,contaminationisnotuniformlydistributedinasystemandthesamplemaynotberepresentativeofthetypeandlevelofcontamination.Acountof10CFU/mLinonesampleand100oreven1000CFU/mLinasubsequentsamplewouldnotbeunrealistic.Thus,inestablishingthelevelofcontaminationallowedinahighpuritywatersystemusedinthemanufactureofanon-sterileproductrequiresanunderstandingoftheuseoftheproduct,theformulation(preservativesystem)andmanufacturingprocess.Fore*ample,antacids,whichdonothaveaneffectivepreservativesystem,requireanactionlimitbelowthe100CFU/mLma*imum.TheUSPgivessomeguidanceintheirmonographonMicrobiologicalAttributesofNon-SterileProducts.Itpointsoutthat,"Thesignificanceofmicroorganismsinnon-sterilepharmaceuticalproductsshouldbeevaluatedintermsoftheuseoftheproduct,thenatureoftheproduct,andthepotentialharmtotheuser."Thus,notjusttheindicatororganismslistedinsomeofthespecificmonographspresentproblems.Itisuptoeachmanufacturertoevaluatetheirproduct,thewayitismanufactured,andestablishanacceptableactionlevelofcontamination,nottoe*ceedthema*imum,forthewatersystem,basedonthehighestriskproductmanufacturedwiththewater.IV.WATERFORINJECTIONSYSTEMS注射用水系統(tǒng)InthereviewandevaluationofWaterForInjectionsystems,thereareseveralconcerns.PretreatmentoffeedwaterisremendedbymostmanufacturersofdistillationequipmentandisdefinitelyrequiredforROunits.Theiningfeedwaterqualitymayfluctuateduringthelifeofthesystemdependinguponseasonalvariationsandothere*ternalfactorsbeyondthecontrolofthepharmaceuticalfacility.Fore*ample,inthespring(atleastintheN.E.),increasesingramnegativeorganismshavebeenknown.Also,newconstructionorfirescancauseadepletionofwaterstoresinoldmainswhichcancauseaninflu*ofheavilycontaminatedwaterofadifferentflora.Awatersystemshouldbedesignedtooperatewithintheseanticipatede*tremes.Obviously,theonlywaytoknowthee*tremesistoperiodicallymonitorfeedwater.Ifthefeedwaterisfromamunicipalwatersystem,reportsfromthemunicipalitytestingcanbeusedinlieuofin-housetesting.V.STILL蒸餾塔Figures3-5representatypicalbasicdiagramofaWFIsystem.Mostofthenewsystemsnowusemulti-effectstills.Insomeofthefacilities,therehasbeenevidenceofendoto*incontamination.Inonesystemthisoccurred,duetomalfunctionofthefeedwatervalveandlevelcontrolinthestillwhichresultedindropletsoffeedwaterbeingcarriedoverinthedistillate.