How to Succeed in vaccine Manufacturing in China

1. How to Succeed in vaccine Manufacturing in China Liaoning Cheng Da Biotechnology Co.,Ltd, Shenyang ,China

2. Content I Vaccine market in China II Vaccine strategy of CDBIO III Government support on vaccine manufacturer IV Sales and Marketing

3. I Vaccine Market in China

4. Vaccine Manufacturer Manufacturers There are 35 local manufacturers which produce more than 40 kinds of vaccines against 26 kinds of diseases ,the biggest manufacturer is China National Biological Group (CNBG),it is a central government owned company which produce almost all kinds of vaccines licensed in China. Additionally, 5 multinational companies are also existing in Chinese market which mainly sell the imported vaccine ,recently , three of them(Sanofi ,GSK and Novatis) have become local companies through direct invest /acquisition or Joint venture

5. Market Size • The total market for human vaccine in China is around 2.7 billion USD in 2011 , the category I * vaccine are around 0.9 billion while the category II** vaccine are 1.8 billion USD. 2011 Vaccine Market Share By Lot Release Volume in China Total = 0.9 Bn doses * Category I vaccines cover all vaccines within the EPI, free and compulsary immunization ; **Category II vaccines cover non-EPI vaccines, need to pay and not compulsary immunization.

6. Competitive Landscape I Note: X% represents the share of lot release of respective products in 2011 for Category I Vaccines Source : National Institutes for Food and Drug Control ,China

7. Competitive Landscape II Note: X% represents the share of lot release of respective products in 2011 for Category II Vaccines

8. II Strategy of CDBIO to enter into vaccine market

9. Introduction CDBIO • CDBIO was established in 2002 , Jointly invested by Liaoning Cheng Da Co., Ltd and Liaoning Bio-Medical Equipment Institute, it is a research-driven company which mainly focuses on manufacturing and marketing of biological and pharmaceutical products. • There are over 600 employees in CDBIO, 50% of them holding bachelor degree,54 of them holding master and doctor degree. The staff who participates in production and quality management are well trained of current GMP

10. Introduction CDBIO PD: Production Dept QA: Quality Assurance Dept QC: Quality Control Dept RD: Research and Development Dept SD: Sales Dept Responsible for life

11. CDBIO Introduction

12. CDBIO Introduction

13. Project selection • In China , the category I vaccine market is almost shared by CNBG and Tiantan Bio*, and for this category, it is purchased by central government through tenders; • For category II vaccine , it is directly purchase by CDC or hospital according to the actual need of patients , the other manufacturers, including the multinational companies, are mainly competing on this market . • Under the circumstance , Why rabies vaccine was selected by CDBIO as the first project? *TianTan Bio is a public company ,which also belong to CNBG.

14. In 2002(when CDBIO established) ,there are around 15 local manufacturers and 2 Multinational companies enrolled in rabies vaccine market , and the market size for the vaccine is around 50-60 million doses /year ,it was very competitive but huge market. • After market analysis ,the management of CDBIO thought there were still good chance to enter into this market as our partner has more advanced technology than the other competitors . • The technology is developed in1984 by world Health Organization and the Rockefeller Foundation ,it is finally succeeded in 1999.This technology is based on the perfusion Vero cell culture on high density microcarriers in bioreactors

15. Technology form in China • In 2002 ,the major technology for rabies vaccine manufacturing in China MNC: Multinational companies L C : Local companies

16. Technology transfer • Program to be Established In June 2002, CDBIO signeda contract with BARI consulting Corp. to produce rabies vaccine by using high density microcarriers in bioreactor. • Cooperate Research In June the same year, a R&D team was organized. The PV-2061, fixed rabies virus and Vero cell were respectively obtained from CDC of USA and ATCC. The specialists under the lead of Dr. Aycardi began to teach the related technology to us. Meanwhile, the constructing of factory was in plan. • Sample testing by NCL In June 2003, after succeeding on a pilot scale, we officially applied to SFDA for the approval. The clinical trials has been carried out. • Training for Production In the early 2004, the new coming staff were well trained. At the same time, the manufacture of commercial batches has been started . • Product on Market In May ,2005 , the product was approved by SFDA and launched in the market.

17. Bioreactor for perfusion cell culture Perfusion cell culture technology can 1. Provide enough medium nutrition for the Vero cell growth to reduce the cell broken ; 2.Keepcontinuously virus harvest to insure the batch consistency; 3. Provide closed pipeline during the whole production process to avoid contamination instead of adding antibiotics.

18. Column Chromatography System Four series column chromatography system can remove more than 99.9% impurities such as residual Vero cell DNA , Bovine serum etc. CDBIO is the first company to use the four column chromatography system for the commercial manufacturing in China .

19. Filling line Washing machine

20. Quality standards

21. Potency result 360 batches of potency result from year 2005- 2010,all the result are more than 4.5IU/dose, and the average value is 6.7IU/dose Potency :IU No. of Batches 360

22. Japanese encephalitis vaccine • China is Japanese encephalitis(JE) epidemic country , and the major vaccine used for the JE prevention is live attenuated vaccine which produced base on PHK cells . The vaccine has good immunogenicity but has the potential risk to use on epidemic season or immunodeficiency people . • With the same technology platform , CDBIO started the development of new generation of inactivated JE vaccine produced on Vero cell to replace the live vaccine ,in 2008 , the “Green” Inactivated JE vaccine was approved by SFDA . The new JE vaccine is only formulated with human serum albumin and dextran 40 as stabilizer , free of thiomersal , adjuvant and antibiotics .

23. Quality standards

24. III Government support for vaccine manufacturers

25. Lands • Usually , the local government will supply the industrial land to vaccine manufacturer at low cost , and the land will be only used for the R&D and manufacture of vaccines . • The price of the land depend on the different policy of each provinces /cities .

26. Financial • 1 Scientific research • For each research of new product , there will be one time research fund from central and local government. • 2. Interest • The local government will provide some loans free of interest , but it depend on companies operation situation /project construction . • Tax • The tax rate for vaccine manufacture is lower than the normal rate .

27. IV Sales and marketing

28. SPEEDA -chromatographically purified Vero cell rabies vaccine • The first product –SPEEDA was launched in May ,2005 ,it is the first rabies vaccine which get the Lot release certificate from National institute for Control of Pharmaceutical and Biological Products (NICPBP) ,China . • Till 2011 , SPEEDA was sold in 20 countries with the quantity more than 100 million doses , and there is no immunization failure case reported after finishing the full schedule, its immunogenicity and safety are well accepted by the doctors .

29. Sales condition of SPEEDA Million dose year

30. Clinical data • After launch of SPEEDA since 2005 , CDBIO has conducted a series of clinical trials/PMS to observe the safety and immunogenicity of the product at different institutes /hospitals / CDCs , the trials including : • 1. Pre-exposure vaccination (IM route on day 0,7 and 28) • 2. Post-exposure treatment (Essen regimen by IM route), • 3. Post-exposure treatment( 2-1-1 regimen by IM route) , • 4. Simulated Post –exposure treatment ( Modified TRCS regimen by ID route) • 5. Post market surveillance in 26 clinics in China.

31. 1. Geometric mean titer (GMT) in Pre-exposure vaccination Regimen : 3 doses on day 0,7,28 by intramuscular route Test Method of GMT : Rapid fluorescent focus inhibition test (REFIT) Research institute : Center for Disease Control ,Zhejiang province

32. 2. Geometric mean titer (GMT) in post-exposure vaccination Chin J Biologicals April 2008,Vol. 21 No.4 Regimen : 5 doses on day 0,3,7,14,28 by intramuscular route Test Method of GMT : Rapid fluorescent focus inhibition test (REFIT) Research institute : Center for Disease Control ,Guangdong province

33. 3. Geometric mean titer (GMT) of Zegrab(2-1-1) regimen Human Vaccines 7:2, 220-224; February 2011; . 2011 Landes Bioscience Regimen : 4 doses(2-1-1) on day 0,3,7,14,28 by intramuscular route Test Method of GMT : Rapid fluorescent focus inhibition test (REFIT) Research institute : Center for Disease Control and prevention ,Guangdong province

