Canada guidance for PV of moist heat sterilization.docx

Canada guidance for PV of moist heat sterilization.docx

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CanadaguidanceforPVofmoistheatsterilization

Processvalidation:

moistheatsterilizationforpharmaceuticals（guidancefromCanada）

1.Introduction

TheHealthProductsandFoodBranchInspectorate（HPFBI）ofHealthCanadarecognizesthatterminalmoistheatsterilization,whenpractical,ispresentlyconsideredthemethodofchoicetoensuresterility.Forthepurposeofensuringsterility,allaqueous-basedsterileproductsaresubjecttoterminalmoistheatsterilization,withthefollowingexceptions:

Instanceswhereterminalmoistheatsterilizationisnotpractical,e.g.,productdegradation.Suchinstancesarefullyevaluatedanddocumented.Andforasepticprocessesthatexcludehumaninterventione.g.,robotics,form-fill-sealandbarriersystem,maybeemployedinlieuofterminalmoistheatsterilizationprovidingthatvalidationdatademonstratedequivalence.

Thisdocumentisintendedtoprovidemanufacturersofpharmaceuticaldosageformswithguidancetoestablishthescientificeffectivenessofmoistheatsterilizationprocesses,asrequiredinSectionsC.02.004,C.02.005,C.02.007,C.02.011andC.02.029oftheFoodandDrugRegulations.Theintentofthisdocumentisnottodetailspecificproceduresordefineelaboratemathematicalprincipleswhicharecriticaltothevalidationprocess,assuchinformationisreadilyavailablefromothersources;rather,thisguidelineisintendedasanoutlineoftheelementsinmoistheatsterilizationprocessesrequiringevaluation,anddescribesapproachestoeffectivelyaccomplishthisgoalinamannerwhichisacceptabletotheHPFBIofHealthCanada.Otherapproacheswhichachieveequivalentresultsmayalsobeacceptable.

Thesection17ofthisguidelinespecifiestheminimumdocumentationrequiredtocertifythatmoistheatsterilizationprocesseshavebeenthoroughlyevaluatedandareadequatelycontrolledandvalidated.Suchdocumentation,asidefrombeinginvaluabletothemanufacturer,isessentialtothespecialistsoftheHPFBIforthepurposeofinspectionandsubmissionevaluation.

Thisguidelineisapplicabletomoistheatsterilizationprocessesonly.Whiletheprinciplesoutlinedinthisdocumentaresharedwithothermethodsofsterilization,thoseprocessesrequirecontrolandassessmentofdifferentparameters.Itmustberecognizedthat,regardlessofthesterilizationprocess,thecontrolofmanufacturingenvironmentsandgoodmanufacturingpracticeswhichprovidebarrierstomicrobialcontaminationremainofutmostimportance.

Environmentsforthemanufactureofdrugssubjecttoterminalsterilization:

DrugssubjecttoterminalmoistheatsterilizationmaybeformulatedinagradeCenvironment,providedthattheformulatedbulkisimmediatelysubjectedtoitssubsequentprocessingstep,e.g.,filtration,sterilization,soastomaintainlowmicrobialandparticularcounts.FormulatingmaytakeplaceinagradeDenvironmentifadditionalmeasuresaretakentominimizecontamination,suchastheuseofclosedsystemsofmanufacture.

ParenteralsarefilledinanasepticareaofatleastagradeBenvironmentorinagradeAzonewithatleastagradeCbackgroundbeforeterminalmoistheatsterilization.

Non-parenteralsmaybefilledinagradeCenvironmentbeforeterminalmoistheatsterilization.

Note:

Thelimitsforthemicrobialcontaminationandforthemaximumnumberofparticules,inthe"atrest"and"inoperation"states,inrelationtodifferentgradesofairstandards,aredefinedintheHPFBIRevisedGuidanceforsectionC.02.029（SterileProducts）oftheGoodManufacturingPracticesRegulations.

2.ValidationApproaches

Thevalidationofmoistheatsterilizationprocessesmaybeperformedusinganyofthethreestrategiesoutlinedbelow.Theapproachselectedshouldbeappropriateandadequatelysupported.Itshouldbestressedthattheintegrityofthecontainer/closuresystembeestablishedpriortovalidatingthesterilizationprocesstoensurethatanappropriatecontainer/closuresystemhasbeenselected.

2.1ProspectiveValidation

Thisapproachappliestonewormodifiedprocessesandnewequipment.Thestudiesareconducted,evaluated,andtheprocessandequipmentsystemcertifiedpriortoinitiatingroutineproduction.

2.2ConcurrentValidation

Thisapproachappliestoexistingprocessesandequipment.Concurrentvalidationstudiesareconductedduringregularproductionandshouldonlybeconsideredforprocesseswhichhaveamanufacturingandtestinghistoryindicatingconsistentqualityproduction.Reworksandfailuresindicatepotentialinconsistenciesintheprocessandshouldbeevaluatedforeffectonthereproducibilityofproductionpriortoestablishingvalidationprotocols.

Althoughsuitablerecordsmaynotbeavailablefortheinstallationofequipment,lackofthisdatamaynotcompromisethebalanceofthestudies.

