Transcript 申报副研究员述职报告

Biopharmaceutical Industrialization and Quality
Requirements Research in China
Wang Jun Zhi (王军志） Ph. D
Deputy Director
National Institute for the Control of
Pharmaceutical & Biological Products
Outline
I. History of Biological Products in China
II. The managements of Biological products
in China.
III. The Progress of Biological Products in China
IV. Established National Quality Control System
for Biotech. Products
V . Developing Trends of Biotech. Products in China
and Challenges in Future
VI. Conclusion
I. Brief Introduction of History of Biological
Productsin China
Before 1949:
The research, production, and application of
biological products in China were since 1919.
Biological products developed slowly and in
small scale, only several kinds of biological
products before 1949.
Achievements during 55 years
Biological products have been developed rapidly. At
present time, China could produce more than 200 kinds of
biological products, and many new prophylaxis and
therapeutic biological products also are under the
development. ( Viral vaccines, Bacterial vaccines,
Antitoxins/Antisera, Blood products, DNA recombinant
products,Brobiotics, Diagnostic reagents.)
•
Before 1980 Almost biological products were produced
by six Biological research institutes . Among these
biological products, the output of bacterial vaccines were
up to 1 billion doses which could vaccinate the whole
nation.
• In the 1980’s,biological products industry was
booming in China, there are more than 200 enterprises
engaged in this field. Varieties, specifications of biological
products increased significantly in number.
• The wide scope of productions and application of
biological products in China are unique in the world .
Biological products play an important role in diseases
prevention, diagnosis and treatments.
• The production value of biological products in China have
achieved 4 billion RMB each year. Most of enterprises
achieved GMP certificates in order to keep quality of
biological products consistent with international level.
Prophylaxis is playing most important role in Chinese strategy
of public health . Vaccination was put in practice throughout the
whole country since People’s Republic of China was founded.
Incidence of a disease and death rate decreased significantly.
(Smallpox has been extinguished ; Poliomyelitis has not found case
infected by wild strain since 1995; In the area of using hepatitis B
vaccine the carriers decreased from 16% to 1% of the population ).
In the therapy aspect clinical application of biological products
have achieved significantly effects. Diagnostic reagents play an
important role in diseases monitoring, diagnosis, curative effect
observation because of its high sensitivity and specificity.
II. The managements of
Biological products in China
1.
Regulation
“The Drug Administration Law of the
People’s Republic of China”
•
•
•
Technical Regulation:
《Chinese Pharmacopoeia》2000、
《Requirements for Biologics of People’s Republic of
China》2000
other technical guidelines issued by SFDA
2、Organization
SFDA、
• NICPBP、
• CDE、
• The committee of Chinese pharmacopia, Experts
of committee
• The center of the validation (GMP,
GCP, GLP)
• ADR
SFDA
药品审评中心
Drug Evaluation Centre
NICPBP
Provincial or
Municipal
Inst. for Drug Control
药典委员会
Chinese Pharmacopeia Committee
Inst. for Import
Drug Control
3. Main Responsibilities
•
Registration and approval
• Technical supervision、
•
Quality Control
生物制品国家管理的6项基本职能
（Functions of national management of
Biologices WHO）
1.一整套有关疫苗和生物制品审批程序和审批标准的法
规文件 (Procedure and standard of documents for
approval)
2.审批结论应以临床试验数据为依据(Conclusion of
review should be basic on data of GCP)
3.对疫苗和生物制品的出厂销售实行国家批签发制度
(Lot release system for vaccine and biological)
4.应有对制品进行质量评价的实验室设施(The quality
control Lab. is necessary.)
5.对企业实施GMP的状况进行定期检查(The examination
of GMP in a period time)
6.对其有效性和不良反应进行上市后监测
(Implementation of ADR)
Legal basis of lot release
“The Drug Administration Law of the People’s
Republic of China”
“The Rules for the Implementation of the Drug
Administration Law”
“The Provision for Lot Release of Biological
Products”
The implementation of Lot Release in
China
Since December 31, 2001, lot release for
the 5 EPI vaccines (DTP, BCG, OPV,
rDNA HepB & Measles) and Human
Serum Albumin have being implemented.
