Comparability for Biotech Products An industry perspective on

Comparability for Biotech Products: An industry perspective on past & future aspects Mary B. Sliwkowski, Ph. D. VP, Regulatory CMC & Info Systems Company logo here

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Agenda • • Comparability: what, why, when, how Experience so far Challenges & lessons learned The future

Why do we need ‘comparability’? • Small molecule drugs – Fully defined by physico-chemical methods • Biotech products – – Complex mixtures of 100 s - 1000 s of forms Post-translational modifications Higher order structure Defined by characterization & process • • • Physico-chemical Biologic (in vitro) Animal (pharmacokinetics, toxicology, immunogenicity) Human (safety, efficacy) Process qualification & validation – Well-characterized but not fully defined

Comparability: What is it? • “Comparability is the demonstration of a high degree of similarity between products produced by different manufacturing processes, equipment and/or sites, such that no adverse impact on quality, safety or efficacy occurs” • Comparability is NOT identity

Comparability: Global Guidance • Comparability is a well established global regulatory mechanism based on ICH Q 5 E “Comparability of Biotechnological / Biological Products Subject to Changes in Their Manufacturing Process” • Per ICH Q 5 E: – “The goal of a comparability exercise is to ascertain that pre- and post-change product is comparable in terms of quality, safety and efficacy” – “The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change are identical, but that they are highly similar…”

Comparability: History of U. S. Biotech Regulation *PTC for Biotech 1986 PDUFA II REGO PDUFA III CBER/CDER Integration FDAMA ICH ‘ 92 1980 First Biotech Drugs • Insulin • Growth hormone ‘ 97 ‘ 98 ‘ 02 ‘ 03 ‘ 04 ‘ 05 ‘ 06 ‘ 07 2000 1990 First Biotech Biologics ‘ 94 PDUFA IV CBER/CDER Inter-center Agreement • Comparability Guidance • Comparability Protocols • First WCBP Symposium • Specified Products • BLA replaced PLA & ELA • Eliminated FDA Lot Release • Created Team Biologics • Quality by Design • Design Space • Process Analytical Technology (PAT) • Expanded Change Protocols

Regulatory Mechanisms • Post-Approval Submission (PAS) – Conduct qualification of change and submit data for approval prior to implementation • Comparability Protocol – Pre-specify testing, validation studies and acceptance criteria for change to be made – Pre-change approval may allow reduced reporting category when implement change – Initially only for specific, pre-defined change to single product – Expanding to broader applications - multi-change, multi-product • Expanded Change Protocol (TBD) – Linked to Quality by Design approach (ICH Q 8) – Provide evidence of sufficient product knowledge (Critical Quality Attributes - CQAs) and process understanding (Critical Process Parameters - CPPs) to define a Design Space in which can operate more freely • EU Variation regulations being revised

Comparability: Throughout the Product Lifecycle Clinical Development • some product variability (lot-to-lot, inter-campaign) is desirable • process changes expected • collecting clinical and non-clinical data Phase III – Registration • process, control system, formulation locked • collecting pivotal clinical data • qualification, validation lot production • process changes will require BE and/or efficacy data Post-Approval • apply comparability guidance (ICH Q 5 E) • match historical data sets

What triggers comparability efforts? • Manufacturing facility changes – Site, scale, equipment • Process changes – Cell culture, fermentation • Cell line changes – Recovery – Formulation – Delivery mechanism or system • Supplier changes – Raw materials – Primary components • Regulatory expectation changes

Hierarchy of Comparability Testing Category Testing Determined on case by case basis A - Basic Package • Co. A • Extended characterization of variants & impurities • Accelerated degradation B - Biological Characterization C - Animal PK/PD • In vitro functional bioassays & binding studies • Real time & accelerated stability D - Human Bioequivalence E - Human Clinical Trials • Direct comparison of pre- and post-change • Adequately powered • Rodent PK • Primate PK/PD • To confirm efficacy, safety, and/or immunogenicity

Chronology of Key Biotech Product Approvals 1982 - 2007 Follistim Forteo Humulin R (1982) Humatrope Glucagon Thyrogen Ceredase Protropin 85 86 87 88 89 Activase Intron A Epogen /Procrit 90 91 92 94 95 96 97 Pulmozyme Betaseron Reo. Pro CDER (N=14) CBER (N=48) 98 Avonex Retavase Proleukin Neupogen Leukine Actimmune Nutropin Cerezyme 93 Mylotarg Ovidrel > $1 Billion Annual International Sales Increlex Natrecor 99 00 01 02 03 04 05 Novo. Seven Ontak Simulect Synagis Remicade Refacto Herceptin Benefix Campath Enbrel Infergen Kineret Neumega Xigris Rituxan Aranesp Zenapax Regranex Fabrazyme Amevive Xolair Bexxar Raptiva Zevalin Elitek Humira Rebif 06 07 Lucentis Myozyme Elaprase Vectibix Abatacept Galsulfase Avastin Erbitux Tysabri

What is the GNE experience • 23 years of commercial manufacture • 14 products with 8 process version changes • Drug substance transfers/sites completed – Within GNE network: 14 across 4 sites – Out to partners/CMOs: 8 across 6 sites – In to GNE: 1 at 1 site • Drug Product transfers/sites completed – Within GNE network: 10 across 3 sites – Out to partners/CMOs: 11 across 8 sites • Submitted 13 PAS & 12 CP • Many transfers planned as rebalance mfg network • GNE internal documents: Quality & Regulatory Standards

What have we learned • Don’t make process changes between Phase III and approval • Platforms have limitations – Each Mab has unique challenges • • • Trastuzumab: Met oxidation, Asn deamidation Omalizumab: unpaired Cys, Asp isomerization Bevacizumab: dissociable aggregates Ranizumab: Trp oxidation Sequence variants can/do occur Minor carbohydrate variation is sometimes important Relevance of differences is situational Maintain frequent dialog with Agency Successful comparability efforts require due diligence Our ultimate responsibility is to our patients

Challenges • Evolution of analytical methods – Increased sensitivity – New forms • Higher order structure • Linkage to safety & efficacy – – When is a difference significant? Mechanism of action Patient population Route of administration • Comparability is still case by case • Global regulatory differences – Change regulations mechanisms – Stability requirements – Timing of transition

Acknowledgements Wassim Nashabeh Kathy Francissen Reed Harris Amita Joshi Ron Taticek Ray Arnold Loel Mc. Phee