Stephen Goldrick - Academia.edu (original) (raw)

Papers by Stephen Goldrick

Bioengineering, Sep 25, 2018

Raman spectroscopy is a novel tool used in the on-line monitoring and control of bioprocesses, of... more Raman spectroscopy is a novel tool used in the on-line monitoring and control of bioprocesses, offering both quantitative and qualitative determination of key process variables through spectroscopic analysis. However, the widespread application of Raman spectroscopy analysers to industrial fermentation processes has been hindered by problems related to the high background fluorescence signal associated with the analysis of biological samples. To address this issue, we investigated the influence of fluorescence on the spectra collected from two Raman spectroscopic devices with different wavelengths and detectors in the analysis of the critical process parameters (CPPs) and critical quality attributes (CQAs) of a fungal fermentation process. The spectra collected using a Raman analyser with the shorter wavelength (903 nm) and a charged coupled device detector (CCD) was corrupted by high fluorescence and was therefore unusable in the prediction of these CPPs and CQAs. In contrast, the spectra collected using a Raman analyser with the longer wavelength (993 nm) and an indium gallium arsenide (InGaAs) detector was only moderately affected by fluorescence and enabled the generation of accurate estimates of the fermentation's critical variables. This novel work is the first direct comparison of two different Raman spectroscopy probes on the same process highlighting the significant detrimental effect caused by high fluorescence on spectra recorded throughout fermentation runs. Furthermore, this paper demonstrates the importance of correctly selecting both the incident wavelength and detector material type of the Raman spectroscopy devices to ensure corrupting fluorescence is minimised during bioprocess monitoring applications.

Journal of Chromatography A, Jul 1, 2019

Chromatography remains the workhorse in antibody purification; however process development and ch... more Chromatography remains the workhorse in antibody purification; however process development and characterisation still require significant resources. The high number of operating parameters involved requires extensive experimentation, traditionally performed at small-and pilot-scale, leading to demands in terms of materials and time that can be a challenge. The main objective of this research was the establishment of a novel High Throughput Process Development (HTPD) workflow combining scale-down chromatography experimentation with advanced decision-support techniques in order to minimise the consumption of resources and accelerate the development timeframe. Additionally, the HTPD workflow provides a framework to rapidly manipulate large datasets in an automated fashion. The central component of the HTPD workflow is the systematic integration of a microscale chromatography experimentation strategy with an advanced chromatogram evaluation method, design of experiments (DoE) and multivariate data analysis. The outputs of this are leveraged into the screening and optimisation components of the workflow. For the screening component, a decision-support tool was developed combining different multi-criteria decision-making techniques to enable a fair comparison of a number of CEX resin candidates and determine those that demonstrate superior purification performance. This provided a rational methodology for screening chromatography resins and process parameters. For the optimisation component, the workflow leverages insights provided through screening experimentation to guide subsequent DoE experiments so as to tune significant process parameters for the selected resin. The resulting empirical correlations are linked to a stochastic modelling technique so as to predict the optimal and most robust chromatographic process parameters to achieve the desired performance criteria.

Biotechnology and Bioengineering, Mar 16, 2016

In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest ste... more In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then employed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterization. A scale-down approach based upon the use of a shear device and a bench-top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large-scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability is limited.

Frontiers in Bioengineering and Biotechnology

Cell line development is an essential stage in biopharmaceutical development that often lies on t... more Cell line development is an essential stage in biopharmaceutical development that often lies on the critical path. Failure to fully characterise the lead clone during initial screening can lead to lengthy project delays during scale-up, which can potentially compromise commercial manufacturing success. In this study, we propose a novel cell line development methodology, referenced as CLD4, which involves four steps enabling autonomous data-driven selection of the lead clone. The first step involves the digitalisation of the process and storage of all available information within a structured data lake. The second step calculates a new metric referenced as the cell line manufacturability index (MICL) quantifying the performance of each clone by considering the selection criteria relevant to productivity, growth and product quality. The third step implements machine learning (ML) to identify any potential risks associated with process operation and relevant critical quality attributes...

Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of ... more Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of affinity-purification tags from high-value biopharmaceuticals. However, recombinant expression in Escherichia coli produces insoluble inclusion bodies, requiring solubilisation, refolding, and autocatalytic activation to recover functional enzyme. Error-prone PCR and DNA shuffling of the EKL gene, T7 promotor, lac operon, ribosome binding site, and pelB leader sequence, yielded 321 unique variants after screening ~ 6500 colonies. The best variants had > 11,000-fold increased total activity in lysates, producing soluble enzyme that no longer needed refolding. Further characterisation identified the factors that improved total activity from an inactive and insoluble starting point. Stability was a major factor, whereby melting temperatures > 48.4°C enabled good expression at 37°C. Variants generally did not alter catalytic efficiency as measured by kcat/Km, which improved for only on...

