Reference Standards: Overview And Strategy For Development .

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Reference Standards: Overview and Strategy forDevelopment to CommercializationJohn RueschAnalytical Research and DevelopmentCASSS / WCBP CMC Strategy Forum: Reference Standards For Therapeutic ProteinsJuly 16th 2013

Topics Covered Review of guidance and regulationsRoadmap (timing, logistics and lessons learned)Characterization TechniquesReference Standard Monitoring and Recertification2

ICH Guidance on Reference Materials“For drug applications for new molecular entities, it is unlikely that aninternational or national standard will be available. At the time of submission,the manufacturer should have established an appropriately characterized inhouse primary reference material, prepared from lot(s) representative ofproduction and clinical materials. .which will serve for biological andphysicochemical testing of production lots.”“The results of biological assays should be expressed in units of activitycalibrated against an international or national reference standard, whenavailable and appropriate for the assay utilized. Where no such referencestandard exists, a characterized in-house reference material should beestablished and assay results of production lots reported as in-house units.”3

Reference Standard Strategy is a Key ProcessDuring Development Minimize the number of reference standards during development Alignment of cell line and process development is critical Maximize the use heightened characterization data of ReferenceStandard in filings by using it in S.3.1 Elucidation of Structure Reference Standards are the bridge back to non-clinical data Reference Standard is always used during comparability exercisesduring development4

Project Cost / Snapshot FTE Cost (*)Alignment of Reference Standards andDevelopment ParadigmBLA-FiledVarious stages during development require more effort (*)and havinga reference standard strategy that aligns with a streamlineddevelopment paradigm is critical*Launch*EarlyDevelopmentPIII t*CandidateTox*Final LaunchPreparationsPhase 1Phase 2Phase 3BLAR Dufield at SBE Conference 2013

Early Development RoadmapINDDraftPre-clinicalRMPilot campaign(Reg Tox)“Release”Testing ofPilot DSINDRM batchselectionand vialingclinical campaign(GMP)RM CharacterizationRM Report Writing/Data VerificationRM reportreview/approval/signoffInventory Control/Expiry/Recertification6

Early Development Project Logistics Drug Substance batch(s) used in non-clinical studies is established as thefirst reference standard Pre-clinical batch(s) use Pre-MCBPlatform manufacturing and purification same as GMP batch but smaller scale Approximately 10 g of material will be required for reference standard (e.g.,4000 vials at 2.5 mg/vial); actual amount will depend on product(concentration, etc.) Reference standard is diluted if the concentration is greater than 50 mg/ml Initial reference standard is used to release clinical batches, establishingcomparability between Toxicology and Clinical batches Data generated during reference standard characterization will be used topopulate S.3.1 in regulatory filings7

Early Development Process: Filling, Storage andMaintenance Reference is filled, stored and maintained and distributed by the QC/Stabilitygroup Pedigree of Drug Substance batch(s) is maintained for all reference standards Filled in PP cryrovials and stored at -70C. Extractable and leachable studies were conducted on vial types to determinesuitability.Automated or manual filling and labeling is utilized8

Early Development Process: Filling, Storage andMaintenance Homogeneity/Uniformity testing is required on filled material to establishconcentration Concentration typically determined by A280 and AAA used to confirm Reference Standard is monitored on stability as a special arm / condition or testedfor recertification 24 month initial use period is given to reference standards Liquid stability is established by leveraging formulation development data Minimum of 100 reference standard vials are maintained through out development BioTherapeutics Development ReferenceStandards are managed in Chesterfield, MOChesterfield, Missouri 40 Reference Standards filled annually Approximately101 Active Reference Standardsequivalent to 290K vials9

LIMS System is Critical in ManagingDevelopment Reference StandardsDevelopment reference standards are managed in PFE LIMS in order to providea single global repositoryBenefits include: Enhanced compliance for approvals, inventory control and trackingOne interface for all ref std tasks: Testing, requests, distribution, inventory, certificates Global inventory and orderingAuto-notification for standard requests and distributionAuto-notification for low inventory levelsElectronic Signatures for authorizing & activatingEnhanced ability to query, track and monitor re-evaluation dates10

Reference Standard Characterization DataPopulates Elucidation of Structure in INDAttributeAnalytical ApproachMethodologyPrimary structureConfirm primary structure and identifyposttranslational modifications at the peptidelevelPosttranslational modifications – Nlinked oligosaccharidesConfirm N-linked oligosaccharide structures andrelative abundancesPosttranslational modifications –Disulfide bondsMolecular massDetermine level of unpaired protein sulfhydrylsMolecular chargeDetermine charge heterogeneityImaged capillary electrophoresis (iCE)Higher order structureAggregation and fragmentationAssess secondary structureDetermine levels of monomer and highmolecular mass species (HMMS), includingaggregates, and characterize molecular form ofthe HMMSFar-UV circular dichroism (CD)Size exclusion HPLC (SE-HPLC),confirmed by multi-angle light scattering(MALS) and analyticalultracentrifugation -sedimentationvelocity (AUC-SV)Determine levels of low molecular mass species(LMMS), including fragmentsCapillary gel electrophoresis (CGE)Assess target bindingEnzyme-linked immunosorbent assay(ELISA) orCell Base AssayBiological activityLiquid chromatography/massspectrometry (LC/MS) – peptidemapping of reduced and alkylatedproteolytic fragmentsHydrophilic interaction liquidchromatography (HILIC) of released, 2aminobenzamide (2-AB)-labeled NglycansEllman’s assayConfirm primary structure, posttranslationalElectrospray ionization massmodifications, and multi-chain architecture of the spectrometry (ESI MS)intact molecule, and identify the major and minorproduct isoforms11

Post Proof of Concept Reference Standard is thePrimary Post POC reference standard process is the same as early development process LIMS Automated or manual filling and labeling utilized Stored and managed by Pharmaceutical Science until commercialization Post POC is the Primary Reference Standard The commercial working reference standard will be compared to primary reference torelease commercial supplies12

Reference Standard: TimelineRegToxCANExploratory DiscoveryPre-clinicalRM Pilot DS (RegTox) Used to release phase 1,2,initial phase 3 materialINDPOCBLAPhase 1 Phase 2 Phase 3 Registration MarketPrimaryWorking Characterization data:phase 3 IND amendmentand BLA Characterization data:populate INDOne RM post-POC (Primary Reference)13

Conclusions Pfizer’s BioTherapueitics Reference Standard Program complementsthe development strategy Reference Standard management is systems and process based dueto number of projects in portfolio Maximize the use of heightened characterization data gained onreference standards in filings Approach is consistent with industry best practices14

AcknowledgmentsBill HopkinsKristen SachsGeNea WarrenHope DodsonMonica R. BrzezinskiJames A. CarrollLucy L. LiuLisa A. MarzilliMichael R. SchlittlerTanya Q. ShangBruce S. TangaroneRob DufieldJason RouseMarta CzuprynThank you to the CASS/WCBP OrganizingCommittee15

AbstractReference standards play a critical role in characterization, comparability, lot release andconfirmation of stability for therapeutic products. Different organizations create and utilize suchstandards in different ways during development, which are sometimes unique to individualorganizations. Pfizer BioTherapeutics Pharmaceutical Sciences has established a referencestandard program that meets the current regulatory guidance and expectations. In thispresentation I will highlight the current reference standard process utilized during development,point out lesions learned along the way and demonstrate that Pfizer’s approach is aligned industrybest practices.The guiding principles critical in developing the current reference standard approach are the following:–Minimize the number of reference standards during development . Maintenance, support and management ofreference standards over a large portfolio takes a large number of FTE’s and adds to the overall cost ofdevelopment.–Assurance that cell line and process development groups are aligned and able to support the minimalreference standard approach.–Maximize the use of heighten characterization data gained on reference standards for use in filings.–Reference standards are the bridge back to non-clinical data and are always used during comparabilityexercises during development.Note: BioSimilars and Vaccine, while they follow similar guiding principles, are out of scope for thispresentation16

The guiding principles critical in developing the current reference standard approach are the following: – Minimize the number of reference standards during development . Maintenance, support and management of reference standards over a large portfolio takes a large number of FTE’s and adds to the overall cost of development.

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