Abstract
Glucose control is vital to ensure consistent growth and protein production in mammalian cell cultures. The typical fed-batch glucose control strategy involving bolus glucose additions based on infrequent off-line daily samples results in cells experiencing significant glucose concentration fluctuations that can influence product quality and growth. This study proposes an on-line method to control and manipulate glucose utilizing readily available process measurements. The method generates a correlation between the cumulative oxygen transfer rate and the cumulative glucose consumed. This correlation generates an on-line prediction of glucose that has been successfully incorporated into a control algorithm manipulating the glucose feed-rate. This advanced process control (APC) strategy enables the glucose concentration to be maintained at an adjustable set-point and has been found to significantly reduce the deviation in glucose concentration in comparison to conventional operation. This method has been validated to produce various therapeutic proteins across cell lines with different glucose consumption demands and is successfully demonstrated on micro (15 mL), laboratory (7 L), and pilot (50 L) scale systems. This novel APC strategy is simple to implement and offers the potential to significantly enhance the glucose control strategy for scales spanning micro-scale systems through to full scale industrial bioreactors.
Highlights
Glucose control is vital to ensure consistent growth and protein production in mammalian cell cultures
Luan et al.[4] initially demonstrated the benefits of successfully incorporated into a control algorithm manipulating the glucose conventional fed-batch operation of mamfeed-rate. This advanced process control (APC) strategy enables the glucose concentration to be maintained at an adjustable set-point and has been found to significantly reduce the deviation in glucose concentration in comparison to conventional operation. This method has been validated to malian cells through enhanced cell viability while maintaining a cell density equal to 2.1 Â 106 cells mLÀ1 in addition to increasing the monoclonal antibody concentration four-fold to 0.140 g LÀ1 produce various therapeutic proteins across cell lines with different glucose compared to similar batch cell cultures
The measurements required for the cumulative glucose consumption rate (Gluccon) and the cumulative glucose added (GlucAdd) are the off-line concentration of glucose (Gluc) and the volume of glucose added (VGluc)
Summary
Glucose control is vital to ensure consistent growth and protein production in mammalian cell cultures. This correlation generates an on-line prediction of glucose that has been the initial media charge supports growth and production while subsequent feed additions prevent nutrient depletion and sustain protein production.[2,3] Luan et al.[4] initially demonstrated the benefits of successfully incorporated into a control algorithm manipulating the glucose conventional fed-batch operation of mamfeed-rate This advanced process control (APC) strategy enables the glucose concentration to be maintained at an adjustable set-point and has been found to significantly reduce the deviation in glucose concentration in comparison to conventional operation. This method has been validated to malian cells through enhanced cell viability while maintaining a cell density equal to 2.1 Â 106 cells mLÀ1 in addition to increasing the monoclonal antibody (mAb) concentration four-fold to 0.140 g LÀ1 produce various therapeutic proteins across cell lines with different glucose compared to similar batch cell cultures
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