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U.S.FoodandDrugAdministration
ProtectingandPromotingYourHealth

HighPurityWaterSystem(7/93)
GUIDETOINSPECTIONSOFHIGHPURITYWATERSYSTEMS
Note:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.Thedocumentdoes
notbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).
Thisguidediscusses,primarilyfromamicrobiologicalaspect,thereviewandevaluationofhighpuritywatersystems
thatareusedforthemanufactureofdrugproductsanddrugsubstances.Italsoincludesareviewofthedesignofthe
varioustypesofsystemsandsomeoftheproblemsthathavebeenassociatedwiththesesystems.Aswithother
guides,itisnotallinclusive,butprovidesbackgroundandguidanceforthereviewandevaluationofhighpuritywater
systems.TheGuideToInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories(May,1993)
providesadditionalguidance.
I.SYSTEMDESIGN
Oneofthebasicconsiderationsinthedesignofasystemisthetypeofproductthatistobemanufactured.For
parenteralproductswherethereisaconcernforpyrogens,itisexpectedthatWaterforInjectionwillbeused.This
appliestotheformulationofproducts,aswellastothefinalwashingofcomponentsandequipmentusedintheir
manufacture.DistillationandReverseOsmosis(RO)filtrationaretheonlyacceptablemethodslistedintheUSPfor
producingWaterforInjection.However,inthebulkPharmaceuticalandBiotechnologyindustriesandsomeforeign
companies,UltraFiltration(UF)isemployedtominimizeendotoxinsinthosedrugsubstancesthatareadministered
parenterally.
Forsomeophthalmicproducts,suchastheophthalmicirrigatingsolution,andsomeinhalationproducts,suchas
SterileWaterforInhalation,wheretherearepyrogenspecifications,itisexpectedthatWaterforInjectionbeusedin
theirformulation.However,formostinhalationandophthalmicproducts,purifiedwaterisusedintheirformulation.
Thisalsoappliestotopicals,cosmeticsandoralproducts.
Anotherdesignconsiderationisthetemperatureofthesystem.Itisrecognizedthathot(6580oC)systemsareself
sanitizing.Whilethecostofothersystemsmaybelessexpensiveforacompany,thecostofmaintenance,testingand
potentialproblemsmaybegreaterthanthecostofenergysaved.Whetherasystemiscirculatingoronewayisalso
animportantdesignconsideration.Obviously,waterinconstantmotionislessliabletohavehighlevelsof
contaminant.Aonewaywatersystemisbasicallya"deadleg".
Finally,andpossiblythemostimportantconsideration,istheriskassessmentorlevelofqualitythatisdesired.It
shouldberecognizedthatdifferentproductsrequiredifferentqualitywaters.Parenteralsrequireverypurewaterwith
noendotoxins.Topicalandoralproductsrequirelesspurewateranddonothavearequirementforendotoxins.Even
withtopicalandoralproductstherearefactorsthatdictatedifferentqualitiesforwater.Forexample,preservativesin
antacidsaremarginallyeffective,somorestringentmicrobiallimitshavetobeset.Thequalitycontroldepartment
shouldassesseachproductmanufacturedwiththewaterfromtheirsystemanddeterminethemicrobialactionlimits
basedonthemostmicrobialsensitiveproduct.Inlieuofstringentwateractionlimitsinthesystemthemanufacturer
canaddamicrobialreductionstepinthemanufacturingprocessforthesensitivedrugproduct(s).
II.SYSTEMVALIDATION

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AbasicreferenceusedforthevalidationofhighpuritywatersystemsistheParenteralDrugAssociationTechnical
ReportNo.4titled,"DesignConceptsfortheValidationofaWaterforInjectionSystem."
Theintroductionprovidesguidanceandstatesthat,"Validationofteninvolvestheuseofanappropriatechallenge.In
thissituation,itwouldbeundesirabletointroducemicroorganismsintoanonlinesystemtherefore,relianceisplaced
onperiodictestingformicrobiologicalqualityandontheinstallationofmonitoringequipmentatspecificcheckpointsto
ensurethatthetotalsystemisoperatingproperlyandcontinuouslyfulfillingitsintendedfunction."
