Unit1 CleaningValidationValidationand Verification ofCleaningProcesses

Trainer:ChandramouliR

Rationale...

Thebasicreasonforhavinggood,effective, consistentcleaningproceduresistopreventthe contaminationofproductsmadesubsequently inthesameequipment.

MECHANISMSOF CONTAMINATION

CrossContaminationwithActiveIngredients MicrobiologicalContamination ContaminationbyCleaningorSanitizingAgents ContaminationbyMiscellaneousOther Materials

Typeoffacilityvs.degreeofriskof crosscontamination

ChangeoversforAPIFacilities

Switchfrombatchtobatchforsameproduct(campaignsituation) Switchfromfinalstepofoneproducttofinalstepofdifferentproduct Switchfromfinalstepofoneproducttointermediatestepofa differentproduct Switchfromfinalstepofoneproducttoinitialstepofadifferent product Switchfromintermediatestepofoneproducttofinalstepofanother product Switchfromintermediatestepofoneproducttointermediatestepof anotherproduct Switchfromintermediatestepofoneproducttoinitialstepofanother product

ChangeoversforAPIFacilities...

Switchfrominitialstepofoneproducttotheintermediatestep ofanotherproduct Switchfrominitialstepofoneproducttothefinalstepof anotherproduct Switchfrominitialstepofoneproducttotheinitialstepof anotherproduct

DosageFormChangeovers

Changeoverfromonebatchofaproductto anotherbatchofthesameproduct Changeoverfromoneproducttoadifferent product Changeoverfromonestrengthofaproducttoa differentstrengthofthesameproduct Changeoverfromaproductgivenbyoneroute ofadministration(oral,topical,ophthalmic,etc.) toaproductgivenbyadifferentrouteof administration

ORGANIZINGCLEANING VALIDATION

riskbasedrationalesincludedincleaning validationprograms strongpoliciesrequiredtohelpdrivethe decisionmaking How?MasterValidationPlanforCleaning

MasterPlan

Provideanoverviewofthesite/facility/areathat isgovernedbytheMasterPlan Provideanoverviewofthetypical manufacturingprocess(es)thataretobe performedintheareaandthedosageforms thatareproduced Provideanoverviewofthetypesofcleaning thataretobeused(e.g.,automatedCleanIn PlaceorCleanOutofPlace,semiautomated cleaningormanualcleaning)

MPCLV

Providetheresponsibilitiesofthevariousdepartments havingaroleincleaningvalidationactivities Providetheminimumrequirementsforthecleaning validationprogram,including:

Necessaryscientificrationalesinsupportofthe program:

Residueselection Equipmentcharacterization Productcontactsurfaceareacalculation Limitscalculation Samplesiteselection

Productgrouping(ifany)

Equipmentgrouping(ifany)

SupportprogramsforCLV

Requiredstudiesinsupportoftheprogram:

Analyticalmethodsvalidation Samplingmethodrecoverstudies Cycledevelopmentforcleaningprocesses

EssentialProgramsthatmaintainthevalidated stateandtheirrequiredelements:

Cleaningandtesting,ifany,tobeconducteduponthe introductionofneworrepairedequipment Monitoringofcleaningaftervalidationcompletion

SupportforCLV

Routinelyconductedcomplianceinitiativeson sitethatmaintainqualityandwillaffectthe companysabilitytomaintainthevalidatedstate

Failureinvestigation Changecontrol Preventivemaintenance Calibration Revalidation

SOPsforCV

ImportantSOPsGoverningCleaningand CleaningValidation

DevelopmentofcleaningSOPs(especiallyfor manualcleaningoperations) Equipmentcleaninganduselogs Visualinspectionrequirementsforcleaned equipment Equipmentquarantineandrelease Equipmentsamplingproceduresforcleaning assessments(e.g.,swab,rinse,etc.)

Cleaningvalidationprocessflow

Validationvs.Verification

documentedevidenceto ensurethatcleaningprocedures areconsistentlyremoving residuestopredetermined levelsofacceptability,taking intoconsiderationsuch elementsasbatchsize,dosing, toxicology,equipmentsize,and thelike.Acleaningvalidationis typicallycompletedbythe accomplishmentofaminimum ofthreeconsecutivesuccessful trials.successfultrials.

documentedevidencetoensure thatcleaningprocedures removeresiduestoa predeterminedlevelof acceptabilitybaseduponthe minimumofasingletrial.Is performedtoassurethatthe cleaningproceduresused adequatelycleantheequipment whenthemanufacturing processorthecleaning proceduresmaybesubjectto change,andthereforecannot beimmediatelysubjectedto validation

Campaignmanufacturing

Campaignproductionisthemanufactureoflots ofthesameproductinaconsecutivefashion suchthat:

(i)nocleaningisperformedbetweenbatches(typicalofAPImanufacture,
forexample), (ii)sufficientcleaningisperformedtoensuremechanicalfunctionalityofthe equipmentbutequipmentdoesnotreachavisiblycleanlevel(also commoninAPImanufacture), (iii)cleaningisconductedtoavisiblycleanlevelwithlimitedtono disassemblyoftheequipment(commontooralsoliddosemanufacture), (iv)fullcleaningisconductedofproductcontactsurfaces,butcleaning environmentalsurfacesandchangeoutofproductassociateddisposable parts(e.g.,gaskets,hoses)isnotperformeduntilendofcampaign (commontohighpotencyproductsand/orproductsassociatedwith morestringentdosageforms).

ResidueIdentification

API(s) Constituentsofthe cleaningagent Preservatives Precursorsorstarting materials Intermediates Processingaids Media Buffer

Cellulardebrisormetabolites Particulate Bioburden Endotoxin Viralparticles TSE Excipients Colorants,dyes,flavorsor fragrances Andmanymore!

Residue...

thoseresiduesthatarepertinenttodosageformor process thoseresiduesthatarethemostactive/toxicand thereforerepresentthemostrisktothenextpatient thoseresiduesthatwoulddamagethequality,purity, efficacy,appearanceofthenextbatchproduced thoseresiduesthatwoulddamagethenextprocess (e.g.,waterinahydrophobicprocess) thoseresiduesthatarethehardesttoremove(difficult toclean

MajorSamplingTechniquesand TheirAttributes

TypicalCleaningValidationAssay Methods

Determination

Commonlycitedlimitsinliteratureandinregulatoryguidance documents thesurfaceoftheequipmentmustmeettherequirementsof being:

Visiblyclean Notmorethan1/1000thofatherapeuticdoseinthe nextbatch,or Notmorethan10ppminthenextbatch,whichever ofthelattertwolimitsislower. Worldwideregulatoryguidelinesindicatethat manufacturersmustdefinetheirownlimitsfor cleaningvalidation.

Equation1:1/1000thofa TherapeuticDoseApproach

Equation2:TypicalUnitsforthe 1/1000thofaTherapeutic DoseApproach

Equation3:SafetyBasedLimit ApproachforAPIStarting MaterialsandIntermediates

Equation4:Fractionofan Interfering/Enhancing SubstanceApproachforinVitro Diagnostics

Equation5:NotMoreThan10ppm intheNextBatch

Equation6:TypicalUnitsfor10ppm Limit

InterpretingCLVresults...

Theequationforthelimitandtheequationfor theresultareoneithersideofacomparator. Limit>Result Baseduponequations(1),(3),(4),and(5),the termsfortheresult

Equation7:TermsfortheResult

Equation8:TypicalUnitsforthe Result

Equation9:SettingmGlimits

Equation10Settingpersample limits