CleanRoomsandZones:

ChangingRegulatoryDemands;

OptimizingSamplingPositions;

AutomatingtheEMprocessPresentedbyJoeGecseyHACHSeptember2012AgendaForthcomingChangestoISO14644-1,-2 CleanroomStandardsBenefitsofISO21501-4CalibrationChoosingsamplepositionsHowautomationcanmaketheEMtaskEasierSimplerMorevaluableClassificationStandardsforAirborneParticlesGeneralAirMonitoringStandards–before1999ForthcomingRevisionsto

ISO14644-1,-21.Frequencyofre-certificationfor“continuedcompliance”:

Now:Ifzoneis≤ISOClass5,every6monthsIfzoneis≥ISOClass6,every12months

Proposed:Removere-certificationperiodRe-certificationtimeframewillbesetbyregulatoryoradvisorycommitteesforaparticularindustry2.EliminateStudent’sTtestforsampleplanswith1to9samplepositions3.MethodofdeterminingnumberofsamplepositionsReplacewithstatednumberofminimumsamplepositionsasalook-upchartBasedon95%confidencelevelsnotonSQRTofareaMaymeanasmallincreaseinthenumberofsamplepointsForthcomingRevisionsto

ISO14644-1,-2A.4.1.1DerivetheminimumnumberofsamplinglocationsNLfromtable3.TableA.1showsthenumberofsamplelocationsrelatedtotheareaofeachcleanroomorcleanzonetobeclassifiedandprovidesatleast95%confidencethatatleast90%ofthetotalareadoesnotexceedtheclasslimit.

Differentlevelsofconfidenceandverificationcanbespecifiedandagreeduponbythecustomerandsupplier.4.Removepossibilitytoclassify at5micronforISOClass5Limitnumberof29removedNote(e):Samplecollectionlimitationsforbothparticlesinlowconcentrationsandsizesgreaterthan1ummakeclassificationinappropriate,duetopotentialparticlelossesinthesamplingsystem.”5.IndicatethatsingledigitlimitsforISOClass1and2createchallengestotimelyexecution

Note(b):Theseconcentrationswillleadtolargeairsamplevolumesforclassification.Sequentialsamplingproceduremaybeapplied;seeAnnexD.ForthcomingRevisionsto

ISO14644-1,-26.Newlabelforclassificationlevel ACP=AirCleanliness(by)Particles ACC=Aircleanliness(by)Chemicals SCP=SurfaceCleanliness(by)Particles SCC=SurfaceCleanliness(by)ChemicalsForthcomingRevisionsto

ISO14644-1,-2CleanroomDesignationsAirSurfacesParticlesChemicalsACPSCPSCCACCISO14644–10DraftISO14644–9ISO14644-1,-2DraftofRevisionISO14644–8Proposednewlimitsandlabels:

ClassificationLimits:ISO14644-1(2013)FS209EClass1007.NormativeReferencetoISO21501-42NormativereferenceThefollowingnormativedocumentcontainsprovisions,which,throughreferenceinthistext,constituteprovisionsofthispartofISO14644.Fordatedreferences,subsequentamendmentsto,orrevisionsof,anyofthesepublicationsdonotapply.However,partiestoagreementsbasedonthispartofISO14644areencouragedtoinvestigatethepossibilityofapplyingthemostrecenteditionsofthenormativedocumentsindicatedbelow.Forundatedreferences,thelatesteditionofthenormativedocumentreferredtoapplies.MembersofISOandIECmaintainregistersofcurrentlyvalidInternationalStandards.ISO21501-4:2007Determinationofparticlesizedistribution–Singleparticlelightinteractionmethods-Part4:Lightscatteringairborneparticlecounterforcleanspaces.

ForthcomingRevisionsto

ISO14644-1,-2ISO21501AdditionalTestsBeforeISO21501-4SizecalibrationSizeresolutionFalsecountrateSamplingtimeISO21501-4SizecalibrationVerificationofsizesettingCountingefficiencySizeresolutionFalsecountrateConcentrationlimitSamplingflowrateSamplingtimeSamplingvolumeISO21501-4

WhattolookforonthecalibrationcertificateRoadMaptoISO21501-4complianceAudityourMethodsandEquipmentTrainingStandardOperatingProcedures(SOPs)Validation(IQ/OQ)CalibrationPoliciesEquipmentUpgradeasneededAudityourCalibrationServiceFactory-trainedandauthorizedCorrectequipmentandstandardsADDITIONALINFORMATION

Whatpricepatientsafety?Injectionsandinfusionsforpeoplewithsuppressedimmunologicalsystems

Injectionstraightintobloodstreambypassesmostofthebody’sdefences.Whymonitorforparticles?GreatestconcernisforviablemicroorganismsTechnologyisnotavailabletodaytomeasureviablecountsinrealtimeTotalparticlecountsusedasasurrogate(non-viable)100,000billionbacteriaonandinthehumanbodyGeneralAirMonitoringViablecountsCanbeculturedWillgrowinto“colonies”requiresoptimumgrowthmediumrequiressufficientincubationEnumeratedasCFU=Colony-FormingUnitsVU=ViableUnitsHowanairborneparticlecounterworks…LaserDiodeDetectorMirrorParticleLightTrapPrinciple:LightScatteringRelativesizesofparticulatematterHumanhair:50-100μmVisible:35-50μmBacteria:1to8μmSkinFlake:about20μmSkinFlakeFiberAlumino-silicatewithKandTiTalcParticleCountingApplicationsWhatParticleCountingApplications

Twotypesofactivitiesperformedwithanairborneparticlecounter:ClassificationfocusesprimarilyontheenvironmentMonitoringfocusesonprocess,peopleandtheenvironmentPeopleEnvironmentProcess

PeopleasaContaminationSourceShed5to10millionskincellseachday2000to5000microorganisms/cm2onskinFilterefficiencyofclothingorgarmentvariesgreatlyClassification:

FS209andISO14644-1ClassificationistheprocessofqualifyingthecleanroomenvironmentbythenumberofparticlesusingastandardmethodDetermineclassificationofroomaccordingtostandards“ISOClass5”or“Class100”Performedonaregularbasisbutnotfrequently6months,yearlyor???StandardsdefineminimumnumberofsamplepointsUsuallybasedonareaofcleanroomorcleanzoneStandardsdefineminimumamountofairtobesampledMinimumvolumesforstatisticallyvalidsamplesClassificationisastandardizedmethodEnvironmentalMonitoringMinimumnumberofsamplepointsdefinedbyQAAreaofcleanroomorcleanzoneActivityRisktoproductFrequencyandvolumeofsamplepointsdefinedbyQAFrequentenoughtoshowcontrolFrequentenoughtoprovidemeaningfultrendinformationDeterminestabilityofroomorzoneovertime;developtrenddataExecutedonascheduledbasis:daily,weekly,monthlyNotcontrolledbyregulation…butneededfortrendinformationProcessMonitoringMinimumnumberofsamplepointsdefinedbyQAAreaofcleanroomorcleanzoneActivityRisktoproductFrequencyandvolumeofsamplepointsdefinedbyQAFrequentenoughtoshowcontrolFrequentenoughtomanagefinancialriskofproductcontaminationDeterminereadinessofroomtocarryoutdesignatedtaskPerformedwheneverrelevantactivityoccurs–dailyworkNotcontrolledbyregulation…butbyrisk!ThreeCommonMethods

ofSamplingManual:withahandheldorportableparticlecounterSequential:withamanifold/scannerandparticlecounterContinuous:withportableorremoteparticlecountersMETONE6000&7000Series

