Toward Autonomous Production of mRNA-Therapeutics in the Light of Advanced Process Control and Traditional Control Strategies for Chromatography.

mRNA-based therapeutics are predicted to have a bright future. Recently, a B2C study was published highlighting the critical bottlenecks of mRNA manufacturing. The study focused on supply bottlenecks of various chemicals as well as shortages of skilled personnel. The assessment of existing messenger ribonucleic acid (mRNA) vaccine processing shows the need for continuous manufacturing processes that are capable of about 80% chemical reduction and more than 70% personnel at factor five more efficient equipment utilization. The key technology to solve these problems is both a higher degree of automation and the maximization of process throughput. In this paper, the application of a quality-by-design process development approach is demonstrated, using process models as digital twins. Their systematic application leads to both robust optimized process parameters, with an increase in productivity of up to 108%, and sophisticated control concepts, preventing batch failures and minimizing the operating workload in terms of personnel and chemicals' consumption. The approach thereby provides a data-driven decision basis for the industrialization of such processes, which fulfills the regulatory requirements of the approval authorities and paves the way for PAT integration. In the process investigated, it was shown that conventional PID-based controls can regulate fluctuations in the input streams sufficiently well. Model-based control based on digital twins may have potential above all in a further increase in productivity, but is not mandatory to implement for the industrialization of continuous mRNA manufacturing. [ABSTRACT FROM AUTHOR]