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Quality by Design
‘Speeding up the process of pharma ceutical and biopharmaceutical development and manufacturing’
A workshop by BioFarmind and Top Institute PharmaWednesday, November 10, 2010 Naturalis, National Museum of Natural History, Leiden
jointly shaping the future of medicine
1
jointly shaping the future of medicine
Quality by Design
‘Speeding up the process of pharma ceutical and biopharmaceutical development and manufacturing’
A workshop by BioFarmind and Top Institute PharmaWednesday, November 10, 2010 Naturalis, National Museum of Natural History, Leiden
3
Content
Preface� 4
Organizing�committee� 6
Program� 7
Speakers� 8
About� 17
List�of�participants� 18
Notes� 22
4
Preface
Quality by Design: the new paradigm for
(bio) pharmaceutical development and
manufacturing.
(Bio) Pharmaceutical process development and manufacture are
traditionally trial & error based activities. This is not an extremely
effective health care strategy, as is exemplified by the long period
before introduction of drugs to the market (12-14 years), nonstop
governmental multilevel interference and controls, moderate product
performance (efficacy-to-safety ratio), patent-directed pricing, the
low success rate in introducing the product on the market, and the
many diseases still to be researched after 50 years of this trial and
error-based manner of practicing.
Globalization and health care effects in terms of demands and costs
have stimulated (bio) pharmaceutical industry to look for alternatives.
Alignment with quality principles practiced in other industrial sectors,
more precisely the semiconductor industries, medical device industries
and automotive industries offer opportunities for substantial
improvement. This approach means both structured development
and manufacturing by using prior knowledge, risk assessment-
guided design control, and a combination of molecular and system
biology-based diagnostics-therapy solutions for disease treatment
during the total life cycle of a product. Gaining thorough understanding
both of the product and of the manufacturing process necessitates
the investment of time and resources upfront in their design and
development, which needs to be both product and process
knowledge-based.
Quality by Design (QbD) and its clinical counterpart Translational
Medicine Research (TMR) are presenting the platform for a new
era of the pharmaceutical and biopharmaceutical industry; QbD
has been shaped by a changing business environment that requires
new marketing strategies for pharmaceutical and biopharmaceutical
5
products, influenced by the input of innovations derived from the life
sciences, and directed towards personalized medicines.
The QbD platform enables the shortening of the development times
by half and, moreover, results in the continuous improvement of
licensed medicines, which will be better suited for the patients.
During the workshop three successful examples of the application
of the new platform and the consequences for the licensing
documentation for the new products will be presented. Special
attention will be given to the A-Mab Case Study in Bioprocess
Development written by the CMC Biotech Working Group, which
appeared a year ago in the United States and describes the impact of
QbD for the development of a new therapeutic monoclonal antibody
(A-Mab). QbD will lower both the development cost and time, will
make production systems more flexible with design control and risk
management, will reduce the costs of clinical evaluation, will reduce
the failure rate of the new products, and will lastly result in simpler
licensing procedures.
The FDA declared QbD as the GMP for the 21st Century. QbD will
induce changes in biopharmaceutical development that will go hand
in hand with regulatory requirements. Regulatory relief becomes a
realistic option and is discussed in the presentation “Dossier 2020”,
which provides a perspective on relevant regulatory policies.
In the panel discussion session a number of statements will be
presented. These statements will reflect on the day’s presentations
and their impact on the biopharmaceutical business. By doing this,
the organizers hope to convince the audience that QbD is not just
a biopharmaceutical mechanism but an engine fuelled by TMR to
provide products fit for patient use.