This data was generated using an advanced mathematical simulation of a 100,000 litre penicillin f... more This data was generated using an advanced mathematical simulation of a 100,000 litre penicillin fermentation system referenced as IndPenSim. All details describing the simulation are available on the following website: www.industrialpenicillinsimulation.com. IndPenSim is the first simulation to include a realistic simulated Raman spectroscopy device for the purpose of developing, evaluating and implementation of advanced and innovative control solutions applicable to biotechnology facilities. This data set generated by IndPenSim represents the biggest data set available for advanced data analytics and contains 100 batches with all available process and Raman spectroscopy measurements (~2.5 GB). This data is highly suitable for the development of big data analytics, machine learning (ML) or artificial intelligence (AI) algorithms applicable to the biopharmaceutical industry. The 100 batches are controlled using different control strategies and different batch lengths representing a t...

2018 UKACC 12th International Conference on Control (CONTROL), 2018

Biopharmaceutical manufacturing is an inherently complex operation with industrial-scale control ... more Biopharmaceutical manufacturing is an inherently complex operation with industrial-scale control strategies often failing to accurately account for faults and product variation that can result in significant economic losses. In response, this work presents a fault-tolerant Model Predictive Control (MPC) strategy which solves a modified version of a Quadratic Programming (QP) problem, using a data-driven adaptive Multivariate Partial Least Square (MPLS) model. The proposed technique is applied to an industrial simulation of a fed-batch process and found to improve operations significantly.

Application of multivariate data analysis in the monitoring and control of mammalian cell process... more Application of multivariate data analysis in the monitoring and control of mammalian cell processes" in "Cell Culture Engineering XV",

Biotechnology and bioengineering, Sep 1, 2016

In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest ste... more In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then deployed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterisation. A scale-down approach based upon the use of a shear device and a bench-top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large-scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability i...

IFAC Proceedings Volumes, 2013

This paper presents a simulation of an industrial scale filamentous fermentation; the simulation ... more This paper presents a simulation of an industrial scale filamentous fermentation; the simulation focuses on modeling a 120,000 litre Penicillium chrysogenum batch process. The simulation attempts to address many of the challenges that that are faced by industrial scale filamentous fermentations; these include the control of dissolved oxygen concentration above its critical value and also controlling substrate feed to an optimum trajectory. Previous unstructured models, that didn't consider the changing morphology of Penicillin fermentations, failed to adequately model the historical Penicillin production batch data presented here. This simulation extends previous structured models by including extra process variables such as gas inlet pressure and viscosity, which are shown to have a significant effect on the control strategy of these large-scale fermentations. The accuracy of the model is verified by successfully predicting both the Penicillin and dissolved oxygen concentration using the input data from two industrial 120,000 litre Penicillium chrysogenum batch fermentations. The overall aim of the simulation is to provide an improved test bed for fed-batch Penicillin fermentations that can be used for process monitoring, control and optimization studies.

Proceedings of the 19th IFAC World Congress, 2014

This work investigates the application of a "Process Analytical Technology" (PAT) analyser to con... more This work investigates the application of a "Process Analytical Technology" (PAT) analyser to control the substrate concentration over traditional sequential batch control for an industrial scale fed-batch penicillin fermentation. A simulation that utilises the historical data from four batches, where a sequential batch control strategy was implemented, was used as the benchmark reference for this comparison. The simulation accurately predicts the main outputs variables of biomass and penicillin, given the inputs from the historical data set. The simulation includes a PAT analyser, used to build a calibration model with the available off-line substrate concentration from one of the batches. The prediction from this calibration model was used as the controlled variable within a proportional integral (PI) controller to manipulate the substrate feed rate for the three remaining batches. Performance of each control strategy was analysed by comparing the final penicillin yield of each batch. An increase of 35, 20 and 9% was observed for the three batches controlled using the PI controller compared with the sequential batch control strategy.

