FDA高纯水检查指南Word文档格式.docx

FDA高纯水检查指南Word文档格式.docx

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ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson（s）.

Thisguidediscusses,primarilyfromamicrobiologicalaspect,thereviewandevaluationofhighpuritywatersystemsthatareusedforthemanufactureofdrugproductsanddrugsubstances.Italsoincludesareviewofthedesignofthevarioustypesofsystemsandsomeoftheproblemsthathavebeenassociatedwiththesesystems.Aswithotherguides,itisnotall-inclusive,butprovidesbackgroundandguidanceforthereviewandevaluationofhighpuritywatersystems.TheGuideToInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories（May,1993）providesadditionalguidance.

I.SYSTEMDESIGN

Oneofthebasicconsiderationsinthedesignofasystemisthetypeofproductthatistobemanufactured.Forparenteralproductswherethereisaconcernforpyrogens,itisexpectedthatWaterforInjectionwillbeused.Thisappliestotheformulationofproducts,aswellastothefinalwashingofcomponentsandequipmentusedintheirmanufacture.DistillationandReverseOsmosis（RO）filtrationaretheonlyacceptablemethodslistedintheUSPforproducingWaterforInjection.However,inthebulkPharmaceuticalandBiotechnologyindustriesandsomeforeigncompanies,UltraFiltration（UF）isemployedtominimizeendotoxinsinthosedrugsubstancesthatareadministeredparenterally.

Forsomeophthalmicproducts,suchastheophthalmicirrigatingsolution,andsomeinhalationproducts,suchasSterileWaterforInhalation,wheretherearepyrogenspecifications,itisexpectedthatWaterforInjectionbeusedintheirformulation.However,formostinhalationandophthalmicproducts,purifiedwaterisusedintheirformulation.Thisalsoappliestotopicals,cosmeticsandoralproducts.

Anotherdesignconsiderationisthetemperatureofthesystem.Itisrecognizedthathot（65-80oC）systemsareselfsanitizing.Whilethecostofothersystemsmaybelessexpensiveforacompany,thecostofmaintenance,testingandpotentialproblemsmaybegreaterthanthecostofenergysaved.Whetherasystemiscirculatingorone-wayisalsoanimportantdesignconsideration.Obviously,waterinconstantmotionislessliabletohavehighlevelsofcontaminant.Aone-waywatersystemisbasicallya"

dead-leg"

.

Finally,andpossiblythemostimportantconsideration,istheriskassessmentorlevelofqualitythatisdesired.Itshouldberecognizedthatdifferentproductsrequiredifferentqualitywaters.Parenteralsrequireverypurewaterwithnoendotoxins.Topicalandoralproductsrequirelesspurewateranddonothavearequirementforendotoxins.Evenwithtopicalandoralproductstherearefactorsthatdictatedifferentqualitiesforwater.Forexample,preservativesinantacidsaremarginallyeffective,somorestringentmicrobiallimitshavetobeset.Thequalitycontroldepartmentshouldassesseachproductmanufacturedwiththewaterfromtheirsystemanddeterminethemicrobialactionlimitsbasedonthemostmicrobialsensitiveproduct.Inlieuofstringentwateractionlimitsinthesystemthemanufacturercanaddamicrobialreductionstepinthemanufacturingprocessforthesensitivedrugproduct（s）.

II.SYSTEMVALIDATION

AbasicreferenceusedforthevalidationofhighpuritywatersystemsistheParenteralDrugAssociationTechnicalReportNo.4titled,"

DesignConceptsfortheValidationofaWaterforInjectionSystem."

Theintroductionprovidesguidanceandstatesthat,"

Validationofteninvolvestheuseofanappropriatechallenge.Inthissituation,itwouldbeundesirabletointroducemicroorganismsintoanon-linesystem;

therefore,relianceisplacedonperiodictestingformicrobiologicalqualityandontheinstallationofmonitoringequipmentatspecificcheckpointstoensurethatthetotalsystemisoperatingproperlyandcontinuouslyfulfillingitsintendedfunction."

Inthereviewofavalidationreport,orinthevalidationofahighpuritywatersystem,thereareseveralaspectsthatshouldbeconsidered.Documentationshouldincludeadescriptionofthesystemalongwithaprint.Thedrawingneedstoshowallequipmentinthesystemfromthewaterfeedtopointsofuse.Itshouldalsoshowallsamplingpointsandtheirdesignations.Ifasystemhasnoprint,itisusuallyconsideredanobjectionablecondition.Thethinkingisifthereisnoprint,thenhowcanthesystembevalidated?

Howcanaqualitycontrolmanagerormicrobiologistknowwheretosample?

