Biological Products

Chinese name:Biological product English name:biological product
Definition: A class of agents used for the diagnosis or prevention of diseases. That is, it can be prepared naturally or by using techniques such as genetic engineering and cell engineering to obtain various microorganisms, cells, animal and human tissue, and liquid and other biological materials.
Subjects: Immunology (a subject); Applied immunity (two subjects); Immune prevention (three subjects)

Biological products are prepared by using ordinary or biological materials obtained by biological techniques such as genetic engineering, cell engineering, protein engineering, and fermentation engineering, and cells and various animal and human tissues and liquids and biological materials for the prevention of human diseases. Treatment and diagnostic drugs. Biological products differ from general medical drugs in that they stimulate the body's immune system and produce immune substances (such as antibodies) to exert their effects. Humoral immunity, cellular immunity, or cell-mediated immunity occur in the human body.

Origin and Development In the 10th century, China invented the technique of vaccination and used smallpox vaccination to prevent smallpox, which was the origin of artificial autoimmunity to prevent infectious diseases. The vaccination not only reduced the condition but also reduced the death. In the 17th century, the Russians came to China to learn about acne, and then spread to Turkey, Britain, Japan, North Korea, Southeast Asian countries, and later to the Americas and Africa. In 1796, the British E. Jenner invented vaccination against cowpox to prevent smallpox. He vaccinated people with attenuated virus (vaccinia) to prevent virulent virus (smallpox) infection and prevent people from becoming smallpox.

This method is safe and effective, and it has quickly spread to all parts of the world. Vaccinia vaccine can be counted as the first safe and effective biological product. The development of microbiology and chemistry has promoted the research and production of biological products. In the middle of the 19th century, the concept of "immune" was basically formed. In 1885, the Frenchman L. Pasteur invented the rabies vaccine and artificially weakened the virus's ability to make it into a vaccine. When a person bitten by a rabies dog is given a vaccine in time, rabies can be avoided. Pasteur used the same method to make a live cholera vaccine or live anthrax vaccine. He changed the way he used to fight poisons to weaker systems. DE Salmon, HO Smith and others studied heat-inactivated vaccines and successfully developed inactivated vaccines such as typhoid and cholera. At the end of the 19th century, the Japanese, Shibuchi Saburo and the German, Behring, E. (A.), used chemical methods to treat diphtheria and tetanus toxins, which caused them to lose their pathogenicity after treatment. The sera of animals vaccinated and neutralized the corresponding toxins. This serum is called an antitoxin and this detoxified toxin is called a toxoid. R. Koch makes tuberculin to check whether the body has TB infection. The emergence of antigen-antibody reaction concept is helpful for clinical diagnosis. These laid the foundation for the development of microbiology and immunology, continue to develop various biological products, and become more and more important in the prevention of diseases. They are one of the indispensable means to control and eradicate infectious diseases.
China's Biological Products China's biological products business began in the early 20th century. In 1919, the Central Epidemic Prevention Service was established. This is China's first biological product research institute. It is a very small scale with only vaccinia vaccines and rabies vaccines. Several bactericidal vaccines, toxoids, and serums are crude products. After the founding of the People’s Republic of China, the Institute of Biological Products was established in Beijing, Shanghai, Wuhan, Chengdu, Changchun, and Lanzhou, and the Central (now China) Biological Products Verification Institute was established. It implemented national quality control and supervision of biological products. Dispensed strains and standard products. Later, the Institute of Medical Biology of the Chinese Academy of Medical Sciences was established in Kunming to produce polio vaccine. Biological products now have a huge production research team, and become the Center for Immunology Applied Research and Planned Immunity Science and Technology. Tang Feifan discovered the trachoma pathogen in 1957 and he made a great contribution to the Chinese biological product industry.

