Jan Hendriks & Claire Boog Jan Hendriks & Claire Boog Netherlands Netherlands Vaccine Vaccine Institute Institute (NVI) (NVI) Influenza Technology Hub a WHO Vaccinology Centre of Excellence Bilthoven, the Netherlands WHO Technology Transfer Workshop 30 November-1 December 2010
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Jan Hendriks & Claire BoogJan Hendriks & Claire Boog
Technology Transfer since 1970Production Processes and/or QC testing
WHO Technology Transfer Workshop, Geneva, 2010 10
“ Lesson” : GMP: a two-edged sword?
Purpose was to introduce (European) GMP into Local
Vaccine Producers, but when full financial consequences
(infrastructure, equipment, training, validation,
documentation, organization) became clear at receiver
during execution, new technology and GMP standard was at
that time not locally sustainable (ex: OPV dose price)
China Vaccine Project 1990-1998
WHO Technology Transfer Workshop, Geneva, 2010 11
China Vaccine Project 1990-1998
GMP Facility Kunming
GMP Facility Lanzhou
GMP Facility Shanghai: now in use for H1N1
pandemic flu productionand other vaccines
WHO Technology Transfer Workshop, Geneva, 2010 12
Transfer of know-how related to polio vaccines
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Bakker et al. submitted to Vaccine (2010)
• Since the 1970’s micro-carrier technology was transferred to different parties. •After that, various courses were organized, and bulk product was supplied to local manufacturers. •Sabin-IPV technology transfer will be the next step.
WHO Technology Transfer Workshop, Geneva, 2010 13
Hib-conjugate vaccine project1999 - now
• Develop an up-scalable and patent free production process for the large-scale production of Hib conjugate vaccine
• Transfer the technology to developing countries to ensure a sustainable supply of affordable and quality vaccine
• Seed capital provided by RIVM/NVI
WHO Technology Transfer Workshop, Geneva, 2010 14
NVI
Bio Farma - Indonesia
Serum Institute - India Biological E - India
Glovax JV / SIBP - China
Hib-conjugate vaccine project1999 - now
WHO Technology Transfer Workshop, Geneva, 2010 15
NVI
Bio Farma - Indonesia
Serum Institute - India Biological E - India
Glovax JV / SIBP - China
Hib-conjugate vaccine project1999 - now
WHO Technology Transfer Workshop, Geneva, 2010 16
Impact of NVI Hib Tech Transfer??
• increased the competition at global market: pricedecrease
• helped start of
other conjugate
tech transfer
projects at
recipient; e.g. MVP
International Technology Platform for Pandemic
Influenza Vaccines (ITPIV)“Hub”
WHO Technology Transfer Workshop, Geneva, 2010 18
• A technology platform for transferring a single robust production process at pilot scalewith relevant documentation (SOPs, Batch Process Records, validation procedures, analytical methods and release criteria)
• A technology package transferable to interested developing country vaccine manufacturers, upon request and without IPR hurdles
• Selected technology: Inactivated whole virion influenza vaccine produced in embryonated eggs
ITPIV, International Technology Platform for Influenza Vaccines, Project
2007 - now
Friede et al. Vaccine 27 (2009), 631 - 632
WHO Technology Transfer Workshop, Geneva, 2010 19
Access
Grantees will have access to:
� Technical advice
� Process and production technology
� Documentation
� Assays
� (Pre)clinical support
•• cleanroomcleanroom designdesign
•• water systemwater system
•• HVACHVAC
•• equipment equipment
•• maintenancemaintenance
•• trouble shootingtrouble shooting
•• etc.etc.
•• seedlot preparationseedlot preparation
•• egg handling systemsegg handling systems
•• zonal ultra centrifugezonal ultra centrifuge
•• virus inactivation virus inactivation
•• process validationprocess validation
•• etc.etc.
•• specificationsspecifications
•• validation plansvalidation plans
•• BPRBPR
•• SOPSOP’’ss
•• risk analysisrisk analysis
•• etc.etc.
•• inin--process and release testsprocess and release tests
•• specificationspecification
•• setset--up up
•• assay validationassay validation
•• etc.etc.
•• IMPDIMPD
•• safety and efficacy studiessafety and efficacy studies
•• clinical plan clinical plan
•• study protocolsstudy protocols
•• etc.etc.
WHO Technology Transfer Workshop, Geneva, 2010 20
ITPIV Training Courses realized 2009/2010
• Generic courses
• 3 week courses on influenza production and QC
• hands-on demonstration run
• 2 volume course manual
• 29 trainees
• Workshop
• 1 week workshop on QA and GMP aspects of
influenza vaccine production
• 13 participants
WHO Technology Transfer Workshop, Geneva, 2010 21
DCVMs participating in NVI Flu Courses
PublicIVACVietnam
PublicThai Red Cross Society Thailand
PublicGPOThailand
PublicTorlakSerbia
PublicCantacuzino InstituteRomania
PublicResearch Institute for Biological Safety Problems Kazakhstan
PublicRaziIran
PublicBio FarmaIndonesia
Private Indian Immunologicals LimitedIndia
PublicVACSERAEgypt
PublicInstitute of Immunology Croatia
PrivateZhejiangTianyuan Bio-pharmaceutical China
PublicChangchun institute of Biological Products China
PublicShanghai Institute of Biological Products China
PublicCentro Nacional de Control de Calidad de Biológicos Argentina
Legal StatusBenificiaryCountryAlso:
bilateral Tech Transfer
consultancy agreements in
place with
VACSERA and IVAC
WHO Technology Transfer Workshop, Geneva, 2010 22
Next Generic Training Course on production and quality control of
whole virion and split egg-based influenza vaccines:
February 7 – 25, 2011
WHO Technology Transfer Workshop, Geneva, 2010 23
Establishment of Hub for flu successful as capacity-building
tool
– Egg-based process development:
• Consistent process
• Meeting industrial standards for yield & purity
• Meeting all international specifications
• Suitable for technology transfer
– Work started on a transferable Vero cell-based flu process
– Training & Tech Transfer
• Generic training meets international need
• Alternative way to stepwise approach starting with fill/finish
Hendriks et al. submitted to Vaccine (2010)
0
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Heam
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Ovalb
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Ovalbumin concentration
WHO Technology Transfer Workshop, Geneva, 2010 24
Collaboration with other WHO “Hub” : University of
Lausanne (UNIL)
NVI and UNIL signed in 2010 a Letter of Intent to collaborate on
technology transfer of generic oil-in-water emulsions
– Collaborative training and tech transfer in vaccine formulation for pandemic
influenza and polio vaccines
• Use of oil-in-water emulsion for dose-sparing in inactivated polio vaccines
– Adjuvanted pandemic influenza vaccine transfer to DCVMs
• NVI consultant on GMP and training in recent awarded BARDA Grant to UNIL
WHO Technology Transfer Workshop, Geneva, 2010 25
Lessons learned (1)
• Critical mass needs to be present at both sides over a long period
– Long term investment and commitment required
• Time-to-market aspect is critical as changing perceptions can jeopardise a
technically feasible approach
• Competition-aspect with Big Pharma is an important factor
– For example comparing the Hib case versus MVP and Flu cases there could be
no clear WHO-role nor significant upfront funding in starting the project
• Generic capacity building can generate unexpected indirect beneficial
effects
– Examples:
• GMP DTP Facility & training in SIBP, Shanghai for H1N1 pandemic vaccines
• Hib conjugation technology training in SII, Puna for the MVP-project
Platform technology (e.g. Verocell manufacturing) relevant forDCVM planning to invest in different new vaccines
WHO Technology Transfer Workshop, Geneva, 2010 26
Lessons learned (2)
• Sustainibility of “hub” model from provider’s point of view
– Transition NVI from local manufacturer to vaccinology centre requires
newr mission and mandate
• Focus now to innovative platforms & technology transfer
– Financial and technical challenges
– TRIPS Art 66.2
• Obliges developed countries to promote technology transfer
• Interested recipient-parties to consult viability criteria established
previously by WHO
WHO Technology Transfer Workshop, Geneva, 2010 27
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0 5,000,000 10,000,000Ex t r a $ I nv e st me nt Annua l l y
Via
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ity
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Viable
Potentially Viable
Not viable
Systematic Evaluation of Viability of Local Vaccine Production
Milstien, Batson and Meaney, Vaccine 1997, 15, Nr 12/13, pg 1358-1363
WHO team evaluated in 1997: 31 facilities in 13 countries
WHO Technology Transfer Workshop, Geneva, 2010 28
Viability of Local Vaccine Production
Critical Elements• Economies of Scale
• GMP and Consistency of Production
• Access to New Technologies
• Historical Ability to Meet National Supply Needs
• Credibility of Quality (NRA competence)
• Management Structure
• Legal Status, adequate autonomy
Milstien, Batson and Meaney, Vaccine 1997, 15, Nr 12/13, pg 1358-1363
•3 year economic plan•Price covers full cost per dose•Research on future demand•Etc.
•Control to set salaries•Control to hire and fire•Political stability•Etc.
•Processdevelopment budget•R&D budget and programme•Added new technology in last
5 years•Etc.
WHO Technology Transfer Workshop, Geneva, 2010 29
Is this WHO evaluation stillapplicable today?
Since then:
– National strategic considerations (vaccine security)
can prevail over market-economics for some products
(e.g. pandemic flu)
– Globalisation has dramatically changed the market-
dynamics with newly emerging competent
manufacturers and newly emerging vaccine markets
WHO Technology Transfer Workshop, Geneva, 2010 30
Acknowledgements
•Tech Transfer Egg-based Influenza vaccine•Marit Holleman, Otto de Boer & Willem Luytjes•www.ITPIV.NL
•Tech Transfer China Vaccine Project•Rudy Tiesjema†, Coen Beuvery & many others
• Tech Transfer Hib-conjugate vaccine•Hans Kreeftenberg, Ahd Hamidi & Michel Beurret
•Tech Transfer Sabin-IPV•Wilfried Bakker, Nico van den Heuvel & Ahd Hamidi•www.Sabin-IPV.nl