About Huatai United Securities Co., Ltd
Hualan Biological Engineering Inc(002007) recommendation letter for stock listing of vaccine Co., Ltd
Shenzhen Stock Exchange:
As a sponsor of Hualan Biological Engineering Inc(002007) vaccine Co., Ltd. (hereinafter referred to as the “issuer”, “company” and “Hualan vaccine”) for initial public offering and listing on the gem, Huatai United Securities Co., Ltd. and its sponsor representatives have Measures for the administration of securities issuance and listing recommendation business, measures for the administration of the registration of initial public offerings on the gem (for Trial Implementation) (hereinafter referred to as the “administrative measures”), rules for the listing of shares on the gem of Shenzhen Stock Exchange (hereinafter referred to as the “listing rules”) Laws and regulations such as the Shenzhen Stock Exchange gem stock issuance and listing review rules and the relevant provisions of the CSRC and Shenzhen Stock Exchange are honest, trustworthy, diligent and responsible, issue the listing recommendation letter in strict accordance with the business rules and industry self-discipline norms formulated according to law, and ensure that the documents issued are true, accurate and complete.
The relevant information is reported as follows: I. Basic information of the issuer (I) overview of the issuer
Name of issuer: Hualan Biological Engineering Inc(002007) vaccine Co., Ltd
Registered address: No. a-1-1, Hualan Avenue, Xinxiang City, Henan Province
Date of establishment: November 9, 2005
Registered capital: 360 million yuan
Legal representative: Ankang
Contact: 0373-3559909
Business scope: producing all kinds of vaccines, genetic engineering biological products and selling self-produced products.
(II) the issuer’s main business, core technology and R & D level
1. Main business of the issuer
Hualan vaccine is a high-tech enterprise specializing in the R & D, production and sales of human vaccines. As of the issuance date of this listing recommendation letter, Hualan vaccine’s listed products mainly include influenza virus split vaccine, tetravalent influenza virus split vaccine, influenza A H1N1 virus split vaccine, recombinant hepatitis B vaccine (Hansen’s yeast), acyw135 group meningococcal polysaccharide vaccine, group a group C meningococcal polysaccharide vaccine, etc; The products that have been approved for clinical trial or have passed clinical registration and listing mainly include human rabies vaccine (Vero cell), adsorbed tetanus vaccine, lyophilized group A and group C meningococcal conjugate vaccine, h7n9 influenza virus cleavage vaccine, h7n9 influenza whole virus inactivated vaccine, adsorbed acellular hundred (three component) white break conjugate vaccine, etc; In the preclinical research stage, the products include New Coronavirus inactivated vaccine (Vero cell), recombinant coronavirus pneumonia vaccine (recombinant human adenovirus vector 5), freeze-dried nasal spray and recombinant New Coronavirus attenuated live vaccine. The product layout covers influenza, epidemic meningitis, hepatitis B, rabies, pertussis, diphtheria and tetanus.
The company has a vaccine production base designed and constructed in strict accordance with GMP specifications. It has successively participated in the development of seasonal influenza vaccine and H1N1 or other subtype influenza combined vaccine (863 plan), the research and development of key technologies and products for h7n9 avian influenza virus vaccine (emergency prevention and control research project of the Ministry of science and Technology) “In depth development of chitosan and its derivatives as vaccine adjuvants” (863 plan) and “Research on key technologies and product development of Vero cell pandemic influenza virus vaccine” (863 plan subproject) and other important national scientific research projects. According to the batch issuance data of biological products released by China Institute of food and drug control, the annual batch issuance quantity of influenza vaccine of the company accounted for 52.77%, 42.02% and 40.16% of the total batch issuance quantity of influenza vaccine in China from 2018 to 2020, ranking first in the industry. Among them, in 2018, the company’s tetravalent influenza virus split vaccine obtained the new drug certificate granted by the State Drug Administration and was exclusively listed in China. From 2018 to 2020, the company’s batch issuance of tetravalent influenza virus split vaccine accounted for 100%, 86.10% and 61.41% of the total batch issuance of similar products in China, respectively.
2. Core technology of the issuer
(1) Influenza virus vaccine R & D and large-scale production technology platform
The company’s “technology platform for influenza virus vaccine R & D and large-scale production” adopts the influenza virus strains newly recommended by who every year. Firstly, chicken embryos are inoculated respectively for virus seed amplification, adaptability and database building research, large-scale culture, virus inactivation, multi-stage purification and cleavage to obtain single type stock solution; Each type of stock solution is prepared and sub packaged according to the standard proportion to obtain the finished vaccine.
