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PharmaDevelopments|Ozone:ANewWaterManagementParadigm|PharmaceuticalManufacturing

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Home/Articles/2013/Ozone:ANewWaterManagementParadigm

Ozone: A New Water Management

Paradigm

Producingandsanitizingpharmaceuticalwaterisn
teasy
butthereare
optionsfordoingbothlessexpensively
ByErikaHanleyOnken,MKSInstrumentsInc.
Jun11,2013
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Accesstocleanwaterisoneofthemostimportantfactorsconsideredinselectionanddevelopmentof
anewmanufacturingfacility.Withoutreadilyavailableappropriatelycleanwater,processingwouldbe
nearlyimpossible,changeoverandcleaningofreusableequipmentwouldcease,andoverall
productionwouldgrindtoastop.
Forexample,intheUnitedStates,incomingwaterintoanymanufacturingfacilitymustmeetaminimum
standardofEPAdrinkingwater.Thismunicipallytreatedwaterisonlyafirststeptotheprocessing
requiredbythepharmaceuticalindustrytobringthiswateruptopharmacopoeiastandardsforPurified
Water(PW)perUSP<1231>.CommonlyusedtechnologiestomanufacturePWandothercompendial
watersincludesoftening,reverseosmosis(RO),deionization(DI),dechlorination,(ultra)filtrationand
evendistillation.
Acomprehensivewatermanagementplanmustaddressallthewaterinthefacility,includingits
treatment,storage,deliveryandhandling.Partofthiscontrolplanrequiresunderstandingtheneedsfor
bothperiodicandcontinuoussanitizationtomitigateandpreventthebuildupofcontaminantssuchas
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biofilmwithinthewatersystem.
Whatisozoneandwhatdoesitdo?
Amongthealternativesavailableforwatersanitization,ozoneisrecognizedasanexcellentoptionfor
disinfectingbiopharmaceuticalwatersystems.Ozone(O3)isahighlyreactivemoleculemadeupof
threeatomsofoxygen,whichdecaysbacktooxygen.Caremustbetakenbecauseozoneisalsoa
toxicgascharacterizedbyastrong,pungentsmell.
Ozoneoccursnaturallybutcanbegenerated.Thetwomostcommongenerationmethodsfor
pharmaceuticaluseincludesilentdischargegenerationandelectrolyticgeneration.Electrolyticozoneis
createdwhenhighvoltagepassesbetweenparallelmetalelectrodesandthroughaliquidcontaining
oxygen,e.g.,theprocesswater.Electrolyticallygeneratedozoneisoftenusedforsmallquantitiesof
ozoneorlowerflows.Ozonegeneratedbysilentdischargeiscreatedwhenacurrentcontrolledelectric
dischargeisreleasedbetweenhighpurityrefractorymetalelectrodesintoagascontainingoxygen.
Theozoneistheninjectedintothewatersystem.Ozonegeneratedbysilentdischargeprovides
greaterflexibilityintermsofcontrollingozoneconcentrationstotheamountneeded,asitisonlylimited
bytheoxygencontentoftheairratherthanbytheoxygenusablefromthewater.
Thetwomethodshavedifferentmaintenancerequirements.Silentdischargegeneratorsdonotdirectly
touchthewaterpathandgenerallyrequirelittlestandardmaintenance.Electrolyticgeneratorsarein
directcontactwiththeprocesswaterandwillrequireanisolationsystemtoremoveitfromthewater
flowforservice.Maintenancerecommendationsfromthemanufacturersshouldbefollowedtoprovide
thegreatestuptimepossible.
Priorindustryconcernisthatozonespecificallythatgeneratedbysilentdischargemaybe
consideredanaddedsubstance,asitisintroducedintotheprocesswatervs.createdfromit.
Accordingtothe"addedsubstances"discussioninUSP<1231>,everyaddedsubstancemustbe
removedwithappropriatemeans.Aslongasitisremoved,ozoneisnotconsideredanadded
substanceintheproductionofpharmaceuticalgradewater.Ozoneisoftenremovedviaadestruct
mechanismsuchas254nmultraviolet(UV)light.
Asozoneisthesamenomatterhowitisgenerated,withthesamestandardCASRegistryNumber
10028156,andbecause,forriskmitigation,mostozonesystemsalreadyhaveaUVdestruct
included,thisaddedsubstanceconcernisalreadyaddressedandcanbeconsideredslightly
outdated.Highpuritysilentdischargegenerationozonesystemsareavailablewithexcellentoperating
historyinotherhighlydemandingindustries(e.g.,semiconductor)andarethestandardformitigating
thehighlevelsofcontaminationinwastewatertreatment.

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Figure1:Ozonemanufacturedbysilentdischargemethod
OzoneAddressesSanitization
Ozoneisusedasanalternativetoheatsanitizationwithhotwaterandsteamorchemicaldisinfection
usingchlorine,chlorides,peroxidesandotherchemicals.Itisoneofthestrongestcommercially
availableoxidants,withadisinfectingstrength3,000timesthatofchlorineduetoitshigheVpotential.
Ozoneeffectivelykillsbacteria,viruses,yeast,fungiandothermicrobesasafunctionoftime,
susceptibilityofthetargetorganisms(action),ozoneconcentrationandwatertemperature.
Whilethereareanumberofpotentialsourcesofcontaminationinstorageanddeliverysystemsfor
purifiedandsterilewater,oneofthemostcommonproblemsfacingpurifiedwater(PW)productionand
deliveryisthepreventionandremovalofbiofilms.Firstdescribedinthemid1930s,biofilmsformon
anysurfacewhereversurfaceassociatedmicrobesarepresent.Biofilmsoccurinawidevarietyof
systems,butareendemictowatersystemsinthebiopharmaceuticalindustry.
BiofilmsaredifficulttoremovefromthewettedsurfacesofPWsystemsforseveralreasons.Themost
prevalentofthesereasonsisthetoughsurfacepolymericexopolysacharrides(EPS)shellbiofilms
excrete.TheEPSprovidesamatrixinwhichnutrientsareretainedandmicrobescanthrive,thereby
continuouslycontaminatingthePWstorageanddistributionsystem.Biofilmremovaltreatmentsmust
notonlypenetratetheEPSbutmustalsobebiocidaltotheheterogenousmicrobialpopulationbelowit.
PartialremovalofthebiofilmsEPSmatrixliberatestheunderlyingcolonizingmicrobes.Unless
destroyed,theseunderlyingmicrobeswillmigrateandreestablishatnewsites,maintainingthe
contaminationofthewatersystem.
Addressingbiofilmsisthuscriticalforthemaintenanceofhighpuritywaterquality.Periodicand
continuoussanitizationsareoptionstomitigatebiofilmgrowthandproliferation.However,targeted
destructionofbiofilmsisdifficultastherearenotmanynonspecifictreatmentsthatcanaddress
biofilmsinherentcompositionalvariability.
Manyindustrialsettingsusestrongoxidantchemistriessuchaschlorineandperoxidesforbiofilm
mitigationandremoval.Recently,however,drawbackswiththeseconventionalapproachessuchas
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watercontaminationconcerns,tighteningenvironmentalregulationsandchemicalcostshaveled
differentindustriestoexploretheuseofozonatedwaterfortheremovalofbiofilmsanddestructionof
microbialcontamination.
Asanonspecificbiocide,ozonereactsrapidlywithmosthydrocarbonstoeffectivelydestroythe
biofilmsEPS,andthemicrobesandorganicresiduematerialwithinthesefilms.

Figure2:Adiagramofspecificdesignconsiderationsforozonebasedsanitationsystems
OzoneSystemsDesign
Ozoneisgeneratedondemand,inambientwatertemperatures,allowingproductionofambient
temperaturePW.OzonesystemsforpharmaceuticalPWproductionrequireozonegenerationinjection
andmixingintowater(ifwithsilentdischarge),ormixingalone(ifwithelectrolyticozone)testingboth
theinitialdissolvedozoneoutputandozonereturnandresidualozonedestructionviaaUVorother
destructsystem.Whereastoragevesselisused,storagevesselconfiguration,ventingandventgas
destructionmayberequired.
Specificdesignconsiderationsforozonebasedsanitizationsystemsincludedissolvedozonesensor
locationforinitialozoneproductionandtoconfirmdestructionplacinganeargeneratorozonegas
monitorforenvironmentalmonitoringandworkersafetyandconsideringthesystemsmaterialsof
construction.Ozonedissociatesbacktooxygen,sooxygensensitivematerialsmaybeaffectedbythe
useofhighorprolongedamountsofozone.Thiseffectshouldbeconsideredduringpredesignrisk
assessmentsandfeasibility.
Configurablesystemsareavailableofferingtwoormoreofthecriticalozonesystemscomponents
integratedandfullytestedpriortoinstallationonsite.Therearealsosystemsavailablewhichinclude
mostofthesecomponentsinasinglepackage,offeringeaseofinstallationanduse.
Determiningtheamountofozoneneededforyoursystemdependsontheefficiencyoftheozone
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dissolutionintothewater,theamountofwaterinthewaterstoragetankandpipingdistribution,the
makeupwaterquality,andflowratesandpressures,includingturnovertime.Ozonegenerators
themselvesmayincluderequirementsforpower,cleanoxygencontainingfeedgassuchas
compressedair,watercoolingandpressure.
Finally,aswithanystandardcriticalwatersystem,systemdesignconsiderationsofautomation
capabilities,power,waterflow,watertemperaturecontrol,andpressuremustbetakenintoaccount.
Monitoringandcontrolparametersforsafety,flowrate,pressure,andallcompendialwaterpurity
requirementsincludingpHandTOCshouldbeincludedinthesystemtoensurecompliancewiththe
monographs.
FeasibilityConsiderations
Inthepharmaceuticalindustry,ozonecanbeusedforgeneralsanitization,forspecifictool/system
cleaning(cleaninplace,orCIP),oraspartofaresolutionplantoresolveaspecificcontamination
incident.ASTMstandardE2500removedanumberofimpedimentstotheimplementationofozone
basedpurificationinpharmaceuticalmanufacturing,encouragingimprovementsinProcessAnalytical
Technology(PAT)throughwelldocumented,robustandflexiblemanufacturingcapabilities.
Whileozoneisveryuseful,itmaynotalwaysbefeasibleforacompanyssystem.Touseozone,the
followingparametersmustbeassessedaspartofariskmanagementevaluation:
Processsensitivitytooxygen
Materialsofconstruction,and
Operatorandenvironmentalsafetyandproceduresarounduse
Regardingprocesssensitivity,thewatersystemmayexperienceapotentialslightincreaseinCO2,O2
andtracenitrates.Thesemaynotbenoticeable,aswithtrace(ppb)levelsoforganicsarealreadyin
water.Perthepharmacopoeia,PW,HPW(HighlyPurifiedWater)andWaterforInjection(WFI)are
allowedtohavespecificlowlevelsofionicimpurities.Ozonedestructionmustbeconfirmedfor
processinguseandaddedsubstances.
Asozonedissociatesbacktooxygen,someoxygensensitivematerialsofconstructionmaybe
affected.Anypotentialozonewettedcomponentsincludingpiping,pumps,seals/gaskets,valveseats,
filtersandsensorsshouldbeassessedandcomparedwithmanufacturersstandardstounderstand
compatibilitywithozone.SomeexamplesofmaterialsthatarecompatiblewithozoneincludePVDF,
316Lstainless,andPTFEandViton.