WHO Collaborating Center for
Drug Quality Assurance
 To collaborate in the development of basis tests
(simplified methodology) for testing essential
drugs in the WHO program.
To coordinate the establishment of reference
substance for drugs.
To collaborate with WHO in research activities
on standardization of drugs,quality control and
development of methodology and techniques.
To accept trainees, requested by WHO.
Reference Materials Issues Of
Biologics In China
• Most of the reference materials for the
testing of biologics in China are available
(listed in the table about 150 ), only 14 are
not(listed below),some of which are under
preparation.
III. The Progress of Biotech
Products in China
Chinese government attached great importance to
biopharmaceutical industry. Biotech. Products research,
development and new drug production were all brought
into “863” and other national science and technology
projects.
The rhIFN-a1b was first gotten the approval in 1992.
Scientific research institutions, universities and
enterprises cooperated with each others are progressing
biotechnological research in different ways.
Following advanced world science and biotechnology
progresses, China had developed prophylaxis ,
therapeutic and diagnostic reagents products
successfully.
For example:
1) Prophylaxis Biological Products :HBV vaccine,
Cholera etc
2) Therapeutic Biological Products :IFN,Insulin,GH etc.
3) Diagnostic Reagents:HBV, HCV, HIV, Japanese
encephalitis, HCG, anti-A and anti-B blood grouping
reagents etc.
1. Marketed Recombinant Biological Products
in China
Cytokines：
•Interlukin-2: tumor chemotherapy
•Interferon(IFN-α1b,IFN-α2a,IFN-α2b,IFN-γ): hepatitis, tumor,
• Erythropoietin(EPO): nephridium anaemia,
•Granulocyte Colony Stimulating Factor(G- CSF): tumor
chemotherapy
• Granulocyte /Macrophage Colony Stimulating Factor(GMCSF):tumor chemotherapy
•Growth Factors：
•Epidermal growth factor（EGF）: burn;
•Basic fibroblast growth factor（bFGF） : burn;
激素 Hormone：
•胰岛素(Insulin )：糖尿病;
Insulin: diabetes ;
•生长激素(GH)：儿童侏儒征;
Growth hormone (GH)：dwardism;
酶 Enzyme：
•尿激酶(Pro-UK ) :溶血栓
Prourokinase（Pro-UK ）: thrombuslysis
•链激酶(SK):溶血栓
Streptokinase（SK ）:thrombuslysis
•葡激酶 (SAK ):溶血栓
Staphylokinase（SAK）:thrombuslysis
疫苗 Vaccine：
•乙肝疫苗 ：预防乙型肝炎;
Hepatitis B virus vaccine: Hepatitis B;
•双价痢疾杆菌疫苗：细菌性痢疾;
Shigella vaccine: bacteria diarrhea;
•轮状病毒疫苗:病毒性腹泻;
Rotavirus vaccine: virus diarrhea;
2. Gene Therapy Products in China
AAV-2/hFIX 因子基因转移治疗血友病 B
AAV-2/hFIX for HemophiliaB
腺病毒 P53 抗癌注射液
Adv-P53 for Tumor
血管内皮生长因子/肢体动脉梗塞病
Adv-VEGF for arterial block
批准 I 期临床研究
Phase I
批准生产
Marketed
V-erbB 反基因寡核苷酸硫代磷酸盐
V-erbB antisense for tumor
申请临床研究
IND
重组腺病毒胸苷激酶基因制剂
Adv-TK for tumor
批准 I 期临床研究
Phase II
重组腺病毒热休克蛋白制剂
Adv-Heat Shock Protein for tumor
批准 I 期临床研究
Phase I
重组腺病毒白细胞介素-2 制剂
Adv-Interleukin 2 for tumor
批准 I 期临床研究
Phase I
批准 I 期临床研究
Phase I
Somatic Cell Therapy Products in China
白细胞介素-2 基因工程人胃癌细胞瘤苗
Somatic cell +Interleukin2 vaccine for
gastric tumor
肝癌细胞和脾细胞融合肿瘤疫苗
gastric tumor cell and spleen cell fusion
vaccine for tumor
细胞因子诱导的杀伤细胞
Cytokines induced cytotoxic cell
免疫活性细胞治疗慢性乙肝
immunologically competent cell for chronic
hepatitis B
自体榄香烯-丝裂霉素 C 复合瘤苗
-mitomycin C fusion vaccine for tumor
批准临床研究
Phase I
批准临床研究
Phase I
批准临床研究
Phase I
批准临床研究
Phase I
申请临床研究
IND
3.
