The bio-economy is in transit from innovation to commercialization. The bioprocess industry is expected to increasingly deliver bio-products to the market, in large amounts, at high quality and at competitive cost levels. This requires flawless start-up of new large-scale bioprocesses and continuous improvement of running processes. Fermentation scale-up and operation can benefit from recent advances in three areas: 1. computation-driven design of scale-down simulators, 2. omics-driven metabolic engineering and 3. sensing and understanding of population heterogeneity. Integration of these fields requires a unified computational approach, linked to big data and simulated reality frameworks, of which the contours are becoming visible today.