Operatorandenvironmentalsafetyandproceduresarealsoanimportantconsideration.Ozoneisa
toxicgasinhighquantitiesorconcentrations,andisregulatedbyOSHAintheUnitedStatesand
similaragenciesworldwide.Forsafetypurposes,gaseousozonedetectionmonitorsareoftenplaced
directlynearozonegeneratorsorintheroomsinwhichtheyoperatetoprovideearlydetectionshould
aleakoccur.Appropriateventingordestructionofunusedozonegasisimportanttomaintainasafe
workingenvironment.Finally,environmentalregulationsmustalsobeconsideredwhenventingozone
gasoutsidethefacilityand/ordisposingofozonatedwater.Ozonecanremaininambientwaterfor
approximately20minutesbeforecompletelyrevertingtooxygen.
Finally,asforanycriticalwatersystem,acomprehensiveriskanalysisshouldbeperformed.Robust
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riskmitigationplansincludingmonitoring,preventativemaintenance,backupconsiderations,spares
andresponseflowchecklistsshouldbedeveloped.Mitigationplansalsoconsiderequipment
protection.Commonwaystoprotecttheozoneequipmentandwatersystemfromcontamination
includewatertrappingdevices,toavoidgeneratorcontaminationwaterlevelmonitorsandautomatic
shutoffvalves.Ozonegeneratorsuppliersshouldbeabletoprovideresultsprovingthoroughtesting
andhighquality,tohelpacompanyensureitisinstallingarobustsystemandhasappropriatesupport
ifandwhenrequired.
Allwatersystems,includingozonebasedsystems,shouldbeintegratedwithfacilitiessafetyand
monitoringsystemsandautomatedwhereappropriateforcontrol,monitoring,andtroubleshooting
purposes.
PotentialtoSave
Ozoneisbothsafeandeconomicaltousesinceitcanbereliablygeneratedonsiteasneeded,
avoidinghandlingandcostsassociatedwithstrongoxidanttransportationandstorage.Itisgenerated
atambienttemperatureandissolubleinambienttemperaturewater,increasingeaseofoperation.The
infrastructurerequirementsforthermochemicalsterilizationandsubsequentdecontaminationare
significant,andtheuseofozonatedwatercangreatlyreducecapital,operationsandmaintenance
costsofwatertreatment.
Ozonatedwaterleavesnochemicalresidues,unlikeotherchemicalsanitizationprocedures,andin
ambientwaterrevertsbacktooxygennaturally.Therefore,itdoesnotneedtobeflushedasdoes
chemicallysanitizedwater.
Anymodelforozonesavingswouldcompareagainstbaselinesystemsanitizationmethodologies,
wateruseandelectricityuse.Baselinecostsincludeoperatingcosts,energyconsumption,utility
requirements,heating,steam,coolingwastewaterandchemicalwaste,aswellasthecosttostore,
handleandmanagechemicalsiftheyareused.Thecomprehensivecostofwatermustalsobe
included,forprocessing,cleaningandsanitization.
Oncethebaselineisdeveloped,thecapitalcostsofozonearecalculatedfortherequiredspecific
components(e.g.,ozonegenerators,ozonemonitorsanddestructsystems).Changesinpower
consumption,netwaterusage,maintenancecostandtime,possiblereductioninsanitizationtimeand
frequencyandincreasedassetutilizationforexistingsystemstodomorewithlesscansupport
abusinesscase.Additionally,ifacompanyisinvestigatingexpansionatanexistingfacility,itmayalso
bepossibletoavoidcapitaloutlayforanexpensivehotwatersanitizedloopifhotwaterisnotexpressly
requiredbytheprocess.
Dependingonwaterusageandneeds,facilitiescanexperiencerapidpaybackperiods.Additional
financialbenefitscancomefromachievingmunicipal,corporateandfacilitygoalsforreducedwater
use.Forexample,LEED(LeadershipinEnergyandEnvironmentalDesign),anecologyoriented
buildingcertificationprogramrunundertheU.S.GreenBuildingCouncil(USGBC)provideswater
efficiencycredits,whichcansupportacompanysorfacilityssustainabilitygoalsandtranslateinto
financialbenefits.
