คนไทยจะได้ใช้วัคซีนไข้หวัดใหญ่ที่ผลิตโดยองค์การเภสัชกรรม?

งานนำเสนอเรื่อง: "คนไทยจะได้ใช้วัคซีนไข้หวัดใหญ่ที่ผลิตโดยองค์การเภสัชกรรม?"— ใบสำเนางานนำเสนอ:

1 คนไทยจะได้ใช้วัคซีนไข้หวัดใหญ่ที่ผลิตโดยองค์การเภสัชกรรม?
การประชุมวัคซีน ครั้งที่4 11-13 กรกฎาคม 2555 ภก.สิทธิ์ ถิระภาคภูมิอนันต์ องค์การเภสัชกรรม

2 วิสัยทัศน์ เป็นผู้นำในธุรกิจยาและเวชภัณฑ์
ที่เป็นประโยชน์และจำเป็นต่อสังคมไทยอย่างเป็นธรรม 2

3 ประเด็นในการอภิปราย ๑.แผนยุทธศาสตร์ป้องกัน แก้ไข และเตรียมพร้อมรับปัญหาไข้หวัดนกและการระบาดใหญ่ไข้หวัดใหญ่กับความมั่นคงของประเทศ ๒. สถานการณ์โรคไข้หวัดนก ไข้หวัดใหญ่ระบาดใหญ่กับการเตรียมความพร้อมการพัฒนาการผลิตวัคซีนป้องกันไข้หวัดนก ไข้หวัดใหญ่ของประเทศไทย ๓.เส้นทางการพัฒนาวัคซีนและสร้างศักยภาพการผลิตที่ผ่านมา ๔.ประสบการณ์และบทเรียนจากปัญหาและอุปสรรคที่สำคัญจาก lab, pilot and industry ๕.คนไทยจะได้ใช้วัคซีนป้องกันไข้หวัดใหญ่ที่ GPO ผลิตเมื่อไร

4 แผนยุทธศาสตร์ป้องกัน แก้ไข และเตรียมพร้อมรับปัญหาไข้หวัดนกและการระบาดใหญ่ไข้หวัดใหญ่
แผนฉบับที่ 1(พ.ศ ): ลดการติดเชื้อและระบาดของสัตว์ปีก การป่วย เสียชีวิตในคน ลดการสูญเสียทางเศรษฐกิจและสังคม ทำให้ได้รับการยอมรับ เชื่อถือจากนานาชาติ มี 6 ยุทธศาสตร์ “การสร้างและจัดการองค์ความรู้เรื่องไข้หวัดนก: การพัฒนาวัคซีนให้พร้อมใช้เมื่อเกิดการระบาดใหญ่ในสัตว์และคน” แผนฉบับที่2(พ.ศ ): เน้นการป้องกันไข้หวัดนก และไข้หวัดใหญ่ระบาดใหญ่ เนื่องจากมีการติดต่อจากสัตว์ปีกสู่คน พัฒนาองค์รวมที่มีคนเป็นศูนย์กลาง สร้างภาคีเครือข่ายทั้งในและต่างประเทศ การอนุมัติโครงการสร้างโรงงานผลิตวัคซีนไข้หวัดนก ไข้หวัดใหญ่ระดับอุตสาหกรรม มาตรฐาน WHO GMP แผนฉบับที่3(พ.ศ ): เตรียมพร้อมรับมือไข้หวัดนก ไข้หวัดใหญ่ระบาดใหญ่ และโรคติดต่ออุบัติใหม่

5 WHO GMP Standard Plant for Influenza Vaccine Production
Thai Cabinet WHO GMP Standard Plant for Influenza Vaccine Production Approved Million Baht for Flu Plant Project 22 May 2007 The Government Pharmaceutical Organization,under MoPH

6 Licensed Seasonal Influenza Vaccines:
Inactivated (IIV): Whole, Split, Sub-unit Live attenuated (LAIV)

7 Flu Vaccine Development Project for Industrial Capacity
Pilot Plant : at Silapakorn University Purpose : R&D and Clinical lot production of IIV and LAIV Supported by 1. WHO: 4 million USD 2. GPO : 150,000 USD + management and labor (b) Industrial-scale Plant ( ) Purpose : Capacity for million doses of Trivalent IIV/yr Capital investment - Thai Government million USD In order to be able to maintain the committed supply, we also proposed to the National Health Security Board in 2008, to support the seasonal flu immunization for elderly and those with 7 chronic diseases. This means around 4 million doses in We don’t use the disease burden or cost effectiveness analysis. What we use are data to confirm that the cost of immunizing the elderly and those with 7 chronic diseases are less than the cost of treating the same group of population who are flu victims. Thanks to the collaborative works with the US CDC, we have enough information from two provinces to justify it. In the first two years, we did not request for any new budget but we cut off less than 0.1 per cent of the In-patient budget to pay for the flu vaccine. With central procurement we can now buy the flu vaccine at 4 USD per dose as compare to 8 USD in 2009. This is the third lesson learnt that we need to ensure adequate ‘demand’ to maintain the supply investment. We must also aware that justifying for increase demand based on BOD, cost effectiveness or even comparative cost like in our case, only ensure that ‘market’ is now available. However, it does not guarantee that there will be investment in local production. It may only means a bigger market for the big vaccine producers. As mentioned earlier, investment to increase supply in developing countries must be based mainly on ‘national security’ purpose.

8 Flu Vaccine Project: Objectives and targets
Objective - To build the Sustainable Capacity on R&D and production of seasonal IIV and LAIV to respond to pandemic Targets Adequate R&D and production capacity Pilot plant and Industrial Scale plant 2-10 million doses of seasonal IIV or not less than 60 million doses of PLAIV at pandemic

9 Flow chart of LAIV production processes
Inoculation of SPF eggs with Working Seeds 2 - 3 days Chill Flow chart of LAIV production processes Overnight Concentrated Vaccine Harvested allantoic fluid C0 Clarification by centrifugation Thaw C1 C6 = After thawing Pre-filtration Formulation C7 = After formulation Defined allantoic fluid C2 Filter sterilisation C8 = After filter sterilisation Ultra-filtration, cut off 1000 Kda, Filling C3 Packaging Addition of stabilizer C4 Finished vaccine C9 = After filling, packaging Filtration Monovalent virus pool C5 9 9

10 The production in the pilot plant
1. SPF eggs Hatching days 3. Inoculation 4. Harvest This pictures show some of the production processes. We would like to thank Dr. Rajeev and Leena from SII of India that allowed us to observe their production processes which we have learned a lot to improve our processes. The first slide showed SPF eggs during hatching, the second showed fertile SPF egg after hatching. The third showed inoculation step and next is harvesting 2. Candling 10 10

11 The production in the pilot plant
5. Clarification by centrifugation 7. Ultrafiltration Then allantoic fluid is centrifuged and the six picture showed characteristc of allantoic fluid after centrifugation. After pre-filtration, allantoic fluid is purified and concentrated using ultrafiltration, then sterile filtration through 0.22 um. The last slide showed monovalent virus pool before keep at minus 80 degree celcius 6. Allantoic fluid after pre-filtration 8. Monovalent virus Pool 11 11

12 Overview of LAIV QC Tests
According to the WHO recommendations, the QC tests for LAIV include testing of control eggs, seed lots, monovalent virus pool, final bulk, and the final products. The necessary tests for each of the products are shown in the table. PLEASE CHECK CAREFULLY ON THE TABLE AND TEXTS BELOW. We assure the quality of eggs for LAIV production by testing haemagglutinin agents in 2% or more of the total eggs. For the seed lots, we fully test for identity, adventitious agents, sterility and infectivity. For the single harvest or C0, we fully test for the adventitious agent. For the concentrated bulk or C5, we test for phenotypic identity, and full test for sterility and infectivity. Then for the final bulk or C8, before filling and packaging, we test only for bacteria and fungi. In the final products we test the identity by H-Ag Neutralization, test for bacteria and fungi, infectivity and all physico-chemical tests. WHO/BS/ , recommendations to assure the quality , safety , and efficacy

13 Checklist of Nonclinical testing (In-vivo)
Nonclinical Study Report (As requested) TFDA GPO WHO Pharmacology Part - Immunogenicity - / Toxicology Part - Single Dose Toxicity - Repeat Dose Toxicity - Local Tolerance (Repeated Tox)

14 Key Achievement on LAIV
May 2009 Jun 2009 Jul 2009 … Oct 2009 Dec 2009 Jul 2011 Aug 2011 Jun 2012 (4) Clinical Study Phase I on GPO H1N1 LAIV (1) 2nd WHO Grant (2.064 million USD) (6) Immunogenicity & Efficacy of GPO H5N2 LAIV in ferrets Challenge test (3) Successfully Developed LAIV Production Process (pilot scale) (8) GPO H5N2 LAIV CT phase I (5) GPO H1N1 LAIV Licensed with Thai FDA (2) Renovate BSL3 Complying to WHO-cGMP standard (7) EC approved CT Protocol of GPO H5N2 LAIV Supported by WHO grant

15 The use of LAIV & its limitations
No information for use of LAIV in children younger than 2 years (3 years for Russian) For use in adults & elderly aged up to 49 years old (GPO pH1N1 LAIV 2-65 years old) Lower immune response in elderly No information for use of LAIV in patients with chronic diseases, pregnancy & lactation Avoid to use in immuno-compromised group

16 Summary of Prelim Consultation with Stakeholders on vaccination program(1)
Two Issues 1. LAIV or IIV 1.1 Pandemic situation need both types of vaccines(Supply/Production) 1.2 Updated road map for country use should be prepared by stakeholders to draft all possibility 1.3 Quality vaccines(registered) with scientific information has to be prepared and submitted/presented for approval 1.4 Need official approval from EPI committee at the end of consultation 1.5 Need National Integrated Work Plan for every parties 1.6 GMP and bio-safety compiled facilities : both pilot and industrial Capacity of LAIV production per batch or period of need. 1.7 For Seasonal LAIV/IIV : full and completed doc(Process, Efficacy) 1.8 Concern risk on the accessible of ca Premaster seed for LAIV

17 Summary of Prelim Consultation with Stakeholders on vaccination program(2)
1.9 Risk assessment of SPF / Clean Eggs 1.10 Environment risk assessment of LAIV 1.11 Applicators evaluation : droplet size vs efficacy 1.12 Plan for new technology of cell based to resolve SPF requirement 1.13 Industrial plant design for IIV, PLAIV but the implementation 1.14 Cost structure of LAIV and IIV

18 Inoculation with 0.2 ml WS which have 103.5 EID50/0.2 ml
Lab scale to Pilot scale process Embryonated eggs, days 11 R&D; 1) Egg Study : -To study pre-hatching and hatching condition of eggs laid from hens at different ages and flocks Candling (Before inoculation) R&D; 2) Seed lot system: -H1N1, H3N2, & B -To study method on preparation of master seed and working seed from original seed -To study duration time of seed stability for indicating holding time for working seed to be used in the inoculation process - To study kind of antibiotic for put them to inoculum Inoculation with 0.2 ml WS which have EID50/0.2 ml Incubation at 34oC for 48 h Post candling (After incubation)

19 Purification by Ultrafiltration
Lab scale to Pilot scale process Chill at 4oC, overnight Harvest infected ALF Centrifugation R&D; 3) Study of Pre-filtration : -To study pore size and material of pre-filter membrane for clarification process Pre-filtration R&D; 4) Study of ultrafiltration: -To study pore size of UF membrane and condition for purification and concentration process Purification by Ultrafiltration

20 Lab scale to Pilot scale process
Highly Purification by zonal ultracentrifugation R&D; 5) Study of splitting process: -To study optimal condition, i.e. concentration, duration, and temperature to obtain completed split influenza virus Diafiltration Splitting process by TritonX-100 Remove HA and NA from inner protein(Pelleting) by UC fix angle R&D; 6) Study of TritonX-100 Removal: -To choose the suitable media in order to remove TritonX-100 - To study appropriate condition for removal process TritonX-100 removal by Amberlite/UF

21 Lab scale to Pilot scale process
Inactivation by formaldehyde R&D; 7) Study of Inactivation : -To study time course, and concentration of formaldehyde for inactivation process Filtration for sterilization Formulation trivalent vaccine Filling Packaging

22 Key Achievement on IIV Jul 2007 … Jul 2008 Sep 2010 Feb 2011 Jun 2011
Apr-Aug 2012 (3) Technical Assistance from KAKETSUKEN BSL3 Pilot plant renovation With 1st grant support from WHO (1.996 million USD) (3.1) Lab study for process development Laboratory Process (3.2) Seed Preparation: H1N1 & Antiserum & Standard Ag Preparation: H1N1 (2) Successfully Developed Subunit IIV in Laboratory Scale (3.3) H1N1, H3N2 and B strains for TIIV Formulation & Pilot Process Optimization

23 CT phase III(Trivalent) (Safety & Immunogenicity)
Milestones of IIV Jul 2012 Sep 2012 Jun 2013 Jun 2014 4 … Mid 2015 Pilot production process Validation & Clinical lot Production Process optimization and Validation Non-Clinical Study Expected time for Vaccine Licensed with Thai FDA CT phase III(Trivalent) (Safety & Immunogenicity) CT phase I/II Feb 2013 May2014 Complete Process Validation with 3 consecutive lots End of Construction of Industrial Scale Plant IQ/OQ of equipments and facilities & Validation at Industrial Scale Plant

24 GPO Flu Vaccine Development under Six Critical Functions
GPO has to prepare our capacity on RD and Product Development according to NRA 6 functions Registration(Marketing Authorization): Dossier GMP Inspection: Facility+Utility+Equipment+Process Lot Release: Batch Production Record Lab testing: QC lab Clinical Study: for Human trial(PhaseI,II,III) Post Marketing Surveillance(AEFI): Phase IV

25 From Rafael Perez Cristia and Celeste Sanchez’s Presentation

26 อาคารระบบสนับสนุนส่วนกลาง
อาคารสัตว์ทดลอง อาคารประกันคุณภาพ อาคารผลิต อาคารบรรจุ อาคารระบบสนับสนุนส่วนกลาง ผู้ก่อสร้าง บ. stepwise ผู้ก่อสร้าง บ. M&W (THAILAND) Co.Ltd

27 Production Admin/QC Animal Filling Utility

28 ภาพรวมระยะเวลาในการดำเนินโครงการ

29 ขอบคุณครับ