Continuous downstream bioprocessing for intensified manufacture of biopharmaceuticals and antibodies

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

doi:10.1016/j.ces.2020.116272

Cited by 40 publications

(24 citation statements)

References 183 publications

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“…The short purification cycles of the SXC method (of about 40 min) allowed simplifying the semi‐continuous purification process. In addition, the less complex bind‐elute steps in single‐column SXC require fewer optimizations than conventional multi‐column chromatography trains (Gerstweiler et al, 2021; Patil & Walther, 2018).…”

Section: Discussionmentioning

confidence: 99%

A high cell density perfusion process for Modified Vaccinia virus Ankara production: Process integration with inline DNA digestion and cost analysis

Gränicher

Babakhani

Göbel

et al. 2021

Biotech & Bioengineering

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By integrating continuous cell cultures with continuous purification methods, process yields and product quality attributes have been improved over the last 10 years for recombinant protein production. However, for the production of viral vectors such as Modified Vaccinia virus Ankara (MVA), no such studies have been reported although there is an increasing need to meet the requirements for a rising number of clinical trials against infectious or neoplastic diseases. Here, we present for the first time a scalable suspension cell (AGE1.CR.pIX cells) culture-based perfusion process in bioreactors integrating continuous virus harvesting through an acoustic settler with semi-continuous chromatographic purification. This allowed obtaining purified MVA particles with a space-time yield more than 600% higher for the integrated perfusion process (1.05 × 10 11 TCID 50 /L bioreactor /day) compared to the integrated batch process. Without further optimization, purification by membrane-based steric exclusion chromatography resulted in an overall product recovery of 50.5%. To decrease the level of host cell DNA before chromatography, a novel inline continuous DNA digestion step was integrated into the process train. A detailed cost analysis comparing integrated production in batch versus production in perfusion mode showed that the cost per dose for MVA was reduced by nearly one-third using this intensified small-scale process.semi-continuous production, steric exclusion chromatography, suspension cell culture in bioreactor, upstream and downstream processing, viral vector | INTRODUCTIONTo date, the implementation of an integrated perfusion process is an option to decrease manufacturing costs and to potentially increase the quality of a product (Bielser et al., 2018;Walther et al., 2015Walther et al., , 2019Xu & Chen, 2016). A considerable amount of research has been conducted on the integrated continuous production of recombinant pro-

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Section: Discussionmentioning

confidence: 99%

A high cell density perfusion process for Modified Vaccinia virus Ankara production: Process integration with inline DNA digestion and cost analysis

Gränicher

Babakhani

Göbel

et al. 2021

Biotech & Bioengineering

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“…Further, we aimed to examine if these gains are further amplified by converting the mode of operation from batch to continuous, as driven by the current and enormous interest in continuous manufacturing. 30,34 Figure 6 summarizes the overall benefits of continuous nonprotein A platform over batch mode. We see a 34% reduction in COGs when the non-protein A platform is operated in a continuous mode, of which 63% of the reduction is in the chromatography step.…”

Section: Resultsmentioning

confidence: 99%

“…The protein A capture step was operated in periodic countercurrent mode. 30,31 The mixing tank for viral inactivation was replaced by a CFIR and ultrafiltrationdiafiltration was replaced by Cadence™ inline concentrator (ILC) and inline diafiltration (ILD) modules (Pall Corporation, USA). The upstream process was modified to use a perfusion cell culture process over the fed-batch process.…”

Section: Economic Parameters and Assumptionsmentioning

confidence: 99%

Contribution of protein A step towards cost of goods for continuous production of monoclonal antibody therapeutics

Bansode

Gupta

Kateja

et al. 2021

J of Chemical Tech & Biotech

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BACKGROUND: Monoclonal antibodies (mAbs) presently dominate the biotherapeutic market. However, biotherapeutics in general, and mAbs in particular, are expensive therapies and outside the realm of affordability for most of the world. In an attempt to lower their cost of manufacturing, a novel in-house non-protein A continuous platform has recently been reported for mAb purification. In this paper, we perform an in-depth evaluation of the process economics to assess the impact of removing the protein A step on the cost of goods (COGs).RESULTS: The non-protein A platform was found to result in significant savings in COGs at about 23% when comparing both platforms in batch mode. Conversion of the non-protein A platform from batch to continuous mode led to a further increase in these savings with about 39% gains in COGs over the conventional protein A platform.CONCLUSIONS: The non-protein A purification platform offers a viable alternative to the standard protein A platform and can be considered when setting up a new facility. The continuous non-protein A platform can especially be considered given the flexibility of the setup and the utility at both small and large scales.

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“…1,2 Protein precipitation has been proven to be an efficient alternative to chromatography A columns. 3 It can be easily adapted and operated in a fully continuous mode with consistent and reproducible results. 4,5 Furthermore, the latest studies have demonstrated that precipitation can achieve a similar yield and purity to protein A chromatography.…”

Section: Introductionmentioning

confidence: 99%

Milliscale reactors for integration of continuous precipitation and filtration

Royo

Montes‐Serrano

Valéry³

et al. 2022

J of Chemical Tech & Biotech

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BACKGROUND The development of integrated continuous biomanufacturing processes faces a significant challenge when the parameters for the design of the process cannot be accurately estimated from those of batch experiments. Process design is even more challenging if the outcome of one unit operation highly influences the performance of the subsequent one, such as in harvesting of a precipitate by filtration. In the case of protein precipitation, results from the batch and continuous experiements deviate and their scale‐down is limited. Microfluidics suffer from poor mixing characteristics. Thus, milliscale devices were developed to maintain mixing performance but at the expense of a slightly larger scale. RESULTS Milliscale devices were developed for the precipitation of antibodies in continuous tubular reactors to compare different dosage times in small scale. The reactors have multiple addition points for precipitant for the continuous, controlled and precise addition of the precipitating agent without valves. The designed devices have a narrow residence time distribution to achieve fast mixing and a small volume that reduces the time and cost for experiments tenfold. Milliscale devices were used to evaluate the most appropriate dosage time for protein precipitation, thus improving purity by a factor of 3 compared to single addition. The resulting filterability of precipitates in tangential flow filtration and depth filtration was improved. CONCLUSION Results demonstrated that multiple additions were more beneficial than single addition because they help to reduce pressure and increase filter capacity. Such devices can be used to determine and adjust the precipitation methodology to optimize floc formation and improve solid–liquid separation while reducing development time and cost. © 2022 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

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Continuous downstream bioprocessing for intensified manufacture of biopharmaceuticals and antibodies

Cited by 40 publications

References 183 publications

A high cell density perfusion process for Modified Vaccinia virus Ankara production: Process integration with inline DNA digestion and cost analysis

A high cell density perfusion process for Modified Vaccinia virus Ankara production: Process integration with inline DNA digestion and cost analysis

Contribution of protein A step towards cost of goods for continuous production of monoclonal antibody therapeutics

Milliscale reactors for integration of continuous precipitation and filtration

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