FDA关于水系统的要求.docx

FDA关于水系统的要求.docx

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FDA关于水系统的要求

PurifiedWater

H2O18.02

NOTE—Formicrobiologicalguidance,seegeneralinformationchapterWaterforPharmaceuticalPurposesá1231ñ.

»PurifiedWateriswaterobtainedbyasuitableprocess.ItispreparedfromwatercomplyingwiththeU.S.EnvironmentalProtectionAgencyNationalPrimaryDrinkingWaterRegulationsorcomparableregulationsoftheEuropeanUnionorJapan.Itcontainsnoaddedsubstance.

NOTE—PurifiedWaterisintendedforuseasaningredientofofficialpreparationsandintestsandassaysunlessotherwisespecified（seeWaterinIngredientsandProcessesandinTestsandAssaysunderGeneralNoticesandRequirements）.Whereusedforsteriledosageforms,otherthanforparenteraladministration,processthearticletomeettherequirementsunderSterilityTestsá71ñ,orfirstrenderthePurifiedWatersterileandthereafterprotectitfrommicrobialcontamination.DonotusePurifiedWaterinpreparationsintendedforparenteraladministration.ForsuchpurposesuseWaterforInjection,BacteriostaticWaterforInjection,orSterileWaterforInjection.ThetestsforTotalorganiccarbonandConductivityapplytoPurifiedWaterproducedonsiteforuseasaningredientofofficialpreparationsandintestsandassays.PurifiedWaterpackagedinbulkforcommercialuseelsewheremeetstherequirementsofallofthetestsunderSterilePurifiedWater,exceptLabelingandSterilityá71ñ.

USPReferencestandardsá11ñ—USP1,4-BenzoquinoneRS.USPSucroseRS.

Totalorganiccarboná643ñ:

meetstherequirements.

Waterconductivityá645ñ:

meetstherequirements.

1231WATERFORPHARMACEUTICALPURPOSES

Wateristhemostwidelyusedsubstance,rawmaterial,oringredientintheproduction,processing,andformulationofcompendialarticles.Controlofthemicrobiologicalqualityofthesewatersisimportantbecauseproliferationofmicroorganismsubiquitoustowatermayoccurduringthepurification,storage,anddistributionofthissubstance.Ifwaterisusedinthefinalproduct,thesemicroorganismsortheirmetabolicproductsmayeventuallycauseadverseconsequences.

WaterthatisusedintheearlystagesoftheproductionofdrugsubstancesandthatisthesourceorfeedwaterforthepreparationofthevarioustypesofpurifiedwatersmustmeettherequirementsoftheNationalPrimaryDrinkingWaterRegulations（NPDWR）（40CFR141）issuedbytheEnvironmentalProtectionAgency（EPA）.ComparableregulationsfordrinkingwateroftheEuropeanUnionorJapanareacceptable.Theserequirementsensuretheabsenceofcoliforms,which,ifdeterminedtobeoffecalorigin,mayportendorindicatethepresenceofothermicroorganismsoffecalorigin,includingvirusesthatmaybepathogenicforhumans.Ontheotherhand,meetingtheseNationalPrimaryDrinkingWaterRegulationswouldnotruleoutthepresenceofothermicroorganisms,which,whilenotconsideredamajorpublichealthconcern,could,ifpresent,constituteahazardorbeconsideredundesirableinadrugsubstanceorformulatedproduct.Forthisreason,therearemanydifferentgradesofpharmaceuticalwaters.

TYPESOFWATER

DrinkingWater—DrinkingWaterisnotcoveredbyacompendialmonographbutmustcomplywiththequalityattributesoftheEPANPDWRorcomparableregulationsoftheEuropeanUnionorJapan.Itmaybederivedfromavarietyofsources,includingapublicwaterutility,aprivatewatersupply（e.g.,awell）,oracombinationofmorethanoneofthesesources.DrinkingWatermaybeusedintheearlystagesofchemicalsynthesisandintheearlystagesofthecleaningofpharmaceuticalmanufacturingequipment.Itistheprescribedsourcefeedwaterfortheproductionofpharmaceuticalwaters.Asseasonalvariationsinthequalityattributesofthedrinkingwatersupplycanoccur,processingstepsintheproductionofpharmaceuticalwatersmustbedesignedforthischaracteristic.

PurifiedWater—PurifiedWater（seeUSPmonograph）isusedasanexcipientintheproductionofofficialpreparations;inpharmaceuticalapplications,suchascleaningofcertainequipment;andinthepreparationofsomebulkpharmaceuticalchemicals.PurifiedWatermustmeettherequirementsforionicandorganicchemicalpurityandmustbeprotectedfrommicrobialproliferation.ItispreparedusingDrinkingWaterasafeedwaterandispurifiedusingunitoperationsthatincludedeionization,distillation,ionexchange,reverseosmosis,filtration,orothersuitableprocedures.PurifiedWatersystemsmustbevalidated.

PurifiedWatersystemsthatproduce,store,andcirculatewaterunderambientconditionsaresusceptibletotheestablishmentoftenaciousbiofilmsofmicroorganisms,whichcanbethesourceofundesirablelevelsofviablemicroorganismsorendotoxinsintheeffluentwater.Thesesystemsrequirefrequentsanitizationandmicrobiologicalmonitoringtoensurewaterofappropriatemicrobiologicalqualityatthepointsofuse.