34. 4. Intradermal Clinical Study of SPEEDA in Thailand by Thai Red Cross Society ,QSMI Seventy healthy volunteers were enrolled into the study. All volunteer subjects were randomly allocated into two groups to receive rabies vaccinations with modified TRC-ID regimen with two distinct kinds of vaccines. Subjects in group I (n=35) received chromatographically purified Vero cell rabies vaccine (Speeda®), Lot no. 200904012-3 of potency 6.4 IU/dose. Subjects in group II (n=35) received purified Vero cell rabies vaccine (Verorab®), Lot no.D0998 of potency 10.6 IU/dose. Blood samples were taken before vaccination on day 0 then day 7, 14, 28, 90, 180 and 360 afterward for serological analysis of rabies neutralizing antibody titers (RNab titers) by the rapid fluorescent focus inhibition test (RFFIT). Tantawichien T, Sibunruang S, Tantawichien T, Limsuwan L. A new chromatographically purified Vero cell rabies vaccine: results of a comparative trial with purified Vero cell rabies vaccine in intradermal post-exposure treatment. Poster presentation ECCMID 2012; London, England

35. GMTs and range of titers of Nab to rabies virus Tantawichien T, Sibunruang S, Tantawichien T, Limsuwan L. A new chromatographically purified Vero cell rabies vaccine: results of a comparative trial with purified Vero cell rabies vaccine in intradermal post-exposure treatment. Poster presentation ECCMID 2012; London, England

36. Evolution of antibodies Tantawichien T, Sibunruang S, Tantawichien T, Limsuwan L. A new chromatographically purified Vero cell rabies vaccine: results of a comparative trial with purified Vero cell rabies vaccine in intradermal post-exposure treatment. Poster presentation ECCMID 2012; London, England

37. 5.Post market surveillance • The PMS of SPEEDA was conducted in 26 clinics from 2005-2006 , totally 65146 cases were enrolled in the observation ,1072 cases of AEFI were reported , the result showed that SPEEDA has good safety after vaccination .

38. JEVAC-Inactivated Japanese Encephalitis vaccine (Vero cell) • The second product –JEVAC , Inactivated Japanese Encephalitis vaccine was launched in 2009 , and it quickly become the first choice for JE prevent in category II market ,more than 4 millions doses were sold in China. • As JEVAC is free of antibiotics ,adjuvant and especially thiomersal ,which highly preferred for the children vaccination . According to the clinical report and post marketing surveillance data , the result can reach a satisfied level on both efficacy and safety after vaccination.

39. Clinical report Research Institute : Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, Thailand Subjects: 152 healthy Thai children aged 1-3 years ,without history of JE vaccination Regimen : Received 3 doses of JEVACTM D0, 7-28, 365 Test method: JEV neutralizing antibodies by PRNT at Center for Vaccine Development, Mahidol University. Observation period: Adverse events 28 d after each vaccination and SAEs throughout the study Chanthavanich P, Limkittikul K, Sirivitchayakul C, et al. Immunogenicity and safety of inactivated chromatographically purified Vero cell derived Japanese encephalitis vaccine in Thai Children. Symposium: Vaccine Preventable Encephalitis. PIDST, 2012 Thailand

40. Subject PRNT50 >1/10 After JEVACTM Vaccination (Sero protection) % 100 100 100 100 5/152 1 month 1 year 1 year 1 month Chanthavanich P, Limkittikul K, Sirivitchayakul C, et al. Immunogenicity and safety of inactivated chromatographically purified Vero cell derived Japanese encephalitis vaccine in Thai Children. Symposium: Vaccine Preventable Encephalitis. PIDST, 2012 Thailand Day 0 D7-28 D365

41. GMT of 3 Doses of JEVAC GMT Chanthavanich P, Limkittikul K, Sirivitchayakul C, et al. Immunogenicity and safety of inactivated chromatographically purified Vero cell derived Japanese encephalitis vaccine in Thai Children. Symposium: Vaccine Preventable Encephalitis. PIDST, 2012 Thailand D0 D7-28 D365

42. Experience to share How to succeed on vaccine manufacturing ? Market Choosing Correct strategy Advanced technology Good quality of the product

43. Thank You !