Research Center Pharmaceutical Engineering
Annual Scientific Report 2010 / 2011
www.rcpe.at
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Annual Scientific Re
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Table of Contents
Introduction
Statement of the Directors
Vision, Mission and Goals
Highlights 2010 / 2011
Statement of the General Assembly
Statement of the Chairperson of the Supervisory / Strategy Board
Statement of the Speaker of the Program Committee
04
06
07
08
10
12
Organization and Management
14
Structure14
Facts and Figures
14
Our shareholders
14
Key Personnel
16
Human Resources
18
Recruiting & Personnel Planning
18
Human Resource Development
19
Gender Mainstreaming
23
Research25
26
Area I “Advanced Simulation Technology”
38
Area II “Products and Structures”
Area III “Process Engineering and Manufacturing Science”
46
RCPS – A Business Unit of the RCPE
64
NonK Services
66
72
Test Facilities & Simulation Tools
Scientific Output of the Center
77
77
Publications
Diploma & Doctoral Theses
86
Patents89
Congresses90
Workshops90
Financial Annex
92
Bilanz92
94
Gewinn- und Verlustrechnung
Boards and Partners
General Assembly
Supervisory Board / Strategy Board Scientific Advisory Board (SAB)
Program Committee Business Partners
Scientific Partners
96
96
96
96
97
98
100
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Statement of the Directors
We cordially want to welcome interested readers to the annual scientific report of the Research
Center Pharmaceutical Engineering GmbH (RCPE or the Center) for the business year 2010/2011!
This report has a twofold mission: it should, on the one hand, provide an overview of the Center’s
achievements and on the other hand, provide a detailed summary of our scientific output. In
the last year the Center has made significant progress, both in terms of science and economic
growth. However, this year we would also like to highlight our young and strong research team
that is always looking for new scientific and technical challenges. As such, the report may be
viewed as an invitation to industrial partners to discuss challenges and problems with us and our
partners.
Over 17% Growth in the K1 Area
Thanks to the dedication of our employees and the scientific expertise of our key researchers,
during the reporting period we successfully secured 3 new K1-projects with a total volume of
over 2.7 million Euros. These new projects will affect the turnover during the second funding
period, and demonstrate the successful concept and operation of the Center. Moreover, due to
our exceptional acquisition performance, the number of partners has increased: this year alone,
we could add 8 new partners. In summary, at the end of the reporting period, 46 enterprises and
10 scientific institutions were our partners in the K1 Area.
Over 12% Increase in Turnover in the NonK Area
As before, turnover in the NonK Area has increased. During the reporting period a 12.3% growth
was achieved, and the turnover doubled compared to the previous year. The emphasis was on
services and paid R&D-services. This significant accomplishment was in part possible thanks to
the Center’s excellent international and national reputation.
Human Resources and Infrastructure
The budget growth of 23.5% compared to the previous year affected human resources. In fiscal
year 2010/2011 the number of employees grew by 30% compared to the previous year. At the
end of the reporting period, 55 FTE (full-time equivalents) were employed by RCPE. Currently, we
have 73 employees, with an average age of 32, an academic quota of 70% and a female quota
of 44%. Moreover, 13 FTE are employed at our industrial and scientific partners.
In addition to highly-qualified personnel, one of RCPE’s main goals is a state-of-the-art infrastructure. Therefore, substantial investments were made during the reporting period. Together with
the research and company partners, RCPE has built an outstanding testing, experimental and
analytical facility. This present top-level infrastructure makes the Center even more attractive for
industrial and academic co-operations and greatly contributes to our long-term development.
Scientific Output
The long-term strategic orientation of RCPE’s research projects is particularly important for the
innovation culture of the national economy. A substantial improvement of products and processing technologies is linked to a targeted generation of new knowledge. The strong integration of
university partners into the Center not only generates knowledge but affects other important
aspects, such as scientific research within the institutional framework of the Center’s partner
universities.
As main strategic focus of the Center, the acquired knowledge is disseminated in peer-reviewed
journals and conference presentations. Publishing research results in top-level journals ensures
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that the newly-generated knowledge is evaluated by and discussed among the international
scientific community, increasing RCPE’s international reputation. 51 scientific papers in reviewed
journals, 49 conference contributions, 39 poster presentations, 22 completed and ongoing doctoral dissertations, and 36 completed and ongoing diploma/master theses clearly demonstrate
that the Center has set new standards of research cooperation between business and science.
We would like to thank all of our partner companies, which make this strategy possible through
their financial contributions, allowing us to prioritize long-term competence building at the Center
over short-term solutions.
Outlook for the Next Year – Preparation for Evaluation
The year 2010/2011 was the time for the COMET evaluation: in the fall of 2010, a review (i.e.,
the assessment of the first two research years) was performed and the Center’s performance
was unanimously approved. The fourth-year evaluation by an international jury of experts will
take place in October of 2011. A detailed “core document” prepared for this evaluation summarizes our operational achievements during the first 2 1/2 years and describes the strategic
and technical ideas for the coming years. As a collective strategy of the Center, this document
was prepared based on several strategy workshops including RCPE’s employees and partners.
As the Center directors we are confident that the evaluation will be positive and will reflect the
Center’s strong performance over the last years.
Acknowledgements
Our achievements have been made possible thanks to the support and cooperation – in kind
and financial – provided by our business and research partners. We would like to express our
gratitude for their commitment to RCPE. Furthermore, the success would not be possible without
the dedicated work of the Center’s 73 employees and their professional project managers. We
would like to thank them for their vigilant scientific work. The awards and prizes that they have
won honor their achievements.
We also wish to express our gratitude to the sponsors, owners and consultants who have
ensured the optimal conditions at the Center and provided trust and support through the years.
Lastly, we also thank the members of the Supervisory/Strategy Board for their dedication and for
allowing us to grow the Center’s international reputation every year. Together, we look forward to
the next business year and we are prepared to meet the new year’s challenges.
Univ.-Prof. Dipl.-Ing. Dr. Johannes G. Khinast
Scientific Director / Leader
Mag. Dipl.-Ing. Dr. Thomas K. Klein
Managing Director
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Vision, Mission and Goals
“RCPE” – We make tomorrow’s drugs possible
It is our aim to transform pharmaceutical product- and process-development from an empirical
approach to a rational science-based endeavor in accordance with ICH’s Quality-by-Design
framework.
Mission
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Combination of multi-disciplinary knowledge for science-based drug-product and process
development
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Close collaboration with Austrian and international partners to foster competitiveness and to
strengthen our partners’ economic success
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Technology and innovation platform for science and industry
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Integration of targeted educational and gender-mainstreaming activities to create tomorrow’s
workforce
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Raising public awareness of the importance of research and science
Goal
To be the national and European focal point for science-based development of structured drug
products and diagnostics, as well as their manufacturing processes.
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Highlights 2010 / 2011
August 6th, 2010
RCPE welcomes “Glatt GmbH” as 40th business partner.
September 15th, 2010RCPE wins the Fast Forward Award 2010 with the project A3.3 “Cellulose based Carrier Matrices for Controlled Drug Delivery” (“Pills on
Paper”).
Sept. 16.-18.th 2010Successful “4th International Congress on Pharmaceutical Engineering
(ICPE)”, as satellite symposium of the “8th Central European Symposium
on Pharmaceutical Technology (CESPT)” at the University of Graz with
more than 300 participants.
October 1st, 2010
Additional office space at Plüddemanngasse 104, 1st floor.
Implementation of the new technical lab (“Pharmaceutical Process
October 1st, 2010
Development Lab”) for scale-up production.
October 13th, 2010Site-Visit in the course of the 2-Year-Evaluation of the RCPE by the
Austrian Research Promotion Agency (FFG).
November 9th, 2010
2nd place in the category “Innovation” of “Tops of Styria 2010”.
January 1st, 2011
Dr. Simon Fraser is appointed as Deputy Director.
January 1st, 2011
Dr.in Christine Voura takes over Area III as Department Head.
February 2011Eva Littringer, MSc., an RCPE employee, is the first graduate of the NAWI
Graz Masters Course in “Chemical and Pharmaceutical Engineering”.
March 3rd, 2011Christiane Loidl, an RCPE intern of Summer 2010, wins the generation.
innovation Award. Stefan Leitgeb, Christiane´s mentor at RCPE is also
awarded.
March 15th, 2011RCPE wins the science2business award (2nd place) in the field of good
cooperation between science and industry.
June 20th, 2011Core Document for the 4-Year-Evaluation is submitted to the Austrian
Research Promotion Agency (FFG).
June 30th, 2011
RCPE successfully completes its 3rd business year.
Staff: 73 (55.21 FTE)
Quota of Female Employees: 43.84%
46 Business Partners, 10 Scientific Partners, 2 Other Partners
Project Volume signed: € 20.80 Mio. (K1 and NonK)
1 Patent granted, 8 Patent Applications
32 Publications in Reviewed Journals
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Statement of the General Assembly
After its first three years of existence RCPE presents itself as a medium-sized research company
internationally renowned in its field of activity. In this capacity it proved fruitful for both its partners
and shareholders. After an initial build-up phase the Center has now consolidated at a volume of
about 4 million Euros per year.
Networking on international and national level
The close cooperation with universities in Graz (the Graz University of Technology and the University of Graz) and JOANNEUM RESEARCH has been intensified in the last fiscal year. This
cooperation included joint public appearances at the successful “Central European Symposium
on Pharmaceutical Technology” (CESPT) in fall 2010. This well-attended event with about 330
participants from 30 different countries was accompanied by the 4th International Congress
on Pharmaceutical Engineering (ICPE) as a satellite symposium. The high-level presentations
of experts from all over the world and from Center employees characterize the high scientific
standards set by the Center and its scientific and industrial partners. This event, which is directed
both at industry and science, is an important instrument for increasing the public’s awareness
of the Center. Planning for the 5th ICPE in September 2011 is underway. Such events support
RCPE’s success in achieving the strategic goal of fostering visibility through networking.
Furthermore, the numerous invitations the RCPE received to present at economic events testify
to the success of ongoing efforts to expand networking in the industrial area. And finally, the
addition of several new international partner companies is proof of the increasing international
visibility of the Center, and therefore of the Center’s owners as well.
The Center not only focuses on international contacts, but is equally engaged in building up and
expanding local partnerships. The level of cooperation between the Center and the institutes
of the universities is best illustrated by 17 ongoing Ph.D. theses and 11 diploma/master theses
of RCPE employees, which are being supervised by faculty members of the Graz University of
Technology and the University of Graz. Cooperation with the JOANNEUM RESEARCH (JR) is
equally strong, as – among other things- JR is an important partner in the ‘Process Optimization for Liquid Formulations’ project in Area II ‘Products and Structures’. Furthermore, Center
publications also reflect the close link with the universities: almost 50% of all publications by the
Center are joint publications with scientific institutions.
In summary, this is clear evidence of the strong integration of the owners and institutes in the
Center.
Research Results
RCPE has again delivered numerous scientific success stories, which is reflected by 51 publications, 1 patent and 8 applications, 36 diploma/master theses and 22 Ph.D. theses either started
or completed, various implemented processes, 49 conference talks and 39 posters at prominent
international conferences. The Center has grown to a well-organized institution of considerable size and high international visibility, and has been able to attract additional international
companies that are interested in partnering to invest in Austria as a pharmaceutical engineering
stronghold. The Center will further provide an exciting environment to carry out leading research
to enhance the interaction between academic research and industrial participation.
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New Building – Building Infrastructure Together
Infrastructure planning is well advanced. As of mid-2012 RCPE will find ideal conditions in the
newly built research premise of TUG on the Inffeldgasse campus. This new production technology
center (PTZ) with more than 1000 m2 will serve as an ideal facility for both offices and laboratories
for the Institute for Process and Particle Engineering of the Graz University of Technology and
the RCPE.
Four-year Evaluation
The fall of 2011 will be a critical time for RCPE, as the four-year evaluation by an international
jury will judge the scientific and economic performance of the Center. However, the General
Assembly is confident that RCPE will pass this evaluation with the highest distinction. In this
context, we will continue to provide the essential conditions RCPE needs in order to establish
an enduring link between science and industry and wish the Center good luck for the four-year
evaluation in the fall of 2011.
Ao. Univ.-Prof.in Mag.a Dr.in Renate Dworczak
University of Graz
Chairperson of the General Assembly
Univ.-Prof. DDipl.-Ing. Dr.Dr.h.c. Harald Kainz
Graz University of Technology
Univ.-Prof. Dipl.-Ing. Dr. Wolfgang Pribyl, MBA
JOANNEUM RESEARCH Forschungsgesellschaft mbH
Page 9
Statement of the Chairperson of the
­Supervisory / Strategy Board
Research, technology and innovation are of extraordinary importance for the economic growth
of a country. From the moment it was founded, the competence center for pharmaceutical
engineering RCPE has contributed to further strengthening Styria’s position as research and
technology location by undertaking numerous R&D projects, developing patents and investing in highly qualified employees, who convert their knowledge into new solutions. RCPE has
become one of the most important focal points for industry-oriented research in Styria and an
internationally-recognized high-performance research institution. Not only companies that do
research with the Center and profit from it, but world-renowned institutions rely on its expert
knowledge. The present scientific report testifies to RCPE’s innovative strength.
RCPE’s Key to Success
The success of the Center is, on the one hand, evident from the many scientific publications and
patents originating from the basic research made within the strategic projects. The RCPE, on the
other hand, also managed to establish the NonK Area as very successful research service outside
of the funded K1 Area. The NonK revenue doubled during the past fiscal year.
The quality of the scientific work of the many outstanding employees is reflected not only by
the relevant characteristic numbers (publications, dissertations, bachelor’s theses, etc.), but
by the continuous development of the partner structure. The Center has over 40 national and
international industrial partners.
One of the most important events for fostering international cooperation is the International Congress on Pharmaceutical Engineering, which took place in September 2010 in Graz for the fourth
time. The Congress (in 2010 together with CESPT) focused on recent developments in the areas
of QbD, continuous processing, process understanding, modeling, pharmaceutical nanotechnology and PAT and attracted some 330 participants. The opening lecture was delivered by Prof.
Carl Djerassi (inventor of the contraceptive pill). The keynote lectures featured internationally-
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renowned scientists, including Iztok Grabnar, Ljubljana (Slovenia), Peter Kleinebudde, Duesseldorf (Germany), Steve Hammond, Pfizer (USA), Klaus Langer, Münster (Germany), Claus Michael
Lehr, Saarbrücken (Germany), Wolfgang G. Kreyling, Helmholtz Zentrum München (Germany),
Thomas Rades, Dunedin (New Zealand), Geza Regdon, Szeged (Hungary), Barbara Rothen
Rutishauser, Bern (Switzerland), Jonathan PK Seville, Warwick (UK), Frantisek Stepanek, London
(UK), Alexander Yarin, Chicago (USA) and Werner Weitschies, Greifswald (Germany).
In summary, a successful mix of the Center’s long-term K1 projects, sponsored NonK projects
and numerous services has created a foundation for successful year three.
The Future / 4-Year Evaluation
The results of the past fiscal year and all relevant parameters demonstrate that 3 years of the
consistent structured work at the competence center RCPE were successful. I thank RCPE’s
team, the partners and sponsors for the successful and trusting co-operation. I wish RCPE much
creativity, commitment and innovative joy with regard to the future developments and, above all,
the 4th year evaluation.
Univ.-Prof. DDipl.-Ing. Dr.Dr.h.c. Harald Kainz
Graz University of Technology
Chairperson of the Supervisory / Strategy Board
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Statement of the Speaker of the
­Program Committee
Strong Development over the last three years
Over the past three years, significant progress has been made. RCPE is now internationally
recognized as a key player in the field of pharmaceutical engineering, supported by the fact that
researchers of the Center are delivering keynote lectures at the top conferences of the field or
are invited to be guest editors of special issues on pharmaceutical engineering in the premier
scientific journals. The Center organized the fourth International Congress on Pharmaceutical
Engineering with internationally renowned speakers in 2010, and will do so again in the Fall of
2011. Most Austrian pharmaceutical companies have joined RCPE and seven of the top ten
pharmaceutical companies are working with RCPE in one way or another, including Roche,
GlaxoSmithKline, Novartis, Sanofi Aventis, Abbott, Bayer and Merck. Projects are underway
with the remaining companies.
RCPE synergistically addresses pharmaceutical product- and process-related research
problems, applications and challenges with a highly interdisciplinary team of researchers by
combining expertise from the pharmaceutical sciences, chemical engineering, materials science, chemistry, nanotechnology and biotechnology.
The Consortium of industrial and academic partners reflects this interdisciplinary approach
and consists of national and international research institutions and company partners working
in the areas of pharmaceutical development, process technology, process design, formulation
science, biotechnology, materials science and modeling and simulation. Thus, the Consortium
includes all critical elements of products and process development, combining this extensive
expertise in a unique new Center.
Due to the multi-disciplinary nature of the Center, spanning all relevant industrial sectors, RCPE
has the ability to tackle “grand-challenge problems” that are relevant for a wide number of
companies. This, for example, may include comprehensive modeling and simulation tools for
rational and science-based product and process development. In that way, RCPE aims at
eliminating the barriers for a science-based product and process development, rather than
focusing on one-at-a-time solutions.
RCPE – as an independent and science-based entity – acts as a mediator between research,
industry and regulatory bodies. Thus, the Center has a unique position, providing “added-value”
to the international community.
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In the first three years RCPE researchers have published or submitted numerous publications
to peer-reviewed journals, have given lectures at international conferences and have excelled at
portraying the RCPE as a vibrant Center with innovative research.
Despite some adaptations of the research program due to changes in company strategy and
state-of-the-art, the overall focus of the center was transformed successfully into an internationally visible research Center, having more than 70 employees and a high women ratio.
In summary, I believe that RCPE has developed into a successful and internationally recognized
research Center in Europe’s scientific landscape.
The Future / 4-year Evaluation
As the Speaker of the Program Committee, I would like to thank all of the participating partners
for their support in the last three years. One important milestone for the Center is the four-year
evaluation in the fall of 2011. In order to build a strong foundation for the future of the RCPE, I
would like to ask all partners to pledge their energetic support for the RCPE in the preparation of
the core-document, strategic workshops, and the definition of specific new projects. In this way,
we can contribute greatly to the Center’s economic security and long-term scientific orientation.
Dipl.-Ing. Alexander Rinderhofer, MBA
Speaker of the Program Committee
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Organization and Management
Structure
For organization and administration, the Center has implemented a lean and modern management structure with the goal of translating research projects into true scientific progress and
technological advantages for RCPE’s industrial partners.
Legal Structure
RCPE is a limited liability company (GmbH). This legal structure was considered the best choice
due to its clear statuatory framework (the GmbH Act) and advantages in terms of liability issues.
In addition, it offers a high degree of flexibility with regard to the reporting system and the tasks,
functions and interactions of the corporate bodies.
Location
RCPE has its main location on TUG campus, which promotes close cooperation with TUG
institutes. RCPE has access to TUG’s well-equipped laboratories and is in close proximity to
the other scientific partners (KFU, JR and the OEAW). In addition, RCPE has established its own
process and analytical laboratory with state-of-the-art equipment, such as a continuous extrusion system, a fully instrumented laboratory tablet press, a batch fluid bed system, a compaction
simulator, granulators, nano-spray driers and many others.
For details regarding RCPE’s state-of-the-art pharma-product and process science lab see
Chapter “Test Facilities & Simulation Tools” on page 71.
Currently, TUG is constructing a new building (1000 m2 of lab and office space exclusively for
RCPE, including a GMP lab) on TUG campus that will be finished in the spring of 2012.
Facts and Figures
73 employees
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Signed projects’ volume K1:
18.2 million Euro (18 projects)
JJ
Signed projects’ volume NonK:
2.6 million Euro
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46 Industrial partners
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10 Scientific partners
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2 other partners
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JJ
JJ
JJ
JJ
JJ
JJ
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1 Patent, 8 Patent Applications
17 ongoing Doctoral Theses
5 finished Doctoral Theses
11 ongoing Diploma & Master Theses
25 finished Diploma & Master Theses
2 ongoing Baccalaureate Papers
4 finished Baccalaureate Papers
Our shareholders
65 % Graz University of Technology
15 % JOANNEUM
RESEARCH
20 % University
of Graz
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Structure of the RCPE
General Assembly
Program Committee
Program Commission
Supervisory/Strategy Board
• Key Account
• Strategic Leadership
CEOs
• Scientific Lead
• Representation
Deputy Director
ITT2 Proteins
ITT3 QbD
• Internal and external
­consulting
Reporting/Accounting
• Area Integration
• Scientific Output
• Coordination of International
Scientific Appearance
• Patents & IPRs
ITT1 Conti. Proc.
Scientific Advisory Board
• Marketing / PR
• Human Resources
• External Reporting
• Accounting / Controlling
Area I
Area II
Area III
Advanced
simulation
Technology
Products and
structures
Process
Engineering
ITT4 PAT
Service & Research
Contracts
• Services
• National Funding
• International Funding
RCPS
• Regulatory Services
• Consulting
• CMC
• Filing
Infrastructure (Laboratory + Process Lab)
A new organizational chart was implemented in January 2011. The structure consists of the
Center’s management, a deputy director and reporting/accounting staff. The General Assembly
and the Supervisory/Strategy Board act as governance bodies. Projects are divided between
three areas. Four ITTs on continuous processing, proteins, QbD and PAT have been set up to
strengthen the interaction between the areas. In order to perform contract work for companies
the Center has created a separate business unit “NonK Area.”
