Design of a Process Qualification and Continued Process ...

1 Design of a Process Qualification and Continued Process VerificationProgram within an Enhanced Development FrameworkCiaran Brady, PhDEli Lilly & Co. Overview control Strategy Development: enhanced Process understanding PPQ Approach Continuous verification/ monitoring Summary Questions2*BioPhorum Operations Group: Paper on Continuous Process Verification: An Industry Position Paper with Example PlanStage 1: control Strategy EvolutionPatient Needs Business Needs Product DesignProcess DesignTechnology TransferProcess Validation/ Process Performance QualificationResearch and clinical Studies Commercial ManufacturingCPV Product LifecycleQTPPP rocess Characterization: cqas , cpps , PARsContinued Process Verification: Maintaining the validated stateProcess Validation (PPQ batches)Stage 1 Stage 2 Stage 3 Increasing Process Understanding/ control Strategy EvolutionControl StrategyQbDWork Flow Leading to control Strategy and CPVPROCESS & ANALTICAL DEVELOPMENTPRODUCT DEVELOPMENTPROCESS & ASSAY IMPLEMENTATIONMANUFACTURING& LIFE CYCLE MANAGEMENTTPPQTPPCQAPIAVMPPCC lassP&A CSPPQI ntroCPMCPVSDMCPIComEngControl StrategyTPPQTPPCQAPIAVMPPCC lassPCSPPQI ntroCPMCPVSDMCPIComEngTarget Product ProfileQuality Target Product Profile (QTPP)Product Quality Attribute Assessment (Identification of cqas ) Process Parameter Impact AssessmentProcess Development and Validation Master PlanningScale-down Model Development and CharacterizationProcess Characterization )Parameter (Criticality) Classification)

2 Engineering DesignProcess IntroductionEquipment Commissioning/ValidationProcess Performance QualificationContinuous Process MonitoringContinued Process VerificationContinuous Process Improvement cqas IPCs PARs/MARs CPPsProduct-specific control Strategy56 Science and Risk Based approach to develop comprehensive control KnowledgeProcess UnderstandingProduct UnderstandingProcessDevelopmentRiskAsses smentProcessCharacterizationRiskAssessme ntRiskAssessmentProcessPerformanceVerifi cationRiskAssessmentLife CycleManagementFinal ControlStrategyProcessParametersQualityA ttributesDesign SpaceDraft ControlStrategyProcess 2 Process 1 2 Process Development and Characterization Scheme7A-mAb Systematic of prior platform knowledge and Process risk assessments to identify those steps that need additional that laboratory scale models are representative of the full-scale operations to determine parameter of Process parameters to product Quality Attributes to create a Design of statistical tools to model data risk assessment and categorization of Process parameters to develop control strategyAggredatesFucosylationGalactosyl ationCEX AVHCPDNAN-1 BioreactorFeedGlucose FeedProduction BioreactorHarvestMediumProceduresTempera turepHSeedIn Vitro Cell AgeSeed DensityViabilityOperationsTime of FeedingVolume of FeedPreparationConcentrationpHAgeDOpHTem peratureCO2 AgitationShear/MixingGas TransferAirflowAntifoamScale EffectsAmount DeliveredNumber of FeedsTimingPreparation[Glucose]Osmolalit yConcentrationProceduresAgeDurationWorki ng Volume[NaHCO3]Pre-filtration hold timeStorage Temperature[Antifoam]

3 ProceduresAgeStorage TemperaturePre-filtration hold timeFiltrationFiltration# of ImpellersVessel DesignBafflesControl ParametersOperationsImpeller DesignSparger DesignNominal VolumneTox500 LPhI/PhII1,000 LOptimization DOE I - 2 LOptimizationDOE II - 2 LPhIII5, s olv Ratio9095100105110100 Basal Strength(Dilution)400420440460480440Os mo9095100105110100 Feed Strength(Dilution) ProfilerHolistic Process control Strategy Forms the Basis for Process Validation CQA criticality Risk AssessmentProcess capabilityRisk AssessmentIn Process testingRisk AssessmentFacility based microRisk AssessmentFacility Fit & Equipment Capability% MonomerHCP rPrACEX VariantsMS VolumeYieldConcentrationpHConductivityCo lumn PackStep ElutionLoadBed HeightQuality Parameters(HETP, Asym.)pH[NaCl]Resin Load (g/L resin)Flow RatepHCVs[Tris]Flow RateVolume[Acetic Acid]Contact TimeFlow RateVolume[NaCl]pHAge & Use History[NaOH]Contact TimeVolume (CV)FrequencyPre-use CleaningProduct, mg/mLVolumeHigh Salt WashRegenerationCharge % MonomerHCPrPrACEX VariantsConcentrationVolumepHConductivit y6 Capto d e esboepH[NaCl]FS Cut[Acetate][NaCl]BS CutFlow RatePre-Equil &EquilibrationSanitization[NaOH]VolumeFl ow RateContact TImeFrequencyFrequency 96979899100MS % pH2025303540455040 Load507090110130150100 Elution[NaCl]0501001500Eq/Ch/Wash [NaCl]200250300350400300 Flow , cm/hrPrediction Profiler Product/ Process Attributes Parameters control Points Matrix.

