3/27/2012

CleaningProcesses andMicrobialControls
RebeccaA.Brewer Director,ConsultancyServices, V lid i &GMPCompliance C li Validation Dober 800.323.4983

FittingthatCleaningisFirst
Cleaningeffectivelyisourfirstandoneofourbestdefenses formicrobialcontrol Removecontaminationthataroseduringthe manufacturingeventbycleaning Preventtheintroductionofcontaminationduringthe cleaningprocessbycontrollingsupplies/conditions Eliminatesourcesoffoodandshelterforflora Eliminatewaterbydryingequipment Preventmicropropagationthroughproperstorage
Cleaningisthefirststepingetting readyforthenextprocess.

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WhatdotheRegulatorssay?
Microbialcontrolmeasuresincleaningand cleaning l i validation lid ti aremorepreventive ti in i natureratherthanfocusingontheremovalor destruction Designingaprocess/processequipmentfor cleanability yisacriticalfirststep p
DontforgetyourASME BioProcessingEquipmentstandards fordesigningforcleanability!

PrinciplesofHACCP
Conduct a Hazard Analysis Determine the Critical Control Points Establish Critical Limits

Risk Analysis
Establish Verification Procedures
Establish Preventive / Corrective Actions

Establish Monitoring Procedures

Risk Ri k Mitigation Miti ti

Risk Assessment Ri k A t
Althoughoriginallydeveloped forFood,goodcontamination controlprogramsallworkonthe sameprinciples.

Establish Record-Keeping

Monitor & Control Change

BPIDisinfectants Sept2003

Ongoing Evaluation

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ElementsofanEffectiveCleaning ProgramthatHelptoControlMicro
DirtyHoldTime ControloverCleaningAgents ControloverUtilities(Water,HVAC,Comp.Air) ValidatedCleaningProcesses OngoingMonitoring f dStorageRequirements Defined CleanHoldTime

DirtyHoldTime
Limitthetimeafterusebeforecleaning
Limitsmicrobialpropagationonsurfaces Limitsongoingenvironmentalexposure Preventsresiduesfrombecominghardertoclean andfallingoutsideofvalidatedprocess performance

Somefirmsrinseafterusethenhavealonger holdtimebeforecleaning
BEWARE!Micropropagationin residualwateronsurfacescanbe intense!

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ControlOverCleaningAgents
Pharmaceuticalcleaningagentsupplierscontroltheir formulations
Consistentmanufacture=validatedcleaning

Cleaningagentscancontainingredientsthathelpto removeordestroymicroorganisms:
CausticorAcid ChelantssuchasEDTA Surfactants Solvents

Getacommitmenttoconsistencyand changecontrolfromyourcleaning agentsupplier.

CleaningisNOTDisinfection
Whilesomeingredientsmayhavebactericidal effects cleaningisNOTdisinfection effects, Youneedtoremovesoilsfromsurfacebefore effectivedisinfectioncanbegin Disinfectionrequiresspecificadherenceto applicationmethodsandtimestogeneratekill Althoughnotdisinfection,cleaningcanhelpto flushorinactivatealargeportionofourbioload

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Cleaning&Disinfection DoNOTDepyrogenate
Primarysourceofendotoxinaregramnegative bacteria Primarysourceofgramnegativebacteriaiswater Destroyingthebacteriareleasesthe lipopolysaccharidesfromthecellmembranewhich haveapyrogeniceffect Pi th d to t d t hot h tcaustic ti for f Primary methods depyrogenate LONGperiodsoftimeordryheat
Result?Waterqualityiskey. DrywaterfromsurfacesASAP.

ControlOverUtilities
Criticalutilitiesusedincleaningincludewaterand compressedair Criticalutilitiesinholdtimesandstorageinclude HVACandhumidification Ensurethattheseutilitiesarequalifiedbeforeyou embarkoncleaningvalidationforthemost consistentcleaningandbioburdenresults
Utilityqualificationshouldincludeaspectsof bothchemicalandmicrobialqualityaswell assufficiency.

