Mechanistic modeling of cation exchange chromatography scale-up considering packing inhomogeneities

In process development and characterization, the scale-up of chromatographic steps is a crucial part and brings a number of challenges. Usually, scale-down models are used to represent the process step, and constant column properties are assumed. The scaling is then typically based on the concept of linear scale-up. In this work, a mechanistic model describing an anti-Langmuirian to Langmuirian elution behavior of a polypeptide, calibrated with a pre-packed 1 ml column, is applied to demonstrate the scalability to larger column volumes up to 28.2 ml. Using individual column parameters for each column size, scaling to similar eluting salt concentrations, peak heights, and shapes is experimentally demonstrated by considering the model's relationship between the normalized gradient slope and the eluting salt concentration. Further scale-up simulations show improved model predictions when radial inhomogeneities in packing quality are considered.