Inthosefacilitiesobservedwithoutupdatedprints,seriousproblemswereidentifiedinthesesystems.Theprintshouldbecomparedtotheactualsystemannuallytoinsureitsaccuracy,todetectunreportedchangesandconfirmreportedchangestothesystem.

Afteralltheequipmentandpipinghasbeenverifiedasinstalledcorrectlyandworkingasspecified,theinitialphaseofthewatersystemvalidationcanbegin.Duringthisphasetheoperationalparametersandthecleaning/sanitizationproceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocessandateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthowthewateristobedrawne.g.ifahoseisusuallyattachedthesampleshouldbetakenattheendofthehose.IftheSOPcallsforthelinetobeflushedbeforeuseofthewaterfromthatpoint,thenthesampleistakenaftertheflush.AttheendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewatersystem.

ThesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesiredwaterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandforthesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproducethedesiredqualityofwater.

ThethirdphaseofvalidationisdesignedtodemonstratethatwhenthewatersystemisoperatedinaccordancewiththeSOPsoveralongperiodoftimeitwillconsistentlyproducewaterofthedesiredquality.Anyvariationsinthequalityofthefeedwaterthatcouldaffecttheoperationandultimatelythewaterqualitywillbepickedupduringthisphaseofthevalidation.Samplingisperformedaccordingtoroutineproceduresandfrequencies.ForWaterforInjectionsystemsthesamplesshouldbetakendailyfromaminimumofonepointofuse,withallpointsofusetestedweekly.Thevalidationofthewatersystemiscompletedwhenthefirmhasafullyearsworthofdata.

Whiletheabovevalidationschemeisnottheonlywayasystemcanbevalidated,itcontainsthenecessaryelementsforvalidationofawatersystem.First,theremustbedatatosupporttheSOPs.Second,theremustbedatademonstratingthattheSOPsarevalidandthatthesystemiscapableofconsistentlyproducingwaterthatmeetsthedesiredspecifications.Finally,theremustbedatatodemonstratethatseasonalvariationsinthefeedwaterdonotadverselyaffecttheoperationofthesystemorthewaterquality.

Thelastpartofthevalidationisthecompilationofthedata,withanyconclusionsintothefinalreport.Thefinalvalidationreportmustbesignedbytheappropriatepeopleresponsibleforoperationandqualityassuranceofthewatersystem.

Atypicalproblemthatoccursisthefailureofoperatingprocedurestoprecludecontaminationofthesystemwithnon-sterileairremaininginapipeafterdrainage.InasystemillustratedasinFigure1,（below）atypicalproblemoccurswhenawasherorhoseconnectionisflushedandthendrainedattheendoftheoperation.Afterdraining,thisvalve（thesecondoffofthesystem）isclosed.Ifonthenextdayorstart-upoftheoperationtheprimaryvalveoffofthecirculatingsystemisopened,thenthenon-sterileairremaininginthepipeafterdrainagewouldcontaminatethesystem.Thesolutionistopro-videforoperationalproceduresthatprovideforopeningthesecondaryvalvebeforetheprimaryvalvetoflushthepipepriortouse.

Anothermajorconsiderationinthevalidationofhighpuritywatersystemsistheacceptancecriteria.Consistentresultsthroughoutthesystemoveraperiodoftimeconstitutetheprimaryelement.

III.MICROBIALLIMITS

WaterForInjectionSystems

Regardingmicrobiologicalresults,forWaterForInjection,itisexpectedthattheybeessentiallysterile.Sincesamplingfrequentlyisperformedinnon-sterileareasandisnottrulyaseptic,occasionallowlevelcountsduetosamplingerrorsmayoccur.Agencypolicy,isthatlessthan10CFU/100mlisanacceptableactionlimit.Noneofthelimitsforwaterarepass/faillimits.Alllimitsareactionlimits.Whenactionlimitsareexceededthefirmmustinvestigatethecauseoftheproblem,takeactiontocorrecttheproblemandassesstheimpactofthemicrobialcontaminationonproductsmanufacturedwiththewateranddocumenttheresultsoftheirinvestigation.

Withregardtosamplesize,100-300mLispreferredwhensamplingWaterforInjectionsystems.Samplevolumeslessthan100mLareunacceptable.

TherealconcerninWFIisendotoxins.BecauseWFIcanpasstheLALendotoxintestandstillfailtheabovemicrobialactionlimit,itisimportanttomonitorWFIsystemsforbothendotoxinsandmicroorganisms.

PurifiedWaterSystems

Forpurifiedwatersystems,microbiologicalspecificationsarenotasclear.USPXXIIspecifications,thatitcomplieswithfederalEnvironmentalProtectionAgencyregulationsfordrinkingwater,arerecognizedasbeingminimal