The biomanufacturing industry has now the opportunity to upgrade its production processes to be in harmony with the latest industrial revolution. Technology creates capabilities that enable smart manufacturing while still complying with unfolding regulations. However, many biomanufacturing companies, especially in the biopharma sector, still have a long way to go to fully benefit from smart manufacturing as they first need to transition their current operations to an information-driven future. One of the most significant obstacles towards the implementation of smart biomanufacturing is the collection of large sets of relevant data. Therefore, in this work, we both summarize the advances that have been made to date with regards to the monitoring and control of bioprocesses, and highlight some of the key technologies that have the potential to contribute to gathering big data. Empowering the current biomanufacturing industry to transition to Industry 4.0 operations allows for improved productivity through information-driven automation, not only by developing infrastructure, but also by introducing more advanced monitoring and control strategies.

The high substrate variability and complexity of fermentation media derived from lignocellulosic feedstock affects the concentration profiles and the length of the fermentation. Failing to account for such variability raises operational and scheduling issues and affects the overall performance of these processes. In this work, a hybrid soft sensor was developed to monitor and forecast the evolution of cellulose‐to‐ethanol fermentation. The soft sensor consisted of two modules (a data‐driven model and a kinetic model) connected sequentially. The data‐driven module used a partial‐least‐squares model to estimate the current state of glucose from spectroscopic data. The kinetic model was recursively fitted to known concentrations of glucose to update the long‐horizon predictions of glucose, xylose, and ethanol. This combination of real‐time data update from an actual fermentation process to a high‐fidelity kinetic model constitutes the basis of the digital twin concept and allows for a better real‐time understanding of complex inhibition phenomena caused by different inhibitors commonly found in lignocellulosic feedstocks. The soft sensor was experimentally validated with three different cellulose‐to‐ethanol fermentations and the results suggested that this method is suitable for monitoring and forecasting fermentation when the measurements provide reasonably good estimates of the real state of the system. These results would allow the flexibility of the operation of cellulosic processes to be increased, and would permit the scheduling to be adapted to the inherent variability of such substrates © 2020 Society of Chemical Industry and John Wiley & Sons, Ltd.

The domain of industrial biomanufacturing is enthusiastically embracing the concept of Digital Twin, owing to its promises of increased process efficiency and resource utilisation. However, Digital Twin in biomanufacturing is not yet clearly defined and this sector of the industry is falling behind the others in terms of its implementation. On the other hand, some of the benefits of Digital Twin seem to overlap with the more established practices of process control and optimization, and the term is vaguely used in different scenarios. In an attempt to clarify this issue, we investigate this overlap for the specific case of fermentation operation, a central step in many biomanufacturing processes. Based on this investigation, a framework built upon a five-step pathway starting from a basic steady-state process model is proposed to develop a fully-fledged Digital Twin. For demonstration purposes, the framework is applied to a bench-scale second-generation ethanol fermentation process as a case study. It is proposed that the success or failure of a fully-fledged Digital Twin implementation is determined by key factors that comprise the role of modelling, human operator actions, and other propositions of economic value.

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Operating lignocellulosic fermentation processes to produce fuels and chemicals is challenging due to the inherent complexity and variability of the fermentation media. Real‐time monitoring is necessary to compensate for these challenges, but the traditional process monitoring methods fail to deliver actionable information that can be used to implement advanced control strategies. In this study, a hybrid‐modeling approach is presented to monitor cellulose‐to‐ethanol (EtOH) fermentations in real‐time. The hybrid approach uses a continuous‐discrete extended Kalman filter to reconciliate the predictions of a data‐driven model and a kinetic model and to estimate the concentration of glucose (Glu), xylose (Xyl), and EtOH. The data‐driven model is based on partial least squares (PLS) regression and predicts in real‐time the concentration of Glu, Xyl, and EtOH from spectra collected with attenuated total reflectance mid‐infrared spectroscopy. The estimations made by the hybrid approach, the data‐driven models and the internal model were compared in two validation experiments showing that the hybrid model significantly outperformed the PLS and improved the predictions of the internal model. Furthermore, the hybrid model delivered consistent estimates even when disturbances in the measurements occurred, demonstrating the robustness of the method. The consistency of the proposed hybrid model opens the doors towards the implementation of advanced feedback control schemes.