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The Government Pharmaceutical Organization

The Government Pharmaceutical Organization. THE GOVERNMENT PHARMACEUTICAL ORGANIZATION. Update on In-country Vaccine Production and Research Direction Sit Thirapakpoomanunt The 3 rd Thailand Human Influenza Research Meeting 14 October 2011. THE GOVERNMENT PHARMACEUTICAL ORGANIZATION.

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The Government Pharmaceutical Organization

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  1. The Government Pharmaceutical Organization THE GOVERNMENT PHARMACEUTICAL ORGANIZATION Update on In-country Vaccine Production and Research DirectionSit ThirapakpoomanuntThe 3rd Thailand Human Influenza Research Meeting14 October 2011

  2. THE GOVERNMENT PHARMACEUTICAL ORGANIZATION

  3. Outline • 1. Rationale of the Influenza vaccine(IV) development • 2. IV Development Project , 1st WHO Grant • 3. LAIV/PLAIV Development Project, 2nd WHO Grant • 4.IV Industrial Plant, Granted by Thai Government and Technical Assistance from Kaketsuken • 5.Research Direction

  4. Objective of the Vaccine Project: • Tocreate the sustainable Capacityon R&D and production of LAIV/IIV for self reliance, in normal situation, and for national security, in time of pandemic

  5. Current types of licensed seasonal Influenza Vaccines: inactivated (IIV) and live attenuated (LAIV) (Source: IFPMA-IVS)

  6. Flow Process of Influenza Vaccine 6.Purification by Zonal Ultracentrifugation 1. Seed Lot 7.Diafiltration 2.Inoculation in embryonated eggs 8.Splitting step 3.Harvesting 9.Inactivation 4.Clarification 10.Monovalent Bulk Vaccine 5.Concentration by UF 3 strains mix Sterile filtration Sterile filtration LAIV/PLAIV IIV, subunit New H1N1

  7. 1st WHO Grant • GPO used BSL3 Lab at Silpakorn University, NakornPathom for process development and quality control for release of IIV by WHO Guideline • Achievements during first grant A process for preparing monovalent, sub-unit vaccine from 2 Influenza A and 1 Influenza B strain was successfully developed at laboratory scale.

  8. 1st WHO Influenza project: 3 Monovalent bulks: H3N2, H1N1 and B strains

  9. Comparison of GPO results to “Process Efficiency- eggs used per dose- for Inactivated Trivalent Seasonal Influenza Vaccine, for Six Manufacturers” 0.7 0.45 Western Standard GPO

  10. Challenges of 1st Grant • 1.Need to scaling up from 500 eggs per batch • 2.Confirm more on splitting process to ensure splitting agent was adequately removed • 3. Consistency and Stability data should be generated further • 4. Immunogenicity in mice should be studied and compared with commercial IIV • 5. Non-clinical Toxicity and Clinical Studies will be further performed

  11. 2nd WHO Grant • Renovation of GMP BSL3 Lab to be Pilot Plant using as BSL2 for development of H1N1 2009 PLAIV as an urgent plan according to the outbreak of H1N1 2009 pandemic • Reassorted Premaster seed of A/17/CA/2009/38 (H1N1) wa • delivered from IEM(Russia) to GPO by WHO License on • July16, 2009

  12. PLAIV H1N1 (2009) Vaccine Development

  13. The National Missions • To have certain amount of PLAIV H1N1 (2009) (1-2 million doses) as a stockpile ready to be formulated for use in compliment of PIIV procurement • To prepare for the second and further wave outbreak • To have the first registration file approved by Thai FDA • To gain the experience and create capacity building for the industrial plant

  14. Vaccine Development Diagram of the H1N1 (2009) H1N1(2009)+H2N2Leningrad17 *egg passage ‘selection’ H1N1(2009) Leningrad17 (1) *egg passage Pre-Master seeds genetic Identity phenotypic markers mice, guinea pig Toxicity and immunogenicity IEM/Russia Immunogenicity ViroClinics /Netherlands Attenuation in ‘animal model’ Ferret (2) genetic Master seed GPO Identity phenotypic Other tests including sterility and potency *egg passage genetic Identity (3) Working seed phenotypic Other tests including sterility and potency *egg passage genetic Identity (4) phenotypic Virus concentrate Other tests including sterility and potency Harvest , Clarification by refrigerated centrifuge and 3 filtration Titration & formulation Adventitious agents Acute Toxicity Bulk vaccine mice Nonclinical test in mice And Ferrets filling Sterility Vaccine products Other tests including sterility and potency Clinical Trail

  15. Development Timeline for H1N1 (2009) vaccine Approved for Pandemic situation On July12, 2011 Vaccine Registration Pre-clinical Safety studies Clinical studies Phases I, II Trop. Med Mahidol Production & QC Formulation 16 July 2009 Seed Received 26 October 2009 Part A (Test for Safety in 24 subjects) - 1st dose on 18th December 2009 - 2nd dose on 7th January 2010 Part B (Test for Safety & Immunogenicity in 1st age gr.x 108 subjects(>18-49Y) - 1st dose on 10th May 2010 - 2nd dose on 30th May 2010 The 2nd&3rd (12-18 and >49) started from Aug.

