Abstract
Oligo-deoxythymidine (Oligo-dT) ligand-based affinity chromatography is a robust method for purifying mRNA drug substances within the manufacturing process of mRNA-based products, including vaccines and therapeutics. However, the conventional batch mode of operation for oligo-dT chromatography has certain drawbacks that reduce this process’s productivity. Here, we report a new continuous oligo-dT chromatography process for the purification of in vitro transcribed mRNA, which reduces losses, improves the efficiency of oligo-dT resin use, and intensifies the chromatography process. Furthermore, the quality by design (QbD) framework was used to establish a design space for the newly developed method. The optimisation of process parameters, including salt type, salt concentration, load flow rate and mRNA load concentration both in batch and the continuous mode, achieved >90% yield (mRNA recovery) along with >95% mRNA integrity and >99% purity. The productivity of continuous chromatography was estimated to be 5.75-fold higher, and the operating cost was estimated 15% lower, when compared to batch chromatography. Furthermore, the QbD framework was further used to map the relationship between critical quality attributes (CQAs) and key performance indicators (KPIs) as a function of critical process parameters (CPPs) and critical material attributes (CMAs).
Published Version
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