Glucose concentration control of a fed-batch mammalian cell bioprocess using a nonlinear model predictive controller

Craven, Stephen; Whelan, Jessica; Glennon, Brian

doi:10.1016/j.jprocont.2014.02.007

Cited by 151 publications

(131 citation statements)

References 21 publications

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“…118,165 In 2014, Craven et al demonstrated the next logical step, a Raman analysis that could be used to control a bioprocess; the ''nonlinear model predictive controller'' (NMPC) used online Raman measurements and a closed-loop feedback control system to maintain the glucose concentration at 11 mM inside a CHO bioprocess (15 L) bioreactor (Figure 11). 166 A similar approach was recently published for the control of lactate concentration during culture. 167 Figure 8.…”

Section: Bioprocess Analysis and Monitoringmentioning

confidence: 98%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein-and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc.) and have spawned a large (>E35 billion sales annually in Europe) and growing biopharmaceutical industry (BioPharma). The structural and chemical complexity of biologics, combined with the intricacy of cell-based manufacturing, imposes a huge analytical burden to correctly characterize and quantify both processes (upstream) and products (downstream). In small molecule manufacturing, advances in analytical and computational methods have been extensively exploited to generate process analytical technologies (PAT) that are now used for routine process control, leading to more efficient processes and safer medicines. In the analytical domain, biologic manufacturing is considerably behind and there is both a huge scope and need to produce relevant PAT tools with which to better control processes, and better characterize product macromolecules. Raman spectroscopy, a vibrational spectroscopy with a number of useful properties (nondestructive, non-contact, robustness) has significant potential advantages in BioPharma. Key among them are intrinsically high molecular specificity, the ability to measure in water, the requirement for minimal (or no) sample pre-treatment, the flexibility of sampling configurations, and suitability for automation. Here, we review and discuss a representative selection of the more important Raman applications in BioPharma (with particular emphasis on mammalian cell culture). The review shows that the properties of Raman have been successfully exploited to deliver unique and useful analytical solutions, particularly for online process monitoring. However, it also shows that its inherent susceptibility to fluorescence interference and the weakness of the Raman effect mean that it can never be a panacea. In particular, Raman-based methods are intrinsically limited by the chemical complexity and wide analyte-concentration-profiles of cell culture media/bioprocessing broths which limit their use for quantitative analysis. Nevertheless, with appropriate foreknowledge of these limitations and good experimental design, robust analytical methods can be produced. In addition, new technological developments such as time-resolved detectors, advanced lasers, and plasmonics offer potential of new Raman-based methods to resolve existing limitations and/or provide new analytical insights.

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Section: Bioprocess Analysis and Monitoringmentioning

confidence: 98%

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

2017

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“…The constituents included in the study had been previously identified as key parameters for development of advanced dynamic feeding strategies. 27 Generic multivariate models were developed to measure glucose and lactate concentrations as well as VCD during fed-batch mammalian cell culture processes. The final Raman models were generic in the sense that they are scale and process independent, and thus can be used at multiple scales and for various processes, regardless if the cell line had been included in the initial calibration dataset.…”

Section: Application Of Raman For Cell Culture Measurementsmentioning

confidence: 99%

Generic Raman‐based calibration models enabling real‐time monitoring of cell culture bioreactors

Mehdizadeh

Lauri

Karry

et al. 2015

Biotechnology Progress

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Raman-based multivariate calibration models have been developed for real-time in situ monitoring of multiple process parameters within cell culture bioreactors. Developed models are generic, in the sense that they are applicable to various products, media, and cell lines based on Chinese Hamster Ovarian (CHO) host cells, and are scalable to large pilot and manufacturing scales. Several batches using different CHO-based cell lines and corresponding proprietary media and process conditions have been used to generate calibration datasets, and models have been validated using independent datasets from separate batch runs. All models have been validated to be generic and capable of predicting process parameters with acceptable accuracy. The developed models allow monitoring multiple key bioprocess metabolic variables, and hence can be utilized as an important enabling tool for Quality by Design approaches which are strongly supported by the U.S. Food and Drug Administration.

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“…In a feasibility study by Craven et al, Raman spectroscopy was integrated with a nonlinear model predictive controller (NMPC) [85]. Raman spectra were collected every 6 min in a 15 L bioreactor growing CHO cells.…”

Section: Bioprocessingmentioning

confidence: 99%

“…In the 2014 study by Iversen et al, the authors noted that the relationship of yeast cell concentration with light extinction could not be adequately described using Beer-Lambert law, that non-linear, wavelength-dependent attenuation necessitated describing the relationship for each individual component using quadratic equations, and that the modeling was valid because the yeast cells were the only Lorenz-Mie scattering particles in the bioprocess [78]. An explicit model for CHO cell culture fed-batch was developed to account for bioprocess nonlinearities, with demonstrated success for in-process control of glucose concentrations [85]. Correcting for turbidity in aqueous media is of interest for Raman spectroscopy of water quality applications, and the developed approaches may be adapted for bioprocessing [92].…”

Section: Chemometric Modeling Of Bioprocessesmentioning

confidence: 99%

Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing

Esmonde-White

Cuellar

Uerpmann³

et al. 2016

Anal Bioanal Chem

232

153

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Adoption of Quality by Design (QbD) principles, regulatory support of QbD, process analytical technology (PAT), and continuous manufacturing are major factors effecting new approaches to pharmaceutical manufacturing and bioprocessing. In this review, we highlight new technology developments, data analysis models, and applications of Raman spectroscopy, which have expanded the scope of Raman spectroscopy as a process analytical technology. Emerging technologies such as transmission and enhanced reflection Raman, and new approaches to using available technologies, expand the scope of Raman spectroscopy in pharmaceutical manufacturing, and now Raman spectroscopy is successfully integrated into real-time release testing, continuous manufacturing, and statistical process control. Since the last major review of Raman as a pharmaceutical PAT in 2010, many new Raman applications in bioprocessing have emerged. Exciting reports of in situ Raman spectroscopy in bioprocesses complement a growing scientific field of biological and biomedical Raman spectroscopy. Raman spectroscopy has made a positive impact as a process analytical and control tool for pharmaceutical manufacturing and bioprocessing, with demonstrated scientific and financial benefits throughout a product’s lifecycle.

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Glucose concentration control of a fed-batch mammalian cell bioprocess using a nonlinear model predictive controller

Cited by 151 publications

References 21 publications

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

Applications of Raman Spectroscopy in Biopharmaceutical Manufacturing: A Short Review

Generic Raman‐based calibration models enabling real‐time monitoring of cell culture bioreactors

Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing

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