SterilePurifiedWater—SterilePurifiedWaterisPurifiedWaterthatispackagedandrenderedsterile.ItisusedinthepreparationofnonparenteralcompendialdosageformswhereasterileformofPurifiedWaterisrequired.

WaterforInjection—WaterforInjection（seeUSPmonograph）isanexcipientintheproductionofinjectionsandforuseinpharmaceuticalapplications,suchascleaningofcertainequipmentandpreparationofsomebulkpharmaceuticalchemicals.ThesourceorfeedwaterforthisarticleisDrinkingWater,whichmayhavebeenpreliminarilypurifiedbutwhichisfinallysubjectedtodistillationorreverseosmosis.ItmustmeetallthechemicalrequirementsforPurifiedWaterandinadditiontherequirementsunderBacterialEndotoxinsTestá85ñ.Italsomustbeprotectedfrommicrobialcontamination.Thesystemusedtoproduce,store,anddistributeWaterforInjectionmustbedesignedtopreventmicrobialcontaminationandtheformationofmicrobialendotoxins,anditmustbevalidated.

SterileWaterforInjection—SterileWaterforInjection（seeUSPmonograph）isWaterforInjectionthatispackagedandrenderedsterile.SterileWaterforInjectionisintendedforextemporaneousprescriptioncompoundingandisdistributedinsterileunits.Itisusedasadiluentforparenteralproducts.Itispackagedinsingle-dosecontainersnotlargerthan1Linsize.

BacteriostaticWaterforInjection—BacteriostaticWaterforInjection（seeUSPmonograph）issterileWaterforInjectiontowhichhasbeenaddedoneormoresuitableantimicrobialpreservatives.Itisintendedtobeusedasadiluentinthepreparationofparenteralproducts.Itmaybepackagedinsingle-doseormultiple-dosecontainersnotlargerthan30mL.

SterileWaterforIrrigation—SterileWaterforIrrigation（seeUSPmonograph）isWaterforInjection,packagedinsingle-dosecontainersoflargerthan1L,thatisintendedtobedeliveredrapidlyandisrenderedsterile.Itneednotmeettherequirementforsmall-volumeinjectionsunderParticulateMatterá788ñ.

SterileWaterforInhalation—SterileWaterforInhalation（seeUSPmonograph）isWaterforInjectionthatispackagedandrenderedsterileandisintendedforuseininhalatorsandinthepreparationofinhalationsolutions.

VALIDATIONANDQUALIFICATIONOFWATERPURIFICATION,STORAGE,ANDDISTRIBUTIONSYSTEMS

Establishingthedependabilityofpharmaceuticalwaterpurification,storage,anddistributionsystemsrequiresanappropriateperiodofmonitoringandobservation.Ordinarily,fewproblemsareencounteredinmaintainingthechemicalpurityofPurifiedWaterandWaterforInjection.However,itismoredifficulttomeetestablishedmicrobiologicalqualitycriteriaconsistently.Atypicalprograminvolvesintensivedailysamplingandtestingofmajorprocesspointsforatleastonemonthafteroperationalcriteriahavebeenestablishedforeachsamplingpoint.

Validationistheprocedureforacquiringanddocumentingsubstantiationtoahighlevelofassurancethataspecificprocesswillconsistentlyproduceaproductconformingtoanestablishedsetofqualityattributes.Thevalidationdefinesthecriticalprocessparametersandtheiroperatingranges.Avalidationprogramqualifiesthedesign,installation,operation,andperformanceofequipment.Itbeginswhenthesystemisdefinedandmovesthroughseveralstages:

qualificationoftheinstallation（IQ）,operationalqualification（OQ）,andperformancequalification（PQ）.AgraphicalrepresentationofatypicalwatersystemvalidationlifecycleisshowninFig.1.

Fig.1.WaterSystemValidationLifeCycle

Avalidationplanforawatersystemtypicallyincludesthefollowingsteps:

1.Establishingstandardsforqualityattributesandoperatingparameters.

2.Definingsystemsandsubsystemssuitabletoproducethedesiredqualityattributesfromtheavailablesourcewater.

3.Selectingequipment,controls,andmonitoringtechnologies.

4.DevelopinganIQstageconsistingofinstrumentcalibrations,inspectionstoverifythatthedrawingsaccuratelydepicttheas-builtconfigurationofthewatersystem,and,wherenecessary,specialteststoverifythattheinstallationmeetsthedesignrequirements.

5.DevelopinganOQstageconsistingoftestsandinspectionstoverifythattheequipment,systemalerts,andcontrolsareoperatingreliablyandthatappropriateAlertandActionLevelsareestablished.Thisphaseofqualificationmayoverlapwithaspectsofthenextstep.

6.DevelopingaprospectivePQstagetoconfirmtheappropriatenessofcriticalprocessparameteroperatingranges.AconcurrentorretrospectivePQisperformedtodemonstratesystemreproducibilityoveranappropriatetimeperiod.Duringthisphaseofvalidation,AlertandActionLevelsforkeyqualityattributesandoperatingparametersareverified.

7.Supplementingavalidationmaintenanceprogram（alsocalledcontinuousvalidationlifecycle）thatincludesamechanismtocontrolchangestothewater