Inthereviewofavalidationreport,orinthevalidationofahighpuritywatersystem,thereareseveralaspectsthat
shouldbeconsidered.Documentationshouldincludeadescriptionofthesystemalongwithaprint.Thedrawing
needstoshowallequipmentinthesystemfromthewaterfeedtopointsofuse.Itshouldalsoshowallsampling
pointsandtheirdesignations.Ifasystemhasnoprint,itisusuallyconsideredanobjectionablecondition.Thethinking
isifthereisnoprint,thenhowcanthesystembevalidated?Howcanaqualitycontrolmanagerormicrobiologist
knowwheretosample?Inthosefacilitiesobservedwithoutupdatedprints,seriousproblemswereidentifiedinthese
systems.Theprintshouldbecomparedtotheactualsystemannuallytoinsureitsaccuracy,todetectunreported
changesandconfirmreportedchangestothesystem.
Afteralltheequipmentandpipinghasbeenverifiedasinstalledcorrectlyandworkingasspecified,theinitialphaseof
thewatersystemvalidationcanbegin.Duringthisphasetheoperationalparametersandthecleaning/sanitization
proceduresandfrequencieswillbedeveloped.Samplingshouldbedailyaftereachstepinthepurificationprocess
andateachpointofusefortwotofourweeks.Thesamplingprocedureforpointofusesamplingshouldreflecthow
thewateristobedrawne.g.ifahoseisusuallyattachedthesampleshouldbetakenattheendofthehose.Ifthe
SOPcallsforthelinetobeflushedbeforeuseofthewaterfromthatpoint,thenthesampleistakenaftertheflush.At
theendofthetwotofourweektimeperiodthefirmshouldhavedevelopeditsSOPsforoperationofthewater
system.
Thesecondphaseofthesystemvalidationistodemonstratethatthesystemwillconsistentlyproducethedesired
waterqualitywhenoperatedinconformancewiththeSOPs.Thesamplingisperformedasintheinitialphaseandfor
thesametimeperiod.Attheendofthisphasethedatashoulddemonstratethatthesystemwillconsistentlyproduce
thedesiredqualityofwater.
Thethirdphaseofvalidationisdesignedtodemonstratethatwhenthewatersystemisoperatedinaccordancewith
theSOPsoveralongperiodoftimeitwillconsistentlyproducewaterofthedesiredquality.Anyvariationsinthe
qualityofthefeedwaterthatcouldaffecttheoperationandultimatelythewaterqualitywillbepickedupduringthis
phaseofthevalidation.Samplingisperformedaccordingtoroutineproceduresandfrequencies.ForWaterfor
Injectionsystemsthesamplesshouldbetakendailyfromaminimumofonepointofuse,withallpointsofusetested
weekly.Thevalidationofthewatersystemiscompletedwhenthefirmhasafullyearsworthofdata.
Whiletheabovevalidationschemeisnottheonlywayasystemcanbevalidated,itcontainsthenecessaryelements
forvalidationofawatersystem.First,theremustbedatatosupporttheSOPs.Second,theremustbedata
demonstratingthattheSOPsarevalidandthatthesystemiscapableofconsistentlyproducingwaterthatmeetsthe
desiredspecifications.Finally,theremustbedatatodemonstratethatseasonalvariationsinthefeedwaterdonot
adverselyaffecttheoperationofthesystemorthewaterquality.
Thelastpartofthevalidationisthecompilationofthedata,withanyconclusionsintothefinalreport.Thefinal
validationreportmustbesignedbytheappropriatepeopleresponsibleforoperationandqualityassuranceofthe
watersystem.
Atypicalproblemthatoccursisthefailureofoperatingprocedurestoprecludecontaminationofthesystemwithnon
sterileairremaininginapipeafterdrainage.InasystemillustratedasinFigure1,(below)atypicalproblemoccurs
whenawasherorhoseconnectionisflushedandthendrainedattheendoftheoperation.Afterdraining,thisvalve

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(thesecondoffofthesystem)isclosed.Ifonthenextdayorstartupoftheoperationtheprimaryvalveoffofthe
circulatingsystemisopened,thenthenonsterileairremaininginthepipeafterdrainagewouldcontaminatethe
system.Thesolutionistoprovideforoperationalproceduresthatprovideforopeningthesecondaryvalvebeforethe
primaryvalvetoflushthepipepriortouse.

Anothermajorconsiderationinthevalidationofhighpuritywatersystemsistheacceptancecriteria.Consistentresults
throughoutthesystemoveraperiodoftimeconstitutetheprimaryelement.
III.MICROBIALLIMITS
WaterForInjectionSystems
Regardingmicrobiologicalresults,forWaterForInjection,itisexpectedthattheybeessentiallysterile.Sincesampling
frequentlyisperformedinnonsterileareasandisnottrulyaseptic,occasionallowlevelcountsduetosamplingerrors
mayoccur.Agencypolicy,isthatlessthan10CFU/100mlisanacceptableactionlimit.Noneofthelimitsforwaterare

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pass/faillimits.Alllimitsareactionlimits.Whenactionlimitsareexceededthefirmmustinvestigatethecauseofthe
problem,takeactiontocorrecttheproblemandassesstheimpactofthemicrobialcontaminationonproducts
manufacturedwiththewateranddocumenttheresultsoftheirinvestigation.
Withregardtosamplesize,100300mLispreferredwhensamplingWaterforInjectionsystems.Samplevolumes
lessthan100mLareunacceptable.
TherealconcerninWFIisendotoxins.BecauseWFIcanpasstheLALendotoxintestandstillfailtheabovemicrobial
actionlimit,itisimportanttomonitorWFIsystemsforbothendotoxinsandmicroorganisms.
PurifiedWaterSystems
Forpurifiedwatersystems,microbiologicalspecificationsarenotasclear.USPXXIIspecifications,thatitcomplies
withfederalEnvironmentalProtectionAgencyregulationsfordrinkingwater,arerecognizedasbeingminimal
specifications.Therehavebeenattemptsbysometoestablishmeaningfulmicrobiologicalspecificationsforpurified
water.TheCFTAproposedaspecificationofnotmorethan500organismsperml.TheUSPXXIIhasanaction
guidelineofnotgreaterthan100organismsperml.Althoughmicrobiologicalspecificationshavebeendiscussed,
none(otherthanEPAstandards)havebeenestablished.Agencypolicyisthatanyactionlimitover100CFU/mLfora
purifiedwatersystemisunacceptable.
Thepurposeofestablishinganyactionlimitorlevelistoassurethatthewatersystemisundercontrol.Anyactionlimit
establishedwilldependupontheoverallpurifiedwatersystemandfurtherprocessingofthefinishedproductandits
use.Forexample,purifiedwaterusedtomanufacturedrugproductsbycoldprocessingshouldbefreeof
objectionableorganisms.Wehavedefined"objectionableorganisms"asanyorganismsthatcancauseinfections
whenthedrugproductisusedasdirectedoranyorganismcapableofgrowthinthedrugproduct.Aspointedoutin
theGuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories,thespecificcontaminant,
ratherthanthenumberisgenerallymoresignificant.
Organismsexistinawatersystemeitherasfreefloatinginthewaterorattachedtothewallsofthepipesandtanks.
Whentheyareattachedtothewallstheyareknownasbiofilm,whichcontinuouslysloughofforganisms.Thus,
contaminationisnotuniformlydistributedinasystemandthesamplemaynotberepresentativeofthetypeandlevel
ofcontamination.Acountof10CFU/mLinonesampleand100oreven1000CFU/mLinasubsequentsample
wouldnotbeunrealistic.

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Thus,inestablishingthelevelofcontaminationallowedinahighpuritywatersystemusedinthemanufactureofa
nonsterileproductrequiresanunderstandingoftheuseoftheproduct,theformulation(preservativesystem)and
manufacturingprocess.Forexample,antacids,whichdonothaveaneffectivepreservativesystem,requireanaction
limitbelowthe100CFU/mLmaximum.
TheUSPgivessomeguidanceintheirmonographonMicrobiologicalAttributesofNonSterileProducts.Itpointsout
that,"Thesignificanceofmicroorganismsinnonsterilepharmaceuticalproductsshouldbeevaluatedintermsofthe
useoftheproduct,thenatureoftheproduct,andthepotentialharmtotheuser."Thus,notjusttheindicator
organismslistedinsomeofthespecificmonographspresentproblems.Itisuptoeachmanufacturertoevaluatetheir
product,thewayitismanufactured,andestablishamacceptableactionlevelofcontamination,nottoexceedthe
maximum,forthewatersystem,basedonthehighestriskproductmanufacturedwiththewater.
IV.WATERFORINJECTIONSYSTEMS
InthereviewandevaluationofWaterForInjectionsystems,thereareseveralconcerns.
