Data reconciliation of concentration estimates from mid‐infrared and dielectric spectral measurements for improved on‐line monitoring of bioprocesses

Abstract

Real-time data reconciliation of concentration estimates of process analytes and biomass in microbial fermentations is investigated. A Fourier-transform mid-infrared spectrometer predicting the concentrations of process metabolites is used in parallel with a dielectric spectrometer predicting the biomass concentration during a batch fermentation of the yeast Saccharomyces cerevisiae. Calibration models developed off-line for both spectrometers suffer from poor predictive capability due to instrumental and process drifts unseen during calibration. To address this problem, the predicted metabolite and biomass concentrations, along with off-gas analysis and base addition measurements, are reconciled in real-time based on the closure of mass and elemental balances. A statistical test is used to confirm the integrity of the balances, and a non-negativity constraint is used to guide the data reconciliation algorithm toward positive concentrations. It is verified experimentally that the proposed approach reduces the standard error of prediction without the need for additional off-line analysis.

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

“…Absorption of IR light in the mid-IR region (approximately 2.5-50 mm) by molecules leads to the generation of unique spectra. 22 MIR absorption spectroscopy provides a molecularly specific analytical technique that has been used for a variety of BioPharma applications including raw material analysis, bioprocess monitoring, 38,39 and the characterization of formulated drug product. [40][41][42] NIR absorption spectroscopy is a near analogue that utilizes shorterwavelength/higher-energy light (800-2500 nm).…”

Simple control of specific growth rate in biotechnological fed-batch processes based on enhanced online measurements of biomass

“…In addition, the amounts of base consumed for pH control and of medium fed into the bioreactor were registered online by placing the reservoirs containing base and medium on analytical balances (PG5001-S, Mettler-Toledo, Greifensee, Switzerland) interfaced to LabVIEW. From the online measurements, a set of online mass and elemental balances (carbon, nitrogen, degree of reduction and charge) were set up [19,21]. The balances served as constraints for a data reconciliation algorithm which adjusted all measurements to their best estimates.…”

“…During fed-batch cultures of three different strains of yeast, biomass concentration measurements provided by dielectric spectroscopy are enhanced in accuracy by reconciling them in real time against online measurements of the concentrations of medium metabolites and off-gas composition [19]. The reconciliation algorithm is based on the closure of mass and elemental balances, while a statistical test is used to confirm the integrity of the balances throughout the process.…”

Real-time monitoring and control of microbial bioprocesses with focus on the specific growth rate: current state and perspectives

“…Mathematical techniques are of utmost importance to provide measurements with enhanced reliability and reduced noise. Ways to achieve noise reduction and increase reliability include data reconciliation (Dabros et al 2009(Dabros et al , 2010, filters (Claes and Van Impe 1999), or ANN. In summary, over the past two decades, important realizations have been achieved in terms of controlling the specific growth rate.…”

“…Carbon source concentration measurements are more difficult to obtain. Fourier-transform mid-infrared (FTIR) and near-infrared (NIR) spectroscopy is gaining importance in the real-time monitoring of metabolites (Hall et al 1996;Finn et al 2006;Dabros et al 2009). In comparison to at-line or off-line HPLC, spectroscopy is faster in terms of measurement time; however, the limit of quantification is higher.…”