In the control and eradication of infectious diseases, the effectiveness of vaccination against biological products is significant, and the benefits are best in public health measures. This is not only a country or region, but also a worldwide measure. The World Health Organization (WHO) issued a declaration in 1966 proposing that the global eradication of smallpox within 10 years, and in 1980 officially announced that smallpox was destroyed on the earth. In 1978, the WHO made the Expanded Immunization Program (EPI), which aims to immunize children around the world. EPI uses four kinds of vaccines to prevent six diseases, namely BCG prevention of tuberculosis; measles live vaccines to prevent measles; polio vaccine to prevent polio; and Baidusan triple to prevent whooping cough, diphtheria and tetanus, systematically starting from children, Make children in the world immune. In 1981, China responded to the WHO's call to implement planned immunizations and to use domestically produced four vaccines as required to prevent six diseases. In 1988, 85% of vaccination coverage was achieved in the province. In counties in 1990, children reached an inoculation coverage of 85%. The increase in the number of diagnostic preparations and the improvement of methods have led to an increase in the diagnostic level of the test; it has been applied to sero-epidemiology and disease surveillance. China has been producing blood products for more than 30 years, and its varieties have increased year by year.
Modern Biological Products With the development of microbiology, immunology and molecular biology and other disciplines, biological products have changed traditional concepts. Microorganism structure, growth and reproduction, and infectious genes are also analyzed at the molecular level. Now, antigenic determinants in proteins can be identified, and they can be isolated and extracted to further synthesize peptide vaccines. The genetics of microorganisms have been further recognized. Artificial genes can be used for gene recombination, the desired antigen genes can be recombined into harmless and easy-to-cultivate microorganisms, their genetic characteristics can be modified, and the desired antigens can be produced during culture. This is called genetic engineering, and new vaccines can be developed. In the late 1970s, hybridomas emerged and hybridized with passaged tumor cells and antibody-producing spleen cells to obtain a hybridoma cell that can pass and secrete antibodies, and the antibodies produced are called monoclonal antibodies. One technique is cell engineering. These monoclonal antibodies can be widely used in diagnostic reagents, and some can also be used for treatment. The rapid advancement of science has made biological products no longer confined to preventing, treating, and diagnosing infectious diseases, but has expanded to non-communicable diseases, such as cardiovascular diseases and cancers, and has even broken through the scope of immune products. The Chinese biological product industry first proposed the concept of biological products, while some countries called it vaccinology.

According to the use of biological products, the classification can be divided into three categories: preventive biological products, therapeutic biological products, and diagnostic biological products.
Preventive biological products are used for the prevention of infectious diseases. Includes vaccines, toxoids, and gamma-globulins.

Vaccines are made from bacteria or viruses. In the past, China's biological product industry and the health and anti-epidemic community used to refer to bacterial preparations as bacterins. The virus preparation is called vaccine. Some countries call both vaccines. Toxoids can also be called vaccines. The vaccine is divided into live inactivated vaccines and live vaccines.
1 inactivated vaccine.
The preparation process is to first isolate the pathogenic bacteria or virus from the patient. After selection, the bacteria are cultured in an artificial medium, a large number of bacteria are harvested, and they are inactivated (killed) by physical or chemical methods. Its pathogenicity is preserved and its antigenicity is preserved (immune principle); viruses can only be cultured in vivo, such as replication in animals, chicken embryos or cell cultures. Viruses are harvested from these cultures, inactivated and made into vaccines.
2 live vaccines.
Refers to artificially attenuated attenuated or naturally non-toxic bacteria or viruses that are immunogenic and not pathogenic and are made by mass culture of harvested viruses or bacteria. A small amount of live vaccine, just inoculated once, can be in the body to achieve the immune effect of proliferation, and a large amount of inactivated vaccine, and the need to inoculate 2 to 3 times to achieve immune efficacy. Both have their own advantages and disadvantages. Vaccines can now be prepared by genetic recombination techniques, mainly for bacteria or viruses that cannot be artificially cultivated yet.
Exotoxins The toxic substances produced by some bacteria in the culture process are called exotoxins. Exotoxins lose their virulence after being chemically treated, while retaining the antigens, which are similar to toxins and have no virulence, are called toxoids, such as toxins. Cold toxins. Inoculation of the human body can produce the corresponding antibodies, and maintain disease-free.
Gamma-globulin is one of blood components and contains various antibodies. People inevitably suffer from some diseases in their lives, and the corresponding antibodies are present in the blood after recovery. The same is true for placental blood. In some infectious diseases, gamma globulin can be used as a preventive agent in the absence of a specific vaccine. Nowadays, blood donors are vaccinated with certain vaccines or toxoids to produce high-titer antibodies. The γ-globulin produced by them is called specific γ-globin, such as tetanus, rabies, and hepatitis B specific γ-globulin. Some people think that γ-globulin is a “supplement” and is used as a health care product. This is wrong.

