Area II – Products and Structures

K1 Competence Center – Initiated by the Federal Ministry of Transport, Innovation & Technology (MMVIT) and the Federal Ministry of Economics & Labour (BMWA). Funded by FFG, Land Steiermark and Steirische Wirtschaftsförderung (SFG).

Area II – Products and Structures

Stefan Leitgeb15.06.2010

RCPE

The Research Center Pharmaceutical Engineering GmbH (RCPE GmbH)

is an interdisciplinary research institute in the area of pharmaceutical

process- and product-development in Graz.

The RCPE focuses on the development and production of

pharmaceuticals using rational, science-based methods derived from a

mechanistic understanding of relevant phenomena at all scales.

Our goals are:

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Our goals are:

• the development of modern pharmaceuticals and therapeutics,

• new drug-delivery methods and diagnostic tools,

• implementation of new quality-based production processes based on

state-of-the-art scientific knowledge.

Vision and Mission

Vision

„RCPE“ – We make tomorrow’s drugs possible

Mission and Approach:

� Combination of multi-disciplinary knowledge from process

engineering, pharmacy, chemistry, biotechnology, materials science and

nanotechnology to develop a coherent scientific basis for process- and

product-development.

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product-development.

� Close collaboration with Austrian and international partners from the

pharmaceutical, biopharmaceutical and diagnostics industry, to develop

methods for design, optimization, scale-up and control of their new

manufacturing processes.

� Development of innovative processes and process simplification.

� Establishment of technology platform for science and industry with

focus on knowledge transfer.

� Integration of targeted education and gender mainstreaming

activities.

Location Graz

Graz is not only the second largest city in

Austria it´s also a leader in the field for life-

sciences. The city hosts the Graz University of

Technology, University of Graz, Medical

University of Graz and the Joanneum

Research. These institutions work closely

together in teaching and research and host

excellent researchers and high-end equipment.

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Additionally Graz is hosting the Austrian

Center for Industrial Biocatalysis (ACIB) and

the cluster human.technology.styria. In recent

years a couple of small companies working in

the fast-growing field of life-science were

founded and settled in Graz. Therefore the city

of Graz can offer a great infrastructure and

facilities for the investigation of life-science

products like pharmaceuticals.

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Area 2 – Products and Structures

Area II nucleates research efforts focusing on experimental and computational studies to obtain

an understanding of product quality and behavior, as well as on structuring methods (e.g., nano-

particle formation, hierarchical particle technology, micro-particle formation, scalable production

processes, etc.). Area 2 can be divided in two divisions:

→ large molecule drugs

Goals:

→ small molecule drugs

Goals:

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→ Protein engineering and analysis for improved

formulation properties

→ Development of stable formulations

→ Investigation of inactivation pathways

→ Understanding aggregation propensities

→ Characterization of API – polymer interactions

→ Nano-particle formation processes

→ Development of stable formulations

→ Development of drug delivery systems

→ particle structuring methods

Pharmaceutical biotechnological products

One of our key research focuses within Area II is located in the field of

recombinant pharmaceutical proteins. The market of pharmaceutical

biotechnological products is an emerging, fast-growing field. These

products can be divided into several classes:

→ Vaccines

→ Therapeutics from blood or animal organs

→ Antibiotics

→ Recombinant proteins

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→ Recombinant proteins

→ Cell and gene therapeutics

Pharmaceutical biotechnological products bear a huge potential in

medical treatments, however, they are often difficult to handle and

show limited lifetimes. We focus our research on the field of

recombinant proteins – which is by far the largest group of

biotechnological pharmaceutical products – and especially on the

improvement of their quality in terms of stability. Examples for

pharmaceutical recombinant proteins are monoclonal antibodies or

insulin.

Production of pharmaceutical proteins

Cloning intoexpression

vectorTrans-formation in

host cell

Fermen-tation and

proteinexpression

Storage

Main field of expertise: pharmaceutical

development

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RCPE - Area 2

Identificationof targetprotein

Isolation ofgene ofinterest

Protein purification

Packaging

Formulationof proteinproduct

Manufacturing

Integrated quality by design approach:

Intelligent product design

Formulation of pharmaceutical proteins

Processengineering level

Stirring+ mixing

(Freeze)-drying

Filtration Refolding

Freeze-thaw

Crystal-lisation

filling

storage transport

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RCPE - Area 2

API FormulationProduct atcustomer

Molecular level

Shearstress

Packagingmaterial

Surfaceinteractions

Hydration effect

Phase transition

Excipients

Formulationconditions

Environ-ment

One-stop shop

Pharmaceutical

proteins

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Formulation

Development

Influence of

process-relevant

parameters of

critical operations

on proteins

Modifications of

proteins for

improved

performance

Stability

investigation and

optimisation of

biopharma-

ceutical products

Formulation development

We offer the knowledge and competence for the development and improvement of liquid

protein or peptide formulations. We can provide you a one-stop-shop with profound

knowledge in several fields of research. Our strength is the combination of a set of

different tools which is outstanding in this field. We benefit from the infrastructure in Graz

where the Graz University of Technology, University of Graz and Joanneum Research build

a large cluster of expertise.

