Inline noninvasive Raman monitoring and feedback control of glucose concentration during ethanol fermentation

Hirsch, Edit; Pataki, Hajnalka; Domján, Júlia; Farkas, Attila; Vass, Panna; Fehér, Csaba; Barta, Zsolt; Nagy, Zsombor Kristóf; Marosi, György; Csontos, István

doi:10.1002/btpr.2848

Cited by 36 publications

(43 citation statements)

References 30 publications

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“…Hirsch et al utilized Raman technology for control of an ethanol producing yeast fermentation. The process was kept at around 100 g/L glucose resulting in a significantly higher ethanol yield ( Hirsch et al, 2019 ). The previously mentioned study of Berry et al also utilized Raman spectroscopy for in-line quantification of glucose.…”

Section: Introductionmentioning

confidence: 99%

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy

Graf

Lemke

Schulze

et al. 2022

Front. Bioeng. Biotechnol.

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Continuous manufacturing is becoming more important in the biopharmaceutical industry. This processing strategy is favorable, as it is more efficient, flexible, and has the potential to produce higher and more consistent product quality. At the same time, it faces some challenges, especially in cell culture. As a steady state has to be maintained over a prolonged time, it is unavoidable to implement advanced process analytical technologies to control the relevant process parameters in a fast and precise manner. One such analytical technology is Raman spectroscopy, which has proven its advantages for process monitoring and control mostly in (fed-) batch cultivations. In this study, an in-line flow cell for Raman spectroscopy is included in the cell-free harvest stream of a perfusion process. Quantitative models for glucose and lactate were generated based on five cultivations originating from varying bioreactor scales. After successfully validating the glucose model (Root Mean Square Error of Prediction (RMSEP) of ∼0.2 g/L), it was employed for control of an external glucose feed in cultivation with a glucose-free perfusion medium. The generated model was successfully applied to perform process control at 4 g/L and 1.5 g/L glucose over several days, respectively, with variability of ±0.4 g/L. The results demonstrate the high potential of Raman spectroscopy for advanced process monitoring and control of a perfusion process with a bioreactor and scale-independent measurement method.

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Section: Introductionmentioning

confidence: 99%

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy

Graf

Lemke

Schulze

et al. 2022

Front. Bioeng. Biotechnol.

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“…Raman spectroscopy is a valuable tool in a process analytical chemist's toolbox. 15 It has been proven benecial for in-line monitoring of various organisms such as bacteria, 16,17 fungi, 18 yeast, [19][20][21][22] or mammalian cells. 23 Raman spectroscopy is a noninvasive, optical method that mirrors the chemical composition of the probed focal volume.…”

Section: Introductionmentioning

confidence: 99%

Non-invasive Raman spectroscopy for time-resolved in-line lipidomics

et al. 2021

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“…To this end, this work differs from the traditional sensor/measurement development and process monitoring developments, which shows the potential benefits of a given monitoring strategy, but in general, fail to show tangible benefits by using the data monitored on-line to carryout closed-loop control [ 23 – 25 ]. Some recent studies have used glucose measurements taken using Raman spectroscopy [ 26 ] or total sugars content measured with the refractive index [ 27 ] together with P-controllers to adjust the feed flow-rate in ethanol fermentations. Although this resulted in faster fermentation processes, P-controllers often show off-set errors that prevent the present value from reaching the set-point and thus from the optimal conditions.…”

Section: Discussionmentioning

confidence: 99%

Promoting the co-utilisation of glucose and xylose in lignocellulosic ethanol fermentations using a data-driven feed-back controller

López

Udugama

Thomsen

et al. 2020

Biotechnol Biofuels

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Background The diauxic growth of Saccharomyces cerevisiae on glucose and xylose during cellulose-to-ethanol processes extends the duration of the fermentation and reduces productivity. Despite the remarkable advances in strain engineering, the co-consumption of glucose and xylose is still limited due to catabolite repression. This work addresses this challenge by developing a closed-loop controller that is capable of maintaining the glucose concentration at a steady set-point during fed-batch fermentation. The suggested controller uses a data-driven model to measure the concentration of glucose from ‘real-time’ spectroscopic data. The concentration of glucose is then automatically controlled using a control scheme that consists of a proportional, integral, differential (PID) algorithm and a supervisory layer that manipulates the feed-rates to the reactor accounting for the changing dynamics of fermentation. Results The PID parameters and the supervisory layer were progressively improved throughout four fed-batch lignocellulosic-to-ethanol fermentations to attain a robust controller able of maintaining the glucose concentration at the pre-defined set-points. The results showed an increased co-consumption of glucose and xylose that resulted in volumetric productivities that are 20–33% higher than the reference batch processes. It was also observed that fermentations operated at a glucose concentration of 10 g/L were faster than those operated at 4 g/L, indicating that there is an optimal glucose concentration that maximises the overall productivity. Conclusions Promoting the simultaneous consumption of glucose and xylose in S. cerevisiae is critical to increase the productivity of lignocellulosic ethanol processes, but also challenging due to the strong catabolite repression of glucose on the uptake of xylose. Operating the fermentation at low concentrations of glucose allows reducing the effects of the catabolite repression to promote the co-consumption of the two carbon sources. However, S. cerevisiae is very sensitive to changes in the glucose concentration and deviations from a set-point result in notable productivity losses. The controller structure developed and implemented in this work illustrates how combining data-driven measurements of the glucose concentration and a robust yet effective PID-based supervisory control allowed tight control of the concentration of glucose to adjust it to the metabolic requirements of the cell culture that can unlock tangible gains in productivities.

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Inline noninvasive Raman monitoring and feedback control of glucose concentration during ethanol fermentation

Cited by 36 publications

References 30 publications

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy

A Novel Approach for Non-Invasive Continuous In-Line Control of Perfusion Cell Cultivations by Raman Spectroscopy

Non-invasive Raman spectroscopy for time-resolved in-line lipidomics

Promoting the co-utilisation of glucose and xylose in lignocellulosic ethanol fermentations using a data-driven feed-back controller

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