Proceedings of 2012 UKACC International Conference on Control, 2012

Journal of biotechnology, Jan 10, 2015

This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used ... more This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used as a benchmark in process systems analysis and control studies. The simulation was developed using a mechanistic model and validated using historical data collected from an industrial-scale penicillin fermentation process. Each batch was carried out in a 100,000L bioreactor that used an industrial strain of Penicillium chrysogenum. The manipulated variables recorded during each batch were used as inputs to the simulator and the predicted outputs were then compared with the on-line and off-line measurements recorded in the real process. The simulator adapted a previously published structured model to describe the penicillin fermentation and extended it to include the main environmental effects of dissolved oxygen, viscosity, temperature, pH and dissolved carbon dioxide. In addition the effects of nitrogen and phenylacetic acid concentrations on the biomass and penicillin production rates ...

Biotechnology Journal

Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance t... more Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance to ensure decisions on meeting product specifications are accurate and hence assure patient safety and product quality. The challenge of ensuring DI within this sector is becoming more complex with the growing amount of data generated given increasing adoption of process analytical technology (PAT), advanced automation, high throughput microscale studies, and managing data models created by machine learning (ML) tools. This paper aims to identify DI risks and mitigation strategies in biopharmaceutical manufacturing facilities as the sector moves towards Industry 4.0. To achieve this, the paper examines common DI violations and links them to the ALCOA+ principles used across the FDA, EMA, and MHRA. The relevant DI guidelines from the ISPE's GAMP5 and ISA‐95 standards are also discussed with a focus on the role of validated computerised and automated manufacturing systems to avoid DI ri...

Current Opinion in Chemical Engineering

Journal of Chromatography A

Processes

Raman spectroscopy has the potential to revolutionise many aspects of biopharmaceutical process d... more Raman spectroscopy has the potential to revolutionise many aspects of biopharmaceutical process development. The widespread adoption of this promising technology has been hindered by the high cost associated with individual probes and the challenge of measuring low sample volumes. To address these issues, this paper investigates the potential of an emerging new high-throughput (HT) Raman spectroscopy microscope combined with a novel data analysis workflow to replace off-line analytics for upstream and downstream operations. On the upstream front, the case study involved the at-line monitoring of an HT micro-bioreactor system cultivating two mammalian cell cultures expressing two different therapeutic proteins. The spectra generated were analysed using a partial least squares (PLS) model. This enabled the successful prediction of the glucose, lactate, antibody, and viable cell density concentrations directly from the Raman spectra without reliance on multiple off-line analytical devi...

Bioengineering, Sep 25, 2018

Raman spectroscopy is a novel tool used in the on-line monitoring and control of bioprocesses, of... more Raman spectroscopy is a novel tool used in the on-line monitoring and control of bioprocesses, offering both quantitative and qualitative determination of key process variables through spectroscopic analysis. However, the widespread application of Raman spectroscopy analysers to industrial fermentation processes has been hindered by problems related to the high background fluorescence signal associated with the analysis of biological samples. To address this issue, we investigated the influence of fluorescence on the spectra collected from two Raman spectroscopic devices with different wavelengths and detectors in the analysis of the critical process parameters (CPPs) and critical quality attributes (CQAs) of a fungal fermentation process. The spectra collected using a Raman analyser with the shorter wavelength (903 nm) and a charged coupled device detector (CCD) was corrupted by high fluorescence and was therefore unusable in the prediction of these CPPs and CQAs. In contrast, the spectra collected using a Raman analyser with the longer wavelength (993 nm) and an indium gallium arsenide (InGaAs) detector was only moderately affected by fluorescence and enabled the generation of accurate estimates of the fermentation's critical variables. This novel work is the first direct comparison of two different Raman spectroscopy probes on the same process highlighting the significant detrimental effect caused by high fluorescence on spectra recorded throughout fermentation runs. Furthermore, this paper demonstrates the importance of correctly selecting both the incident wavelength and detector material type of the Raman spectroscopy devices to ensure corrupting fluorescence is minimised during bioprocess monitoring applications.

Journal of Chromatography A, Jul 1, 2019

Chromatography remains the workhorse in antibody purification; however process development and ch... more Chromatography remains the workhorse in antibody purification; however process development and characterisation still require significant resources. The high number of operating parameters involved requires extensive experimentation, traditionally performed at small-and pilot-scale, leading to demands in terms of materials and time that can be a challenge. The main objective of this research was the establishment of a novel High Throughput Process Development (HTPD) workflow combining scale-down chromatography experimentation with advanced decision-support techniques in order to minimise the consumption of resources and accelerate the development timeframe. Additionally, the HTPD workflow provides a framework to rapidly manipulate large datasets in an automated fashion. The central component of the HTPD workflow is the systematic integration of a microscale chromatography experimentation strategy with an advanced chromatogram evaluation method, design of experiments (DoE) and multivariate data analysis. The outputs of this are leveraged into the screening and optimisation components of the workflow. For the screening component, a decision-support tool was developed combining different multi-criteria decision-making techniques to enable a fair comparison of a number of CEX resin candidates and determine those that demonstrate superior purification performance. This provided a rational methodology for screening chromatography resins and process parameters. For the optimisation component, the workflow leverages insights provided through screening experimentation to guide subsequent DoE experiments so as to tune significant process parameters for the selected resin. The resulting empirical correlations are linked to a stochastic modelling technique so as to predict the optimal and most robust chromatographic process parameters to achieve the desired performance criteria.

