This article is from The Circle of Biological Products

In 2020, the COVID-19 epidemic spread relentlessly around the world, a public health emergency that instantly put people around the world on alert. According to Worldometers, as of October 14, 2021 (GMT+8), the total number of confirmed cases of COVID-19 worldwide has reached 239,863,590 with a death toll of 4,887,927 deaths. Faced with such a horrible "enemy", people's attention on vaccines has surged. On the other side, it brought opportunities to China's biopharmaceutical industry which has naturally been pushed to the forefront.

Affected by the pandemic, many countries implemented the policy of lockdown and industries stagnated. Among them, China is undoubtedly the first and the best to recover from the pandemic. With national policies and resources inclined to epidemic control and prevention, China's biopharmaceutical industry plays an indispensable role in the fight against the virus, especially by providing vaccines and antibody products.

While the biopharmaceutical industry receiving more attention, the demand for biopharmaceutical equipment in China is also expanding. This brings opportunities for the biopharmaceutical equipment industry, but also highlights its inherent problems: the underdevelopment of mid and high-end market, weak innovation momentum of the industry as a whole, and lack of trust by pharmaceutical companies on domestic equipment. This poses new requirements on quality of domestically manufactured core pharmaceutical equipment.

The most important one is biological reactor as the upstream core equipment of antibody production, which must be able to maximize the potential of cell lines and process level. The core design concept of a bioreactor is to provide optimal conditions for bacterial or cell growth to enable rapid and large-scale production. The conditions include the appropriate temperature, pressure, DO, pH, osmotic pressure, effective substrate, nutrient salts, vitamins, and appropriate metabolite concentration, helping cells to grow and metabolize.

As the key equipment in biopharmaceutical production, the benefactor needs to ensure proper multi-parameter control at the same time, which puts forward high requirements for the hardware design, software design and culture process. Especially for culture of mammalian cell, it has a long culture cycle, is highly sensitive to shear force, and also features high foaming tendency and toxicity. Cell growth is more susceptible to shear forces, environmental pollution, temperature fluctuations and other factors, all posing big challenges for bioreactor suppliers.

According to incomplete statistics, there are nearly 20 domestic bioreactor enterprises, but almost all of them provide stainless steel stirred reactors. The competition is extremely fierce, but the quality and technical level is not high. Among them, Shanghai Morimatsu Pharmaceutical Equipment Engineering Co., Ltd. is a typical representative.

As a leader in core equipment and digital intelligent engineering solutions, Morimatsu recognized the great development potential of bioreactor in biopharmaceutical industry more than 10 years ago. As early as in 2012, Morimatsu has introduced advanced technology and talents from Japan, Europe and the United States through cooperation, and established a bioengineering laboratory for cell culture using Morissone Pharmadule's modular plant technology. Through actual cell culture, it has conducted systematic development, production testing and continuous iterative improvement for the biological reactor. After more than ten years of development, Morimatsu has established a complete system of high-quality bioreactor experimental testing, process scale-up design, automatic control design, manufacturing, quality management, and taken the lead in realizing the domestic manufacturing of core equipment. It has formed a mature design of world level in the gas supply, stirring, temperature control, exhaust gas, sampling, harvesting and software control and other aspects of biological reaction.

In 2019, Morimatsu delivered 6,000L bioreactors to the largest CDMO enterprise in the world. This project changed the history that no domestic large-scale bioreactor was exported to Europe and America. After two years, Morimatsu again received the order for several sets of 20KL bioreactor for antibody production from Swiss giant CDMO, which is one of the largest bioreactor projects in the world.

So why did the international CDMO giants choose Morimatsu? What's the difference that distinguishes Morimatsu’s bioreactor from its competitors at home and abroad?

For domestic bioreactor companies, the biggest problem is the lack of research on biological process and research system integrating process, engineering and equipment. Domestic bioreactors can not achieve the development capacity of bioreactors in line with the development of biotechnology that meet the requirements of GMP. In addition, domestic enterprises lack in-depth research and engineering capacity for highly automated laboratory devices deeply combined with biotechnology, and are more based on simple imitation. Some experts pointed out that, due to a lack of technology innovation and core technology, coupled with mixed qualities of reaction tanks and major accessories, domestic bioreactors are only applied in industries like animal vaccines with fierce price competition. At present, the domestic bioreactor market is mainly dominated by foreign brands such as the United States ABEC, Germany Sartorius, Switzerland Bioengineering. Most domestic bioreactors still have a certain gap with imported brands in terms of production quality and production efficiency.

Its main characteristics are:

① Safety of materials used is low;

② The design of function, structure and industrial is poor and the non-pollution design of the interface is difficult to be guaranteed;

③ The accuracy and stability of the control system are poor;

So how to break the monopoly by foreign brands and win some market share for domestic brands? In addition to establishment of experimental testing, automatic control design, production and manufacturing of the complete system mentioned above, Morimatsu put great efforts in both process scale-up design and quality management to establish their core competitiveness.

