Continuous Animal Cell Perfusion Processes: The First Step Toward Integrated Continuous Biomanufacturing

Castilho, Leda R.

doi:10.1002/9783527673681.ch06

Cited by 19 publications

(25 citation statements)

References 91 publications

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“…1 In spite of the higher technical complexity in comparison to batch and fed-batch processes, perfusion processes can provide a higher throughput, lower costs and product/scale flexibility, and that is why in recent years in the biopharmaceutical industry the interest in perfusion technology for the production of both stable and labile proteins has been significantly growing. 1 In spite of the higher technical complexity in comparison to batch and fed-batch processes, perfusion processes can provide a higher throughput, lower costs and product/scale flexibility, and that is why in recent years in the biopharmaceutical industry the interest in perfusion technology for the production of both stable and labile proteins has been significantly growing.…”

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confidence: 99%

“…productivities, lower footprint, better utilization of subsequent downstream processing equipment, and have thus been more and more investigated in the last decade for the production of animal cell-derived biopharmaceuticals. 1 In spite of the higher technical complexity in comparison to batch and fed-batch processes, perfusion processes can provide a higher throughput, lower costs and product/scale flexibility, and that is why in recent years in the biopharmaceutical industry the interest in perfusion technology for the production of both stable and labile proteins has been significantly growing. 1,2 Intensification of perfusion culture processes can be achieved by increasing cell specific productivity (q p ), viable cell density (VCD) or both (q p and VCD), which is the best case scenario.…”

mentioning

confidence: 99%

“…1 In spite of the higher technical complexity in comparison to batch and fed-batch processes, perfusion processes can provide a higher throughput, lower costs and product/scale flexibility, and that is why in recent years in the biopharmaceutical industry the interest in perfusion technology for the production of both stable and labile proteins has been significantly growing. 1,2 Intensification of perfusion culture processes can be achieved by increasing cell specific productivity (q p ), viable cell density (VCD) or both (q p and VCD), which is the best case scenario. The volumetric productivity (P v ) in a perfusion culture operating in steady state can be calculated by means of Equation (1).…”

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confidence: 99%

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Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production

Coronel

Heinrich²,

Klausing³

et al. 2019

Biotechnology Progress

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Perfusion operation mode remains the preferred platform for production of labile biopharmaceuticals (e.g., blood factors) and is also being increasingly adopted for production of stable products (e.g., monoclonal antibodies). Regardless of the product, process development typically aims at maximizing production capacity. In this work, we investigated the impact of perfusion cultivation conditions on process productivity for production of human factor VIII (FVIII). Recombinant CHO cells were cultivated in bioreactors coupled to inclined settlers and the effects of reducing the temperature to 31 C with or without valeric acid (VA) supplementation were evaluated. Increases in cell specific productivity (q p ) up to 2.4-fold (FVIII concentration) and up to 3.0-fold (FVIII biological activity) were obtained at 31 C with VA compared to the control at 37 C. Biological activity is the most important quality attribute for FVIII and was positively affected by mild hypothermia in combination with the chemical inducer. The low temperature conditions resulted in enhanced product transcript levels, suggesting that the higher q p is related to the increased mRNA levels. Furthermore, a high-producer subclone was evaluated under the perfusion conditions optimized for the parental clone (31 C with VA), yielding increases in q p of 6-fold and 15-fold compared to the parental clone cultivated under the same condition and at 37 C, respectively. The proposed perfusion strategy enables increased product formation without increasing production costs, being potentially applicable to perfusion production of other CHO-derived biopharmaceuticals. To the best of our knowledge, this is the first report showing the benefits of perfusion combining mild hypothermia with VA supplementation. K E Y W O R D SCHO perfusion cultivation, mild hypothermia, productivity, recombinant factor VIII, valeric acid

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confidence: 99%

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confidence: 99%

“…1 In spite of the higher technical complexity in comparison to batch and fed-batch processes, perfusion processes can provide a higher throughput, lower costs and product/scale flexibility, and that is why in recent years in the biopharmaceutical industry the interest in perfusion technology for the production of both stable and labile proteins has been significantly growing. 1,2 Intensification of perfusion culture processes can be achieved by increasing cell specific productivity (q p ), viable cell density (VCD) or both (q p and VCD), which is the best case scenario. The volumetric productivity (P v ) in a perfusion culture operating in steady state can be calculated by means of Equation (1).…”

mentioning

confidence: 99%

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Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production

Coronel

Heinrich²,

Klausing³

et al. 2019

Biotechnology Progress

Self Cite

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“…Contributing factors include the generally much lower titers that can be achieved in cell culture, the lack of an affinity chromatography option, and the often complex nature and limited stability of the molecule. Changing the upstream process from a traditional fed‐batch bioreactor to a perfusion process can create significant opportunities for enhanced productivity and improved product quality . This change can present, however, considerable challenges for downstream processing, not the least being the handling of large volumes of dilute feedstock.…”

Section: Introductionmentioning

confidence: 99%

“…Changing the upstream process from a traditional fed-batch bioreactor to a perfusion process can create significant opportunities for enhanced productivity and improved product quality. [1][2][3] This change can present, however, considerable challenges for downstream processing, not the least being the handling of large volumes of dilute feedstock. The integration of a perfusion upstream process with a continuous downstream capture operation has the potential to Additional supporting information may be found online in the Supporting Information section at the end of the article.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of continuous nonaffinity capture chromatography for a recombinant enzyme—optimization for a changing perfusion feedstream and comparison to batch processing

Thompson¹,

Wilson²,

Larkin

et al. 2018

Biotechnology Progress

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This work presents the optimization and critical evaluation of continuous capture chromatography in the downstream process of a recombinant enzyme. For the upstream manufacturing of this molecule, a perfusion process was implemented due to benefits for product quality and productivity. This process is, however, characterized by low titer and significant changes over the course of the harvest duration in terms of active enzyme concentration and impurity content. We evaluated the feasibility and benefits of a continuous capture operation. This case study illustrates the design approach that can be utilized to address challenges presented by a changing feedstream, and the statistical measures that can be employed to characterize and optimize the operating space under material and time constraints. Process economic modeling in conjunction with Monte Carlo simulations indicate that even for a nonaffinity capture step utilizing a relatively cheap ion-exchange resin, the smaller column volume used in a continuous set-up results in cost savings compared to the batch process. We compare this option to the scenario of repeated processing using a small capture column in batch mode. Our analysis establishes that continuous processing becomes economically attractive for processes where only a small portion of the potential column lifetime can be utilized or for column steps with slow mass transport and shallow breakthrough curves. In cases where column breakthrough is sharp and resin lifetime is relatively short, continuous processing may offer an improvement over traditional batch processing, but much of the productivity and cost savings can be realized through repeated column cycling. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1195-1204, 2018.

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Potential of Continuous Manufacturing for Liposomal Drug Products

Worsham

Thomas

Farid

2018

Biotechnology Journal

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Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g., improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application.

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Continuous Animal Cell Perfusion Processes: The First Step Toward Integrated Continuous Biomanufacturing

Cited by 19 publications

References 91 publications

Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production

Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production

Evaluation of continuous nonaffinity capture chromatography for a recombinant enzyme—optimization for a changing perfusion feedstream and comparison to batch processing

Potential of Continuous Manufacturing for Liposomal Drug Products

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