Pretreatmentoffeedwaterisrecommendedbymostmanufacturersofdistillationequipmentandisdefinitelyrequired
forROunits.Theincomingfeedwaterqualitymayfluctuateduringthelifeofthesystemdependinguponseasonal
variationsandotherexternalfactorsbeyondthecontrolofthepharmaceuticalfacility.Forexample,inthespring(at
leastintheN.E.),increasesingramnegativeorganismshavebeenknown.Also,newconstructionorfirescancause
adepletionofwaterstoresinoldmainswhichcancauseaninfluxofheavilycontaminatedwaterofadifferentflora.
Awatersystemshouldbedesignedtooperatewithintheseanticipatedextremes.Obviously,theonlywaytoknowthe
extremesistoperiodicallymonitorfeedwater.Ifthefeedwaterisfromamunicipalwatersystem,reportsfromthe
municipalitytestingcanbeusedinlieuofinhousetesting.
V.STILL

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Figures35representatypicalbasicdiagramofaWFIsystem.Mostofthenewsystemsnowusemultieffectstills.In
someofthefacilities,therehasbeenevidenceofendotoxincontamination.Inonesystemthisoccurred,dueto
malfunctionofthefeedwatervalveandlevelcontrolinthestillwhichresultedindropletsoffeedwaterbeingcarried
overinthedistillate.
Figure3(/ICECI/Inspections/InspectionGuides/ucm091052.htm)
Figure4(/ICECI/Inspections/InspectionGuides/ucm091054.htm)
Figure5(/ICECI/Inspections/InspectionGuides/ucm091055.htm)

Inanothersystemwithendotoxinproblems,itwasnotedthattherewasapproximately50litersofWFIinthe
condenseratthestartup.Sincethiswatercouldlieinthecondenserforuptoseveraldays(i.e.,overtheweekend),it
wasbelievedthatthiswasthereasonforunacceptablelevelsofendotoxins.
Morecommon,however,isthefailuretoadequatelytreatfeedwatertoreducelevelsofendotoxins.Manyofthestill
fabricatorswillonlyguaranteea2.5logto3logreductionintheendotoxincontent.Therefore,itisnotsurprisingthat
insystemswherethefeedwateroccasionallyspikesto250EU/ml,unacceptablelevelsofendotoxinsmay
occasionallyappearinthedistillate(WFI).Forexample,recentlythreenewstills,includingtwomultieffect,were
foundtobeperiodicallyyieldingWFIwithlevelsgreaterthan.25EU/ml.Pretreatmentsystemsforthestillsincluded
onlydeionizationsystemswithnoUF,ROordistillation.Unlessafirmhasasatisfactorypretreatmentsystem,itwould
beextremelydifficultforthemtodemonstratethatthesystemisvalidated.
TheaboveexamplesofproblemswithdistillationunitsusedtoproduceWFI,pointtoproblemswithmaintenanceof
theequipmentorimproperoperationofthesystemindicatingthatthesystemhasnotbeenproperlyvalidatedorthat
theinitialvalidationisnolongervalid.Ifyouseethesetypesofproblemsyoushouldlookverycloselyatthesystem
design,anychangesthathavebeenmadetothesystem,thevalidationreportandtheroutinetestdatatodetermineif
thesystemisoperatinginastateofcontrol.
Typically,conductivitymetersareusedonwatersystemstomonitorchemicalqualityandhavenomeaningregarding
microbiologicalquality.
Figures35alsoshowpetcocksorsmallsamplingportsbetweeneachpieceofequipment,suchasafterthestilland
beforetheholdingtank.Theseareinthesystemtoisolatemajorpiecesofequipment.Thisisnecessaryforthe
qualificationoftheequipmentandfortheinvestigationofanyproblemswhichmightoccur.
VI.HEATEXCHANGERS
Oneprincipalcomponentofthestillistheheatexchanger.Becauseofthesimilarionicqualityofdistilledand
deionizedwater,conductivitymeterscannotbeusedtomonitormicrobiologicalquality.Positivepressuresuchasin
vaporcompressionordoubletubesheetdesignshouldbeemployedtopreventpossiblefeedwatertodistillate
contaminationinaleakyheatexchanger.
AnFDAInspectorsTechnicalGuidewiththesubjectof"HeatExchangerstoAvoidContamination"discussesthe
designandpotentialproblemsassociatedwithheatexchangers.Theguidepointsoutthattherearetwomethodsfor
preventingcontaminationbyleakage.Oneistoprovidegaugestoconstantlymonitorpressuredifferentialstoensure
thatthehigherpressureisalwaysonthecleanfluidside.Theotheristoutilizethedoubletubesheettypeofheat
exchanger.
