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ProcessValidation: PracticalAspectsofthe NewFDAGuidance

ISPEBostonChapterMeeting April18,2013 RustyMorrison CommissioningAgents,Inc.

Objectives/Summary
WhatisProcessValidation? RegulatoryBasisandGuidanceDocuments Definitions ReviewoftheFDA2011PVGuidance ApplyingNewGuidancetoOldProducts

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RegulatoryBasis
21CFR211.110a: ... control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of inprocess material and the drug product.
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ProcessValidation OldDefinition
Process validation is establishing documented

evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.

GuidelinesonGeneralPrinciplesofProcessValidation,FDA(1987)
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NewFDAProcessValidationGuidance
InJanuary, 2011FDA issuednew guidancefor industry regarding process validation

ProcessValidation Today
NewFDAguidancefocusedonproductqualitythroughprocess understandingandcontrol:

Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product. (emphasisadded)
GuidelinesforIndustry ProcessValidation:GeneralPrinciplesandPractices FDA(January2011)
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ProcessValidation Today
Summaryofsignificantchanges:
Addemphasistoprocessdesign Includesdiscussionofrisk Involveactivitiesoverentireprocesslifecycle(ongoing program,inthreedefinedstages) Emphasizesroleofobjectivemeasuresandstatisticaltools Emphasizesknowledge,detectionandcontrolofvariability

Asalways,newguidancewilltaketimetoworkits waydowntotraditionalprocessvalidation
Howtoapplynewguidanceforlegacyproducts?

EMADraftProcessValidationGuidance
InMarch2012 FDAissueda draftguideline forprocess validation

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USFDAvs.EMA
Significantdifferencesexistbetweentheissued FDAguidanceanddraftEMAguideline Theremainderofthispresentationwillbebased ontheFDAguidance.

Definitions

ManufacturingProcess
Thesequenceofactivities,people,andsystemsinvolved incarryingoutsomebusinessorachievingsomedesired result.

INPUTS Process

OUTPUTS

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Definitions
ProcessParameters(akaOperatingParameters)
Theconditionsunderwhichaprocessisperformed Canbephysicalorchemical
pH,temperature,pressure,agitatorrpm,flowrate,etc.

Processparametersareusuallycontrolled withindefined operatingrangestosetpointvalues

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Definitions
CriticalQualityAttributes(CQAs)
Aphysical,chemical,biological,ormicrobiologicalproperty orcharacteristicthatshouldbewithinanappropriatelimit, range,ordistributiontoensurethedesiredproduct quality.(ICHQ8) NotalloutputsareCQAs
Process Parameters INPUTS Process CQAs
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OUTPUTS

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Definitions
CriticalQualityAttributes(CQAs)
Acronymsforappropriatelimit,range,ordistribution
AcceptanceCriterion(plural:Criteria) Specification

Process Parameters INPUTS Process CQAs

OUTPUTS

Definitions
Critical(orKey)ProcessParameters (CPPs)
Aprocessparameterwhosevariabilityhasanimpactona criticalqualityattributeandthereforeshouldbe monitoredorcontrolledtoensuretheprocessproduces thedesiredquality(ICHQ8) Example:pHduringionexchangechromatographysteps
Process Parameters INPUTS Process CQAs
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OUTPUTS

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Definitions
NonCritical/NonKeyProcessParameters
Thoseprocessparameterswhichdonothaveadirect impactonproductquality Example:Flowrateduringbioreactorinoculation

Process Parameters INPUTS Process CQAs

OUTPUTS

CPPsandCQAs

CPPs Typically, setpoint with an operating range Inputs Controlled to achieve consistent, repeatable, reliable results

CQAs Acceptance Criteria / Specifications Outputs Used to demonstrate process control, repeatability, and reliability

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ProcessValidation NewGuidance
KeyConcepts:
Understandthesourcesofvariation Detectandmeasuresourcesofvariation Understandtheimpactofvariationontheprocess andfinalproductattributes Controlthesourcesofvariationcommensuratewith therisktheyrepresenttotheprocessandfinal productattributes

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ProcessValidation NewGuidance
Processvalidationinvolvesaseriesofactivities takingplaceoverthelifecycleoftheproduct:
Stage1:ProcessDesign Stage2:ProcessQualification Stage3:ContinuedProcessVerification

