Digital Twins for Continuous mRNA Production
Digital Twins for Continuous mRNA Production
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用于连续 mRNA 生产的数字孪生
作者：
H. Helgers;A. Hengelbrock;A. Schmidt;J. Strube
全球冠状病毒大流行继续限制着世界各地的公共生活。限制大流行的一个有效手段是接种疫苗。目前市场上可用的信使核糖核酸(MRNA)疫苗已被证明是一种耐受性良好和有效的2型冠状病毒(CoV2)疫苗。因此，目前的需求超过了信使核糖核酸疫苗的产量。提高生产率的一种方法是从目前进行的批量转录切换到连续的体外转录，这已被证明是一个关键的耗材步骤。本文提出了管式反应器中体外转录的物理化学模型，并与传统的间歇转录和搅拌槽中的连续体外转录进行了比较。这三个模型是基于不同的量化验证工作流程进行验证的。统计上有意义的参数被确定为参数确定概念的一部分。蒙特卡罗模拟结果表明，该模型具有较高的精度，误差小于1%。通过对时空产率的优化，指出了连续生产相对于分批体外转录的优势。在连续搅拌釜式反应器的情况下，提高了56倍(0.011微米/分钟)，而在推流式反应器的情况下，提高了68倍(0.013微米/分钟)。
The global coronavirus pandemic continues to restrict public life worldwide. An effective means of limiting the pandemic is vaccination. Messenger ribonucleic acid (mRNA) vaccines currently available on the market have proven to be a well-tolerated and effective class of vaccine against coronavirus type 2 (CoV2). Accordingly, demand is presently outstripping mRNA vaccine production. One way to increase productivity is to switch from the currently performed batch to continuous in vitro transcription, which has proven to be a crucial material-consuming step. In this article, a physico-chemical model of in vitro mRNA transcription in a tubular reactor is presented and compared to classical batch and continuous in vitro transcription in a stirred tank. The three models are validated based on a distinct and quantitative validation workflow. Statistically significant parameters are identified as part of the parameter determination concept. Monte Carlo simulations showed that the model is precise, with a deviation of less than 1%. The advantages of continuous production are pointed out compared to batchwise in vitro transcription by optimization of the space–time yield. Improvements of a factor of 56 (0.011 µM/min) in the case of the continuously stirred tank reactor (CSTR) and 68 (0.013 µM/min) in the case of the plug flow reactor (PFR) were found.