Insomesystems,heatexchangersareutilizedtocoolwateratusepoints.Forthemostpart,coolingwaterisnot
circulatedthroughthemwhennotinuse.Inafewsituations,pinholesformedinthetubingaftertheyweredrained(on
thecoolingwaterside)andnotinuse.Itwasdeterminedthatasmallamountofmoistureremaininginthetubeswhen

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combinedwithaircausedacorrosionofthestainlesssteeltubesonthecoolingwaterside.Thus,itisrecommended
thatwhennotinuse,heatexchangersnotbedrainedofthecoolingwater.
VII.HOLDINGTANK
Inhotsystems,temperatureisusuallymaintainedbyapplyingheattoajacketedholdingtankorbyplacingaheat
exchangerinthelinepriortoaninsulatedholdingtank.
Theonecomponentoftheholdingtankthatgeneratesthemostdiscussionistheventfilter.Itisexpectedthatthere
besomeprogramforintegritytestingthisfiltertoassurethatitisintact.Typically,filtersarenowjacketedtoprevent
condensateorwaterfromblockingthehydrophobicventfilter.Ifthisoccurs(theventfilterbecomesblocked),possibly
eitherthefilterwillruptureorthetankwillcollapse.Therearemethodsforintegritytestingofventfiltersinplace.
Itisexpected,therefore,thattheventfilterbelocatedinapositionontheholdingtankwhereitisreadilyaccessible.
JustbecauseaWFIsystemisrelativelynewanddistillationisemployed,itisnotproblemfree.Inaninspectionofa
manufacturerofparenterals,asystemfabricatedin1984wasobserved.RefertoFigure6.
(/ICECI/Inspections/InspectionGuides/ucm091056.htm)Whilethesystemmayappearsomewhatcomplexonthe
initialreview,itwasfoundtoberelativelysimple.Figure7
(/ICECI/Inspections/InspectionGuides/ucm091057.htm)isaschematicofthesystem.Theobservationsatthe
conclusionoftheinspectionofthismanufacturerincluded,"OperationalproceduresfortheWaterForInjectionsystem
failedtoprovideforperiodiccompleteflushingordraining.Thesystemwasalsoopentotheatmosphereandroom
environment.Compoundingequipmentconsistedofnonsealed,opentankswithlids.TheWaterforInjectionholding
tankwasalsonotsealedandwasneversampledforendotoxins."Becauseoftheseandothercomments,thefirm
recalledseveralproductsanddiscontinuedoperations.
VIII.PUMPS
Pumpsburnoutandpartswear.Also,ifpumpsarestaticandnotcontinuouslyinoperation,theirreservoircanbea
staticareawherewaterwilllie.Forexample,inaninspection,itwasnotedthatafirmhadtoinstalladrainfromthe
lowpointinapumphousing.Pseudomonassp.contaminationwasperiodicallyfoundintheirwatersystemwhichwas
attributedinparttoapumpwhichonlyperiodicallyisoperational.
IX.PIPING
PipinginWFIsystemsusuallyconsistofahighpolishedstainlesssteel.Inafewcases,manufacturershavebegunto
utilizePVDF(polyvinylidenefluoride)piping.Itispurportedthatthispipingcantolerateheatwithnoextractablesbeing
leached.AmajorproblemwithPVDFtubingisthatitrequiresconsiderablesupport.Whenthistubingisheated,it
tendstosagandmaystresstheweld(fusion)connectionandresultinleakage.Additionally,initiallyatleast,fluoride
levelsarehigh.Thispipingisofbenefitinproductdeliverysystemswherelowlevelmetalcontaminationmay
acceleratethedegradationofdrugproduct,suchasintheBiotechindustry.
Onecommonproblemwithpipingisthatof"deadlegs".TheproposedLVPRegulationsdefineddeadlegsasnot
havinganunusedportiongreaterinlengththansixdiametersoftheunusedpipemeasuredfromtheaxisofthepipe
inuse.Itshouldbepointedoutthatthiswasdevelopedforhot7580ocirculatingsystems.Withcoldersystems(65
75oC),anydropsorunusedportionofanylengthofpipinghasthepotentialfortheformationofabiofilmandshould
beeliminatedifpossibleorhavespecialsanitizingprocedures.Thereshouldbenothreadedfittingsina
pharmaceuticalwatersystem.Allpipejointsmustutilizesanitaryfittingsorbebuttwelded.Sanitaryfittingswillusually
beusedwherethepipingmeetsvalves,tanksandotherequipmentthatmustberemovedformaintenanceor
replacement.Therefore,thefirm'sproceduresforsanitization,aswellastheactualpiping,shouldbereviewedand
evaluatedduringtheinspection.

