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Multi-stage continuous high cell density culture systems: a review.

Ho Nam Chang1, Kwonsu Jung1, Jin-Dal-Rae Choi1

  • 1Department of Chemical and Biomolecular Engineering, KAIST, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.

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|January 28, 2014
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Summary

Multi-stage continuous high cell density culture (MSC-HCDC) enables high productivity and product titers. Stable strains and decoupled retention times are key for long-term operation of these bioprocesses.

Keywords:
High cell density cultureMulti-stage continuous bioreactorsProduct titer improvementProductivity improvement

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Area of Science:

  • Biotechnology
  • Bioprocess Engineering
  • Cell Culture Technology

Background:

  • Multi-stage continuous high cell density culture (MSC-HCDC) systems offer potential for enhanced bioproduct manufacturing.
  • Achieving high productivity and high product titers are critical goals in bioprocess development.
  • Long-term operational stability requires decoupling cell and hydraulic retention times and ensuring strain stability.

Purpose of the Study:

  • To highlight the capabilities and requirements of multi-stage continuous high cell density culture (MSC-HCDC) systems.
  • To discuss the suitability of MSC-HCDC for diverse bioproducts, including extracellular and intracellular products.
  • To emphasize the importance of understanding fermentation kinetics and developing robust high-density culture methods for industrialization.

Main Methods:

  • Review and synthesis of principles governing MSC-HCDC systems.
  • Analysis of factors critical for sustained continuous operation, including retention time decoupling and strain stability.
  • Identification of diverse bioproducts amenable to MSC-HCDC, spanning various categories.

Main Results:

  • MSC-HCDC systems can achieve high productivity and high product titers for a wide range of bioproducts.
  • Decoupling cell and hydraulic retention times and maintaining strain stability are essential for long-term MSC-HCDC operation.
  • The technology is applicable to both low-value, high-volume products (e.g., fuel ethanol, lactic acid) and high-value products (e.g., monoclonal antibodies, therapeutics).

Conclusions:

  • MSC-HCDC represents a powerful platform for efficient biomanufacturing.
  • Further research into fermentation kinetics and high-density culture methods is crucial for broader industrial adoption.
  • Optimized MSC-HCDC can facilitate the transition of products from fed-batch to continuous manufacturing processes.