Analysis Of Innovative Application Of Biopharmaceutical Technology In Pharmaceutical Process

Biopharmaceutical engineering requires practitioners to integrate knowledge systems and technologies in pharmacy, biochemistry, and medicine, and the technical threshold is relatively high. Practitioners in the biopharmaceutical industry need to be proficient in biological knowledge and apply innovative biotechnology to process biological raw materials to produce biological drugs. The biopharmaceutical industry is currently in short supply of these innovative technical talents. China’s biopharmaceutical technology started relatively late. With the improvement of the country’s economic level in recent years, biopharmaceutical technology has also developed rapidly, but there is still a big gap compared with developed countries. China’s biopharmaceutical industry is still in its infancy. The gap still needs to be filled by the continuous efforts of practitioners, the steady improvement of enterprise competitiveness, and the continuous support of national preferential policies, so that the broad masses of the people can fully enjoy the benefits brought by technological development.

Part 1 China’s Pharmaceutical Technology Development Achievements And Common Types

1.1 Development Achievements Of Biopharmaceutical Technology

Among developing countries, China’s biomedical technology level has gained significant advantages, and the proportion of biotech pharmaceuticals has increased significantly. At this time, its sales profit margin in the entire industry has approached the level of first-class enterprises in the same period. Biological medicine has become a “rising star” in the industry after chemical medicine and traditional Chinese medicine. Nevertheless, China’s biopharmaceutical industry has limited financing channels, poor industrial structure, and lack of innovative talents, which have seriously hindered the development of the entire industry. The R&D (Research and Development) expenses of enterprises have increased, and many innovative achievements have emerged. A large number of vaccines such as hepatitis E vaccine, EV71 inactivated vaccine, cervical cancer vaccine, and polio inactivated vaccine have been launched or achieved clinical research progress, and anti-lymphoma A number of antibody drugs and related key technologies have made major breakthroughs. During the “13th Five-Year Plan” period, the new crown epidemic swept the world and brought many challenges and lessons to the entire industry. The emergence of the epidemic has put forward higher requirements for corresponding diagnostic, preventive and therapeutic drugs. Transportation restrictions, cooperation with related industries, and dependence on imports of equipment have become industry pain points that need to be resolved urgently.

Based on the present and looking forward to the future, in the 21st century, China’s biopharmaceutical technology will surely achieve substantial and standardized development.

1.2 Common Types Of Biopharmaceutical Technologies

1.2.1 Microbial Engineering Pharmaceuticals

Microbial engineering, that is, fermentation engineering, is formed by the intersection of multiple disciplines. Its technology type and application type are highly open, and it is a branch of bioengineering. Microbial engineering technology is commonly used in the production of antibiotics in large quantities by using microorganisms. With the continuous innovation of technology, people are target-oriented, screening and cultivating microorganisms that can produce target drug molecules, such as interferon, insulin and other polypeptide molecules.

1.2.2 Genetic Engineering Pharmaceuticals

Genetic engineering is a process in which exogenous genes and specific carriers are combined outside the receptors and then introduced into recipient cells to stably express target products or obtain new traits through genetics. The eight basic processes of genetic engineering pharmaceuticals are: the first step is to obtain the target gene, the second step is to construct the recombinant plasmid, the third step is to select and construct the genetically engineered bacteria group, the fourth step is to cultivate the engineered bacteria group, and the fifth step is to separate and purify the product In the sixth step, the product is sterilized and filtered, the semi-finished product obtained in the seventh step is tested, and the final product obtained in the eighth step is tested. Traditional genetic engineering pharmaceutical technology mainly prepares hormones, active factors, and inactivated vaccines necessary for human metabolism. In recent years, under the background of the new crown epidemic sweeping the world, biotechnology innovation has driven the emergence of new vaccine products, such as human vaccines for SARS-CoV-2 and AIDS vaccines based on mRNA technology.

