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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.
Publication year - 2021
Publication title -
biotechnology and bioengineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.136
H-Index - 189
eISSN - 1097-0290
pISSN - 0006-3592
DOI - 10.1002/bit.27698
Subject(s) - pichia pastoris , biopharmaceutical , stability (learning theory) , biochemical engineering , seeding , population , computer science , biological system , biology , computational biology , microbiology and biotechnology , engineering , genetics , machine learning , agronomy , demography , sociology , gene , recombinant dna
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.