Here is what we can offer:

� Complete formulation development for your needs

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� Complete formulation development for your needs

� Statistical optimisation

� Extensive biophysical characterisation of pharmaceutical proteins

� Stability and aggregation investigations

� Accompanying computer simulations

� taking these parameters together we not only can give a formulation recipe at the end

of the project but also a deep insight into the structure-activity-stability relationship of

your pharmaceutical protein.

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Influence of process-relevant parameters of critical operations on proteins

Pharmaceutical proteins have to face several steps after purification of the bulk product until

they are used by humans. Those steps are a source for stress that is applied to the proteins and

which can have negative effects on the product.

Critical standard operations can be:

� Freezing and thawing

� Stirring

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� Stirring

� Freeze-drying

� Filtration

� Storage and transport

We offer a detailed characterisation of the influence of critical parameters on pharmaceutical

products. The combination of statistical methods, simulation tools and biophysical

characterisation is used for the efficient investigation of the protein and its properties. The use

of diverse techniques and approaches offers a high potential for detailed understanding of the

effect of stress parameters on proteins leading to detailed solutions and improvement of the

final product.

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Stability investigation and optimisationof biopharmaceutical products

A main drawback for the use of pharmaceutical proteins in therapy is their often limited

stability. The cause for the loss of function is often poorly understood and can be assigned

to diverse reasons. However, even if the reason is identified the mechanism for

inactivation or reduced stability remains mostly elusive. There are several factors that can

influence pharmaceutical proteins on a molecular level:

� Liquid environment (buffer type and pH)

� Surface interactions (liquid – gas, liquid – solid)

� Environmental influence (temperature, light)

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� Environmental influence (temperature, light)

� Interaction with storage / packaging material

� Physical stress (shear stress)

� …

� We offer a detailed mechanistic investigation on a molecular level of the inactivation /

loss of stability of pharmaceutical proteins. We will not only identify critical influences on

the target proteins performance but will also work on revealing the underlying mechanism

to get a better understanding for the process. Based on these results we will provide

possible solutions for improved performance of the pharmaceutical proteins

Modifications of proteins forimproved performance

Proteins are getting a lot of attraction in the pharmaceutical industry due to their high

potency. The main problems when working with proteins are usually their stability and

solubility which limit the use of proteins as therapeutics. Improving these properties is

usually very time-costly and needs a lot of ressources. Processes that lead to

destabilisation or aggregation of proteins are usually poorly understood and therefore the

improvement of proteins is based on trial and error.

To overcome these problems we can offer you the following:

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� Detailled characterisation of the problem using a set of biophysical techniques and

computer simulations.

� Modification of proteins for improved performance.

� Optimisation of proteins for/by pegylation

� We can offer you a complete package that includes the capturing of the state of the art,

detailled characterisation of an inactivation mechanism and target-oriented protein

modification leading to improved performance and lifetime.

IPRS AND FUNDING MODEL

� Defined IPRs(Intellectual Properties Rights)

� Project Financing (Example)

� Full IPR to industry partners

� Gratuitous, non-exclusive, timely unlimited non-transferable right of use to RCPE

� Exploitation and utilization rights to RCPE after 12-24 months

� Details must be singularly clarified in cooperation contract

Project Volume € 500.000,-

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Project Volume € 500.000,-

Funding 49% € 245.000,-

Inkind University 5% € 25.000,-

Cash Industry 26% min. € 130.000,-

Inkind Industry 20% max. € 100.000,-

3 Industry Partners:

Cash per each industry partner € 43.333,-

Inkind per each partner € 33.333,-

2 Industry Partners:

Cash per each industry partner € 65.000,-

Inkind per each partner € 50.000,-

49% fundings

min. 26% cash5% scientific

max. 20% in-kind

RCPE - KEY BENEFITS

� RCPE provides independent R&D in the field of pharmaceutical engineering, bridging the gap between science and industrial applications

� Defined IPRs provide maximum benefit for industrial partners

� Long-term cooperation with the RCPE possible (funding period of 7+ years)

� Diversity in research activities: small preparatory studies

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(literature review, initial measurements, proof of concept) up to extensive multi-year research programs are possible

� Only 26% cash contribution required in joint research projects

� No time-consuming project application procedures; project work plan can be defined bilaterally and the project can be started immediately

� RCPE can provide additional scientific partners if expertise is required

� RCPE can provide additional industrial partners if industrial cooperation is desired and/or for project cost-sharing