Shifting Sands Scales: Manufacturing Considerations For Small-Scale mRNA Production
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
There are a lot of impressive development and regulatory milestones we can celebrate about mRNA’s meteoric rise to fame. But I never cease to be struck by one seemingly simple way the mRNA industry continues to flaunt development norms. Most pharma sectors start by homing in on smaller indications/development scales in the hopes that, with biological and technical advancements, they’ll be capable of advancing each novel modality/technology into larger indications. However, now that mRNA has been used to vaccinate billions of people around the world, we are facing the opposite problem: We’ve now set our sights on smaller patient populations and, in some cases, personalized medicine.
Though we regularly celebrate the flexibility of mRNA production, the process of “scaling down” and getting to know our mRNA/RNA as a therapeutic product (as opposed to a vaccine) is much easier said than done. It’s been said before and was reiterated during a recent panel I attended that we are only at “the beginning of the beginning.” In fact, one speaker on the panel went so far as to say they still see current mRNA-LNPs as “demo versions” of what they can and will be.
Though mRNA may, in theory, be the “perfect technology” for scaling up/out and down, several industry experts from a panel during Cytiva’s recent RNA-LNP Summit explained that the successful transition from large to small-scale, high-quality mRNA production demands specific manufacturing capability improvements/advancements. In the first of this two-part article, I outline a few of these important manufacturing and outsourcing considerations that must accompany our shift to smaller scales. Part two will focus specifically on regulatory considerations accompanying such technological and manufacturing advancements — stay tuned!
Infrastructure & Capability Needs For Shifts In mRNA’s Economies Of Scale
Arguably, one of the coolest aspects of mRNA is that we can cater development to meet an individual patient’s needs, as well as scale up to meet the needs of millions or billions. However, despite the promise that mRNA could literally be “everyone’s therapy,” the panelists during Cytiva’s RNA-LNP day argued that our ability to achieve such a large range of production volumes demands much more strategic consideration about how we establish our manufacturing footprints and select our CDMOs, particularly as we explore small-scale and/or personalized therapies. Afterall, such a shift to smaller scales changes up the economies of scale we’ve grown used to in the vaccine space which permit shipping large batches of drug product globally for localized fill-finish. (During the pandemic, Moderna formulated and shipped bulk drug product to local jurisdictions to perform fill-finish.) Rather, manufacturing for smaller indications may necessitate localized manufacturing within/for a single country in a facility that can be equipped to tackle both small and large-scale DS/DP production needs.
Likewise, our goals of broadening access to mRNA-LNP therapeutics around the globe will also likely place greater pressure on fill-finish capabilities. As one speaker pointed out, the fill-finish process was the predominant bottleneck in the process of preparing the COVID vaccines for the market — and, as this previous Advancing RNA article shared briefly, fill-finish capabilities can still be hard to track down, particularly for large-scale LNP production. Likewise, the shift to small-scale production necessitates the flexibility and capability to handle aseptic fill-finish operations for a small number of vials — and quickly.
“It’s important that our drug product manufacturing sites have the capabilities to do downstream processing, small scale mixing, and aseptic fill-finish and provide the same level of stringent sterility assurance as is expected for a large production batch,” one speaker shared. “It’s of paramount importance that quality makes it into the vial for these small-scale products.”
The speakers went on to discuss some of the benefits of establishing a centralized manufacturing infrastructure in which we can flexibly produce both small and large-scale mRNA-LNPs and (ideally) carry out fill-finish locally, as well. Such infrastructure could assume multiple forms, whether it be akin to BioNTech’s BioNTainer (localized drug product production with fill-finish carried out by local partners), or taking advantage of a local CDMO’s infrastructure within a specific country (as opposed to, for example, working with a U.S.-based CDMO and shipping to EU, in turn triggering the need to redo release testing).
“There are many people who know what they’re doing and have been spending their entire lives working on RNA development,” another speaker added. “Just because mRNA production is just now coming onto a lot of companies’ radars post-COVID doesn’t mean that those capabilities, the know-how, and the capacity isn’t there to support all the needs from personalized cancer vaccines to global pandemic-level readiness.”
A Quick Note On mRNA-LNP COGS
We’ve heard it said before across the ATMP space, but we’re also starting to hear it in the mRNA-LNP world as we transition into smaller therapeutic indications/production scales: We must not underestimate the amount of product we will ultimately need to characterize and demonstrate the safety/quality of our products. In fact, as one speaker shared, it’s often the case that biotechs approach a CDMO with a production volume in mind that falls short of the amount needed to sufficiently carry out quality control testing — with stability and bioburden being big “burdens,” if you will. On the one hand, as we explore personalized therapeutic approaches, the danger exists that we could “test ourselves out of product,” one speaker warned. However, overlooking the necessary product volume needs is also a surefire way to see an outsourcing project budget go wildly awry.
Though there may be some early alignment in the industry around CQAs for LNPs (with USP and BioPhorum publications covering such topics), our regulatory immaturity — particularly for the variety of therapeutic approaches we’re exploring — means there’s still little certainty or standardization of analytical approaches today. And, frankly, as one speaker kindly reminded us, this should be expected, given the nature of mRNA-LNPs. Once upon a time, the API was “the star of the show,” he explained. But on the therapeutics side, we’ve seen increasing scrutiny on the characterization and safety of the LNP delivery vehicle. There’s arguably no better example of this increasing scrutiny on LNP safety than Verve’s decision to prioritize a different candidate & LNP delivery system following a potential LNP-inspired toxicity in a Phase 1 trial.
“There’s a lot to take into consideration when the drug delivery vehicle and drug product go hand-in-hand,” the speaker concluded. “Characterizing and demonstrating safety and efficacy is not going to be as cost effective as it used to be.”
Stay tuned for part two in which I’ll share some of the panelists’ thoughts on the roles advanced manufacturing technologies can play in the mRNA space, as well as the resulting regulatory considerations these innovations may provoke.