7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING http://slidepdf.com/reader/full/iabs-conference-3rs-and-consistency-testing-in-vaccine-lot-release-testing 1/104 1 IABSCONFERENCE3R S AND C ONSISTENCY T ESTING IN V ACCINE L OT RELEASE T ESTINGEgmond aan Zee, The Netherlands September 16 – 18, 2015
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IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Vaccine development and quality control include models based on studies in laboratory animals, substantial numbers of which are used. Increasingly, however, regulations on animal experimentation and testing now urge the use of non-animal methods, reduction of animal numbers in tests still being performed and refinement of animal procedures and animal husbandry practices; the principle which is generally known as the 3Rs. This need for humane science aligns with a broad wish to make vaccine development and quality control more science based, more economic and less time consuming. Substantial progress in 3Rs implementation in vaccine development and quality control has been achieved; several non-animal models are being validated and a new testing strategy which integrates analytical tools, in vitro assays and quality systems; the consistency approach, is now under study. The IABS conference is the focal point for well recognised experts presenting the latest developments on the most important 3Rs topics in vaccine development and quality control. The conference is THE platform for exchange of information on the 3Rs and testing strategies with representatives from industry, academia, guideline bodies and regulatory authorities. A mix of presentations and interactive sessions offered an excellent opportunity for all those who are interested in state of the art vaccine quality control in the context of improving animal welfare.
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7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
We are delighted to welcome you all to the Hotel Zuiderduin in Egmond aan Zee for what will
be a stimulating and successful three days. Many people think that a radical change to theprocess of vaccine lot release testing is long overdue. The stepwise approach of replacing
each animal test by a non-animal method is painfully slow and ultimately unsatisfactory when
these new tests are incorporated into an existing framework that emphasises the testing of
the final lot rather than the consistency of production. Over the next few days, we will hear
about and discuss many new non-animal methods since these are still badly needed to
replace several animal tests that are scientifically, economically and ethically inadequate
whether they are used for final lot testing or as in-process controls. But we will also discuss
the concept of the consistency approach and see whether we can at last move from theory to
examples of practice, and, most importantly, to define what will be needed for more general
acceptance and use of the approach.
We have an exceptional list of speakers and panellists and we hope that everyone will
participate openly and honestly in our efforts to deal with this important issue. We look
forward to your arrival and to an excellent meeting.
The Organisers
Coenraad Hendriksen, Catrina Stirling, Ian Ragan,
Intravacc, The Netherlands Zoetis, Uk NC3Rs, UK
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Early work on 3Rs started from a one-to-one approach: developing a 3Rs alternative to
replace an existing animal test, all within the existing paradigm of vaccine lot release testing.
Although this approach has been successful, animal use for vaccine development and quality
successful, control remained extensive, estimated to be now about 15%of total animal use
for biomedical research and testing. Work is not done yet.
For several reasons we are now moving to another level of 3Rs development. The objective
is no longer replacing an individual animal test by a 3R alternative, but modifying the concept
of lot release testing. The base line of this approach is replacement of safety and potency
testing by a set of non-animal models demonstrating consistency in production and product
quality. This approach starts from the assumption that subsequent lots of vaccine producedcan be compared to a clinical/historical lot, which is thoroughly tested and has a well defined
profile. The consistency approach has come into reach by improvements in production and
control: optimised production processes, a tight protocol for in-process testing using
innovative analytical and cell-based techniques and a state-of-the-art quality monitoring
system (GMP, QA). In my presentation I will elaborate on the principle of consistency testing,
the various techniques that can be used and the way forward.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Testing for adventitious agents is one major pillar to ensure the viral safety of Vaccines. The
recent contamination case of a rotavirus vaccine by a porcine circovirus has highlighted the
limitations of the current testing package. Moreover current developments and
implementation of new broad molecular methods such as High Throughput Sequencing, aswell as a recent study (Gombold et al . 2014) illustrating the poor sensitivity of in vivo
adventitious agent tests are new elements supporting the need for a change in adventitious
agents testing strategy implemented for cell banks and seed lots used for vaccine
manufacturing. The presentation will discuss the use and development of HTS as a
promising platform to address these elements as well as potential approaches for
streamlining the adventitious agent testing package including the removal of in vivo tests for
The use of animals in batch release testing of vaccines very often is a regulatory obligation
and represents around 80% of the total number of animals used in the vaccine industry. 1
This heavy reliance on animal experimentation meets serious ethical, scientific and economic
objections. Additionally the use of 3R models is stimulated through European legislation.
Nonetheless, the acceptance and use of available 3R methods is highly challenging, raising
the question which factors influence the acceptance and use of 3R models for regulatory
purposes and how to optimise this process? To examine the influencing variables and to
define optimizing options, this presentation focusses on a survey (1.) and a case study (2.)
regarding rabies vaccine potency testing to elucidate the factors influencing the acceptance
and use of 3R models for rabies vaccine potency testing purposes in general and the Serum
Neutralisation Test developed by the Paul Ehrlich Institut in Germany, in particular. The
findings are put into the broader perspective of technology acceptance. Through thisadditional step, the broader mechanism behind the existing inertia is described and input is
given for the discussion between regulatory authorities and industry on how to enhance the
remain consistent with the one used in clinical studies. Proposal of risk identification
statement could be as follow: There is a risk of intoxication of the patient that receive vaccine
due to the failure of detection of residual or reversion to toxicity following replacement of an
in vivo method by an in vitro method or due to the waiving of in vivo assay from the control
strategy.
Unclear mechanistic understanding of in vivo assay is sometimes viewed as a major
regulatory hurdle to propose and / or approve replacement model. Yet, taking a step back
and shedding a broader light on the overall risk of implementing replacement method may
help the decision and the acceptance of the risk.
Risk analysis must encompass the potential immediate and potentially delayed harm to the
patient Risk evaluation should take into consideration, the manufacturing process and itsvalidation including stability data, the extent of available safety record data base, the quality
system in place, and the control strategy. This latest element is key to understand from one
process to another the barriers that are in place to both reduce probability and eventually
THE PH. EUR.’S STANCE ON CONSISTENCY TESTING AND 3RS
Karl-Heinz Buchheit
European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe,
Strasbourg, France
The European Pharmacopoeia (Ph. Eur.) sets legally binding quality standards for all
medicinal products in the European Union (EU) and all states who have signed the Ph. Eur.
Convention. The Ph. Eur. seeks to reduce animal usage wherever possible. To assess
compliance with the Ph. Eur. not all tests in monographs need to be performed. With the aimto minimise animal usage as much as possible, assurance that a product is of Ph. Eur.
quality can also be obtained on the basis of its design, control strategy and data derived, e.g.
from validation studies of the manufacturing process, with agreement of the competent
authorities. Furthermore with the agreement of the competent authorities, alternative
methods (e.g. 3Rs methods) may be used. By means of the Biological Standardisation
Programme (BSP), alternative methods applying the 3Rs principles are elaborated for the
Quality Control (QC) of biologicals, in collaboration with industry and public Official Medicines
Control Laboratories (OMCLs). In conclusion, the 3Rs approach and the application of the
consistency approach are supported by the Ph. Eur.; the BSP actively promotes the
validation of 3Rs methods for the QC of biologicals.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
USE OF PHYSICO-CHEMICAL METHODS FOR CONSISTENCY TESTING
John G. Hoogerheide
PhD, Research Fellow, Zoetis
We present examples of the application of sensitive and selective physico-chemical methods
for determining levels of antigens and adjuvants in formulated vaccines. These results are
used to establish the consistency of the manufactured product. Gas chromatography with
flame ionization detection is used for the determination of mineral oil. High performance
liquid chromatography (HPLC) with charged aerosol detection is used for a variety of
adjuvant components, including an oil, a poloxamer, a sterol, a glyocolipid, and a quaternaryamine. HPLC with tandem mass spectrometry (LC-MS/MS) of antigens is applied to both
identification and quantitation.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Increasing numbers of vaccines are being produced in developing countries and especially
by manufacturers from emerging economies. Serum Institute of India Ltd is a long term
collaborator on 3R initiatives and consistency testing in vaccines. My presentation will give
an overview of 3Rs initiatives by way of successful case studies at Serum Institute of IndiaLtd. Implementation of consistency based approaches in vaccine testing needs global
harmonization to develop newer tools, technologies and interfaces to bring closer
communication between different stakeholders such as compendia, regulators, academia
and industry. DCVMN can play an important role for such initiatives. My presentation will give
an overview of global expectations for implementation of such approaches.
FUNCTIONAL IN VITRO TESTING OF VACCINES WITHIN THE CONSISTENCY
APPROACH: A PROOF-OF-PRINCIPLE USING A WHOLE CELL BORDETELLA
PERTUSSIS VACCINE
M.E. Hoonakker
1,3 , L. Verhagen 1,3 , W. Han 3 , A Sloots 1 , C.F.M. Hendriksen 1,2
1 Institute for Translational Vaccinology (Intravacc), P.O. Box 450, 3720 AL Bilthoven,
The Netherlands
2 Utrecht University, Faculty of Veterinary Medicine, Department Animals in Science
and Society, P.O. Box 80.166, 3508 TD Utrecht, The Netherlands
3 Centre for Immunology of Infectious Diseases and Vaccines, National Institute for
Public Health and the Environment, Bilthoven, The Netherlands
Batch release testing of several classical vaccines is still based on animal models that are
costly, time-consuming, sometimes of questionable relevance and pose concern regarding
animal welfare, while accounting for approximately 10% of the animal use. The consistency
approach is based on the integrated strategy of thorough process- and product-
characterization and in vitro testing of vaccine quality rather than potency testing usinganimal models. Though a panel of physico-chemical assays has been developed for
diphtheria vaccines, these assays do not assess the capacity of the vaccines to induce
immune responses and they are not applicable for complex vaccines such as whole cell
pertussis vaccines. To assess the quality of whole cell Bordetella pertussis vaccines (wP) by
this approach we used physico-chemical and immuno-chemical assays in combination with
several functional in vitro assays to evaluate various product-parameters of wP vaccines. We
analysed a panel of experimental wP vaccines of varying quality that were produced by
deliberate modulation of the production process, resulting in altered expression of virulence
proteins that are regarded as important for the induction of protective immunity. Testing of
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
For Tetanus and Diphtheria potency tests, the replacement of the challenge tests by a single
immunogenicity assay involving antibodies titration using non-animal methods e.g. ELISA
has been described in European Pharmacopeia for several years as an alternative for therelease of combination vaccines. Pertussis activity is already assessed with an
immunogenicity test where the lot is compared to a reference vaccine.
The implementation of such immunogenicity assays for the routine control of vaccines is
difficult and not always successful mainly due to the variability of these in vivo tests and their
current design.
The limitations of current in vivo immunogenicity assays involving a reference vaccine and
the alternative approaches based on unidose assays (Geometric mean titer - GMT- of
antibody responses) as consistency tools will be presented. For Pertussis vaccines, the
unidose assay with GMT read-out is already accepted in North America and described in
WHO recommendations. Establishment of the specifications for the antibody response to
each antigen claimed to contribute to efficacy will be discussed, including the issues
encountered when using subpotent batches.
Reduction and refinement of the in vivo methods currently used for vaccines quality control
are important improvements and their complete replacement with in vitro consistency assayswill be the ultimate target for the future.
Tetanus toxin (Ttx) is a highly potent neurotoxin, and the inactivated toxin (toxoid) is used in
production of tetanus vaccines. Currently, safety testing of tetanus vaccines and functional
assessment of tetanus antitoxins requires the use of in vivo assays. An in vitro assay that
can detect tetanus toxin, especially one which incorporates all stages of in vivo toxin action
(i.e. receptor binding, translocation and enzyme action) would be highly desirable and could
fully replace some existing in vivo assays. The aim of this study was to develop a highly
sensitive in vitro assay for the detection of tetanus toxin based on the cleavage of the
intracellular target for Ttxn (vesicle associated membrane protein, VAMP-2) in differentiated
mouse embryonic stem cells.
Methods:
Mouse embryonic stem cells (E14TG2a) were cultured in the presence of leukemia inhibitoryfactor, differentiated into motor neurons after the formation of embryoid bodies (EBs) and
treated sequentially with retinoic acid, Sonic hedgehog/purmorphamine, brain-derived and
glial-derived neurotrophic factors. For final differentiation, EBs were dissociated to form
single cells, and cultured in the presence of nerve growth factor-β. Uptake of Ttx by neuronal
cells was determined by use of Ttx heavy chain (Hc) conjugated to mCherry. Neuronal cells
were treated with a range of Ttx concentrations (for 24 h) and cell lysates were examined for
VAMP-2 expression by western blotting. The specificity of VAMP-2 cleavage by Ttx was
confirmed by neutralisation with tetanus antitoxin.
*French Agency for Food, Environmental and Occupational Health Safety (ANSES), Nancy
Laboratory for Rabies and Wildlife, Technopôle Agricole et Vétérinaire, Domaine de
Pixérécourt, CS 40009, 54220 Malzéville, France. E-mail: [email protected]
The mouse challenge test is still the reference method for the potency determination of
human and animal inactivated rabies vaccines and is still widely used throughout the world.
This test suffers from many disadvantages: expensive, time consuming, use of a large
number of mice, significant animal distress and high variability. Recently the European
Pharmacopoeia has recognised the use of a serological potency assay (SPA) as an
alternative method to the challenge test. This new test is based on the determination of the
rabies neutralising antibody titres in vaccinated mice using a modification of the Rapid
Fluorescent Focus Inhibition Test (mRFFIT). In the present study, we evaluated the
performance of this SPA on a large collection of rabies vaccines currently assessed in our
laboratory. The Fluorescent Antibody Virus Neutralisation test (FAVNt) was used in parallelto the mRFFIT and results were compared to the mouse challenge test. Our results
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
General batch safety tests for veterinary vaccines as the Laboratory Animal Batch Safety
Test (LABST) or the Target Animal Batch Safety Test (TABST) are supposed to demonstrate
that a vaccine does not cause abnormal local or systemic reactions. They have been
introduced decades ago during the development of the first veterinary vaccines. However,
over the last 25 years, the relevance of the TABST and LABST was questioned due to the
introduction of more specific safety tests, strict control of starting material and the
introduction of Good Manufacturing Practice. Retrospective analysis of LABST and TABST
data revealed that the two tests are no longer relevant and not able to detect problematic
batches. The LABST (or abnormal toxicity test) had been removed from European
Pharmacopoeia monographs for veterinary vaccines in 1997, and the TABST in a stepwise
approach until its complete deletion in 2013.
In 2008, Europe proposed to The International Cooperation on Harmonisation of Technical
Requirements for Registration of Veterinary Medicinal Products (VICH) to aim atharmonisation of general batch safety tests across the VICH regions (USA, Japan, Europe)
in order to minimise the need to perform separate studies for regulatory authorities of
different countries. However, due to the great divergence in requirements between the
regions it was concluded to adopt a phased approach with the first step to harmonize the
criteria on data requirements for waiving of the TABST for inactivated vaccines in regions
where it is required, and the respective VICH GL50 came into force in 2014. A comparable
guideline for live vaccines is under development and discussions on steps towards waiving
Salmonella enterica serovar Typhi (S . Typhi) is estimated to cause 26.9 million cases of typhoid
fever per year. The lack of an effective vaccine remains a serious problem in developing
countries, and development of new vaccines is hindered by the lack of a suitable animal model
and correlates of protection. The Oxford Vaccine Group has set up a human challenge model to
test the efficacy of new vaccines against S . Typhi.
The serum bactericidal assay (SBA) measures antibody-mediated complement-dependent
bacterial killing by sera. Several studies using animal sera as an exogenous complement sourcefor the S . Typhi SBA have been published, but animal sera have several limitations, including
As new strategies emerge for the consistent production and testing of biologics batches
using non-animal methods, currently available non-animal approaches have still not been
widely implemented. In some cases, available non-animal methods have not been
implemented at all, despite significant public investments toward validation. Resistance toconsistency measures also contributes to the difficulty in implementing non-animal batch
tests for manufacturers and regulators alike. Referencing the non-animal methods validated
for use by the U.S. Department of Agriculture Center for Veterinary Biologics (CVB), we
describe progress and obstacles influencing the implementation of these methods since
2008. Our work in this area has shown that non-governmental organizations operating
outside of the direct regulation or manufacturing of biologics are uniquely poised to identify
and resolve implementation issues not directly addressed by manufacturers, regulators, or
cooperative efforts between these groups. Here, we present our work towards eliminating
barriers to the implementation of non-animal methods. With particular focus on leptospira
vaccine batch potency testing, we discuss the challenges and opportunities faced by
manufacturers and regulators in the pursuit of integrating consistency measures and non-
animal batch tests into biologics production and testing guidelines.
For conventional vaccines containing diphtheria and tetanus components, in vivo potency
assays are gold standard methods to confirm biological activity. Antigen and adjuvant are
the major components contributing to vaccine potency although their precise contribution to
the measured potency of a vaccine is difficult to predict and will be influenced by other
factors. Consistency of production is also an important criteria for vaccine manufacture and
the amount of antigen and degree of adsorption are critical factors that should be monitored
in final vaccine products. Traditional immunochemical methods can be used to identify the
presence of antigen in a vaccine, but do not necessarily provide quantitative information in
support of consistency of production. We have developed a simple and sensitive Enzyme
Linked Immunosorbent Assay (ELISA) to quantify diphtheria and tetanus antigens in
combined vaccine products and measure the degree of adsorption to adjuvant. The assay
has been applied to various combined vaccine final products and is robust, specific and
highly sensitive, with a limit of quantification of approximately 0.001 Lf/ml for both diphtheria
and tetanus antigens. Compared to in vivo potency assays, in vitro assays are often
inherently less variable and are therefore better suited to providing information on product
consistency and batch-to-batch variation. In routine use as a consistency test for a
pentavalent vaccine, the antigen ELISA has a GCV for total diphtheria antigen content of
12.1% compared to 38.8% for diphtheria potency (challenge assay, n=22) and a GCV of
7.3% for tetanus antigen content compared to 40.4% for potency (challenge assay, n=22).
The in vitro antigen ELISA may also be applied to predict the stability of diphtheria and
tetanus vaccines and we have observed a correlation between the antigen content andimmunogenicity for some artificially degraded and real-time aged vaccine samples. For
REPORTER CELL LINES FOR ASSESSMENT OF PERTUSSIS TOXIN-INDUCED C-AMP
IN ACELLULAR PERTUSSIS VACCINES AS AN ANIMAL-FREE ALTERNATIVE TO THE
HIST
M.E. Hoonakker
1,3
, L. Verhagen 1,3 , A Sloots 1 , C.F.M. Hendriksen 1,2
1 Institute for Translational Vaccinology (Intravacc), P.O. Box 450, 3720 AL Bilthoven, The
Netherlands
2 Utrecht University, Faculty of Veterinary Medicine, Department Animals in Science and
Society, P.O. Box 80.166, 3508 TD Utrecht, The Netherlands
3 Centre for Immunology of Infectious Diseases and Vaccines, National Institute for Public
Health and the Environment, Bilthoven, The Netherlands
Safety is a characteristic that is essential for vaccine quality and has to be monitored toguarantee consistent vaccine production. Safety testing for pertussis toxin (PTx) in acellular
vaccine batches relies on the histamine sensitisation test (HIST). Within this test, mice
receive an injection with an acellular pertussis vaccine followed by a challenge with a fixed
dose of histamine. This in vivo test is based on the empirical finding that PTx reduces the
lethal histamine dose. Studies into the mechanism of this test showed that decreased
contractile properties of arteries and increase blood pressure both contribute to PTx induced
histamine sensitization. Intracellularly, PTx ADP-ribosylates G i proteins, leaving an
ineffective protein that is unable to inhibit its target enzyme adenylate cyclase. This results in
accumulation of cAMP, which disturbs intracellular signalling pathways. It is likely that PTx
mediated ADP ribosylation of Gi proteins is involved in the regulation of the vasoconstriction
of vascular smooth muscle cells.
Based on this information, the cell-based in vitro cAMP assay was developed, as an
alternative to the HIST. In this assay, the cAMP response of a rat vascular smooth muscle
cell line to PTx is studied. Since binding, internalization and ADP ribosylation are necessary
for enhancing cAMP levels, the assay assesses aspects crucial for toxicity. The assayproved to be specific for PTx and was able to detect up to 25 ng of PTx (Hoonakker et al.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Rationale: Tuberculins are biological products derived from culture material of mycobacteria.
When injected intradermally, tuberculins are capable to evoke delayed hypersensitivity in
individuals infected by mycobacteria of the same or closely related species. Tuberculins are
thus used for diagnostic purposes in human and veterinary medicine. To assess batchpotency, compendial methods stipulate evaluation of skin lesions in previously sensitized
Dr. Juan L. Arciniega is a Microbiologist at the Center for Biologics Evaluation and Research
of the US Food and Drug Administration. He received an undergraduate degree in
chemistry, bacteriology and parasitology in 1982, a Master of Science degree in clinical
biology in 1985 and a Doctor of Science degree in the same specialty in 1987, all from the
National School of Biological Sciences in Mexico City. Before joining the Laboratory ofPertussis at CBER in 1989 as a Visiting Fellow, he worked for nine years in different
capacities at the Mexican National Public Health Laboratory, most recently as Underdirector
for Biological Control, in charge of two departments with responsibility for sanitary testing of
food and biologics. He was also a founding member of the Permanent Commission of the
Mexican Pharmacopoeia (Biologics and Bioassay and Statistics Committees).
His research and regulatory activities have focused on pertussis, diphtheria and anthrax
vaccines and the development of alternatives to animal tests. Currently Dr. Arciniega is a
member of the Laboratory of Respiratory and Special Pathogens, Division of Bacterial,
Parasitic, and Allergenic Products, where he works as a CMC reviewer with special
emphasis on methods development, validation and quality control. Additionally, he
participates in other regulatory activities such as batch release, and acts as a liaison with the
US Pharmacopeia (General Chapters – Biological Analysis Expert Committee). He has
published more than 20 papers in his field and cooperated with the World Health
Organization and the Pan American Health Organization as a Temporary Advisor, and with
the European Center for the Validation of Alternative Methods (ECVAM) and the European
Directorate for the Quality of Medicines and Healthcare (EDQM). Dr. Arciniega has mentored
several young Latin American vaccine regulators and other scientists.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Dr. Lukas Bruckner got his degree in veterinary medicine from the University of Berne
in Switzerland in 1982.Before his recent retirement, he worked as the head of the
Vaccine Control Department at the Institute of Virology and Immunology (IVI), the
competent authority for licensing and batch release for immunological veterinary
medicinal products in Switzerland. One of his main interests was in in vitro alternatives
to classical in vivo tests for the quality control of vaccines.Lukas still participates in
several activities of the European Directorate for the Quality of Medicines & Health
Care, the European Pharmacopoeia Commission, as well as the expert groups on
vaccines and sera for veterinary and human use. These activities allow Lukas to
actively promote the 3R philosophy in the regulatory framework."
Buchheit, Karl-Heinz
Dr. Karl-Heinz Buchheit obtained his degree in pharmacy from the Goethe University in
Frankfurt/M. (Germany) and his Ph.D. in pharmacology in 1984 from the same university.
From 1984 until 1999 he worked as research scientist and group leader in preclinical
pharmacology for Novartis/Sandoz in Basel (Switzerland). From December 1999 to August2013, he was Deputy Head of the Department Biological Standardisation, OMCL Network &
HealthCare at the EDQM (Council of Europe, Strasbourg, France) and secretary of the
Steering Committee of the Biological Standardisation Programme. Since August 2013 he is
Head of the same department which is responsible for the activities of the EDQM in the fields
of biological standardisation, the OMCL network, blood transfusion, organ-, tissue and cell
transplantation, pharmaceutical care, anti-counterfeit measures and consumer health
protection.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Diploma in Biology (1977) at the Faculty of Exact and Natural Sciences, University of Buenos
Aires- Argentina
Doctorate with specialization in Microbiology in the same University (1984).
Diploma in Health Systems Management at the London School of Tropical Medicine and
Hygiene, United Kingdom (2006).
After initial training in diagnostics of enteric diseases, she specialized in the field of vaccineproduction, quality control and quality assurance in which she worked for more than 30
years. Adviser to WHO since 1993, joined the organization in 1996 as the Scientist
responsible for the Vaccines Prequalification Programme, which she led for 17 years.
Appointed at WHO as Coordinator of the Regulatory Systems Strengthening team since
September 2013. She is currently and independent consultant focused on vaccine quality
and regulation of Biological Products. Contracted by Serum Institute of India LTD as Senior
Regulatory Advisor since June 2015.