On behalf of the of the organizing committee,
Jan Willem Dorpema
November 2010, Leiden
6
Organizing committee
Jan�Willem�Dorpema
Vice Chairman
BioFarmind
The Hague, The Netherlands
Coen�Beuvery
BioFarmind
The Hague, The Netherlands
Daan�Crommelin
Scientific Director
Top Institute Pharma
Leiden, The Netherlands
Martijn�Holleman
Program Information Coordinator
Top Institute Pharma
Leiden, The Netherlands
7
Program
09.00�-�09.30 Registration
09.30�-�09.45 Opening by Daan Crommelin, Top Institute Pharma
09.45�-�10.30 Jan�Willem�Dorpema, BioFarmind:
‘GMP for the 21st Century: Quality by Design‘
10.30�-�11.15 Ken�Seamon, University of Cambridge:
‘A-MAB: a case study in process development:
opportunities and challenges for quality by design’
11.15�-�11.45 Coffee break
11.45�-�12.30 Patrick�van�Berkel, Genmab:
‘Quality by Design applied to the lead candidate selection of
monoclonal antibodies’
12.30�-�13.15 Hanns-Christian�Mahler, Roche:
‘QbD approaches for biotech drug products’
13.15�-�14.00 Lunch
14.00�-�14.45 Steffen�Gross, Paul Ehrlich Institut:
‘New challenges for regulatory agencies when evaluating QbD
approaches within licensing documentation’
14.45�-�15.15 Huub�Schellekens, Utrecht University:
‘Introduction panel discussion’
15.15�-�16.15 Panel discussion with all the speakers
16.15�-�16.20 Summary & closing
16.20�-�17.30 Drinks
8
Jan Willem Dorpema
‘GMP for the 21st Century:
Quality by Design’
Speakers
The FDA declared Quality by design (QbD) as the GMP for the
21st Century. It means that there must be a paradigm change
for pharmaceutical and biopharmaceutical development and
manufacturing. The patient instead of the substance of the drug
becomes the starting point for new medicines. The approach,
which is still optional, covers the total product life cycle. It combines
science with risk assessment. With its focus on design it provides
considerable innovation power and offers industry an environment
of continuous quality improvement and regulatory relief. Being
connected to the advantages of Translational Medicine Research
QbD is an essential tool in the restructuring process of the pharma
and biopharma business and living out its “better, faster and
cheaper” mandate.
Short�resume�Jan�Willem�Dorpema
Dorpema furthered his career as a microbiologist as head of the
Dutch National Control Laboratory for Medicines and Medical
Devices between 1975 and 1997. In this position, he was involved in
the standardization and licensing of medicines of biological origin
for over 20 years. He was a member of the Eur. Ph. group of experts
on human vaccines and remains a member of the working group on
allergens, respectively.
From 1984, he has also participated in the creation of national and
EU legislation for medicines and worked on the standardization
of medical devices (e.g. as a member of the Health Care Board
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Kenneth B. Seamon
‘A-MAB: a case study in process
development: opportunities and
challenges for quality by design’
CEN BTS3 and as chairman of CEN TC 206 on biocompatibility).
Moreover, he chaired the national standardization commission on
medical devices for many years.
From 1997, he has been vice chairman of the Dutch Delegation to
the European Pharmacopoeia Commission. Concurrently he served
until 2006 as chairman of the Eur. Ph. group of experts on Biological
Substances and was member of the Steering Committee of the
Biological Standardization Program, a framework in which Eur. Ph.,
EMEA and EMEA carry out projects on standardization of products
and tests.
In 1997, he joined Hal Allergy, a company manufacturing allergy
vaccines and diagnostics; there he held several positions including
Supervisory Board member and Board member of the European
Allergen Manufacturing Group. He retired in 2010. In 2001,
he created MDS, a company that designs and develops robotic
dispensing machines for personalized medicines. Currently he acts
as vice chairman of BioFarmind and is a board member for the Dutch
Vaccines Group where his focus is on building Dutch infrastructure
for medical biotechnology.
Quality�by�design has been recognized as a rational approach
for developing a manufacturing process based on knowledge and
implemented using well designed controls to ensure the appropriate
quality of a pharmaceutical for its intended purpose.
10
Although the concepts of QbD are clear, the practice of implementation
can mean different things to different stakeholders, and there is no
standard or clearly defined end point for what constitutes a quality
by design pharmaceutical and biopharmaceutical development plan.