Part 2 Innovative Application Of Biopharmaceutical Technology

2.1 Disposable Bioreactor Instead Of Stainless Steel Bioreactor

Based on modern biotechnology, bioreactors are devices that use enzymes or specific biological functions of organisms (such as microorganisms) to perform biochemical reactions, and are mostly used for in vitro culture of cells. The main types of bioreactors for culturing cells are: ventilated stirring type, dialysis type, air lift type, etc. Among them, the aeration and stirring device made of stainless steel is developed from the corresponding small device, which reduces the shear force on the cultured cells, but the inherent shortcomings of the sterilization process of the stirring device have not been completely overcome: First, the online Cleaning (SIP) and in-line disinfection (CIP) processes will generate high energy consumption; second, when performing necessary offline detection of cell culture, the risk of equipment contamination is high. With the development and technical improvement of disposable bioreactors, their good performance and the characteristics that are more conducive to enterprises to reduce production costs and gain market competitive advantages have won the favor of many biopharmaceutical enterprises.

In the biopharmaceutical industry, many companies have devoted themselves to the research and development of various disposable bioreactors made of polymer materials certified by the US Food and Drug Administration (FDA) based on disposable technology. There are three common types of single-use bioreactors in the field of fermentation or cell culture: wave type, orbital shaking type and stirring type, and the common specifications are between 10 mL and 2000 L. The most important feature of the single-use bioreactor is the built-in pre-sterilized, non-reusable single-use bioreactor bag. Compared with traditional stainless steel bioreactors, disposable bioreactors have the following advantages: online disinfection or online cleaning facilities are less important to disposable bioreactors; disposable bioreactors have high sustainable design and equipment footprint Smaller area, lower operation and maintenance costs; shorter verification time and delivery time for single-use bioreactors; less liquid waste generated by single-use bioreactors, lower risk of contamination. The main shortcomings of disposable bioreactors are: high reliance on suppliers, and strict material storage conditions; a large amount of solid waste is generated, and companies with specific qualifications are required to use sterilizers after collecting solid waste deal with it in a living way. Due to the above-mentioned main advantages and no obvious disadvantages compared with traditional stainless steel bioreactors, disposable bioreactors are widely used in the field of biopharmaceuticals to cultivate patient somatic cells, produce monoclonal antibodies, and produce vaccines. Although the disposable bioreactor appeared late, some developed countries abroad have obtained advanced theoretical research and equipment manufacturing systems through rapid development. Under the general trend of replacing stainless steel reactors with disposable bioreactors in the world, China’s biomedical industry is also in the midst of reform and innovation opportunities, gradually shifting from the pursuit of production scale to production specialization, and gradually catching up with the international advanced level craft technology.

2.2 Application Of Humanized Mouse Models In The Development Of New Drugs

The development of early medicine is attributed to people’s research on animal experiments. In the field of biomedicine, people use animal models such as animal experimental materials to study the manifestations of the same pathogen in different organisms, so that people can deeply understand a certain disease or abnormal state. pathogenic mechanism. This is an indirect research model. Commonly used common experimental mice have only about 60% homology level with human genes, which cannot reproduce all the manifestations of human diseases. At this stage, animal models are still the most ideal substitutes for studying human physiological systems. The most common animal models are rats and mice among rodents, which have good reproducibility, high replication rate, and life cycle to meet research needs, etc. It is widely used in biology, medicine and other fields. For example, in the initial stage of the outbreak of the new crown epidemic in China, Academician Zhong Nanshan’s team constructed a non-transgenic mouse model of new coronavirus pneumonia, and carried out emergency in vivo verification of antiviral drugs, protective neutralizing antibodies, and vaccines. This model effectively alleviates the problem of lack of animal models in the study of new coronaviruses in China, and also provides a basis for the later research on the immune response and pathogenic mechanism of new coronaviruses in vivo.

Since the genetic differences between rodents and humans cannot be ignored, people need an animal model that has a human immune system and can better express the function of the human immune system. It is against this background that the humanized mouse model was developed. Build it out. Humanized mouse models can be defined as immunodeficient mice transplanted with human hematopoietic stem cells or tissues, or as transgenic mice expressing human genes. The humanized mouse type is constructed by transplanting human tissues, hematopoietic stem cells (Hematopoietic stem cells, HSCs) or peripheral blood mononuclear cells (Peripheral blood mononuclear cells, PBMCs). In order to fully understand the pathogenic mechanism of the disease before the disease occurs, so as to facilitate the detection of preventive and therapeutic measures for related diseases, researchers have constructed a humanized mouse model as a platform, which has a wide range of uses. Among them, the humanization of drug target genes through gene editing technology, and mice with human drug targets have shown great development prospects in the field of biopharmaceuticals. For example, more and more mice with immune function have been genetically modified to encode one or more humanized positive and negative immune regulatory receptors or ligand genes, such as PD-L1, CD40, TIM3, Ox40, OX40L, etc., currently Has been put into commercial use. CD40 is a kind of co-activation signal molecule related to B cell and T cell function, which is mainly presented to cells by antigen. Studies have shown that the construction of CD40 humanized mouse model can successfully evaluate the efficacy of specific antibodies in monoclonal antibodies and tumor therapy. In addition, for TIM3, an extramembrane protein structure that spans the cell membrane, relevant researchers have also designed a monoclonal antibody paired with it. Relevant studies have pointed out that the construction of TIM3 extracellular region model mice and the use of B cell production technology to prepare human TIM-3 monoclonal antibodies can be used to detect antibody activity, laying a solid experimental foundation for the development of immune checkpoint drugs and providing important scientific basis.

2.3 Development And Application Of Proteolysis Targeting Chimera (PROTAC) Technology

In the fight against tumor-like diseases, it has been found that for drugs that inhibit the activity of disease-causing proteins, recipient cells will develop resistance to the drugs. The reason is that traditional inhibitory drugs need to bind to the target protein to inhibit its activity. However, the pathogenic protein itself has multiple functions. The drugs developed at this stage can only inhibit one or several functions of the pathogenic protein. Cells, and traditional targeted drugs are used in a large amount, the drug off-target rate is high, and the risk of harm to the human body after use is high. For the development of alternative treatment methods for drugs that more efficiently remove disease-causing proteins, people urgently need a technical means to solve the above problems from the source.

After researchers deeply studied the mechanism of how cells degrade harmful proteins, researchers discovered an important mechanism for cells to use ubiquitin to regulate the degradation of harmful proteins: the ubiquitin-proteasome system. On this basis, American scientists first proposed the concept of proteolysis targeting chimera (PROTAC). PROTAC molecules are composed of three parts: a linker located in the middle of the molecule, a binding ligand molecule connected to E3 ubiquitin ligase at one end, and a ligand binding to the target protein at one end. Its mechanism of action is: after the ligand for the pathogenic protein at one end binds to the pathogenic protein, the ubiquitin ligase at the other end continuously connects the ubiquitin molecules in the space into a chain so that the ubiquitin chain can be chained after the protease recognizes it. The degradation of the protein is equivalent to providing “precise coordinates” for the protease. In addition, PROTAC molecules can be reused after the protease completes the entire degradation process of the pathogenic protein, which provides a theoretical basis for reducing the dosage of drugs. Today, PROTAC has become an increasingly mature means of new drug development that subverts traditional drugs. In addition to the application in tumor therapy, PROTAC technology also provides a possible way for the treatment of viruses. Taking the new coronavirus as an example, the active ingredients such as rhein and forsythin in the traditional Chinese medicine preparation Lianhua Qingwen Capsules can effectively curb the infection of the new coronavirus. These active small molecules of traditional Chinese medicine can be combined with viral proteins. If PROTAC molecules with one end linked to active molecules of traditional Chinese medicine are designed according to this characteristic, then it is possible to realize the idea that viral proteins can be directly degraded by proteases in vivo.

At present, PROTAC molecules still need to be prepared by means of chemical synthesis, and the preparation cost is relatively high. Although it can theoretically reduce the dosage of traditional drugs, there are still few studies on its toxic and side effects on the human body, and the risk in the later stage of drug development is relatively high. Therefore, the function of PROTAC drugs needs to be further tested and verified in clinical trials. In the global upsurge of PROTAC drug research, many Chinese biopharmaceutical companies have carried out research and development layout, clinical verification, and drug patent submission for PROTAC molecules with different targets, which are innovative drugs, and have achieved considerable results.