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Key Personnel
Prof. Dr. Johannes G. Khinast
Scientific Director/Leader
Dr. Thomas K. Klein
Managing Director
Dr. Simon D. Fraser
Deputy Director
Page 16
Dr. Daniele Suzzi
Department Head Area I
Dr.in Christine Voura
Department Head Area III
Dr. Gerold Koscher
Group Leader ITT1 Continuous Processing
Dr. Stefan Leitgeb
Group Leader ITT2 Proteins
Dr. Siegfried Adam
Group Leader ITT3 QbD
Dr. Daniel Koller
Group Leader ITT4 PAT
Key Researcher
Prof.in Dr.in Gabriele Berg
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Biotechnology
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Clean room technology
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Microbiology
Prof. Dr. Günter Brenn
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Multiphase flows and stability
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Rheology and rheometry
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Heat and mass transfer
Prof. Dr. Johannes G. Khinast
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Pharmaceutical engineering
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Multiscale simulation
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Particle technology
Prof. Dr. Robert Schennach
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Infrared spectroscopy
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Surface analysis
Prof. Dr. Bernd Nidetzky
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Protein technology
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Biochemical engineering
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Molecular and applied enzymology
Prof.in Dr.in Nora Urbanetz
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Pharmaceutical technology
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Particle engineering
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Pharmaceutical processing
Assoc.- Prof.in Dr.in Michaela Flock
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Computational chemistry
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Material design
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Property predictions
Prof. Dr. Wolfgang Bauer
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Paper and pulp technology
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Fibre characterization
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Specialty products
Prof. Dr. Andreas Zimmer
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Pharmaceutical nanotechnology
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Drug delivery and drug targeting
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Drug formulation
Ass.-­ Prof.in Dr.in Eva Roblegg
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Solid oral dosage forms
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Oral biological barriers
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Extrusion
Prof. Dr. Peter Kleinebudde
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Pharmaceutical technology
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Solid dosage forms
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Tablet coating
Prof. Dr. Christoph Herwig
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Integrated bioprocess design
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Quality by Design
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Integrated biotechnology
Doz.in Dr.in Ruth Prassl
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Biophysical chemistry
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Nanostructure analysis
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Process monitoring
Priv.-Doz. Dr. Frank Sinner
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Nanoanalytics
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Biomedical technology
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Nanosystems
Prof. Dr. Benjamin J. Glasser
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Granular flows
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Powder drying
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Continuous manufacturing
Prof. Dr. Fernando J. Muzzio
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Pharmaceutical engineering
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Powder technology
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Particle engineering
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Human Resources
Qualified and motivated employees ensure RCPE’s success and future performance. To this
end, the following strategies and policies have been implemented:
Core teams: A highly-qualified core team in each area is crucial for the Center. The core team
consists of permanent staff that maintains the knowledge base in the respective area and of
various Ph.D. and Master students.
Critical mass: Achieving a critical mass in a particular area is crucial for RCPE. Thus, it is of
strategic interest to structure each area such that a critical mass be reached in a respective
field, e.g., in the simulation of pharmaceutical processes via CFD or in the area of powder
characterization.
Qualification: Special emphasis has been placed on building and maintaining a highly qualified
team. It is accomplished by hiring senior and key researchers from all sectors, i.e., both from
universities and the industry, and by providing access to continuing education for a wide range
of topics, from leadership to simulation.
Recruiting and Personnel Development
Motivated and skilled staff members are a key factor to RCPE’s success. Thus, special emphasis was placed on personnel recruitment. The Center’s staff was primarily hired through
(1) existing networks and contacts of the academic partners, (2) contacts with the associated
partners, such as Rutgers University and the University of Birmingham, (3) contacts with the
industrial partners and (4) the human.technology.styria cluster. Newspaper ads played only a
minor role in successful recruiting.
Personnel Development
10
0
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January 09
20
July 08
30
October 08
40
April 09
50
July 09
60
October 09
June 11
April 11
January 11
October 10
July 10
70
January 10
80
April 10
90
R&D K1
R&D NonK
Admin
Service
Contracts
Human Resource Development
Continuing education is critical to RCPE’s success. As such, a targeted qualification program
was created and implemented in 2008.
The Center’s employees are encouraged to take advantage of the diverse training opportunities available to our staff. At RCPE, human resource development comprises two synergistic
components: (1) formal education that incorporates activities associated with a specific educational program and (2) experiential education that allows individuals to informally participate in
activities that broaden their general abilities to succeed in a contemporary society and today’s
workplace environment.
Non-Technical Continuing Education Program
RCPE encourages employees to take part in non-technical continuing education courses. The
following courses were offered to RCPE employees as part of continuing education: (a) communication and presentation skills, (b) teamwork, (c) English (advanced level I+II), (d) self- and
time-management, (e) project management seminars, (f) leadership courses for area managers
and (g) participation in MBA programs (e.g., one of the group leaders is attending the “Generic
Management” MBA).
Technical Training – Master’s Course in Pharmaceutical and Chemical Engineering
In the fall of 2008, the Center supported the introduction of a new Master’s course in pharmaceutical and chemical engineering, which is run jointly by TUG and KFU (NAWI Graz). Until then,
Austria (and most of Europe) had no such program at a university level.
The concise Master of Science in Pharmaceutical Engineering offers engineers and pharmaceutical scientists the skills required for working in the rapidly evolving field of pharmaceutical
product design and manufacturing processes. The curriculum emphasizes “Process Understanding” and “Risk-Based Regulation,” which have been identified by the US FDA and EMA
as guiding principles for awarding licenses to manufacture and commercialize drug products
in the 21st century. This program is free of charge to RCPE employees, who are encouraged to
participate.
We offer our team another unique opportunity: to teach courses at TU Graz (the Chemical and
Pharmaceutical Engineering curriculum). Examples of high-level Masters and Ph.D. courses
taught (or partially taught) by the Center’s staff include
JJ
Dr. Daniele Suzzi: “Modern Simulation Tools for Multiphase Systems”
JJ
Dr. Siegfried Adam: “Course on Quality by Design”
JJ
Dr. Daniel Koller: “Pharmaceutical Process and Analytical Technology”
In-house Knowledge Transfer
Regularly scheduled internal RCPE seminars on a wide variety of technical topics, from Multivariate Data Analysis (MVDA) to formulation development, promote the internal exchange of
scientific excellence. They are scheduled via RCPE’s intranet and serve as a communication
platform and a forum for scientific discussions.
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Career Opportunities for Scientific and Technical Staff
RCPE offers dual career paths, i.e., technical/scientific and managerial.
JJ
Technical/scientific career path: scientific careers, including the completion of Master’s and
Ph.D. theses, habilitations (equivalent of tenure at US universities) or post-graduate studies,
with different levels of seniority (technician, junior researcher, senior researcher and key
researcher).
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Managerial career path: due to RCPE’s lean management structure, only limited opportunities exist for area managers and group leaders. Nevertheless, extensive training is available
to those who choose a managerial career.
International Mobility
Today’s research organizations rely on a high level of international communication and mobility
to keep pace with the global research community. To that end, personnel exchange programs
have been established between the Center and the company and academic partners. For example, an international exchange program with Rutgers University funds 3-12 months’ visits of
students and researchers and visiting scientists. To date, 9 students have been sent to Rutgers.
One of our Senior Scientists, Dr. N. Heigl, was on a one-year assignment at Rutgers University
(from April of 2010 to April of 2011).
Staff Loan to the Industry Partners
In order to facilitate efficient knowledge transfer between RCPE and its company partners,
personnel may be loaned (e.g., to implement a new technology at partner companies). This
approach helps strengthen the ties between RCPE and its partners.
Education & Training
41 % Technician
25 % JR
24 % SR
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4 % KR
3 % Area Manager
3 % GF
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Gender Mainstreaming
Since gender mainstreaming is of critical importance to RCPE, hiring female researchers has
vigorously been pursued. Apart from a flexible work schedule, we offer part-time employment,
telecommuting, day-care and flexible day-care opportunities.
Based on our belief that equal opportunities must exist independent of gender, RCPE takes
proactive measures to balance the gender ratio of its scientific and non-scientific staff. A low
percentage of female students in the area of engineering is a well-known and internationally
recognized problem. Thus, dynamic recruitment strategies are especially important. RCPE has
developed the following plan to recruit and retain women:
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RCPE takes part in the existing TUG gender mainstreaming efforts initiated by the Office of
Gender Equality and Affirmative Action (director: Johanna Klostermann).
RCPE is an equal opportunity employer. When several candidates have the same qualifications, the preference is given to female candidates.
RCPE participates in a program offered by TUG that places small children of their employees at TUG childcare facilities and/or flexible daycare. Furthermore, the Center offers flexible
working hours or telecommuting to working parents of young children.
New employees are mentored by and receive on-the-job training from experienced colleagues. During the 2nd Funding Period, a comprehensive mentoring / coaching program
will be developed.
Through the recruitment and integration of female junior staff, especially in the R&D area, RCPE
currently has 40.63% of female employees in the scientific field and 43.84% of the total Center
staff, which demonstrates the success of RCPE’s policies.
RCPE enforces the use of gender-neutral language for company presentations, profiles, alerts,
information materials and folders.
In 2010 RCPE completed a regional project (generation innovation), which targeted talented
young female high school students, and one FEMtech Career Project, whose aim was to increase the proportion of women in science and to strengthen the awareness regarding internal
gender-related issues.
Gender Mainstreaming:
4.55 % male admin
6.82 % female admin
38.64 % female R&D
50 % male R&D
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Research
As a link between science and industry, RCPE performs applied R&D projects in the area of
pharmaceutical and diagnostic product and process development. Our work extends over three
areas of competence, (1) advanced simulation technology, (2) products and structures and (3)
process engineering and manufacturing science. Our aim is to transfer our scientific results into
innovations utilized by our industrial partners.
Funded (K1) and non funded (NonK) projects
In the RCPE we distinguish between:
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a sponsored project area (K1) and
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a non-sponsored (NonK) project area
In the sponsored projects we are working on pre-competitive R&D projects with our partners
from industry and academic institutions. These projects are supported by public funding. The
NonK project area focuses on industry-oriented contract research and development. In this area
we offer consulting, development or analytical services.
Clearly, the interaction between the funded and non-funded project areas is of key importance to
the organization, as in both areas we develop competence that can be used for other or future
projects.
In the area of the funded projects, we distinguish between two types of projects: industrial
cooperation projects and strategic projects. In the industrial cooperation projects we work on
pre-competitive R&D projects together with one or more industrial partners. These projects are
intended to strengthen the innovative capabilities of our partners. The partnership agreement that
all our partners have signed guarantees identical conditions for all partners. Strategic projects
define projects that deal with basic scientific research which may be relevant in the future for our
industry partners. In that sense, the strategic projects allow the RCPE to build up a profound scientific base for the future. Clearly, we cooperate closely with our scientific partners in the strategic
projects. In the year 2010/11 75% of our project budget was spent on industrial cooperation
projects. With the remaining 25%, we funded selected strategic projects in cooperation with our
scientific partners.
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area I
Advanced Simulation
Technology
Process optimization
n
Numerical simulatio
Granular flow
Multi-scale
Quality-by-Design
Suzzi
Dipl.-Ing. Dr. Danielea Manager
Are
t
[email protected]
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The ultimate goal and the “grand challenge problem” of pharmaceutical engineering are to develop
products and processes in silico, i.e., based on
computer simulations. Many industries, such as
automobile and aircraft manufacturers and producers of microelectronics, are already designing their
products using computational tools. However, little
progress has been made in the field of pharmaceuticals and diagnostic products, primarily since
the associated scientific questions are particularly
difficult to answer. Some of them are:
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How do process parameters affect the quality of pharmaceutical products?
How can models for scale-up, control and optimization
of processes be used within the QbD and PAT framework?
How do the level of structuring, the composition and
the interaction of ingredients in a product affect its
functionality and stability?
How do different levels of structuring (molecular aggregate-nanostructure-microstructure) interact with each
other, and what level of noise or structure needs to be
considered with regard to the structure-functionality
relationships?
Thus, the goals of the Center include:
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Development of multi-scale simulation/optimization
tools for biopharmaceutical processes
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Numerical simulation of multiphase flows
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Simulation and design of controlled and robust particle
synthesis processes
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Computational analysis of powder and granular flows
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Virtual Quality by Design
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Compound property prediction
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Molecular dynamics simulation
Key Researcher:
Univ.-Prof. Dipl.-Ing. Dr. Günter Brenn
Univ.-Prof. Dipl.-Ing. Dr. Johannes Khinast
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Project
Simulation of Mixing and ­Dissolution
Processes for the Production of
­Pharmaceutical Products
Project Manager:
Dipl.-Ing. Thomas Hörmann
Duration: ​01.03.2009 to 28.02.2011
Business Partners:AVL List GmbH
Baumgartner & Co. GmbH
Baxter AG
Scientific Partner:
Institute for Process and Particle Engineering (TUG)
Associated Partner:Zeta Biopharma GmbH
Abstract
The production of highly concentrated bio-molecular solutions is a complex process due to
variations between different batches (batch-to-batch variability) of the input materials. The
resulting product and filtration losses reduce the efficiency of the process. Thus, the aim of this
project is to optimize industrial mixing and dissolution processes for different tank geometries,
impeller types and physico-chemical systems, including non-Newtonian rheology. In order to
tackle this problem, advanced simulations and experimental tools are required to characterize mixing and dissolution in highly viscous non-Newtonian fluids and with shear-sensitive,
dissolving materials. A tool that was developed to optimize such a production process is a
novel three-dimensional CFD model for complex multi-phase systems in a stirred tank. Another
aspect of the project is the scale-up of the process from the laboratory to the manufacturing
scale, including the powder-conveying and mixing and dissolution steps. The combination of a
high-level process understanding via simulation and advanced process analytics offers efficient
optimization, as required by a modern regulatory framework.
Project Goals
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Development of a mechanistic understanding for selected production processes of solid /
fluid pharmaceutical formulations.
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Development of a deep understanding of the relationships between the physicochemical
properties of a bulk powder, the process parameters and the quality of the final mixing
product.
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Development of a mathematical dissolution model for solids in liquids to be used as a basis
for the up-scaling to the industrial process.
Development of a CFD simulation method to optimize typical mixing processes.
Application of the CFD method for the selected use case.
Present Project Results
One of the main achievements of the project was the development of a CFD simulation method
to calculate the liquid flow of non-Newtonian suspensions with dissolving particles in a pharmaceutical stirred tank reactor. In order to evaluate the quality of the numerical results, an
experimental validation was performed. The fluid flow within a glass tank was analyzed by
applying the Particle Image Velocimetry (PIV) technique. The experimental results agreed very
well with the corresponding simulation outcome. Therefore, the simulation method has proved
to be suitable for calculating the flow in different tank-impeller combinations and may be used
for optimizing mixing operations. In the course of this project, the simulation method has already
been used to characterize various mixing systems used in the pharmaceutical industry.
In addition, physicochemical properties of different bulk powders were investigated experimentally. In order to understand and characterize the mass transfer phenomena between a bulk
material and a buffer liquid, a model system equipped with an online NIR (near-infrared)
spectroscopy probe was studied. Analyzing the dissolution behavior helps verify the numerical
results and forms the basis of future control strategies for an industrial process.
The information concerning the entire mixing system obtained via CFD simulations is much more
powerful when coupled with Design of Experiment (DOE) techniques. DOE offers a relevant
simulation plan that involves only the significant. The CFD-DOE coupling provides a refined and
robust process control design. Finally, a mixing system (tank geometry, impeller type, process
parameters, etc.) was defined and successfully introduced into an industrial production process.
Project Challenges
Mixing solids into liquids is a complex stirring operation with numerous critical process and
material parameters. Yet bulk powder (i.e., biopharmaceutical protein) is expensive, making
large-scale experiments impossible. Simulation techniques expand the knowledge of mixing
effects occurring in real production tanks.
The challenge to this project has been the development of a CFD simulation method that
predicts the flow and mixing scenarios within a stirred tank. It requires considering all relevant
effects, i.e., the rotating impellers, the temporally and locally changing non-Newtonian viscosity,
the transport and dissolution of solid particles as a function of the temperature, the Reynolds
number and the local mass concentration of the dissolving substances.
Finally, the simulation method needs to be suitable for different selected use cases in the pharmaceutical industry.
Project related Publications
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T. Hörmann, D. Suzzi, M. Gsöll, J. Hofer, J.G. Khinast. Simulation of Fluid Mixing and Dissolution Processes. Poster Presentation at CESPT 2010, Graz (A) on Sep 16th-18th, 2010
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M. Gsöll: Optimization of Mixing and Dissolution Processes – Investigation of Physicochemical Properties. Master Thesis, Graz University of Technology (successfully completed)
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T. Hörmann: 3D Simulation of Mixing-, and Dissolution Processes within the Pharmaceutical
Industry. Doctoral Thesis, Graz University of Technology (ongoing)
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J. Redlinger Pohn: Mixing of High Viscous Fluids. Bachelor Thesis, Graz University of Technology (successfully completed)
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T. Hörmann, D. Suzzi, J.G. Khinast. Mixing and Dissolution Processes of Pharmaceutical
Bulk Materials in Stirred Tanks: Experimental and Numerical Investigations. – Industrial &
Engineering Chemistry Research 50 (21), p 12011–12025 (2011)
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Project
A PAT STRATEGY FOR MICROPARTICLE
­PRODUCTION PROCESSES
Project Manager:
Duration: Business Partners:
Scientific Partners:
Prof. Dr. Günter Brenn
01.06.2009 to 31.05.2012
Sandoz GmbH
qpunkt GmbH
Institute for Process and Particle Engineering (TUG)
Institute of Fluid Mechanics and Heat Transfer (TUG)
Institute of Biophysics and Nanosystems Research (OEAW)
Abstract
Microparticles are widely used in the pharmaceutical industry as delivery forms for proteins,
peptides or drugs. Polymeric microparticles have extensively been studied as drug carriers in
the pharmaceutical field, and microparticles show promise as carriers of active pharmaceutical
ingredients (APIs). The idea behind a controlled drug delivery system is to incorporate the drug
into a polymeric carrier that controls the drug’s delivery and release rate in the therapeutic
window.
Among the various classes of biodegradable polymers, poly(lactide-co-glycolide) (PLGA) is a
most commonly-used drug carrier due to its excellent biocompatibility, biodegradability and
mechanical strength. Solvent evaporation method is the most popular technique of preparing
microparticles. Microsphere preparation via solvent extraction/evaporation consists of four
major steps:
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Dissolution or dispersion of the bioactive compound (API) in an organic solvent containing
the matrix-forming material (PLGA polymer);
Emulsification of the organic phase in the second continuous (often aqueous) phase.
Emulsification is the most important step of the process because it determines the size
(distribution) of the microspheres, which significantly affects the rate of drug release and the
encapsulation efficiency;
Extraction of the dispersed phase via solvent removal and transforming the droplets into
solid microspheres;
Harvesting and drying the microspheres.
The aim of the project is to analyze the above steps in detail for a better understanding of
microparticle production processes. Another objective is to establish a predictive model of the
emulsion and particle formation.
The ultimate goal of the project “A PAT Strategy for Microparticle Production Processes” is to
develop product and process design spaces according to the Quality by Design (QbD) principles,
both theoretically via simulation models and experimentally via laboratory measurements.
Project Goals
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Process Analytical Technology (PAT) and QbD: establishing a quantitative relationship between the process parameters (design variables) and the product properties (particle size
distribution, morphology, residual moisture content of the particles, etc.)
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Definition of the Critical Quality Attributes (CQAs)
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Definition of design spaces
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Development of a robust and scalable production process resulting in microparticles with
tight particle size distribution and homogenous API
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Research of simulation models and experimental verification to predict the particle size and
the particle size distribution
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Research of the extraction process step in order to optimize the particle’s properties (size,
porosity, etc.)
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Research of the effects of the microparticle harvesting on the product size and morphology
Present Project Results
The first work package of the project analyses the emulsification step using a static mixer with
the objective of characterizing oil-in-water emulsions produced with SMX static mixers in the
laminar flow regime. Dimensional analysis was applied to characterize and quantify this complex
engineering exercise. This analytical method involves the conversion of process parameters into
a smaller number of dimensionless groups. We used it to predict scale-up processes, to establish a relationship between the dimensionless groups and the resulting microparticle diameter
and to minimize the experimental effort for future process optimization steps. Material properties
(density, viscosity, interfacial tension, etc.) were measured and the experimental design was
developed. Emulsion production experiments were carried out using SMX static mixers of two
different diameters, with the mixing of the two liquids taking place in the laminar flow regime.
In our first paper [1] we provided the results covering a wide range of all process parameters
that influenced the droplet size of the emulsion. The obtained correlation related to the nondimensional drop-size based Ohnesorge number of the emulsification process and provided
an accurate prediction of the mean oil droplet size, offering crucial information regarding the
emulsion properties required for pharmaceutical applications.
The studied emulsification process is the first step in the production of polymeric microparticles via the emulsion extraction method, which is a common technique for the preparation of
controlled-release biodegradable microparticles for pharmaceutical applications.
In the second part of our work particle formation experiments were carried out in an agitated
vessel involving different agitation speeds, emulsion injection points and droplet size spectra of
the initial emulsion as particle precursor. The local flow conditions during these experiments, i.e.,
local shear rates, dissipation rates and the particle-liquid mass transfer rates, were examined
using a computer simulation.
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Scanning Electron Microscopy (SEM) analysis showed that the API distribution in the cross section of the particles strongly depended on the extraction rate and the local flow in the stirred
vessel, into which the emulsion was injected.
The particle size spectra, porosity, residual solvent and API content were also affected by the
controlling flow regime. Our results demonstrate how the stirrer’s speed, the emulsion injection
point and the droplet size of the initial emulsion affect particle properties.
Project Challenges
The release behavior of polymer-based biodegradable microparticles is strongly affected by the
final particle properties, which are determined during the production process. In order to control
the process accordingly, it is important to understand the influence of the manufacturing process
parameters on the microparticle properties. Such parameters as porosity, particle size and API
distribution in relation to the release behavior of controlled release microspheres have been well
investigated. However, the influence of the process parameters of the emulsion extraction technique on the above particle properties has rarely been considered. Numerous scale-up difficulties
arise since the final particle properties strongly depend on the formation parameters that relate
to the batch size.
Computer simulation tools offer control over the particle formation process in different batch
sizes and provide a basis for its the scale-up and optimization. In this work we will incorporate
computer simulation results into the particle formation lab experiments. CFD (Computational
Fluid Dynamics) models will enhance the understanding of the flow in the extraction vessel, in
which the polymeric microparticles are produced.