Recognizing that there was a gap in this area, several pharmaceutical
companies worked together to develop a case study to exemplify
the development of a monoclonal antibody using the principles of
quality by design. The result was a unique, data rich document that
illustrates the application of a number of different QbD approaches
throughout the product development life cycle and includes the final
definition of a control strategy based on the gained product and
process understanding. The regulatory considerations that result
from this type of development plan were also explored with regard
to implications for control strategy and data necessary to support
manufacturing changes post approval.
The case study was meant to be inspirational and to challenge
current paradigms in development and regulatory expectations.
As the case study stimulates discussions among industry and
regulatory agencies, it is expected that there will be continued
evolution of regulatory acceptance of various QbD approaches.
Similarly, QbD adoption within different companies will evolve and
mature as organizations define the business processes required for
implementation and assess economic considerations and potential
gains for life cycle management.
Short�resume�Dr.�Kenneth�Seamon�
Kenneth B. Seamon is an accomplished biotechnology executive:
highly experienced in the science of product characterization,
manufacturing, drug development, and regulatory affairs. Dr
Seamon was Vice President for Regulatory Affairs at Amgen
Corporation, with responsibility for the Regulatory CMC Group and
interactions with operations as well as for developing policy for
Follow-on Biologics and Biosimilars. Prior to this, Dr. Seamon was
Senior Vice President, Drug Development at Immunex Corporation,
Seattle, Washington State. Earlier in his career Dr. Seamon spent 13
years with the Food and Drug Administration (FDA) and served there
as the Director of the Office of Therapeutics Research and Review
11
Patrick H. C. van Berkel
‘Quality by Design applied to
the lead candidate selection of
monoclonal antibodies’
and as the Associate Director for Research at the Center for Biologics
Research and Review at Bethesda, Maryland. He received his Ph.D.
in Chemistry from Carnegie Mellon University and has carried out
research and published extensively on molecular pharmacology.
He currently works as a Senior Associate at the Institute of
Biotechnology, University of Cambridge, England. In this position
he acts as Science and Technology Module Coordinator for the
MPhil program in Bioscience Enterprise on drug development and
technology management. Dr. Seamon received his Ph.D. in Chemistry
from Carnegie Mellon University and has published extensively in
molecular pharmacology.
Quality�by�Design (QbD) means that product and process
performance characteristics are scientifically designed to meet
specific objectives, and QbD emphasizes the need to understand
the sources of variation in the production process that may affect
the quality and safety of a product. Preferably the QbD strategy
has already been applied before the pilot plant stage, since it may
anticipate and/or prevent problems that arise during development
and scale-up. Ideally, QbD is implemented during lead candidate
selection of a monoclonal antibody. In this stage, the goal is to
screen a panel of lead candidates for issues that may introduce
variation during manufacturing, for physicochemical parameters
that are required for the proposed application (high concentration,
compatibility with certain devices etc), and for comparison of
expression levels (to ensure sufficient production capacity and low
cost of goods).
12
Hanns-Christian Mahler
‘QbD approaches for biotech
drug products’
Such an assessment, together with in vitro and in vivo functional
data, will allow selection of a clinical candidate with an optimum
balance between potency, safety and manufacturability. This
presentation will present examples of such manufacturability
assessments during late stage clinical candidate selection.
Short�resume�Dr.�Patrick�van�Berkel
In 2003, Van Berkel joined Genmab BV, a biotechnology company
developing therapeutic human antibodies. At Genmab BV he
has held various positions with increasing management-related
responsibilities and focused on antibody discovery, antibody
technology innovation, antibody platform development, and
antibody manufacturing. Currently, Patrick serves as Vice President,
Global CMC R&D.
Prior to joining Genmab, he held positions as Senior Scientist
Antibody Technology (from 2001-2003) at Crucell (Leiden, The
Netherlands) and Director, Technology at Pharming BV (Leiden,
The Netherlands), where he started in 1992. Based on the scientific
work performed at Pharming, Patrick received his Ph.D. from the
University of Leiden in 1998.
Companies have always used science and risk-based processes to
develop new products and gain process understanding with a focus
on minimum controversy registration, launch, and then compliance.