TherecentISPECriticalUtilitiesconferenceinFebruary2013highlightedthemanysavingsattributable
toozone.Casestudieswerepresentedshowingdailyandannualsavingsfornewbuildsandevenafter
conversionfromnonozonesanitizingmethodologies.FurtherreferencesareavailableinISPEGood
PracticeGuideentitledOzoneSanitizationofPharmaceuticalWaterSystems.
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Ozoneisaviableandacceptedtechnologicaloptionforwatersanitizationandoneofthemosteffective
technologiesagainstbiofilmmitigation.Itsrapidlyincreasingpopularityandacceptanceasasolution
forPWdisinfectionisduetoitscostsavingspotential,includingitsabilitytosavesignificanttimeduring
thecleaningcycle.Totalcostofownershipmodelsforozoneshouldincludenotonlyitsupfrontcapital
costs,butalsooveralllowerorreducedannualmaintenancecosts,increaseduptimeavailabletothe
facilityfrombothshortenedcleaningtimes,andthepossibilityforshorterand/orlessfrequent
sanitizationsduetoimprovedwaterqualityandreliability.Theupsidepotentialofincreasednumberof
batches,plusbenefitsfromlongtermgoalssuchasLEEDrecommendedwaterreductionmayalsobe
includedincost/benefitcalculations.
Ozonecanhelpaddressthe4Rsofwateruseinapharmaceuticalfacility:reduce,reuse,recycleand
reclaim.Usingozoneatambienttemperatureforsanitizationwillreducenetwastewaterandelectricity
usedinhotwaterandchemicalsanitization.Withouttheadditionofchemicals,ozonecanhelpreuse
criticalwaterwithinthefacility,andifthecapabilitiesareavailable,cansupportreclaimingwater
(effluent)comingoutoftheplant.
Withitsprovenresultsagainstbiofilm,ozonesystemsareacrediblesanitizationoptionforwater
expansions,greenfieldsitesandconversionfromexistinghotwaterorchemicalsystems.Ozone
technologyisavailableanditsbenefitsreadilyquantifiablesoshouldbecloselyconsideredasa
feasibleoptionforfuturecriticalwaterneeds.
PublishedintheJune2013editionofPharmaceuticalManufacturingmagazine

References:
ISPEBaselinePharmaceuticalEngineeringGuideforNewandRenovatedFacilities:Volume4,Water
andSteamSystems,SecondEdition,December2011
ISPEGoodPracticeGuide,OzoneSanitizationofPharmaceuticalWaterSystems,July2012
ASTMStandardE2500,2012,StandardGuideforSpecification,DesignandVerificationof
PharmaceuticalandBiopharmaceuticalManufacturingSystemsandEquipment,ASTMInternational,
WestConshohocken,PA,DOI:10.1520/E250007R12,www.astm.org
ISPEKnowledgeBriefKB0022June10:OzoneSanitizedPharmaceuticalWaterSystems:Tank
VentingConcerns
A.K.Greene,Z.P.GuzelSeydimandA.C.Seydim,ChemicalandPhysicalPropertiesofOzonein
OzoneinFoodProcessing,ColimODonnell,B.K.Tiwari,P.J.CullenandR.G.RiceEditors,John
WileyandSons,Oxford,UK(2012)pp1931.
M.W.Mittelman,Biofilmdevelopmentinpurifiedwatersystems,inMicrobialBiofilms,H.M.Lappin
ScottandJ.WilliamCosterton,Eds.,CambridgeUniversityPress,Cambridge,UK,(1995)pp133147.
SamuelStucki,DirkSchulze,DieterSchuster,andChristianStarkOzonationofPurifiedWater
SystemsinPharmaceuticalEngineering,January/February2005,Vol.25,No.1
JoeManfredi,CostOptimizationAlternativesforCriticalUtilities,presentationattheISPECritical
Utilitiesconference,February2013
NissanCohen,EconomicEfficacyComparisonBetweenOzoneandHotwaterSanitization,
presentationattheISPECriticalUtilitiesconference,February2013

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