Modeling of copy number variability in Pichia pastoris
Author(s)
Lu, Amos E.; Maloney, Andrew J.; Dalvie, Neil C.; Brady, Joseph R.; Love, Kerry R.; Love, J. Christopher; Braatz, Richard D.; ... Show more Show less
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Development of continuous biopharmaceutical manufacturing processes is an area of active research. This study considers the long-term transgene copy number stability of Pichia pastoris in continuous bioreactors. We propose a model of copy number loss that quantifies population heterogeneity. An analytical solution is derived and compared with existing experimental data. The model is then used to provide guidance for stable operating timescales. The model is extended to consider copy number dependent growth such as in the case of Zeocin supplementation. The model is also extended to analyze a continuous seeding strategy. This study is a critical step towards understanding the impact of continuous processing on the stability of Pichia pastoris and the resultant products.
Date issued
2021-02-02Department
Massachusetts Institute of Technology. Department of Chemical Engineering; Koch Institute for Integrative Cancer Research at MITJournal
Biotechnology and Bioengineering
Publisher
Wiley
Citation
Lu, A. E., Maloney, A. J., Dalvie, N. C., et al. Modeling of copy number variability in Pichia pastoris. Biotechnology and Bioengineering. 2021; 118: 1832– 1839.
Version: Author's final manuscript
ISSN
0006-3592
1097-0290