Nowadays, especially in light of ICH Q9,Q10 and Q8(R1), more
rigorous and well documented science-, knowledge- and risk-based
approaches are followed for the development of biotech drug
substance and drug product development.
13
This talk will include aspects for the application of Quality-by-Design
(QbD) approaches for Biotech Drug Products.
Short�resume�Dr.�Hanns-Christian�Mahler
Since March 2010, Dr. Mahler has held the position of Head of
Pharmaceutical & Device Development and been responsible for
late-stage pharmaceutical, formulation and process development, for
clinical supplies (Phase 2 and 3), for production support of biotech
R&D projects, and for packaging and device development.
He joined Roche (Basel, Switzerland) in 2005, as Head of Formulation
R&D Biologics in Technical Sciences (Pharma Research) and was
promoted to Head of Pharmaceutical R&D Biologics in 2008.
From 2000 until 2005, he worked as Principal Scientist and Lab
Manager at Merck KGaA (Darmstadt, Germany) in Formulation
Development of Sterile Dosage Forms and as CMC team leader,
which finally led to the launch of “Erbitux.” He has technical
experience in formulation development of sterile dosage forms
including biologics, production of clinical trial and non-clinical study
material, technical registration, upscaling and validation.
Since 2003, he has additionally held a university teaching position for
“Pharmaceutical Biotechnology” at the University of Frankfurt/Main,
Germany. Dr. Mahler is also an associated adjunct Professor at the
University of Kansas, USA. Dr. Mahler obtained his “venia legendi” with
his habilitation work in Pharmaceutical Technology at the University of
Frankfurt in February 2010; he also holds a Ph.D. in Pharmacology &
Toxicology obtained at the Johannes Gutenberg-University of Mainz,
Germany, a degree in Pharmacy, and “Fachapotheker” specialization
degrees in “Toxicology & Ecology” and “Pharmaceutical Technology.”
14
Steffen Gross
‘New challenges for regulatory agencies
when evaluating QbD approaches
within licensing documentation’
The regulatory framework for the comparability of the product is
set by the ICH harmonized tripartite guideline Q5E “Comparability
of biotechnological/biological products subject to changes in their
manufacturing process” and the “Guideline on comparability
of biotechnology-derived medicinal products after a change in
the manufacturing process (non-clinical and clinical issues)”.
The goal of the comparability exercise is to ensure the quality,
safety, and efficacy of a drug product produced by a changed
manufacturing process. Comparability refers to a product made
within a manufacturer’s validated process. The concept does not
mean identical, but it implies that physical-chemical similarity and
functional biological, pharmacological and toxicological results are
indistinguishable between pre and post-production changes.
Biosimilars are complex molecules and the comparability approach
is a challenge for the manufacturers of these products. Currently,
the first monoclonal antibodies are entering the field and the
comparability approach is a manner for debate. Comparability
based on biophysical and biochemical characterization only is not
sufficient and should be accompanied by appropriate preclinical
and clinical studies. The quality by design approach is a harmonized
pharmaceutical quality system applicable across the life cycle of
the product and emphasizes an integrated approach to quality risk
management and science. A “design space” depends on a particular
manufacturing process, and ICH Q8, Q9 and Q10 are applicable for
biosimilars’ manufacturers own developments in the same way as
for the originators. Recent experiences and discussion of general
questions will be discussed.
15
Huub Schellekens
‘Introduction panel discussion’
Short�resume�Steffen�Gross�
Gross has extensive experience in molecular and cell biology. He joined
the Paul-Ehrlich-Institut in 2005 and became deputy Head of the
Section monoclonal and polyclonal antibodies in 2007. He is involved
in the assessment of the quality and the preclinical issues of marketing
authorization and clinical trial applications. He is also involved in the
testing of immunoglobulins, immunsera and monoclonal antibodies
as well as in planning and performing research projects. The Paul-
Ehrlich-Institut also performs official experimental batch testing
independently of the manufacturer. Due to his experience, he also
often supports inspections as an expert for certain products. Mr.
Gross has participated extensively as a speaker at scientific and
regulatory meetings; he also co-authored “Quality for Biologics”.