Biochips Approved in China
• 多肿瘤标志物蛋白芯片检测系统
Tumor Specific Antigen Diagnosis Chip
• 丙型肝炎病毒抗体片段检测试剂盒
Antibody Fragments of HCV virus Diagnosis Chip
• 幽门螺旋杆菌抗体蛋白芯片检测系统
Helicobacter pylori antibody Diagnosis Chip
• 人HPV，沙眼衣原体抗体检测系统
Human HPV, Diagnosis Chip
• 地中海贫血基因检测试剂盒
Thalassemia gene Diagnosis Chip
• SPGC-200型基因芯片
SPGC-200 Diagnosis Chip
Biochips Applied for IND
• 丙型肝炎病毒多抗体蛋白芯片检测试剂盒
HCV multi clone antibody diagnosis Chip
• 乙型肝炎病毒基因多态性检测芯片
HBV gene polymorphsim diagnosis Chip
• 乙型肝炎病毒DNA及拉米夫定耐药基因芯片检测试剂盒
HBV multi drug resistant gene diagnosis Chip
• 乙、丙型肝炎双检基因(诊断)芯片
HBV,HCV diagnosis Chip
• 结核多种抗原IgG抗体蛋白芯片检测系
Tuberculosis antigen IgG antibody diagnosis Chip
• 肌酸激酶同工酶、肌红蛋白、心肌肌钙蛋白I、高敏C反应蛋白检测系统
Creatine phosphate isozyme,Mb, cordis troponin I, hypersensitive Creactive protein diagnosis Chip
• SARS冠状病毒基因芯片检测试剂盒
SARS coronal virus gene diagnosis Chip
• HLA-DRB1基因分型芯片试剂盒
HLA-DRB1 gene diagnosis Chip
Pre clinical Biochips R&D
•SARS冠状病毒,甲型流感病毒,乙型流感病毒,肠道病毒核酸检测试剂盒
SARS coronal virus,influenza virus A,B,enteric virus diagnosis Chip
•HLA-DR分型基因芯片
HLA-DR diagnosis Chip
•泌尿生殖道感染基因芯片诊断试剂盒
Genitourinary infection diagnosis Chip
•唐氏综合症蛋白芯片检测试剂盒
Down’s syndrome diagnosis Chip
•TORCH蛋白芯片检测试剂盒
TORCH diagnosis Chip
•肝纤维化相关细胞因子蛋白芯片检测试剂盒
Hepatocirrhosis correlated cytokines diagnosis Chip
4. Effect of Marketed Chinese Biological
Products
1) Break the monopoly of imported biological products.
Due to development of Biotech. Products industry in China,
import biological products monopoly was broken.
It is good for public in China.
(1) Price of biological products decreased
significantly by competition in market, such as
interferon etc. More and more patients could afford
the drugs manufactured by top biotechnology .
(2) The rate of imported biological products decreased
continuously in recent years. (From 60% 1996 to
36% 2003). Local manufacture is one of the reasons.
2)、DNA recombinant drugs would become important
aspect in national medicine economy growth.
• Sale volume of IL-2 in China were 3 million to 4 million vials
each year, total sales were more than 100 million RMB per year.
• Sale volume of HBV vaccine was more than 70 million vials and
the tendency of HBV vaccine usage was still booming. 130
million in near future.
• 30 million patients suffer from diabetes in China,10% patients
were TypeⅠ diabetes who needed to use recombinant human
insulin successively and the therapy of 40% patients in the rest of
Type Ⅱ diabetes patients were insulin dependent.
3). Improved national medicine economy growth
Eight kinds of top 10 sale volume of Biotech. Products in world
could be produced in China. Sales volume increased reach 80%
each year, from 220 million RMB in 1996 to 2.3 billion RMB
in 2000.
In 2000, sales volume of genetics engineering products increased
21.6%, much higher than 12% of medicine industry annual
increase.
