© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 1
Contichrom® as process solution for 2nd generation drug
substance such as biosimilars/biobetters and
conjugated/PEGylated biologics
Case Study
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 2
ChromaCon at a Glance
• Private Life Science Tool company located in Zürich, Switzerland
• Strategic partnership with Resin and Equipment manufacturers for marketing of preparative chromatographic process solutions
Company
• Development and marketing of LC Contichrom® equipment/software with novel processes for drug discovery and for the intensification of drug substance manufacturing
• Development of superior production platforms
• Commercialization of proprietary technologies with equipment sales and licensing business
Business
• MCSGP process for ternary chromatographic separations • CaptureSMB® for efficient product capture by affinity chromatography • Broad IP on process principle and manufacturability of product classes
Technology
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 3
MCSGP Technology Key Advantages for Biosimilars
Enabler
• Large volume processing requiring high selectivity
• Difficult purifications with complex feed
• Interchangeability of biosimilar to originator drug in the US
• Legal/IP de-risking of biosimilars in the US
Cost Saver
• Saves on average 30% CAPEX
• Saves on average 50% of OPEX
• Increases purity and yield on average by 50%
• Increases on average throughput 10-fold
• Reduces process development time by up to 50%
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 4
Contichrom® applications
Product enabler
Orphan drugs from plasma proteom
Bi-specific antibody production
Large volume manufacturing of complex generics and biologics
(fatty acids, plasma)
2nd generation product by narrowing isoform profile (mAb)
de-risking of biosimilar products
Product process improvement step change
Purification of PEGylated/ conjugated proteins with high yield
(Factor VIII, mAb fragments)
Economic isolation of large synthetic peptides
Automated process development
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 5
USP - Unique Sales Proposition
ENABLES
• the large volume purification
of chemicals and biologics
• the generation of lifecycle
extensions for marketed biologics
SAVES
• 30% CAPEX & 50% OPEX
• Purity increase by 50%
• Yield increase by 50%
• Throughput increase 10x
• Buffer reduction -75%
ACCELERATES
• Discovery of leads
• Development retaining
product profile at upscaling
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 6
Contichrom® & MCSGP explained
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 7
Contichrom®: All-in-one proces capabilities
Contichrom® Preparative HPLC/FPLC
MCSGP
Capture-SMB/ SMB
Sequential chromato-
graphy
Batch Batch
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 8
The process principle: recycle until it‘s pure
Conventional batch chromatography
Chromacon‘s novel internal recycling chromatography
(MCSGP)
time
more and purer product
Reprocess impure
product
time
pure product
impure
product
to waste
Cut narrow
= obtain purer product
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 9
Contichrom® & MCSGP explained
Full animation: click here
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 10
Purification challenge
Capture step (large
selectivities)
Sharp breakthrough
curve Batch
Diffuse breakthrough
curve CaptureSMB
Polish step
Ternary separation
Very difficult separation MCSGP
Difficult separation MCSGP
Baseline separated Batch
Binary separation
Difficult separation SMB
Baseline separated Batch
Contichrom®: all-in-one process solutions
Contichrom®
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 11
Batch to MCSGP process switch
Record “design” batch chromatogram
Fraction analysis
Separation?
MCSGP run
Yield/ Purity OK MCSGP fine-tuning
End
yes
no
no
yes
MCSGP Design (Wizard)
Resin / buffer / loading conditions
Batch
MCSGP
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 12
MCSGP process development
product
quality
Required
Threshold
quality
Time of process
development
Threshold quality = scalable process
+ purity
+ controlled impurities
+ economic yield
In order to achieve a required threshold quality with an
optimized batch process, extensive process development has
to be performed. Switching to MCSGP from a simple, non-
optimized batch process yields a superior product quality in a
shorter time
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 13
Contichrom Software
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 14
Contichrom® software
• Wizards with graphical user interface for easy method programming
• Automated conversion from batch to MCSGP process
• Extensive library of pre-defined methods for all standard operations
Fast and secure process development
• Intuitive software for operation of batch and MCSGP
• Active flow path highlighted in flowsheet
• Pause/continue functionality, even for continuous chromatographic operations
Easy to operate
• Detailed evaluation capabilities with standardized PDF reports
• Data export functions
Integrated evaluation and reporting
• Full audit trail and change control
• User management hierarchy provides high operational and data security
• FDA 21 CFR Part 11 compliant
Full data security and traceability
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 15
Step 1:
retrieve chosen
chromatogram of
batch run from
database
Step 2: interactive definition
of product range (red) and
recycling fractions (blue):
pull bars to define
boundaries (dotted lines)
Step 3:
push button to convert batch to
MCSGP process
Automated conversion of batch to MCSGP method
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 16
Contichrom Equipment
Segmentation
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 17
Contichrom® segmentation
API Output
1 g/day 10 g/day 100 g/day 1 kg/day 10 kg/day
Contichrom® lab (10/100)
Contichrom® pilot 500
Contichrom® process (180 L/hr)
Launched
03/2012
Customized
equipment
Customized
equipment
Contichrom® pilot Customized
equipment
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 18
Biosimilars
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 19
Biosimilar Development Aims
Global Development: one product that can be
sold worldwide
Interchangeability: the biosimilar product is so
similar that it is interchangeable and can tap the
originator product market
De-risked IP: access to US market without
infringement of originator patents
Economics: competitive COG, low CAPEX
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 20
Biosimilar Development for a Global Market
Biosimilar products are developed with the aim of
marketing them worldwide
EU: Biosimilar guidelines have provided guidance
for the development and registration of products
US: Biologics Price Competition (BPC) and
Innovation Act of 2009 – signed into law March 23,
2010: unclear development path for biosimilar vs
interchangeable products . Legislation requires
biosimilar applicant to disclose manufacturing
process to reference product sponsor
These additional legal constraints increase the
project /litigation risk and costs
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 21
Biosimilar Classification
Differentiation between „Biosimilar“ and „Interchangeable Biosimilar“
„Biosimilar“ – „highly similar“ to a reference biological product where
„highly similar“ means minor differences in clinically inactive components
for which there are no „clinically meaningful differences between the
biological product and the reference product in terms of safety, purity and
potency of the product“
„Interchangeable Biosimilar“ – a „Biosimilar“ that is expected to
produce the same clinical results as the reference products in „any given
patient“, and the risk of safety or diminished efficacy is not greater than
the risk of using the innovator product without switch
An Interchangeable Biosimilar may be distributed without intervention by
professionals who prescribed the reference drug
The first „Interchangeable Biosimilar“ can claim 1 year Market Exclusivity
in the US and has a much brighter prospect for commercial success than
a normal biosimilar
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 22
How similar should a Biosimilar be?