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X.REVERSEOSMOSIS
AnotheracceptablemethodformanufacturingWaterforInjectionisReverseOsmosis(RO).However,becausethese
systemsarecold,andbecauseROfiltersarenotabsolute,microbiologicalcontaminationisnotunusual.Figure8
(/ICECI/Inspections/InspectionGuides/ucm091059.htm)showsasystemthatwasinuseseveralyearsago.There
arefiveROunitsinthissystemwhichareinparallel.SinceROfiltersarenotabsolute,thefiltermanufacturers
recommendthatatleasttwobeinseries.ThedrawingalsoillustratesanUltraviolet(UV)lightinthesystem
downstreamfromtheROunits.Thelightwasneededtocontrolmicrobiologicalcontamination.
Alsointhissystemwereballvalves.Thesevalvesarenotconsideredsanitaryvalvessincethecenterofthevalvecan
havewaterinitwhenthevalveisclosed.Thisisastagnantpoolofwaterthatcanharbormicroorganismsandprovide
astartingpointforabiofilm.
AsanadditionalcommentonROsystems,withtherecognitionofmicrobiologicalproblems,somemanufacturers
haveinstalledheatexchangersimmediatelyaftertheROfilterstoheatthewaterto7580oCtominimize
microbiologicalcontamination.
Withthedevelopmentofbiotechnologyproducts,manysmallcompaniesareutilizingROandUFsystemstoproduce
highpuritywater.Forexample,Figure9(/ICECI/Inspections/InspectionGuides/ucm091062.htm)illustratesawall
mountedsystemthatisfedbyasinglepassROunit.
Asillustrated,mostofthesesystemsemployPVCorsometypeofplastictubing.Becausethesystemsaretypically
cold,themanyjointsinthesystemaresubjecttocontamination.AnotherpotentialproblemwithPVCtubingis
extractables.LookingattheWFIfromasystemtoassurethatitmeetsUSPrequirementswithoutsomeassurance
thattherearenoextractableswouldnotbeacceptable.
Thesystemsalsocontain0.2micronpointofusefilterswhichcanmaskthelevelofmicrobiologicalcontaminationin
thesystem.Whileitisrecognizedthatendotoxinsaretheprimaryconcerninsuchasystem,afilterwillreduce
microbiologicalcontamination,butnotnecessarilyendotoxincontamination.Iffiltersareusedinawatersystemthere
shouldbeastatedpurposeforthefilter,i.e.,particulateremovalormicrobialreduction,andanSOPstatingthe
frequencywithwhichthefilteristobechangedwhichisbasedondatageneratedduringthevalidationofthesystem.
Aspreviouslydiscussed,becauseofthevolumeofwateractuallytested(.1mlforendotoxinsvs.100mlforWFI),the
microbiologicaltestoffersagoodindexofthelevelofcontaminationinasystem.Therefore,unlessthewateris
sampledpriortothefinal0.2micronfilter,microbiologicaltestingwillhavelittlemeaning.
Atareinspectionofthisfacility,itwasnotedthattheycorrectedthedeficientwatersystemwithacirculatingstainless
steelpipingsystemthatwasfedbyfourROunitsinseries.Becausethismanufacturerdidnothaveaneedforalarge
amountofwater(thetotalsystemcapacitywasabout30gallons),theyattemptedtoletthesystemsitfor
approximatelyoneday.Figure9(/ICECI/Inspections/InspectionGuides/ucm091062.htm)showsthatatzerotime
(at9AMon3/10),therewerenodetectablelevelsofmicroorganismsandofendotoxins.Afteroneday,thisstatic
noncirculatingsystemwasfoundtobecontaminated.Thefourconsecutiveonehoursamplesalsoillustratethe
variabilityamongsamplestakenfromasystem.Afterthelastsampleat12PMwascollected,thesystemwas
resanitizedwith0.5%peroxidesolution,flushed,recirculatedandresampled.Nolevelsofmicrobiological
contaminationwerefoundondailysamplesafterthesystemwasputbackinoperation.Thisisthereasontheagency
hasrecommendedthatnonrecirculatingwatersystemsbedraineddailyandwaternotbeallowedtositinthesystem.
XI.PURIFIEDWATERSYSTEMS
ManyofthecommentsregardingequipmentforWFIsystemsareapplicabletoPurifiedWaterSystems.Onetype
systemthathasbeenusedtocontrolmicrobiologicalcontaminationutilizesozone.Figure10
(/ICECI/Inspections/InspectionGuides/ucm091064.htm)illustratesatypicalsystem.Althoughthesystemhas

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purportedtoberelativelyinexpensive,therearesomeproblemsassociatedwithit.Foroptimumeffectiveness,itis
requiredthatdissolvedozoneresidualremaininthesystem.Thispresentsbothemployeesafetyproblemsanduse
problemswhendrugsareformulated.
PublisheddataforVicksGreensboro,NCfacilityshowedthattheirsystemwasrecontaminatedintwotothreedays
aftertheozonegeneratorwasturnedoff.Inaninspectionofanothermanufacturer,itwasnotedthatafirmwas
experiencingacontaminationproblemwithPseudomonassp.Becauseofpotentialproblemswithemployeesafety,
ozonewasremovedfromthewaterpriortoplacingitintheirrecirculatingsystem.Ithasbeenreportedthatdissolved
ozoneatalevelof0.45mg/literwillremaininasystemforamaximumoffivetosixhours.
Anothermanufacturer,aspartoftheirdailysanitization,removesalldropsoffoftheirozonatedwatersystemand
disinfectstheminfiltersterilized70%isopropylalcohol.Thismanufacturerhasreportedexcellentmicrobiological
results.However,samplingisonlyperformedimmediatelyaftersanitizationandnotattheendofoperations.Thus,
theresultsarenotthatmeaningful.
Figure11(/ICECI/Inspections/InspectionGuides/ucm091065.htm)andFigure12
(/ICECI/Inspections/InspectionGuides/ucm091067.htm)illustrateanotherpurifiedwatersystemwhichhadsome
problems.Unlikemostoftheothersystemsdiscussed,thisisaonewayandnotrecirculatingsystem.Aheat
exchangerisusedtoheatthewateronaweeklybasisandsanitizethesystem.Actually,theentiresystemisa"dead
leg."
Figure11alsoshowsa0.2microninlinefilterusedtosanitizethepurifiedwateronadailybasis.Inadditiontothe
filterhousingprovidingagoodenvironmentformicrobiologicalcontamination,atypicalproblemiswaterhammerthat
cancause"ballooning"ofthefilter.Ifavalvedownstreamfromthefilterisshuttoofast,thewaterpressurewill
reverseandcancause"ballooning".Pipevibrationisatypicalvisiblesignofhighbackpressurewhilepassageof
upstreamcontaminantsonthefilterfaceisarealproblem.Thissystemalsocontainsseveralverticaldropsatuse
points.Duringsanitization,itisimportantto"crack"theterminalvalvessothatalloftheelbowsandbendsinthe
pipingarefullofwaterandthus,getcompleteexposuretothesanitizingagent.
Itshouldbepointedoutthatsimplybecausethisisaonewaysystem,itisnotinadequate.WithgoodStandard
OperationalProcedures,basedonvalidationdata,androutinehotflushingsofthissystem,itcouldbeacceptable.A
verylongsystem(over200yards)withover50outletswasfoundacceptable.Thissystememployedadailyflushing
ofalloutletswith80oCwater.
Thelastsystemtobediscussedisasystemthatwasfoundtobeobjectionable.Pseudomonassp.foundasa
contaminantinthesystem(afterFDAtesting)wasalsofoundinatopicalsteroidproduct(afterFDAtesting).Product
recallandissuanceofaWarningLetterresulted.Thissystem(Figure13)
(/ICECI/Inspections/InspectionGuides/ucm091069.htm)isalsoonewaythatemploysaUVlighttocontrol
microbiologicalcontamination.Thelightisturnedononlywhenwaterisneeded.Thus,therearetimeswhenwateris
allowedtoremaininthesystem.Thissystemalsocontainsaflexiblehosewhichisverydifficulttosanitize.UVlights
mustbeproperlymaintainedtowork.Theglasssleevesaroundthebulb(s)mustbekeptcleanortheireffectiveness
willdecrease.Inmultibulbunitstheremustbeasystemtodeterminethateachbulbisfunctioning.Itmustbe
rememberedthatatbestUVlightwillonlykill90%oftheorganismsenteringtheunit.
XIII.PROCESSWATER
Currently,theUSP,pg.4,intheGeneralNoticesSection,allowsdrugsubstancestobemanufacturedfromPotable
Water.ItcommentsthatanydosageformmustbemanufacturedfromPurifiedWater,WaterForInjection,oroneof
theformsofSterileWater.Thereissomeinconsistencyinthesetwostatements,sincePurifiedWaterhastobeused
forthegranulationoftablets,yetPotableWatercanbeusedforthefinalpurificationofthedrugsubstance.

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TheFDAGuidetoInspectionofBulkPharmaceuticalChemicalscommentsontheconcernforthequalityofthewater
usedforthemanufactureofdrugsubstances,particularlythosedrugsubstancesusedinparenteralmanufacture.
Excessivelevelsofmicrobiologicaland/orendotoxincontaminationhavebeenfoundindrugsubstances,withthe
sourceofcontaminationbeingthewaterusedinpurification.Atthistime,WaterForInjectiondoesnothavetobe
usedinthefinishingstepsofsynthesis/purificationofdrugsubstancesforparenteraluse.However,suchwater
systemsusedinthefinalstagesofprocessingofdrugsubstancesforparenteraluseshouldbevalidatedtoassure
minimalendotoxin/microbiologicalcontamination.
Inthebulkdrugsubstanceindustry,particularlyforparenteralgradesubstances,itiscommontoseeUltrafiltration
(UF)andReverseOsmosis(RO)systemsinuseinwatersystems.Whileultrafiltrationmaynotbeasefficientat
reducingpyrogens,theywillreducethehighmolecularweightendotoxinsthatareacontaminantinwatersystems.As
withRO,UFisnotabsolute,butitwillreducenumbers.Additionally,aspreviouslydiscussedwithothercoldsystems,
thereisconsiderablemaintenancerequiredtomaintainthesystem.
Forthemanufactureofdrugsubstancesthatarenotforparenteraluse,thereisstillamicrobiologicalconcern,
althoughnottothedegreeasforparenteralgradedrugsubstances.Insomeareasoftheworld,Potable(chlorinated)
watermaynotpresentamicrobiologicalproblem.However,theremaybeotherissues.Forexample,chlorinated
waterwillgenerallyincreasechloridelevels.Insomeareas,processwatermaybeobtaineddirectlyfromneutral
sources.
Inoneinspection,amanufacturerwasobtainingprocesswaterfromariverlocatedinafarmingregion.Atonepoint,
theyhadaproblemwithhighlevelsofpesticideswhichwasarunofffromfarmsintheareas.Themanufacturing
processandanalyticalmethodologywasnotdesignedtoremoveandidentifytracepesticidecontaminants.Therefore,
itwouldseemthatthisprocesswaterwhenusedinthepurificationofdrugsubstanceswouldbeunacceptable.
XIV.INSPECTIONSTRATEGY
Manufacturerstypicallywillhaveperiodicprintoutsortabulationsofresultsfortheirpurifiedwatersystems.These
printoutsordatasummariesshouldbereviewed.Additionally,investigationreports,whenvaluesexceedlimits,should
bereviewed.
Sincemicrobiologicaltestresultsfromawatersystemarenotusuallyobtaineduntilafterthedrugproductis
manufactured,resultsexceedinglimitsshouldbereviewedwithregardtothedrugproductformulatedfromsuch
water.Considerationwithregardtothefurtherprocessingorreleaseofsuchaproductwillbedependentuponthe
specificcontaminant,theprocessandtheenduseoftheproduct.Suchsituationsareusuallyevaluatedonacaseby
casebasis.Itisagoodpracticeforsuchsituationstoincludeaninvestigationreportwiththelogicforrelease/rejection
discussedinthefirm'sreport.Endproductmicrobiologicaltesting,whileprovidingsomeinformationshouldnotbe
relieduponasthesolejustificationforthereleaseofthedrugproduct.Thelimitationsofmicrobiologicalsamplingand
testingshouldberecognized.
Manufacturersshouldalsohavemaintenancerecordsorlogsforequipment,suchasthestill.Theselogsshouldalso
bereviewedsothatproblemswiththesystemandequipmentcanbeevaluated.
Inadditiontoreviewingtestresults,summarydata,investigationreportsandotherdata,theprintofthesystemshould
bereviewedwhenconductingtheactualphysicalinspection.Aspointedout,anaccuratedescriptionandprintofthe
systemisneededinordertodemonstratethatthesystemisvalidated.
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