A "Flight Plan" For Achieving These 3 mRNA Development Milestones
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
“We’re building the plane as we’re flying it.”
It’s a phrase we’ve relied upon heavily the last few years as we’ve strived to bring cell and gene therapies into/through the clinic while also establishing new technologies, manufacturing platforms, and a regulatory paradigm.
I was thinking about this phrase once more as I collected my thoughts following Cytiva’s recent RNA-LNP virtual summit. As I discussed in part one, our push into mRNA-based therapeutics moves us from larger scale manufacturing to small-scale development — and in some cases, personalized manufacturing. In turn, we’re faced with additional considerations around how we can establish our manufacturing footprints and improve existing manufacturing paradigms to achieve high-quality and (even more) efficient manufacturing and fill-finish of mRNA drug products. Because regulatory affairs runs undercurrent to all things manufacturing, part two reminded us that, despite a dearth of mRNA-specific guidance from regulatory agencies, we’re hardly lost in an oasis-free (i.e., regulation-free) desert; there are certainly paths in the sand to water — albeit a number of ours in the mRNA world may be less well-worn than others.
As the panel continued, it became clear(er) to me that we in the mRNA space are smack-dab in the early days of building our own plane as we’re accelerating down the runway. There are still many steps forward before we get into the air —whether these incremental advancements be as “routine” as getting a candidate into the clinic or as regulatorily complicated as introducing advanced manufacturing technologies into our processes. Bottom line: We are an industry in a constant state of flux. But fortunately, there have been a few contextual clues or regulatory footholds we can and should be holding tight to as we pursue whatever milestone is up next for our products/companies.
Here, in the final installment of this three-part series, I’ll share the panelists’ greatest learning experiences and regulatory advice (so far) on what we should be looking out for as we strive to achieve three big milestones: Entering the clinic; implementing advanced manufacturing technologies into our processes; and standardizing our manufacturing platforms.
On Entering The Clinic
If we consider patient population size and real-world evidence/pharmacovigilance efforts post-COVID, the COVID vaccines — regardless of technology — were some of the most highly scrutinized vaccines to hit the market. As we transition into therapeutics — which will demand repeat dosing — it’s only natural that questions about RNA-LNP safety and efficacy would increase in volume. However, as one speaker reminded us, despite these concerns (which, to be clear, should be expected), “We’re in a better place than we were a few years ago, and we’ve seen vast development in this area.”
As we enter phase 1 trials, we’re striving to understand our therapy’s overall safety profile, including biodistribution, toxicology, and immunogenicity profiles. In the RNA space, we’ll likely be faced with some of our own unique considerations in these areas, particularly as they relate to the LNP portion of our products. For example, one speaker posed the question: “Have we changed around proportions of lipids that could make this candidate perform dramatically different than perhaps a candidate that is arguably highly similar?”
We have benefited from the fact that mRNA technology first launched as a global vaccine, the enormous scale of which has provided us with a breadth of real-world evidence and safety data. Not to mention, such data has been and will continue to be essential for providing insights into different ethnicities and patient populations. As one speaker reminded us, this is not only complementary to the FDA’s efforts to increase overall diversity in clinical trials, but broad patient population data exposes us to additional safety information that wouldn’t necessarily be seen in an early phase study. (A great example is this piece from Nature investigating safety following mRNA-based COVID vaccination in Korea.)
“As we mature in this field, we’ll have a better sense of what the safety effects are from these medicines,” they added. “The regulators will take the safety information they glean from the post-market reporting and include it in their reviews and assessments of our candidates.”
On Exploring Advanced Manufacturing Technologies
The dialogue around advanced manufacturing technologies — namely process analytical technologies and continuous manufacturing — is hardly novel. The 2023 publication and FDA & EMA adoption of the ICH Q13 guidance on Continuous Manufacturing of Drug Substance & Drug Products, in particular, underscored regulators’ abilities to align around a standardized approach to such technologies. However, the conversation around advanced manufacturing technologies has been reinvigorated industry-wide and in the mRNA space given the publication of the FDA’s Advanced Manufacturing Technologies Designation program guidance. In fact, last summer, the mRNA space celebrated its own continuous manufacturing milestone: A CBER grant for MIT and ReciBioPharm to create a fully integrated, continuous mRNA manufacturing platform.
