A non-linear model predictive controller (NMPC) was investigated as a route to delivering improved product quality, batch to batch reproducibility and significant cost reductions by providing a means for better controlling the bioreactor environment in a Chinese hamster ovary (CHO) mammalian cell fed-batch process. A nonlinear fundamental bioprocess model was developed to represent the CHO mammalian cell fedbatch bioprocess under study. This developed nonlinear model aided in the configuration and tuning of a NMPC through off-line simulation. The tuned NMPC was applied to a 15 L pilot-plant bioreactor for glucose concentration fixed set-point control. Traditionally, bioprocesses are characterized by long critical process parameter (CPP) measurement intervals (24 h). However, advances in PAT have helped increase CPP measurement frequency. An in situ Kaiser RXN2 Raman spectroscopy instrument was used to monitor the glucose concentration at 6 min intervals. Glucose concentration control of a bioreactor is not a trivial task due to high process variability, measurement noise and long measurement intervals. Nevertheless, NMPC proved successful in achieving closed loop fixed set-point control in the presence of these common bioprocess operation attributes. (C) 2014 Elsevier Ltd. All rights reserved.