Quality by Design for enabling RNA platform production processes

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

“…For the mRNA vaccines, WHO committees took the initiative during the pandemic, but we now see mRNA-LNP vaccine manufacturing experts starting to share quality attributes, analytical methods and some data in the scientific literature 39 , 42 , 50 , 51 , 152 . Moreover, the US Pharmacopeia has recently released their first draft chapter on Analytical Procedures for mRNA Vaccine Quality as discussed in detail above (see Tables 2 and 3 ) 49 .…”

“…When these standards are in place and more data are published, it will become more clear what ranges are achievable and which limits may be acceptable. While suggested specifications for the currently approved vaccines have been summarized by Daniel et al 42 , it should be noted that the mRNA technology is advancing rapidly and the currently used analytical methodologies, and their associated specifications, will be further developed to keep pace with the progress.…”

“…In a recent review, a Quality-by-Design (QbD) framework for future development, design and control of manufacturing processes for mRNA and LNP products was proposed. In order to implement this approach, a thorough understanding of process parameters (Critical Process Parameters, CPPs), analytical methods, and Critical Quality Attributes (CQAs) is also required 42 . To ensure rapid regulatory convergence of the currently approved mRNA-based COVID-19 vaccines, they were developed under a more conventional Quality-by-Testing paradigm due to the unprecedented speed with which they were developed and the fact that these products were “first-in-class”.…”

“…This DP manufacturing process can be performed at large scale, but requires specific equipment and multiple down-stream processing steps. This complexity is the reason why, up until now, mRNA-LNP vaccines are presented as ready-to-use formulations, that are manufactured in a few dedicated factories 39 , 42 , 50 .…”

Challenges and emerging trends in liquid chromatography-based analyses of mRNA pharmaceuticals

“…This is a significant assay because the poly-A tail is involved in the initiation of translation and because its length correlates with stability and translation efficiency [84] . The 3’ end of IVT synthesized mRNA is often designed to have a 120 nucleotide long poly-A tail, whether it be added by polyadenylation or through the use of a DNA template and polyT-nucleotides [85] . Measurements of poly-A tail heterogeneity is generally limited if attempted at the intact level.…”