Before joining the Paul-Ehrlich Institut, he worked in the Netherlands
for three years as a postdoc. During that same time, he also worked
for several months at the National Institute of Health in Bethesda.
After his return to Germany, he became a research group leader at
the University of Frankfurt.
Short�resume�Prof.�Huub�Schellekens,�M.D.�,Ph.D.
Dr. Huub Schellekens is professor of Pharmaceutical Biotechnology
at Utrecht University in the Netherlands. He teaches Medical
Biotechnology at the Department of Innovation Studies and has a
research position at the Faculty of Pharmaceutical Sciences at the
same university. He is a member of the Dutch Medicine Evaluation
Board and National Expert of the European Medicine Evaluation
Agency. He is member of the Board of the European Immunogenicity
Platform. He is a medical microbiologist by training and works on the
preclinical development of biopharmaceuticals. He published more
than 300 papers in peer reviewed international journals concerning
many aspects of the development of therapeutic proteins. During the
last years his work has included the immunogenicity of protein drugs
and the problem of biosimilars.
16
Prior to joining Utrecht University, he was deputy director of the
Dutch Primate Center, director of Medscand Ingeny and medical
microbiologist at the Reinier de Graaf Hospital in Delft the Netherlands.
In 1992-1997 he coordinated a EU concerted action on the antigenicity
of r-DNA derived pharmaceuticals
He studied medicine at Erasmus University in Rotterdam, The
Netherlands (1967-1973). There he also did his training in Medical
Microbiology (1976-1980) and received his Ph.D. in 1980.
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About
BioFarmind is an association for the biotech, pharmaceutical, and
life science industry—in short, for the medical biotechnological
industry in The Netherlands. We want to be the network for medical
biotechnology across the board, “From Patient to Pill” and from the
basic research to experienced marketing. The association has as its
goal the general promotion of biotech pharmaceutical enterprises to
all interested institutions and organizations. For more information,
go to www.biofarmind.nl
Top�Institute�Pharma (TI Pharma) is a public-private partnership
in which the scientific and business worlds work together on
groundbreaking, multidisciplinary research aimed at improving the
development of socially valuable medicines. This research precedes the
stage in which companies develop individual medicines commercially.
Our institute acts as an essential link in combining the knowledge
present in science and industry. Collaboration within our research
projects provides unique opportunities to strengthen the scientific
foundation of pharmaceutical research in the Netherlands.
Our research projects are, for a large part, focused on research
that is difficult or impossible for individual companies to perform.
Our portfolio is based on the disease areas as specified in Priority
Medicines, a report by the World Health Organization (WHO). These
projects create knowledge that is important for better, faster and
less-expensive development of valuable new medicines. For more
information, please visit www.tipharma.com
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Participants per October 26Family�name First�name Company E-mail
Albanese Beatrice MEB [email protected]
Baars, van Harrie Van Baars Medical BV [email protected]
Barlingen, van Harrold Thuja Capital [email protected]
Berge, ten Ronald NOTOX BV [email protected]
Bloemen Pauline GSK [email protected]
Boer, de Sjoerdtje RIVM [email protected]
Buist Girbe University Medical Center Groningen
Callant Conchita ANL-Innovation [email protected]
Christensen Anders BioCMC sciences - consulting in bioprocesses
Cox Eugene Quantitative Solutions BV [email protected]
Damen Carola Teva Pharmachemie [email protected]
Driessen-Engels Lilian MSD [email protected]
Elsas, van Andrea MSD [email protected]
Engela Jean Kinesis Pharma [email protected]