forproductionmonitoringGradeA&BareasMETONE3400Series

CleanroomclassificationEnvironmentalmonitoringShort-termonlinesamplingMETONEHHPC+HandheldparticlecounterUsedfortroubleshootingManualMonitoringAdvantageDisadvantageSimpleVaryingintervalsFlexibleInconsistentinprobepositionLowinitialinvestmentIntrusivetoworkprocessTraditionalmethodofsamplingProductionworkeroftennotinformedofhighcountsHighlaborcostUsuallynotcontinuousManualMonitoringConsistentlysamplesfixedpositionsSampleseverypositiononeormoretimesperhourCanoperate24hoursperdaySequentialMonitoringAdvantageDisadvantageFrequentsamplingSamplesatfixedlocationsConsistentsamplingpositionCanmisseventsStatisticaldataforhistoricalpurposesParticlelossintubingConsistencyofdataallowsSPCanalysisRequiresauxiliarypump(s)tomaintainconstantflowthroughalltubesCanbepartofFMSSinglecountertocalibrateSequentialMonitoringTubingTransportLossAbletodetectfast,intermittenteventsUsesdedicatedcounterateachsamplepointAvoidseffectsoflongtubingrunsContinuousMonitoringContinuousMonitoringAdvantageDisadvantageConsistentsamplepointsRequireslotsofinitialplanningAllpointsaremonitoredsimultaneouslyLargerinitialinvestmentBuildstatisticaldatabaseCalibrationforeachcounterRelateparticleeventstoprocessactivityGenerateslargeamountsofdatatoprocessandanalyzeQuickoperatorfeedbackPlacementofIsokineticProbesinaPharmaceuticalFillingArea

forthePurposeofMonitoringNumberofSampleProbes

forMonitoringNoregulatoryguidelinesNorequirementsoradvicefrom

FS209E,ISO14644-1,FDAGuidelines,EUGMPAnnexI,etc.whenconductingmonitoringoftheprocess2.SamplenearpointsofinterventionbyoperatorsExamples:VialturntableFillingneedlesStopperingprocess1.SamplenearexposedproductGenerallyatworkheightandnearexposedproductIfliquidsterilefill,guidanceistosampleairapproachingtheproductwithin1foot(12”or30cm)ofexposedcomponents[USA]PlacementofSampleProbesLessthan1foot(12inchesor30cm)3.StorageorstagingareasExposedproductorcomponentRiskofparticulatedepositionovertimePlacementofSampleProbesThreemajordeterminantsofrisk 1.WhereProductorComponentsarevulnerable 2.Activity -Introductionofcontaminantsbypersonnel -Introductionofcontaminantsbyprocessequipment -Affectonprotectiveairflowpatterns 3.PotentialforDepositionovertime -WherecomponentsarestoredorheldPlacementofSampleProbesOnelastconsideration: Willyoudosomethingwiththedata???? Ifyouarenotgoingtoreacttothedata, don’tsample!!!

Never,ever,ever“forinformationonly”!!PlacementofSampleProbesSelectingMonitoringPositionsPresenceoflyophilizersindicatevialsmaynotbefullystopperedsotheholdingpositionnear“5”representssomeriskPosition“6”providesevaluationofGradeBzoneandprobablyearlyindicationofpressurebalanceproblemsduetoproximitytodoorsPositions“7”and“8”areneededbecauseloadingareainfrontoflyophilizersshouldbeGradeAifproductisnotfullystoppered12345678FreezeDryer1FreezeDryer2FreezeDryer3VialWashingSystemIfthiswereafillingoperationforwhichthefinalproductremainsliquid,somepointswouldnotbeneeded.

12345VialWashingSystemSelectingMonitoringPositions132SelectingMonitoringPositionsAbout4metersSelectingMonitoringPositions:

RABSSelectingMonitoringPositions:RABSPlacementofsamplepoint,counterandtubingConcerns:MustbeabletoremoveMustbeabletosterilize;autoclavingpreferredMustnotinterferewithworkflowMustbeabletosampleinareawithpoorflowcharacteristics;verticalorientationSelectingMonitoringPositions:

IsolatorsHoldingorTemporaryStorageAreaSelectingMonitoringPositionsMonitoringPowderFillSection9ofAnnex1:“ForGradeAzones,particlemonitoringshouldbeundertakenforthefulldurationofcriticalprocessing,includingequipmentassembly,exceptwherejustifiedbycontaminantsintheprocessthatwoulddamagetheparticlecounterorpresentahazard,e.g.liveorganismsandradiologicalhazards.Insuchcasesmonitoringduringroutineequipmentsetupoperationsshouldbeundertakenpriortoexposuretotherisk.Monitoringduringsimulatedoperationsshouldalsobeperformed.InterferencefromProduct:

PowderFillingExposedproductorvials/ampoulesUnidirectionalairbathingtheexposedproductduringmanufacturingHighersampleprobeformonitoringduringproductionSampleprobetodemonstrateairqualitybeforefillingprocessLessthan305mmRecommendations:

PowderFillLine

InletHEPAFilter

Outfeed

from

tunnel

=Positionofmonitoringduringfilling

=Positionsofmonitoring‘a(chǎn)trest’

?InterferencefromProcess:

CappingAnnex1(2009):Paragraph120.Vialcappingcanbeundertakenasanasepticprocessusingsterilisedcapsorasacleanprocessoutsidetheasepticcore.Wherethislatterapproachisadopted,vialsshouldbeprotectedbyGradeAconditionsuptothepointofleavingtheasepticprocessingarea,andthereafterstopperedvialsshouldbeprotectedwithaGradeAairsupplyuntilthecaphasbeencrimped.FDAAsepticGuidance(2004):Ifstopperedvialsexitanasepticprocessingzoneorroompriortocapping,appropriateassurancesshouldbeinplacetosafeguardtheproduct,suchaslocalprotectionuntilcompletionofthecrimpingstep.StopperedvialsGradeAUnidirectionalairbathingthestopperedproductHighersampleprobeformonitoringduringcapping

CappingMachineInterferencefromProcess:

CappingIsokineticprobesMinimizeturbulenceMatchingairflowwithparticlecounterflowrateDifferentsizeopeningsforcounterswithdifferentflowratesOrientedtointersectairflow80-120fpm(0.4-0.6m/sec)0.1to3cfm(2.83to80lpm)80-120fpm(0.4-0.6m/sec)0.1to3cfm(2.83to80lpm)IsokineticprobesOptimizingSamplingof

AirborneParticleCountsEUAnnex12009“TheGradeAzoneshouldbemonitoredatsuchafrequencyandwithsuitablesamplesizethatallinterventions,transienteventsandanysystemdeteriorationwouldbecapturedandalarmstriggeredifalertlimitsareexceeded.Note:RevisionofEUAnnex12003completed,effectivedateof01March2009=“continuous”!!!FDA’sGuidanceforIndustry:

SterileDrugProductsProducedbyAsepticProcessingContainsNonbindingRecommendationsAirintheimmediateproximityofexposedsterilizedcontainers/closuresandfilling/closingoperationswouldbeofappropriateparticlequalitywhenithasaper-cubic-meterparticlecountofnomorethan3520inasizerangeof0.5μmandlargerwhencountedatrepresentativelocationsnormallynotmorethan1footawayfromtheworksite,withintheairflow,andduringfilling/closingoperations.ThislevelofaircleanlinessisalsoknownasClass100(ISO5).Werecommendthatmeasurementstoconfirmaircleanlinessincriticalareasbetakenatsiteswherethereismostpotentialrisktotheexposedsterilizedproduct,containers,andclosures.Theparticlecountingprobeshouldbeplacedinanorientationdemonstratedtoobtainameaningfulsample.Regularmonitoringshouldbeperformedduringeachproductionshift.Werecommendconductingnonviableparticlemonitoringwitharemotecountingsystem.Thesesystemsarecapableofcollectingmorecomprehensivedataandaregenerallylessinvasivethanportableparticlecounters.FromSectionIV.BuildingsandFacilities,Sub-partA,CriticalArea–Class100(ISO5)“Werecommendconductingnonviableparticlemonitoringwitharemotecountingsystem.Thesesystemsarecapableofcollectingmorecomprehensivedataandaregenerallylessinvasivethanportableparticlecounters.”EUGMPAnnexI:DiscussionForum"Reactiontocounts"PaulHargreaves,MHRA:"Thereisnoabsolute.Nobodyissaying,"You'regoingtorejectabatchbecause,onyourparticlecounter,youfoundtwoparticles".It'stheretodemonstratewhatishappeningatthatpointintime.Nowif,forexample,youhaveasterilitytestfailureforaparticularbatch,andyouknowwhichpartofthebatchwhereitwentdown,andyouhavethesesignificantlydifferentcountsfromthatpartofthebatch,thenthatisgoingtohelptherootcauseinvestigation.Andit'sreallytherootcauseinvestigationsthatcompaniesreallyneedtoimproveupon,…"Andit'sreallytherootcauseinvestigationsthatcompaniesreallyneedtoimproveupon,…"TheRoleofAutomationinComplianceCompliancerequiresconsistencyMinimizehumanvariabilityintheprocessReduceoreliminateerrorsHumansarenotgoodatrepeatingmundanetasks—computersareCompliancegeneratesalotofpaperworkSOPs—documenttheprocessSchedulesandchecklists—humancontrolProductiondatarecords—generatesthemostpaperApprovalsandverificationformsAutomationofparticlemonitoringimproves

