Control strategy for multi-column continuous periodic counter current chromatography subject to fluctuating inlet stream concentration

Gerstweiler, Lukas; Billakanti, Jagan; Bi, Jian; Middelberg, Anton P. J.

doi:10.1016/j.chroma.2022.462884

Cited by 7 publications

(6 citation statements)

References 36 publications

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“…As can be seen the concentration of the inlet stream obtained from the surge vessel after Capto™ Q flow‐through chromatography fluctuates slightly, caused by the cyclic nature of the prior flow‐through unit operation. The control strategy developed for unsteady inlet feed concentrations, reliably triggered column switching (Gerstweiler et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

“…For the actual continuous processing, the switching times of the PCC process were controlled based on the dynamic UV control method developed by Cytiva (Bangtsson & Lacki, 2012) using column inlet UV absorbance and the column outlet UV absorbance of the first column in a connected set‐up to calculate the column breakthrough. However, we found that the proposed method with ΔUV as a controlling signal is error prone if the inlet feed concentration is not constant, which is a result of the integrated process; therefore, loading to approximately 70% breakthrough was controlled with a new approach developed by our group (Gerstweiler et al, 2022). A cycle of the PCC process consists of the following phases: Loading at a flowrate between 0.4 and 0.8 ml min −1 til breakthrough level triggered; Post loading wash of 2 CV at 1 ml min −1 ; Washing with 5 CV at 1 ml min −1 with equilibration buffer containing no DTT (lysis buffer pH 8.9 containing 0.35 M NaCl); Elution with 20 CV of elution buffer (40 mM di sodium hydrogen phosphate (SA026, ChemSupply), 1 M NaCl, 5% w w −1 glycerol, 1 mM EDTA) at 1 ml min −1 ; Cleaning with 1 M sodium hydroxide (SA178, ChemSupply) for 15 CV at 1 ml min −1 ; Washing with water for 5 CV at 1 ml min −1 , and; Re‐equilibration for with equilibration buffer for 5 CV at 1 ml min −1 .…”

Section: Methodsmentioning

confidence: 99%

“…developed for unsteady inlet feed concentrations, reliably triggered column switching (Gerstweiler et al, 2022).…”

Section: Evaluating Integrated Process Performancementioning

confidence: 99%

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An integrated and continuous downstream process for microbial virus‐like particle vaccine biomanufacture

Gerstweiler

Billakanti²,

et al. 2022

Biotech & Bioengineering

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In this study, we present the first integrated and continuous downstream process for the production of microbial virus‐like particle vaccines. Modular murine polyomavirus major capsid VP1 with integrated J8 antigen was used as a model virus‐like particle vaccine. The integrated continuous downstream process starts with crude cell lysate and consists of a flow‐through chromatography step followed by periodic counter‐current chromatography (PCC) (bind‐elute) using salt‐tolerant mixed‐mode resin and subsequent in‐line assembly. The automated process showed a robust behavior over different inlet feed concentrations ranging from 1.0 to 3.2 mg ml−1 with only minimal adjustments needed, and produced continuously high‐quality virus‐like particles, free of nucleic acids, with constant purity over extended periods of time. The average size remained constant between 44.8 ± 2.3 and 47.2 ± 2.9 nm comparable to literature. The process had an overall product recovery of 88.6% and a process productivity up to 2.56 mg h−1 mlresin−1 in the PCC step, depending on the inlet concentration. Integrating a flow through step with a subsequent PCC step allowed streamlined processing, showing a possible continuous pathway for a wide range of products of interest.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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An integrated and continuous downstream process for microbial virus‐like particle vaccine biomanufacture

Gerstweiler

Billakanti²,

et al. 2022

Biotech & Bioengineering

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“…This resulted in a PCC process using four columns during six cycles. Additionally, due to the high UV signal found in the sample detector and no visible breakthrough of AAV found in the frontal experiments, the dynamic control capabilities of the ÄKTA pcc (as reported elsewhere [ 19 , 27 , 28 ]) were not used. In this sense, a time-based loading was performed.…”

Section: Discussionmentioning

confidence: 99%

Continuous Affinity Purification of Adeno-Associated Virus Using Periodic Counter-Current Chromatography

Mendes

Bergman²,

Solbrand³

et al. 2022

Pharmaceutics

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Replacing batch unit operations of biopharmaceuticals by continuous manufacturing is a maturing concept, with periodic counter-current chromatography (PCC) favoured to replace batch chromatography. Continuous affinity capture of adeno-associated virus (AAV) using PCC has the potential to cope with the high doses required for AAV therapies thanks to its inherent high throughput. The implementation of continuous AAV affinity capture using a four-column PCC process is described herein. First, elution buffer screening was used to optimize virus recovery. Second, breakthrough curves were generated and described using a mechanistic model, which was later used to characterize the loading zone of the PCC. The experimental runs achieved a stable cyclic steady state yielding virus recoveries in line with the optimized batch process (>82%), with almost a three-fold improvement in productivity. The PCC affinity capture process developed here can bolster further improvements to process economics and manufacturing footprint, thereby contributing to the integrated continuous manufacturing concept.

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“…First a breakthrough of the impurities is observed and when the column is close saturation a second breakthrough is caused by the product. This signal can be used as a control algorithm for switching columns (Chmielowski et al, 2017;Gerstweiler et al, 2022;Godawat et al, 2012). This will only work when rather pure feedstock such as an antibody produced in chemical defined media is purified.…”

Section: Impact Of Different Sensorsmentioning

confidence: 99%

Monitoring Product Quantity, Purity and Potency of Biopharmaceuticals in Real-time by Predictive Chemometrics and Soft sensors

Dürauer¹,

Jungbauer²,

Scharl

2023

Preprint

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The biopharmaceutical industry is still running in batch mode, mostly because it is a highly regulated industry sector. In the past, sensors were not readily available and in-process control was mainly executed off-line. The most important product parameters are quantity, purity and potency besides adventitious agents and bioburden. There is increasing economic pressure on time-to-market and also on the environmental sustainability of biopharmaceutical manufacturing. New concepts for manufacturing using disposable single-use technologies and integrated bioprocessing will dominate the future of bioprocessing. In order to ensure the quality of pharmaceuticals initiatives such as Process Analytical Technologies, Quality by Design and Continuous Integrated Manufacturing have been established. The vision must be that these initiatives together with technology development pave the way for process automation and autonomous bioprocessing without any human intervention. Then a real-time release would be realized leading to a highly predictive and robust biomanufacturing system. The steps toward such automated and autonomous bioprocessing are reviewed in context of monitoring and control. Starting from statistical treatment of single and multiple sensors, establishing soft sensors with predictive chemometrics and hybrid models. A scenario is described how to integrate soft sensors and predictive chemometrics into modern process control. This will be exemplified by selective downstream processing steps such as chromatography and membrane filtration, the most common unit operations for separation of biopharmaceuticals.

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Control strategy for multi-column continuous periodic counter current chromatography subject to fluctuating inlet stream concentration

Cited by 7 publications

References 36 publications

An integrated and continuous downstream process for microbial virus‐like particle vaccine biomanufacture

An integrated and continuous downstream process for microbial virus‐like particle vaccine biomanufacture

Continuous Affinity Purification of Adeno-Associated Virus Using Periodic Counter-Current Chromatography

Monitoring Product Quantity, Purity and Potency of Biopharmaceuticals in Real-time by Predictive Chemometrics and Soft sensors

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