4 Defines the PPQ validation Quality Attribute CQAP roduction BioreactorProtein ALow pH/VICEXAEXN anofiltrationUF/DFCompoundingFiltrationF illing, stopper, capTesting elementsAggregateYesFormRemoveFormRemove RemoveFormFormLRDeamidated isoformsNoFormPMOligosaccharideYesFormPM CHO HCPYesFormRemoveRemoveRemoveRemovePMDNAN oFormRemoveNoneProtein ANoFormRemoveRemoveNoneViral safetyYesInactClearClearBiorx. IPC Unit Operation functional claims Parametric Controls: cpps / OPPs In- Process hold times Testing Strategy IPCs and validation limits Biochemical testing Microbiological testing IP Specifications Release specifications Demonstrate consistent Process performance over 3- 5 consecutive lotsOther Elements to Stage Reprocessing PV Protocol Final Filtration Reprocessing PV Protocol Downstream PV ProtocolColumn 2 Lifetime PV ProtocolMembrane Lifetime PV ProtocolColumn 1 Lifetime PV ProtocolUpstream / DownstreamApproval to ValidateDS ProcessingUpstream PV ProtocolViral Clearance ValidationComparability Protocol Stage 3: CPV Program OverviewAnnual Product ReviewTech rep presence on the floor and at Operations meetingsCross functional data review meetingsOngoing (quasi) real time SME monitoring of parameters and attributesObjective.

5 Demonstrate ongoing assurance that Process remains in state of control for commercial manufacturingUpstream & Downstream Process Monitoring (~150 additional parameters/ attributes)Ongoing Process Validation/ Verification (~100 parameters/ attributes)Critical parameter and Process consistency indicators: trending and assessment of state of controlProcess Monitoring Report after each campaignOrthogonal/ leading indicators of Process performanceData oversight Establish control limits when Process variability established (~30 lots) Measure of Process capability (CpK) Drives continuous improvement to improve robustness (if needed) Process Data acquisition and analysisHistorianManualData EntryAnalysis / ResultsReadOnlyLIMSSAPS ource SystemsMDIPI SADH ierarchyProcess DrivenRoadmap for CPVA nnualQuantitativeVariablesEventsCQAsCPPI PCC hangesDeviationsComplaintsCPVPROTOCOL respond toperformancecorrelate events vs. CQAsand facilitate PQR/APRCPVREPORT capture datamaintaincontrol chartsquantifyvariabilityreassess variables andupdate control limitsrespond toexcursionsrespond to trends, shiftsBatchPeriodic| IBEC PharmaChem Ireland | Fionnuala Langford, Novartis | 15 Jun2015 | Business Use OnlyPerformance IndicatorsStage 3a and 3b: reduced testing once variability established14 Stage IStage IIStage IIID evelopmentValidation: PPQC ommercial Mfg: CPVIIIaIIIbHeightened Sampling & Testing until variability establishedRoutine Monitoring Program110310030100030010000300010000030 0001000000300000100000003000000 QualityAttribute 2 ABDFGUnit operationOneway Analysis of Quality Attribute 2 By Unit operationKey control points: Unit operation D Unit operation FNo change during DS storage or DP manufacturing and storage024681012 QualityAttribute 3 DFGUnit operationOneway Analysis of Quality Attribute 3 By Unit operationKey control point.

6 Unit operation GNo change during DS storage or DP manufacturing and storageSpikeResidualUnit Operation F2x<LOQ5x<LOQUnit Operation G2x<LOQ5x<LOQS pikeResidualUnit Operation G2x<LOQ5x>LOQR emove from in- Process and DS analytical testing after variability establishedRemove from in- Process analytical testing after variability establishedInclude in enhanced DS analytical testing programPreventativeMaintenanceandCalibra tionEnsuresequipmentandsystemsaremaintai nedin a ,measureandanalysemanufacturingprocesses andproducts,usingstatisticaltechniques,o na ,equipment,methodorprocessareevaluatedto ,determinationoftherootcause,documentati on,identificationandimplementationofanyr esultantcorrectiveactionandpreventiveact ions(CAPAs)foralldeparturesPeriodicRevie wofFacilities,Utilities,EquipmentandComp uterSystemsEvaluatetrends,comparedatawit hhistoricalinformationtodetermineshiftsa ndassessthestateofcontrolofthefacility,u tility, within the Quality System key to maintain the validated Change Management Process changes can result from following: Low Process capability Special cause variability Monitoring program detects Process shift/ trend Process optimization to improve yields Raw material supplier change or second source New working cell bank Equipment changes Scale-up or Qualification of second site Changes assessed based on risk and science, controlled via change management system Small scale model data may be required to support Assess impact to control strategy and validated state Assess regulatory reporting category based on registered commitments and impact to control strategy16*BioPhorum Operations Group.

7 Paper on Continuous Process Verification: An Industry Position Paper with Example PlanSummary Enhanced development program results in well understood, holistic and robust control strategy development PPQ program demonstrates Process performance consistency prior to commercial manufacture CPV program and quality systems ensure Process remains in state of control and continuous improvement opportunities identified and implemented appropriatelyResults in a well understood and controlled Process that produces high quality medicine over the lifecycle of the product17 Lessons Excellent feedback from regulators on control strategy and validation approach Strong regulatory and business drivers to adopt QbDapproach Strong data packages will allow for some regulatory relief Testing strategies: validate out Process -related impurities Learning and open questions Non- cpps expected as commitments in and What parameters to pick? 2 tier parameter classification system does not line up with this approach Significant variability in these requirements exist between regulatory bodies Requirements emerging for additional data/ risk assessments: examples raw materials, extractablesand leachables Release specifications: balance between manufacturing history and clinical history Common cause variability at time of filing may not be completely understood: examples: raw material variably and impact charge and glycosylation variants PALM plan: consider including elements in filing: address in Q1218 AcknowledgementsMike De FelippisTongtong Wang/ BR&DRA-CMC ColleaguesMatt OsborneGraham McCartneyStephen GalvinTheresa AhernMarie MurphySeamus Malone20