Erpelinck Steven TNO-Pharma [email protected]
Flohil Jaap FOLDYNE RESEARCH B.V. [email protected]
Flohil Jaap Virtual Proteins BV [email protected]
Folkerts Gert UU Faculty of Science UIPS Dept Pharmacology
Garritsen Anja MSD [email protected]
Gebbink Martijn Crossbeta Biosciences [email protected]
Goedings Peter Synthon BV [email protected]
Graaf, van der Rieke UMC Utrecht [email protected]
Halim Vincentius UMC Utrecht [email protected]
Hallard Didier Prosensa Therapeutics BV [email protected]
Hamminga Johan BAC BV [email protected]
Hastings Ann Astellas [email protected]
Hauben Ehud LUMC [email protected]
Henneman Ko Healthy Ageing Network [email protected]
Herpen, van Paul NVI [email protected]
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Family�name First�name Company E-mail
Honing Maarten Merck Sharpe & Dohme [email protected]
Hoogdalem, van Ewoud-Jan Clinical Reach Drug Development
Jansen Maurice Erasmus MC [email protected]
Juttmann Rikard Erasmus MC [email protected]
Kooijman Marlous UU [email protected]
Koppelman Stef HAL Allergy [email protected]
Kramer Patricia TI Pharma [email protected]
Kruger Patrick Ministerie VWS [email protected]
Lammers-Johnson Louise TI Pharma [email protected]
Langoor Marcel PROXY Laboratories B.V. [email protected]
Lans, van der Gerard FeyeCon D I [email protected]
Leede, De Leo Exelion Bio-Pharmaceutical Consultancy BV
Leeuwen, van Remko AMC-CPCD [email protected]
Lillin - de Vries Otilia MSD [email protected]
Luykx Dion HAL Allergy [email protected]
Man Sue Bioceros [email protected]
Meer Lies BSDL [email protected]
Mejan Esther MGS Consultancy [email protected]
Moolenaar Semme Stichting Business Generator Groningen (SBGG)
Mulder Dorine Dorian Regulatory Affairs BV [email protected]
Nanninga Rene Xendo Pharma Services [email protected]
Nicastia Alexander UMC St Radboud [email protected]
Nooren Irene Darwin Digits and LIACS [email protected]
Oosterhout Ypke Xenikos B.V. [email protected]
Park Cyrus Kendle International [email protected]
PERRISSIN-FABERT Marc-Antoine Product Development & Support
Pieters Mark TI Pharma [email protected]
Plas, van der R. Martijn RIVM [email protected]
Reman Fred BioFarmind [email protected]
ruppert martijn kinesis pharma [email protected]
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Family�name First�name Company E-mail
Schippers Davey Ministerie VWS [email protected]
Schmidt Stephan LACDR [email protected]
Schmitt Siegfried PAREXEL [email protected]
Schooten, van Harry European Vaccine Initiative and Euvadis
Schuitmaker Hans Euro Tissue Bank [email protected]
Schwamborn Klaus Pepscan [email protected]
Seegers Jos Falco Biotech [email protected]
Sharma Hari S VUMC University Medical Center
Simons Charles Prosensa Therapeutics BV [email protected]
Snoeij Niek TNO Quality of Life [email protected]
Stassen Mario Recuper [email protected]
Steen Herman Nyken BV [email protected]
Steen Herman Nyken Holding BV [email protected]
Steinbach Oliver Philips Research [email protected]
Stokman Peter MSD [email protected]
Tenthof van Noorden
Els TNO Quality & Safety [email protected]
Verheij Herman TI Pharma [email protected]
Vliet Andre PRAInternational [email protected]
Vries, de Jan PROXY Laboratories B.V. [email protected]
Vromans Lisette Merck Sharp and Dohme [email protected]
Wanner Brigitte Prosensa Therapeutics BV [email protected]
Weerdenburg Sjaak Tevapharmachemie [email protected]
Wellink Antoine NOTOX [email protected]
Wezel, van Edward Biogeneration Ventures [email protected]
Wielhouwer Eric Marijn Leiden university [email protected]
Wientjes Klaas Jan Citeq biologics [email protected]
Wittevrongel Christiaan Dutch society for replacement of animal testing Proefdiervrij
Xavier Hulhoven ABBOTT [email protected]
22
Notes
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Top Institute Pharma | Galileiweg 8, 2333 BD Leiden | The Netherlands
t +31 71 332 2030 | [email protected]
BioFarmind | Plein 22d | 2511 CS The Hague | The Netherlands
t +31 70 363 4850 | [email protected]
