The Challenges of Demonstrating Comparability of Biosimilar Products Patricia Seymour BioProcess Technology Consultants, Inc. BIO 2010 BioProcess Theater May 5, 2010
Overview ¾
Why Develop a Biosimilar Product
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Challenges of Demonstrating Comparability for Biosimilar Products
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Manufacturing Strategies/Alliances Being Employed in Biosimilar Development
From Clone to Commercial®
Why Biosimilars?
Why Biosimilars ¾ ¾ ¾ ¾ ¾
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Major blockbusters coming off patent • Enbrel ($4.4 B), Herceptin ($3.1B), Rituxan ($3.9B), etc. Emerging markets growing US healthcare spending exceeded 16% GDP in 2008 Prescription pharmaceuticals in 2015 forecast forecasted to be ~$446B (>10% total healthcare expense) Biologics drug expenditure • already accounts for >14% pharmaceutical spend • >33% of all drugs in development Biologics Price Competition and Innovation Act (BPCIA) enacted March 2010 as part of the Patient Protection and Affordable Care Act
From Clone to Commercial®
Key Features of BPCIA ¾
Twelve years of market exclusivity (possibility for additional six months of pediatric exclusivity) for pioneer [innovator] products during which time FOB applications cannot be approved
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Two standards of FOB approval – biosimilarity and interchangeability
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One year exclusivity for the first FOB product found to be interchangeable with the pioneer [innovator] product
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Patent information exchange regime prior to FOB patent litigation
From Clone to Commercial®
Comparability
Biosimilarity ¾
The BPCIA defines a “biosimilar” product as • one that is “highly similar to the [pioneer] product despite minor differences in clinically inactive components” and one in which “there are no clinically meaningful differences . . . in terms of safety, purity, and potency of the product”. • It also defines an “interchangeable” product as one that is both “biosimilar” and may be substituted for the pioneer product, without the intervention of a health care provider.
→This could potentially permit some minor structural variation from the reference product.
From Clone to Commercial®
Comparability ¾
ICH Q5E: COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS • “The demonstration of comparability does not mean that the quality attributes of the pre‐change and post‐change products are identical, but that they are highly similar and that the existing knowledge (about the product and process) is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon the safety or efficacy of the drug…”
From Clone to Commercial®
Factors in Biosimilar Comparability Evaluation ¾
A comparability evaluation is based on the ability to characterize the product by • Biochemical characterization Product and process knowledge • Nonclinical characterization Relevant species model • Clinical characterization Severity of condition (cancer versus autoimmune) Heterogeneity of patient population Feasibility of trial design (e.g., # of pts)
From Clone to Commercial®
Elements to Successful Biosimilar Comparability ¾
Product Knowledge • Critical quality attributes: what matters and why?1 • Structure‐function understanding • Product stability profile: real‐time and accelerated • Historical ranges: leverage innovator supplement ranges
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Process Understanding • Critical process parameters • Link between process parameters and critical quality attributes • Where are the sources of variability 1Ref:
A-Mab: A Case Study in Bioprocess Development CMC Working Group 2009
From Clone to Commercial®
Process Comparability ¾ Cell Culture Metrics
• Host cell and expression system • Growth profile • Final production titer • Pre‐harvest viability ¾ Recovery and Purification
• Harvest • Affinity chromatography • Virus filtration (mammalian production) • Other chromatography steps • UF/DF formulation • Overall yield From Clone to Commercial®
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Impurity Profiles •
Residual amounts of HCP, DNA and other process and product related impurities must be ‘similar’ to the amounts measured in the reference product’s manufacturing process
What if these are lower for FOB!?
FDA recognizes that demonstrating the similarity of FOB to RP is more complex than innovator comparability since FOB manufacturer not able to compare intermediate stages of its production process to the initial manufacturer’s process. Testimony of Janet Woodcock, Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United States: Hearing Before the Subcommittee on Health, Committee on Energy and Commerce (May 2, 2007).
Product Comparability Primary structure • Amino acid sequence ¾ Secondary structure • Three‐dimensional structure of the protein (alpha helices, beta sheets, loops/turns) ¾ Tertiary structure • 3‐D structure of protein through interaction of the secondary structures ¾ Quaternary structure • Describes the three‐dimensional arrangement of protein subunits ¾
From Clone to Commercial®
Product Comparability: Assessing Protein Structure ¾ Primary Structure
• Mass spectrometry • Chromatography • Capillary electrophoresis ¾ Higher order structure (secondary, tertiary, quaternary)
• Circular dichroism (CD) • Fluorescence spectroscopy • Fourier transform infrared spectroscopy (FT‐IR) • Differential scanning calorimetry (DSC) • Nuclear magnetic resonance (NMR) spectroscopy ¾ Higher order structure can be studies as a function of a variety of
parameters such as pH, temperature or added salts From Clone to Commercial®
Product Comparability: Assessing Protein Purity/Potency ¾ Size
• Analytical ultracentrifugation • Size exclusion chromatography ¾ Charge
• Ion‐exchange chromatography • Isoelectric focusing ¾ Hydrophobicity
• Reverse phase HPLC • Hydrophobic interaction chromatography
From Clone to Commercial®
¾ Glycosylation
• Mass spectrometry • NMR ¾ Impurities • HPLC • SDS‐PAGE • LAL • Bioburden ¾ Bioassay / binding assay
Immunogenicity ¾ Biologics by their nature (whether intended or not) have the
potential to provoke an immune response ¾ Antibody formation can
• bind to product and alter the half life in vivo • lengthen product half life by reducing clearance • increase clearance through removal of the antibody/product complex • bind to functional regions preventing binding to ligands and altering biodistribution, resulting in loss of efficacy (e.g., neutralizing antibodies – particularly harmful if against an endogenous protein like EPO) adverse events (e.g., anaphylaxis), or no clinical symptoms at all From Clone to Commercial®
Factors Influencing Immunogenicity ¾ Patient and disease related
• underlying disease • genetic background • immune status, e.g., immunomodulating therapy ¾ Product related
• intensity of treatment (route of administration) • dose, dosing interval and duration of treatment • manufacturing process
From Clone to Commercial®
Manufacturing and Immunogenicity ¾ Manufacturing can affect attributes known to be involved in
immunogenicity (aggregation, impurities, degradants) • Processes that could affect aggregation Changes in formulation Changes in virus/adventitious agent removal • Heat treatment, filter shear force, low pH Changes in source material/cell line • High yields, culture conditions Changes in storage containers Changes in purification • Buffers, hold times, load concentrations
From Clone to Commercial®
Manufacturing and Immunogenicity ¾ Processes that could alter primary sequence or post translational
modifications • Fermentation conditions • Purification processes Buffers, temperature, hold times • Storage and delivery devices ¾ Processes/materials that alter impurity profiles
• Fermentation conditions • Purification processes • Raw materials • Excipients
From Clone to Commercial®
Strategies in Biosimilar Development
Business Model Differences Key Activities
Traditional Generic
Biosimilar Model
Active Ingredients (API/DS)
Internal capacity Easy to manufacture Commoditization
Limited internal capacity Difficult to manufacture Expensive
Scientific Expertise
Analytical/chemistry
Molecular biology/biology
Straightforward
More complex/evolving
Clinical Development
