Nonlinear state estimation as tool for online monitoring and adaptive
feed in high-throughput cultivations
Abstract
Robotic facilities that can perform advanced cultivation (e.g.,
fed-batch or continuous) in high throughput have drastically increased
the speed and reliability of the bioproduct development pipeline in the
last decades. Still, developing reliable analytical technologies, that
can cope with the throughput of the cultivation system, has proven to be
very challenging. On the one hand, the analytical accuracy suffers from
the low sampling volumes, and on the other hand, the number of samples
that must be treated rapidly is very large. These issues have been a
major limitation to implement feedback control methods in miniaturized
bioreactor systems, where the observations of the process states are
typically obtained after the experiment has finished. In this work, we
implement a Sigma-Point Kalman filter in a high-throughput platform with
24 parallel experiments at the mL-scale to demonstrate its viability and
added value in high throughput experiments. This method exploits the
information generated by the ammonia-based pH control to enable the
continuous estimation of biomass, a critical state to monitor the
specific rates of production and consumption in the process. The
objective in our case study is to ensure that the selected specific
growth rate is tightly controlled throughout the complete
Escherichia coli cultivations for recombinant production of
antibody fragment.