Biotechnology and Bioengineering, Mar 16, 2016

In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest ste... more In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then employed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterization. A scale-down approach based upon the use of a shear device and a bench-top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large-scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability is limited.

Frontiers in Bioengineering and Biotechnology

Cell line development is an essential stage in biopharmaceutical development that often lies on t... more Cell line development is an essential stage in biopharmaceutical development that often lies on the critical path. Failure to fully characterise the lead clone during initial screening can lead to lengthy project delays during scale-up, which can potentially compromise commercial manufacturing success. In this study, we propose a novel cell line development methodology, referenced as CLD4, which involves four steps enabling autonomous data-driven selection of the lead clone. The first step involves the digitalisation of the process and storage of all available information within a structured data lake. The second step calculates a new metric referenced as the cell line manufacturability index (MICL) quantifying the performance of each clone by considering the selection criteria relevant to productivity, growth and product quality. The third step implements machine learning (ML) to identify any potential risks associated with process operation and relevant critical quality attributes...

Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of ... more Bovine enterokinase light chain (EKL) is an industrially useful protease for accurate removal of affinity-purification tags from high-value biopharmaceuticals. However, recombinant expression in Escherichia coli produces insoluble inclusion bodies, requiring solubilisation, refolding, and autocatalytic activation to recover functional enzyme. Error-prone PCR and DNA shuffling of the EKL gene, T7 promotor, lac operon, ribosome binding site, and pelB leader sequence, yielded 321 unique variants after screening ~ 6500 colonies. The best variants had > 11,000-fold increased total activity in lysates, producing soluble enzyme that no longer needed refolding. Further characterisation identified the factors that improved total activity from an inactive and insoluble starting point. Stability was a major factor, whereby melting temperatures > 48.4°C enabled good expression at 37°C. Variants generally did not alter catalytic efficiency as measured by kcat/Km, which improved for only on...

This data was generated using an advanced mathematical simulation of a 100,000 litre penicillin f... more This data was generated using an advanced mathematical simulation of a 100,000 litre penicillin fermentation system referenced as IndPenSim. All details describing the simulation are available on the following website: www.industrialpenicillinsimulation.com. IndPenSim is the first simulation to include a realistic simulated Raman spectroscopy device for the purpose of developing, evaluating and implementation of advanced and innovative control solutions applicable to biotechnology facilities. This data set generated by IndPenSim represents the biggest data set available for advanced data analytics and contains 100 batches with all available process and Raman spectroscopy measurements (~2.5 GB). This data is highly suitable for the development of big data analytics, machine learning (ML) or artificial intelligence (AI) algorithms applicable to the biopharmaceutical industry. The 100 batches are controlled using different control strategies and different batch lengths representing a t...

2018 UKACC 12th International Conference on Control (CONTROL), 2018

Biopharmaceutical manufacturing is an inherently complex operation with industrial-scale control ... more Biopharmaceutical manufacturing is an inherently complex operation with industrial-scale control strategies often failing to accurately account for faults and product variation that can result in significant economic losses. In response, this work presents a fault-tolerant Model Predictive Control (MPC) strategy which solves a modified version of a Quadratic Programming (QP) problem, using a data-driven adaptive Multivariate Partial Least Square (MPLS) model. The proposed technique is applied to an industrial simulation of a fed-batch process and found to improve operations significantly.

Application of multivariate data analysis in the monitoring and control of mammalian cell process... more Application of multivariate data analysis in the monitoring and control of mammalian cell processes" in "Cell Culture Engineering XV",

Biotechnology and bioengineering, Sep 1, 2016

In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest ste... more In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then deployed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful characterisation. A scale-down approach based upon the use of a shear device and a bench-top centrifuge has been extended in this work towards a preparative methodology that successfully predicts the performance of the continuous centrifuge and polishing filters. The use of this methodology allows the effects of cell culture conditions and large-scale centrifugal process parameters on subsequent filtration performance to be assessed at an early stage of process development where material availability i...

