From The Editor | June 12, 2024

A "Hot Take" On mRNA Scale-Up

ARW Edit Headshot 2

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


Had more of my colleagues been in the office when I was invited to join the BioPhorum ATMP Member Event this past March, they most likely would’ve heard me erupt with a loud YES and seen me do a fist pump. Not only have I been an admirer of BioPhorum’s work/publications for the good of the ATMP community, but I was excited to start off the new year at the helm of Advancing RNA by attending this RNA-focused event and getting the “inside scoop” on the many challenges that have the industry scratching its head. And this event certainly didn’t disappoint.

As I wrote in a previous article, I was given the honor of kicking off the BioPhorum ATMP Event with a keynote presentation on where the mRNA space currently is, where we must go, and how I see us moving closer to achieving some of these goals. But one critical takeaway that I gleaned from all the other panels and presentations over this two-day event is that the devil is in the details when it comes to developing mRNA. Amidst all the glitz and glamour of the COVID vaccines’ whirlwind approval, it’s important to remain grounded as we embark upon a more realistic journey toward a well-rounded mRNA vaccines & therapeutics space.

In the following multi-part “mini-series” of RNA industry “Hot Takes,” I share several aspects that jumped out at me from the BioPhorum ATMP Event. Though you may not find these takeaways worthy of the dramatic moniker, “hot takes,” I’d argue that they do not get the attention/acknowledgement that they deserve in the RNA space and are worthy of much more conversation and experience sharing in the future.

Hot Take #1: There Are More Pitfalls In Scaling mRNA/RNA Than We Admit

It was no mean feat to scale-up the COVID vaccines to billions of doses — and our industry is wiser, more capable, and, yes, significantly better funded thanks to the vaccine approvals. But as is often the case following a significant triumph, we tend to fall prey to overly optimistic generalizations about the ease at which we can develop, scale-up, and deliver future mRNA and next-gen RNA products. Our scaling efforts are much less clear cut than the typical (often utopic) narrative would have us believe.

To be fair, a significant percentage of our industry is working on linear mRNA prophylactic vaccines for large populations — at least at this stage of the industry. In turn, the learnings from COVID and Moderna’s recently approved RSV vaccine can certainly be more linearly applied. But it’s also worth noting that the next closest mRNA products to market approval are on the opposite end of the scale spectrum: scaled-out, personalized cancer vaccines. Likewise, as we gravitate toward alternative RNA modalities like self-amplifying RNA for vaccines and/or therapeutics, it’s problematic for our space to argue that our experience scaling linear mRNA means we’ve mastered analytical characterization and large-scale (or just commercial scale) production of all encoding RNA modalities. In other words, as a space, we’re learning a lot — but we’re learning about a lot of different things all at once.

This is why I appreciated the BioPhorum event for reminding us that, to successfully scale-up an mRNA or saRNA prophylactic vaccine, we must get a firm handle on the small details beyond volume changes that can impact the quality of our drug substances and drug products. Some of the topics broached throughout this two-day event included vessel geometry; container leachables; mixing duration and pumping; raw material quality (namely GMP-compliant vs. non-GMP); and drug substance/drug product handling. However, as important as each of these factors are to the quality of our products, I was predominantly struck by one seemingly simple topic that came up in a few different ways: Time.

When we discuss “time” in relation to mRNA manufacturing, it’s often in reference to the general efficiency of the manufacturing process compared to cell-based processes. We can certainly think about “time” in terms of the process itself. After all, the larger the scale, the longer the processing, filtration, and fill-finish steps will take — especially in a GMP setting. Temperature ramp-up will always take much more time than anticipated when scaling-up an mRNA drug substance. On the drug product side, the larger the scale, the longer the mixing/LNP assembly time. As such, it’s important to understand the formulation equipment’s abilities to sustain longer development times and to produce comparable mRNA-LNPs to small scale development. In fact, as several experts shared, encapsulation efficiency and potency were some of the critical quality attributes most likely to be impacted by longer exposure to shear forces.

But beyond the amount of time each unit of operation will take, it behooves us to not forget how much time passes between each unit of operation. Accounting for and building these intermediate hold times into our processes is exceptionally important given that we’re working with a drug substance/product that gets finicky when the temperature changes and hold times need to be less than a few hours.

Overall, there are a lot of reasons as to why our experience with COVID vaccine scale-up should be taken with a grain of salt — the fact that we’re all working with different modalities and there’s little to no consensus on critical process parameters for our mRNA/next-gen RNA products being two big ones. Likewise, given the current lack of standardization we’re facing in platform development today, I’d argue that it’s the smaller, easily overlooked factors — like the challenges associated with physical processing and hold times when scaling up — will be the most variable from company to company and, in turn, could be some of the greatest sources of risk to the overall quality of our RNA products.

Continue on to Hot Take #2 about personalized mRNA production