Integrated continuous biomanufacturing on pilot scale for acid‐sensitive monoclonal antibodies

Schwarz, Hubert; Gomis-Fons, Joaqúın; Isaksson, Malin; Scheffel, Julia; Andersson, Niklas; Andersson, Andreas; Castan, Andreas; Solbrand, Anita; Hober, Sophia; Nilsson, Bernt; Chotteau, Véronique

doi:10.1002/bit.28120

Cited by 30 publications

(28 citation statements)

References 51 publications

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“…The molecular weight and isoelectric point of GA-Z are 11,865 Da and 4.5, respectively [38]. The monoclonal antibody trastuzumab was supplied by Bernt Nilsson (Lund University, Sweden) [39,40] at a stock concentration of 8.4 mg/mL in a buffer with 25 mM sodium phosphate buffer, 25 mM sodium acetate, and 120 mM NaCl at pH 6.2. Trastuzumab has a molecular weight of 148,300 Da and an isoelectric point of 8.7 [41].…”

Section: Materials and Reagentsmentioning

confidence: 99%

Investigation of native and aggregated therapeutic proteins in human plasma with asymmetrical flow field-flow fractionation and mass spectrometry

et al. 2022

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Physiochemical degradation of therapeutic proteins in vivo during plasma circulation after administration can have a detrimental effect on their efficacy and safety profile. During drug product development, in vivo animal studies are necessary to explore in vivo protein behaviour. However, these studies are very demanding and expensive, and the industry is working to decrease the number of in vivo studies. Consequently, there is considerable interest in the development of methods to pre-screen the behaviour of therapeutic proteins in vivo using in vitro analysis. In this work, asymmetrical flow field-flow fractionation (AF4) and liquid chromatography–mass spectrometry (LC-MS) were combined to develop a novel analytical methodology for predicting the behaviour of therapeutic proteins in vivo. The method was tested with two proteins, a monoclonal antibody and a serum albumin binding affibody. After incubation of the proteins in plasma, the method was successfully used to investigate and quantify serum albumin binding, analyse changes in monoclonal antibody size, and identify and quantify monoclonal antibody aggregates. Graphical abstract

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Section: Materials and Reagentsmentioning

confidence: 99%

Investigation of native and aggregated therapeutic proteins in human plasma with asymmetrical flow field-flow fractionation and mass spectrometry

et al. 2022

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“…Several advances in integrated and continuous bioprocessing technologies have been reported and reviewed in recent years, especially for mAbs [ 21 , 22 , 23 ]. While the focus has mainly been directed toward establishing continuous production bioreactors, it is necessary to extend intensified processing to downstream unit operations as well.…”

Section: Introductionmentioning

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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“…Besides, the integrated control of continuous processes including ILC and ILDF technologies are not well discussed. Therefore, going further than previous studies, [28][29][30][31][32][33][34] we describe an integrated continuous downstream process, which has the following advantages: (1) process modeling and PAT were used to covert batch process to continuous process; (2) an overall continuous downstream process was established including ILC and ILDF; and (3) different technologies were integrated into a DeltaV system for process automation.…”

Section: Introductionmentioning

confidence: 99%

Converting a mAb downstream process from batch to continuous using process modeling and process analytical technology

Chen

Shi

et al. 2022

Biotechnology Journal

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The biopharmaceutical market is driving the revolution from traditional batch processes to continuous manufacturing for higher productivity and lower costs. In this work, a batch mAb downstream process has been converted into an integrated continuous process with the combination of multiple techniques. For process intensification, two batch mode unit operations (protein A capture chromatography, ultrafiltration/diafiltration) were converted into continuous ones; for continuity, surge tanks were used between adjacent steps, and level signals were used to trigger process start or stop, forming a holistic continuous process. For process automation, manual operations (e.g., pH and conductivity adjustment) were changed into automatic operation and load mass was controlled with process analytical technology (PAT). A model-based simulation was applied to estimate the loading conditions for the continuous capture process, resulting in 21% resin capacity utilization and 28% productivity improvement as compared to the batch process. Automatic load mass control of cation exchange chromatography (CEX) was achieved through a customized in-line protein quantity monitoring system, with a difference of less than 1.3% as compared to off-line analysis. Total process time was shortened from 4 days (batch process) to less than 24 hours using the continuous downstream process with the overall productivity of 23.8 g mAb per day for the bench-scale system. Comparable yield and quality data were obtained in three test runs, indicating a successful conversion from a batch process to a continuous process. The insight of this work could be a reference to other similar situations.

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Integrated continuous biomanufacturing on pilot scale for acid‐sensitive monoclonal antibodies

Cited by 30 publications

References 51 publications

Investigation of native and aggregated therapeutic proteins in human plasma with asymmetrical flow field-flow fractionation and mass spectrometry

Investigation of native and aggregated therapeutic proteins in human plasma with asymmetrical flow field-flow fractionation and mass spectrometry

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

Converting a mAb downstream process from batch to continuous using process modeling and process analytical technology

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