Abstract
Since the COVID-19 pandemic, the interest in RNA-lipid nanoparticle (LNP) based drug products has increased drastically. While one RNA-LNP drug product, Onpattro, was already on the market in 2018, high volume manufacturing was only initiated end of 2020 with the approval of the mRNA-LNP vaccines, Comirnaty and Spikevax. As such, deep product knowledge for RNA-LNPs is continuously increasing. In this article the effect of large-scale mixing and lab-scale shaking on mRNA-LNP drug product quality characteristics is investigated. It is shown that mixing and shaking can have a profound impact on both LNP size distribution and mRNA encapsulation, suggesting a direct correlation between both quality characteristics, and further supported by a proposed underlying mechanism. An in-depth investigation of different drug product (DP) presentations reveals a consistent effect of headspace volume and LNP content on the shaking stress sensitivity. Results reported in this study are of utter importance for both small- and large-scale manufacturers but also for care givers and patients using these products.