Project related Publications
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N. Kiss; G. Brenn; H. Pucher; J. Wieser; S. Scheler; H. Jennewein; D. Suzzi; J. Khinast.
Formation of O/W emulsions by static mixers for pharmaceutical applications. – in: Chemical
Engineering Science 66 (2011) 5084-5094 (2011, in press)
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N. Kiss; G. Brenn; S. Scheler; H. Jennewein; D. Suzzi; J. Khinast. Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Poster presentation
at the 8th European Congress of Chemical Engineering, Berlin (2011)
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N. Kiss; G. Brenn; S. Scheler; H. Jennewein; D. Suzzi; J. Khinast. Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Presentation at the
5th International Congress on Pharmaceutical Engineering (ICPE), Graz (2011)
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N. Kiss; G. Brenn; S. Scheler; H. Jennewein; D. Suzzi; J. Khinast. Formation of O/W Emulsions and Production of Microparticles for Pharmaceutical Applications. Presentation at the
AIChE Annual Meeting, Minneapolis, MN (2011)
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Project
Development and Application of Advanced
Quality by Design Concepts
Project manager: Dr. Siegfried Adam
Duration: 01.01.2011 to 31.12.2012
Business Partners:Ortner Reinraumtechnik GmbH
VTU Engineering GmbH
Zeta Biopharma GmbH
Automatik Plastics Machinery GmbH
Pharmig
Scientific Partner: Institute for Process and Particle Engineering (TUG)
Associated Partner: AGES PharmMed
Abstract
The new concept of Quality by Design (QbD) ensures the quality and performance of a medicinal product by designing effective and efficient manufacturing processes, whose product and
process specifications are based on a mechanistic understanding of how the formulation and
process factors affect the product’s performance. Based upon preliminary theoretical and practical work of project A1.5, project A1.5b primarily focuses on establishing practical approaches
to QbD implementation in routine pharmaceutical manufacturing and quality management
processes. The main objectives are to (i) develop and further elaborate process models for
a systematic pharmaceutical development in the line of QbD and (ii) apply these models and
associated expert tools to establish process knowledge with regard to the specific industrial
partners’ use cases and (iii) leverage this understanding to generate quality-increasing and
cost-saving benefits for the internal development and quality assurance approaches. The key
focus is on using computer simulations to perform reliable data generation within a regulated
pharmaceutical environment using efficient validation methods to prove the predictive capability
and robustness of a simulation within a sufficiently small confidence interval.
Project Goals
A detailed generic process model that guides the systematic and science-based performance
of an efficient and effective pharmaceutical development and the establishment of optimized
manufacturing processes
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Documented experience on leveraging QbD-generated process and product understandJJ
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ing for the implementation in routine pharmaceutical manufacturing and quality assurance
processes and with regard to regulatory expectations
Establishment of added-value benefits for the industrial project partners with respect to
understanding and controlling their specific products and processes
Application strategies for computer simulations in a GMP-environment
Present Project Results
Based on the QbD guideline document established in the former project A1.5, the proposed concepts have been further developed and implemented with a special emphasis on the industrial
partners’ use cases. Innovative tools for process and equipment development and optimization have systematically been used to achieve a sound understanding and to define process
conditions and equipment design for optimized pharmaceutical manufacturing. Furthermore,
computer-simulations-based data generation has been challenged. On the one hand, simulations have been used in combination with risk assessment tools at an early stage of process
characterization as a screening application to determine potentially critical input factors (e.g.,
raw material characteristics, process parameters, equipment design) and to prioritize them for
further “real-life” process characterization. On the other hand, simulation approaches have been
used directly during the main phase of process characterization. In the pharmaceutical process
development, both applications have great potential with regard to the streamlining development
and the manufacturing resources and costs.
Project Challenges
An efficient validation strategy to prove the predictive capability and robustness of a simulation
within a sufficiently small confidence interval is an indispensable prerequisite for using computer
simulation tools in a pharmaceutical environment. To that extent, additional project activities will
be performed to define verification strategies for the simulation approaches. The ultimate goal is
to include simulations along with real-life data generation into a pharmaceutical dossier. Although
much remains to be done with that regard, this project has laid an important foundation for future
work.
Project related Publications
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S. Adam, D. Suzzi, C. Radeke, J.G. Khinast. An integrated Quality by Design (QbD) approach
towards design space definition of a blending unit operation by Discrete Element Method
(DEM) simulation. – in: European Journal of Pharmaceutical Science 42 (2011) 106-115 (Nov
4, 2010)
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S. Adam, D. Suzzi, G. Toschkoff, J.G. Khinast. Application of Advanced Simulation Tools for
Establishing Process Design Spaces within the Quality-by-Design Framework. – Submitted
as book chapter (2011)
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T. Hörmann, Suzzi D., S. Adam., J.G. Khinast. DOE-based CFD optimization of pharmaceutical mixing processes. Journal to be defined.
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S. Adam, D. Suzzi, G. Toschkoff, T. Hörmann, C. Radeke, J.G. Khinast. An Integrated Qualityby-Design (QbD) Approach towards Design Space Definition of three Key Unit Operations in
the manufacturing of solid and liquid dosage forms by Discrete Element Method (DEM) and
Computational Fluid Dynamics (CFD) Simulation. CESPT 2010, Graz (A) on Sep 16th, 2010
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B. Gübitz, H. Schnedl, J.G. Khinast. A Risk Management Ontology for Quality-by-Design
Based on a New Development Approach According GAMP 5.0. – Risk Analysis (2011,
submitted)
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Project
Optimization and Scale-Up of a Coating
­Process Based on Detailed Experimental
and Numerical Analysis
Project manager: Dr. Daniele Suzzi
Duration: 01.09.2010 to 31.08.2013
Business Partner:L.B. Bohle Maschinen + Verfahren GmbH
Scientific Partners: Institute of Pharmaceutics and Biopharmaceutics (HeinrichHeine-University Düsseldorf)
Institute for Process and Particle Engineering (TUG)
Abstract
In the pharmaceutical industry, drum coating is a common unit operation for the production of
tablet films. The applied coating layer(s) may have various functions, such as taste masking and
coloring, Active Pharmaceutical Ingredient (API) release modification or applying an additional
API. The uniformity of the coating is crucial. In recent years, parallel to an increased experimental
effort, numerical simulations of particle motion using the Discrete Elements Method (DEM) have
proven to be an important tool for studying the tablet coating process. This project combines
lab- and pilot-scale experiments with DEM simulations to investigate the influence of different
process parameters and to optimize the coating uniformity.
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Project Goals
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Understanding the influence of process parameters on the morphology and inter- and intratablet uniformity of the coating layer.
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Development of a modeling tool for the prediction of the coating process performance with
regard to coating uniformity and coating quality.
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Investigations of the scale-up performance of the process (moving from lab- to pilot- to
industrial scale)
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Application of experiments and computational simulations to investigate and optimize the
product quality
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Definition of Critical Quality Attributes (CQAs), i.e., those that must be ensured regardless of
the system and operational parameters, description of the interconnections of product quality
using a Quality-by-Design approach and application of Process Analytical Technology (PAT)
to the monitoring and control of the process.
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Development of a reliable and scalable process for the production of tablets with a welldefined coating mass distribution.
Present Project Results
During the current first phase of the project, measurements of important material properties that
are crucial for the process and are needed as input for the DEM simulation (e.g., friction coefficients, coefficient of restitution, Young’s modulus) have been performed. For the experimental
coating studies, a Bohle BFC5 lab coater has been set up. Various measurement techniques
have been applied and evaluated. As for the simulation part, DEM investigations of Bohle
BFC5/50 apparatus have been performed. The first simulation results have provided insights
into the tablets’ behavior in a coating drum. Based on this, novel methods for the description of
sprays for DEM simulations have been developed.
Project Challenges
Optimization of the coating process and, especially, of the coating uniformity requires a detailed
understanding of how the process parameters affect the output quality. The challenges are the
novel combination of experimental and computational investigations and the development of
methods for obtaining new information regarding coating uniformity from both experiments and
simulations.
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area II
ures
Products und Struct
ractions
Product - process inte
ent
Formulation developm
Product stability
Protein aggregation
ractions
Product - device inte
Dipl.-Ing. Dr. Stefan
LEITGEB
eins
Group Leader ITT2 Prot
[email protected]
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The main focus of Area II is product engineering.
Pharmaceuticals are complex products (or rather
complex substance delivery systems) that deliver
active pharmaceutical ingredients ranging from
small molecules to complex proteins, which are
often marginally soluble in water and yet must be
delivered to patients by transport to and across cellular membranes or by injection. For that purpose,
the active substance is frequently combined with
solvents, fillers, disintegrants, surfactants or modified release agents. This makes pharmaceutical
products complex systems that need to be carefully
designed. Furthermore, manufacturing processes
can significantly affect the product’s performance
and quality. Area II nucleates research efforts
focusing on experimental and computational studies to acquire an understanding of the product’s
quality and behavior under process conditions, thus
evaluating the process parameters that determine
the product’s Critical Quality Attributes.
Goals:
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Product engineering
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Development of stable formulations
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Development of new delivery concepts
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Improved understanding of the product-process interactions
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Understanding protein aggregation propensities
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Characterization of product-device interactions
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Improvement of product performance and quality
Source: picture taken in the laboratory of the Institute
of Biotechnology and Biochemical Engineering, Graz
University of Technology
Key Researcher:
Univ.-Doz.in Dipl.-Ing.in Dr.in Michaela Flock
Univ.-Prof. Dipl.-Ing. Dr. Christoph Herwig
Univ.-Prof. Dipl.-Ing. Dr. Bernd Nidetzky
Ass.-Prof.in Mag.a Dr.in Eva Roblegg
Priv.-Doz. Dipl.-Ing. Dr. Frank Sinner
Univ.-Prof.in Dr.in Nora Urbanetz
Univ.-Prof. Mag. Dr. Andreas Zimmer
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Project
Molecular Design Approaches to Improve
Functionality and Manufacturing Process
Compatibility of Pharmaceutical Proteins –
Enzymes in Biosensors
Project manager: Duration: Business Partner:
Scientific Partner:
Prof. Dr. Bernd Nidetzky
01.11.2008 to 31.08.2011
Roche Diagnostics GmbH
Institute of Biotechnology and Biochemical Engineering (TUG)
Abstract
Protein stability has been a major challenge for medical applications of biomolecules. In the
field of pharmaceuticals, the main problems are the loss of bioactive compounds and possible
adverse immune reactions through aggregation of proteins. In diagnostics, the destabilization of
proteins leads to imprecise results and determines the lifetime of medical devices. In biosensors
enzymes are immobilized on a matrix and catalyze the conversion of substrates upon contact
with the target fluid. The products trigger a response that is converted into a measurable signal
(e.g., the amperometric measurement of H2O2 after reduction at an electrode).
The current project’s objective was to extend the lifetime of biosensors by addressing the stability
of the enzymes used for measuring. In multi-enzyme systems the limiting enzyme must be identified, and the critical process parameters for the activity loss – a consequence of destabilization
– were evaluated. The results of the root-cause analysis were the basis for a rational approach to
extend the lifetime of enzymes incorporated in medical devices.
The initial focus of the project was to investigate the inactivation pathways of enzymes used
in medical devices. This mechanistic approach was used to gain a profound understanding of
factors that were responsible for the activity loss. Based on this investigation, several approaches
were designed to tackle the activity loss during an operation. We used molecular dynamics
simulations, chemical modifications and rational protein design.
In addition to working on protein stability, we focused on protein selectivity. Further research
efforts were targeted on the use of alternative electron acceptors rather than molecular oxygen.
Project Goals
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Detailed understanding of the inactivation mechanism of enzymes used in biosensors
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Identification of factors influencing the stability of enzymes in biosensors
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Detailed understanding of the enzymes’ reaction mechanism to avoid undesired sideproducts that lead to inaccurate results
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Generation of enzyme variants with changed (A) and improved (B) substrate selectivity to be
used in biosensors for new substrates (A) and for more accurate results (B)
Generation of enzyme variants with improved stability
Generation of a biosensor with improved selectivity and longer lifetime
Present Project Results
The initial investigations revealed the critical process parameters that were responsible for the
activity loss of enzymes used in biosensors and, therefore, for the enzymes’ limited lifetime.
To gain a profound understanding of the interactions between the proteins and the process
conditions, the inactivation mechanism was investigated in detail. A multi-step mechanism was
discovered, upon which the design of further experiments was based.
A combination of various methods was used in order to extend the lifetime of enzymes used in
biosensors. Molecular dynamics simulations indicated regions in proteins that were susceptible
to critical process components. An approach based on the rational design of proteins incorporated those results (as input parameters) and structural information on the enzymes investigated
and the closely related ones. Chemical modifications were introduced to the enzyme using a
complementary approach with the same goal of increasing its stability. These efforts identified 2
enzyme variants which showed improved stability compared to the reference enzyme used in a
commercial biosensor. The patent covering these modifications is underway.
In addition to the stability, the selectivity of enzymes used in biosensors has always been an issue
since accepting other molecules than the target substrate can lead to substantially incorrect
results. Using a similar approach, we identified an enzyme variant that showed an improved
acceptance of the target substrate over undesired ones.
Project Challenges
Enzymes are very complex systems that are very difficult to predict. There are various levels of
information in each enzyme / protein that are defining its properties. However, even when this
information is available, in many cases it is impossible to predict the characteristics and behavior
of enzymes in vivo and in vitro. Currently, the primary structure (sequence) of an enzyme can easily be established, and there is a variety of methods to determine the global structure of proteins.
However, an enzyme’s functionality can only be predicted if there are similar enzymes that have
been thoroughly studied. Improving enzymes requires a good understanding of their functionality
and is usually based on a detailed biochemical investigation. Interpretation of the data generates ideas of how to improve the enzyme’s characteristics. The next step is to generate mutant
enzymes that must be re-tested to determine if the approach was successful.
The main challenge to the improvement of enzymes is to acquire a very good understanding of
this very complex system. This requires a lot of information, including structural and biochemical
data, that is not always available. To date, the behavior of enzymes could not be predicted
without this data. Very often the exchange of a single amino acid can lead to total loss of activity,
whereas the exchange of a different amino acid can change the substrate’s selectivity. The key
is to identify and understand the most important interactions of the target enzyme to create a
good basis for a knowledge-based product optimization. Another critical issue is the results’
transferability from in vitro to in vivo.
Project related Publications
JJ
B. Unterweger, T. Stoisser, S. Leitgeb, R. Birner-Grünberger, B. Nidetzky. Engineering of
Aerococcus viridans L-lactate oxidase for site-specific PEGylation: characterization and
chemical modification of a S218C mutant. – Biotechnology Journal (2011, submitted)
JJ
S. Leitgeb, T. Stoisser, D. Neuhold, B. Nidetzky. Structure-function relationships of α-hydroxy
acid oxidizing enzymes. (2011, in preparation)
JJ
Patent in preparation: Mutant Lactate Oxidase with Increased Stability and product, methods
and uses involving the same
Page 41
Project
Molecular Design Approaches to Improve
Functionality and Manufacturing Process
Compatibility of Pharmaceutical Proteins Aggregation
Project manager:
Prof. Dr. Bernd Nidetzky
01.01.2009 to 31.10.2011
Duration: Business Partner:Sandoz GmbH
Scientific Partners:Institute of Biotechnology and Biochemical Engineering (TUG)
Institute of Pharmaceutical Sciences (KFU)
Abstract
Pharmaceutical biotechnological products, such as proteins, have great potential with regard
to medical treatments. However, they are often difficult to handle and have limited lifetimes. Our
research focuses on recombinant pharmaceutical proteins and, especially, on improving their
quality in terms of stability.
The functionality of pharmaceutical proteins is governed, on the one hand, by its bioavailability
and efficiency and, on the other hand, by the stability during production, storage and application.
An important task for the pharmaceutical industry is to eliminate the weaknesses that affect the
functionality of formulations. This includes problems both in product and process development
and in quality control. The main problem is the aggregation of pharmaceutical proteins that can
reduce bioactive compounds and lead to immunogenic responses. The aim of this project is to
develop reliable prediction methods for aggregation propensities of therapeutic proteins under
well-defined process conditions. The scientific approach includes a combination of computer
simulation tools with an experimental validation of the predictions.
The basis for a successful implementation of a simulation tool for the prediction of the aggregation
propensity of proteins is the reduction of the complexity of the system, otherwise the simulation
time would be by orders of magnitude too long for a routine operation. The focus of the simulation work, therefore, is to develop a reliable and fast routine. Our experimental work focuses on
the investigation of aggregation mechanisms to gain a better understanding of the underlying
mechanisms and to use the results as input for the simulation. The predictions of protein stability
Page 42
under varying conditions must be verified experimentally. The other part of the project aims at
the optimization of protein formulations to improve stability. The results of the stability data for
different excipients will be used as input for later-stage simulations as well.
Project Goals
JJ
Development of a simulation tool for the prediction of aggregation propensities
JJ
Simulation as the basis for in-silico formulation development
JJ
Experimental validation of the predictions
JJ
Identification of critical parameters for the aggregation of selected therapeutic proteins
JJ
Better understanding of the aggregation mechanism for selected therapeutic proteins
JJ
Development of formulations with higher stability that are less susceptible to aggregation
Present Project Results
Various simulation routines have been developed within the framework of this project based on
molecular dynamics simulations and coarse-grained models. These models can be used for
qualitative predictions of a protein’s stability under different conditions. The simulation routines
are based on models that have been developed in the course of the current work and will be
used to rank proteins according to their aggregation propensities and to predict conditions of
the improved stability.
The experimental work identified critical process parameters of protein stability for a set of pharmaceutical proteins. It has been shown that different proteins react variably to the same stressing
method and that different kinds of stress applied to the same protein trigger variable responses.
The current work greatly helps to understand the underlying aggregation mechanisms of pharmaceutical proteins. A high-throughput method for formulation development and optimization
has been developed, and its results have been correlated with the long-term stability data.
Project Challenges
Aggregation of biomolecules is a big problem for the pharmaceutical industry. In addition to the
limited patients’ acceptance of turbid protein solutions, it bears a high risk of immune responses.
Aggregates have an altered structure compared to the native protein and, therefore, may bind
at different receptors or initiate non-predictable immune reactions. Aggregation mechanisms are
very complex and extremely difficult to understand and model. Aggregation can include degradation of proteins, modifications, unfolding, dissociation of subunits and many more effects. The
problem is that, generally, it is not a single defined process but rather several processes running
in parallel, which can lead to different aggregation products. The lack in uniformity is another big
challenge to the characterization of aggregates.
As such, the pharmaceutical industry is extremely interested in a better understanding of the
aggregation mechanism and, even more importantly, of the factors that lead to the aggregation
of therapeutic proteins. A better insight into the aggregation pathway would make predictions for
new drug candidates easier and would help reduce the risk of the aggregate formation that may
lead to an immune response.
Project related Publications
JJ
E. Ablinger, S. Wegscheider, W. Keller, R. Prassl, A. Zimmer: Effect of protamine on the
solubility of human growth hormone. – European Journal of Pharmaceutics and Biopharmaceutics (2011, submitted)
JJ
U. Roessl, J. Wiesbauer, S. Leitgeb, R. Birner-Gruenberger, B. Nidetzky. Non-native Aggregation of Recombinant Human Granulocyte-Colony Stimulating Factor (rhG-CSF) under
Simulated Process Stress Conditions. – Biotechnology and Bioengineering (2011, submitted)
Page 43
Project
Interaction between Packaging Materials and Pharmaceutical Formulations ­Disposable Freeze/Thaw Systems: Design
and Experimental Analysis
Project manager: Dr. Stefan Leitgeb
01.11.2008 to 30.06.2012
Duration: Business Partner:Zeta Biopharma GmbH
Scientific Partners: Institute of Biotechnology and Biochemical Engineering (TUG)
Institute for Process and Particle Engineering (TUG)
Abstract
The freezing of biologics is an increasingly common unit operation in the production of protein
therapeutics, which is used for storing bulk solutions before they are processed into the final
drug product. Proteins are interacting with water in the liquid phase as well as with the frozen ice
matrix and are subject to structural perturbations that can induce freeze damage. The freezing
process leads to the cryoconcentration of proteins and solutes, inducing hot spots with higher
concentrations than in the bulk solution. The concentration effects may lead to pH shifts of the
buffering solutions, which may harm the proteins. A change in ionic strength or in the protein
concentration itself may also have adverse effects on the product’s quality. The cryoconcentration can be explained by the dendritic ice formation that moves the solute in front of the ice. The
solutes become trapped and form the local maxima since water is their only compound that can
change its aggregation state. The solutes and proteins can either crystallize or form a glassy
state. It has been proposed that proteins tend to unfold at the hydrophobic ice patches, which
induce the unfolding of the native state. This unfolding is not always reversible and may lead
to the protein damage that can eventually result in the protein aggregation. Protein aggregates
have been addressed by regulatory agencies due to their potential to trigger adverse immune
reactions.
During the formulation step of new protein drugs, the freezing and thawing are standard tests
during the protein’s investigation. However, due to the lack of small-scale freezing units, these
tests are commonly carried out in uncontrolled conditions by placing simple flasks in a freezer,
which often makes working under defined boundary conditions impossible. Additionally, it is
impossible to transfer the results of such a system to a large-scale unit. Small-scale tests are
performed because of the high costs of protein therapeutics.
To date, the influence of the freezing and thawing unit operations on pharmaceutical proteins has
remained poorly understood. There is very limited evidence of structural changes occurring in
Page 44
proteins under these conditions. Therefore, a better overall understanding of the freezing process
and of its influence on the protein structure and quality in general is of great interest to the
pharmaceutical industry. It is crucial to know at each point in time what the quality of the product
is, which calls for a system that can transfer the results from a small scale to an industrial scale.
Project Goals
JJ
Development of a simulation routine for the prediction of the freezing and thawing processes
in a commercial freeze container
JJ
Prediction of the solute distribution in a frozen matrix
JJ
Investigation of the freezing and thawing effects on model proteins
JJ
Development of a lab-scale freeze container
JJ
Development of a scale-down model of the commercial freeze container based on the simulation results
JJ
Experimental validation of the simulations
Present Project Results
A simulation routine has been developed that can predict the freezing behavior of water in a commercial freeze container. The simulation results have been verified using the published literature
data. The multi-phase model involves the liquid and solid phases. Further improvement of the
simulation routine made it possible to predict the movement of the proteins, the evolution of the
ice front, the convective effects and the zone of the phase transition.
