Advancement of sensor technology for monitoring and control of upstream bioprocesses

Abstract: In bioprocesses, the upstream process part with cultivation and harvesting steps has decisive influence on the final process outcome, including the quality of the product, the productivity and the yield. To ensure stable product quality of biopharmaceuticals, the U.S. Food and Drug Administration (FDA) encourages the industry to apply the process analytical technology (PAT) guidelines. These guidelines strongly recommend advancements in sensor monitoring and control technology as the important means for improving performance of pharmaceutical manufacturing.The aim of this thesis is to contribute to this advancement of sensor technology, by proposing alternative ways to apply existing sensors for monitoring and control of upstream bioprocesses. Cutting-edge sensor technologies are evaluated with respect to their suitability for process monitoring of critical process parameters. The sensor technologies are compared with other analytical techniques, mainly based on their performance and applicability for monitoring as well as control of common bioprocesses.To cover diverse bioprocess conditions and requirements, a range of organisms, including bacteria, yeast and mammalian cells, have been used in the thesis. Through this, different needs, obstacles and challenges have been unraveled when culturing these organisms. One of these challenges is the wide span of growth rates of the cells used in production, which limits the number of the sensor technologies that are suitable for accomplishing efficient process monitoring and control. The mammalian cells for example, grow at a low rate, and may therefore allow the use of an at-line measurement technology as the presented screen-printed single-use enzyme biosensor for monitoring of metabolite formation. On the contrary, rapidly growing microorganisms, for example bacteria and yeasts, require faster analytical techniques, such as the in-line capacitance and near-infrared sensors used in the presented studies.This thesis emphasizes the current needs and the importance of providing new and more advanced sensor technology for upstream bioprocess monitoring. The parallel advancements of bioreactor designs, with both stainless steel and disposable bioreactors, further emphasizes the need for a high degree of adaptability of the sensors. As highlighted in the thesis, the advancement of the sensors should also contribute to improve process stability and quality of the product by applying process control methods that efficiently can handle unexpected variations in biological production systems.