高純水系統(tǒng)檢查指南注意：本文件只是審查員與其他FDA官員的參考材料。本文件不能約束FDA，也不授予任何人任何權(quán)利、特權(quán)、利益或者豁免權(quán)。該指南主要從微生物方面來評估用于藥物制劑和藥物生產(chǎn)的高純水系統(tǒng)，包括不同類型系統(tǒng)的設(shè)計審核和與這些系統(tǒng)相關(guān)的一些問題。與其它指南一樣，該指南只對高純化水系統(tǒng)的評估提供背景資料和指導(dǎo)作用，但并不包括一切。另外可參考“制藥質(zhì)量控制實驗室的微生物檢查指南〞〔May，1993〕。I.系統(tǒng)設(shè)計在設(shè)計一個系統(tǒng)時，首先要考慮的是生產(chǎn)的產(chǎn)品類型。對注射用藥品來說，應(yīng)重點關(guān)注熱原物質(zhì)，所以使用注射用水。注射用水應(yīng)用于產(chǎn)品的配制，部件及生產(chǎn)設(shè)備的最終沖洗。USP中規(guī)定的生產(chǎn)注射用水方法只有蒸餾法和反滲透法。然而，在大宗制藥工業(yè)、生物技術(shù)工業(yè)及一些國外公司中，采用超濾法將注射用藥物的毒素減到最少。在一些眼用制劑〔如眼用灌洗劑〕和一些吸入制劑〔如吸入用無菌水〕中，由于有熱原標(biāo)準(zhǔn)，所以在其配制中要用注射用水。但是，大局部吸入制劑及眼用制劑都使用純化水配制。純化水還用于外用制劑、化裝品及口服制劑的生產(chǎn)。另一個設(shè)計關(guān)注點是系統(tǒng)溫度。溫度在65～80℃的熱水系統(tǒng)被認(rèn)為是自凈系統(tǒng)。對一個公司來說，雖然其它水系統(tǒng)本錢可能更廉價，但是系統(tǒng)的維護(hù)、檢測和潛在問題產(chǎn)生的費(fèi)用可能會比節(jié)省的能量費(fèi)更高。系統(tǒng)是循環(huán)或是單向也是設(shè)計系統(tǒng)時所要考慮的重點。顯然，讓水持續(xù)流動就不易受到高水平的污染。一個單向水系統(tǒng)根本上是“死角〞。最后，設(shè)計系統(tǒng)的風(fēng)險評估及期望的質(zhì)量水平可能是最重要的考量局部。應(yīng)該認(rèn)識到不同產(chǎn)品需要不同質(zhì)量的水。注射用藥需要無毒素的高純水，外用制劑和口服制劑所需水沒有毒素的要求，純度要求稍低。即使是外用制劑和口服制劑，也有影響要用不同質(zhì)量的水的各種因素，例如，在抗酸劑中防腐劑幾乎不起作用，所以得制定更嚴(yán)格的微生物指標(biāo)。質(zhì)量控制部門應(yīng)評估采用水系統(tǒng)中的水生產(chǎn)的每一種產(chǎn)品，根據(jù)對微生物最敏感的產(chǎn)品制定水系統(tǒng)的微生物糾偏限度。代替制定嚴(yán)格的水系統(tǒng)微生物糾偏限度的另一種方法是：對于微生物敏感的藥品，生產(chǎn)者可在生產(chǎn)過程中增加一步去除微生物的步驟。II.系統(tǒng)驗證高純化水系統(tǒng)的驗證的根本參考物事"注射用藥協(xié)會技術(shù)報告"第4號文件，名為“注射用水系統(tǒng)驗證的設(shè)計概念〞。緒論提供了指導(dǎo)并指出：“驗證經(jīng)常包括恰當(dāng)?shù)奶魬?zhàn)方法的使用。在這里，沒有必要把微生物引入在線系統(tǒng)進(jìn)展挑戰(zhàn)試驗，因此，主要依靠微生物質(zhì)量的定期檢測以及在特定檢查點安裝監(jiān)測設(shè)備，以確保整個系統(tǒng)處于正確的運(yùn)行狀態(tài)和持續(xù)執(zhí)行其預(yù)定功能。〞在審核驗證報告時或在高純水系統(tǒng)的驗證過程中，有多個方面需要得到考慮。文件記錄應(yīng)包括對系統(tǒng)的描述和打印的圖紙。圖紙應(yīng)顯示系統(tǒng)中從進(jìn)水到使用點的所有設(shè)備，也應(yīng)標(biāo)明所有的取樣點及其名稱。如果系統(tǒng)沒有圖紙，通常是不能令人承受的。檢查官會認(rèn)為如果圖紙都沒有，怎么進(jìn)展系統(tǒng)驗證呢？質(zhì)量控制者或微生物檢驗者怎么知道哪里可以取樣呢？在被觀察到?jīng)]有更新圖紙的那些設(shè)施中，從這些系統(tǒng)里檢查出了很多嚴(yán)重問題。每年應(yīng)該將圖紙和實際系統(tǒng)相比照，以確保圖紙的準(zhǔn)確性，及時發(fā)現(xiàn)系統(tǒng)中未報告的變更和證實已報告的變更。在確定所有的設(shè)備和管道都正確安裝并按預(yù)定要求工作后，水系統(tǒng)驗證的第一階段就可以開場了。在此期間，將制定運(yùn)行參數(shù)和清潔消毒程序、頻率。每天在水純化過程中的每一步驟之后以及每個使用點進(jìn)展取樣，取2-4周。使用點的取樣程序應(yīng)該描述水是怎么取出來的，例如，如果使用軟管取樣，應(yīng)該在軟管末端抽取。如果標(biāo)準(zhǔn)操作程序要求使用點用水前要先沖洗，則樣品應(yīng)在沖洗后取。