Process-Scale Chromatography

Strube, Jochen; Zobel-Roos, Steffen; Ditz, Reinhard

doi:10.1002/14356007.b03_10.pub2

Cited by 3 publications

(4 citation statements)

References 69 publications

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“…To determine the parameters for the competitive Langmuir isotherms, frontal analyses at different modifier concentrations were used [26,40,41]. At least five different protein concentrations were investigated per modifier concentration.…”

Section: 2 Adsorption Equilibriummentioning

confidence: 99%

“…These were performed on the multi-purpose chromatography prototype shown in Figure 8. The system contains six pumps, up to 60 valves and an array of different detectors and is, therefore, able to run a variety of continuous chromatography processes like MCSGP, PCC, SMB and more [41]. For this validation, only four pumps and two UV detectors were needed.…”

Section: Experimental Validationmentioning

confidence: 99%

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Digital Twin Based Design and Experimental Validation of a Continuous Peptide Polishing Step

et al. 2023

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Optimizing or debottlenecking existing production plants is a challenging task. In this case study, an existing reversed phased chromatography polishing step for peptide purification was optimized with the help of a digital twin. The existing batch chromatography was depicted digitally with the general rate model. Model parameter determination and model validation was done with dedicated experiments. The digital twin was then used to identify optimized process variants, especially continuous chromatography steps. MCSGP was found to achieve high purities and yield but at the cost of productivity due to column synchronization. An alternative Continuous Twin Column chromatography process (CTCC) was established that eliminates unnecessary waiting times. Ensuring the same or higher purity compared to the batch process, the continuous process achieved a yield increase of 31% and productivity increase of 27.6%. Experimental long runs confirmed these results.

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Section: 2 Adsorption Equilibriummentioning

confidence: 99%

Section: Experimental Validationmentioning

confidence: 99%

Digital Twin Based Design and Experimental Validation of a Continuous Peptide Polishing Step

et al. 2023

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“…Several process analytical technology (PAT) applications in recent literature require flexibility in unit operation flowrates, and thus can only be implemented if surge tanks are present to decouple the process flow streams. Instances include variable loading in Protein A chromatography to handle upstream titer variations (Rathore et al, 2020), variable pooling in polishing chromatography in case of changes to the product charge variant profile (Brestrich et al, 2018; Mendhe et al, 2015; Strube et al, 2000), or variable flowrate and pressure in ultrafiltration to handle membrane fouling and concentration deviations (van Reis et al, 1997). Since such controls are necessary for achieving consistent critical quality attributes (CQAs), it can be surmised that surge tanks are critical enablers of PAT and quality by design (QbD) in continuous biopharmaceutical manufacturing, in line with the US FDA guidelines (FDA, 2004; Rathore & Winkle, 2009; Rathore, 2009; Rathore et al, 2010; Read et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Control of surge tanks for continuous manufacturing of monoclonal antibodies

Thakur

Nikita

Tiwari

et al. 2021

Biotech & Bioengineering

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Surge tanks are critical but often overlooked enablers of continuous bioprocessing. They provide multiple benefits including dampening of concentration gradients and allowing process resumption efforts in case of equipment failure or unexpected deviations, which can occur during a continuous campaign of weeks or months. They are also useful in enabling steady‐state operation across a continuous train by facilitating mass balance between unit operations such as chromatography which have periodic loading and elution cycles. In this paper, we propose a design of a system of surge tanks for a monoclonal antibody (mAb) production process consisting of cell culture, clarification, capture chromatography, viral inactivation, polishing chromatography, and single‐pass ultrafiltration and diafiltration. A Python controller has been developed for robust control of the continuous train. The controller has four layers, namely data acquisition, process scheduling, deviation handling, and real‐time execution. A set of general guidelines for surge tank placement and sizing have been proposed together with process control strategies based on the design space of the individual unit operations, failure modes analysis of the different equipment, and expected variability in the process feed streams for both fed‐batch and perfusion bioreactors. The control system has been successfully demonstrated for several continuous runs of up to 36 h in duration and is able to leverage surge tanks for robust control of the continuous train in the face of product variability as well as process errors while maintaining critical quality attributes. The proposed set of strategies for surge tank control are adaptable to most continuous processing setups for mAbs, and together form the first framework that can fully realize the benefits of surge tanks in continuous bioprocessing.

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“…Nevertheless, those statistical tools are a major aid in maintenance planning and prediction [82,83]. Moreover, this equipment related data is of use for down-scale or up-scale predictions [84,85].…”

mentioning

confidence: 99%

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

et al. 2019

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Innovative biologics, including cell therapeutics, virus-like particles, exosomes,recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the maintherapeutic entities in manufacturing over the next decades. This molecular variety causes agrowing need for a general change of methods as well as mindset in the process development stage,as there are no platform processes available such as those for monoclonal antibodies. Moreover,market competitiveness demands hyper-intensified processes, including accelerated decisionstoward batch or continuous operation of dedicated modular plant concepts. This indicates gaps inprocess comprehension, when operation windows need to be run at the edges of optimization. Inthis editorial, the authors review and assess potential methods and begin discussing possiblesolutions throughout the workflow, from process development through piloting to manufacturingoperation from their point of view and experience. Especially, the state-of-the-art for modeling inred biotechnology is assessed, clarifying differences and applications of statistical, rigorousphysical-chemical based models as well as cost modeling. “Digital-twins” are described and effortsvs. benefits for new applications exemplified, including the regulation-demanded QbD (quality bydesign) and PAT (process analytical technology) approaches towards digitalization or industry 4.0based on advanced process control strategies. Finally, an analysis of the obstacles and possiblesolutions for any successful and efficient industrialization of innovative methods from processdevelopment, through piloting to manufacturing, results in some recommendations. A centralquestion therefore requires attention: Considering that QbD and PAT have been required byauthorities since 2004, can any biologic manufacturing process be approved by the regulatoryagencies without being modeled by a “digital-twin” as part of the filing documentation?

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Process-Scale Chromatography

Cited by 3 publications

References 69 publications

Digital Twin Based Design and Experimental Validation of a Continuous Peptide Polishing Step

Digital Twin Based Design and Experimental Validation of a Continuous Peptide Polishing Step

Control of surge tanks for continuous manufacturing of monoclonal antibodies

Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?

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