Likewise, as one speaker during the Cytiva panel shared, our desire to monitor and adjust our processes in real-time has encouraged greater exploration of PAT. While prior to the pandemic we were “doing the best with what we had” (i.e., relying on non-USP-driven methods), following the conclusion of the pandemic, we started to see novel and improved PAT for measuring mRNA-LNP CQAs like particle size. However, as this speaker went on to explain, integrating these technologies raises compliance questions, especially seeing as many PATs take us out of the realms of single use. As such, we must carefully consider our cleaning strategies, possibly growing accustomed to additional cleaning validation costs.
“We have to ensure we’ve cleaned properly to eliminate batch-to-batch carry-overs,” the speaker furthered. “mRNA is relatively easy to destroy during the cleaning process, but how do you make sure you’ve gotten rid of the lipids? Do you have to autoclave these pieces of equipment?”
Similarly, seeing as some of these technologies are modular and can be used offline in the lab, they offer opportunities earlier in development to optimize and introduce greater control into our processes. However, “You have to be careful you’re not collecting data that can’t be explained in a GMP setting,” another speaker added. “You don’t want to get stuck in a place where you’re continually collecting data and you get a spike in something that you can’t explain to regulators when they inevitably ask for an explanation.”
Overall, this panel underscored the regulatory agencies’ willingness to work with the industry on the “smart ways” to implement these technologies. There’s a long way to go until we reach complete maturation for more established technologies, like continuous manufacturing (CM), let alone until we achieve consensus/harmonization across regulators for CM and other innovative manufacturing technologies. Not to mention, there remain great uncertainties around how introducing such technologies into our processes will be received by regulators and impact our regulatory filings. As one speaker offered, there’s a lot for us to discuss with regulatory quality teams (e.g., the EMA’s quality innovation group) around how we anticipate using or not using the data generated by specific technologies.
Though we often wax poetic about the importance of harmonization between regulatory agencies, we cannot overlook the cross-stakeholder alignment necessary to ensure seamless implementation of these technologies. As one expert shared, “We’re always thinking about how we create alignment between our regulatory reviewers, the people working at a CDMO site and releasing our products, as well as GMP inspectors who may be from another authority and/or country looking at this advanced technology and asking, ‘Is this acceptable? Have we met our reporting requirements? Is this technology working in the way we expect it to within a GMP environment?’”
On Technological/Manufacturing Standardization
As many — including myself — have emphasized, there is still a lot of innovation to be done in the RNA world, and especially in the realms of nonviral delivery. (In fact, I’m a big proponent of what one expert said in a previous article: the RNA space will greatly benefit from embracing a “delivery agnostic” mindset.)
I was happy to hear this perspective shared by a speaker during the Cytiva event. So often we talk about the importance of technological and manufacturing standardization. After all, this is an important step for any therapeutic space to accomplish to reliably achieve the necessary quality thresholds for a product and to streamline operations and cut costs. So far, we’ve been trying to move mountains and align around CQAs & analytical methods and potential CPPs for mRNA-LNPs. But I loved the panelists’ reminders that we’re still early in the technological life cycle for mRNA/RNA-LNPs, in general. Just because the LNP has garnered the most of our attention today doesn’t necessarily mean it’s the “best” or “only” technology that will demand standardization down the road.
“We should be standardizing the absolute best,” one speaker concluded. “But what is the best? We do talk about LNPs, but that isn’t to say that liposomes or polymeric nanoparticles have become irrelevant. We’re working with a complex drug product formulation, and because of that, standardization may take several years if not decades, especially since we’re relatively early in the technological life cycle.”
Missed Part 1 and Part 2? Check them out below: