By Anna Rose Welch, Director, Cell & Gene Collaborative
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This is the final installment of a three-part series showcasing Moderna’s regulatory experiences approving its mRNA vaccine. At the September 2022 mRNA Process Development and Manufacturing Summit, Moderna’s Global Director of Regulatory CMC Chris Kelly shared his experiences working with his colleagues around the clock to scale the company’s manufacturing process, supply chain, and regulatory filings globally. There were many unique aspects to Moderna’s experience that we likely won’t experience with our own products — namely the super-sonic speed at which development occurred for emergency approval. However, the details Kelly provided around the as-yet unclear regulatory pathway for mRNA vaccines and therapeutics shed some light on where we as an industry need to prepare our minds, set expectations, and future-proof our development for more mRNA-specific regulatory guidance. Each article in this series will be framed as an individual takeaway for the industry based off a specific aspect of Moderna’s regulatory story. For a quick “crash course” on the current state of the mRNA regulatory paradigm and to find takeaways #1 and #2, check out this previous post.
Takeaway #3: Prepare for supply chain “growing pains” beyond scale & availability
In the ATMP space today, we cannot attend conferences, listen to webinars, or read articles about manufacturing (including this one) without hearing how critical it is to begin with the end in mind. In other words, we must always be thinking about what industrialization of our processes will look like and what it will take to get there. But we tend to limit our definition of a commercial manufacturing process to scale alone.
One of the most important reminders I took away from Moderna’s experiences ushering its mRNA vaccine onto the global market is that a commercial manufacturing process must also be accompanied by (or rather incorporate/comprise) a commercially ready supply chain. Though sufficient physical volumes of each raw material and a redundant supplier network are necessities, physical scale is not the only “CQA” for which we must account when commercializing our supply chain. We must also be prepared to confront a few of the less “sexy” but still significant aspects of future-proofing the mRNA supply chain for the commercial market. Particularly, we will need to achieve more consistent raw material specifications and strive for more standardized regulatory documentation across vendors (i.e., COAs). In some cases, we may also have to advocate for greater consistency in how regulators define/classify certain raw materials and excipients.
Moderna’s experience working with multiple vendors across the globe to scale its raw material supply exemplifies the regulatory complexities that can arise from embracing a global, multi-source supply chain.
“We had to qualify multiple vendors to ensure we had adequate supply,” Kelly explained. “However, each vendor had slightly different COAs. How you present that variability in a regulatory filing can be tricky. Differences in COAs and in the specifications for your materials can raise red flags for regulators.”
For Moderna, the differences in COAs and material specifications across vendors led the company to develop master specifications for all raw materials. In turn, all incoming raw materials needed to meet Moderna’s specifications as opposed to just the vendor’s specifications. The company also established a qualification program to ensure compendial compliance in cases where non-compendial materials were the only available option. Now, relying upon non-compendial products is always an option available to us and, in some cases, may be a necessity in the near-term as the mRNA supply chain continues to mature. However, as Kelly emphasized, we will also have to embrace the extra regulatory documentation (i.e., analytical method descriptions) that comes with this choice — or necessity.
Likewise, our ambitions to localize and decentralize mRNA manufacturing (e.g., the BioNTainer) may mean we will also face documentation growing pains in working with different regulatory agencies. At the root of (some of) these growing pains are differences in regulators’ definitions and regulation of individual raw materials.
“In some regions, certain non-compendial raw materials — for example, your lipid components — are regulated as novel agents and, therefore, require their own separate, full CTD sections with validated analytical methods,” Kelly said. However, depending on a supplier’s experience (or lack thereof) with GMP requirements and/or their willingness/abilities to provide the information required in a CTD, it may not necessarily be the easiest information for a sponsor to provide.
Similarly, whether a lipid component belongs with the other raw materials in the drug substance section or belongs in the drug product section as an excipient are points of (friendly) contention between FDA and EMA.
“FDA considered the lipid components for the LNPs as starting materials that would live in your control of materials section,” Kelly offered. “The EMA defined the lipids as drug product intermediates that should be documented as excipients. So, in this case, there are two different flavors of regulatory guidance sponsors must follow.”
While multiple flavors may be delightful on an ice cream cone, it’s much less desirable in the regulation and commercialization of medicines — especially in the mRNA space, which craves greater clarity and standardization in many aspects of development. There is still plenty of room (and a blatant need) for RNA-specific regulatory guidance, which will, no doubt, boast some unique considerations in measuring and demonstrating quality of the mRNA drug substance and product.
In these early days sans regulatory guidance and broader experience, we are regularly evaluating and reevaluating “how pure is pure enough” for our raw materials and products. However, though we may not always be able to directly apply all biologics and ATMP regulatory learnings to the mRNA experience, one thing does remain the same across modalities: the regulators’ expectations for high-quality processes and supply chains. I particularly loved Kelly’s parting reminder:
“The FDA expects the same level of GMP readiness for mRNA products as it does other drugs,” Kelly concluded. “Even though our development was accelerated, we still faced the same burden of proof in demonstrating quality. We were still submitting the same types of reports as we would any other development program in a non-pandemic time.”
We in the mRNA space will no doubt be confronted by regulatory questions and situations we won’t be able to solve by simply “checking a box.” However, just as the heroics of COVID-era mRNA vaccine production will always be celebrated, Kelly’s reminder to take advantage of the FDA’s pre-IND, INTERACT, and/or Type C meetings will never go out of style in the ATMP space.
Missed takeaways 1 & 2? Check them out here!
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