Mechanistic Modeling of Tangential Flow Filtration to Guide Process Development

Ultrafiltration (UF) and Diafiltration (DF) are key unit operations for bioprocess development that use tangential flow filtration (TFF) to provide a fast, efficient, and economical means of concentrating and buffer exchanging proteins. Each protein that undergoes TFF process development has buffer-dependent biophysical properties that requires unique operational conditions for efficient TFF performance. In addition, the application of TFF can be viscosity limited by active pharmaceutical ingredients (APIs) that require high concentration formulations (> 150 g/L), leading to additional process development.

Here we present a modeling workflow, performed in early-stage development of UF and DF unit operations, that allows us to connect the physical components and solution properties of the drug substance (e.g. buffer composition and solution viscosity) to the operational set points of the experiment. Using the workflow, we can run a minimal number of experiments and use these results to simulate how the filtration will operate under a range of set points.

The results from the simulations are then fed back into the experimental design to guide further process development. Connecting protein biophysics with TFF operation not only allows for quickly identifying molecule specific operational set points, but also minimizes material usage, ensures product yield and process robustness, and can inform other development decisions such as membrane selection.