Mechanistic Modeling of Preparative Column Chromatography for Biotherapeutics

Abstract

Chromatography has long been, and remains, the workhorse of downstream processing in the production of biopharmaceuticals. As bioprocessing has matured, there has been a growing trend toward seeking a detailed fundamental understanding of the relevant unit operations, which for some operations include the use of mechanistic modeling in a way similar to its use in the conventional chemical process industries. Mechanistic models of chromatography have been developed for almost a century, but although the essential features are generally understood, the specialization of such models to biopharmaceutical processing includes several areas that require further elucidation. This review outlines the overall approaches used in such modeling and emphasizes current needs, specifically in the context of typical uses of such models; these include selection and improvement of isotherm models and methods to estimate isotherm and transport parameters independently. Further insights are likely to be aided by molecular-level modeling, as well as by the copious amounts of empirical data available for existing processes.

Modeling the Impact of Holdup Volume from Chromatographic Workstations on Ion-Exchange Chromatography

“…The mass transfer coefficient to and from the resin bead is k flim , i . The column porosity and bead porosities are given by ϵ c and ϵ p , respectively, while the interstitial velocity is given by u The linear driving force model (eq ) describes the kinetics of adsorption, while the equilibrium of adsorption is modeled by the colloidal isotherm , (eq )­ Here, c p , i * and q i * are solute i ’s concentration in the pore space and on the adsorbent surface at equilibrium, respectively. The adsorption rate constant and equilibrium binding constant are given by k kin and K eq , respectively.…”

Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies

“…There are two main approaches to downstream process modelling, the use of statistical methods, including Design of Experiments (DoE; [ 41 ]) and first-principles mechanistic modelling (reviewed in [ 42 , 43 , 44 ]). Mechanistic models incorporate both mass transport properties within the column as well as protein-resin (adsorption/desorption/diffusion) characteristics, captured as a series of differential equations that quantitatively define time-dependent changes in solute concentration.…”

Advanced control strategies for bioprocess chromatography: Challenges and opportunities for intensified processes and next generation products

“…Mechanistic modelling of chromatography processes for process optimisation and robustness studies is a prevalent area of research [87,88]. However, with first-principle modelling accuracy and the efficiency of mathematical solvers improving, mechanistic models are finding a growing number of applications for chromatography process control for biopharmaceutical products [89].…”