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22 Pharmaceutical Technology ® The Real Message Behind Commercial mRNA Products April eBook 2023 PharmTech.com SCIENCEDISPL AY - STOCK.ADOBE.COM F or messenger RNA (mRNA) therapeutics and vaccines formulated as lipid nanoparticles (LNPs), the excipients receiving the most at- tention are the encapsulating lipids. While these compounds are crucial to the stability and deliv- ery of mRNA-LNPs, the non-lipid excipients also play crucial roles in the function of final drug products. They impact the morphology and stability of these delivery systems, which in turn affects in vivo perfor- mance and the overall usefulness of mRNA drugs de- veloped using nanoparticle technology. A number of non-lipid excipients needed Non-lipid excipients used to formulate mRNA-LNP products include solvents, salts, and sugars/cryopro- tectants, according to David Jung, senior manager RD&I, nucleic acids at Evonik. Overall, these excipients serve the function of controlling the pH during the ini- tial mixing and formation of the particle and ensuring stability upon storage of the material, he notes. More specifically, rapid mixing is the predominant technique for lipid nanoparticle–mRNA formulations: an ethanol phase (lipid components) and an aqueous phase (mRNA molecules, usually in acetate or citrate buffers) are mixed under specific conditions (pH and f low rate), explains Luca Bruno, segment marketing manager, MilliporeSigma, the Life Science business of Merck KGa A, Darmstadt, Germany. Rapid mix- ing, he adds, allows scalability and reproducibility of mRNA-LNP formulation. Organic solvents and residual components are then removed by ultrafiltration. The mRNA-LNP drug sub- stance is then formulated using a more physiological buffer, typically tris(hydroxymethyl)aminomethane- Excipients Impact Stability in mRNA-LNP Formulations Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years and contributes regularly to BioPharm International and Pharmaceutical Technology. Lipids aren't the only important ingredients influencing stability and in vivo performance.