• One or two new Biotech. Products will get approval annually.
4. Improved competitive capability
• After decades development, China has narrowed the gap with
developed country which not only include the facility but also
in R&D technical level.
• We acquired experiences and trained a lot of technician skillful
of biotechnology through R&D practice of Biotech. Products,
which are basis of development in future.
IV.
Established National Quality
Control System for Biotech.
Products in China
R&D
Bulk Production Process
Effectiveness
Quality Control and Standard
IND
GCP
Approval
Safety Evaluation
NICPBP established a series of quality control methods and
requirements for biotech. products under the support of more
than ten national science and technology funds including
projects “863” project.
• These researches involved 6 speciesand more than 60 biological
products totally, including cytokines, gene therapy products,
humanization anti-body, genetic engineering vaccine, substitute
for blood, synthesized peptide etc. The 30 kinds of national
standards were also set up.
• The quality of biotech. products in market could be ensured by
means of using of the quality control system.
1.
Foundation of Biotech. Products Quality Control
Rebsearch
1). Domestic Guidelines
The Guideline for quality control of recombinant DNA
products
《Requirements For Biologics of PRC 》 2000)
《 Chinese Pharmacopoeia 》
《Good Practice in Manufacturing an Quality Control of
Drug,GMP 》
Other Technical Guidelines issued by SFDAbb
2). International Guidelines
Guidelines established by WHO, FDA, ICH, and U.S.
Pharmacopoeia, European Pharmacopoeia, etc.
2. The points of Quality Control of Biological
Products
1)、Quality Control of Raw Material
•
Quality control for host cell,such as bacteria,
yeast, mammal cell
• The form, origin, stability of cell bank.
• Genetic stability between vector and host cell.
• Describing the sequence of inserted gene and
control region in vector.
2) Quality control of host cell culture process
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•
•
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Seeds Lot—Master Cell Bank—Main Working
Cell Bank
Origin,storage of Seeds Lot.
Identification of Seeds Lot.
Sequencing of inserted DNA.
Mycoplasma,fungi,virus,other carcinogen
examination in seeds lot.
3) Quality control in purification process
•
Considering of removing virus, nucleic acid, host
cell protein, and other residue impurities.
• The purity and yield of products in each
purification steps.
4) Quality control of final products
（1）Physical and chemical character identification
1）Identification: electrophoresis mobility, Western b1ot ；
2） Purification: HPLC, non-reducing SDS-PAGE ;
3） Molecular Weight: reducing SDS-PAGE , MS;
4）pI: isoelectric electrophoresis,CE;
5 ） Peptide mapping: HPLC analysis after CNBr or trypsin
digestion
6） UV spectroscopy: UV scan;
7）N-terminal: Edman methods(15aa); C-terminal(1-3 aa)
（2） Bioassay/Specific bioassay （ IU/mg,U/mg）
（3）Impurities test
1） Host cell DNA residue:dot bolt ;
2) Host cell protein residue: Sandwich ELISA;
3) Murine IgG residue:Sandwich ELISA; murine IgG affinity
chromaography
purification
4）Bovine serum albumin residue:Indirect hemagglutination test
5） Endotoxin: LAL
6）Activity of antibiotics: diameter of bacterium inhibiting rings
7）Other impurities(such as ACN): gas chromatography;
8) Related products:HPLC;
（4）Safety test
1）Sterility test ：
2）pyrogen test ：
3）Abnormal toxicity test ：
3. Main achievements in Biotech. Products
Quality Control Research
1)
Established technique platform for quality control of
genetic engineering products . These quality control
researches involved more than 40 biological products
totally, including recombined EGF,bFGF,TNF αetc.
2) Established technique platform for quality control of viral
vectors gene therapy products. These researches including
quality control of Adv, AAV,Retrovirus, HSV vector etc.
Ⅱ. Quality control for viral vectors gene therapy
products: (especially Adv、AAV vectors)
80 nm
Adv
AAV
20 nm
1. Quality control for production cell lines
包括细菌、真菌、外源病毒等检查；细胞鉴别实验（遗传特征或指纹图谱）等;
The Identification and Determination of Bacteria,fungi, mycoplasma , etc in production
cell lines.
