We investigate means to control critical quality attributes and to apply Process Analytical Technology (PAT) on the basis of online dielectric spectroscopy (DS) probe feedback control system that has been intensively explored and successfully implemented in GMP manufacturing processes at Biogen. The present bioreactor application of DS probe is basic and only allows the prediction of biomass. More and more studies recently illustrated that DS probes can be used to measure not only the biomass but also the physiological state of mammalian cells. To further enhance the cell culture process robustness, we investigated the feasibility of using full-spectrum dielectric spectroscopy data to detect dielectric changes in the cells associated with shifts in cell health and/or metabolism. In this study, the on-line multi-frequency permittivity scanning data were collected from several culture processes in which apoptosis was induced by several approaches. In the meantime, key parameters of delta capacitance (△ε), critical frequency (fc), and Cole-Cole Alpha (α) factor in the β-dispersion curve were calculated on-line and correlated to cell growth information got from offline methods (trypan blue exclusion and fluorescent flow cytometry). The results from the multi-frequency scanning data showed that the early apoptotic changes in cells could be reflected in one or more of the key parameters. This enables a potential application of full-spectrum dielectric spectroscopy for earlier detection of physiological changes, allowing for timelier bioreactor feed adjustments.

Feasibility study of dielectric spectroscopy as a tool for monitoring and controlling of mammalian cell culture processes

253rd National Meeting (2017)

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