Part 3 Analysis Of China’s Biopharmaceutical Technology Innovation And Development

3.1 Risk Analysis Of Chinese Biopharmaceutical-Related Enterprises

The biopharmaceutical technology industry is a knowledge-intensive and capital-intensive industry, which urgently needs a virtuous circle of funds. Due to factors such as high investment risks in this industry, relatively small strength of Chinese venture capital companies, and high thresholds for relevant financing conditions, companies engaged in the R&D and production of biopharmaceuticals are prone to difficulties. On the one hand, relevant enterprises need to continuously guarantee their own R&D investment; on the other hand, the government needs to strengthen the supervision and adjustment of financing, and strengthen the protection of intellectual property rights in the biopharmaceutical industry, in order to ensure the standardization of relevant enterprises.

3.2 Analysis Of Innovative Talents In Biopharmaceutical Reserve Universities

Biology majors in colleges and universities, especially bioengineering majors, have been listed as red-card majors in the “China University Student Employment Report” for several consecutive years. It is difficult for students to engage in the field of work they majored in after graduation. The reason is that China’s bio-related industries have not yet been fully and standardizedly developed. With the five-year plan promulgated by the country, the employment environment of the biopharmaceutical industry has been improved. The still large number of students majoring in biology in Chinese colleges and universities also provides sufficient guarantee for the reserve talents of the industry. In recent years, the state has vigorously organized innovation and entrepreneurship competitions in colleges and universities, and a large number of biopharmaceutical-related product development based on new technologies and pharmaceutical enterprise management optimization based on new models have emerged. Enterprises can start with outstanding student entrepreneurial groups. Cooperation and long-term school-enterprise cooperation with schools can optimize R&D methods, share R&D risks, and save R&D funds to a certain extent, and continue to inject vitality and power into their own innovation and development.

3.3 Analysis Of Internationalization Strategy Of Biopharmaceutical Enterprises

In the tide of globalization, Chinese biopharmaceutical companies are facing the double pressure brought by severe competition in the international market and abundant and unintegrated R&D resources. At present, most biopharmaceutical companies in China are still in a relatively low position in the international value chain, and they assume more roles in the international trade system to accept outsourcing and produce low-value-added biopharmaceuticals. As the COVID-19 epidemic sweeps the world, the international value system has been severely damaged by force majeure factors and forced to turn to reconstruction. This environment provides opportunities for Chinese biopharmaceutical companies to further enter the international market and deepen their international influence. As mentioned above, the biopharmaceutical industry requires intensive high-tech industrial personnel and a high-investment capital operation system. This industry has the characteristics of high risk and high return. In order to reduce this risk, international mainstream large-scale biopharmaceutical companies have gradually shifted from a “high-rise” industrial layout to a decentralized and differentiated international R&D system layout, that is, they themselves need urgent industrial upgrading and industrial transfer. Chinese biopharmaceutical companies have Opportunity to introduce advanced production technology and management methods to international leading biopharmaceutical companies, which not only improves the competitiveness of the industry, but also provides a broad idea for its own long-term development. Relying on China’s strict epidemic control, Chinese biopharmaceutical companies have more unique advantages to attract international hot money for financing. On this basis, Chinese biopharmaceutical companies can integrate foreign biopharmaceutical companies through acquisitions, mergers and acquisitions, etc., so as to obtain a batch of Advance technology, enhance the share of Chinese enterprises in the international industrial chain, and expand overseas marketing channels. In addition to the way of purchase, active cooperation with international giants cannot be ignored. Advanced experience accumulated in cooperation will also provide more reference channels in the process of gradually deepening integration into the global market.

Part 4 Conclusion

To sum up, technological innovation that meets market demand is an important driving force for the advancement of the biopharmaceutical industry. The development time of China’s biopharmaceutical industry is relatively short, and it still needs to continuously learn international advanced technologies, focusing on the localization and mass production of high-end equipment; It is still necessary to continuously summarize the experience in China and the world, focus on the urgent market demand in China, seize the market opportunities and the development window of enterprises in China and the world, enrich the path of drug innovation research and development on the basis of updating and applying biopharmaceutical technology, and reduce the production of biopharmaceuticals Cost and sales price, and expansion of marketing channels can create the core advantages of the industry and make greater contributions to the development of biopharmaceutical technology.