Deming, Stanley
Stanley N. Deming, Ph.D. is president of Statistical Designs, Houston, TX, through which he
consults and offers short courses in the areas of experimental design, optimization, and the
statistical analysis of laboratory data, with emphasis on bioassays. Dr. Deming received his
B.A. degree in chemistry from Carleton College, Northfield, MN, and his M.S. and Ph.D.
degrees in analytical chemistry from Purdue University, West Lafayette, IN. He has been on
the chemistry department faculties of Emory University (1970-1974) and the University of
Houston (1974-2001) where he is Professor Emeritus. Over his academic career he was the
major research advisor for 16 Ph.D. students and 19 M.S. students. Since 1975 he has
taught (with Stephen L. Morgan) over 650 short courses.
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Vaughn Kubiak has over 30 years of experience in global animal health, with a primary focus
on development, licensure, and maintenance of global veterinary biologicals. He has helped
develop conventional and innovative immunological veterinary medicinal products for all
major species during his career. Vaughn has worked for a number of global animal health
companies, with positions in R&D, QA/QC, regulatory affairs, product management, and
commercial organisations. Vaughn has spent the last 13 years with Zoetis Inc., where he
has held management positions in US Regulatory Affairs, Biologicals Process Development,
and Biological Analytical Development. Since 2009, he has been responsible for the
European, Middle East, and African Biological Regulatory Affairs team in Sandwich, England
and then Zaventem, Belgium. He holds a Bachelor of Science and a Master of Science in
Microbiology from the Ohio State University and Emory University, respectively.
Lei, Dianliang
Dr Dianliang Lei is currently working in the Department of Essential Medicines and Health
Products of World Health Organization, Geneva, Switzerland responsible for the
development of international standards for biological products to ensure the quality, safetyand efficacy of the products since 2003. He has been in charge of development of WHO
Guidelines for Lot Release of Vaccines by Regulatory Authorities, WHO Recommendations
for acellular pertussis vaccines, Recommendations for DTP based combined vaccines,
Manual for establishment of national standards, Manual for laboratory testing of DTP
vaccines, Guidelines for post-approval changes of vaccines, GMP for biologicals and
establishment of measurement standards.
He had been working in the field regulation and quality control of vaccine in the National
Institute for the Control of Pharmaceutical Products, Beijing China for more than 20 years till
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2003. His work was focused on the regulation system for vaccines in China, especially on the
national requirements (pharmacopeia), standards and lot release system. He was the
executive member of Chinese Pharmacopoeia and the deputy director of the Institute.
He holds a Ph D in medical science from Osaka University, Japan in 1996.
Mallet, Laurent
Dr. Laurent MALLET obtained his Master Degree of Science in Biochemistry from Claude
Bernard Lyon University in France. He completed his PhD work in Virology and Molecular
Biology under the co-direction of Pr Michèle Aymard (National Reference Center for
Enterovirus, Lyon, France) and Dr. François Pelloquin (Sanofi Pasteur, formerly Pasteur
Mérieux Connaught). He obtained his PhD in 1996. After several positions within Sanofi
Pasteur in France and in Canada, he is currently Head of Analytical R&D Europe.
He is also a member of several expert committees, Group 15 “Sera and Vaccines” atEuropean Pharmacopoeia and part of the French Pharmacopoeia Committee “Biological
Products and Innovative Therapies”. Recently, he has been involved in several WHO
working groups (e.g. IPV, Dengue and Yellow Fever vaccines) including the WHO Study
Group on Cell Substrates and the associated Adventitious Agent sub-group.
Metz, Bernard
Bernard Metz was born on November 18th 1972 in Dokkum, The Netherlands. In 1993 he
started to study Chemistry of the Faculty of Mathematics and Natural Sciences, University of
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Groningen. He graduated in 1998. From 1999 until 2000, he was involved as research
associate in the project entitled ‘Random mutagenesis of gonadotrophins in Dictyostelium
discoideum ’ (a collaboration between the Department of Biochemistry, University of
Groningen and Organon, Oss). In the period between 2000 and 2004, he was working as a
graduate student on his thesis ‘Structural Characterisation of diphtheria toxoid’. This project
was a collaboration between the Department of Pharmaceutics of the Faculty of
Pharmaceutical Sciences of the Utrecht University and the Unit Research and Development
of the Netherlands Vaccine Institute in Bilthoven (NVI). Since 2004, he is working at R&D of
the NVI focussing on test development and characterisation of vaccines. From 2013, Bernard
is working as a research scientist at Intravacc (formerly part of NVI).
Morgeaux, Sylvie
Dr. S. Morgeaux worked and prepared her PhD in the Rabies Unit at Pasteur Institute in
Paris and obtained her PhD on Animal Viruses in Paris VII University. In 1995, she joined
ANSM (formerly Agence du Médicament) as a scientist in charge of the control and release
of various live and inactivated viral vaccines. During eleven years she was the Head of the
Viral Vaccine Control Unit and was also a Temporary Adviser at the Expert Committee on
Biological Standardization meeting for vaccines of WHO, at others working groups and for
NRAs’ assessment and training for vaccines control and lot release. Presently, she is in
charge of the release of Rabies, Hepatitis A vaccines, equine anti-rabies immunoglobulins
and of the 3Rs strategy at the Batch Release and Market Surveillance for Biological ProductsDepartment of the Laboratory Control Division of ANSM. She is also involved as an expert in
the regulation assessment of Rabies, Hepatitis A and B, Varicella, Tick-Born, Japanese
Encephalitis, Rotavirus, Papillomavirus and Smallpox vaccines. Dr S. Morgeaux is a member
of the European Pharmacopoeia Group 15, of the EDQM Drafting Group for human vaccines
and of the Technical Committee of EPAA.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Dr Ian Ragan is a neuropharmacologist and an independent consultant in the biomedical
sector. He spent nearly 20 years in the pharmaceutical industry, most recently with Eli Lilly
as Executive Director, Neuroscience Research, Europe, and Executive Director, European
Scientific Affairs. He was the Lilly representative on the Research Directors’ Group of the
European Federation of Pharmaceutical Industries and Associations (EFPIA). Until recently
he was the co-ordinator of the European Partnership for Alternative Approaches to Animal
Testing (EPAA) project on the application of the 3Rs and the consistency approach for
improved vaccine quality control. Currently he is a Board Member of the National Centre for
the 3Rs and Director of the UK National Autism Project.
Dr C. Ian Ragan 51 Slaidburn St London SW10 0JW UK Office: +442073514985 Mobile:
+44(0)7793314727
Redhead, Keith
Keith Redhead was, from 1980, a Senior Scientist at the National Institute for Biological
Standards and Control, UK, responsible for research on Diphtheria, Tetanus and Pertussis
vaccines. It was the large numbers of mice necessary for the control testing of Pertussis
vaccines that first stimulated his interest in alternative testing methods. Since 1995, he hasbeen a researcher at a number of companies working on bacterial veterinary vaccines, with
particular emphasis on clostridial products. Once again the high number of animals used in
this area has driven his interest in applying the principles of the 3Rs to vaccine research and
testing. He is on various 3Rs advisory bodies, a member of the British Pharmacopoeia Panel
of Experts, a Project Leader of the EPAA Working Group for Clostridial Vaccines and has
authored over 70 scientific publications.
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING
Eddy Rommel is Doctor in Veterinary Medicine and Master in Animal Production. He is also
graduated in lab animal sciences and in Business Administration.
Eddy has been involved in animal research, In-vivo Quality Control of vaccines and
Regulatory Affairs for the last 30 years, starting his career as research assistant at the
University of Liège, then moving to GlaxoSmithKline Biologicals where he was Associate
Director In-vivo Quality Control and responsible for animal research before being in charge of
a regulatory affairs department.
Since 2002 Eddy is Founder and Managing Director of Rommel Consulting Partners,
providing consultancy services in preclinical development of Biologicals and Advanced
Therapies, in Quality Control of vaccines for human and veterinary use and in lab animal
sciences.
Eddy is member of the Vaccines Technical Committee of EPAA Vaccines Project and of
several Belgian and European committees and professional associations.
Schiffelers, Marie-Jeanne
Marie-Jeanne Schiffelers has a master’s degree in Environmental Policy Sciencesand is a senior consultant and lecturer at the Utrecht University School of
Governance. She works as a consultant and researcher in the field of policy
science, organizational change and technology transitions.
She has been involved in several projects in the field of acceptance and use of 3R
methods for regulatory purposes e.g.:
Project manager research Regulatory Animal Testing (2004-2005)
Member research team ‘Evaluatie Besluit Biotechnologie bij Dieren’ (2005 -
2006)
7/21/2019 IABS CONFERENCE 3RS AND CONSISTENCY TESTING IN VACCINE LOT RELEASE TESTING