Transcript Name of presentation

How to Succeed in vaccine
Manufacturing in China
Liaoning Cheng Da Biotechnology Co.,Ltd,
Shenyang ,China
Content
I Vaccine market in China
II Vaccine strategy of CDBIO
III Government support on vaccine manufacturer
IV Sales and Marketing
I Vaccine Market in China
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
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.
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
Competitive Landscape II
Note: X% represents the share of lot release of respective products
in 2011 for Category II Vaccines
II Strategy of CDBIO to enter into
vaccine market
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
Introduction
CDBIO
180
160
140
120
100
80
60
40
20
0
PD
QA
PD: Production Dept
QC
RD
SD
Others
QA: Quality Assurance Dept QC: Quality Control Dept
RD: Research and Development Dept
10
SD: Sales Dept
Responsible
CDBIO Introduction
CDBIO Introduction
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.
• 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
Technology form in China
•
In 2002 ,the major technology for rabies vaccine manufacturing in China
Type of
Company
Cell culture technology
Purification method
Whether adding
Antibiotics
Residual Host cell
DNA
MNC type 1
Vero cell by large scale
fermentor
Centrifugation
Adding
Less than 10 ng
MNC Type 2
Chicken Embryo cell
culture
Centrifugation
Adding
No requirement
LC 1
Vero cell by roller bottle
Centrifugation
Adding
Less than 10 ng
LC 2
PHK cell by roller bottle
Centrifugation
Adding
Less than 10 ng
CDBIO
Perfusion Vero cell
culture by Bioreactor
Chromatography
No
Less than 0.1 ng
(100pg)
MNC: Multinational companies
L C : Local companies
Technology transfer
 Program to be Established
In June 2002, CDBIO signed a 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.
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.
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 .
Filling line
Washing machine
Quality standards
Item
CDBIO’s Standards
WHO’s Standards
Sterile test
Negative
Negative
Inactivation test
The total mice were alive on day 14
after inoculation
Same as NRA’s requirement
Residual BSA
 50ng/dose
 50ng/dose
Abnormal toxicity
All the test animals are alive and their
weights are also increased.
Same as NRA’s requirement
Potency test
≥ 4.5 IU/dose (Ex work)
≥ 2.5 IU/dose
Residual DNA
 100 pg/dose
 10 ng/dose
Endotoxin
 50 EU/dose
Same as NRA’s requirement
Thermal stability test
(37℃ for 4 weeks)
≥2.5 IU/dose
≥2.5 IU/dose
Identity test
NIH test
NIH test
pH
7.2~8.0
Same as NRA’s requirement
Moisture content
 3.0%
 3.0%
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
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 .
Quality standards
Items
Appearance
Standards
The Vaccine looks like a white crisp cake. The reconstituted
vaccine is a clear liquid, free of foreign matters
Identification
Same as potency test
pH
7.2 – 8.0
Moisture Content
≤ 3.0%
Residual Vero cell DNA
<100pg/dose
Residual Bovine Serum Albumin
Content
≤ 30 ng/dose
Sterility
Should be sterile
Abnormal Toxicity
All animals should survive the observation period and with
increase of body weight
Bacterial Endotoxin
≤ 25 EU/dose
Potency Test
Not less than the reference vaccine
Residual Protein Content of Vero Cell
≤ 1 μg/dose
• III Government support for vaccine
manufacturers
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 .
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 .
IV Sales and marketing
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 .
Sales condition of SPEEDA
Million dose
50
40
30
20
10
0
Sr.1
year
2005
2006
2007
2008
2009
2010
2011
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.
1. Geometric mean titer (GMT) in
Pre-exposure vaccination
Day 42
Age
20～
40～
No.
Patients
27
32
Sero-conversion Rate
(%)
100.00
100.00
GMT
（IU/ml）
95% CI
14.03
11.53～16.53
17.19
12.12～22.26
15.7
12.8～18.6
100.00
Total
59
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
2. Geometric mean titer (GMT) in
post-exposure vaccination
Chin J Biologicals April 2008,Vol. 21 No.4
No.
93 volunteers
(Negative
antibody level
in Day 0)
DAY 0
DAY 3
DAY 7
DAY 14
DAY 45
GMT
（IU/ml）
≤0.11
≤0.11
2.12
8.52
15.43
Seroconversion
（%）
-
0%
22.8%
100%
100%
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
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
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
GMTs and range of titers of Nab
to rabies virus
Rabies vaccination with
TRC-ID
GMTs of rabies Nab titers (IU/ml) on days (range)
D0
D7
D14
D28
D90
Group A: SPEEDA
without ERIG (n=30)
Neg
< 0.5
12.69
(2.18-49.35)
6.03
6.95*
(1.35-33.42) (2.00-22.63)
Group B: VERORAB
without ERIG (n=31)
Neg
< 0.5
8.97
(1.09-28.10)
4.58
2.73
(1.61-13.45) (0.50-8.72)
Group C: SPEEDA
with ERIG (n=33)
Neg
< 0.5
9.98**
6.95**
2.84**
(1.14–69.79) (0.74-49.35) (1.09-20.75)
Group D:VERORAB
with ERIG
(n=20)
Neg
< 0.5
4.36
(0.62-19.87)
2.67
1.18
(0.40-16.00) (0.35-7.34)
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
Evolution of antibodies
Potency:
SPEEDA:6.4IU/dose
VERORAB:10.6 IU/dose
Nab titer ( IU/mL)
14
12
10
Group A: SPEEDA
Group B: VERORAB
Group C: SPEEDA plus ERIG
Group D: VERORAB plusERIG
* p<0.05 ( A&B )
** p<0.05 ( C & D )
**
8
**
6
4
*
**
2
<0.5
0
0
7
14
28
90
180
360
Day after
vaccination
Figure 1 GMTs of Nab to rabies virus for subjects who received either SPEEDA
(group A and C) or VERORAB (group B and D)
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
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 .
Local reaction
Vaccination
From 2005.06 No.
To 2006.05
Total
Total ratio
65146
1.65%
Systematic reaction
Pain
Itch
Induration
Fever
Tetter
Debilitation
486
166
53
284
17
66
0.75%
0.25%
0.08%
0.44%
0.03%
0.10%
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.
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
Subject PRNT50 >1/10 After JEVACTM
Vaccination (Sero protection)
%
100
100
100
100
5/152
1 month
Day 0
D7-28
1 year
1 year 1 month
D365
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
GMT of 3 Doses of JEVAC
GMT
D0
D7-28
D365
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
Experience to share
• How to succeed on vaccine
manufacturing ?
• Market Choosing
• Correct strategy
• Advanced technology
• Good quality of the product