The closer a biosimilar product is to an originator
product in terms of its physicochemical
characteristics, the more likely it is to be registered
and the lower the risk of inferior safety and efficacy
The closer a biosimilar product is to an originator
product in terms of its physicochemical
characteristics, the more likely to be granted an
interchangeable status
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 23
Notification and Patent Assertion
Unlike the BLA process, filing under the aBLA pathway
requires the disclosure and publication of the full
dossier of the biosimilar manufacturer and immediately
opens the door for the innovator or even third parties
(universities, other companies) to file infringement suits.
The innovator company can sue at any time, even
waiting to file suit 2 weeks before the biosimilar
launches. Because the litigation process starts after the
completion of development, losing on a single patent
may actually require the biosimilar developer to
redesign the product entirely and consequently conduct
new clinical trials.
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 24
Risk of Patent Litigation
Originator attempts to protect its product through
numerous process patents that will continue even
after the substance patent has expired
Using conventinal off-patent processes to circumvent
the existing process patents may not yield a product
that is biosimilar enough
Only a patented new process principle can provide a
biosimilar product and reduce the risk of infringing
originator process patents
ChromaCon offers a novel and patented process
principle that reduces the risk of litigation for
biosimilar products
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 25
Biosimilar Economics
The MCSGP Technology offers:
a 50% reduced COG: higher yield at given quality
a 50% reduced OPEX: faster processing, 70%
lower buffer consumption
A 30% reduced CAPEX: lower utilities and solvent
infrastructure
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 26
Uses of MCSGP technology for Biosimilars
Generation of complex biosimilars including MAbs
which are highly similar to the originator product
Enabling technology: fractionation of variants of
monoclonal antibodies for second generation products
(“bio-better”) case study Herceptin variants
Fractionation of PEGylated proteins Neulasta
Purification of PEGylated glyco-proteins (e.g. 2nd
generation Epo, Glucocerebrosidase, Factor VIII)
Complex generics (omega-3 FA, Enoxaparin)
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 27
Key Advantages of MCSGP for Biosimilars
1. Reduces the risk of patent litigation in the US
through the legal requirement of patent and
process disclosure to the originator
2. Allows to design an IP-protected process that
yields a biosimilar product that is very close to the
originator product
3. Facilitates the claim of interchangeability of
biosimilar products in the US
4. Provides the best DSP solution resulting in
competitive COG for API and lower CAPEX and
operating costs
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 28
Biobetters
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 29
Example : varying mAb profiles
Feed Product
Erbitux®
(Cetuximab)
Herceptin®
(Trastuzumab)
Avastin®
(Bevacizumab)
(variable isoform content) (Contichrom-purified)
Ref: T. Müller-Späth, M. Krättli, L.
Aumann, G. Ströhlein, M.
Morbidelli: Increasing the Activity
of Monoclonal Antibody
Therapeutics by Continuous
Chromatography (MCSGP),
Biotechnology and
Bioengineering, Volume 107,
Issue 4, pages 652-662, 1
November 2010
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 30
Example: Biobetter mAB «Herceptin»
Originator mAb product
«Herceptin» contains 7 isoforms
with different activities (10%-
150%)
Using Contichrom, a
homogeneous biobetter product
has been isolated with high yield
and purity, having 140% activity
Potential for a Biobetter
„Herceptin“ with lower dosing and
better safety profile shown
Isoform heterogeneity applies to
all therapeutic mAbs
100%
140%
12-30%
Activity of Herceptin isoforms
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 31
Application Example: PEGylated proteins
Constraints:
Low yield of desired species at expensive production
step using batch chromatography
Contichrom technology provides 50% higher yield and
purity with 5x higher throughput
© ChromaCon AG // Contichrom® for biosimilars and biobetters // www.chromacon.ch // ver. May 2013 32
Contichrom provides 50% higher yield with 5x higher
throughput
Contichrom: Purification of PEGylated protein
Analytical SEC of feed and
Contichrom product
Prep. AIEX Batch elution of feed (load 4.3 g/L)
Contichrom: +10% purity
Contichrom:
+30% yield