Validation of a CFD model for cell culture bioreactors at large scale and its application in scale-up.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Publishers Country of Publication: Netherlands NLM ID: 8411927 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4863 (Electronic) Linking ISSN: 01681656 NLM ISO Abbreviation: J Biotechnol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier Science Publishers, c1984-
    • Subject Terms:
      Bioreactors* ; Cell Culture Techniques*/methods ; Cell Culture Techniques*/instrumentation ; Hydrodynamics* ; Oxygen*/metabolism ; Oxygen*/analysis; Carbon Dioxide/metabolism ; Computer Simulation ; CHO Cells ; Cricetulus ; Models, Biological ; Animals
    • Abstract:
      Among all the operating parameters that control the cell culture environment inside bioreactors, appropriate mixing and aeration are crucial to ensure sufficient oxygen supply, homogeneous mixing, and CO 2 stripping. A model-based manufacturing facility fit approach was applied to define agitation and bottom air flow rates during the process scale-up from laboratory to manufacturing, of which computational fluid dynamics (CFD) was the core modeling tool. The realizable k-ε turbulent dispersed Eulerian gas-liquid flow model was established and validated using experimental values for the volumetric oxygen transfer coefficient (k L a). Model validation defined the process operating parameter ranges for application of the model, identified mixing issues (e.g., impeller flooding, dissolved oxygen gradients, etc.) and the impact of antifoam on k L a. Using the CFD simulation results as inputs to the models for oxygen demand, gas entrance velocity, and CO 2 stripping aided in the design of the agitation and bottom air flow rates needed to meet cellular oxygen demand, control CO 2 levels, mitigate risks for cell damage due to shear, foaming, as well as fire hazards due to high O 2 levels in the bioreactor gas outlet. The recommended operating conditions led to the completion of five manufacturing runs with a 100% success rate. This model-based approach achieved a seamless scale-up and reduced the required number of at-scale development batches, resulting in cost and time savings of a cell culture commercialization process.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no known financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Carbon dioxide stripping; Computational fluid dynamics; Gas entrance velocity; Impeller flooding; Oxygen demand model; Process scale-up; Volumetric oxygen transfer coefficient
    • Accession Number:
      S88TT14065 (Oxygen)
      142M471B3J (Carbon Dioxide)
    • Publication Date:
      Date Created: 20240406 Date Completed: 20240427 Latest Revision: 20240427
    • Publication Date:
      20240428
    • Accession Number:
      10.1016/j.jbiotec.2024.02.006
    • Accession Number:
      38582408