complianceandincreasesproductivityIntegrationofautomatedsystemsfurtherincreases

productivitywhilereducingsystemsupportFindingtheRightMixShouldyouuseonlyportables?TherearegoodautomationoptionsforportablesTraditionallyonlyavailableforonlinesensorsPortablescannowbeoperatedas“online”sensorsbyonlinesoftwarePortablesaremoveable,flexibleButportablesareless“sterile”HumaninvolvementPrinter,screen,exhaustflow(turbulence),non-sealedchassis,etcDoyouneedamixedapproach?Onlinesensors&portablesCharacterizetheapplicationsmixinyourmanufacturingoperations/facilityCleanroomclassificationEnvironmentalmonitoringAsepticproductionmonitoringWhyContinuousMonitoringSystem?ShowsthattheenvironmentisundergoodcontrolSatisfyneedfor“comprehensive”dataSatisfydemandfor“continuous”dataSatisfyneedforaccuratedataProvidesreal-timenotificationofalertsandalarmsProvideshistoricalrecordstoprovethatcontrolofcriticalareashasbeenmaintainedSignalspersonneltotakecorrectiveactionatanydeviationfromtheacceptablerangeProvideenoughdatafor“rootcause”ReportsofdataandexceptionsAbilitytoretrievedataforanalysisImprovequality,lowercostsContinuousMonitoringAnFMSSystemcanmonitor:Airborneparticulates,RoompressuresandairflowRoomtemperatureandhumidityOtherparameterssuchasdoorinterlocks,etcSystemconfigurationsavailable:MultiplePumps:Multiplesamplingpositions,greatestflexibility/redundancy,buthigherinstallcostCentralVacuum:Multiplesamplingpositions,goodflexibility/redundancyandmediuminstallcostIntegratedPumps:Multiplesamplingpositions,goodflexibility/redundancyandlowestinstallcostMETONE6000/7000SeriesDesignedtomeetISO21501requirements.BuiltforsterileprocessingenvironmentswithVHP-resistantoptics,automaticflowcontrolvalveandNEMA-rateenclosure(7000)Built-inusernotificationofmeasurementalarms,flowproblems,andsensorconditionMultiplecommunicationandmechanicalinstallationoptionsExternalalarmandenvironmentalsensorcapabilitiesreducemonitoringsystemcomplexityandcostsBuilt-inmemoryandHachOPCServerprovidecompletedatasecurityduringnetwork/computerproblemsFeaturingLongLifeLaser?technologyEnvironmentalSensorsMeasurementofTemp/RH,DifferentialPressure,AirFlowandTemperatureofFridges,FreezersandIncubatorsDifferentialPressureSensorTemp/RHSensorUpto1kmand1000channelsSimpleAsepticMonitoringSystemAutomatedIndependentcontrolofparticlecountersoneachfilllinePaperreportswithsignatureFillLineAFillLineBSoftwarewithDatabaseEasilyachievedusingenVigil-LiteorasimpleUltraVisionOnlineintegrationFullOnlineMonitoringSystemCombinedasepticproductionandfacilitymonitoringwithportabledatacaptureClient#1FillLineAServer/clientwithdatabasePortablesforcleanroomclassificationoronlinemonitoringFillLineAFillLineBGradeC&DmonitoringBuildingmonitoring,fillmachinecontrol,alarmindicatorsClient#2FillLineBClient#3QAorMicroPharmaceuticalFMSInstallationsManyhundredssince1987EverymajorpharmaceuticalcompanyoneverycontinentCaseStudy:

EvolutionofanAsepticOnlineSystemThree-phasedeploymentatGenzymeBiosurgeryPhase1:SinglefillinglinePhase2:AddsecondfillinglinePhase3:AddthirdfillinglineandgeneralfacilitymonitoringSystemenhancementswitheache