Case Study - Bruckner Analysentechnik · Application Example: PEGylated proteins Constraints: Low yield of desired species at expensive production step using batch chromatography

© 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 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


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%


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


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


Contichrom® & MCSGP explained


Contichrom®: All-in-one proces capabilities

Contichrom® Preparative HPLC/FPLC

MCSGP

Capture-SMB/ SMB

Sequential chromato-

graphy

Batch Batch


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


Contichrom® & MCSGP explained

Full animation: click here

http://www.chromacon.ch/media-2/process-animations/




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®


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


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


Contichrom Software


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


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


Contichrom Equipment

Segmentation


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


Biosimilars


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


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


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


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


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.


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


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


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)


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


Biobetters


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


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


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


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

Documents

Case Study - Bruckner Analysentechnik · Application Example: PEGylated proteins Constraints: Low yield of desired species at expensive production step using batch chromatography