Based on the simulation results, a lab-scale freeze container was built to investigate the freezing
process on a smaller scale and, especially, to evaluate the freezing damage to the proteins. It has
a working volume of 200 ml and offers a controlled freezing and thawing process, temperature
mapping and an easy sample removal.
A set of enzymes was tested experimentally to function as a reference protein. Biochemical and
biophysical methods were established to address especially the freezing-induced protein damage. First experiments in the lab-scale freeze container successfully reproduced the expected
cryo-concentration of the solutes at the last point of freeze.
Project Challenges
The freezing of protein solutions is a common process for both industry and science. However,
this process is typically not considered a key process and, therefore, the research effort in that
field has been limited. Scientific publications dealing with the freeze-damage of proteins are very
rare. Companies do not pay much attention to this process and accept a certain amount of
product loss during the freeze step.
A big challenge to a scientific investigation of the freezing and thawing process is the limited
availability of methods to evaluate changes in the protein. Most biophysical methods are aiming
at proteins in the solution. For structure characterization of proteins in the solid state (e.g., X-ray
crystallography) a well-ordered crystal state is required. It is therefore necessary to establish
methods to evaluate changes in the protein structure in the ice state. The next step is the development of tools for process control. Currently, the only parameter that can be followed is the
temperature, which only provides limited information.
Project related Publications
JJ
M. Iannuccelli; D. Suzzi; B. Sirnik; A. Rinderhofer; J.G. Khinast. Numerical Simulation of
Freeze-Thaw Biopharmaceutical Process. – in: Chemical Engineering Transactions 24 (2011)
907-912
Page 45
area III
and
Process Engineering
ce
Manufacturing Scien
t
Process developmen
Process analysis
Process control
t
Process improvemen
chnology (PAT)
Process Analytical Te
n)
turing (e.g., Extrusio
Continuous Manufac
in
in
tine Vour a
Dipl.-Ing. Dr. Chris
Area Manager
.at
christine.voura@rcpe
Page 46
Area III is devoted to developing, testing, optimizing and controlling (bio)pharmaceutical production
processes. A wide range of methods and tools is
developed and applied to overcome the limitations
of the current pharmaceutical production technology. State-of-the-art process analyzers with online
and inline capabilities are used in real-time process
and product analysis applications. Predictive modeling tools that are jointly developed with Area I
are coupled with advanced process analysis tools
for robust and knowledge-based process control
with real-time quality assurance and continuous
checking of the product for compliance with respect to predefined Critical Quality Attributes. In
addition, innovative processes and conceptually
new approaches to process design and control are
developed in order to make future pharmaceutical
production operations more effective and efficient.
Area III also focuses on the implementation of a
continuous operation mode for the manufacture
of pharmaceutical end and intermediate products,
such as the production of pellets by extrusion.
Goals:
JJ
Development and analysis of processes and concepts
for future pharmaceutical production applications (e.g.,
continuous manufacturing approaches)
JJ
Development and implementation of Process Analytical Technology (PAT) tools for robust and knowledgebased process control
JJ
Development and implementation of Quality by Design
(QbD) concepts for advanced processing
JJ
Coupling of experimental analysis and predictive
modeling tools for process improvement, scale-up and
process control applications
JJ
Design of engineering prototypes and operation of
lab-scale process equipment for experimental investigations
JJ
Implementation and development of continuous processing of pharmaceutical products (e.g., extrusion)
Key Researcher:
Univ.-Prof. Dipl.-Ing. Dr. Wolfgang Bauer
Univ.-Prof.in Dipl.-Biol.in Dr.in Gabriele Berg
Univ.-Prof. Dipl.-Ing. Dr. Günter Brenn
Univ.-Prof. Dipl.-Ing. Dr. Christoph Herwig
Univ.-Prof. Dipl.-Ing. Dr. Johannes Khinast
Ass.-Prof.in Mag.a Dr.in Eva Roblegg
Univ.-Prof. Mag. Dr. Robert Schennach
Univ.-Prof. Mag. Dr. Andreas Zimmer
Page 47
Project
Particle Technology, Process Analytics
and Continuous Manufacturing
Project Manager: Dr. Simon Fraser
Duration: 15.09.2008 to 30.09.2011
(strategic part extended to 31.03.2012)
Business Partners: G.L. Pharma GmbH
Hecus X-Ray Systems GmbH
Scientific Partner:
Institute for Process and Particle Engineering (TUG)
Associated Partner:AVL List GmbH
Abstract
In the future, pharmaceutical manufacturing operations will be developed and controlled based
on a mechanistic understanding of how the formulation and process factors affect the product’s
performance, rather than on the predominantly empirical approaches applied to the state-of-the
art production process design. In addition, real time quality assurance concepts will replace testing samples collected from raw materials and products. However, a mechanistic understanding
of the production processes is quite limited with regard to solid pharmaceutical formulations,
and the tools for real time quality assurance are unavailable or have not yet reached the level of
maturity required for the actual process integration.
The aim of this project is to expand the limited understanding of manufacturing processes and to
develop a detailed understanding of the complex interdependency between raw materials, production processes and the product’s properties. The project is primarily focused on two aspects:
(1) the development of a mechanistic understanding of selected production processes for solid
formulations based on combined particle and process models, and
(2) the investigation of Process Analytical Technology (PAT) in laboratory conditions and using
industrial manufacturing equipment.
Specifically, the processes under investigation are granular mixing steps and tablet coating
operations. The PAT tools applied include NIR and Raman spectroscopy as well as Small- und
Wide-Angle X-Ray Scattering (SWAXS). The combination of a comprehensive process understanding and advanced process analytical tools with online or inline capabilities will offer up-todate pharmaceutical production techniques based on the concepts of PAT and QbD.
Project Goals
Development of a mechanistic understanding of selected production processes for solid
pharmaceutical formulations based on particle and process models
JJ
Development of simulation tools to investigate selected production processes based on
validated mechanistic models
JJ
Development and implementation of process analytics for particulate systems
JJ
Page 48
JJ
JJ
Application of simulation-based and process analytical tools in the combined analysis and
optimization of industrial-scale production equipment
Conceptual development of PAT and QbD approaches for industrial production equipment
Present Project Results
To gain a deeper understanding of the tablet compaction process, numerical simulations based
on the Finite Element Method have been applied. A Drucker-Prager Cap model with adjusted
parameters was used to capture the compaction behavior of a powder. Based on data gathered
from detailed measurements, a simulation of the compaction process for lactose at different
compaction speeds and forces was performed. The results for the force-displacement curves
are in good agreement with the experiment. One main advantage of the simulation is that it
yields data that is difficult or impossible to measure. For example, an investigation of the internal
stress distribution was performed to study the mechanisms that lead to certain failures in tablet
compaction.
Parallel to the simulation-based investigations, Near-Infrared spectroscopy is used for inline process monitoring applications under realistic operating conditions. A special emphasis is placed
on investigating powder homogeneity inside the filling shoe of a tablet press and on monitoring
the moisture content of powder granules to determine the end point of a fluidized bed granulation
in real time. The results are promising in terms of process time reduction and quality assurance.
Moreover, significant progress has been made with regard to the application of SWAXS to the
pharmaceutical raw material and product analysis. The European patent application submitted in
2010 for SWAXS-based analysis of granular material was further developed and filed as a PCTApplication in 2011. Furthermore, an applications catalog for the use of SWAXS and SWAXS/
DSC in pharmaceutical laboratories was compiled to describe the benefits of this method for
product characterization and the fields of its application.
Project Challenges
The key challenge is to bridge the gap between theoretical and/or lab-based investigations and
industrial manufacturing processes. Significant progress has been made with regard to understanding the fundamental processes and parameters governing pharmaceutical manufacturing
operations based on simulations and process as well as product analysis. The next step will be
to move away from specific processes and process conditions in order to develop a general
understanding of production processes for solid formulations. This know-how can then be applied to analyzing, optimizing and ultimately developing robust production processes for the
pharmaceutical industry.
Project related Publications
JJ
D.M. Koller, A. Posch, G. Hörl, C. Voura, S. Radl, N. Urbanetz, S.D. Fraser, W. Tritthart, F.
Reiter, M. Schlingmann, J.G. Khinast. Continuous quantitative monitoring of powder mixing
dynamics by near-infrared spectroscopy. – in: Powder Technology 205 (2011) 87-96 (Sep
16, 2010)
JJ
N. Heigl, G. Hoerl, D.M. Koller, G. Toschkoff, S.D. Fraser, W. Tritthart, F. Reiter, M. Schlingmann,
J.G. Khinast. Comparison of Raman Spectroscopic Sub-Sampling with NIR Spectroscopy
for the Tablet Coating Thickness Determination. – International Journal of Pharmaceutical
Sciences (2011, accepted)
JJ
A. Hodzic, P. Laggner, W. Tritthart, 2010. A System for Analyzing a Granulate for Producing a
Pharmaceutical Product. EP 10 152 977.4
JJ
A. Hodzic, M. Llusa, S.D. Fraser, O. Scheibelhofer, D. M. Koller, F. Reiter, J.G. Khinast and
P. Laggner, 2011. Small- and Wide-Angle X-Ray Scattering (SWAXS) for Quantification of
Aspirin Content in a Binary Powder Mixture. To be submitted.
JJ
A. Hodzic, M. Llusa, N. Heigl, W. Tritthart, S.D. Fraser, J.G.Khinast and P. Laggner, 2011. Effect of process variables on the Small-Angle X-Ray Scattering patterns of powders, granules
and pharmaceutical tablets. To be submitted.
JJ
G. Toschkoff, D. Suzzi, J.G. Khinast, 2010. Numerical and Experimental Analysis of Spray
Losses in Pharmaceutical Coating Processes. To be submitted to Chemical Engineering
Science.
Page 49
Project
Development of a Pharmaceutical
Production Technology Platform for
Value-Added Products
Project manager: Dr. Gerold Koscher
Duration: 01.12.2009 to 31.12.2012
Business Partners: G.L. Pharma GmbH
Coperion GmbH
Automatik Plastics Machinery GmbH
Scientific Partners: Institute for Process and Particle Engineering (TUG)
Institute of Pharmaceutical Sciences (Uni Graz)
Abstract
Value-added products will play an increasingly important role in the future pharmaceutical manufacturing. These include retard formulations, controlled release formulations, flexible dosing and
multi-unit dosage forms primarily supplied as pellets or capsules. The objective of this cooperation project between a pharmaceutical company, two equipment manufacturing companies and
two scientific partners is to develop a production technology platform based on extrusion and to
demonstrate the potential of this technology with regard to future pharmaceutical manufacturing applications using a specific value-added product developed within the framework of this
cooperation project.
The objective of the process engineering part of the project is to develop, investigate and test a
production technology platform in a lab-scale system that has all of the elements of an industrial
production system (e.g., a twin-screw extruder, powder feeders, a pelletizing system and process
monitoring and control systems). The lab-scale production system has been extensively tested
under a wide range of operating conditions, applying the state-of-the-art design of experiments
principles in order to obtain as much information as possible from a limited number of experiments. The concept of Process Analytical Technology (PAT) has been directly implemented from
the very beginning, providing real time process monitoring based on Near-Infrared and/or Raman
spectroscopy. In addition, a wide range of offline analytics has been applied to investigate raw
materials and products. Generating a comprehensive and mechanistic process understanding is
a key issue of this project. Thereby, scale-up and transfer of the production technology to other
products can easily be performed, creating an effective platform for future production of a wide
range of value-added products.
The objective of the formulation part of the project is to develop two specific value-added products defined on the basis of a market analysis. These products will specifically be developed in
Page 50
close interaction with the production technology platform. Once the project is completed, the
products will be transferred to the pharmaceutical company and produced using an industrial
version of the production technology platform. As such, the cooperation project ideally bridges
the gap between scientific research required to develop the product and the process and the
actual industrial production.
Project Goals
JJ
Development of a production technology platform based on (hot-melt) extrusion
JJ
Development of value-added products according to a defined target product profile and
specifically designed for the production technology platform
JJ
Development of a comprehensive process understanding based on experimental investigations with design-of-experiment methods, offline raw material and product analysis and inline
process analytics
JJ
Conceptual development of PAT and QbD approaches for the production technology platform
Present Project Results
In June of 2011, a new die face pelletising system, which was specified based on the initial
results of the process and formulation development, was installed in the RCPE technical center.
The system provides an opportunity to gain a deep understanding of the pellet formation process
and to investigate the optimal process parameters.
Formulation development has been pursued in parallel to the process engineering applications,
investigating Active Pharmaceutical Ingredients (APIs) alone and in combination with relevant
excipients. State-of-the-art methods, such as Differential Scanning Calorimetry (DSC), for raw
material and product characterization have been applied to identify advantageous formulations,
which have subsequently been tested in the extrusion system and the corresponding pelletising
system under realistic production conditions. The feedback from these tests has been directed
to the formulation development, closing the loop between product and process development.
Project Challenges
The key challenge is to successfully develop an innovative production technology platform, to
test this platform with specific value-added products developed within the framework of the
project and to generate a comprehensive process understanding required to achieve an efficient
transfer to industrial production applications. This can only be achieved by assuring a very close
interaction between the two key disciplines of the RCPE, process engineering and pharmaceutical sciences, in combination with an application-oriented implementation of the PAT and QbD
concepts.
Project related Publications
JJ
S. Adam, S.D. Fraser, D. Koller, S. Radl, D. Suzzi, E. Roblegg, J.G. Khinast. Continuous
Manufacturing & the Role of HME in Pharmaceutical Production. Hot Melt Extrusion Congress, Stuttgart (D) on Apr 15th, 2010
JJ
E. Roblegg, E. Jäger, S. Mohr, A. Hodzic, A. Zimmer, J.G. Khinast. Development of lipophilic
calcium stearate pellets via hot melt extrusion – in: European Journal of Pharmaceutical and
Biopharmaceutical (2011, in press)
Page 51
Project
Development of an Industrial HME Process
for Pharmaceutical Pellet Production
Project manager: Dr. Gerold Koscher
Duration: 01.06.2010 to 31.05.2012
Business Partners:AstraZeneca UK Limited
Automatik Plastics Machinery GmbH
Scientific Partners: Institute for Process and Particle Engineering (TUG)
Institute of Pharmaceutical Sciences (Uni Graz)
Abstract
A formulation platform for melt-extruded pellets helps to rapidly select and develop Active Pharmaceutical Ingredient (API) formulations without extensive work specific to each API. Developing a
novel continuous pelletisation process and gaining an in-depth knowledge of it allow the process
optimisation to be rapidly completed. The experimental work conducted using the HME system
and the associated downstream process will not only provide extensive information about the
process and the product’s properties derived from online and offline analytics, but will be used
as the basis for process optimization procedures. For a continuous pelletisation process, a die
face pelletizing system employs a knife that rotates directly in front of a die plate. A blend of an
active ingredient, a polymeric matrix and several processing aids are heated and melted inside
the extruder and then extruded through the die into a strand. The strand is cut immediately at the
outlet of the die plate with the rotating knife and is formed into small pellets. The size and shape
of the pellets are determined by the properties of the molten mass, the rotation speed of the
knife, the cooling and the direction of the airflow inside the pelletising system. In order to expand
the process understanding, a mechanistic model will be developed and extensively used for the
simulation-based and simulation-assisted process optimization.
Project Goals
JJ
Identify and develop a generic formulation platform(s) for drug products, such as directly
usable melt-extruded pellets.
JJ
Develop a robust, scaleable, transferable, cost-effective continuous process
JJ
Develop modeling and simulation predictive tools for the extrusion and pelletisation processes
JJ
Develop workflows for the selection of an initial formulation based on the API characteristics
Page 52
Present Project Results
In the course of an Failure Mode and Effects Analysis (FMEA), critical process parameters have
been identified. Based on the results, an adequate screw configuration has been developed and
the first tests with different matrix polymers and several excipients have been performed. The
results have been used as the basis for the next steps in the formulation development. A novel
hot die face pelletiser was specified and built, making it possible to investigate the influence of
the critical process parameters on the pellet formation and to gain a deep understanding of the
pellet formation process.
The first steps in the simulation of the processes inside the extruder have been completed. A
1-D model of the basic processes has been developed, and validation experiments have been
defined. Approaches to full 3-D simulations of extrusion processes have been identified.
Project Challenges
Several challenges must be overcome to obtain pellets with the desired properties. The accuracy
of the feeding systems for the dosing of raw materials, the cooling regime of the die cut system,
the inline process control (PAT) and the selection of the screw configuration are some of the
factors that must be taken into account. Another issue is the development of an adequate formulation since not every polymeric matrix can be processed using die face pelletizing technology
(the processability of the extrudate depends on various parameters, such as the glass transition
temperature and the viscosity, stickiness and elasticity of the materials used).
Page 53
Project
Cellulose-Based Carrier Matrices
for Controlled Drug Delivery
Project manager: Duration: Business Partner:
Scientific Partners:
Dr.in Christine Voura
01.01.2009 to 31.03.2011
G.L. Pharma GmbH
Institute of Pharmaceutical Sciences (KFU)
Institute for Paper, Pulp and Fibre Technology (TUG)
Institute of Fluid Mechanics and Heat Transfer (TUG)
Institute for Process and Particle Engineering (TUG)
Abstract
A new method for the production of personalized medicine using microdrop technology has
been developed. Drug solutions or suspensions containing Active Pharmaceutical Ingredients
(APIs) and excipients are printed on eatable paper carrier materials utilizing ultra-precise printing
techniques. The printed paper can then be inserted into a gelatine capsule for peroral application.
One objective of this project is the production of personalized drugs that are tailored to age,
gender or lifestyle of the individual patient. It is achieved by a precise dosing of the API.
Another aspect of this technology is the formulation and exact dosing of low-dose medicines
with the API contents of less than 2 mg or 2% w/w. Compared to powder dosing, liquid formulations provide much better dose homogeneity and a higher accuracy, especially for drug products
with a low therapeutic dose range. Liquid dosing can successfully be used in the formulation
development of clinical trial studies supplies to reduce the costs and of the development time.
In addition, this new pharmaceutical dosage form allows applying multiple drugs or APIs in one
dosage form using barrier coatings. Drug release can be controlled with barrier coatings by
applying time-release layers. Moreover, barrier coatings can separate single deposits of different
drugs, reducing the number of drugs that must be taken per day and thus leading to less effort
and error when taking the medications.
Various paper grades have been evaluated as a pharmaceutical carrier material, considering
the intended registration as a pharma-excipient. Furthermore, models have been developed to
describe the main phenomena during the printing process and to simulate the application to,
impact of, penetration into and drying of fluids on porous materials.
Project Goals
Development of a procedure for applying pharmaceutical solutions or suspensions to paper
with sufficient accuracy
JJ
Page 54
JJ
JJ
JJ
Identification of suitable paper grades and production, characterization and further development of adequate solutions and suspensions
Analytical examination of paper structure, distribution and release of an API, and the interaction between pharmaceutical ingredients and paper
Process modeling describing the penetration behavior of fluids in porous materials
Present Project Results
During the last stages of the project, the application of the microdrop technology to the production of pharmaceutical dosage forms has been tested. In the area of formulation, pharmaceutical
solutions or suspensions were prepared from the three model drugs (vitamin B6, vitamin B12
and folic acid), which were suitable for processing using a microdosing system. The prepared
solutions and suspensions have been extensively characterized, e.g., in terms of surface tension,
density and viscosity.
The dosing of the drug-containing solutions and suspensions on paper has been performed
using the microdosage system, which has a sufficient pharmaceutical dosing accuracy. The
aim was to define suitable operating windows and to develop predictive models for the droplet
diameter and droplet velocity.
The analytical detection of disintegration properties, drug release, stability and of interactions
between drugs and paper have been carried out by means of HPLC and MS analysis of the
paper printed with the model drugs. Furthermore, paper that consists only of fibers or is filled with
different pigments has been analyzed to determine the influence of these two main components
on the drug absorption and release.
Project Challenges
A faster and more cost-effective development of drugs that are tailored to age, gender or lifestyle
of the individual patient will be achieved by developing a new production method and by using
accurate dosing of active compounds on cellulose-based paper carrier materials.
This new technology for the production of personalized medicine, which is customized and individually tailored to the physique and habits of a single patient, can significantly reduce problems
caused by a medical treatment, such as drug overdose and minimized or negative effects of the
pharmaceuticals. Drugs are targeted at a desired place in the body, and the active ingredients
are distributed with a well-defined time profile for controlled drug-delivery.
Optimizing the development and production of new pharmaceuticals can not only reduce the
costs and the development time but expedite the response to new diseases and epidemics.
Moreover, this development opens new possibilities in the fields of low-dose medicine and
multidosing of different APIs with regard to dose accuracy and homogeneity and the reduction
or avoidance of negative interactions of single APIs. This form of liquid dosing can also be successfully used in formulation development of clinical trials studies supplies to reduce of the costs
and the development time.
Project Related Publications
JJ
N. Schrödl, 2010. Charakterisierung und Dosierung von pharmazeutischen Lösungen und
Polymer-Coatings auf Papier zur Herstellung von personalisierten Medikamenten. Diploma
Thesis (ongoing)
JJ
D. Strohmeier, 2011. Nanosuspensionen als Druckertinte zur exakten Dosierung von schwerlöslichen Arzneistoffen. Diploma Thesis (ongoing)
JJ
C. Voura, N. Schroedl, M. Gruber, D. Strohmeier, B. Eitzinger, W. Bauer, G. Brenn, J.G.
Khinast, A. Zimmer. Printable medicines: a microdosing device for producing personalised
medicines. – in: Pharmaceutical Technology Europe 23 (2011) 32 - 36 (Jan 7, 2011)
JJ
J. Pardeike; D.M. Strohmeier; N. Schroedl; C. Voura; M. Gruber; J.G. Khinast; A. Zimmer.
Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in
personalized medicines. – in: International Journal of Pharmaceutics (2011, in press)
JJ
G. Brenn, N. Schrödl, C. Voura, M. Gruber, J.G. Khinast, A. Zimmer. Scaling Laws in drop
formation by drop-on-demand generators, Physics of fluids (2011, submitted).