Manyactivitiesoccurinmorethanonestage (thinklifecycle)

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Stage1:ProcessDesign
Thecommercialmanufacturingprocessisdefined duringthisstagebasedonknowledgegained throughdevelopmentandscaleupactivities

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Stage1:ProcessDesign
Element1:Building/CapturingProcessKnowledge

QualityTargetProductProfile(ICHQ8)
Intendeddosageform Routeofadministration Expecteddrugproductqualityattributes Generalmanufacturingpathway

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Stage1:ProcessDesign
Element1:Building/CapturingProcessKnowledge

Activities(Characterization)
DesignofExperiments
DesignSpace/ControlSpace

RiskAssessments Laborpilotscaleexperiments Computermodeling

Documentationofresultsisessential

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Stage1:ProcessDesign
Element2:EstablishProcessControlStrategy

Controlsourcesofvariation
Reduceinputvariation Adjustforinputvariationduringmanufacturing Combinationofboth

ProcessAnalyticalTechnology(PAT) implementation

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Stage2:ProcessQualification
Theprocessdesignisevaluatedtodetermineifthe processiscapableofreproduciblecommercial manufacturing

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Stage2:ProcessQualification
Element1:Utility/EquipmentQualification

Demonstrationthatutilitiesandequipmentare suitablefortheirintendeduse,andperform properly.

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Stage2:ProcessQualification
Element2:ProcessPerformanceQualification(PPQ)

Thisstagehastraditionallybeenknownas conformancerunsordemonstrationbatches AmanufacturermustsuccessfullycompletePPQ beforecommencingcommercialdistributionof thedrugproduct ApproachtoPPQshouldbebasedon

Stage2:ProcessQualification
Element2:ProcessPerformanceQualification(PPQ) Inmostcases,PPQwillhaveahigherlevelof sampling,additionaltesting,andgreaterscrutinyof processperformancethanwouldbetypicalof routinecommercialproduction Theincreasedlevelofscrutiny,testing,andsampling shouldcontinuethroughtheprocessverification stageasappropriate,toestablishlevelsand frequencyofroutinesamplingandmonitoringfor theparticularproductandprocess.
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Stage2:ProcessQualification
Element2:ProcessPerformanceQualification(PPQ)

HowmanyPPQruns?
Considerationsforthedurationoftheheightened samplingandmonitoringperiod:
volumeofproduction processcomplexity levelofprocessunderstanding experiencewithsimilarproductsandprocesses

Morevariability moreruns Moreuncertainty moreruns

Stage2:ProcessQualification
Element2:ProcessPerformanceQualification(PPQ)

PPQProtocol
Manufacturingconditions Datacollectionandevaluation Testing,includingacceptancecriteria Samplingplan
Intra andinterbatchquality

PPQReport
Summarizedata/resultsfromPPQruns Stateaclearconclusionregardingstateofcontrol
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Stage2:ProcessQualification
Element2:ProcessPerformanceQualification(PPQ)

ReleaseofPPQBatches
Normally,completionofallPPQbatchesand approvalofPPQreportsisrequiredfor commercialdistributionofaproduct Underspecialcircumstances,concurrentrelease ofPPQbatchesmaybeacceptable
Infrequentlymanufactured(orphandrugs) Shorthalflives Drugshortage
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Stage3:ContinuedProcessVerification(CPV)
GoalofCPV:Continualassurancethattheprocess remainsinastateofcontrol(thevalidatedstate) duringcommercialmanufacture

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Stage3:ContinuedProcessVerification(CPV)
Howisthisaccomplished? System(s)fordetectingunplanneddepartures fromtheprocessasdesigned Ongoingprogramtocollectandanalyzeproduct andprocessdatathatrelatetoproductquality
Processtrends Inprocessmaterial Finishedproducts

Statisticaltrendingwithreview
StatisticianorpersonwithSPCtraining
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Stage3:ContinuedProcessVerification(CPV)
Othermeanstodetectvariation
Deviations/nonconformances OutofSpecificationresults Batchrecords Defectcomplaints Adverseeventreports etc.

