FDA高纯水系统检查指南-中英

-.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注射用水系统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纯化水系统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注射用水系统InthereviewandevaluationofWaterForInjectionsystems,thereareseveralconcerns.PretreatmentoffeedwaterisremendedbymostmanufacturersofdistillationequipmentandisdefinitelyrequiredforROunits.Theiningfeedwaterqualitymayfluctuateduringthelifeofthesystemdependinguponseasonalvariationsandothere*ternalfactorsbeyondthecontrolofthepharmaceuticalfacility.Fore*ample,inthespring(atleastintheN.E.),increasesingramnegativeorganismshavebeenknown.Also,newconstructionorfirescancauseadepletionofwaterstoresinoldmainswhichcancauseaninflu*ofheavilycontaminatedwaterofadifferentflora.Awatersystemshouldbedesignedtooperatewithintheseanticipatede*tremes.Obviously,theonlywaytoknowthee*tremesistoperiodicallymonitorfeedwater.Ifthefeedwaterisfromamunicipalwatersystem,reportsfromthemunicipalitytestingcanbeusedinlieuofin-housetesting.V.STILL蒸馏塔Figures3-5representatypicalbasicdiagramofaWFIsystem.Mostofthenewsystemsnowusemulti-effectstills.Insomeofthefacilities,therehasbeenevidenceofendoto*incontamination.Inonesystemthisoccurred,duetomalfunctionofthefeedwatervalveandlevelcontrolinthestillwhichresultedindropletsoffeedwaterbeingcarriedoverinthedistillate.高纯水系统检查指南注意：本文件只是审查员与其他FDA官员的参考材料。本文件不能约束FDA，也不授予任何人任何权利、特权、利益或者豁免权。该指南主要从微生物方面来评估用于药物制剂和药物生产的高纯水系统，包括不同类型系统的设计审核和与这些系统相关的一些问题。与其它指南一样，该指南只对高纯化水系统的评估提供背景资料和指导作用，但并不包括一切。另外可参考“制药质量控制实验室的微生物检查指南〞〔May，1993〕。I.系统设计在设计一个系统时，首先要考虑的是生产的产品类型。对注射用药品来说，应重点关注热原物质，所以使用注射用水。注射用水应用于产品的配制，部件及生产设备的最终冲洗。USP中规定的生产注射用水方法只有蒸馏法和反渗透法。然而，在大宗制药工业、生物技术工业及一些国外公司中，采用超滤法将注射用药物的毒素减到最少。在一些眼用制剂〔如眼用灌洗剂〕和一些吸入制剂〔如吸入用无菌水〕中，由于有热原标准，所以在其配制中要用注射用水。但是，大局部吸入制剂及眼用制剂都使用纯化水配制。纯化水还用于外用制剂、化装品及口服制剂的生产。另一个设计关注点是系统温度。温度在65～80℃的热水系统被认为是自净系统。对一个公司来说，虽然其它水系统本钱可能更廉价，但是系统的维护、检测和潜在问题产生的费用可能会比节省的能量费更高。系统是循环或是单向也是设计系统时所要考虑的重点。显然，让水持续流动就不易受到高水平的污染。一个单向水系统根本上是“死角〞。最后，设计系统的风险评估及期望的质量水平可能是最重要的考量局部。应该认识到不同产品需要不同质量的水。注射用药需要无毒素的高纯水，外用制剂和口服制剂所需水没有毒素的要求，纯度要求稍低。即使是外用制剂和口服制剂，也有影响要用不同质量的水的各种因素，例如，在抗酸剂中防腐剂几乎不起作用，所以得制定更严格的微生物指标。质量控制部门应评估采用水系统中的水生产的每一种产品，根据对微生物最敏感的产品制定水系统的微生物纠偏限度。代替制定严格的水系统微生物纠偏限度的另一种方法是：对于微生物敏感的药品，生产者可在生产过程中增加一步去除微生物的步骤。II.系统验证高纯化水系统的验证的根本参考物事"注射用药协会技术报告"第4号文件，名为“注射用水系统验证的设计概念〞。绪论提供了指导并指出：“验证经常包括恰当的挑战方法的使用。在这里，没有必要把微生物引入在线系统进展挑战试验，因此，主要依靠微生物质量的定期检测以及在特定检查点安装监测设备，以确保整个系统处于正确的运行状态和持续执行其预定功能。〞在审核验证报告时或在高纯水系统的验证过程中，有多个方面需要得到考虑。文件记录应包括对系统的描述和打印的图纸。图纸应显示系统中从进水到使用点的所有设备，也应标明所有的取样点及其名称。如果系统没有图纸，通常是不能令人承受的。检查官会认为如果图纸都没有，怎么进展系统验证呢？质量控制者或微生物检验者怎么知道哪里可以取样呢？在被观察到没有更新图纸的那些设施中，从这些系统里检查出了很多严重问题。每年应该将图纸和实际系统相比照，以确保图纸的准确性，及时发现系统中未报告的变更和证实已报告的变更。