IFAC Proceedings Volumes, 2013

This paper presents a simulation of an industrial scale filamentous fermentation; the simulation ... more This paper presents a simulation of an industrial scale filamentous fermentation; the simulation focuses on modeling a 120,000 litre Penicillium chrysogenum batch process. The simulation attempts to address many of the challenges that that are faced by industrial scale filamentous fermentations; these include the control of dissolved oxygen concentration above its critical value and also controlling substrate feed to an optimum trajectory. Previous unstructured models, that didn't consider the changing morphology of Penicillin fermentations, failed to adequately model the historical Penicillin production batch data presented here. This simulation extends previous structured models by including extra process variables such as gas inlet pressure and viscosity, which are shown to have a significant effect on the control strategy of these large-scale fermentations. The accuracy of the model is verified by successfully predicting both the Penicillin and dissolved oxygen concentration using the input data from two industrial 120,000 litre Penicillium chrysogenum batch fermentations. The overall aim of the simulation is to provide an improved test bed for fed-batch Penicillin fermentations that can be used for process monitoring, control and optimization studies.

Proceedings of the 19th IFAC World Congress, 2014

This work investigates the application of a "Process Analytical Technology" (PAT) analyser to con... more This work investigates the application of a "Process Analytical Technology" (PAT) analyser to control the substrate concentration over traditional sequential batch control for an industrial scale fed-batch penicillin fermentation. A simulation that utilises the historical data from four batches, where a sequential batch control strategy was implemented, was used as the benchmark reference for this comparison. The simulation accurately predicts the main outputs variables of biomass and penicillin, given the inputs from the historical data set. The simulation includes a PAT analyser, used to build a calibration model with the available off-line substrate concentration from one of the batches. The prediction from this calibration model was used as the controlled variable within a proportional integral (PI) controller to manipulate the substrate feed rate for the three remaining batches. Performance of each control strategy was analysed by comparing the final penicillin yield of each batch. An increase of 35, 20 and 9% was observed for the three batches controlled using the PI controller compared with the sequential batch control strategy.

Proceedings of 2012 UKACC International Conference on Control, 2012

Journal of biotechnology, Jan 10, 2015

This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used ... more This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used as a benchmark in process systems analysis and control studies. The simulation was developed using a mechanistic model and validated using historical data collected from an industrial-scale penicillin fermentation process. Each batch was carried out in a 100,000L bioreactor that used an industrial strain of Penicillium chrysogenum. The manipulated variables recorded during each batch were used as inputs to the simulator and the predicted outputs were then compared with the on-line and off-line measurements recorded in the real process. The simulator adapted a previously published structured model to describe the penicillin fermentation and extended it to include the main environmental effects of dissolved oxygen, viscosity, temperature, pH and dissolved carbon dioxide. In addition the effects of nitrogen and phenylacetic acid concentrations on the biomass and penicillin production rates ...

Biotechnology Journal

Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance t... more Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance to ensure decisions on meeting product specifications are accurate and hence assure patient safety and product quality. The challenge of ensuring DI within this sector is becoming more complex with the growing amount of data generated given increasing adoption of process analytical technology (PAT), advanced automation, high throughput microscale studies, and managing data models created by machine learning (ML) tools. This paper aims to identify DI risks and mitigation strategies in biopharmaceutical manufacturing facilities as the sector moves towards Industry 4.0. To achieve this, the paper examines common DI violations and links them to the ALCOA+ principles used across the FDA, EMA, and MHRA. The relevant DI guidelines from the ISPE's GAMP5 and ISA‐95 standards are also discussed with a focus on the role of validated computerised and automated manufacturing systems to avoid DI ri...

Current Opinion in Chemical Engineering

Journal of Chromatography A

Processes

Raman spectroscopy has the potential to revolutionise many aspects of biopharmaceutical process d... more Raman spectroscopy has the potential to revolutionise many aspects of biopharmaceutical process development. The widespread adoption of this promising technology has been hindered by the high cost associated with individual probes and the challenge of measuring low sample volumes. To address these issues, this paper investigates the potential of an emerging new high-throughput (HT) Raman spectroscopy microscope combined with a novel data analysis workflow to replace off-line analytics for upstream and downstream operations. On the upstream front, the case study involved the at-line monitoring of an HT micro-bioreactor system cultivating two mammalian cell cultures expressing two different therapeutic proteins. The spectra generated were analysed using a partial least squares (PLS) model. This enabled the successful prediction of the glucose, lactate, antibody, and viable cell density concentrations directly from the Raman spectra without reliance on multiple off-line analytical devi...