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ControlOverUtilities DuringCleaningValidation
Considerincludingcontrolsamplesforcritical utilitiesthatmightinfluencecleaning validationoutcomes:
Samplesupplysourceforrinsewater Collectcompressedairsamplesfromsourcefor dropsthatmightbeusedforblowingdown equipment q p

Cleanandstoreequipmentonlyinareaswith validatedHVACthathasanongoing monitoringprogram

ValidatedCleaningProcesses
Havingavalidatedcleaningprocessisyourbest defense ensuringcleaningissufficientfor:
Worstcasedirtyholdtimes Worstcasesoilloads Worstcaseprocessexcursionsinaction,time,temperature (aschallengedduringthevalidation) p Variationsbetweenpersonnel Worstcasecleanholdtimes

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WhatMakesa ValidatedCleaningProcedure?
T.A.C.T. CriticalProcessParameters
Time Action Concentration/Chemistry Temperature Water Individual NatureoftheSoil Surface

W.I.N.S. CriticalQualityElements

RegulatoryExpectations
Equipmentbioburdenvalidationwillbeincludedin yourcleaningvalidationprogram
Validationofbioburdenismorelikeafirststeponalong journeythanitisastudytocompleteandputinthe drawer SocalledRuleof3haslittlerelevancehere

Manyfirmskeeptheirequipmentbioburdensampling underaseparateprotocol Failuresinchemicalcleaninghavefewpotentialcauses; failuresinmicrobialvalidationhavemanypossible explanationsbecausemicroisliterallyallaroundus

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OngoingMonitoring
Monitoring:
Occursaftervalidationiscomplete Ensuresthatcleaningremainsconsistentover time(changesinpersonnel,training,wearin,etc.) Provestheefficacyofscientificapproachessuch asgroupingorbracketing Performed(mostcommonly)formanualcleaning processesduetoinherentvariability

ChallengeswithMonitoring
Studydesign:
Howmanyproductstostudy? Howfrequently? Whatnoninvasivesampling/testmethods canbeused? Allequipmentorasubset?
Monitoringisariskbasedstudydesign.

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LettheDataDirectYou
Whatproductsaremostlikelytohavehighbioloads afterprocessingoraftercleanholdtimes?
(e.g., (e g highwateractivityornonpreservedformulae)

Whatequipmentisdifficulttocleanordifficulttodry? Whatmaterialsofconstructionorsurfacefinishes mightharborcontamination? Whatequipmentisstoredinasusceptible environment?Orinatatriskfashion? Whatdidoriginalvalidationresultsshow? Whatdoespreviouslycollectedmonitoringdatashow?

RememberHACCPorsimilartools.

DefinedStorageConditions
Guidancesagreethatequipmentshouldbestored:
Dried Coveredorclosed

HVACshouldbepositivetosurroundings Equipmentshouldbeclearlytaggedwithexpiration Guidancecantcontrol(theseshouldbemanagedbyyourSOPs):

Organizationwithinthespace Personnelinterventionstofindequipment

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CleanHoldTime
Riskbaseddecisiondrivenby:
Definedstorageconditions Criticalityofpossibleparticulateandmicro residuestonextproduct Poststoragetreatment (e.g.,sterilization,preuseflush) CleanHoldTimehistoricaldata
Productbioburdenresults Equipmentbioburdenresults

EquipmentExpiration andthePreUseFlush
Justificationfornocleanholdtimeorfor prolonged l dclean l hold h ldtimes ti arefrequently f tl basedontheuseofapreuseflush Bewarethatyouensurethatthepreuseflush willbeaggressiveenoughtoremovethe p g potentialresiduesleftbehindafterstorage
(includingenvironmentaldust,microandendotoxin)

Proveit!Whatdoesyourmicrobial monitoringshowyou?

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KeystoSuccess
Soundriskbaseddecisionmaking
Documented PeriodicallyReevaluated

Monitoringtoproveongoingconsistency
Rememberflorachangeandadapt Trendingandinterpretation

Questions?
RebeccaA.Brewer Director,ConsultancyServices, Validation V lid i &GMPCompliance C li Dober 800.323.4983

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