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Stage3:ContinuedProcessVerification(CPV)
FDArecommendscontinuedmonitoringand samplingofprocessparametersandquality attributesatthelevelestablishedduringPPQuntil sufficientdataisavailabletogeneratevariability estimates. Theseestimatescanprovidethebasisfor establishinglevelsandfrequencyofroutinesampling andmonitoringfortheparticularproductand process. Monitoringcanthenbeadjustedtoastatistically appropriateandrepresentativelevel.
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ProcessValidationSampling
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AmountofSampling
8 6 4 2 0

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LotNumber

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ApplyingNewGuidancetoOldProducts
ApprovedproductimpliesthatStages1and2 complete HowtoimplementStage3
Thegoalofthethirdvalidationstageiscontinual assurancethattheprocessremainsinastateofcontrol (thevalidatedstate)duringcommercialmanufacture. Asystemorsystemsfordetectingunplanned departuresfromtheprocessasdesignedisessentialto accomplishthisgoal.
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ApplyingNewGuidancetoOldProducts
Theory:Continuetogainknowledgethroughout productlifecycle
Manufacturingexperienceshouldyieldincreased knowledgeandprocessimprovements Lackofprocessimprovementsindicateslackof processunderstandingandfailuretolearn(implement learning)

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ApplyingNewGuidancetoOldProducts
Practice:Dontfixitifitsnotbroke
Traditionallymanufacturersarereluctanttochangea processoncevalidated Reluctancetolookbackwardatreleasedlots(what willwefind?) Analysis,trending,andassessingvariabilityare typicallyadhoc Onlyimpetusforchangeweredeviations/OOS results

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ApplyingNewGuidancetoOldProducts
Challenge:IdentifyingCPPsandCQAs Sources:
Originalprocessvalidation Specifications Batchrecords/SOPs Deviations/CAPAs/ChangeControls

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ApplyingNewGuidancetoOldProducts
Challenge:ObtainingData
Executedbatchrecords Annualproductreview

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ApplyingNewGuidancetoOldProducts
Challenge:EstablishingaCPVProgram
Howwilltheprogrambesetup? Whowillimplementit?
Whataretherequiredqualifications?

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ApplyingNewGuidancetoOldProducts
Recommendations
Assembleamultidisciplinaryteam
Validation,PD,Manufacturing,QA,QC

Getabasicprograminplace(SOPorValidation Plan?)
Datacollection/recording Plotting Analysis Responsetooutofcontrolresults ReportingFrequency(review&approval)? Pathwayforprocessimprovements

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ApplyingNewGuidancetoOldProducts
Recommendations
SmallSteps
Obtaindata,eitherretrospectivelyorprospectively Plotdatawithspecificationlimits Lookforobviousissues: Trends Visualmeanvalueoffsetfromtargetor specificationcenterline Bimodalresults Insufficientresolution(pHonlyrecordedto0.1unit)
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ApplyingNewGuidancetoOldProducts
Recommendations
SmallSteps,continued
Assessnormalityofdata Establishcontrollimits(2030datapointsneeded)

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ApplyingNewGuidancetoOldProducts
OtherChallenges
SPCassumesprocessisinastateofstatistical control.However,noteveryelementofevery processwillbe. Dataisnotnormallydistributed
Observedvariationwellwithinspecificationlimits

Dataindicatesspecificationlimitexcursionsare likely

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ApplyingNewGuidancetoOldProducts
Challenges:Artifactsarefoundindatareview:Trends

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ApplyingNewGuidancetoOldProducts
Challenges:Artifactsarefoundindatareview:BimodalResults

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References
GuidelinesforIndustry ProcessValidation:General PrinciplesandPractices FDA(January2011) EMADraftGuidelineonProcessValidation (March2012) ICHQ8:PharmaceuticalDevelopment(QBD) ICHQ9:QualityRiskManagement ICHQ10:PharmaceuticalQualitySystem ASTME2500:StandardGuideforSpecification,Design,and VerificationofPharmaceuticalandBiopharmaceutical ManufacturingSystemsandEquipment PDATechReport60:ProcessValidation ALifecyle Approach PDATechReport59:UtilizationofStatisticalMethodsfor ProductionMonitoring
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OtherResources
ISPEProcessValidationDiscussionPapers (http://www.ispe.org/publications/discussionpapers) ISPEProductQualityLifecycleImplementation(PQLI)Guides ISPECommunitiesofPractice

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Questions/Conclusions

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