Page 55
Project
Innovative Concepts for
Clean Room Technology
Project manager:
Dr. Stefan Liebminger
Duration: 01.01.2009 to 30.06.2012
Business Partners:Ortner Reinraumtechnik GmbH
Dastex Reinraumzubehör GmbH & Co. KG
Scientific Partners: Institute for Environmental Biotechnology (TUG)
Institute for Process and Particle Engineering (TUG)
Institute of Fluid Mechanics and Heat Transfer (TUG)
Abstract
Existing concepts for personnel lockers in clean rooms involve costly and time-consuming
procedures. Clean room personnel must change their clean room garments in personnel lockers when moving from one clean room class to another. The changing process is a source of
contamination. In fact, the major source of airborne microbes in the clean room environment is
the human body. Clean room clothing is intended to hinder contaminating the environment with
particles from the wearer’s body. To avoid the spreading of microbes in a clean room, new concepts of textiles and innovative personnel locker systems are necessary. Innovation will require
either the modification of the textile or the design of new cleaning systems for personnel lockers.
Much progress has been made with regard to understanding microbial ecology of natural habitats
and artificial environments hidden in microbial communities. Clean rooms, in which the number of
particles and microbes is drastically reduced via chemical and physical management, are used to
produce pharmaceuticals, food or spacecraft. All of them harbor specifically adapted microbial
communities. Sterility – the total absence of microbes – is only possible in small systems. On
a large scale, such as in production clean rooms with human workers, alternative solutions to
control microbial communities are necessary. We adapted the concept of a naturally-occurring
antagonist to control plant pathogens to clean room conditions, combined with non-conventional
approaches for surface disinfection.
Our interdisciplinary team will completely reconsider common processes to create new standards
in clean room technology. This will be achieved by screening for new bio-based antimicrobials,
using light-activated disinfection and modeling the behavior of particles on textiles and in the
clean room environment. The great challenge is to create an innovative concept with the basic
requirement of maximum safety for the wearer’s body and the associated processes.
Page 56
Project Goals
JJ
Development of new fabrics and textiles for clean room facilities
JJ
Development and evaluation of new decontamination methods for clean room lockers
JJ
Development of new technology and design for clean room lockers
JJ
Development of new materials for clean room lockers
JJ
Development of new garment systems for clean rooms
JJ
Adapting and optimizing the established clothing systems
Present Project Results
Natural Resources
Ecological niches on and in plants are characterized by a great diversity of organisms. Various biotic and a-biotic stresses negatively affect plant growth and vitality. Bacterial antagonists
suppress the growth of other organisms, including plant pathogens, by secreting antimicrobial
substances, siderophores and lytic enzymes. In this context, volatile organic compounds demonstrate a novel mechanism for “biological control agents” and their use in man-made artificial
environments.
Screening for Naturally-Occurring Antagonists
A new test method has been developed to identify antagonistic microbes releasing gaseous
antimicrobials. Based on a dual-culture assay, pathogens have been applied to textile carriers
and co-incubated with potential antagonists. Isolates from plants proved to be very potent in
producing highly active volatile antimicrobials, which irreversibly inhibited the growth of (multiresistant) bacteria, yeast and fungi.
Antimicrobial Activity of Volatiles on Textiles
A two-color fluorescent assay of bacterial viability was used to demonstrate the antimicrobial action of volatile organic compounds. This very sensitive type of determination in combination with
fluorescent microscopy allows a fast and reliable qualitative and quantitative distinction between
living and dead cells.
Light-Induced Disinfection
Clean room textiles based on polyester have been modified using photosensitisers, which upon
irradiation with visible light have a strong antimicrobial effect based on the production of singlet
oxygen. The multi-target mechanism of those radical species has inactivated both Gram type
bacteria within minutes. This unconventional approach of self-sterilizing surfaces is a powerful
tool for contamination control in clean rooms.
Project Challenges
The main challenge to this project is to guarantee maximum safety, not only for related production processes but, first and foremost, for the clean room personnel. The application of new
sterilization techniques and the design of innovative personnel locker systems require a deep
and critical assessment.
Project related Publications
Patent
JJ
G. Berg, K. Hartenberger, S. Liebminger. Methods and compositions for biologically controlling microbial growth on clean room equipment. EP 09 180 492.2 – 22.12.2009
Patent applications
JJ
G. Berg, S. Liebminger, L. Oberauner, T. Klein, R. Stampf. Photodynamic control of microbial
growth on surfaces. EP 10 196 674.5 – 22.12.2010
JJ
G. Berg, S. Liebminger, M. Fürnkranz, M. Aichner. Volatile organic compounds as antagonists
for controlling microbial growth. EP 10 196 672.9 – 22.12.2010
Page 57
Publications
JJ
G. Berg, K. Hartenberger, S. Liebminger, C. Zachow. Antagonistic endophytes from mistletoes as bio-resource to control clean room pathogens. – in: IOBC/WPRS Bulletin (2010)
JJ
M. Aichner, L. Oberauner, S. Liebminger, M. Fürnkranz, G. Berg. Volatile organic compounds
of plant-associated bacteria to reduce microbial contamination on clean room textile. – in:
IOBC/WPRS Bulletin (2010)
JJ
S. Liebminger, M. Aichner, L. Oberauner, M. Fürnkranz, M. Cardinale, G. Berg. A new assay
to assess antimicrobial activity of volatiles on textiles. – Journal of Textile Research (2011,
submitted)
Oral presentations
JJ
S. Liebminger. Antimikrobielle Textilien unter der Lupe. Intensivtraining – Reinraumbekleidung/
Der einzige Filter zwischen Mensch und Produkt, Heidelberg (D) on Dec 2nd, 2010
Poster
JJ
S. Liebminger, D. Suzzi, S. Fraser, G. Schinagl, S. Radl, L. Oberauner, M. Aichner, M.
Cardinale, J.G. Khinast, G. Berg. Innovative Concepts for Personnel Locks in Clean Room
Technology. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
JJ
S. Liebminger, M. Cardinale, L. Oberauner, C. Moschner, G. Berg. Survival of HumanAssociated and Environmental Bacteria on Clean Room Textiles. International Microscopy
Conference, Rio de Janeiro (Brasilien) on Sep 19th, 2010
JJ
S. Liebminger, M. Aichner, L. Oberauner, G. Berg. How much sterility is possible? New concepts for clean room environments based on plant-associated bacteria. 11th Conference on
Bacterial Genetics and Ecology – BAGECO11. Corfu (Greece) on May 29th, 2011
Award
JJ
Science2Business Award 2011. Innovative Konzepte in der Reinraumtechnologie. Vienna (A)
on Mar 15th, 2011
Page 58
Page 59
Project
Online Monitoring and Modeling
of Selected Pharmaceutical
­Manufacturing Processes
Project manager: Duration: Business Partner:
Scientific Partner:
Associated Partner:
Prof. Dr. Johannes Khinast
01.01.2009 to 31.12.2011
none – 100% strategic project
Institute for Process and Particle Engineering (TUG)
Rutgers University, ERC for Structured Organic Particulate
Systems
Abstract
The goal of this project is to investigate fluid-bed processes both experimentally and theoretically.
The experimental part deals with the development of an online monitoring system for pharmaceutical manufacturing processes based on Near-Infrared (NIR) spectroscopy. Once tested in
laboratory conditions, the monitoring system will be transferred to the production facility of an
RCPE industrial partner and evaluated with regard to selected industrial applications. Parallel to
developing the monitoring system, a coupled Discrete Element Modeling / Computational Fluid
Dynamics (DEM/CFD) simulation tool for fluid-bed processes will be developed. Via a combination of particle and fluid dynamics simulations, fluid-bed drying systems can be studied in
unprecedented detail, which CFD simulations alone cannot offer. The coupled models will be
used to investigate relevant process design issues, such as optimal drying and gas feeding
strategies, scale-up and reactor design. In addition, the models will be applied to developing and
analyzing concepts for continuous drying systems.
Project Goals
JJ
Development and implementation of an online NIR process monitoring system
JJ
Investigation of fluid-bed drying systems via an online NIR process monitoring system
JJ
Using a NIR process monitoring system for laboratory- and production-scale applications
JJ
Development of a DEM/CFD simulation tool for fluid-bed processes
JJ
Investigation of fluid-bed drying processes using a combined DEM/CFD tool
Present Project Results
An assessment of NIR systems with regard to applying Process Analytical Technology (PAT) to
monitoring granular manufacturing processes was carried out by conducting both NIR equipment performance (i.e., spectral resolution, sensitivity, measurement time, detector stability, etc.)
and measurement probe design (i.e., directly attached spectrometer, single fiber probe, multiple
Page 60
fiber probe systems, etc.). These different monitoring principles were experimentally implemented
and tested on a fluidized bed process at Rutgers University to monitor powder particle size
and moisture content. Based on the assessment and evaluation, a PAT approach to an industrial fluidized bed granulation process was developed. Thereby, an industrial NIR spectrometer
was successfully utilized for in-line process monitoring in GMP environment. For spectral data
analysis, multivariate data analysis (MVDA) software packages were utilized for powerful data
preprocessing and statistical model building. An emphasis was placed on qualitative analysis
based on principal component analysis (PCA) to determine the granulation end point. Currently,
the PAT monitoring strategy is tested for robustness and will further be developed for real-time
process monitoring.
The DEM code, which runs on a single graphics processing unit (GPU), can now incorporate two
million particles per GigaByte of graphics memory in a single-phase operation. For two-phase
operations, a two-way coupled simulation of over 600,000 particles forming a bubbling bed in an
air stream was performed. In tandem with the experimental research, we will continue working
on realistically simulating and understanding the processes in a fluid bed dryer.
Project Challenges
The application of PAT to pharmaceutical manufacturing processes yields a mechanistic process
understanding and provides not only a feedback but feed-forward control of a process that allows
to meet product quality for direct release. However, for a robust and valid monitoring, knowledgebased selection of parameters that are critical to the quality, appropriate equipment for in-line
measurements and powerful data management tools must be developed and implemented. With
regard to process monitoring based on spectral data acquisition, such as NIR spectroscopy,
external influences (e.g., temperature, humidity, etc.) have a strong impact on the monitoring
performance, which must be incorporated according to the product’s design space. In addition to these experimentally challenging issues, data logging for licensed processes and model
handling on different levels with univariate (e.g., temperature, pressure, etc.) and multivariate
(e.g., spectra, images, etc.) data must be correlated and organized through smart meta-models.
Numerical simulations have been applied to understand granular flows better. We are using
the Discrete Element Method (DEM). Thereby, particles are (still) modeled as spheres, and their
translational and rotational motions are computed based on the forces exerted on the interparticle contacts. In the DEM algorithm all particles scan for their neighbors independently, which
allows parallelization. Due to the cutting-edge Nvidia/CUDA technology, our unique DEM code
can include up to 8 million particles in a simulation.
Suitable extensions for spraying and wetting of powders are developed to study the influence
of liquid bridges between particles, blending homogeneity and mixedness of the spheres. The
calibration of simulation parameters plays an important role. The adjustments require the PAT
and NIR data from the experimental project branch in order to predict process simulation results
using DEM.
Numerical simulations of drying in fluidized beds require the coupling of CFD and DEM. Our
development strategy is to use the lattice-Boltzmann Method (LBM) as CFD solver because of
its numerical robustness and excellent parallelization features. A CUDA implementation of an
LBM solver is under development. In order to apply simulations to production processes, further
development will target the inclusion of complex geometrical shapes and validations of the fluid
phase.
Project related Publications
JJ
C.A. Radeke, B.J. Glasser, J.G. Khinast. Large-scale Powder Mixer Simulations Using Massively Parallel GPU Architectures. – in: Chemical Engineering Science 65 (2010) 6435-6442
(Oct 1, 2010)
Page 61
JJ
JJ
JJ
D. Koller, N. Balak, O. Scheibelhofer, J.G. Khinast. Spatially Resolved Real-time Monitoring
of Pharmaceutical Processes with a Multiple NIR-Probe Setup. – in: Journal to be defined
(2011)
N. Heigl, D. Koller, B.J. Glasser, F.J. Muzzio, J.G. Khinast. Quantitative On-line vs. Off-line NIR
Analysis of Fluidized Bed Drying with Consideration of the Spectral Background. – in: Journal
to be defined (2011)
N. Heigl, D. Koller, B.J. Glasser, F.J. Muzzio, J.G. Khinast. Near-infrared Spectroscopy with
Experimental Design for the Characterization of Fluidized Bed Dried Dibasic Calcium Phosphate Anhydrous. – in: Journal to be defined (2011)
Doctoral Thesis
JJ
O. Scheibelhofer: Spectroscopical Methods in Pharmaceutical Applications (ongoing)
Diploma Theses
JJ
J. Moor: Application of NIR-Imaging and Multivariate Data Analysis for Pharmaceutical Products (2010)
JJ
A. Monitzer: Integration of the Lattice-Boltzmann-Method and the Discrete Element Method
in CUDA (2010)
JJ
O. Scheibelhofer: Combining Rheometric Powder Characterisation Techniques with NearInfrared Spectroscopy based on Experimental Design and Multivariate Data Analysis (2010)
JJ
H. Preiß: Untersuchung von Pulvergemischen hinsichtlich deren Homogenität mittels spektroskopischer Methoden (2011)
Page 62
Page 63
RCPS – A Business Unit of the RCPE
Objective
The potential that Graz offers in the fields of analytics, toxicology, biomedicine and clinical studies called for the creation of a new business unit focusing on drug-approval-process related
services. The available resources and know-how led to the establishment of the Business Unit
“Research Center Pharmaceutical Services” (RCPS).
The goal of the Business Unit RCPS is to offer the pharmaceutical industry evaluation/production/refiling services with regard to the drug’s certification documents. Certification documents
provided by RCPS comply with the latest requirements and the relevant European and international guidelines (ICH). They are prepared in close co-operation with the clients.
Furthermore, expertise in new areas within the certification field, such as Quality by Design (QbD)
or electronic submission (eCTD), is developed and can be offered to clients in the context of
RCPS’s service.
Implementation
The starting phase (the first 6 months) begun in September of 2009 and was financed by the
State of Styria. To achieve the above-mentioned goals, a search for experienced specialists from
the pharmaceutical industry was conducted. Currently, Business Unit RCPS has 3 employees (1
Business Unit manager and 2 Regulatory Affairs managers).
During the startup phase, contacts with numerous pharmaceutical companies were established,
offers were made, and projects were planned. After establishing the employee structure, positioning and defining the RCPS service areas and networking with all relevant Graz research
organizations, the first projects were started and completed at RCPS.
Today RCPS is a One-Stop-Shop for drug certification. In many areas RCPS offers international
and national pharmaceutical companies a complete package of certification services, from the
production of documentation relevant for certification, reformatting existing documents, liaising
with other scientific research organizations, obtaining certification-supporting documentation to
providing post-certification support or finalizing a variation/renewal.
Page 64
Service Focus
Today, with regard to the service activity, RCPS is a service provider, where industry and research
units can effectively and efficiently exchange ideas, complete projects and implement them in
accordance with the appropriate guidelines. The emphasis is placed on 4 areas:
Consulting
Data Collection
Documentation
Submission
Generally, every certification issue can be addressed. A special emphasis is placed on upgrading
of old certification dossiers, reformatting existing dossiers in electronic formats (eCTD) and applying data generation based on Quality by Design.
Outlook
After successfully establishing the Business Unit RCPS, the next step is its supervisory-boardapproved spin-off as an independent enterprise. The preparations for the spin-off are underway,
and the establishment of a separate company is planned for January of 2012. This highlights the
significance of the RCPE as competence Center that serves as a starting point of economically
independent enterprises.
Page 65
NonK-Services
Page 66
NonK-Services
In addition to the K1 research area, it is our intention to make our research capabilities and
technological background available for companies in other funded and contractual research
projects, as well as on a service basis. Typical examples include measurements using our vast
experimental and analytical capabilities, literature studies, feasibility studies, design studies,
simulation work and other types of services. Our state-of-the-art experimental facilities include:
• Full biomolecular and biophysical characterization
• Biopharmaceutical properties
• Particle analysis
• Powder analysis
• Process characterization and online methods
• Detailed chemical characterization
• Bench- & pilot-scale process lab
• Scale-up facility
Furthermore, numerical simulations and design studies for industrial processes are part of our
services. Some examples are:
• Mixing processes, both for fluids and granular matters
• Bubbly and multiphase flows
• Spraying, drying and wetting processes
• Computer-aided analysis of room air flows
• Model development
• Feasibility studies
Our highly-motivated and experienced research team assures rapid results and customer satisfaction. In summary, we see ourselves as a “one stop shop” for our customers by providing
whole package solutions for the scientific, research and development challenges of the future.
customer
RCPE
RCPs
one stop shop for …
Research
Projects
Funded­and
­Con­tractual
R
­ esearch
RCPE connects customers to …
TU GRAZ, KF UNI, JR, ...
RESEARCH FACILITIES
K1
Services
INDUSTRIAL PARTNERS
Page 67
Research Project
“SIMNET Styria”
Abstract
The project “SIMNET Styria”, founded by the Styrian government, is developed together with
the coordination partners University of Leoben (Montanuniversität Leoben) and JOANNEUM
RESEARCH Forschungsgesellschaft mbH. The purpose is to create a scientific and industrial
network dealing with numerical and mathematical simulation.
Research Project
“NANOHEALTH”
Abstract
The network-project “Nano-Structured Materials for Drug Targeting, Release and Imaging” aims
at creating a platform for the development of new multifunctional nanoparticles for non-invasive
targeted drug administration in the therapy of chronic diseases. The RCPE’s contribution deals
with the development and the scale-up of a suitable production process. The project is initiated
and coordinated by the BioNanoNet network.
Page 68
Service Project
“Engineering services in the field of
­chemical and biochemical engineering”
Abstract
The objective of this service project is to support one of the Center’s industrial partners in
internal research and production projects. Based on the Center’s expertise in chemical and
biochemical engineering, the RCPE can thus provide target-oriented engineering services in a
very quick and efficient way.
Service Project
“A preliminary study on surface
­modification of glass vessels for
­preventing alkali diffusion”
Abstract
One of the leading manufacturers for pharmaceutical glasses in Europe, Stölzle-Oberglas
GmbH, requested a contractual service for an intelligent and manufacturing-process-aligned
surface modification of their products to prevent alkali diffusion into pharmaceutical liquids. On
the basis of smart surface modification techniques, developed at the RCPE, follow-up projects
were initiated aiming at improvements and development of strategies for an implementation
within the manufacturing process.
Page 69
Research Project
“Fast Forward PAT”
Abstract
The project ‘Fast Forward PAT’ is accomplished together with the company EVK DI KERSCHHAGGL GmbH and funded by the Austrian Research Promotion Agency (FFG). The objective
is the development of a process analytical measurement system for continuous pharmaceutical
manufacturing processes. A prototype system based on an already established near-infrared
camera technology will be further developed towards a flexibly applicable for divers measurement probes enabling spatially resolved, fast and simultaneous process monitoring.
Service Project
“Numerical Simulation and Up-Scale of a
crystallization process”
Abstract
The project “Numerical Simulation and Up-Scale of a Crytallization Process” with the company
Boehringer Ingelheim RCV GmbH & Co KG dealt with the numerical CFD-simulation of crystal
suspensions in a stirred tank. The objective was to optimize the reactor geometry, as well as to
identify the optimal process parameters at different equipment scales.
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Service Project
“Development of a Pharma Qualification
and Validation Package”
Abstract
The objective of the service project with Anton Paar was the shared development of GMPcompliant qualification documents. Both generic templates as well as documents for specific
existing instruments used in the pharmaceutical applications were created and reviewed.
Page 71
Analytics
The RCPE’s analytical equipment allows characterization of a wide variety of materials and
samples from our partners. Four main fields of analysis are available: Spectroscopy, SWAXS,
Chromatography and Powder Analysis.
In the field of spectroscopy, the laboratory is equipped with Near Infrared Spectroscopy (NIR),
Ultraviolet and Visible (UV-Vis) as well as Raman Spectroscopy, furthermore facilitated by NIR
and Raman imaging technology. Spectroscopic methods are widely used as process analyzers
in Process Analytical Technology (PAT), which is an important research area at the RCPE. A
Zetasizer, based on photon correlation spectroscopy, enables the measurement of Zetapotential and size of nanoparticles and emulsions.
For small and wide angle X-ray-scattering (SWAXS) we have a Hecus S3 Micro apparatus which
renders information on structure, specific inner surface, average pore size, radius of gyration
and polymorphism. Fields of application are pharmaceutical technology, structural biology,
proteomics, nanomaterials, nanoparticle sizing, thin films, liquid crystals, phase transitions and
heterophase characterization.
In the area of powder technology, the RCPE provides measurement techniques for particle
size distribution, particle shape, powder rheology and moisture analysis on a cutting-edge
level. Particle size distributions are measured by sieve analysis, laser diffraction and direct
imaging systems. Our Helos and QicPic systems are made by Sympatec, one of the leading
manufacturers of imaging systems, and thus widely used for standard tests in industry. Powder
Rheology-measurements are carried out by a FT 4 powder rheometer manufactured by Freeman Technology.
The FT 4 combines multiple aspects of powder characterization in an innovative simple unit
design. Powder Rheology, for example, gives information on flowability, segregation, influence
of ambient conditions on powders, storage and processing parameters.
Furthermore, GC and HPLC analyses are available. A Waters Acquity Ultra High Pressure Liquid
Chromatography (UPLC) with Mass Spectrometer (MS) is available to investigate, e.g., degradation products, dissolution rates and identification of by-products.
Page 72
Analytics
Equipment
Raman
Infrared Spectrometer
NIR
NIR Probes
UV/VIS spectrometer
Porosimeter
Porosimeter
Spray dryer
Powder Rheometer
Rheometer
SWAXS
Dissolution Tester
Friability Tester
Contact angle measurement
Microscope
Stirring Device
Refrigerated Centrifuge
Scales
UPLC + MS
GC
Shape and Size Image Analysis
Laser Diffraction Size Analysis
Zetasizer
Gas Pycnometer
DSA
Name
RamanStation 400
Spectrum 400
SentroPAT FO
DR LS 300
PE 950
Tristar II 3020
ASAP 2000
Nano Spray Dryer B-90
FT4
Physica MCR300
S3-Micro
DT 840 low head
PTF10E
Easydrop
DM4000
RZR 2102
Universal 320 R
High Precision Scales
Acquity UPLC + MS
Clarus500
QicPic
Helos
NanoZS
AccuPic II 1340
DSA 5000M
Manufacturer
PerkinElmer
PerkinElmer
Sentronic
Dynisco
PerkinElmer
Micromeritics
Micromeritics
BÜCHI Labortechnik
Freeman
Anton Paar
Hecus
Erweka
Pharmatest
Krüss
Leica
Heidolph
Hettich
Sartorius
Waters
PerkinElmer
Sympatec
Sympatec
Malvern
Micromeritics
Anton Paar
Page 73
Process Equipment
The RCPE’s process equipment allows experimental investigations of pharmaceutical production processes at pilot-plant scale. Thus, the gap between laboratory-scale investigations
and production-scale applications can be closed and state-of-the-art process analytical and
simulation tools can be tested under realistic operating conditions. A pharmaceutical extrusion
system from Coperion is extensively used for process development, testing of process analytical
tools and model validation. A fluid bed system from Glatt Process Technology is used in similar
applications. A laboratory tablet press from Fette Compacting and a compaction simulator
from Medelpharm are applied in experimental investigations of tableting operations. Additional
process equipment will be included in the future, if required.
Equipment
Strand Granulator
Die Face Pelletizer
Conditioning Cabinet
Extrusion system
High Shear Mixer
Laboratory tablet press
Batch fluid bed system
Extrusion system
Compaction simulator
Shake Mixer
Page 74
Name
P60E
Prototype
ZSK 18
P25
102i
GPCG1
Micro 27
STYLCAM 200R
Turbula T2F
Manufacturer
Automatik
Automatik
Binder
Coperion
Diosna
Fette Compacting
Glatt Process Technology
Leistritz
MEDELPHARM
WAB
Simulation Tools
The RCPE’s simulation tools cover the multiscale nature (i.e., from the molecular towards the reactor scale) of the production processes in the pharmaceutical industry. Different computational
approaches are used to reproduce the physical behavior of:
JJ
Multiphase flows:
Computational Fluid Dynamics (CFD) and Lattice Boltzmann Method (LBM)
Software: AVL FIRE®
JJ
Granular flows:
Discrete Element Method (DEM)
Software: EDEM, XPS (in-house code)
JJ
Molecular Modeling:
Molecular Dynamics (MD)
Software: AMBER, GROMACS
The focus is the development and integration of computational methods for the description,
simulation, design, optimization and control of product function and the corresponding manufacturing processes. The targeted coupling of different tools (e.g. CFD-DEM) is also a main issue
of RCPE’s computational development. In this way we are able to reproduce the intrinsic nature
of multiscale phenomena. The strong interaction with the Quality by Design (QbD) team allows
the development of in-silico design spaces, leading to a deep understanding of the correlations between process parameters, material attributes and the quality of the final product. Some
example of our established know-how in modeling and simulation are:
JJ
Development of multi-scale simulation/optimization tools for biopharmaceutical processes
(e.g., stirred vessels, bio reactors)
JJ
Tools for the prediction of powder flow properties (blending, feeding, cohesive materials)
JJ
Coupled simulations of granular/multiphase flows (coating, granulation, fluidized bed)
JJ
Simulation and design of controlled and robust particle synthesis processes
JJ
Design, testing and optimization of complex three-dimensional sensors
JJ
Virtual Quality by Design
Spray drying /
granulation
Spray
Multiphase flow
CFD (Computational
Software: AVL-Fire®
Fluid
Bubbly flows
Room flow
Dynamics)
Coating
Molecular modeling
MD (Molecular dynamics)
Software: AMBER, GROMACS
Mixing
Blending
Particle flow
DEM (Discrete Element Method)
Software: EDEM, XPS (in-house code)
Page 75
source: Graz University of Technology
Page 76
Scientific Output of the Center
Publications
In the year to be reported the scientific output was shown in:
51 refereed Publications in international journals
49 Conference Talks
39 Poster Presentations
3 Other Publications
The exact quotations of the publications, lectures and poster presentations can be found in the
list below.
Publications (refereed)
JJ
E. Ablinger, S. Wegscheider, W. Keller, R. Prassl, A. Zimmer: Effect of protamine on the
solubility of human growth hormone. – European Journal of Pharmaceutics and Biopharmaceutics (2011, submitted)
JJ
S. Adam, D. Suzzi, C. Radeke, J.G. Khinast. An integrated Quality by Design (QbD) approach
towards design space definition of a blending unit operation by Discrete Element Method
(DEM) simulation. – in: European Journal of Pharmaceutical Science 42 (2011) 106-115 (Nov
4, 2010)
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S. Adam, D. Suzzi, G. Toschkoff, J.G. Khinast. Application of Advanced Simulation Tools for
Establishing Process Design Spaces within the Quality-by-Design Framework. – Submitted
as book chapter (2011)
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M. Aichner, L. Oberauner, S. Liebminger, M. Fürnkranz, G. Berg. Volatile organic compounds
of plant-associated bacteria to reduce microbial contamination on clean room textile. – in:
IOBC/WPRS Bulletin (2010)
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G. Berg, K. Hartenberger, S. Liebminger, C. Zachow. Antagonistic endophytes from mistletoes as bio-resource to control clean room pathogens. – in: IOBC/WPRS Bulletin (2010)
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J. M. Bolivar; J. Wiesbauer; B. Nidetzky. Biotransformations in microstructured reactors: more
than flowing with the stream?. – in: Trends in Biotechnology 29/7 (2011) 333-342 (2011, in press)
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G. Brenn, N. Schrödl, C. Voura, M. Gruber, J. Khinast, A. Zimmer. Scaling laws in drop
formation by drop-on-demand generators. – Physics of Fluids (2011, submitted)
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R.J.P. Eder, E.K. Schmitt, J. Grill, S. Radl, H. Gruber-Woelfler, J.G. Khinast. Seed Loading
Effects on the Mean Crystal Size of Acetylsalicylic Acid in a Continuous-Flow Crystallization
Device. – in: Crystal Research and Technology 46/3 (2011) 227 - 237 (Feb 11, 2011)
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A. Eitzlmayr; C. Petschacher; S. Radl; D. Suzzi; A. Zimmer; J. G. Khinast. Modeling and
simulation of polyacrylic acid/protamine nanoparticle precipitation. – in: Soft Matter (2011)
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P. Feenstra, M. Brunsteiner, J. Khinast. Prediction of Drug-Packaging Interactions via Molecular Dynamics (MD) Simulations. – Journal of Chemical Physics (2011, submitted)
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B. Gübitz, H. Schnedl, J.G. Khinast. A Risk Management Ontology for Quality-by-Design
Based on a New Development Approach According GAMP 5.0. – Risk Analysis (2011,
submitted)
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N. Heigl, G. Hoerl, D.M. Koller, G. Toschkoff, S.D. Fraser, W. Tritthart, F. Reiter, M. Schlingmann,
J.G. Khinast. Comparison of Raman Spectroscopic Sub-Sampling with NIR Spectroscopy
for the Tablet Coating Thickness Determination. – International Journal of Pharmaceutical
Sciences (2011, accepted)
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A. Hodzic, M. Llusa, N. Heigl, W. Tritthart, S.D. Fraser, J.G.Khinast, P. Laggner. Effect of
process variables on the Small-Angle X-Ray Scattering patterns of powders, granules and
pharmaceutical tablets. – Powder Technology (2011, submitted)
T. Hörmann, D. Suzzi, J.G. Khinast. Mixing and Dissolution Processes of Pharmaceutical
Bulk Materials in Stirred Tanks: Experimental and Numerical Investigations. – Industrial &
Engineering Chemistry Research (2011, submitted)
M. Iannuccelli; D. Suzzi; B. Sirnik; A. Rinderhofer; J.G. Khinast. Numerical Simulation of
Freeze-Thaw Biopharmaceutical Process. – in: Chemical Engineering Transactions 24 (2011)
907-912
S. Karner, N.A. Urbanetz. The impact of electrostatic charge in pharmaceutical powders with
specific focus on inhalation-powders. – in: Journal of Aerosol Science 42 (2011) 428-445
(Mar 3, 2011)
J. Khinast, F. Muzzio. Pharmaceutical engineering science— New approaches to pharmaceutical development and manufacturing. – in: Chemical Engineering Science 65 (2010) 4-7
(Nov 1, 2010)
N. Kiss; G. Brenn; H. Pucher; J. Wieser; S. Scheler; H. Jennewein; D. Suzzi; J. Khinast.
Formation of O/W emulsions by static mixers for pharmaceutical applications. – in: Chemical
Engineering Science 66 (2011) 5084-5094 (2011, in press)
D.M. Koller; G. Hannesschläger; M. Leitner b; J.G. Khinast. Non-destructive analysis of tablet
coatings with optical coherence tomography. – in: European Journal Pharmaceutical Science
44 (2011) 142-148 (2011, in press)
D.M. Koller, A. Posch, G. Hörl, C. Voura, S. Radl, N. Urbanetz, S.D. Fraser, W. Tritthart, F.
Reiter, M. Schlingmann, J.G. Khinast. Continuous quantitative monitoring of powder mixing
dynamics by near-infrared spectroscopy. – in: Powder Technology 205 (2011) 87-96 (Sep
16, 2010)
S. Liebminger, M. Aichner, L. Oberauner, M. Fürnkranz, M. Cardinale, G. Berg. A new assay
to assess antimicrobial activity of volatiles on textiles. – Journal of Textile Research (2011,
submitted)
E.M. Littringer, A. Mescher, S. Eckhard, H. Schröttner, C. Langes, M. Fries, U. Griesser, P.
Walzel, N.A. Urbanetz. Spray drying of mannitol as a drug carrier – The impact of process
parameters on the product properties. –Drying Technology (2011, submitted)
S. G. Maas; G. Schaldach; E.M. Littringer; A. Mescher; U.J. Griesser; D.E. Braun; P.E. Walzel;
N.A. Urbanetz. The impact of spray drying outlet temperature on the particle morphology of
mannitol. – in: Powder Technology 213 (2011) 27-35 (2011, in press)
S.G. Maas, G. Schaldach, P.E. Walzel, N.A. Urbanetz. Tailoring dry powder inhaler performance by modifying carrier surface topography by spray drying. – in: Atomization and Sprays
20 (2010) 763-774
V. Mykhaylova; K. Dresely; F. Klar; N.A. Urbanetz. Carrier-free Formulation of Dry Powder
Inhalates. – in: Pharmaceutical Industry (2011, in press)
J. Pardeike; D.M. Strohmeier; N. Schroedl; C. Voura; M. Gruber; J.G. Khinast; A. Zimmer.
Nanosuspensions as advanced printing ink for accurate dosing of poorly soluble drugs in
personalized medicines. – in: International Journal of Pharmaceutics (2011, in press)
K.E. Pickl, V. Adamek, R. Gorges, F.M. Sinner. Headspace-SPME-GC/MS as a simple
cleanup tool for sensitive 2,6-diisopropylphenol analysis from lipid emulsions and adaptable
to other matrices. – in: Journal of Pharmaceutical and Biomedical Analysis 55 (2011) 12311236 (Mar 17, 2011)
C. Potamitis, P. Chatzigeorgiou, E. Siapi, K. Viras, T. Mavromoustakos, A. Hodzic, G. Pabst,
F. Cacho-Nerin, P. Laggner, M. Rappolt: Interactions of the AT1 Antagonist valsartan with
dipalmitoyl-phosphatidylcholine bilayers. – in: Biochimica et Biophysica Acta 1808 (2011)
1753 - 1763 (Feb 18, 2011).
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C.A. Radeke, B.J. Glasser, J.G. Khinast. Large-scale Powder Mixer Simulations Using Massively Parallel GPU Architectures. – in: Chemical Engineering Science 65 (2010) 6435-6442
(Oct 1, 2010)
S. Radl, D. Suzzi, J.G. Khinast. Fast Reactions in Bubbly Flows: Film Model and Micromixing
Effects. – in: Industrial & Engineering Chemistry Research 49 (2010) 10715-10729 (Sep 15,
2010)
S. Radl, J.G. Khinast. Multiphase Flow and Mixing in Dilute Bubble Swarms. – in: AIChE
Journal 56/9 (2010) 2421–2445 (Sep, 2010)
S. Radl, S. Larisegger, D. Suzzi, J.G. Khinast. Quantifying Absorption Effects during Hydrogen Peroxide Decontamination. – in: Journal of Pharmaceutical Innovation (2011, accepted)
B. Remy, J.G. Khinast, B.J. Glasser. Polydisperse Granular Flows in a Bladed Mixer: Experiments and Simulations of Cohesionless Spheres. – in: Chemical Engineering Science 66
(2011) 1811-1824 (Dec 22, 2010)
B. Remy, J.G. Khinast, B.J. Glasser. Wet granular flows in a bladed mixer: Experiments and
simulations of monodisperse spheres. – Chemical Engineering Science (2011, submitted)
E. Roblegg, E. Jäger, A. Hodzic, G. Koscher, S. Mohr, A. Zimmer, J.G. Khinast: Development
of sustained-release lipophilic calcium stearate pellets via hot melt extrusion. – in: European
Journal of Pharmaceutics and Biopharmaceutics (2011)
E. Roblegg, S. Schrank, M. Griesbacher, S. Radl, A. Zimmer, J.G. Khinast: Use of the Direct
Compression Aid Ludiflash® for the preparation of pellets via wet extrusion/spheronization.
– in: Drug Development and Industrial Pharmacy (2011, accepted)
E. Roblegg, E. Jäger, S. Mohr, A. Hodzic, A. Zimmer, J.G. Khinast. Development of lipophilic
calcium stearate pellets via hot melt extrusion – in: European Journal of Pharmaceutical and
Biopharmaceutical (2011, in press)
U. Roessl, J. Wiesbauer, S. Leitgeb, R. Birner-Gruenberger, B. Nidetzky. Non-native Aggregation of Recombinant Human Granulocyte-Colony Stimulating Factor (rhG-CSF) under
Simulated Process Stress Conditions. – Biotechnology and Bioengineering (2011, submitted)
S. Schrank, A. Hodzic, A. Zimmer, B. Glasser, J. Khinast, E. Roblegg. Calcium Stearate
Pellets for Oral Administration: Drying-Induced Variations in Dosage Form. – International
Journal of Pharmaceutics (2011, submitted)
M.S. Siraj; S. Radl; B.J. Glasser; J.G. Khinast. Effect of blade angle and particle size on
powder mixing performance in a rectangular box. – in: Powder Technology 211 (2011) 100113 (Apr 9, 2011)
M. Smikalla, A. Mescher, P. Walzel, N.A. Urbanetz. Impact of excipients on coating efficiency
in dry powder coating. – in: International Journal of Pharmaceutica 405 (2011) 122-131 (Dec
8, 2010)
S. Stegemann, F. Ecker, M. Maio, P. Kraahs, R. Wohlfart, J. Breitkreutz, A. Zimmer, D. BarShalom, P. Hettrich, B. Broegmann. Geriatric drug therapy: Neglecting the inevitable majority.
– in: Ageing Research Reviews 9 (2010) 384-398
S. Stegemann, I. Klebovich, I. Antal, H. H. Blume, K. Magyar, G. Németh, T. L. Paál, W.
Stumptner, G. Thaler, A. Van de Putte, V. P. Shah: Improved therapeutic entities derived from
known generics as an unexplored source of innovative drug products. – in: European Journal
of Pharmaceutical Sciences (2011, accepted)
R. Sungkorn; J.J. Derksen; J.G. Khinast. Euler–Lagrange Modeling of a Gas–Liquid Stirred
Reactor with Consideration of Bubble Breakage and Coalescence. – in: AIChE Journal (2011)
R. Sungkorn, J.J. Derksen, J.G. Khinast. Modeling of Aerated Stirred Tanks with NonNewtonian Liquids. – Industrial & Engineering Chemistry Research (2011, submitted)
D. Suzzi, S. Radl, J.G. Khinast. Local analysis of the tablet coating process: Impact of operation conditions on film quality. – in: Chemical Engineering Science 65 (2010) 5699-5715 (Aug
6, 2010)
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D. Suzzi, G. Toschkoff, S. Radl, D. Machold, S.D. Fraser, B.J. Glasser, J.G. Khinast. DEM
Simulation of Continuous Tablet Coating: Effects of Tablet Shape and Fill Level on Inter-Tablet
Coating Variability. – Chemical Engineering Science (2011, submitted)
G. Toschkoff; D. Suzzi; W. Tritthart; F. Reiter; M. Schlingmann; J.G. Khinast. Detailed Analysis
of Air Flow and Spray Loss in a Pharmaceutical Coating Process. – in: AIChE Journal (2011,
in press)
G. Toschkoff, D. Suzzi, S. Adam, J.G. Khinast. Numerical Simulation of Pharmaceutical
Tablet Coating Processes: First Steps Towards an in-silico Design Space. – Pharmaceutical
Technology Europe (2011, submitted)
B. Unterweger, T. Stoisser, S. Leitgeb, R. Birner-Grünberger, B. Nidetzky. Engineering of
Aerococcus viridans L-lactate oxidase for site-specific PEGylation: characterization and
chemical modification of a S218C mutant. – Biotechnology Journal (2011, submitted)
C. Voura, N. Schroedl, M. Gruber, D. Strohmeier, B. Eitzinger, W. Bauer, G. Brenn, J.G.
Khinast, A. Zimmer. Printable medicines: a microdosing device for producing personalised
medicines. – in: Pharmaceutical Technology Europe 23 (2011) 32 - 36 (Jan 7, 2011)
Conference Talks
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E. Ablinger, A. Zimmer, R. Prassl. Stabilization of human growth hormone against deamidation by interaction with strongly basic protamines from salmon. CESPT 2010, Graz (A) on
Sep 17th, 2010
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S. Adam, D. Suzzi, S. Radl, G. Toschkoff, T. Hörmann, J.G. Khinast. Quality-by-Design Based
Characterization of Pharmaceutical Processes by Means of Numerical Simulations. CESPT
2010, Graz (A) on Sep 16th, 2010
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S. Adam, D. Suzzi, G. Toschkoff, T. Hörmann, C. Radeke, J.G. Khinast. An Integrated Qualityby-Design (QbD) Approach towards Design Space Definition of three Key Unit Operations in
the manufacturing of solid and liquid dosage forms by Discrete Element Method (DEM) and
Computational Fluid Dynamics (CFD) Simulation. CESPT 2010, Graz (A) on Sep 16th, 2010
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S. Adam, S.D. Fraser, D. Koller, S. Radl, D. Suzzi, E. Roblegg, J.G. Khinast. Continuous
Manufacturing & the Role of HME in Pharmaceutical Production. Hot Melt Extrusion Congress, Stuttgart (D) on Apr 15th, 2010
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N. Balak, O. Scheibelhofer, D.M. Koller, J.G. Khinast. Quantitative Quasi-Simultaneous and
Spatially Resolved Real-time Monitoring of Powder Mixing Processes with a Multiple NIRProbe Setup. AIChE 2010, Salt Lake City (USA) on Nov 9th, 2010
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M. Besenhard, A. Eitzlmayer, D. Suzzi, J.G. Khinast, R. Eder. Theory and Application of
Population Balance Equations in Chemical Engineering. 7. Minisymposium VT, Graz (A) on
Jun 30th, 2011
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A. Eitzlmayr, D. Suzzi, J.G. Khinast. CFD-Simulation eines Nanopartikel-Präzipitationsprozesses. ProcessNet-Jahrestagung 2010 und 28. Jahrestagung der Biotechnologen, Aachen
(D) on Sep 21st, 2010
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N. Heigl, G. Hörl, D. Koller, G. Toschkoff, S.D. Fraser, J.G. Khinast, W. Tritthart, F. Reiter, M.
Schlingmann. Raman Chemical Mapping vs. NIR Spectroscopy for Assessing the API Distribution and Coating Thickness of Tablets. AIChE 2010, Salt Lake City (USA) on Nov 7th, 2010
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N. Heigl, A. Hodzic, M. Lachmann, S.D. Fraser, J.G. Khinast, M. Kriechbaum, P. Laggner, W.
Tritthart. Raman Spectroscopy Combined with Small-and Wide-Angle X-Ray Scattering as
a Non-destructive Quality Control Tool for Powder Compression in Pharmaceutical Applications. AIChE 2010, Salt Lake City (USA) on Nov 7th, 2010
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A. Hodzic. SAXS and SWAXS/DSC Laboratory Pharmaceutical Applications. Workshop on
SAXS Laboratory Practice, New Approaches and Integrated Techniques, Graz (A) on May
3rd, 2011
Page 80
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D. Koller, N. Balak, O. Scheibelhofer, J. Moor, G. Hörl, N. Heigl, S.D. Fraser, J.G. Khinast.
Real-time Monitoring of Powder Mixing Dynamics with Spectroscopic PAT-Tools. CESPT
2010, Graz (A) on Sep 16th, 2010
D. Koller, N. Balak, J. Moor, N. Heigl, S.D. Fraser, J.G. Khinast, M. Burgstaller P. Kerschhaggl.
Real-time Process Monitoring with Spatially Resolved Spectroscopic PAT-Tools. AIChE 2010,
Salt Lake City (USA) on Nov 8th, 2010
D. Koller, N. Balak, O. Scheibelhofer, J.G. Khinast. Quantitative Monitoring of Batch and
Continuous Powder Mixing Processes with Spatially Resolved Spectroscopic PAT-Tools.
IFPAC – Process Analytical Technology, Baltimore (USA) on Jan 18th, 2011
D. Koller, O. Scheibelhofer, S. Fraser, J.G. Khinast. Spatially Resolved Process Monitoring
with Spectroscopic PAT-Tools. European Conference on Process Analytics and Control
Technology, Glasgow (UK) on Apr 28th, 2011
S. Leitgeb, T. Stoisser, D. Neuhold, B. Nidetzky. Structure-function relationships for substrate
selectivity in 2-hydroxy acid oxidizing enzymes. The 24th Annual Symposium of the Protein
Society, San Diego (USA) on Aug 5th, 2010
S. Leitgeb, M. Iannuccelli, B. Sirnik, D. Suzzi, J.G. Khinast, A. Rinderhofer. Validation of the
freezing process of bio-pharmaceuticals in a scale-down container. PepTalk 2011, San Diego
(USA) on Jan 11th, 2011
S. Liebminger. Antimikrobielle Textilien unter der Lupe. Intensivtraining – Reinraumbekleidung/
Der einzige Filter zwischen Mensch und Produkt, Heidelberg (D) on Dec 2nd, 2010
S. Liebminger, B. Nidetzky, G. Straganz. The 3-His iron center – a distinct motif of catalytic
function in non-heme metal dependent enzymes. Transition metals in biochemistry, Norwich
(UK) on Jun 25th, 2011
E. Littringer, N.A. Urbanetz, H. Schröttner, P. Walzel, A. Mescher. Kinetic Pathway Analysis of
Aggregation of Therapeutic Proteins. Drug delivery to the lungs 21, Edinburgh (UK) on Dec
9th, 2010
E. Littringer, N.A. Urbanetz. Influence of surface roughness on the quality attributes of dry
powder inhalers. Summerschool/workshop “Rheologie und Phasengrenzen bei der Zerstäubung”, Bremen (D) on Jun 9th, 2011
E. Littringer, N.A. Urbanetz, Schrötter, P. Walzel, A. Mescher. Tailoring particle morphology
of spray dried mannitol carrier particles by variation of the outlet temperature. ILASS Europe
2010, Brno (CZ) on Sep 6th, 2010
E. Littringer, N.A. Urbanetz, H. Schröttner, M. Maier, P. Walzel, A. Mescher. Surface modification of dry powder inhaler carrier particles by spray drying. 2. Workshop des SPP ProzessSpray, Erlangen (D) on Sep 13th, 2010
E. Littringer, H. Schröttner, P. Walzel, A. Mescher, A. Maas, R. Paus. Influence of droplet
size on the crystallization behaviour of aqueous D-mannitol solutions during spray drying. 7.
Minisymposium VT, Graz (A) on Jun 30th, 2011
C. Radeke, J.G. Khinast. Parcel-Based Approach for the Simulation of Gas-Particle Flows.
8th International Conference on CFD in Oil & Gas, Metallurgical and Process Industries,
Trondheim (N) on Jun 22nd, 2011
C. Radeke, J.G. Khinast. Wet-Mixing of Powders, a Sarge Scale GPU Implementation.
DEM5, London (UK) on Aug 25th, 2010
C. Radeke, J.G. Khinast. Wet-Mixing Simulations of Powders in a Blade Mixer. AIChE 2010,
Salt Lake City (USA) on Nov 9th, 2010
S. Radl, J.G. Khinast, B. Glasser, H. Haimburg, D. Brandl. Single Blade Experiments on
Granular Flow and Mixing. AIChE 2010, Salt Lake City (USA) on Nov 8th, 2010
D. Reischl, S. Adam, S. Windhaber, E. Roblegg, J.G. Khinast. Quality by Design based Study
on the Optimization of a Tablet Formulation. PharmSciFair, Prag (CZ) on Jun 16th, 2011
Page 81
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Page 82
E. Roblegg, G. Koscher, K. Hirmann, J.G. Khinast, E. Jäger. Continuous Manufacturing and
Hot Melt Extrusion. APV Experts’ Workshop on Hot Melt Extrusion, Tarrytown (USA) on Apr
12th, 2011
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Aggregation of Recombinant Human Granulocyte-Colony Stimulating Factor under Process Conditions. Annual Meeting AIChE 2010, Salt
Lake City (UT, USA) on Nov 10th, 2010
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Kinetic Pathway Analysis of Aggregation of
Therapeutic Proteins on CESPT 2010, Graz (A) on Sep 17th, 2010
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Aggregation of Recombinant Human
Granulocyte-Colony Stimulating Factor under Process Conditions. XV School of Pure and
Applied Biophysics, Venice (I) on Jan 26th, 2011
S. Schrank, J.G. Khinast, E. Roblegg, A. Zimmer. Entwicklung eines Extrusions-Spheronisationsprozesses zur Herstellung von rasch zerfallenden Pellets. ProcessNet-Jahrestagung
2010 und 28. Jahrestagung der Biotechnologen, Aachen (D) on Sep 21st, 2010
W. Stumptner, S. Adam, D. Koller, D. Suzzi, J.G. Khinast. Use of Advanced Quality by Design
Concepts and Tools in Generic Drug Development. 1st Open Forum on Pharmaceutics and
Biopharmaceutics Supergenerics – the Space for Innovative Medicines Hungarian Academy
of Sciences, Budapest (HU) on May 24th, 2011
D. Suzzi, G. Toschkoff, D. Machold, S. Radl, J.G. Khinast. Combined Numerical Method for
Multi-Scale Analysis of Tablet Coating Processes. CESPT 2010, Graz (A) on Sep 16th, 2010
D. Suzzi, S. Adam, M. Iannuccelli, G. Toschkoff, C. Radeke, J.G. Khinast, S. Radl. Use of
Computer Simulations as Process Characterization Tool for Generation of Mechanistic Process Understanding within the Quality by Design Environment. 2nd European Conference on
Process Analytics and Control Technology (EuroPact 2011), Glasgow (UK) on Apr 27th, 2011
D. Suzzi. Multi-Phase and Multi-Scale Simulation in the Pharmaceutical Industry. SIMNET
Days 2011, Leoben (A) on May 3rd, 2011
G. Toschkoff, D. Suzzi, D. Machold, S. Radl, J.G. Khinast. Investigation of a Tablet Coating
Processes using a Multi-Model Simulation Approach. AIChE 2010, Salt Lake City (USA) on
Nov 8th, 2010
G. Toschkoff, D. Suzzi, J.G. Khinast. A deeper understanding of tablet coating processes
through Discrete Element Method simulations. EDEM Conference, Glasgow (UK) on Mar
31st, 2011
G. Toschkoff, D. Suzzi, J.G. Khinast. Investigation of tablet coating processes using Discrete
Element Method simulations. 7. Minisymposium VT, Graz (A) on Jun 30th, 2011
N.A. Urbanetz, E. Littringer, H. Schröttner, P. Walzel, A. Mescher. The use of design of experiments to study the effect of process parameters on surface topography and size of spray
dries D- mannitol, Conference Proceedings. International Drying Symposium, Magdeburg (D)
on Oct 4th, 2010
N.A. Urbanetz, E. Littringer. Carrier particle engineering for pulmonary drug delivery via spray
drying. Pharmazeutisches Kolloquium – Uni Innsbruck (A) on Jan 24th, 2011
N.A. Urbanetz. Development of sustained release formulations by dry powder coating in a
rotary fluid bed. AAPS Annual Meeting, Los Angeles (USA) on Nov 9th, 2010
N.A. Urbanetz, E. Littringer. Sprühtrocknungsverfahren zur Erzeugung inhalierbarer Pulver.
Sprühtrocknung zur Herstellung fester Arzneiformen, Fulda (D) on Feb 28th, 2011
N.A. Urbanetz, E. Littringer. Tailoring the performance of carrier based dry powder inhalates
by surface modification of the carrier using spray drying. Berichterstattung und Begutachtung
zur zweiten Periode des SPP 1423 “Prozess-Spray”, Frankfurt/Main (D) on Jan 10th, 2011
P. Wahl, T. Traußnig, S. Landgraf, S. Electrochemical tuning of the electrical resistance of
nanoporous gold prepared by dealloying. International Conference on Nanostructured Materials, Rome (I) on Sep 13th, 2010
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P. Wahl, O. Scheibelhofer, D. Koller, J.G. Khinast. Application of Process Analytical Technology (PAT) in Pharmaceutical Production. 7. Minisymposium VT, Graz (A) on Jun 30th, 2011
J. Wiesbauer, S. Leitgeb, B. Nidetzky. Human growth hormone – insights into its aggregation
behavior using denaturation pathway characterization. CESPT 2010, Graz (A) on Sep 17th,
2010
J. Wiesbauer, U. Rößl, S. Leitgeb, B. Nidetzky. Kinetic Pathway Analysis of Aggregation of
Therapeutic Proteins. AIChE 2010, Salt Lake City (USA) on Nov 8th, 2010
Poster Presentations
E. Ablinger, S. Wegscheider, T. Pavkov, A. Zimmer, W. Keller. Electrostatic complexation of
human growth hormone with protamine for stabilization against deamidation. 2010 Workshop
on Protein Aggregation and Immunogenicity, Breckenridge (USA) on Jul 21st, 2010
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E. Ablinger, S. Wegscheider, T. Pavkov, A. Zimmer, W. Keller, R. Prassl. Stabilization of human growth hormone against deamidation by interaction with strongly basic protamines from
salmon. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
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N. Balak, O. Scheibelhofer, D. Koller, J.G. Khinast. Quantitative Quasi-Simultaneous and
Spatially Resolved Real-time Monitoring of Powder Mixing Processes with a Multiple NIRProbe Setup. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
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M. Besenhard, S. Schrank, H. Gruber-Wölfler, J.G. Khinast. API-Kristallisation in einem Rohr.
7. Minisymposium VT, Graz (A) on Jun 30th, 2011
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M. Brunsteiner, M. Eichinger, H. Gruber-Wölfler, J.G. Khinast, P. Feenstra. Investigation of the
interaction between drug product solutions and packaging materials. 7. Minisymposium VT,
Graz (A) on Jun 30th, 2011
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A. Eitzlmayr, D. Suzzi, J.G. Khinast. Modeling of Pharmaceutical Hot Melt Extrusion. 7. Minisymposium VT, Graz (A) on Jun 30th, 2011
JJ
G. Hörl, N. Heigl, D. Koller, J.G. Khinast, W. Tritthart, F. Reiter, M. Schlingmann. Evaluation
of API-Distribution and Coating Thickness by NIR Spectroscopy and Raman Chemical Mapping. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
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T. Hörmann, D. Suzzi, M. Gsöll, J. Hofer, J.G. Khinast. Simulation of Fluid Mixing and Dissolution Processes. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
JJ
S. Leitgeb, T. Stoisser, D. Neuhold, B. Nidetzky. Structure-function relationships for substrate
selectivity in 2-hydroxy acid oxidizing enzymes. The 24th Annual Symposium of the Protein
Society, San Diego (USA) on Aug 4th, 2010
JJ
S. Leitgeb, M. Iannuccelli, B. Sirnik, D. Suzzi, J.G. Khinast, A. Traußnig, A. Rinderhofer.
Validation of the freezing process of bio-pharmaceuticals in a scale-down container. PepTalk
2011, San Diego (USA) on Jan 9th-13rd, 2011
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S. Liebminger, D. Suzzi, S. Fraser, G. Schinagl, S. Radl, L. Oberauner, M. Aichner, M.
Cardinale, J.G. Khinast, G. Berg. Innovative Concepts for Personnel Locks in Clean Room
Technology. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
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S. Liebminger, M. Aichner, L. Oberauner, G. Berg. How much sterility is possible? New concepts for clean room environments based on plant-associated bacteria. 11th Conference on
Bacterial Genetics and Ecology – BAGECO11. Corfu (GR) on May 29th, 2011
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S. Liebminger, G. Berg. How much sterility is possible? New concepts for clean room environments based on plant-associated bacteria. 11th Conference on Bacterial Genetics and
Ecology – BAGECO11, Corfu (GR) on May 29th, 2011
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S. Liebminger, M. Cardinale, L. Oberauner, C. Moschner, G. Berg. Survival of HumanAssociated and Environmental Bacteria on Clean Room Textiles. International Microscopy
Conference, Rio de Janeiro (BR) on Sep 19th, 2010
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E. Littringer, N.A. Urbanetz, M. Maier, H. Schröttner, A. Mescher P. Walzel. Influence of carrier
particle morphology on the performance of dry powder inhalers. CESPT 2010, Graz (A) on
Sep 16th-18th, 2010
E. Littringer, N.A. Urbanetz, H. Schröttner, P. Walzel, A. Mescher. Surface modification of
mannitol inhaler carrier particles via spray drying. Drug delivery to the lungs 21, Edinburgh
(UK) on Dec 8th, 2010
E. Littringer, N.A. Urbanetz, H. Schröttner, P. Walzel, A. Mescher A., A. Maas, R. Paus. Studien zur Ausbildung der Partikelmorphologie im Sprühtrocknungsprozess zur Steuerung der
Leistungsmerkmale von Pulverinhalaten. Berichterstattung und Begutachtung zur zweiten
Periode des SPP 1423 “Prozess-Spray”, Frankfurt (D) on Jan 10th, 2011
J. Mohr. Qualification of NIR Spectral Imaging for the Pharmaceutical Industry. CESPT 2010,
Graz (A) on Sep 16th-18th, 2010
J. Moor, D. Koller, N. Heigl, N. Balak, J.G. Khinast, M. Burgstaller P. Kerschhaggl. Qualification of NIR Spectral Imaging for the Pharmaceutical Industry. CESPT 2010, Graz (A) on Sep
16th-18th, 2010
C. Radeke, J.G. Khinast. Particle Simulations using DEM on GPUs. Gpu Technologie Conference 2010 (GTC), NVIDIA Research Summit, San Jose (USA) on Sep 22nd-27th, 2010
E. Roblegg, B. Teubl, E. Fröhlich, A. Zimmer. Transport Studies of Polystyrene Nanoparticles
across the Buccal Mucosa. PharmSciFair, Prag (CZ) on Jun 14th, 2011
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Aggregation of Recombinant Human Granulocyte-Colony Stimulating Factor under Process Conditions. Annual Meeting AIChE 2010, Salt
Lake City (USA) on Nov 10th, 2010
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Kinetic Pathway Analysis of Aggregation of
Therapeutic Proteins. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
U. Rößl, J. Wiesbauer, S. Leitgeb, B. Nidetzky. Aggregation of Recombinant Human Granulocyte-Colony Stimulating Factor under Process Conditions. XV School of Pure and Applied
Biophysics, Venice (I) on Jan 24th-28th, 2011
O. Scheibelhofer, N. Balak, D. Koller, S.D. Fraser, J.K. Khinast, T. Freeman. Linking Rheological Key Parameters of Pharmaceutical Powders to Mixing Properties. CESPT 2010, Graz (A)
on Sep 16th-18th, 2010
S. Schrank, J.G. Khinast, E. Roblegg, A. Zimmer. Development of micropellets for buccal
drug delivery. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
S. Schrank, J.G. Khinast, E. Roblegg. Calcium Stearate Micro-pellets: Impact of Drying
Conditions on Pellet Dissolution. ProcessNet, Aachen (D) (2011)
S. Schrank, E. Roblegg, P. Heidinger. Preparation of Fast Disintegrating Micro-Pellets using
Ludiflash® and Functional Additives. PharmSciFair, Prag (CZ) on Jun 15th, 2011
S. Schrank, J.G. Khinast, E. Roblegg, D. Reischl, A. Zimmer. Calcium-Stearate Micro-pellets:
Impact of Drying on Final Pellet Characteristics. PharmSciFair, Prag (CZ) on Jun 15th, 2011
S. Schrank, E. Roblegg, M. Besenhard, H. Gruber-Wölfler, J. Khinast, R. Eder, J. Grill, E.
Schmitt. Continuous Flow Crystallization of Active Pharmaceutical Ingredients. PharmSciFair,
Prag (CZ) on Jun 16th, 2011
G. Toschkoff, D. Suzzi, J.G. Khinast, M. Schlingmann, F. Reiter, W. Tritthart. Numerical simulation of film formation in tablet coating. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
N.A. Urbanetz, S. Karner. Electrostatic charge on pharmaceutical powders for pulmonary
application. CESPT 2010, Graz (A) on Sep 16th-18th, 2010
N.A. Urbanetz. Sustained release formulations by dry powder coating – Influence of starter
cores on dissolution behavior. AAPS 2009 Annual Meeting and Exposition, Los Angeles
(USA) on Nov 8th-12th, 2010
N.A. Urbanetz. Sustained release formulations by dry powder coating – Influence of starter
cores on dissolution behavior. AAPS 2009 Annual Meeting and Exposition, Los Angeles
(USA) on Nov 8th-12th, 2010
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N.A. Urbanetz, S. Karner. Dry Powder Inhalers –the dependence of particle size and mixing
time on triboelectrification. Drug delivery to the lungs 21, Edinburgh (UK) on Dec 8th, 2010
N.A. Urbanetz, S. Karner. Einflussgrößen auf die triboelektrische Aufladung von Mannitol als
Trägerstoff für Dry Powder Inhaler. 7. Minisymposium VT, Graz (A) on Jun 30th, 2011
P. Wahl, O. Scheibelhofer, D. Koller, J.G. Khinast. Application of Process Analytical Technology (PAT) in Pharmaceutical Production. 7. Minisymposium VT, Graz (A) on Jun 30th, 2011
J. Wiesbauer, S. Leitgeb, B. Nidetzky. Stirred, not shaken –process-relevant parameters and
their effects on stability of human growth hormone. 2010 Workshop on Protein Aggregation
and Immunogenicity, Breckenridge (USA) on Jul 20th, 2010
J. Wiesbauer, S. Leitgeb, B. Nidetzky. Human growth hormone – insights into its aggregation
behavior using denaturation pathway characterization. CESPT 2010, Graz (A) on Sep 16th18th, 2010
Other Publications
C. Radeke, S. Radl, J.G. Khinast. Wet Mixing of Powders. Proceedings of DEM5 (2010,
submitted)
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S. Radl, J.G. Khinast. Mathematische Modellierung und Simulationstechniken. Roadmap der
chemischen Reaktionstechnik (Tagungsbericht) (2010)
JJ
S. Radl, J.G. Khinast, M.C. Gruber. Scalar Variance and fast Chemical Reactions in Bubble
Column Reactors. 12th Workshop on Two-Phase-Flow-Predictions (Tagungsbericht) (in Press)
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Page 85
Diploma & Doctoral Theses
Baccalaureate Papers
JJ
Gruber Michael: Quantitative Bestimmung von oxidiertem und reduziertem Glutathion (successfully completed)
JJ
Redlinger-Pohn Jakob: Mixing of high viscous fluids (ongoing)
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Reiter Eva: Zytotoxizitäts- und Permeabilitätsstudien von pflanzlichen Arzneistoffen (successfully completed)
JJ
Rieger Thomas: Microwave Resonance Technology for Moisture Content Analysis of Pharmaceutical Products (successfully completed)
JJ
Taucher Thomas: Validierung, Analyse und Lösung von linearen Gleichungssystemen (successfully completed)
JJ
Treschnitzer Karin: Dosiersysteme (ongoing)
Diploma & Master Theses
JJ
Aichner Martin: Screening of new bio-based antimicrobials from plant endophytes (successfully completed)
JJ
Cernava Tomislav: Identifikation von flüchtigen organischen Verbindungen aus Bakterien
(ongoing)
JJ
Dobersberger Stefan: Entwicklung eines gastrointestinalen Modells zur Untersuchung von
nanostrukturierten Materialien (successfully completed)
JJ
Eitzlmayr Andreas: Modellierung und Scale-up eines Prezipitationsprozesses zur Herstellung
von Nanopartikeln (successfully completed)
JJ
Fuchs Katrin: Schmelzextrustion (ongoing)
JJ
Gärtner Stephanie: Role of Tyr-215 in the catalytic cyle of lactate oxidase (ongoing)
JJ
Gsöll Martina: Optimierung von Misch- und Lösungsprozessen – Physikalisch-chemische
Parameter (successfully completed)
JJ
Hellweger Monika: Thermostability-Screening of therapeutical proteins (ongoing)
JJ
Jäger Evelyn: Buccale Permeabilitätsstudien von nanostrukturierten Materialien (successfully
completed)
JJ
Jedinger Nicole: Entwicklung eines Überzugverfahrens für Kaliumchlorid Kristalle zur oralen
Applikation mit retardiertem Freisetzungsprofil (successfully completed)
JJ
Judmeier Christine: Entwicklung eines buccalen alternativen in-vitro Systems (successfully
completed)
JJ
Knauss Günter: Simulation und experimentelle Validierung eines Mischprozesses für pulverförmige Substanzen (ongoing)
JJ
Larisegger Silvia: Kondensations- und Absorptionseffekte bei der Reinraumdekontamination
mittels Wasserstoffperoxid (successfully completed)
JJ
Markl Daniel: Demonstration of a Pharmaceutical Hot Melt Extrusion Process with SIPAT
(ongoing)
JJ
Martinez Alberto: Untersuchungen zur Partikelablösung (successfully completed)
JJ
Metzler Michael: SWAXS / Nano-Analytik (successfully completed)
JJ
Michelitsch Stefan: Entwicklung von lipophilen Mikropellets in Kombination mit Arzneistoffen
des biopharmazeutischen Klassifizierungssystems (successfully completed)
JJ
Monitzer Andreas: Development of an Efficient Neighbor List Implementation for ParticleParticle Interactzions in coupeld Discrete Element and Fluid Dynamics Simulation Tools
(successfully completed)
JJ
Moor Johann: Application of NIR-Imaging and Multivariate Data Analysis for Pharmaceutical
Products Master’s thesis (successfully completed)
Page 86
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Neuhold Daniela: Improving the substrate selectivity of an oxidase used in commercially available biosensors (successfully completed)
Oberauner Lisa: Survival of Staphylococcus aureus on clean room textiles (successfully
completed)
Preiß Hannes: Untersuchung von Pulvergemischen hinsichtlich deren Homogenität mittels
spektroskopischer Methoden (successfully completed)
Pucher Hannes: Modeling of the hardening process of microparticles (successfully completed)
Rößl Ulrich: Prozesskinetische Analyse des Aggregationsverhaltens von therapeutischen
Proteinen (successfully completed)
Scheibelhofer Otto: Combining Rheometric Powder Characterisation Techniques with near
Infrared Spectroscopy based on Experimental Design and Multivariate Analysis (successfully
completed)
Schinwald Christoph: Validation of Tablet Coating Charateristics (ongoing)
Schitnig Verena: Influence of formulation excipients on protein degradation (ongoing)
Schrank Simone: Development of an extrusion process for fast disintergrating pellets (successfully completed)
Schrödl Nina: Charakterisierung und Dosierung von pharmazeutischen Lösungen und Polymer - Coatings auf Papier zur Herstellung von personalisierten Medikamenten (ongoing)
Strohmeier Daniela: Nanosuspensionen als Druckertinte zur exakten Dosierung von schwerlöslichen Arzneistoffen (ongoing)
Unterweger Birgit: Improving the operational stability of oxidases in biosensors (successfully
completed)
Velasco Roberto: Simulation of Pharmaceutical Tableting Processes (successfully completed)
Waal Andreas: Untersuchung der prinzipiellen Anwendbarkeit eines innovativen onlineViskosimeters beim Prozessmonitoring von Bioreaktoren (successfully completed)
Windhaber Katharina: QbD basierte Reformulierung von Neurobion: Etablierung eines Formulierungsdesignspace (ongoing)
Zäuner Julia: Untersuchung der Dissolutionseigenschaften von Fenofibrat Pellets (successfully completed)
Zaversky Michaela: Permeabilitätsstudien an Franz Zellen mit nanostrukturierten Materialien
(successfully completed)
Doctoral Theses
JJ
Ablinger Elisabeth: Entwicklung von Strategien zur Stabilisierung von Proteinen in flüssigen
Arzneiformen (ongoing)
JJ
Feenstra Peter: Tailoring and Characterisation of Silica Based Monoliths for the Use in Continuous Annular Electro-Chromatography (ongoing)
JJ
Gübitz Brigitte: Die Rolle des Risikomanagements im Quality by Design (ongoing)
JJ
Hörmann Thomas: 3D Simulation of Mixing-, and Dissolution Processes within the Pharmaceutical Industry (ongoing)
JJ
Jäger Evelyn: Development of a Pharmaceutical Production Technology Platform for ValueAdded Products (ongoing)
JJ
Jakobs Markus: Thermoanalytische Untersuchungen zu Reaktionskinetiken in Formulierungen (ongoing)
JJ
Kiss Nikolett: The formation of particles with highly controlled properties in stirred reactors
(ongoing)
Page 87
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Lachmann Marek: Synthese, Anwendung und Untersuchung von neuartigen Disulfidpolymeren zur gezielten Wirstofffreisetzung im Dickdarmbereich (ongoing)
Leitgeb Stefan: Structure-function relationships for the atypical 3-His non-heme Fe(II) catalytic
site of beta-diketone-cleaving dioxygenase (successfully completed)
Littringer Eva Maria: Steuerung der Leistungsmerkmale trägerbasierter Pulverinhalate durch
gezielte Oberflächenmodifikation des Trägers mittels Sprühtrocknung (ongoing)
Mohr Stefan: Entwicklung und Validierung von chromatographischen und elektrophoretischen
Trennmethoden zur Wirkstoffbestimmung (ongoing)
Mürb Reinhardt-Karsten: Entwicklung eines Pelletierverfahrens für organische Partikel (ongoing)
Radl Stefan: Modeling of Multiphase Systems in Pharmaceutical Applications (successfully
completed)
Schaffer Markus: Einsatz der 3D-CFD Simulation zur Optimierung von Großdieselmotoren
(successfully completed)
Scheibelhofer Otto: Spectroscopic Methods for Pharmaceutical Process and Product Quality
Monitoring (ongoing)
Schinagl Gerhild: Innermotorische Massnahmen zur Reduktion von Formaldehydemissionen
von Großgasmotoren (successfully completed)
Schrank Simone: Entwicklung von Mikropellets (ongoing)
Stoisser Thomas: Improvement of stability and optimization of oxidases for usage in biosensors (ongoing)
Suzzi Daniele: Diesel Nozzle Flow and Spray Formation: Coupled Simulations with Real
Engine Validation (successfully completed)
Toschkoff Gregor: Investigation of pharmaceutical tablet-coating processes using numerical
simulations based on CFD and Discrete Element methods (ongoing)
Wahl Patrick: Measuring and controlling critical process parameters of pharmaceutical manufacturing by PAT (ongoing)
Wiesbauer Johanna: Prozesskinetische Analyse des Aggregationsverhaltens von therapeutischen Proteinen (ongoing)
Patents
Patent Application EP 10152 977.4: A System for Analyzing a Granulate for Producing a Pharmaceutical Product. Europ. Filing Date Feb 8th, 2010, Applicant: Hecus X-Ray Systems GmbH.
