The Challenges of Demonstrating Comparability of Biosimilar Products Patricia Seymour BioProcess Technology Consultants, Inc. Biosimilars: Manufacturing and Sourcing Dynamics DCAT Parsippany, NJ December 2, 2009
Introduction ¾
Why Develop a Biosimilar Product
¾
Challenges of Demonstrating Comparability for Biosimilar Products
¾
Strategies Being Employed in Biosimilar Development
From Clone to Commercial®
Why Biosimilars?
Why Biosimilars ¾
Major blockbusters coming off patent • Enbrel ($4.4 B), Herceptin ($3.1B), Rituxan ($3.9B), etc.
¾
Scale/globalization is key
¾
Emerging markets growing Country
Share of World GDP in 2005
Share of World GDP in 2035
US
21%
15%
China
11%
27%
India
6%
15%
Source: “Tri‐Polar World” by Arvind Virmani, Working Paper, ICRIER, New Delhi, 2005; Burrill & Co.
From Clone to Commercial®
Why Biosimilars US healthcare spending by 2015 forecast to be ~15% GDP (~$4T) ¾ Prescription pharmaceuticals in 2015 forecast to be ~$446B (>10% total healthcare expense) ¾ Biologics drug expenditure • already accounts for >14% pharmaceutical spend • >33% of all drugs in development ¾
From Clone to Commercial®
Hospital Care 31%
Dental Services 4%
Nursing Home Care 6% Investment 7% Program Administration 7%
Physician & Clinical Services 21%
Other Spending* 14%
Prescription Drugs 10%
*Other spending: Other professional services, other personal healthcare, home healthcare, durable medical products, government public health activities Source: Center for Medicare & Medicaid Services
World-wide Sale of Biologics Coming Off Patent 20
Significant business opportunity for biosimilars
58 ($B)
9 17
8
# of mlc
1
1
2
2009
2010
2011
2012
2013
2014
2015
Total
1
4
2
3
9
7
16
44
From Clone to Commercial®
Generics versus Innovator Profiles
Source FTC Report 2009 and C. Pinnow Hospira
From Clone to Commercial®
Comparability
Comparability – What Is It? 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®
Biosimilar Comparability ¾ The Biosimilar product must:
• Be (bio)similar to the reference product What to do when slightly different products approved in the same territories, e.g., EPO, hGH? • Be for same indication as reference product Limits biosimilar approval for products with multiple approved indications, e.g., Enbrel®/etanercept. • Have same route of administration, dosage form and strength as reference product What if pre‐filled syringes would be better for the patient • Be manufactured in GMP‐compliant facility Not too difficult to achieve
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? • Structure‐function understanding • Product stability profile: real‐time and accelerated • Historical ranges ¾
Process Understanding • Critical process parameters • Link between process parameters and critical quality attributes • Where are the sources of variability
From Clone to Commercial®
Process Comparability ¾ Cell Culture Metrics
•
Host cell and expression system
•
Growth profile
•
Final production titer
•
Pre‐harvest viability
¾ Impurity Profiles
¾ Recovery Step Yields and Overall Yield
•
Harvest
•
Affinity chromatography
•
Virus filtration (mammalian production)
•
Other chromatography steps
•
UF/DF formulation
•
Overall yield
From Clone to Commercial®
•
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!?
Product Comparability ¾ 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
From Clone to Commercial®
Assessing Protein Structure ¾ Primary Structure
• Mass spectrometry • Chromatography • Capillary electrophoresis ¾ Higher order structure (secondary, tertiary, quaternary)
• Circular dichroism (CD) • Fluorescence spectroscopy • FT‐IR • Differential scanning calorimetry (DSC) • 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®
Assessing Protein Purity / Potency ¾ Size
• Analytical ultracentrifugation (AU) • Size exclusion chromatography ¾ Charge
• Ion‐exchange chromatography • Isoelectric focusing ¾ Hydrophobicity
• Reverse phase HPLC • Hydrophobic interaction chromatography (HIC)
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
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