在2-4周的末期，公司應(yīng)該已經(jīng)制定出水系統(tǒng)運(yùn)行的標(biāo)準(zhǔn)操作程序。系統(tǒng)驗證的第二階段是證明當(dāng)按SOP操作時，系統(tǒng)能持續(xù)生產(chǎn)出所期望的水質(zhì)。取樣和取樣周期與第一階段一樣。該階段末期的數(shù)據(jù)應(yīng)該證明系統(tǒng)能持續(xù)生產(chǎn)出所需質(zhì)量的水。第三階段的驗證被設(shè)計用于證明當(dāng)按SOPs操作時，系統(tǒng)在很長時期能持續(xù)生產(chǎn)出所設(shè)計質(zhì)量的用水。在本驗證階段中，進(jìn)水質(zhì)量的任何變化都會影響系統(tǒng)的運(yùn)行并且最終的水質(zhì)將將被檢出。取樣按照例行規(guī)程和頻率進(jìn)展。注射用水系統(tǒng)每天至少取樣一個使用點，每周對所有使用點應(yīng)進(jìn)展取樣。當(dāng)公司有一套數(shù)年的有價值的數(shù)據(jù)時，水系統(tǒng)的驗證就完成了。雖然以上的驗證規(guī)劃不是驗證水系統(tǒng)的唯一方式，但它包含了一個水系統(tǒng)驗證必需的要素。首先，必須有數(shù)據(jù)支持SOP；其次，必須有數(shù)據(jù)證明SOP是合理的且系統(tǒng)能持續(xù)生產(chǎn)出符合設(shè)計質(zhì)量要求的用水；最后，必須有數(shù)據(jù)證明進(jìn)水的季節(jié)偏差不會影響系統(tǒng)的運(yùn)行或水質(zhì)。驗證的最后局部是數(shù)據(jù)的匯編，在最終報告中寫入假設(shè)干結(jié)論。最終的驗證報告必須由能對水系統(tǒng)運(yùn)行和質(zhì)量保證負(fù)責(zé)的人簽字。發(fā)生的典型問題是排水后非無菌的空氣殘留在系統(tǒng)管道中造成預(yù)防系統(tǒng)污染的操作程序失敗。在一個系統(tǒng)中，如圖1所示，一個常見問題發(fā)生在當(dāng)用密封圈或軟管連接進(jìn)展沖洗，然后在該操作的末期進(jìn)展排水的時候。排水之后，該閥門〔系統(tǒng)的第二個閥門〕已經(jīng)關(guān)閉。如果第二天或操作啟動時，循環(huán)系統(tǒng)下面的第一個閥門開著，則排水后殘存在管道中的非無菌空氣就會污染系統(tǒng)。解決該問題的方法是規(guī)操作程序，規(guī)定在翻開第一個閥門沖洗管道之前必須先翻開第二閥門。高純水系統(tǒng)驗證所需考慮的另外一個主要問題是驗收標(biāo)準(zhǔn)。一段時期，整個系統(tǒng)從始至終的持續(xù)一致的結(jié)果構(gòu)成了驗收標(biāo)準(zhǔn)的主要要素。III.微生物限度注射用水系統(tǒng)對注射用水來說，微生物指標(biāo)要求本質(zhì)上無菌。由于經(jīng)常在非無菌區(qū)進(jìn)展取樣操作，偶爾產(chǎn)生的取樣錯誤會導(dǎo)致低水平微生物污染。行政政策可承受的糾偏限度為小于10CFU/100ml。水的限度沒有所謂的合格/失敗限度，所有的限度都是指糾偏限度。當(dāng)超過糾偏限度時，公司必須調(diào)查問題的原因并采取行動糾正問題，評估微生物污染對使用這些水生產(chǎn)的產(chǎn)品造成的影響，并記錄調(diào)查處理的結(jié)果。關(guān)于取樣體積，100～300ml是注射用水取樣的首選，樣品體積不可少于100ml。注射用水中真正關(guān)注的是毒素。因為注射用水可以既通過鱟試劑毒素測試又通不過上述的微生物糾偏限度，所以對注射用水系統(tǒng)來說監(jiān)控毒素和微生物同樣重要。純化水系統(tǒng)對純化水系統(tǒng)來說，微生物規(guī)定不是很明確。USP**II的標(biāo)準(zhǔn)遵從"聯(lián)邦環(huán)境保護(hù)署法規(guī)"關(guān)于飲用水的標(biāo)準(zhǔn)，該標(biāo)準(zhǔn)被認(rèn)為是最低限度標(biāo)準(zhǔn)。一些人嘗試為純化水建立有意義的微生物標(biāo)準(zhǔn)。CFTA建議不超過500CFU/ml，USP**II有一個不超過100CFU/ml的指導(dǎo)方針。盡管微生物標(biāo)準(zhǔn)已經(jīng)被討論過，但除了EPA〔環(huán)境保護(hù)署〕標(biāo)準(zhǔn)外并未建立任何標(biāo)準(zhǔn)。從政策上來說，糾偏限度超過100CFU/ml即為不合格。建立任何糾偏限度或水平的目的都是確保水系統(tǒng)處于可控狀態(tài)。任何糾偏限度的建立都要依據(jù)整個純化水系統(tǒng)以及制劑產(chǎn)品的進(jìn)一步加工工藝和使用用途。例如，經(jīng)冷凍工藝處理用來生產(chǎn)藥品的純化水應(yīng)該是無有害有機(jī)體的。“有害有機(jī)體〞定義為在指導(dǎo)下用藥時會導(dǎo)致感染的任何有機(jī)體或在藥品生產(chǎn)過程中能繁殖的任何有機(jī)體。