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 100s - 1000s 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 Q5E

“Comparability of Biotechnological / Biological Products Subject to Changes in Their Manufacturing Process”

• Per ICH Q 5E: – “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

1980

• •

First Biotech Drugs Insulin Growth hormone *PTC for Biotech 1986 ICH PDUFA I REGO PDUFA II FDAMA PDUFA III CBER/CDER Integration PDUFA IV First Biotech Biologics 1990 CBER/CDER Inter-center Agreement

• • • • •

‘92 ‘94 ‘97 ‘98 2000 ‘02 ‘03

• •

Comparability Guidance Comparability Protocols First WCBP Symposium Specified Products BLA replaced PLA & ELA Eliminated FDA Lot Release Created Team Biologics ‘04 ‘05 ‘06 ‘07

• • • •

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 Q8) – 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 Q5E) • 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

A - Basic Package B - Biological Characterization C - Animal PK/PD D - Human Bioequivalence E - Human Clinical Trials

Testing

Determined on case by case basis • CoA • Extended characterization of variants & impurities • Accelerated degradation • In vitro functional bioassays & binding studies • Real time & accelerated stability • Rodent PK • Primate PK/PD • Direct comparison of pre- and post-change • Adequately powered • To confirm efficacy, safety, and/or immunogenicity

Chronology of Key Biotech Product Approvals

1982 - 2007

Follistim Forteo

Humulin R

(1982) Humatrope Glucagon Thyrogen Mylotarg Ovidrel Increlex Nutropin Protropin Ceredase Cerezyme Natrecor 85 86 87

Intron A

88 Activase 89

Epogen /Procrit

CDER (N=14) CBER (N=48) 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 Proleukin

Neupogen

Leukine Actimmune Pulmozyme Betaseron ReoPro NovoSeven Ontak

Avonex

Retavase Benefix Infergen Neumega

Rituxan

Zenapax Regranex Simulect Synagis Remicade

Herceptin Enbrel

Refacto Campath Kineret Xigris Aranesp > $1 Billion Annual International Sales Fabrazyme Amevive Xolair Bexxar Raptiva Zevalin Elitek

Humira

Rebif 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 McPhee