The DIA/FDA conference on oligonucleotide therapeutics, held in Washington DC in October 2024, provided an opportunity for industry and agency experts to exchange insights on how the knowledge gained in addressing the CMC challenges of mRNA COVID-19 vaccines can be leveraged in the therapeutics arena.
At a session of the conference focused on “CMC considerations in the development of mRNA-based therapeutics,” participants highlighted the common structural characteristics and processes between mRNA vaccines and therapeutics, which offer the potential to extrapolate CMC learnings involving purity/impurity profiles and other CQAs, lipid nanoparticle (LNP) stability, phase appropriate specifications, and shelf-life.
However, the session also spotlighted the unique CMC challenges posed by the expanding diversity of mRNA therapeutic modalities and several important differences in their development and application compared to vaccines.
Differences highlighted include: ● differing mechanisms of action ● the substantially higher doses, more frequent administration, and extended treatment durations typically required for mRNA therapeutics compared to vaccines ● differing routes of administration ● different scales of manufacture, and ● differing immunogenicity profiles – with vaccines requiring an immune response, while mRNA therapeutics typically need to minimize it.
As a result, key CMC issues such as potency control, impurity control, presence of particulates, and stability – applicable not only to the mRNA API but also to the lipid components and LNP carriers in the final drug product – become significantly more complex when moving from mRNA vaccines for infectious diseases to mRNA therapeutics.
There was broad agreement that a tailored control strategy will be essential in addressing these challenges – customized to each specific mRNA therapeutic product. This includes setting product-specific limits and applying tighter controls for process impurities, particulate matter, and stability and shelf-life parameters. The need for a multi-faceted approach to potency assays was underscored.
Also drawing discussion was how mRNA platform technologies and prior knowledge could allow for more streamlined processes, ensure consistency across multiple therapeutic products, and expedite regulatory submissions.
At a roundtable session on the final day of the conference, clarification was provided on current FDA and EMA thinking on platform designations and technology, and an industry case study was discussed on the use of a platform approach for process performance qualification (PPQ) in mRNA manufacturing.
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