Abstract
The purification of therapeutic peptides represents a major bottleneck in biopharmaceutical downstream processing due to the structural similarity between target products and closely related impurities. In this study, a shortcut dynamic simulation model of a two-column Multi-Column Countercurrent Solvent Gradient Purification (MCSGP) process is implemented in Aspen Chromatography for peptide separation. Each column is described using a one-dimensional axial dispersion model coupled with mass transfer kinetics and a modulated Langmuir adsorption equilibrium, while time-dependent boundary conditions are applied to represent solvent gradient elution. The model explicitly incorporates internal recycle streams between columns using the cycle organizer approach, capturing the defining operational features of MCSGP. This enables a unified representation of chromatographic transport phenomena, gradient operation, and discrete recycle logic within a single flowsheet-based framework. The novelty lies in treating MCSGP as a hybrid dynamic process rather than a purely chromatographic unit, providing a transferable modelling framework suitable for operability analysis, process comparison, and future optimization of continuous peptide purification systems. Dynamic simulation results for a model mixture of closely eluting peptides demonstrate stable cyclic operation and a substantial improvement in mass recovery compared with conventional batch chromatography under identical transport assumptions. In particular, systematic recycling of intermediate fractions leads to an order-of-magnitude increase in recovered target product.