By Anna Rose Welch, Editorial & Community Director, Advancing RNA
This is part two 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 read Takeaway #1, check out this previous post.
Takeaway #2: Keep reproducibility at the center of your mission
The manufacturing-related benefits of mRNA therapeutics are oft-proclaimed today. Whether it be rapid production, a small manufacturing footprint, or a predominantly cell free process [sans the plasmid DNA production], developing mRNA therapeutics could seem too good to be true for those of us who have spent our lives working with cell-based therapies. In fact, if it weren’t for Moderna’s and BioNTech/Pfizer’s successes in rapidly producing the mRNA vaccines, mRNA may have remained relegated to the realms of the mythical.
Having recently learned about Moderna’s scale-up process in more detail, I daresay the company’s experience is a testament to our ability to make large quantities of mRNA using smaller volume equipment — which, when done smartly, can translate to lower utility costs, raw material usage, etc.
As Moderna’s Kelly outlined, the company started its journey at the “personalized vaccine scale”— a 70 mL IVT process. From there, the company progressed upward, moving from 70 mL IVT to 10 L IVT for Phase 2 studies. This was followed by a stepwise climb from 20 L to 60 L to 75 L IVT to meet demand for Phase 3 trials and to prepare for the commercial market. This was just for the drug substance; the company also needed to scale its LNP production and raw material supplies in parallel. (More on the raw material side to come in takeaway #3!)
To better understand the significance of these IVT volumes, remember that biologics manufacturing facilities come equipped with 10,000, 15,000, or 20,000 L bioreactors for large-scale biologic production. Even small-scale biologics production translates to working with bioreactors that boast a few zeros in their volume (i.e., 1,000L or 2,000L).
Given our tendencies to extrapolate our biologics experiences into the ATMP space, it’s no surprise we’d automatically equate global production with scaling-up to larger and larger volume equipment. But as Moderna’s experience demonstrates, we can also achieve the necessary volumes — and process consistency and reproducibility — by relying on a scale-out process. As Kelly outlined, Moderna worked with regulators to establish a “kit” approach to meet global demand. Each kit comprised a grouping of identical equipment, and each manufacturing site typically contained multiple kits. As you perhaps already guessed, the scale, critical process parameters, in-process controls, and testing were identical across kits. “The agency was very amenable to this approach, as long as each kit was constructed the same way, included the same materials and equipment, and was the same scale,” Kelly explained.
To establish and demonstrate the consistency of the kit approach, the company carried out a massive process performance qualification (PPQ) effort, validating three batch runs on the first kit, followed by one run on each subsequent kit. “In total, we conducted 19 PPQ studies,” Kelly added. “There were 88 lots generated for 14 production kits at 10 different sites in seven different countries. This approach was essential for global scale-up and manufacturing consistency.”
But beyond the consistency of the product itself, the kit process also offered consistent manufacturing and characterization data — a benefit that could easily be left unspoken but certainly shouldn’t be given the implications it could have for our comparability pursuits. In fact, as Kelly emphasized, it was thanks to the quality and reliability of this data across kits that Moderna was able to garner the FDA’s buy-in for any process changes (i.e., scaling up its IVT process, or adding a new kit to the mix). Given how tight the data was across manufacturing sites, the company was able to rely upon data generated across all its global manufacturing sites when proposing any changes to the agencies.
“Even though the EU sites weren’t utilized for U.S. manufacturing, the agency was accepting of the data because of the approach we took,” Kelly said. “Because the data was so tight, the whole body of data was able to be utilized to demonstrate comparability, which is huge.”
I’ve written it and heard it said many a time that we must begin with the end in mind, and I’d argue Moderna’s approach is a real-life depiction of this industry goal. Yes, it’s scale-out/scale-up story gives us a lot of specific details to wrap our brains around and/or marvel at — especially given the time constraints the company and its manufacturing partners faced. But if we look at “the forest beyond the trees” of each specific IVT volume or PPQ run, at the heart of Moderna’s strategy was the desire to balance the two critical — albeit antithetical — “virtues” of manufacturing: flexibility/nimbleness (especially in terms of scale) and great control over process, data, and product. Even for those of us working with other ATMP modalities beyond mRNA, Moderna’s story can and arguably should serve as a model to us all as we strive to keep reproducibility of our processes top of mind.
Stay tuned for Takeaway #3!
Like what you’re reading? Sign up to continue following ARW’s writings on the CGT + mRNA manufacturing paradigm.