For a long time, the basic idea and method of optimization and amplification of fermentation process is a static operation method based on classical dynamics and optimal process control points. In essence, this is just an extension of the concept of chemical macro-kinetics in fermentation engineering. For example, when adjusting pH with ammonia water, we pay attention to the optimal pH value, but ignore the dynamic change of ammonia water consumption and its relationship with other parameters. In the measurement and control of dissolved oxygen concentration (DO), the best DO value or critical value is concerned, while the oxygen consumption rate during cell metabolism is ignored. Obviously, it has great limitations when it is used in fermentation process with living cell metabolism as the main body, so we should pay attention to the existence of cell metabolic flow. With the development of process sensing technology and computer technology, the National Research Center of Biochemical Engineering Technology (Shanghai) designed a new concept fermentation device (produced by Shanghai Guoqiang Biochemical Engineering Equipment Co., Ltd., with the shape of FUS-50L(A)) for multi-scale research of biological processes. This device has more than 14 online parameter detection or control from the point of view of logistics detection in bioreactor, and is committed to developing a device that adapts to various reactor characteristics and integrates various process theories and control theories. In the process of guanosine fermentation, the cell metabolic flow migration was found from the measured parameters of the reactor, thus realizing the process optimization []. This product has been successfully applied to penicillin, erythromycin, feed chlortetracycline, streptomycin, flavomycin, tylosin, clavulanic acid, guanosine, inosine, genetically engineered albumin, genetically engineered malaria vaccine, genetically engineered phytase, proinsulin (PIP), genetically engineered spiramycin and other products. The fermentation unit capacity has been greatly improved, and the optimization results can generally be directly scaled up from dozens of liters fermenters to hundreds of cubic meters of industrialized production fermenters.

2. Bioreactor for large-scale culture of animal cells

Due to the defects in transcription and modification of prokaryotic expression systems such as bacteria, the development of many important protein, especially the need for glycosylated genetic engineering drugs, vaccines and antibodies, have made mammalian cell expression systems more suitable tools, so mammalian cell expression systems have attracted everyone's attention. The biopharmaceutical industry based on large-scale mammalian culture technology has developed rapidly in the United States and other western countries. Dozens of products have entered the market and achieved great economic and social benefits. Animal cell bioreactors used in foreign countries have tended to be large-scale (up to tons), multi-parameter and highly automated computer control systems, and reactors adapted to the high sensitivity of animal cells to environmental factors have been exquisitely designed and manufactured, and have been commercialized for users. During the "Seventh Five-Year Plan" to the "Eighth Five-Year Plan", China started the research on animal cell bioreactor and made great progress. However, due to the high technical requirements and technical barriers of mammalian cell culture, it is difficult for related companies to work only by simulation without mastering the core technology. The amount of drugs expressed by cells such as antibodies is large, and the early biopharmaceutical development technology mastered by scientific research units in China is difficult to be applied to the production of new drugs, which needs to be explored again; Due to the backwardness of upstream supporting technologies such as cell lines, the gap in reactor development technology and the lack of biochemical engineering research, it is difficult to master the construction of high-expression cell lines and large-scale cell culture technology, and it is difficult to break through the technical bottleneck. The animal cell bioreactor industry in China is almost blank.

3.pH measurement and feeding control shaker-development of shaker application technology.

Since its appearance in the 1930s, the shaker has been used as an indispensable special equipment in the biological reaction process, such as the screening of microorganisms, plant and animal cell strains, and expanded seed culture. Because of the characteristics of shaking table equipment, it is impossible to measure the relevant parameters in the culture process and control the feeding in the process in real time, so the bottle release results of shaking table have been used as experimental data for a long time. When it is used as the basis for studying the changes of physiological characteristics of strains, the role of culture medium components and the changes of environmental conditions such as temperature and pH, it is actually a static analysis method lacking process research. The limitations of this method are obvious. For example, when this method is used as the post-breeding technology of strains, the traditional shake flask screening method often lacks feeding or oxygen supply, which is not necessarily in the most reasonable state of metabolic flow distribution, so there will be a serious phenomenon of high-yield strains missing screening. Therefore, related companies at home and abroad have paid attention to the development of pH measuring shaker and formed products.

4. Pilot system design of bioreactor.

For traditional biotechnology products with large production capacity, in order to optimize the process of products that have passed the preliminary research (laboratory research and market analysis), reach a higher production level or quality on the pilot scale, further provide the basis for process amplification and equipment design for workshop production, and carry out small batch production when necessary, and provide application test samples or some products for market sales. Therefore, in recent years, many enterprises related to the production of fermented products urgently need to establish a multifunctional pilot fermentation workshop.

5. Research on design and manufacturing technology of large-scale bioreactor.

With the rapid development of fermentation industry for decades, fermentation engineering tends to be large-scale, efficient and automatic. In terms of traditional biotechnology products, some amino acids, antibiotics or fermented light products are developing in dozens to hundreds of M3. Some old factories that used to be small-scale fermenters moved to new factories, and generally required to expand the scale of fermenters. Genetic engineering products generally have high added value and do not need large bioreactors. However, in recent years, with the development of genetically engineered enzyme production technology, such as the successful research of genetically engineered phytase, and the large demand for feed additives, it is imperative to develop large-scale bioreactors with high density and high expression for genetic engineering. Especially in the future, with the exhaustion of mineral energy, the production of fuel ethanol from biomass has been put on an important strategic agenda. The application of large-scale fermentation devices with high efficiency and energy saving is an indispensable key technology to reduce production costs, such as fermentation devices with a capacity of more than 2000M3 in the United States and Brazil.