(165b) Investigation into the Critical Process Parameters for Lipid Nanoparticle Precipitation in Impinging Jet Mixers

Lipid nanoparticles (LNPs) are currently the most advanced delivery platform for several novel therapeutic modalities, including mRNA vaccines ¹. LNPs can encapsulate the therapeutic ingredients to protect them from degradation and to deliver them safe and effectively into the target cells. Formulation of mRNA-loaded LNPs involves a rapid antisolvent precipitation by mixing an ethanolic lipid mixture with dissolved mRNA in an aqueous acidic buffer. During mixing, lipids interact with the anionic mRNA, forming complexes while simultaneously self-assembling into distinct nanostructures. For obtaining control over critical quality attributes—such as encapsulation efficiency, particle size and size distribution—mixing must occur faster than the assembly process itself.

In the early development phase, process screening is performed using microfluidic chips; however, these systems scale poorly to large-scale production. For the actual manufacturing impinging jet mixers (IJMs) are commonly employed ². These mixers allow two process streams to collide at high velocities, ensuring the rapid and efficient mixing ² necessary for the successful production of mRNA-loaded LNPs. There is however still limited clarity on the rationale behind the specific manufacturing conditions applied for mRNA-loaded LNPs, which leaves room for deeper investigation into the precipitation process. In this presentation we will present our work on investigating the critical process parameters for lipid nanoparticle precipitation in IJMs.

Acknowledgement: This research was supported by the U.S. Food and Drug Administration under the FDA BAA-22-00123 program, Award Number 75F40122C00200.

(1) Hou, X.; Zaks, T.; Langer, R.; Dong, Y. Lipid Nanoparticles for mRNA Delivery. Nat. Rev. Mater.2021, 6 (12), 1078–1094. https://doi.org/10.1038/s41578-021-00358-0.

(2) Devos, C.; Mukherjee, S.; Inguva, P.; Singh, S.; Wei, Y.; Mondal, S.; Yu, H.; Barbastathis, G.; Stelzer, T.; Braatz, R. D.; Myerson, A. S. Impinging Jet Mixers: A Review of Their Mixing Characteristics, Performance Considerations, and Applications. 2024.