1. Development and Manufacturing
Strategies for Biosimilars
Thomas Vanden Boom, Ph.D.
Vice President,
Hospira Global Biologics R&D
CBI’s 5th
Summit on Biosimilars and
Follow-on Biologics
Washington, D.C.
October 18, 2010

2. Overview
 Introduction
 Biosimilars Process Development
 Manufacturing Technology platforms
 Key biosimilar development topics
– Surveillance of originator lots
– Scalability
– Optimization of glycosylation profiles
– Post-approval CMC landscape for biosimilars
 Conclusions

3. Hospira Biosimilars Business
 Only U.S. company marketing a biosimilar
– Leading biosimilar EPO IV product, Retacrit™, in the
EU with recently approved SC presentation
– Biosimilar filgrastim (G-CSF) product, Nivestim™,
approved in the EU and Australia
 Hospira’s 11-compound biosimilars pipeline is one of the
industry’s largest
 Key partnerships and licensing deals established to
enable development of full range of biologic products

4. Hospira Global Biologics Development
and Manufacturing Network
Lake Forest, IL
Zagreb, Croatia
Rockville, MD
(HGS)
McPherson, KS
Adelaide, Australia
South Korea
(Celltrion)
Germany
(Stada)
Partner
Hospira Facility

5. Biosimilars Represent a Distinct New Sector
of the Biopharmaceutical Industry
Biosimilars
Originator
Products
Generics
Development
Environment
Development
Environment
Probability of
Success
Cost
Time
Development
Low (~30%)High (~90%)
High (>$800 M)Low (<$5 M)
Long (8-12 yrs)Short (3-4 yrs)
Barriers to
Entry
Point of
Differentiation
Other
Dynamics
HighLow
Product profile,
marketing
Price, breadth
of portfolio
Competitors
Investment
Pricing
Marketing
Few, well differentiated
Many, little
differentiation
HighLow
PremiumCommodity
Source: FTC Report June 2009 and HSP internal analysis

6. The biosimilar space is currently defined by
regulatory and market uncertainties
 Future competitive environment uncertain
 World wide Health Authorities and clinicians have
limited experience with biosimilar products
 Regulatory framework for biosimilars in U.S. is
still pending
 Complex biopharma patent landscape exists
 Companies have limited commercial experience
in introducing biosimilar products

7. What does this mean for
biosimilar companies?
 The quality and level of the science is critical
 Development and manufacturing strategies must
be flexible
– Manufacturing processes should be designed for
ease of scale-up (and scale-down) and technology
transfer
– Excellence in execution of post-approval CMC
changes will offer a competitive advantage to
biosimilar developers

8. Biosimilars Process Development
Biosimilar Process Development Phases
From cell … … to biosimilar product
Genetic and Bioanalytical Characterization
Comparability
Intellectual Property Clearance
Large-scale
Process
Validation
Reverse
Genetics
Drug Product
Development
Drug Substance
Development
Cell Line
Development

9. Current Biologic Production Systems
E. coli
Yeast Chinese Hamster Ovary
(CHO) Cells
Approximately 90% of currently approved biologic products
are produced from 3 living systems

10. Alternative Expression Systems
 More than 340 new expression technologies
currently under development*
 Use of alternative systems may be associated
with increased technical and regulatory risk
–Dramatic changes in expression system may
preclude development of product as
biosimilar
 Significant process improvements possible using
current systems
*E. Langer, BioPharm International, June 2009

11. Biosimilar Manufacturing Opportunities
 Biosimilar companies have access to modern
biologic manufacturing technologies
– Lower cost-of-goods
– Enhanced process consistency
– Reduced facility capital costs
 Originator companies may be trapped in legacy
manufacturing platforms
 Biosimilar and originator companies should be
subject to the same regulatory guidelines for
implementation of post-approval changes

12. Emerging Biologic Manufacturing
Technologies
 Upstream technologies: disposable bioreactors
 Buffer dilution systems : alternative to large buffer tank
capacity
 Bioseparation technologies: membrane chromatography
capsules
Disposable Bioreactors
Buffer Dilution Skid
Membrane
Chromatography
Capsules
Example technologies from GE Healthcare, Xcellerex, Technikrom and Pall

13. Where do new technology platforms fit in
the biosimilars space?
 The benefits of deploying new technology
platforms should be carefully weighed against
potential increased technical and regulatory risks
 Selective deployment of new technologies will
result in higher quality and lower cost biosimilar
products
 Biosimilar companies with the scientific and
regulatory expertise to make effective technology
decisions will have a competitive edge

14. Building Noticeable Differentiation
through Incremental Innovation
Non-clinical
differentiators
can be
designed into
biosimilar
offerings to
improve on
originator
products

15. Key Biosimilar Development Topics
 Surveillance of originator lots
 Scalability
 Optimization of glycosylation profiles
 Post-approval CMC landscape for biosimilars

16. Retacrit®
Surveillance of Originator Lots
Examination of Manufacturing Batch Consistency using
Capillary Zone Electrophoresis
epoetin zeta: N = 67 batches
epoetin alfa: N = 9 batches
epoetin alfa
epoetin zeta

17. Scalability of a Biosimilar MAb Product
70
75
80
85
90
95
100
NormalizedTiter
250 mL 2 L 10 L 15 L 100 L 400 L
Scale

18. Optimization of Glycosylation Profiles
for a Biosimilar MAb Product
Media
Normalized
Titer
G0 Difference from
Reference Product
(%)
Control 1.0 24.7
A 1.2 4.6
B 1.2 -2.0
C 1.2 -4.2
D 1.1 -6.5
N-acetylglucosamine
Fucose
Mannose
Galactose
G0
G1,G2

19. Post-approval CMC Landscape for
Biosimilars
 The same regulatory guidelines for post-approval CMC
changes are anticipated to apply to biosimilar
manufacturers
 WHO Guidelines on Evaluation of Similar
Biotherapeutic Products (SBPs), October 2009
– “For changes in the manufacturing process ICH Q5E
should be followed”
 Health Canada Guidance for Sponsors:
Information and Submission Requirements for
Subsequent Entry Biologics (SEBs), March 2009
– “Comparisons with the original reference biologic
drug are not required.”

20. Conclusions
 Biosimilar companies will continue to face
significant uncertainties in the near term
 Companies with the scientific, technical and
commercial competencies to effectively
manage these uncertainties will be successful
in this space
 The benefits of deploying new technology
platforms should be carefully weighed against
potential increased technical and regulatory
risks

21. Conclusions
 Layered incremental innovations to biosimilar
products may offer significant value to patients
and customers
 Extended surveillance and characterization of
originator lots is essential to defining
“biosimilarity”
 The anticipated post-approval CMC landscape
will enable biosimilar companies to continue to
drive innovation to provide patients with high
quality and lower cost biologic products

22. Acknowledgments
Hospira Biosimilars Team
Stada Arzneimittel AG