正如"藥物質(zhì)量控制實驗室的微生物檢查指南"所指出的那樣，污染物的種類通常比污染物數(shù)量更重要。水系統(tǒng)中存在的有機(jī)體可能懸浮在水中或者吸附在管道壁或罐壁上。吸附在壁上的就是我們所知道的生物膜，可持續(xù)脫落出有機(jī)體。因而，在一個系統(tǒng)中污染并不是均勻分布的，取樣也可能無法真實反映系統(tǒng)的污染類型和水平。在一個樣品中10CFU/ml的量，然后在繼后樣品中出現(xiàn)100甚或1000CFU/ml的量都不是不可能的。因而，建立用于生產(chǎn)非無菌產(chǎn)品的高純水系統(tǒng)允許的污染水平時，需要理解產(chǎn)品的用途、配方〔防腐系統(tǒng)〕和生產(chǎn)工藝。比方，抗酸劑沒有一個有效的防腐系統(tǒng)，要求的糾偏限度在最大值100CFU/mL之下。USP在其關(guān)于“非無菌產(chǎn)品的微生物特征〞專論中給出一些指導(dǎo)，它指出“在非無菌藥品中，微生物的重要性應(yīng)該結(jié)合產(chǎn)品的用途、產(chǎn)品的自然屬性和對患者的潛在危害進(jìn)展評估〞。因而，不僅僅是在一些特定專論中列舉的指示性微生物提出問題，文章還要求每個生產(chǎn)廠商應(yīng)該評估他們的產(chǎn)品和制造方式，并在用該水生產(chǎn)的風(fēng)險最大產(chǎn)品根底上，給水系統(tǒng)建立不超過最大糾偏限度的可行的污染行動水平。IV.注射用水系統(tǒng)；在注射用水系統(tǒng)的審核和評估中，有幾個關(guān)注點。大多蒸餾設(shè)備的生產(chǎn)商推薦對進(jìn)水進(jìn)展預(yù)處理，并明確要求使用RO單元。原水質(zhì)量可能會隨季節(jié)的變動以及其它超越設(shè)備本身控制的外部因素而波動。例如，在春季〔至少在N.E.時〕，大家知道革蘭氏陰性菌會繁殖增多，同時，新建筑或火災(zāi)會消耗老舊主管道中的存水，這會導(dǎo)致污染嚴(yán)重的水以不同形式流入。一個好的水系統(tǒng)應(yīng)能在這些預(yù)計到的的極端情況下保持正常運(yùn)轉(zhuǎn)。顯然，唯一能確認(rèn)極端情況的方法是定期監(jiān)測原水質(zhì)量。如果原水來自市政水系統(tǒng)，則市政當(dāng)局的測試報告可以代替公司部測試報告。V.蒸餾塔圖3-5是WFI系統(tǒng)的一個典型圖紙。大多數(shù)新系統(tǒng)使用多效蒸餾塔。在這些設(shè)施中，已經(jīng)證實有毒素污染的案例。在一個發(fā)生毒素污染的系統(tǒng)中，由于進(jìn)水閥故障和蒸餾塔的控制不當(dāng)，導(dǎo)致蒸餾水中攜帶有原水的小液滴。Inanothersystemwithendoto*inproblems,itwasnotedthattherewasappro*imately50litersofWFIinthecondenseratthestart-up.Sincethiswatercouldlieinthecondenserforuptoseveraldays(i.e.,overtheweekend),itwasbelievedthatthiswasthereasonforunacceptablelevelsofendoto*ins.Moremon,however,isthefailuretoadequatelytreatfeedwatertoreducelevelsofendoto*ins.Manyofthestillfabricatorswillonlyguaranteea2.5logto3logreductionintheendoto*incontent.Therefore,itisnotsurprisingthatinsystemswherethefeedwateroccasionallyspikesto250EU/ml,unacceptablelevelsofendoto*insmayoccasionallyappearinthedistillate(WFI).Fore*ample,recentlythreenewstills,includingtwomulti-effect,werefoundtobeperiodicallyyieldingWFIwithlevelsgreaterthan.25EU/ml.PretreatmentsystemsforthestillsincludedonlydeionizationsystemswithnoUF,ROordistillation.Unlessafirmhasasatisfactorypretreatmentsystem,itwouldbee*tremelydifficultforthemtodemonstratethatthesystemisvalidated.Theabovee*amplesofproblemswithdistillationunitsusedtoproduceWFI,pointtoproblemswithmaintenanceoftheequipmentorimproperoperationofthesystemindicatingthatthesystemhasnotbeenproperlyvalidatedorthattheinitialvalidationisnolongervalid.Ifyouseethesetypesofproblemsyoushouldlookverycloselyatthesystemdesign,anychangesthathavebeenmadetothesystem,thevalidationreportandtheroutinetestdatatodetermineifthesystemisoperatinginastateofcontrol.Typically,conductivitymetersareusedonwatersystemstomonitorchemicalqualityandhavenomeaningregardingmicrobiologicalquality.Figures3-5alsoshowpetcocksorsmallsamplingportsbetweeneachpieceofequipment,suchasafterthestillandbeforetheholdingtank.Theseareinthesystemtoisolatemajorpiecesofequipment.Thisisnecessaryforthequalificationoftheequipmentandfortheinvestigationofanyproblemswhichmightoccur.VI.HEATE*CHANGERS熱交換器Oneprincipalponentofthestillistheheate*changer.Becauseofthesimilarionicqualityofdistilledanddeionizedwater,conductivitymeterscannotbeusedtomonitormicrobiologicalquality.Positivepressuresuchasinvaporpressionordoubletubesheetdesignshouldbeemployedtopreventpossiblefeedwatertodistillatecontaminationinaleakyheate*changer.AnFDAInspectorsTechnicalGuidewiththesubjectof"HeatE*changerstoAvoidContamination"discussesthedesignandpotentialproblemsassociatedwithheate*changers.Theguidepointsoutthattherearetwomethodsforpreventingcontaminationbyleakage.Oneistoprovidegaugestoconstantlymonitorpressuredifferentialstoensurethatthehigherpressureisalwaysonthecleanfluidside.Theotheristoutilizethedouble-tubesheettypeofheate*changer.Insomesystems,heate*changersareutilizedtocoolwateratusepoints.Forthemostpart,coolingwaterisnotcirculatedthroughthemwhennotinuse.Inafewsituations,pinholesformedinthetubingaftertheyweredrained(onthecoolingwaterside)andnotinuse.Itwasdeterminedthatasmallamountofmoistureremaininginthetubeswhenbinedwithaircausedacorrosionofthestainlesssteeltubesonthecoolingwaterside.Thus,itisremendedthatwhennotinuse,heate*changersnotbedrainedofthecoolingwater.VII.HOLDINGTANKInhotsystems,temperatureisusuallymaintainedbyapplyingheattoajacketedholdingtankorbyplacingaheate*changerinthelinepriortoaninsulatedholdingtank.Theoneponentoftheholdingtankthatgeneratesthemostdiscussionistheventfilter.Itise*pectedthattherebesomeprogramforintegritytestingthisfiltertoassurethatitisintact.Typically,filtersarenowjacketedtopreventcondensateorwaterfromblockingthehydrophobicventfilter.Ifthisoccurs(theventfilterbeesblocked),possiblyeitherthefilterwillruptureorthetankwillcollapse.Therearemethodsforintegritytestingofventfiltersinplace.Itise*pected,therefore,thattheventfilterbelocatedinapositionontheholdingtankwhereitisreadilyaccessible.JustbecauseaWFIsystemisrelativelynewanddistillationisemployed,itisnotproblem-free.Inaninspectionofamanufacturerofparenterals,asystemfabricatedin1984wasobserved.RefertoFigure6.Whilethesystemmayappearsomewhatple*ontheinitialreview,itwasfoundtoberelativelysimple.Figure7isaschematicofthesystem.Theobservationsattheconclusionoftheinspectionofthismanufacturerincluded,"OperationalproceduresfortheWaterForInjectionsystemfailedtoprovideforperiodicpleteflushingordraining.Thesystemwasalsoopentotheatmosphereandroomenvironment.poundingequipmentconsistedofnon-sealed,opentankswithlids.TheWaterforInjectionholdingtankwasalsonotsealedandwasneversampledforendoto*ins."Becauseoftheseandotherments,thefirmrecalledseveralproductsanddiscontinuedoperations.VIII.PUMPS泵Pumpsburnoutandpartswear.Also,ifpumpsarestaticandnotcontinuouslyinoperation,theirreservoircanbeastaticareawherewaterwilllie.Fore*ample,inaninspection,itwasnotedthatafirmhadtoinstalladrainfromthelowpointinapumphousing.Pseudomonassp.contaminationwasperiodicallyfoundintheirwatersystemwhichwasattributedinparttoapumpwhichonlyperiodicallyisoperational.I*.PIPING管路PipinginWFIsystemsusuallyconsistofahighpolishedstainlesssteel.Inafewcases,manufacturershavebeguntoutilizePVDF(polyvinylidenefluoride)piping.Itispurportedthatthispipingcantolerateheatwithnoe*tractablesbeingleached.AmajorproblemwithPVDFtubingisthatitrequiresconsiderablesupport.Whenthistubingisheated,ittendstosagandmaystresstheweld(fusion)connectionandresultinleakage.Additionally,initiallyatleast,fluoridelevelsarehigh.Thispipingisofbenefitinproductdeliverysystemswherelowlevelmetalcontaminationmayacceleratethedegradationofdrugproduct,suchasintheBiotechindustry.Onemonproblemwithpipingisthatof"dead-legs".TheproposedLVPRegulationsdefineddead-legsasnothavinganunusedportiongreaterinlengththansi*diametersoftheunusedpipemeasuredfromthea*isofthepipeinuse.Itshouldbepointedoutthatthiswasdevelopedforhot75-80ocirculatingsystems.Withcoldersystems(65-75oC),anydropsorunusedportionofanylengthofpipinghasthepotentialfortheformationofabiofilmandshouldbeeliminatedifpossibleorhavespecialsanitizingprocedures.Thereshouldbenothreadedfittingsinapharmaceuticalwatersystem.Allpipejointsmustutilizesanitaryfittingsorbebuttwelded.Sanitaryfittingswillusuallybeusedwherethepipingmeetsvalves,tanksandotherequipmentthatmustberemovedformaintenanceorreplacement.Therefore,thefirm'sproceduresforsanitization,aswellastheactualpiping,shouldbereviewedandevaluatedduringtheinspection.*.REVERSEOSMOSIS反滲透AnotheracceptablemethodformanufacturingWaterforInjectionisReverseOsmosis(RO).However,becausethesesystemsarecold,andbecauseROfiltersarenotabsolute,microbiologicalcontaminationisnotunusual.Figure8showsasystemthatwasinuseseveralyearsago.TherearefiveROunitsinthissystemwhichareinparallel.SinceROfiltersarenotabsolute,thefiltermanufacturersremendthatatleasttwobeinseries.ThedrawingalsoillustratesanUltraviolet(UV)lightinthesystemdownstreamfromtheROunits.Thelightwasneededtocontrolmicrobiologicalcontamination.Alsointhissystemwereballvalves.Thesevalvesarenotconsideredsanitaryvalvessincethecenterofthevalvecanhavewaterinitwhenthevalveisclosed.Thisisastagnantpoolofwaterthatcanharbormicroorganismsandprovideastartingpointforabiofilm.AsanadditionalmentonROsystems,withtherecognitionofmicrobiologicalproblems,somemanufacturershaveinstalledheate*changersimmediatelyaftertheROfilterstoheatthewaterto75–80℃tominimizemicrobiologicalcontamination.Withthedevelopmentofbiotechnologyproducts,manysmallpaniesareutilizingROandUFsystemstoproducehighpuritywater.Fore*ample,Figure9illustratesawallmountedsystemthatisfedbyasinglepassROunit.Asillustrated,mostofthesesystemsemployPVCorsometypeofplastictubing.Becausethesystemsaretypicallycold,themanyjointsinthesystemaresubjecttocontamination.AnotherpotentialproblemwithPVCtubingise*tractables.LookingattheWFIfromasystemtoassurethatitmeetsUSPrequirementswithoutsomeassurancethattherearenoe*tractableswouldnotbeacceptable.Thesystemsalsocontain0.2micronpointofusefilterswhichcanmaskthelevelofmicrobiologicalcontaminationinthesystem.Whileitisrecognizedthatendoto*insaretheprimaryconcerninsuchasystem,afilterwillreducemicrobiologicalcontamination,bu