FDA关于水系统的要求.docx
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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
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