Post on 06-Feb-2018
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Case study-CMC challenges when a small biosimilar developer must rely on outsourcing for development and manufacturing
CMC WorkshopApril 24-26, 2017
Patricia Seymour
Session 07B
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© 2016 DIA, Inc. All rights reserved.
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Market Dynamics Favor Biosimilars Growth
Global Trends in the Pharma and Health Care Fields
① Global pharmaceutical sales forecast to reach ~$1.4T by 2020
• Currently, biologics drug expenditure already accounts for ~28%a of
pharmaceutical spend and are >33% of all drugs in development
• MAbs are largest and fastest growing segment
② Continuous financial pressure on healthcare systems to make significant
and sustained cost reductions
• US healthcare spending by 2025 forecast to be ~20% GDP
③ Major biopharmaceutical products are losing patent protection coupled with
new regulatory approval pathways for biosimilars in major markets
• Biosimilar market is expected to grow to ~$40 billion by 2020a
© 2016 DIA, Inc. All rights reserved.
a IMS: Delivering on the Potential of Biosimilar Medicines. 2016 Mar
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Biosimilars Market is Highly Competitive
© 2016 DIA, Inc. All rights reserved.
➢ Transition underway from early
recombinant proteins to MAbs and
competition is significant
➢ Significant growth of programs targeting
developed markets
Pharmsource 2016
Biosimilars may represent a big
eventual market opportunity, but
CDMO-dependent developers
may be at a disadvantage to
established global bio/pharma
companies.
➢Global and large regional generic-drug companies
dominated the first-wave biosimilars approved in Europe
➢Teva, Sandoz, Stada, and Hospira account for
more than 70% of the biosimilars approvals in 1st
wave
➢Dominance of the large companies reflects the
high cost of developing biosimilars as well as the
need for established infrastructure and experience
to generate sales
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Current Manufacturing Landscape for Biosimilars
~66% of the “first wave” of approved biosimilars in Europe manufacture bulk drug substance
(DS) in-house
~45% of the “first wave” approved biosimilars in Europe perform the fill/finish in-house
For the “second wave” of biosimilars, manufacturing arrangements appear that
• ~55% possess large molecule DS manufacturing capability
• ~33% have a joint venture partner or licensor that has manufacturing capability
• Many joint ventures involve partners with manufacturing assets in Asia, including
Mylan with Biocon (India), Hospira with Celltrion (South Korea), Biogen/Idec with
Samsung Bioepsis (South Korea), and Oncobiologics with Strides Arcolab
(Malaysia).
Small biosimilar developers and CDMOs must develop a strategy that enables them to
participate more meaningfully in the “third wave” of the biosimilar opportunity that will begin
in 2020
• Proprietary cell line and expression technologies, which help them deliver biosimilar DS
more quickly and cheaply than in the past
• Strengthened analytical capabilities.
© 2016 DIA, Inc. All rights reserved.
But, how far can a biosimilar developer
stray from the innovator technology?
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Biopharmaceuticals/Biosimilars are Produced through a Complex Series of Steps
1. Isolate and identify the genetic code of the
therapeutic protein.
2. Insert the genetic code into a living cell.
3. Isolate specific cells that have integrated the
genetic code of the therapeutic protein into their
genome and produce large quantities of the
target protein.
4. Isolate the therapeutic protein from the cells and
other nutrients through a series of purification
processes.
5. Package protein into sterile vials.
© 2016 DIA, Inc. All rights reserved.
Source: Slide by Nanna Aaby Kruse, Mediacademy, Oct 2011
Different Process…Different Product?
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Inherent Variability of Biopharmaceutical Products
It is not possible to make an identical copy of a reference product given the
inherent structural and functional variability of biopharmaceutical products.
Biosimilars must fall within a range of values across important structural and
functional parameters compared to those of the reference drug.
© 2016 DIA, Inc. All rights reserved.
➢ VL and VH are the variable regions which together comprise the antibody recognition and binding site
VL
CL
VH
CH1
CH2
CH3
Hinge Region
Carbohydrate
Disulfide Bond
O
D
O
D
E
G
G
D
K
Identification of Known Post-translationalModifications (total number)
D Deamidation (Asparagine) (6)
E Glutamate or Pyroglutamate (2)
G Glycation (4)
Glycosylation (5+5)
K Lysine or Des-lysine (2)
O Oxidation (Methionine)(2)
From Kozlowski and Swann
2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600 (9600)2 108 Variants
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Biosimilarity is Based on the ‘Totality of Evidence’
© 2016 DIA, Inc. All rights reserved.
