Moderna's Regulatory Journey: 3 Takeaways To Foster The mRNA Renaissance

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

The story of how Moderna brought one of the first mRNA vaccines to the market has all the makings of a legend we will pass down through generations. However, unlike the legends of King Arthur or The Fountain of Youth, we can celebrate that Moderna’s legendary journey was — and still is — real. Not only did the mRNA vaccines help return life to normal, but they also kickstarted the mRNA therapeutic renaissance we’re happily experiencing today.

The basic “plot points” of Moderna’s journey to the market are relatively well documented. Young(ish) mRNA company meets a promising sequence and sees a potential future together. The company explores the relationship in clinical trials; requests the wisdom — and permission — of the regulatory agencies to “make it official” on the market; and, finally, a novel product is born. For a more traditional but still wonderful take on the company’s story, I’d refer you to this TED Talk hosted by Moderna’s Melissa Moore.

But there remains a critical piece of this story that demands greater elaboration, particularly for those of us with hopes of bringing more mRNA medicines to market in the years ahead: What can we learn from Moderna’s whirlwind journey through the current “black box” of the mRNA regulatory paradigm?

There is a certain amount of angst accompanying the regulatory paradigm for every modality across the ATMP space. However, there remains a dearth of clear-cut mRNA therapeutic regulatory guidelines — a factor which places mRNA therapeutic developers in an interesting spot. On the one hand, the lack of guidance and compendial standards lends companies a certain amount of “freedom to operate” when it comes to the development of internal standards and quality thresholds. But, on the flip side, establishing a process and an analytical platform without a clear sense of what the FDA/EMA defines as a high-quality mRNA drug substance/product can also feel like (and/or be) a perilous game of “Regulatory Roulette.”

Last fall, I attended Hanson Wade’s mRNA Process Development and Manufacturing conference, at which I had the great fortune to hear Moderna share its global regulatory experiences. We may no longer be living in the fast-and-furious days of Emergency Use Authorization, nor are we all working strictly on mRNA vaccines. But after listening to Moderna’s Director of Regulatory CMC Chris Kelly share his whirlwind regulatory experiences, there were still several broad takeaways for companies navigating this nascent space. Kelly’s insights not only provide more definition around where regulators (the FDA in particular) stand on mRNA, but they also bring to light the considerations we as companies may eventually face as the mRNA regulatory paradigm clarifies.

The Regulatory Background, In Brief                                             

Before we embark upon this epic regulatory journey, it’s important to identify the current “knowns” of mRNA/RNA therapeutics regulations today. There are several key facts to note:

1. Currently, there are no mRNA/RNA-specific FDA or EMA guidances.
2. mRNA is considered a biologic regulated under FDA’s CBER; the review division depends on indication (i.e., rare disease, oncology, vaccine). In turn, from a CGMP perspective, companies should expect to be held to the same quality standards as that of a protein therapeutic or monoclonal antibody.
3. The EMA defines mRNA as a vaccine or an ATMP (gene therapy), and an mRNA product is/would be approved via the centralized procedure.  
4. There are two RNA-specific guidelines that companies currently can rely upon:
   1. WHO Draft Guidance, “Evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases.”
   2. U.S. Pharmacopeia Draft Guidelines: “Analytical Procedures for mRNA Vaccine Quality. At present, these guidelines are just for drug substance, but there are plans afoot to expand it to include mRNA drug product, as well.
5. In the meantime, there are a smattering of other guidelines, standards, or pharmacopeial efforts that can be applied to mRNA/LNP vaccines and/or therapeutic products, including:
   1. WHO Guideline for plasmid DNA vaccines (2020);
   2. FDA Final Guidance on Liposome Drug Products (2018); and
   3. FDA Final Guidance on drug/biological products containing nanomaterials.
6. On the Standards side, we can feast our eyes on:
   1. ASTM E2859-11: Standard Guide for Size Measurement of Nanoparticles Using Atomic Force Microscopy;
   2. ISO 22412:2017: Particle Size Analysis-Dynamic Light Scattering;
   3. International Pharmaceutical Excipients Council (IPEC) Good Manufacturing Practices Guide.  
7. Additional efforts to note:
   1. I heard recently that EMA is at work on a guidance document for mRNA vaccines.
   2. USP is eyeing several future chapters on testing molecular size, zeta potential, and polydispersity of LNPs.
   3. ISO is fleshing out a preliminary work item, “Guide for methods for the measurements of mRNA-LNPs” (ISO PWIP 16921-3). 

As we look at this somewhat scattered list, it’s hard to not think about the current mRNA regulatory landscape as a (very “grown-up”) word search puzzle. Though there are a few RNA-centric guidelines we can turn to, our current regulatory expedition involves sifting through large banks of information for the golden nuggets most relevant to our mRNA- or mRNA/LNP-specific efforts. As such, much of the heavy lifting in the next few years will be for the industry and regulators to arrive at a more thorough and scientifically aligned RNA-specific set of regulatory expectations. What RNA-specific means, however, remains a question that could — and no doubt will — spark a thousand conversations in the upcoming years.

3 Best Practices From Moderna’s mRNA Regulatory Experiences

1. Brace For More “Realistic” Post-Pandemic Regulatory Interaction
2. Keep Reproducibility At The Center Of Your Mission
3. Prepare For Supply Chain “Growing Pains” Beyond Scale & Availability

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