Development of a new modeling framework to describe sterile filtration of mRNA-Lipid nanoparticles

Abstract

Sterile filtration is one of the critical steps in the production of lipid nanoparticle (LNP)-based biotherapeutics. However, LNP fouling can limit the overall capacity of the sterilizing-grade filter. Effective design and control of this unit operation enables a robust manufacturing process. The objective of this study was to examine the sterile filtration of mRNA-LNP through the dual-layer Sartopore 2 XLG membrane during both constant flux and constant transmembrane pressure (TMP) filtration experiments. The complete pore blockage model effectively described the fouling behavior at constant TMP, with the rate of pore blockage decreasing with increasing TMP. However, a novel modification of the complete pore blockage model was needed to describe the fouling behavior during constant flux operation, with the rate of pore blockage found to be a function of both the instantaneous TMP and the TMP gradient. This new model successfully describes the TMP profiles during constant flux operation at multiple fluxes and the flux profiles during constant TMP operation at multiple TMPs, all using the same model parameters. These findings establish a foundational framework that mathematically describes the fouling behavior of mRNA-LNP and can be used to design and optimize sterile filtration processes for this class of biotherapeutic.