Patent Application WO 2010/012470 A1: A System and Method for Manufacturing a Medication.
Int. Filing Date Jul 30th, 2008, Int. Publication Date Feb. 4th, 2010, Applicant: Research Center
Pharmaceutical Engineering GmbH.
Patent Application US61 155 780: Clean Room Suit and Clean Room Lock for Mutual Cooperation in a Clean Room. Filing Date Feb 26th, 2009, Assignor: Josef Ortner.
Patent Application EP 09180492.2: Methods and Compositions for Biologically Controlling
Microbial Growth on Clean Room Equipment. Europ. Filing Date Dec 22nd 2009, Applicant:
Research Center Pharmaceutical Engineering GmbH.
Patent EP 11 413 67 B1: Synthetic Nucleic Acid Particle. Filing Date Dec 13th, 1999, Publication.
Date Oct 10th, 2001. Applicant: Andreas Zimmer.
Patent Application EP 10 169 097.2: Multi-layer tablet formation by adhering tablet bodies together. Filing Date Jul 9th, 2010, Applicant: Research Center Pharmaceutical Engineering GmbH.
Patent Application EP 10 196 672.9: Volatile organic compounds from bacterial antagonists for
controlling microbial. Filing Date Dec 22nd, 2010, Applicant: Research Center Pharmaceutical
Engineering GmbH.
Patent Application EP 11 162 850.9-1223: Photodynamic control of microbial growth on surfaces. Filing Date Apr 18th, 2011, Applicant: Ortner Reinraumtechnik GmbH.
Patent Application R58816: Oral retardierende Formulierung. Filing Date May 26th, 2011
Page 89
Congresses
4th International Graz Congress for Pharmaceutical Engineering (ICPE) as a Satellite Symposium
of 8th Central European Symposium on Pharmaceutical Technology (CESPT)
Sep 16th-18th, 2010
http://www.cespt2010.org
Graz, Austria
Hosted by the Institute for Process and Particle Engineering (TUG), Institute of Pharmaceutical
Sciences (KFU) and the RCPE
Workshops
Quality by Design: New Concepts for Development & Manufacturing – A Hands-on Course for
Pharma (a joint DIA/Pharmig Academy training course)
Dr. Siegfried Adam (RCPE, Austria)
Dr. Fritz Erni (Consultant, Switzerland)
Prof. Dr. Johannes Khinast (TUG and RCPE, Austria)
Nov 4th-5th, 2010
Graz, Austria
Continuous Manufacturing in the Pharmaceutical Industry
Prof. Dr. Johannes Khinast (TUG and RCPE, Austria)
Feb 8th, 2011
Graz, Austria
Ausgewählte Aspekte der pharmazeutischen Technologien und ihre biopharmazeutische
­Relevanz
Dr. Jörg Breitenbach (Abbott, Germany)
Apr 6th-8th, 2011
Graz, Austria
QbD Workshop
Dr. Siegfried Adam (RCPE, Austria)
Dr. Fritz Erni (Consultant, Switzerland)
Prof. Dr. Johannes Khinast (TUG, Austria)
Dr.in Christa Wirthumer-Hoche (AGES PharmMed, Austria)
June 9th-10th, 2011
Basel, Switzerland
Page 90
Page 91
Financial Annex
Bilanz
AKTIVA
1. Immaterielle Vermögensgegenstände
2. Sachanlagen
3. Finanzanlagen
4. Summe Anlagevermögen
5. noch nicht abrechenbare Leistungen
6. Forderungen aus Lieferungen und Leistungen
7. Forderungen aus Geld u.Sachleistungen Partner K1
8. Forderungen aus Projektförderungen und ­Subventionen
9. sonstige Forderungen und Vermögensgegenstände
10. Kassenbestand Guthaben bei Kreditinstituten
11. ARA
SUMME AKTIVA
Page 92
30.06.2011
EURO
62.428,10
1.015.338,15
31.903,90
1.109.670,15
99.733,58
101.571,29
629.851,54
145.034,82
367.525,52
904.271,57
25.939,94
30.06.2010
EURO
99.856,27
1.001.843,15
17.037,67
1.118.737,09
27.170,64
90.912,35
807.490,01
128.684,85
227.355,45
404.800,29
8.235,00
3.383.598,41
2.813.385,68
Passiva
12. Kapital
13. Unversteuerte Rücklagen
14. Investitionszuschüsse
15. Rückstellungen
30.06.2011
EURO
-923.526,19
-17.797,75
-588.996,43
-393.432,00
30.06.2010
EURO
-486.653,09
-16.350,40
-916.511,70
-250.010,00
16.
17.
18.
19.
-244.039,20
-235.102,55
-554.839,54
-425.864,75
-61.802,00
-417.137,42
-333.274,54
-331.646,53
-3.383.598,41
-2.813.385,68
erhaltene Anzahlungen auf Bestellungen
Verbindlichkeiten aus Lieferungen und Leistungen
sonstige Verbindlichkeiten
PRA
SUMME Passiva
Page 93
Gewinn- und Verlustrechnung
Nr Bezeichnung
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Umsatzerlöse
Erträge aus Geld und Sachleistungen K1
Förderungen und Zuschüsse öffentl. Hand
Veränderung des Bestandes an noch nicht
abrechenbaren Leistungen
andere aktivierte Eigenleistungen
sonstige betriebliche Erträge
Aufwendungen für Material und bezog.Leistungen
Personalaufwand
Abschreibungen
sonstige betriebliche Aufwendungen
Zwischensumme aus 1 bis 10 Betriebserfolg
Zinsen und ähnliche Erträge
Zinsen und ähnliche Verspätungszuschläge
Zwischensumme aus 11 bis 12 Finanzerfolg
Ergebnis der gewöhnlichen Geschäftstätigkeit
Steuern vom Einkommen
Jahresüberschuss
18.
19.
20.
21.
22.
Auflösung unversteuerter Rücklagen
Zuweisung zu unversteuerten Rücklagen
Zuweisung zu Gewinnrücklagen
Jahresgewinn
Gewinnvortrag aus dem Vorjahr
23. Bilanzgewinn
Page 94
30.06.2011
EURO
550.409,69
2.433.403,56
2.305.952,28
72.562,94
0,00
1.137.454,88
-1.490.273,38
-2.896.633,88
-727.254,13
-921.562,74
464.059,22
8.328,31
-2,46
8.325,85
472.385,07
-34.064,62
438.320,45
34.148,17
-35.595,52
30.06.2010
EURO
263.815,28
2.070.119,22
1.260.647,17
27.170,64
590.732,51
-1.101.721,34
-1.941.047,22
-384.839,71
-502.501,50
282.375,05
8.505,39
8.505,39
290.880,44
-26.009,74
264.870,70
436.873,10
86.653,09
21.435,67
-16.350,40
-100.000,00
169.955,97
116.697,12
523.526,19
286.653,09
Page 95
Boards and Partners
The main objective of the consortium of industrial, scientific and associated partners is the development of the scientific base for the effective and cost-efficient development of next-generation
drugs and the corresponding manufacturing technology. By equally involving partners with
scientific and industrial background, not only the development, but also the subsequent implementation in industrial development and manufacturing is assured. RCPE’s partner structure has
been developed to achieve this goal.
General Assembly
Renate DWORCZAK, Ao. Univ.-Prof.in Mag.a Dr.in
Chairperson
University of Graz (20%)
Harald KAINZ, Univ.-Prof. DDipl.-Ing. Dr.Dr.h.c.
Graz University of Technology (65%)
Wolfgang PRIBYL, Univ.-Prof. Dipl.-Ing. Dr. MBA
JOANNEUM RESEARCH Forschungsgesellschaft mbH (15%)
Supervisory Board / Strategy Board
Harald KAINZ, Univ.-Prof. DDipl.-Ing. Dr.Dr.h.c.
Chairperson
Graz University of Technology
Renate DWORCZAK, Ao. Univ.-Prof.in Mag.a Dr.in
Representative Chairperson
University of Graz
Karin SCHAUPP, Mag.a pharm. Dr.in
Graz University of Technology
Wolfgang PRIBYL, Univ.-Prof. Dipl.-Ing. Dr. MBA
JOANNEUM RESEARCH Forschungsgesellschaft mbH
Thomas KRAUTZER, Mag. Dr.
Land Steiermark
Scientific Advisory Board (SAB)
Karin SCHAUPP, Mag.a pharm. Dr.in
Chairperson
Fernando J. MUZZIO, Prof. Dr.
Rutgers University, USA
Jonathan SEVILLE, Prof. Dr.
Warwick University, United Kingdom
Peter KLEINEBUDDE, Prof. Dr.
University of Duesseldorf, Germany
Sven STEGEMANN, Dr.
Pfizer / Capsugel, Germany
Fritz ERNI, Dr.
Novartis, Switzerland
Alois JUNGBAUER, Prof. Dipl.-Ing. Dr.
University of Natural Resources and Applied Life Sciences, Austria
Page 96
Program Committee
The Program Committee consists of at least 14 representatives of academic and industry
partners which are involved in the research projects. The Graz University of Technology has the
right to nominate 5 of the members. Each of the other academic and industrial partners at the
RCPE involved in projects has the right to send one member.
Chairperson
Alexander RINDERHOFER, Dipl.-Ing. MBA
Program Commission
Chairperson:
Johannes G. KHINAST, Univ.-Prof. Dipl.-Ing. Dr.
Representatives Scientific Partners
Ferdinand HOFER, Ao.Univ.-Prof. Dipl.-Ing. Dr.
Graz University of Technology
Christoph HERWIG, Univ.-Prof. Dipl.-Ing. Dr.
Vienna University of Technology
Bernd NIDETZKY, Univ.-Prof. Dipl.-Ing. Dr.
Graz University of Technology
Andreas ZIMMER, Univ.-Prof. Mag. Dr.
University of Graz
Representatives Business Partners
Karl-Heinz HOFBAUER, Dipl.-Ing.
Baxter Austria AG
Peter KARLE, Dr.
Sandoz GmbH
Franz REITER, Dr.
G.L. Pharma GmbH
Norbert RASENACK, Dr.
Novartis Pharma AG
Page 97
Business Partners
RCPE has attracted 46 company partners to date. It is important to state that the company
consortium equally reflects national and international companies. RCPE has already managed
to engage a major share of the Austrian companies in a cooperation and has also successfully
attracted major international companies. Melt extrusion projects, for instance, are currently
carried out for Austrian and British companies in combination with German process equipment
manufacturers. Additional extrusion projects are underway with various partners. The company consortium also reflects the various elements of product and process development and
includes (bio-)pharmaceutical companies, as well as companies developing or manufacturing
process equipment, measurement and control technology and simulation tools. It is important
to note that some companies prefer to cooperate with the RCPE on a non-K-service contract
basis, rather than joining the company consortium.
Abbott GmbH
http://www.abbott.at
Acino Holding AG
http://www.acino-pharma.com
Anton Paar GmbH
http://www.anton-paar.com
AstraZeneca UK Limited
http://www.astrazeneca.co.uk
Automatik Plastics Machinery GmbH
http://www.automatikgroup.com
AVL List GmbH
http://www.avl.com
Baumgartner & Co GmbH
http://www.baumgart-co.at
Baxter AG
http://www.baxter.at
Bayer Schering Pharma AG
http://www.bayerpharma.com
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Bioland d.o.o.
BIRD-C GmbH
http://www.bird-c.com
Boehringer Ingelheim RCV GmbH & Co KG
http://www.boehringer-ingelheim.at
Coperion GmbH
http://www.coperion.com
Dastex Reinraumzubehör GmbH & Co KG
http://www.dastex.de
Dr. Franz Feurstein GmbH
http://www.delfortgroup.com/lang_en/mills_
feurstein.htm
DRIAM Anlagenbau GmbH
http://www.driam.com
Düsen-Schlick GmbH
http://www.duesen-schlick.de
Fette Compacting GmbH
http://www.fette.com
Freeman Technology Ltd.
http://www.freemantech.co.uk
Fresenius Kabi Austria GmbH
http://www.fresenius-kabi.at
G.L. Pharma GmbH
http://www.gl-pharma.at
Gericke Holding AG
http://www.gericke.net
Glatt GmbH
http://www.glatt.com
GlaxoSmithKline Research & D
­ evelopment
Limited
http://www.glaxosmithkline.at
Innojet Herbert Hüttlin
http://www.innojet.de
Innoweld Metallverarbeitung GesmbH
http://www.innoweld.at
L.B. Bohle Maschinen + Verfahren GmbH
http://www.lbbohle.de
The Lifecycle Intelligence Group GmbH
http://www.lifecycle-ig.com
Merck KGaA
http://www.merck.at
MG2 s.r.l.
http://www.mg2.it
Microinnova Engineering GmbH
http://www.microinnova.com
Montavit Ges.m.b.H.
http://www.montavit.com
Mynadis Thomas Tritthart
Novartis Pharma AG
http://www.novartis.com
onepharm Research & Development
GmbH
http://www.onepharm.com
Ortner Reinraumtechnik GmbH
http://www.ortner-cls.de
qpunkt GmbH
http://www.qpunkt.at
Roche Diagnostics Graz GmbH
http://www.roche.at
SamTech Extraktionstechnik GmbH
http://www.samtech.at
Sandoz GmbH
http://www.sandoz.at
Sanochemia Pharmazeutika AG
http://www.sanochemia.at
Sanofi Aventis GmbH
http://www.sanofi-aventis.at
Savira Pharmaceuticals GmbH
http://www.savira.at
Stölzle-Oberglas GmbH
http://www.stoelzle.com
VTU Technology GmbH
http://www.vtu.com
ZETA Holding GmbH
http://www.zeta.com
RECREATE PMS(FROM PDF)
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Scientific Partners
Scientific partners are academic or non-academic research facilities, which participate in our
research projects through their key, senior and junior researchers and technicians. They bring
to the table their scientific competence and thus assure a research programme at the highest
scientific level. Moreover, they provide a wide range of laboratory and technical infrastructure.
The relevant institutes of the participating universities and research facilities have significantly
shaped the RCPE. Their commitment is an important source for success and provides the
Center with a constant stream of young and dedicated staff.
Austrian Academy of Sciences
http://www.oeaw.ac.at
Institute of Biophysics and Nanosystems Research
Joanneum Research Forschungsgesellschaft mbH
http://www.joanneum.at
Institute of Medical Technologies and Health Management
University of Graz
http://www.uni-graz.at
Institute of Pharmaceutical Sciences
Graz University of Technology
http://www.tugraz.at/
Institute for Process and Particle Engineering
Institute of Biotechnology and Biochemical Engineering
Institute of Fluid Mechanics and Heat Transfer
Institute for Chemical Engineering and Environmental Technology (TVTUT)
Institute for Electron Microscopy and Fine Structure Research (FELMI)
Institute for Chemistry and Technology of Materials
Institute for Inorganic Chemistry
Institute for Paper, Pulp and Fibre Technology
Institute for Environmental Biotechnology
Institute of Solid State Physics
Page 100
Vienna University of Technology
http://www.tuwien.ac.at
Department of Pharmaceutical Technology and Biopharmaceutics
Rutgers University
http://www.rutgers.edu
Department of Chemical and Biochemical Engineering
FH Joanneum – University of Applied Sciences
http://www.fh-joanneum.at
University of Duesseldorf
http://www.uni-duesseldorf.de
Institute of Pharmaceutics and Biopharmaceutics
University of Cambridge
http://www.cam.ac.uk
Research Center for Non Destructive Testing
http://www.recendt.at
Other Partners
AGES, Österreichische Agentur für Gesundheit und
Ernährungssicherheit GmbH
http://www.ages.at
Pharmig, Verband der Pharmazeutischen Industrie Österreichs
http://www.pharmig.at
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Research Center Pharmaceutical Engineering GmbH
Managing Director: Mag. Dipl.-Ing. Dr. Thomas K. KLEIN
Scientific Director: Univ.-Prof. Dipl.-Ing. Dr. Johannes G. KHINAST
Inffeldgasse 21a/II
8010 Graz, Austria
Telephone: +43 316 873 9701
Telefax: +43 316 873 9702
E-Mail: [email protected]
Internet: http://www.rcpe.at
Legal Reg: FN 312899x, LGZRS Graz
VAT (UID): ATU64272307
Funding Institutions:
within the framework of the Austrian K1 - Program:
FFG Austrian Research Promotion Agency, Structural Programs
Land Steiermark (Styrian provincial government – Dept. for Science and Research) –
SFG – Steirische Wirtschaftsförderung (Styrian Business Promotion Agency)
Shareholders:
Graz University of Technology (65%)
University Graz (20%)
JOANNEUM RESEARCH (15%)
Share capital: € 100.000,–
Page 102
Published by:
Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 21a/II, A-8010 Graz
Printed by: Medienfabrik Graz GmbH, Dreihackengasse 20, A-8020 Graz
Design-Layout: Rubikon Werbeagentur GmbH, Schumanngasse 26, A-8010 Graz
Photos: Research Center Pharmaceutical Engineering GmbH, Salon Deluxe, Das Kunztfoto
Photos of test facilities: copyright belongs to the respective manufacturer
www.rubikon.at
Inffeldgasse 21a/II
A-8010 Graz
Telefon: +43 316 873 9701
Telefax: +43 316 873 9702
E-Mail: [email protected]
www.rcpe.at