To culture aerobic cells, a system must contain an adequate supply of dissolved oxygen. Tracking the oxygen uptake by the cells—crucial as it is—takes more effort than might be expected, but scientists at Bilfinger Industrietechnik Salzburg make the process easier and more accurate.

Recently, Bilfinger’s R&D supervisor in the field of bioprocessing, Wolfgang Sommeregger, and his colleagues described an oxygen uptake rate (OUR) software-sensor that can provide continuous, real-time data. “The oxygen uptake rate of the cultured cells is commonly determined using a mass balance equation,” Sommeregger says. “This necessitates the measurement of the gas influx as well as the oxygen concentration in the off-gas stream over time.” That poses a couple of challenges. First, Sommeregger points out, off-gas analyzers are expensive. Plus, the low cell densities in mammalian cell cultures can be characterized with low oxygen consumption that makes “the establishment of an exact mass balance challenging,” Sommeregger explains. Therefore, he and his colleagues established a software-sensor that “is based on standard sensor data and an adequate kLa [volumetric mass transfer coefficient] characterization of the bioreactor within the process design space.”

Wolfgang Sommeregger chart
On-line application of the OUR soft-sensor in a mammalian bioprocess using Bilfinger’s Advanced Process Monitoring and Control software named Qubicon. A recombinant Chinese Hamster Ovary (CHO) process was subjected to temperature shifts in order to explore the impact on specific oxygen uptake rates. The OUR profile (blue) is compared to cell concentrations, which were manually obtained (red). [Wolfgang Sommeregger]

This so-called OUR soft-sensor—soft for software—provides several benefits. First, this method does not require off-gas analysis. “Another advantage of the published method is that once a standard bioreactor system is characterized, the model can be easily transferred to structurally identical units, given that the process design space is the same,” Sommeregger says. Beyond mammalian cell culture, this OUR soft-sensor can also be applied to any other aerobic bioprocess.

Plus, biomanufacturers don’t need much to make use of this technique. “Besides standard sensors, only the characterization of the culture system is required, which is done in most cases anyway,” Sommeregger says. “Due to the absence of off-gas measurements, the determination of the OUR value with the soft-sensor becomes possible even in miniaturized culture systems or high-throughput systems.”

Turning to this technique can help a biomanufacturer analyze a process. “Knowledge about the OUR progression throughout the process may be exceedingly informative during medium optimization or clone development,” Sommeregger explains. “Finally, upon combination with biomass measurements, the OUR progression may also be used to identify metabolic transitions in the culture.”

That’s a lot of information from advanced software and standard sensors. As Sommeregger and his colleagues wrote, this OUR soft-sensor “can provide broad information on cultured cells.”

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