Multi-Attribute Monitoring of Therapeutic mRNA by Liquid Chromatography–Mass Spectrometry

Therapeutic mRNA is receiving growing interest in various therapeutic applications such as genome editing, cancer immunotherapy and prophylactic vaccines. As with other drugs, it is essential to guarantee product quality. Among the critical quality attributes of therapeutic mRNA, characterisation of the capping and poly(A) tail are of the greatest importance because of their involvement in mRNA stability and in the efficiency of protein synthesis. This article presents a method for the simultaneous characterisation of both attributes in a single sample preparation workflow. The method involves lipid extraction, various RNAse enzymes, purification steps and LC–MS to analyse the capping and poly(A) tailing.

The methodologies developed offer comprehensive characterisation of two essential quality attributes of mRNA, demonstrating versatility because they can be applied to a wide range of mRNA types without any a priori conditions. The optimized workflow seamlessly integrates the analysis of both drug substances and drug products while minimising sample requirements, sample preparation effort, and analysis time. This streamlining is of particular importance given the often-limited availability of sample quantities and the high demand for mass spectrometry resources.

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