Novel Strategy for the Calorimetry-Based Control of Fed-Batch Cultivations of Saccharomyces cerevisiae

Jérémy Kottelat,Brian Freeland,Michal Dabros

doi:10.3390/pr9040723

Abstract

Typical controllers for fed-batch cultivations are based on the estimation and control of the specific growth rate in real time. Biocalorimetry allows one to measure a heat signal proportional to the substrate consumed by cells. The derivative of this heat signal is usually used to evaluate the specific growth rate, introducing noise to the resulting estimate. To avoid this, this study investigated a novel controller based directly on the heat signal. Time trajectories of the heat signal setpoint were modelled for different specific growth rates, and the controller was set to follow this dynamic setpoint. The developed controller successfully followed the setpoint during aerobic cultivations of Saccharomyces cerevisiae, preventing the Crabtree effect by maintaining low glucose concentrations. With this new method, fed-batch cultivations of S. cerevisiae could be reliably controlled at specific growth rates between 0.075 h−1 and 0.20 h−1, with average root mean square errors of 15 ± 3%.

Highlights

Biotechnology is a science that has developed remarkably in recent decades thanks to a wide range of applications including the production of complex organic molecules with high selectivity, such as proteins for biomedical purposes [1], functional foods and alcohols via the industrial fermentation of Saccharomyces cerevisiae [2]
With the vision of encouraging Quality by Design [7], the Federal Drug Administration (FDA) proposed in 2004 a uniform initiative named Process Analytical Technology (PAT), aiming to promote bioprocess monitoring to an integral component of all industrial processes [8]
As discussed by Dabros et al (2010), the estimation and control of the specific growth rate is highly desirable in order to maximise cell growth or product formation; it proves difficult due to signal noise [9]

Summary

Introduction

Biotechnology is a science that has developed remarkably in recent decades thanks to a wide range of applications including the production of complex organic molecules (biologics) with high selectivity, such as proteins for biomedical purposes [1], functional foods and alcohols via the industrial fermentation of Saccharomyces cerevisiae [2]. Since microorganisms release a specific amount of heat during their growth, biocalorimetry is a promising method to monitor bioprocesses [10]. The measured heat signal can be used for the direct control of fed-batch cultures [11] or coupled with other monitoring methods to consolidate data [12]. Crabtree-positive microorganisms such as S. cerevisiae experience a change in metabolism when the glucose concentration in the culture medium is increased above a critical value. Enthalpies of these metabolisms are significantly different and could be used to detect a change in metabolism during microbial cultures [13]

Objectives

Methods

Results