  16. Result from Nonclinical Study THE GOVERNMENT PHARMACEUTICAL ORGANIZATION Ferret test: Attenuation test: pass Challenge test(Protective immunity): pass Mouse toxicity test Single dose toxicity: pass Repeated dose toxicity:passpass

  17. Clinical Study

  18. Clinical Study : Part A • The study is a double blind randomized study involving 24 participants with the main objective of assessing safety-tolerability and optimal immune response. • Using 5.0-6.5 log10 EID50 or 6.6-7.5 log10 EID50 and given two doses 21 days apart. • Conclusion • LAIV Candidate Strain A/17/CA/2009/38 (H1N1) appeared to be safe in small number of healthy adults • Viral shedding rate was low since it was found only in two cases at D2 afterfirst vaccination. • In term of immune responses , it is difficult to conclude since the sample size was small and there may be other immune responses that should be measured other than HAI and MN for LAIV vaccine i.e. cell mediated immunity

  19. Clinical Study : Part B THE GOVERNMENT PHARMACEUTICAL ORGANIZATION

  20. Combination of all 3 assays for GPO vaccine evaluation = 5 (4.7%) = 17 (16.5%) = 24 (23.1%) = 26 (24.3%) Total positive cases for HI = 20/107 (18.7%), 8/40 (20.0%) NT = 7/40 (17.5%) sIgA = 6/40 (15.0%) Positive = titer 4 folds as compared to day 1 HI; result of GPO vaccine strain NT; result of A/Thailand/104 and/or A/CA/07/2009

  21. Combination of all 3 assays for GPO vaccine evaluation = 19 (17.9%) = 41 (39.8%) = 47 (45.2%) = 47 (43.9%) Total positive cases for HI = 31/107 (29.0%), 10/40 (25.0%) NT = 24/40 (60.0%) sIgA = 6/40 (15.0%) Positive = titer 2 folds as compared to day 1 HI; result of GPO vaccine strain NT; result of A/Thailand/104 and/or A/CA/07/09

  22. Development Timeline for H5N2 (2010-2011) vaccine Vaccine Registration Production & QC Formulation Pre-clinical Safety studies Clinical studies Phases I, II Trop. Med Mahidol 1.NC in mice at GPO Sep 2010 1st Jan 2011 2nd : Retest Sep 2010 Seed Received Protocol of CT was submitted to WHO EC and Faculty of Tropical Medicine, Mahidol University By Prof. Dr.Punnee Pittisuthitham, principal investigator:Approved 2. In parallel with NC in Ferret at NVI: Pass

  23. Challenges of LAIV • Further development of LAIV – higher yields, better stabilizers or lyophilization, more consistent sterile production, better capacity for all tests, development of multi-doses sprayers to be used in pandemic, etc. We will need to develop and implement a ‘research and development package’. • We need strong technical supports for the success of industrial scale plant – who, where, when and how? • How to implement the continual improvement in the core capacity building in the future?

  24. IIV Development with KK Assistance • Technical Assistance Agreement was official signed on Oct3, 2011 after starting cooperation under MOU from Sep 24,2010 • Site training at KK Flu Production Plant and Sending expert team to train at pilot scale and process validation at Industrial Plant

  25. Timeline of Master Plan • Seed preparation and Lab process study • Pilot scale production for Optimization and Stability • Nonclinical Study • Clinical Study Phase I/II(including Phase III if allowed by FDA ) • Industrial Production: Ready to do Process Validation in 2013 (with Clinical Study Phase III ) and Registration • Vaccine launched for commercial in 2014

  26. Influenza Vaccine Plant &Goal Pilot Plant : BSL3 lab with WHO-GMP Purpose: To build capacity on Production & R&D of IIV and LAIV • WHO Grant: • 1st grant ($US 1.96 million) for research and development production technology in 2007 • 2nd grant ($US 2.04 million) for Development of LAIV (according to Pandemic) in 2009 Successfully developed and produced subunit IIV in laboratory scale and plan to upscale into industrial scale in 2011 GPO Investment: $US 0.5 million for management & labor cost Purpose: Adequate sustainable capacity in response to flu pandemic Target: 2-10 million doses of Trivalent IIV annually using Egg-based technology Investment: supported from Thai Government US $42 million or 1,411.70 million baht for Industrial Plant

  27. Lesson Learned from the project • We can not work and build up GPO capacity alone. We must involve and build up capacity of partners like TFDA, NCL, Bureau of Epidemiology, Department of Livestock Development, and universities. • The capacity building has to be comprehensive involving institutional and individual capacity building as well as networking. That is the main reason for the formulation of capacity building program. • International supports are essential for our future success.

  28. Future Plan for IV • Further development of LAIV – higher yields, better stabilizers or lyophilization, more consistent sterile production, better capacity for all tests, development of multi-doses sprayers to be used in pandemic, etc. • Adjuvant formulation will be studied with IIV • We will need to develop and implement a ‘research and development package’

  29. Thank you for your attention

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