Hybrid-EKF: Hybrid Model coupled with Extended Kalman Filter for real-time monitoring and control of mammalian cell culture.

: In a decade when industry 4.0 and Quality by Design are major technology drivers of biopharma, automated and adaptive process monitoring and control are inevitable requirements and model-based solutions are key enablers in fulfilling these goals. Despite strong advancement in process digitalization, in most cases, the generated data sets are not sufficient for relying on purely data-driven methods, while the underlying complex bioprocesses are still not completely understood. In this regard, hybrid models are emerging as a timely pragmatic solution to synergistically combine available process data and mechanistic understanding. In this work we show a novel application of Hybrid-EKF framework, that is hybrid models coupled with extended Kalman filter for real-time monitoring, control and automated decision making in mammalian cell culture processing. We show that, in the considered application, the predictive monitoring accuracy of such framework improves by at least 35% when developed with hybrid models with respect to industrial benchmark tools based on PLS models. Additionally, we also highlight the advantages of this approach in industrial applications related to conditional process feeding and process monitoring. With regards to the latter, for an industrial use case we demonstrate that the application of Hybrid-EKF as a soft sensor for titer shows a 50% improvement in prediction accuracy compared to state-of-the-art soft sensor tools. This article is protected by copyright. All rights reserved.