在确定所有的设备和管道都正确安装并按预定要求工作后，水系统验证的第一阶段就可以开场了。在此期间，将制定运行参数和清洁消毒程序、频率。每天在水纯化过程中的每一步骤之后以及每个使用点进展取样，取2-4周。使用点的取样程序应该描述水是怎么取出来的，例如，如果使用软管取样，应该在软管末端抽取。如果标准操作程序要求使用点用水前要先冲洗，则样品应在冲洗后取。在2-4周的末期，公司应该已经制定出水系统运行的标准操作程序。系统验证的第二阶段是证明当按SOP操作时，系统能持续生产出所期望的水质。取样和取样周期与第一阶段一样。该阶段末期的数据应该证明系统能持续生产出所需质量的水。第三阶段的验证被设计用于证明当按SOPs操作时，系统在很长时期能持续生产出所设计质量的用水。在本验证阶段中，进水质量的任何变化都会影响系统的运行并且最终的水质将将被检出。取样按照例行规程和频率进展。注射用水系统每天至少取样一个使用点，每周对所有使用点应进展取样。当公司有一套数年的有价值的数据时，水系统的验证就完成了。虽然以上的验证规划不是验证水系统的唯一方式，但它包含了一个水系统验证必需的要素。首先，必须有数据支持SOP；其次，必须有数据证明SOP是合理的且系统能持续生产出符合设计质量要求的用水；最后，必须有数据证明进水的季节偏差不会影响系统的运行或水质。验证的最后局部是数据的汇编，在最终报告中写入假设干结论。最终的验证报告必须由能对水系统运行和质量保证负责的人签字。发生的典型问题是排水后非无菌的空气残留在系统管道中造成预防系统污染的操作程序失败。在一个系统中，如图1所示，一个常见问题发生在当用密封圈或软管连接进展冲洗，然后在该操作的末期进展排水的时候。排水之后，该阀门〔系统的第二个阀门〕已经关闭。如果第二天或操作启动时，循环系统下面的第一个阀门开着，则排水后残存在管道中的非无菌空气就会污染系统。解决该问题的方法是规操作程序，规定在翻开第一个阀门冲洗管道之前必须先翻开第二阀门。高纯水系统验证所需考虑的另外一个主要问题是验收标准。一段时期，整个系统从始至终的持续一致的结果构成了验收标准的主要要素。III.微生物限度注射用水系统对注射用水来说，微生物指标要求本质上无菌。由于经常在非无菌区进展取样操作，偶尔产生的取样错误会导致低水平微生物污染。行政政策可承受的纠偏限度为小于10CFU/100ml。水的限度没有所谓的合格/失败限度，所有的限度都是指纠偏限度。当超过纠偏限度时，公司必须调查问题的原因并采取行动纠正问题，评估微生物污染对使用这些水生产的产品造成的影响，并记录调查处理的结果。关于取样体积，100～300ml是注射用水取样的首选，样品体积不可少于100ml。注射用水中真正关注的是毒素。因为注射用水可以既通过鲎试剂毒素测试又通不过上述的微生物纠偏限度，所以对注射用水系统来说监控毒素和微生物同样重要。纯化水系统对纯化水系统来说，微生物规定不是很明确。USP**II的标准遵从"联邦环境保护署法规"关于饮用水的标准，该标准被认为是最低限度标准。一些人尝试为纯化水建立有意义的微生物标准。CFTA建议不超过500CFU/ml，USP**II有一个不超过100CFU/ml的指导方针。尽管微生物标准已经被讨论过，但除了EPA〔环境保护署〕标准外并未建立任何标准。从政策上来说，纠偏限度超过100CFU/ml即为不合格。建立任何纠偏限度或水平的目的都是确保水系统处于可控状态。任何纠偏限度的建立都要依据整个纯化水系统以及制剂产品的进一步加工工艺和使用用途。例如，经冷冻工艺处理用来生产药品的纯化水应该是无有害有机体的。“有害有机体〞定义为在指导下用药时会导致感染的任何有机体或在药品生产过程中能繁殖的任何有机体。正如"药物质量控制实验室的微生物检查指南"所指出的那样，污染物的种类通常比污染物数量更重要。水系统中存在的有机体可能悬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们所知道的生物膜，可持续脱落出有机体。因而，在一个系统中污染并不是均匀分布的，取样也可能无法真实反映系统的污染类型和水平。在一个样品中10CFU/ml的量，然后在继后样品中出现100甚或1000CFU/ml的量都不是不可能的。因而，建立用于生产非无菌产品的高纯水系统允许的污染水平时，需要理解产品的用途、配方〔防腐系统〕和生产工艺。比方，抗酸剂没有一个有效的防腐系统，要求的纠偏限度在最大值100CFU/mL之下。USP在其关于“非无菌产品的微生物特征〞专论中给出一些指导，它指出“在非无菌药品中，微生物的重要性应该结合产品的用途、产品的自然属性和对患者的潜在危害进展评估〞。因而，不仅仅是在一些特定专论中列举的指示性微生物提出问题，文章还要求每个生产厂商应该评估他们的产品和制造方式，并在用该水生产的风险最大产品根底上，给水系统建立不超过最大纠偏限度的可行的污染行动水平。IV.注射用水系统；在注射用水系统的审核和评估中，有几个关注点。大多蒸馏设备的生产商推荐对进水进展预处理，并明确要求使用RO单元。原水质量可能会随季节的变动以及其它超越设备本身控制的外部因素而波动。例如，在春季〔至少在N.E.时〕，大家知道革兰氏阴性菌会繁殖增多，同时，新建筑或火灾会消耗老旧主管道中的存水，这会导致污染严重的水以不同形式流入。一个好的水系统应能在这些预计到的的极端情况下保持正常运转。显然，唯一能确认极端情况的方法是定期监测原水质量。如果原水来自市政水系统，则市政当局的测试报告可以代替公司部测试报告。V.蒸馏塔图3-5是WFI系统的一个典型图纸。大多数新系统使用多效蒸馏塔。在这些设施中，已经证实有毒素污染的案例。在一个发生毒素污染的系统中，由于进水阀故障和蒸馏塔的控制不当，导致蒸馏水中携带有原水的小液滴。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热交换器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反渗透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