Registration Category
1. Vaccines that have not been marketed domestically or abroad.

2. DNA vaccines.

3. The vaccine has been marketed and sold as an adjuvant for newer vaccines, and the carrier for the vaccine has been updated.

4. Change from a non-purified or whole cell (bacteria, virus, etc.) vaccine to a purified or component vaccine.

5. Use vaccines that have not been approved by the domestic strains (except influenza vaccines, Leptospira vaccines, etc.).

6. Vaccines that have been marketed abroad but not marketed domestically.

7. Use conjugate vaccines or combination vaccines prepared from domestically marketed vaccines.

8. Recombinant vaccines with different spectrum of vaccine protective antigens that have been marketed.

9. Replacement of vaccines that have other approved expression systems or that have been approved for cell matrix production; vaccines that have been prepared using new processes and that have laboratory studies that demonstrate a significant increase in product safety and efficacy.

10. Change the vaccine for inactivating agents (methods) or detoxification agents (methods).

11. Change the route of administration of the vaccine.

12. Change the dosage forms of vaccines that have been marketed domestically but do not change the route of administration of vaccines.

13. Change vaccine dose or immunization program.

14. Expand the use of vaccines in the population (increased age group).

15. There is a national drug standard vaccine.
Therapeutic biological products include various blood preparations, immunological preparations such as interferons. According to the therapeutic mechanism can be divided into specific (such as antitoxin and γ-globulin) and non-specific (such as interferon and human albumin, etc.). Clinicians will use anti-toxins and gamma-globulins as conventional therapeutic drugs, and they actually have a preventive effect. Blood preparations account for a very large proportion of therapeutic biological products. There are more than 50 blood preparations being produced and under development in China. Some monoclonal antibodies have been used for treatment. Some components in the blood with low levels are integrated into microbial genes and can be produced in large quantities, such as □. The main biologics for prevention and treatment are listed in the main biological products for prevention and treatment

Registration Category:
1. Biological products that have not been marketed domestically or abroad.

2. Monoclonal antibodies.

3. Gene therapy, somatic cell therapy and its products.

4. Allergen products.

5. Bioactive multicomponent products extracted from human, animal tissue or body fluids, or prepared by fermentation.

6. The new compound product is composed of the biological products that have been marketed and sold.

7. Biological products that have been listed on foreign markets but have not been marketed domestically.

8. Microecological products containing unapproved strains.

9. Products that are not identical to the structure of products that have been marketed and are not marketed at home and abroad (including mutations and deletions of amino acid sites, generation, elimination, or modification of post-translational modifications due to different expression systems, chemical modification of products, etc.) .

10. Articles that are different from the methods of preparation of products that have been marketed (for example, using different expression systems, host cells, etc.).

11. Products prepared using DNA recombination technology for the first time (for example, recombinant technology instead of synthetic technology, biological tissue extraction or fermentation technology, etc.).

12. Products that have not been marketed at home or abroad have been changed from non-injection to injection, or from topical to systemic.

13. Change the dosage forms of products that have been marketed but do not alter the route of administration of the biologics.