The production technology of the platform is independently developed by the company and produced with world-class production equipment. Advanced automation equipment and rigorous quality assurance system ensure the safety, efficiency, uniformity and stability of products. The company has built its own egg breeding base, selected high-quality breeding chickens for careful feeding and strict management, and used free and antibiotic free breeding eggs for the production of influenza vaccine. The whole process conforms to the quality management standards of EU, who and China to ensure the product quality. The virus is inactivated automatically under the premise of low temperature to ensure the maximum effect of virus inactivation; International advanced purification combination modes are adopted to improve the purity and safety of the product and reduce the incidence of adverse reactions. At the same time, the company selects high-quality pre filled syringes, which is not only convenient to use, but also eliminates iatrogenic pollution and ensures the safety of users. The company has established a perfect cold chain transportation system to ensure the stability of the whole life cycle of vaccine products. Using this platform technology, the company has successively listed influenza virus splitting vaccine, influenza A H1N1 virus splitting vaccine, tetravalent influenza virus splitting vaccine and other vaccines. The tetravalent influenza virus splitting vaccine exclusively listed in 2018 has filled the gap of tetravalent influenza vaccine in China and is reducing bacterial endotoxin Ovalbumin content and other indicators that are easy to cause adverse reactions are at the leading level in China in terms of control technology.
(2) Multi linked multivalent vaccine technology platform
The company has developed a multi linked and multivalent vaccine technology platform based on the adsorption of acellular hundred (three component) leucorrhea combined vaccine. Its core technology is to comprehensively upgrade the purification process of pertussis, diphtheria, tetanus and other vaccines on the basis of the existing adsorbed acellular DPT combined vaccine in China, so as to prepare a safer and more efficient component DPT vaccine, so as to ensure the consistency and stability of the antigen content of each batch of products. On the basis of DPT vaccine, it can be combined with meningitis, Haemophilus influenzae type B and other vaccines, which has the basis of preparing a multi linked and multivalent vaccine.
The multi linked and multivalent vaccine technology platform developed by the company is the upgrading technology of DPT vaccine in China. Compared with the traditional production process of acellular DPT vaccine, the technical advantages are mainly reflected in the following aspects: (1) the production process of pertussis, diphtheria and tetanus vaccines of the company adopts column chromatography, in which pertussis adopts component extraction process, That is to purify Pt, FHA and PRN respectively, and then prepare them with appropriate proportion to ensure accurate quantification of effective antigen, less nonspecific protein and consistency between batches.
(2) The company’s adsorbed acellular hundred (three component) leucorrhea combined vaccine did not add any preservative similar to thiomersal in the production process, making the product safer.
(3) This technology ensures the integrity of natural biological function of Pt antigen before detoxification and ensures no residual toxicity after detoxification.
(4) The new adsorption mode is used for adjuvant adsorption of pertussis, diphtheria and tetanus vaccine stock solution. Compared with the traditional stock solution CO adsorption mode, its adsorption efficiency is higher.
In addition, the company’s core technology “multi linked and multivalent vaccine platform” is not limited to the production technology of single products. This technology can be successfully applied to the R & D and production of a series of multi linked and multivalent vaccine products such as DPT + Haemophilus influenzae type B vaccine, DPT + meningitis + Haemophilus influenzae type B vaccine, forming the company’s core technology, Enrich the company’s product structure and improve the company’s core competitiveness. (3) Genetic engineering vaccine technology platform
Genetic engineering vaccine is a vaccine prepared by using DNA recombination technology to insert natural or synthetic genetic material into bacteria, yeast or mammalian cells, express it and purify it. Genetic engineering vaccine is a new way of vaccine research. Compared with the vaccine developed by attenuated or inactivated live virus, after purification and inactivation, genetic engineering vaccine does not contain infectious substances and has no risk of self infectious diseases. It can be safe. At the same time, it has the characteristics of high yield, high purity and high safety, and can solve the problems of yield and cost of vaccine production. The platform can be used to develop genetic engineering recombinant subunit vaccine, recombinant live vector vaccine, gene deletion or mutation vaccine, gene (nucleic acid) vaccine, synthetic peptide vaccine and so on.
