Modeling transitional fouling mechanisms for mRNA-lipid nanoparticles during sterile filtration

Sterile filtration is a critical step in the purification of lipid nanoparticles (LNP) for mRNA vaccines and therapeutics. The relatively large size (50–200 nm) of LNP compared to traditional biologics can lead to significant fouling of 0.2 μm-rated sterilizing-grade filters. The objective of this study was to mathematically model the sterile filtration behavior of two different mRNA-LNP formulations (LNP A and LNP B) using the Sartopore 2 XLG dual layer (0.8/0.2 μm) membrane at both constant flux and constant transmembrane pressure (TMP). LNP A fouling at constant TMP was consistent with the complete pore blockage model, with the rate of pore blockage decreasing with increasing TMP as described previously. In contrast, resistance derivative plots for LNP B showed a shift in slope from n ≈ 2 at low TMP to n ≈ 1 at high TMP, indicating a transition from complete to intermediate pore blockage with increasing pressure. This novel behavior was described mathematically by introducing a pressure-dependent exponent to the pore blockage equation, enabling the model to effectively describe the observed change in curvature observed in the resistance derivative plot. This modified model successfully describes the different fouling behaviors observed with LNP A and LNP B during both constant flux and constant TMP. These findings highlight the sensitivity of LNP fouling mechanisms to operating conditions and demonstrate that the proposed modeling framework can describe complex fouling behavior in sterile filtration of multiple types of LNPs.