14. Biologics that alter the route of administration (not including the 12 items above).

15. Biological products that already have national drug standards.
Diagnostic use of biological products are mostly used to detect the corresponding antigen, antibody or organism immune status, belonging to the diagnosis of immunological methods. With the development of immunological techniques, the number of types of diagnostic biological products is increasing, not only for infectious diseases but also for other diseases. There are two main categories: 1 Diagnostic sera, including bacteria, viral rickettsia, antitoxins, tumors, hormones, blood group and HLA, immunoglobulin diagnostic serum, transferrin, erythrolysin, biochemicals Wait. 2 Diagnostic antigens include bacteria, rickettsia, toxins, syphilis diagnostic antigens, and plague bacteriophages. In addition, there are red blood cells, fluorescent antibodies, enzymatically labeled enzyme preparations, radionuclide labeled radioimmunochemicals, pregnancy diagnostics (hormones), and diagnostic monoclonal antibodies.

The application is divided into three aspects: prevention, treatment and diagnosis.
The invention of vaccines (including toxoids) was designed to prevent infectious diseases. Most of the infectious diseases have vaccines. According to the characteristics of various infectious diseases, the source of infection, and the mode of transmission, there are the following vaccines for prevention:

1 Eradicate the vaccine against infectious diseases. Some human infectious disease pathogens do not have intermediate hosts, and it is possible to highly immunize people with vaccines so that the pathogens cannot be transmitted in the human population and eventually eliminated, such as smallpox has been eliminated. After measles and polio vaccines are highly immunized, they may be completely eliminated.

2 Protect the population's vaccine. Such as Chinese JE vaccine, hepatitis B vaccine, influenza polysaccharide vaccine, meningitis polysaccharide vaccine, BCG and so on. For example, infectious diseases with insects as intermediate hosts are often difficult to eradicate their source of infection, but when the population reaches a certain level of immunity, that is, when the coverage rate of vaccination of vulnerable groups reaches 85% or more, the epidemic can be controlled. Although a small number of people in the population are not vaccinated, they can also be protected because the population has sufficient immunity to block the source of infection.

3 Global and localized or regional infectious disease vaccines. For typhoid fever, cholera, plague, forest encephalitis, yellow fever, typhus and other diseases, vaccine immunity is targeted in the population, such as epidemic populations, vulnerable populations in the often-occurring areas for universal vaccination.

4 Protect the individual's vaccine. Some diseases only infect certain types of people, or some people are infected with certain diseases. They are very dangerous. For example, influenza is a frail to older people, and varicella virus is a frail child in wards. Such vaccines include multivalent inactivated influenza vaccines, varicella vaccines, pneumococcal polysaccharide vaccines, and streptococcal vaccines.

5 Vaccine to control congenital diseases. Such as rubella live vaccine. The rubella virus does not cause much harm to the affected person, but if the pregnant woman is infected, it can invade the fetus in the uterus and cause congenital malformations of the newborn.

