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Liquid–liquid extraction has proven to be an aid in biologics manufacturing for cell and component separation. Because distribution coefficients and separation factors can be appropriately adjusted via phase screening, especially in aqueous two-phase systems, one stage is frequently feasible. For biologics separation, aqueous two-phase systems have proven to be feasible and efficient. The simple mixer–settler equipment type is still not standard in biologics manufacturing operations. Therefore, a scalable digital twin would be of aid for operator training, process design under the regulatory demanded quality by design approach for risk analysis, design and control space definition, and predictive maintenance. Autonomous operation is achieved with the aid of process analytical technology to update the digital twin to real time events and to allow process control near any optimal operation point. Autonomous operation is first demonstrated with an experimental feasibility study based on an industrial type example of pDNA manufacturing via lysis from E. coli with and without cell separation performance.

Process chromatography modelling for process development, design, and optimization as well as process control has been under development for decades. Still, the discussion of scientific potential and industrial applications needs is open to innovation. The discussion of next-generation modelling approaches starting from Langmuirian to steric mass action and multilayer or thermodynamic consistent real and ideal adsorption theory or colloidal particle adsorption approaches is continued.