The company’s recombinant genetic engineering vaccine technology adopts eukaryotic expression system, and has developed a series of production processes with independent intellectual property rights on this basis. Relying on this technology platform, the company has developed recombinant hepatitis B vaccine (Hansen’s yeast). The genome of Hansen’s yeast integrates surface antigen genes with multiple copy numbers, which can be fermented at high density and expressed at high level. It has the characteristics of high safety, less impurities and less side effects; Production equipment such as automatic fermentation system, high-pressure homogenization system and multi combination chromatography system are used to obtain high-purity stock solution. Compared with other process methods, the production is more stable, the difference between batches is smaller and the output is higher. The product was awarded the new drug certificate in 2007, and is China’s second enterprise that has obtained the new HBV vaccine certificate. At the same time, the technology platform can also be applied to other genetically engineered vaccines.
(4) Large scale culture of mammalian cells and vaccine preparation technology platform
The traditional vaccine preparation process is roughly divided into four steps, including the culture and purification of pathogens or engineering bacteria, the preparation of semi-finished products, sub packaging and lyophilization, among which large-scale culture and purification are the core technologies in the vaccine preparation process. The company adopts low generation mammalian cells (such as Vero cells, 293 cells, etc.) and carries out production process optimization, amplification and industrialized production through independent innovation, so as to gradually form the core technology “large-scale mammalian cell culture and vaccine preparation process platform technology” with independent intellectual property rights.
This technology of the company is a large-scale mammalian cell culture technology, which adopts world-class production equipment and high standard quality management standards, and combines a series of advanced technologies such as bioreactor high-density cell culture technology, virus perfusion harvest, concentration, inactivation and multi-step column chromatography purification. Compared with traditional culture technology, The advanced nature of the technology is mainly reflected in the following aspects:
1) It has the advantages of low comprehensive cost, large batch, small difference between batches and high content of virus antigen.
2) International advanced perfusion technology is adopted to provide sufficient nutrients for cell growth, the virus can be continuously expressed and the productivity can be significantly improved.
3) The cell density cultured by this technology can be increased to more than 107 cell / ml, which lays a foundation for the efficient amplification of virus. The multi-step combined chromatography purification process is adopted to effectively remove impurities such as cell debris, host protein, bovine serum protein and DNA, improve the purity of vaccine products, ensure the safety and effectiveness of the vaccine, and significantly reduce the adverse reactions after vaccination.
4) In terms of product quality, the company’s registration standard for human rabies vaccine is significantly higher than the national pharmacopoeia standard. The vaccine does not contain any antibiotics and has better safety. Human rabies vaccine has developed 5-shot and 4-shot immunization procedures, which can be accurately handled in combination with the actual clinical situation.
In addition, “large scale mammalian culture and vaccine preparation technology platform technology” is not limited to the production technology of single products, but can also be successfully applied to the R & D and production of new virus vaccines and other products.
3. Research and development level of the issuer
(1) Research and development expenses of the issuer
In 2018-2020, the company’s R & D expenses were 52.9765 million yuan, 73.042 million yuan and 110.9375 million yuan respectively. The proportion of R & D expenses in operating revenue is as follows:
Project 2020 2019 2018
R & D expenses (10000 yuan) 11093.75 7304.20 5297.65
Operating income (10000 yuan) 242632.89 104898.82 80273.82
Project 2020 2019 2018
Proportion (%) 4.57 6.96 6.60
(2) Awards and honors received by the issuer
The company focuses on the R & D, production and sales of human vaccine products, which has been recognized by the competent departments of governments at all levels. The company is recognized as “high-tech enterprise” and “science and technology-based small and medium-sized enterprise in Henan Province”; He also won the “Henan industrial and information technology achievement award”, “Henan Medical Science and Technology Progress Award”, “excellent team award for the implementation of the eleventh five year national science and technology plan” and other honors; The split vaccine of influenza A (H1N1) virus produced by the company has won the first prize of “Xinxiang science and Technology Progress Award” and “national key new products”.
Based on its own scientific research ability and core technology, the company has undertaken or participated in a number of national and provincial scientific research projects. As of June 30, 2021, the accumulated scientific research projects undertaken or participated by the company are as follows:
Project type project name project initiation department start and end date
International certification construction project of protein biological drugs and vaccines: National Development and Reform Commission, Ministry of finance, Ministry of industry and information technology and Ministry of health of the special development project from January 2012 to December 2016
Development of bivalent vaccine for hand, foot and mouth disease in the Department of “major new drug creation”. The Ministry of science and technology of the people’s Republic of China issued and studied the junior college project of technical and heavy education from January 2014 to December 2016
National Science and technology support plan joint prevention and control of influenza A (H1N1) Ministry of science and technology 2009.06-2010.12