6 Have vaccines for people who are at risk of certain infectious diseases. If exposed to rabies or to the affected area, the vaccine should be vaccinated. There is no yellow fever in China, but personnel going to Africa and South America must be vaccinated against yellow fever. Vaccine preparations contain antigens. After inoculation, the body stimulates the cells of the immune system to produce humoral or cellular immunity to prevent the infection of the corresponding pathogens. This kind of immunity is called autoimmune. Gamma-globulin (including some antitoxins) is a preventive antibody that does not infect patients after injection. This type of immunity is called passive immunity. Due to the body's metabolism, the half-life of the injected antibody is very short and disappears within 1 to 2 weeks, but its advantage is that it takes effect quickly. The use of various vaccines has a certain target, and different vaccines have different routes of inoculation. Inoculation methods include muscle, subcutaneous, intradermal, and skin scratches; oral administration of sugar pills, capsules, or liquids; aerosol aerosol aerosolization (such as mumps live vaccines), nasal spray (such as flu vaccines). In general, a larger concentration of vaccine should be administered intramuscularly or deep subcutaneously. If a subcutaneous layer is injected, a lump or sterile pus may appear locally. Skin scratch vaccine is not injectable. Intradermal vaccines are used in small quantities, but some may have strong reactions and some have poor persistence of immunity. Oral vaccines are simple and ideal. Only polio vaccines and oral BCG vaccines are routinely used. Oral typhoid vaccines, oral dysentery and cholera vaccines are being developed. Biological products for treatment include various blood preparations, antitoxins and other immunological preparations. According to its mechanism of action can be divided into specific immunotherapy and non-specific treatment. The former include various antitoxins and specific gamma globulin; the latter include interferons, transfer factors, albumin, and the like. Blood preparation refers to a variety of effective blood components made from healthy people or placental blood after purification. Each ingredient has its unique physiological properties. For patients, except for a large number of blood loss patients, the vast majority need only one or more components. For example, patients with hemophilia A only have deficiency factors, and supplementation with â–¡ factors can meet their needs. This saves blood, Can improve the efficacy. Plasma can replace whole blood function and albumin can replace plasma. In addition to the use of gamma globulin in the prevention and treatment of certain infectious diseases, it can also be used to treat gamma-globulin deficiency. Interferon has a wide spectrum of anti-virus, anti-tumor growth, regulating the body's immune response and other substances activity, is one of the immune response media. Transfer factors are important mediators in cellular immunity and can activate cellular immune responses. Any disease caused by low cellular immunity can be used. Transfer factors can also be anti-infective (enhance cellular immune function) and can be used to treat malignant tumors and autoimmune diseases.
Diagnosis of biological products used for diagnosis can be divided into the following categories:

1 In vivo test for diagnostic preparations. Commonly used are brucedin, tuberculin and Sikh test toxin (diphtheria) three, intradermal injection of 0.1ml, observe the reaction, to determine whether the corresponding disease or immunization success.

2 General diagnostic agents for infectious diseases. Includes various diagnostic broths, virus fluids, and diagnostic sera.

3 diagnosis of tumor preparations. Such as alpha fetoprotein serum, carcinoembryonic antigen diagnostic kit.

4 Determination of immune levels of diagnostic preparations. Determination of the five immunoglobulins (IgG, IgA, IgM, IgD, IgE) in the human body, and the use of Ig monovalent diagnostic serum and patient serum for quantitative determination for disease diagnosis, treatment, and determination of immune function. Clinical diagnosis of certain diseases is an important indicator.

5 Hormone diagnostic preparations. Such as pregnancy diagnosis preparations. Adverse reactions may cause adverse reactions after the use of biological products. This is in contrast to the product strain species, type, antigen concentration, culture medium used, inactivation or attenuating process, adjuvant, protective agent, recipient individual differences, age , gender, vaccination history, history of infectious diseases, passive access to antibodies and other factors. Common reactions to vaccination and toxoids, such as toxic reactions caused by bacterial endotoxins, can cause fever and localized swelling, pain, and thermal inflammatory reactions in all bacterial preparations and generally occur within 48 hours of inoculation. The purified toxoid and viral vaccines are generally mildly reactive. Live vaccines actually produce a mild infection after vaccination. There are often days or longer incubation periods before live bacteria or viruses proliferate to cause fever or other reactions. These infections are often accompanied by low fever, and some have rashes. , swollen lymph nodes and so on.
Bacterial Polysaccharides Vaccines Bacterial polysaccharide vaccines are used to extract effective antigen components and remove endotoxins. The reactions are also mild. The major adverse reaction caused by the antitoxin prepared from horse serum is serum disease. Nowadays, products are refined and purified, reactions are reduced, and human blood preparations overcome heterosexual protein reactions. The reaction of these products is sometimes accompanied by fever, urticaria, asthma, a few occasional transient blood pressure reduction, anaphylactic shock and angioedema are rare, interferon and other treatment immune preparations, the reaction is similar to the vaccine, the response is slight.