Process simulation and evaluation of scaled-up biocatalytic systems: Advances, challenges, and future prospects.

With the increased demand for bio-based products and the rapid development of biomanufacturing technologies, biocatalytic reactions including microorganisms and enzyme based, have become promising approaches. Prior to the scale-up of production process, environmental and economic feasibility analysis are essential for the development of a sustainable and intelligent bioeconomy in the context of industry 4.0. To achieve these goals, process simulation supports system optimization, improves energy and resource utilization efficiencies, and supports digital bioprocessing. However, due to the insufficient understanding of cellular metabolism and interaction mechanisms, there is still a lack of rational and transparent simulation tools to efficiently simulate, control, and optimize microbial/enzymatic reaction processes. Therefore, there is an urgent need to develop frameworks that integrate kinetic modeling, process simulation, and sustainability analysis for bioreaction simulations and their optimization. This review summarizes and compares the advantages and disadvantages of different process simulation software and models in simulating biocatalytic processes, identifies the limitations of traditional reaction kinetics models, and proposes the requirement of simulations close to real reactions. In addition, we explore the current state of kinetic modeling at the microscopic scale and how process simulation can be linked to kinetic models of cellular metabolism and computational fluid dynamics modeling. Finally, this review discusses the requirement of sensitivity analysis and how machine learning can assist with optimization of simulations to improve energy efficiency and product yields from techno-economic and life cycle assessment perspectives.