Advances in the theory, implementation, and application of mechanistic models in downstream bioprocessing of monoclonal antibodies
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Authors
Zhang, Wendi
Issue Date
2024-07
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Chemical engineering
Alternative Title
Abstract
Mechanistic models are powerful tools for process characterization and optimization. Although their usage in academia is common, their widespread use in the biopharmaceutical industry is hindered by several factors. First, derivation of first-principles models is very difficult, sometimes due to insufficient understanding of the underlying phenomena or limitations in the experimental techniques or instruments. Deriving empirical models also requires instinct and experience in relevant fields. Second, there are many unit operations involved in the production process. There is a lack of a powerful, yet flexible and shared platform to perform these simulations. Third, the workflow for using these developed models is not clear. Applying these models in an already established industry workflow and interpreting the results require advanced knowledge in multiple disciplines. In this thesis, we aim to address these challenges, particularly for protein A chromatography and precipitation capture purification operations in the downstream bioprocessing of monoclonal antibodies. In protein A chromatography, we derived a novel isotherm model and implemented it with the general rate model in well-known chromatography modelling software packages including GoSilico and CADET. Experiments are designed and performed to demonstrate that the model is compatible with an array of resins, mAbs and experimental conditions. We show that the model can be easily trained and that it offers excellent chromatogram predictions. We further established an intuitive workflow showing how to use the model for process development. Beyond these practical applications, we also used models of varying complexity to understand the heterogeneous surface properties of the protein A resins and tried to determine what compromises are needed when applying complicated semi-empirical and first-principles mechanistic models to practical situations where speed, simplicity and accuracy are required simultaneously. In precipitation, we focused on the solution, implementation and benchmarking of a mechanistic model for solid particle formation kinetics called the population balance model in the free and open-source software package CADET. CADET already supports the solution of many models for other unit operations, and introducing population balance model to the CADET family drives integrated in silico process development. In addition to this, we also applied the model to characterize antibody precipitation kinetics: experiments were conducted and a workflow was established to apply the model. The results were further used to inform future process development directions.
Description
July2024
School of Engineering
School of Engineering
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY