From Spatial-Temporal Multiscale Modeling to Application: Bridging the Valley of Death in Industrial Biotechnology.

The Valley of Death confronts industrial biotechnology with a significant challenge to the commercialization of products. Fortunately, with the integration of computation, automation and artificial intelligence (AI) technology, the industrial biotechnology accelerates to cross the Valley of Death. The Fourth Industrial Revolution (Industry 4.0) has spurred advanced development of intelligent biomanufacturing, which has evolved the industrial structures in line with the worldwide trend. To achieve this, intelligent biomanufacturing can be structured into three main parts that comprise digitalization, modeling and intellectualization, with modeling forming a crucial link between the other two components. This paper provides an overview of mechanistic models, data-driven models and their applications in bioprocess development. We provide a detailed elaboration of the hybrid model and its applications in bioprocess engineering, including strain design, process control and optimization, as well as bioreactor scale-up. Finally, the challenges and opportunities of biomanufacturing towards Industry 4.0 are also discussed.