On-line monitoring of process parameters during fermentation

Fermentation is a complex process, requiring strict control of metabolites and nutrients to achieve optimal cell growth and thus maximize product yields. However, when comparing full-scale operation to pilot and lab-scale, the number of on-line sensors for monitoring of full-scale bioreactors is usually limited, consisting of traditional sensors to measure temperature, pH, and dissolved oxygen, combined with off-gas analysis. The detailed monitoring of cell performance is usually achieved by taking regular samples from the fermentation medium during the process, followed by off-line measurement of substrate, metabolite, and product levels in the samples. Thus real-time monitoring of such critical process parameters is often lacking, and therefore, control actions are often manual tasks based upon experience rather than data. Besides impeding optimal processing, this approach entails highly resource-intensive analyses/assays. Therefore, due to the potential benefits of improved on-line monitoring of fermentation processes, a large body of research has focused on developing improved on-line monitoring strategies. Soft sensors, biosensors, instruments for on-line monitoring of particles, and spectroscopic sensors combined with chemometrics are great examples of promising on-line monitoring methods, and will be reviewed. In this work, we review up-to-date advances in on-line strategies developed for the monitoring of critical fermentation-related parameters. Furthermore, in the future perspectives section, we highlight the potential of using data-driven modeling in monitoring and control, an endeavor to bring the biomanufacturing industry one step closer to Industry 4.0.