case study-cmc challenges when a small biosimilar ... · pdf file1 case study-cmc challenges...

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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


a IMS: Delivering on the Potential of Biosimilar Medicines. 2016 Mar

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Biosimilars Market is Highly Competitive


➢ 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.


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.


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.


➢ 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’


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


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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


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


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


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


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


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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