AUTHOR=Nold V. , Junghans L. , Bayer B. , Bisgen L. , Duerkop M. , Drerup R. , Presser B. , Schwab T. , Bluhmki E. , Wieschalka S. , Knapp B.
TITLE=Boost dynamic protocols for producing mammalian biopharmaceuticals with intensified DoE—a practical guide to analyses with OLS and hybrid modeling
JOURNAL=Frontiers in Chemical Engineering
VOLUME=4
YEAR=2023
URL=https://www.frontiersin.org/journals/chemical-engineering/articles/10.3389/fceng.2022.1044245
DOI=10.3389/fceng.2022.1044245
ISSN=2673-2718
ABSTRACT=Introduction: For the implementation of robust bioprocesses, understanding of temporal cell behavior with respect to relevant inputs is crucial. Intensified Design of Experiments (iDoE) is an efficient tool to assess the joint influence of input parameters by including intra-experimental changes.
Methods: We applied iDoE to the production phase of a monoclonal antibody in a mammalian bioprocess. The multidimensional design space spanned by temperature, dissolved oxygen (DO), timing of change, and growth category was investigated in 12 cultivations. We built ordinary least squares (OLS) and hybrid models (HM) on the iDoE-data, validated them with classical DoE (cDoE)-derived data, and used the models as in silico representation for process optimization.
Results: If the complexity of interactions between changing setpoints of inputs is sufficiently captured during planning and modeling, iDoE proved to be valid for characterizing the mammalian biopharmaceutical production phase. For local behavior and flexible composition of optimization goals, OLS regressions can easily be implemented. To predict global and interconnected dynamics while incorporating mass balances, HM holds potential.
Discussion: iDoE will boost protocols that optimize inputs for different bioprocess phases. The described key aspects of OLS- and HM-based analyses of iDoE-data shall guide future applications during manufacturing.