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Dynamic crossflow filtration (DCF) is the state-of-the-art technology for solid–liquid separation from viscous and sensitive feed streams in the food and biopharma industry. Up to now, the potential of industrial processes is often not fully exploited, because fixed recipes are usually applied to run the processes. In order to take the varying properties of biological feed materials into account, we aim to develop a digital twin of an industrial brownfield DCF plant, allowing to optimize setpoint decisions in almost real time. The core of the digital twin is a mechanistic–empirical process model combining fundamental filtration laws with process expert knowledge. The effect of variation in the selected process and model parameters on plant productivity has been assessed using a model-based design-of-experiments approach, and a regression metamodel has been trained with the data. A cyclic program that bidirectionally communicates with the DCF asset serves as frame of the digital twin. It monitors the process dynamics membrane torque and transmembrane pressure and feeds back the optimum permeate flow rate setpoint to the physical asset in almost real-time during process runs. We considered a total of 24 industrial production batches from the filtration of grape juice from the years 2022 and 2023 in the study. After implementation of the digital twin on site, the campaign mean productivity increased by 15% over the course of the year 2023. The presented digital twin framework is a simple example how an industrial established process can be controlled by a hybrid model-based algorithm. With a digital process dynamics model at hand, the presented metamodel optimization approach can be easily transferred to other (bio)chemical processes. [ABSTRACT FROM AUTHOR]