Abstract
In 2004, the FDA published a guideline to implement process analytical technologies (PAT) in biopharmaceutical processes for process monitoring to gain process understanding and for the control of important process parameters. Viable cell concentration (VCC) is one of the most important key performance indicator (KPI) during mammalian cell cultivation processes. Commonly, this is measured offline. In this work, we demonstrated the comparability and scalability of linear regression models derived from online capacitance measurements. The linear regressions were used to predict the VCC and other familiar offline biomass indicators, like the viable cell volume (VCV) and the wet cell weight (WCW), in two different industrially relevant CHO cell culture processes (Process A and Process B). Therefore, different single-use bioreactor scales (50–2000 L) were used to prove feasibility and scalability of the in-line sensor integration. Coefficient of determinations of 0.79 for Process A and 0.99 for Process B for the WCW were achieved. The VCV was described with high coefficients of determination of 0.96 (Process A) and 0.98 (Process B), respectively. In agreement with other work from the literature, the VCC was only described within the exponential growth phase, but resulting in excellent coefficients of determination of 0.99 (Process A) and 0.96 (Process B), respectively. Monitoring these KPIs online using linear regression models appeared to be scale-independent, enabled deeper process understanding (e.g. here demonstrated in monitoring, the feeding profile) and showed the potential of this method for process control.
Highlights
Scalability is a key aspect for biopharmaceutical companies to transfer a process that is producing an important protein or product from development stage to production scale
It was shown that the online permittivity signal is capable to describe different key performance indicator (KPI) for biomass dynamics during process scale-up of different CHO cell culture processes
The sensor integration was successfully demonstrated for single-use bioreactor scales ranging from 50 L up to 2000 L reactor volume and scale-independence of the method was shown
Summary
Scalability is a key aspect for biopharmaceutical companies to transfer a process that is producing an important protein or product from development stage to production scale. The viable cell concentration (VCC) is one of the most important key performance indicator (KPI) during upstream technologies in mammalian cell culture [3]. The limited samples per cultivation day as well as the time delay to respond to process changes are significant limitations of offline measurements that prevent efficient process monitoring and control of important CPPs. Several online methods to monitor the cell concentration of mammalian cell cultures have been investigated and developed in the last years (e.g. radio frequency impedance, Raman spectroscopy or near-infrared spectroscopy) [16,17,18,19,20,21,22]
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