Unlocking The Future Of mRNA
A conversation with BioPhorum members Pamela Hamill and Conor Lake
mRNA therapies and vaccines are experiencing rapid and sustained growth, building on their proven success in infectious disease prevention and expanding into broader therapeutic areas, such as oncology, rare diseases, and autoimmune disorders. Advances in lipid nanoparticle (LNP) delivery, sequence design, and scalable manufacturing have positioned mRNA as a flexible and powerful platform capable of responding quickly to emerging medical needs. As clinical pipelines mature and investment continues, mRNA‑based products are becoming a permanent and increasingly important component of the biopharmaceutical landscape.
With this growing importance, however, comes a clear need for continued regulatory and technological evolution. Many regulatory frameworks, manufacturing controls, and analytical approaches were not originally designed for highly modular, rapidly adaptable platforms like mRNA. Opportunities remain to improve regulatory alignment, strengthen platform‑based CMC strategies, advance analytical and digital tools, and enhance global consistency in expectations. Addressing these gaps will be essential to fully realize the potential of mRNA technologies — ensuring speed, quality, and patient access while maintaining confidence in safety and life cycle management.
These challenges are being explored across the industry, including within the BioPhorum ATMP collaboration. We took the opportunity to speak with some members of this collaboration by posing a series of questions to two experts — Pamela Hamill, technical consultant, scientific and regulatory consultancy at MilliporeSigma, and Conor Lake, associate director regulatory affairs CMC at Daiichi Sankyo — about issues such as innovations in analytics, regulatory challenges, and trends in RNA therapeutics in the ATMP space.
What innovations in analytics, digital tools, and quality control are critical for ensuring RNA therapeutic consistency and safety?
Next-generation sequencing (NGS), particularly long-read sequencing, could potentially become increasingly applied for mRNA LNP analytics. Advantages include the ability to assess multiple attributes simultaneously, giving information about identity, fragmentation, and impurities, and you can also look at structural features like the poly-A tail and 5’ prime capping.
For mRNA LNP vaccine applications, there may be a real demand for rapid or accelerated development supported by technologies that can avoid sequence- or mRNA-specific optimization needed for other technology platforms such as mass spectrometry or liquid chromatography. So potentially there are some advantages here in terms of speed and simplification. Analytics, such as mass spectrometry, would still be needed to provide detail that sequencing can’t provide, but having more off-the-shelf approaches can be helpful to support rapid process development and final quality control.
Another area that will be important is detecting and better understanding impurities. An example where we have limitations in current quality control methods is double-stranded RNA. There is no optimal method available, and this is important because immunogenicity is a significant risk for this type of modality, especially as the field expands rapidly into mRNA-based therapeutics that may involve multiple-dosing scenarios. Therefore, understanding double-stranded RNA impurities and having better technologies to measure them, avoiding the limitations of antibody-based assays, will be important. Understanding physiological relevance of dsRNA will also be valuable, so any methods or analytics that improve our understanding of the potential for these impurities to cause adverse responses will be useful.
At the moment, it is hard for developers to set meaningful specifications for impurities like double-stranded RNA because we do not know what a safe limit is, given its structural and sequence variability between different products and processes. This is potentially an attribute that NGS approaches may also be useful for, allowing you to gauge not only the identity but also the size of these impurities.
How are manufacturing processes evolving to support scalable RNA therapeutic production?
Lake: There is a broader adoption of continuous or more efficient purification concepts, such as multicolumn countercurrent solvent gradient purification (MCSGP) and increased automation in oligonucleotide synthesis. There are also the expansion and standardization of large-scale manufacturing facilities in CDMOs and an evolution of enzyme ligation approaches for potential future use. This approach can address both scalability and sustainability in the future. Another evolution is the use of new nucleic acid phosphate modifications that conserve stereochemistry for shorter RNA oligonucleotides.
How should the industry tackle the regulatory challenges unique to RNA medicines and how should they approach regulatory engagement?
Hamill: Although there have been approvals for mRNA LNP vaccines, the area is expanding into therapeutic applications for mRNA LNP and mRNA as tools for in vivo editing of cells. This is extremely exciting, but it increases complexity because current regulatory guidance does not cover these expanding applications. Some attributes such as impurities may have different risks based on different therapeutic applications, so it is challenging without more specific guidance on expectations for different types of RNA-based products.
For pioneers in this area, it is unlikely you will have specific regulatory guidance or much precedent for the approval of a similar type of therapy to support your development, so it is more a case of how you cope with those gaps. Taking any opportunity to speak with regulators to discuss your strategies will be important, for example, to get early feedback on your proposed analytical strategy, and might help avoid issues down the line. Early discussions are being encouraged by regulatory agencies, especially for novel therapeutic approaches.
Engaging with industry organizations, industrywide events, and forums can also be important for consolidating ideas or insights into possible solutions for common issues. For example, USP has recently organized symposia that brought manufacturers and service providers together to share insights, and organizations like BioPhorum have been useful in facilitating industry discussions to propose solutions to common issues in RNA. These initiatives may also increase the chance of interacting with regulators as part of industry organizations, rather than individual companies.
Lake: Industry sponsors should continue to engage with local health authorities to collaborate on draft guidance that will establish long-term expectations for the modality. Also, sponsors should take advantage of all options to meet with health authorities to discuss specific topics. We see there are varying levels of guideline details from global regulators and it’s necessary to engage with local health authorities when discussing a specific CMC challenge.
What key strategies are accelerating the development of next-generation RNA therapeutics and oligonucleotides?
Hamill: An emerging, possibly impactful, trend is using alternatives to plasmid DNA as templates for in vitro transcription, which could bring advantages such as increasing speed to manufacturing and reducing the cost of goods.
From a quality control perspective, this approach also reduces the burden of residual testing, e.g., for E. coli-related impurities, so it may help to streamline QC packages and development.
Further progress in the ability to target LNPs and mRNA and other RNA-based approaches, such as miRNA and ASOs, will be key for novel therapeutic approaches. One approach that looks interesting is the potential use of exosomes as delivery vehicles for RNA-based therapies.
Lake: An additional key strategy to accelerate development would be enzymatic ligation synthesis of shorter oligonucleotides. Both sponsors and CDMOs are motivated to use enzyme ligation technology as it could lead to more predictable product quality attributes while improving sustainability and material handling of solvents used in the production of synthetic oligonucleotides.
What trends do you predict for RNA therapeutics and oligonucleotides over the next three to five years?
Hamill: What I find exciting is not just mRNA as a therapeutic or vaccine directly, but the use of mRNA as a tool to deliver components needed for gene editing or the ability to generate cell therapies, such as in vivo CAR-T, which could be very impactful in simplifying manufacturing associated with viral vector-mediated delivery.
Lake: A key trend will be the industry adapting to evolving global health authority guidelines. Also, although there is yet to be an approved therapy using this synthesis platform, oligonucleotide manufacturing by enzymatic ligation should also be achieved.