CMC is the first, and
most crucial, step in
establishing
biosimilarity to an
innovator’s marketed
product
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Example Case Study – Development of infliximab Biosimilar by Small Developer Relying on CDMOs
Infliximab is a chimeric human-mouse IgG1 kappa
monoclonal antibody targeting TNF-α
• Reference product manufacturing process
• Expressed in S/P2.0 murine myeloma cell line
• Continuous perfusion cell culture
• Seven step down stream purification process
Remicade® (Centocor/Janssen, infliximab) has been
marketed in the US since 1998
Inflectra (Pfizer/Celltrion, infliximab) approved for US
sale in April 2016 and EU sale in Sept 2013
Flixabi (Samsung Bioepis, infliximab) approved for
EU sale in May 2016
© 2016 DIA, Inc. All rights reserved.
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So, Where Does a Small Developer Begin Working with a CDMO to Develop an infliximab Biosimilar?
Considerations When Selecting a CDMO
• Speed and Cost
• Greater portion of time is spent upfront developing a process and
characterizing a biosimilar molecule
• Once in clinical testing, timeline to commercialization will be faster
than that of an innovator molecule
• Cost of goods (CoG) must be low for a biosimilar to compete in the
market with comparator molecules
• Need for existing commercial manufacturing capabilities
• No time for technology transfers
• Need appropriate scale
• Need available capacity
• FTE equivalents approach
• Allows rapid turnaround and responsiveness
• Exclusivity / non-compete contract / Quality Agreements
• One-stop-shop© 2016 DIA, Inc. All rights reserved.
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Developing the Process to Achieve Biosimilarity
Match the innovator’s manufacturing
process as much as possible, such as the
choice of cell line, use of the same
formulation excipients, etc.
• All MAbs and –cept fusion proteins
used in rheumatology have had
changes in their manufacturing
processes after initial approval
Collect numerous batches of the
innovator’s drug product over many years
• Celltrion collected 41 lots of EU-
approved Remicade and 45 lots of US-
licensed Remicade to compare against
their biosimilar version
© 2016 DIA, Inc. All rights reserved.
Schneider, C. K. (2013) 'Biosimilars in rheumatology: the w ind of change‘ in Ann Rheum Dis, England: 315-8.
Number of Process Changes
Since Initial Approval
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When “Old Technology” Just Won’t Do
BUT…often the innovator’s technology is 20+ years old and many advances
have been made in cell line development and processes since then
© 2016 DIA, Inc. All rights reserved.
First Movers Second tier
General acceptance
Aging Technologies
Adapted from: Morten Munk, NNE Pharmaplan: “Continuous Bioprocessing –What is holding the industry back from implementing CBP more broadly?”
Outsourcing to CMOs is another flexibility-enabling strategy of importance to industry
Many technologies
being adopted by
industry today enable
more flexible
operations
Better cell
line
technologies
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Facilities of the Future? Manufacturing and Technology Trends
© 2016 DIA, Inc. All rights reserved.
Flexible
Modular
Disposable
Continuous
From Aspen Brook Alert Survey,
Oct 10, 2014
Courtesy: Tarpon Biosystems
Courtesy: Pall Corp
Courtesy: KSep
Simulated moving bed
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Additional Challenges
Access to Manufacturing Capacity
• Most CDMOs are in high
demand, not just for biosimilar
products
Limited manufacturing know-how
Lack of leverage with buyers
• A single digit market share
might seem attractive to a small
company but payers may not
want to deal with an unproven
supplier with a single product
• It remains to be seen just how
many players the field can
accommodate once it matures
© 2016 DIA, Inc. All rights reserved.
Manufacturing Capacity Control
2016
Rank
2021
RankCompany
2016
Volume
(1,000s L)
2021
Volume
(1,000s L)
1 1 Roche 673 909
2 5 Lonza 261 281
3 8 Johnson & Johnson 230 230
4 6 Sanofi 223 243
5 3 Boehringer Ingelheim 205 338
6 9 Amgen 204 225
7 4 Biogen 196 316
8 - Pfizer 149 -
9 - Celltrion 140 -
10 - Lilly 137 -
- 2 Samsung - 362
- 7 Bristol-Myers Squibb - 237
- 10 Novartis - 205
All Others (120/128) 1,214
(33%)
2,106
(39%)
Source: BPTC bioTRAK®
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Summary – Challenges of Developing a Biosimilar via an Outsourcing Strategy
© 2016 DIA, Inc. All rights reserved.
Speed, Cost and Access to Capacity are major impediments to
successfully developing a biosimilar and being a serious competitor
Ability to achieve biosimilarity can be at risk if
manufacturing technologies different from the
innovator are selected
Industry is consolidating via acquisition,
atrophy and partnerships leaving some small
developers without a dance partner…
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