2. Identification
vectors
Capsid Identification
Gene Identification
Virus particle Purity
Virus particle
numbers/titer
of physical and chemical characters of viral
Adv vector
AAV vector
Serum Neutralization，UV SDS-PAGE
Electrophoresis
RestrictionEnzyme
mapping、Inserted
PCR
ssDNA Fragments PCR
Gene
Anion Exchange HPLC
Cation Exchange HPLC
UV、TCID50
Dot Blot
3)、 Established technique platform for quality control of
biochips.
These established technique platform for quality control
ensured the quality of domestic Biotech. Products identical
with international advanced level, also ensured the safety of
applications.
4). Established applicable methods and technique for
quality control
These methods all accorded with the advanced bioassay
system in the world, part of established assay methods were
firstly used in Biotech. Products quality control. The repetition,
reliability and accuracy of these innovative or improved methods
were identical with ICH, WHO and FDA criteria.
5).Research on national standard material
National standard substance prepared according to criteria of
international standard. We have developed 33 kinds of national
standard substance by stability evaluation and collaborative
determination,including SAK ,TNF α,etc.
Partial biologics standard substance authorized by SFDA
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•
•
•
•
•
•
•
•
•
•
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Recombinant human bFGF
9800 IU/vial
Recombinant bovine bFGF
7000 IU/vial
Recombinant human Interferonα
1000 IU/vial
Recombinant human IL-2
12000 IU/vial
Recombinant human TNFα
7500 IU/vial
Recombinant human EGF
400 IU/vial
Recombinant human G-CSF
2000 IU/vial
Recombinant human GM-CSF
3500 IU/vial
Recombinant human EPO
6800 IU/vial
Recombinant SK
5000000 IU/vial
Recombinant SAK
180000 IU/vial
Recombinant hepatitis B Vaccine
5.5 ug/vial
Implementation of
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GLP, GCP in China
Protect the safety,health,rights and interests of the trail subjects.
Ensure the safety & effectiveness of different drugs. ；
Ensure the reliability of preclinical & clinical data ；
Participate in international corporation,and promote Chinese
biological products to international market.
The safety & effectiveness evaluation of biological products
applied for IND were all followed GLP/GCP guidelines.
Over 10 Center for Safety Evaluation of Drugs in China have
passed GLP authorization ,and more will be in the future.
Developing Trends of Biotech. Products
in China and Challenges in Future
More and more new biopharmaceutical products
developed in China possessed independent patents.
Transform from imitate to innovation
Several Biotech. Products hotspots in 21century
1、The new Recombinant Protein drugs approved
to clinical trail continuously.
• More and more recombinant protein approved to
clinical trail,including hirudin , ANP, Endostatin,
cytokine-toxin fusion protein, AIDS therapeutic
vaccines, etc.
2 、DNA vaccines and antisense nucleic acid drugs
Animal test results of DNA vaccines and telomerase
antisense nucleic acid drugs were under the
development.
3 、 Recombinant human monoclonal antibodies
Cytokine antibody or cytokine receptor antagonist
were hotspot of arthritis therapy(Rheumatoid
arthritis),such as antibody of 4,6, TNF α,and
IL-1ra.
4、 Gene therapy products
•
Adv-P53 has been approved in China 2003, It is first gene
therapy product in market in the world. Over dozen
institutions are working on Adv,AAV vectors in China.
•
DNA vaccines for HIV therapy has applied for IND in
China,and China also participate in international corporations
for HIV therapy.
•
5. Other biological products
• Biochip products
• Tissue culture engineering & somatic cell therapy
products
• Nanotechnology Products
• Targeted biological products
• With the completion of human genomic plan(HGP),
more and more gene and control elements would be
discovered. Gene therapy would optimized at same time.
Therefore gene therapy will become the crucial aspect in
national Biotech. Products industry growth.
Conclusion
Biotechnology are hotspot and will be the
crucial aspect in national economy growth in
21century. After finishing of HGM, the more and
more new biotech products will be developed in
the market. In order to ensure safety, efficiency,
quality control . Therefore biopharmaceutical
industry improvements need government’s
support . It is well known that that the
international cooperation and communication are
necessary and also important. Biosafety problems
should be recognized during the development of
Biotechnology.
Thank you！