Research On Modular Plant Model Based On The Standardization Of Production Process Of COVID-19 MRNA Vaccine

Since December 2019,the outbreak of a pneumonia-like illness in Wuhan,China has caused serious damage to human health,social development,and economic conditions worldwide.Studies have confirmed that the pneumonia is caused by a novel coronavirus,SARS-Co V-2,which is highly contagious and presents great challenges to epidemic prevention and control by interrupting transmission chains.Vaccination has been proven to provide protection to susceptible individuals and alleviate symptoms of the infection.Currently,over 200 COVID-19 vaccines have entered clinical trials,and many have been approved for emergency use or market authorization in different regions.mRNA vaccines,which have the advantages of simple production processes,high production efficiency,good immunogenicity,and high safety,and have played an important role in the SARS-Co V-2 epidemic period.Under this circumstance,it is urgent to quickly transform vaccine development into mass production.Large-scale production of mRNA vaccines requires the establishment of a suitable production system,including production equipment,modular clean plant,and process flow.Modular clean plant has become the mainstream choice for vaccine production due to their short construction period,high space utilization efficiency,expandable,and mobile.Nonetheless,there is a lack of practical experience and specific cases on large-scale biopharmaceutical production in China,especially in terms of vaccine production technologies.In addition,the iterative effects of new vaccine preparation technologies,processes,and equipment require most biotech companies to adjust their production structure,especially the upgrade of modular plant.Futhermore,there is no standardized implementation plan for modular clean room construction in China,and there is a lack of cases that combine mRNA vaccine technology platforms with modular clean plant.Therefore,this paper focuses on mRNA vaccine production technology,optimizing functional layouts and equipment lists of modular plant according to the production process of the mRNA COVID-19 vaccine,combined with the best total output value and intensification and intelligent innovation technology of the production process.It further combines upstream production technology of mRNA vaccines with modular clean plant and conducts an analysis of actual modular clean plant implementation cases of mRNA vaccine production,demonstrating that the combination of mRNA vaccine large-scale production and modular clean room construction can greatly improve the efficiency of industrialization transformation,reduce overall production costs,and provide a valuable reference for large-scale production of mRNA vaccines.The main study contents are:(1)Considering the production process of the COVID-19 mRNA vaccine and the production capacity and scheduling plan of 120 million doses,the product production process is determined.The key process technologies and equipment are summarized from upstream and downstream production processes respectively,and the functional layout of the key technology’s clean room is designed.Upstream technologies mainly include strain fermentation,plasmid extraction and purification,in vitro transcription,and DNA digestion.The process equipment mainly includes fermentation systems,lysis systems,ultrafiltration systems,and chromatography systems.Downstream technologies include uncapped mRNA purification,mRNA capping and purification,dilution of mRNA stock solution,encapsulation module,and penicillin bottle filling linkage line.The functional layout of the clean room mainly includes fermentation culture,cell collection and lysis,plasmid purification,plasmid linearization,in vitro transcription and capping,mRNA encapsulation,and formulation areas.(2)From the conceptual design,basic design and detailed design,the path design scheme of the modular plant conforming to the biopharmaceutical was developed.At the same time,according to the characteristics of the modular plant,the construction process in line with the modular plant is formulated.The first step is to analyze the needs of the end users,the second step is to complete the functional division,and the third step is to refine the process plan combined with the detailed process and regulatory requirements,and the fourth step is to deepen the construction drawing.Meanwhile,the BIM system can be used for 3D model construction.According to the requirements of module size,the plant is divided into 95 modules for modular plant design as a result.At the same time of the design period,the corresponding equipment and supporting systems are installed into the modules simultaneously.(3)In the actual case study of the mRNA vaccine modular plant composed of 95 core modules in WALVAX Biotechnology Co Ltd,the design adopts the synchronous design method of architectural design,process design and 3D modeling,which greatly improves the utilization rate of space,integrates the professional guidance for construction.It reduces the operation and maintenance cost and frequency while improving construction efficiency.In terms of construction,the strategy of simultaneous construction of on-site construction foundation and modular workshop was adopted,which shortened the overall construction period and staggered the maintenance time of on-site foundation in advance.Finally,the workshops were installed in 18 days.In terms of management,the virtual factory and the real factory can interact with data by using digital technology on 3D modeling.VR visit,training,maintenance and other functions are realized,at the same time,it can also be managed remotely through the engineering data center,which can achieve preventive maintenance and reduce the risk of downtime.As a more cutting-edge technology biomedicine field,only a few enterprises in western countries are capable to industrialize mRNA vaccines production in the world.China is still in the early stage in this field,and no products have been industrialized.The industrialization of mRNA vaccines is especially important,because this platform can not only be aimed at SARS-Co V-2,it can also be used for other diseases.This study is to explore the integration of mRNA vaccine and modular plant technology.Through actual participation in the project,the highlights in the implementation process and the direction that can be optimized are summarized.The intention is to provide an exploration direction for vaccine manufacturers when humans deal with emergent infectious diseases in the future.