2.3RetrospectiveValidation

Thisapproachcanonlybeappliedtoexistingproducts,processesandequipmentandisbasedsolelyonhistoricalinformation.Normalprocessingrecordsgenerallylacksufficientdetailtopermitretrospectivevalidation.

a.Itmustbeestablishedthattheprocesswasnotmodifiedandthatthesterilizingequipmentisoperatingunderthesameconditionsofconstructionandperformanceasdocumentedintherecordstobeconsidered.Maintenancerecordsandprocesschangecontroldocumentsshouldbeavailabletosupporttheseclaims.

b.Periodsinwhichfailuresoccurredshouldnotbeexcluded.Theincidenceoffailuresorreworkingattributedtounsatisfactoryprocessingindicatesinconsistencyintheprocess.Thereshouldbeanevaluationoftheseconditionsfortheperiodtobeusedforvalidation.

c.Themanufacturing,maintenanceandtestingdatashouldbecapableofdemonstratingcalibrationofequipmentanddevices,andestablishinguniformityandconsistencyofsterilizingconditionsequivalenttothoserequiredinSections7through14.

Note:

AdditionaldetailedinformationinrelationtodifferentvalidationapproachesisprovidedintheHPFBIValidationGuidelinesforPharmaceuticalDosageForms.

3.ValidationProtocolDevelopmentandControl

Eachstageoftheevaluationoftheeffectivenessandreproducibilityofasterilizationprocessshouldbebasedonapre-establishedandapproveddetailedwrittenprotocol,developedinaccordancewiththevalidationapproachchosenasoutlinedinSection2.Awrittenchangecontrolprocedureshouldbeestablishedtopreventunauthorizedchangetotheprotocolorprocessandrestrictchangeduringanyphaseofthestudiesuntilallrelevantdataareevaluated.

Theprotocolshouldspecifythefollowingindetail:

3.1theprocessobjectivesintermsofproducttype,batchsize,container/closuresystem,andprobabilityofsurvivaldesiredfromtheprocess;

3.2pre-establishedspecificationsfortheprocesswhichincludethecycletime,temperature,pressuresandloadingpattern;

3.3adescriptionofalloftheequipmentandsupportsystemsintermsoftype,model,capacityandoperatingrange;

3.4theperformancecharacteristicsofeachsystem,sub-systemorpieceofequipmentinSection3.3;performancecharacteristicsincludingpressuregaugesensitivityandresponse,valveoperation,alarmsystemsfunctions,timerresponseandaccuracy,steamflowratesand/orpressures,coolingwaterflowrates,cyclecontrollerfunctions,doorclosuregasketing,andairbreaksystemsandfilters;

3.5fornewequipment:

installationrequirementsandinstallationcheckpointsforeachsystemandsub-system;

3.6forexistingequipment:

thenecessaryupgradingrequirementsoranycompensatoryprocedures;justificationforalternateproceduresshouldbeavailable;

3.7methodologyformonitoringtheperformanceofequipmentandoftheprocessasoutlinedinSections7through14;

a.alllaboratorytestingmethodology;

3.8thepersonnelresponsibleforperforming,evaluatingandcertifyingeachstageofthevalidationprotocolandforfinalevaluationpriortocertificationoftheprocess.

4.Personnel

Documentedevidenceoftheexperienceandtrainingofallpersonnelinvolvedinvalidationstudiesshouldbemaintained.

4.1Qualifiedpersonnelshouldensurethatthevalidationprotocolandtestingmethodologyaredevelopedinasoundengineeringandscientificmannerandthatallstudiesareproperlyevaluatedandcertified.

4.2Allpersonnelconductingtestsshouldbetrainedandexperiencedintheuseoftheequipmentandmeasuringdevices.

4.3Engineering/mechanicalpersonnelshouldbequalifiedintheoperationandmaintenanceofsterilizersandsupportsystems.

5.DataReviewandStudyCertification

Allinformationordatageneratedaspartofthevalidationprotocolshouldbeevaluatedbyqualifiedindividualsagainstprotocolrequirementsandjudgedasmeetingorfailingtherequirements.Writtenevidencesupportingtheevaluationandconclusionshouldbeavailable.

5.1Theevaluationsshouldbeperformedastheinformationbecomesavailable.

5.2Ifevaluationsshowthatthevalidationprotocolcriteriawerenotmet,theimpactontheprocessandthesuitabilityoftheprotocolparametersshouldbeinvestigatedandtheconclusiondocumented.

5.3Failuretoadheretotheprocedureaslaiddowninthevalidationprotocolmustbeconsideredaspotentiallycompromisingthevalidityofthestudyitself,andrequirescriticalevaluationoftheimpactonthestudy.

5.4Thefinalcertificationofthevalidationstudyshouldspecifytheestablishedprocessparameters.Thisinformationisrequiredforpost-validationmonitoringasdescribedinSection15.

6.LaboratoryConsiderations

6.1Alllaboratorytests,including"D"valueanalysis,shouldbeperformedbyacompetentlaboratory.Thelaboratoryshouldhavedetailedmethodologyandprocedurescoveringalllaboratoryfuncti