Scale-up design is the core technology of bioreactor. In terms of lab-scale test or pilot production, it is relatively easy to fulfill the requirements on cell growth environment. However, it is rather difficult to maintain the same growth conditions as lab-scale test or pilot reactions in the growth environment of thousand liter or ten thousand liter scale. The requirements on mass and heat transfer uniformity conflicts with that on tolerance for cell shear. pH control and CO2 removal are also challenged. In the process of scale-up design, CFD flow field simulation is needed to determine the optimal tank height-diameter ratio, model and specification of stir-blade, ventilation rate, type and specification of ventilation structure for each cell culture condition. Taking the tank height-diameter ratio as an example, the height-diameter ratio has a direct impact on the solubility of oxygen and carbon dioxide in the tank. Large height-diameter ratio contributes to the residence time and solubility of gas in the tank, as well as the heat transfer area; however, large height-diameter ratio also tends to increase the gas solubility difference between the bottom and the surface of the tank, enlarge the concentration difference of media components between the bottom and the surface of the tank, and double the difficulty of achieving uniformity of key parameters such as pH and temperature.

The stability of scale-up design is a very important consideration for domestic enterprises to choose imported bioreactors. According to insiders, Morimatsu, based on more than 20 years of engineering experience, has never failed to meet the requirements of process design scale-up.

According to market data, the proportion of cooperation between Morimatsu and the world's top 20 pharmaceutical giants in international projects exceeds 80%. It is the preferred supplier for many leading biopharmaceutical companies both at home and abroad. So why is Morimatsu able to win orders from many large international manufacturers? I think it mainly attributes to Morimatsu's quality management concept and high-quality service.

Compared with other domestic suppliers, difference may be explained from the following three aspects:

① Material selection

Leveraging its leading position in the industry, Morimatsu effectively controls the channels of raw materials to ensures a stable quality. For example, for the selection of panels, panels with stable quality and defect-free at the bottom is used to effectively control the dot pits on the surface, which is conducive to ensuring the corrosion resistance and cleaning verification of the reactor.

② Industrial design

Industrial design is carried out with Morimatsu Pharmadule's resources to constantly improve the overall appearance, detail design, and operability.

③ The accuracy and stability of the control system

In terms of automatic control, Morimatsu modularizes the functions of bioreactor systems, such as temperature control, pH control, DO control, and association control of feeding, which have been standardized and verified by a large number of projects. A customized formulation system can be built according to the customer's process to ensure system stability and flexibility. At the same time, Morimatsu establishes cooperation with universities to study PAT (Process Analytics Technologies) technology of bioreactors. Through online detection of process parameters, automatic feedback control after software analysis, technical support is provided for customer process optimization and automatic execution of optimization process, accelerating the development process and reducing user workload.

As a matter of fact, the market access of the manufacturing industry is also being relaxed in the context of China's opening-up. Going global, participating in international cooperation and competition and domestic manufacturing of core equipment are "compulsory courses" for China's manufacturing enterprises. Facing with more extensive and complex competitive environment, the key is to deepen and drive innovation according to Morimatsu International.

In order to help customers achieve lean construction and production and accelerate industrialization, Morimatsu takes the lead in implementing digital services in the industry. According to the domestic and foreign market situation and the national "Intelligent Manufacture 2025" policy, Morimatsu has proposed the strategy of intelligent modular manufacturing and digital factory to provide customers with digital services of whole life cycle from program design, project delivery and operation and maintenance. This helps the company successfully transforms from traditional manufacturing to high-end intelligent manufacturing.

By integrating the value chain, Morimatsu provides high-end bioreactors from four dimensions of digital design, digital manufacturing, digital installation, and digital operation and maintenance. In terms of digital design, Morimatsu integrates all information in the project life cycle into the digital management platform with powerful data model library and professional design software, presents it to users in a visual and modular way, and ensures the consistency of data in all stages. The 3D model in the design can be shared in real time through the cloud. Customers can enter the 3D scenarios to participate in the design of the factory through the Internet no matter where they are. Morimatsu's entire digital manufacturing can greatly improve production efficiency and product quality stability. It is known that Morimatsu's digital manufacturing production orders can be send to each station uniformly by MES, and the automatic manufacturing equipment can call required processing information in real time.

In the meanwhile, Morimatsu extends two O's, namely operation and optimization, on the basis of EPC. In the operation stage, we provide electronic batch records, equipment operation and maintenance, operation training, etc. In terms of optimization, we provide services such as process analysis and fault analysis. Finally, the results of these analyses will feed back our design. This way, it can provide theoretical and decision-making basis for the upgrade and transformation of factories and core equipment, so as to form a closed loop and truly achieve digital operation and maintenance.

It seems that there is no accepted leader in the field of bioreactors. However, Morimatsu, with its cutting-edge engineering concepts and advanced construction methods, has made incomparable achievements. It took the lead in realizing the localization of high-end bioreactor technology, making breakthroughs in high-quality key equipment in China and playing a leading role in the development of the industry. With this epidemic, the biopharmaceutical industry has entered a shift period, which is probably not too much to say that it hides the secret key to the future world economic development. Bioreactor and other core product in the industry have also entered the era of brand competition. In the new market environment, both domestic and foreign upstream and downstream enterprises should conform to the development trend, form a unique brand competitiveness combined with their own characteristics, and promote a more diversified development.

About Shanghai Morimatsu Pharmaceutical Equipment Engineering Co., Ltd.

Founded in Japan and basing in China, Morimatsu has developed into a diversified multinational company which has rich experience and core technology in core equipment, process system and project solutions. Replying on the advanced manufacturing base in China, Morimatsu opened affiliated companies in Sweden, USA, India and Italy. It has delivered different products and services for more than 40 countries to date. Shanghai Morimatsu Pharmaceutical Equipment Engineering Co., Ltd. is a wholly-owned subsidiary of Morimatsu International Holdings Company Limited. Morimatsu International Holdings Company Limited (stock abbreviation: Morimatsu International, stock code: 2155.HK) was successfully listed in June 2021.