The mRNA Industry's Three Wishes: Can CDMOs Play The "Genie?"

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

We all likely know the story of Aladdin. (At least the Disney version…)

Boy meets out-of-his-league girl.

Boy is imprisoned by an evil sorcerer to keep love from blossoming.

Boy is tricked into getting his freedom by said sorcerer, but only if he can find and bring back a magic lamp from The Cave of Wonders.

Boy finds and (of course) rubs the magic lamp and — voila! — a genie emerges to grant Aladdin 3 wishes.

Now, I’m not going to go so far as to say the CDMO industry is currently playing the role of the genie in the mRNA industry… or maybe I am.

At the Alliance for mRNA Medicines Ascent conference last fall, I attended a panel discussion on manufacturing, CMC, and analytics featuring three CDMO executives. Those of us at biotechs know that finding an experienced and collaborative partner that will treat our molecule as if it’s their own is no mean feat. In fact, we dug into this challenge in our last Advancing RNA Live panel discussion on RNA outsourcing. But listening to the conversation at the AMM conference, it wasn’t lost on me that CDMOs may find themselves playing the role of the “magical genie” required to grant us our three wishes when summoned. Our wishes, broadly speaking, are to make our vaccines and/or therapeutics in an efficient, high-quality, and cost-effective manner. But let’s be honest; the therapeutic versatility of mRNA is both a blessing and an added challenge — especially when it comes to manufacturing.

During the panel discussion last November, three CDMO execs shared the biggest scientific, regulatory, and technological complexities barring a “magical” solution to each biotech’s wishes. However, as each of the AMM panelists pointed out, there are short- and long-term technological innovations in the works that will be essential in advancing the manufacturing infrastructure for mRNA therapeutics in all their shapes, forms, and scales.

“Genie, I wish for micrograms, and milligrams, and grams of mRNA!”

In recent weeks, AMM released a report on the future of the mRNA space, sharing insights from 27 senior biotech leaders. As this report revealed, a majority (67 percent) of the executives surveyed identified manufacturing complexity and scalability as one of the key barriers to mRNA adoption.

It’s interesting to see the word “complexity” applied to manufacturing of RNA, considering most of the time we speak in an enamored way about the relative simplicity of producing RNA compared to cell-based products. This complexity, however, goes beyond the typical talking points of manufacturing efficiency (i.e. production time) or scaling up/out — even though, to be clear, scale-out for personalized therapies and downstream scale-up remain pain-points in the RNA space. Rather, as multiple speakers pointed out multiple times throughout the conversation, the many different therapeutic applications we’re pursuing still demand highly custom process parameters and smaller scale RNA production than was needed for the vaccines.

“There are so many uses for RNA, and, as such, the manufacturing requirements will vary widely for high dose in vivo applications compared to personalized cancer vaccines,” one expert said.

While an mRNA-based gene editing program may require the production of 50-gram batches, companies producing personalized cancer vaccines will only need 100 or 200 milligrams of mRNA. In fact, as one expert mentioned, CDMOs are now occasionally receiving production requests for even smaller production amounts (e.g., think 200 micrograms). Not only do technological constraints hinder small scale mRNA production, but continually clarifying regulatory requirements, high COGS, and the rush to the clinic also remain big impediments to production at these small scales.   

“We don’t have one solution that can cover all these scales, and we’re limited by some of the machines we’re working with,” the expert admitted. “Obviously, we want to get to a point where we can GMP manufacture very small amounts of product. We don’t want to just say, ‘Oh, we have this ice cream machine, and it only makes a cone’s worth. We can’t give you a scoop.’”

Manufacturing technology innovation will be the topic “du jour” during the next Advancing RNA Live; register for free here and tune in to learn more!

“Genie, I wish for standardized and meaningful analytical measurements!”

In addition to challenging our manufacturing in terms of scale, mRNA’s diverse therapeutic applications also throw our analytical testing strategies for a loop. The initial years of any nascent therapeutic sector are always marked by conversations on “how much is too much” when it comes to analytical characterization and release. There’s no clearer indication that the mRNA industry is currently in the “test everything!” phase than the amount of attention this panel of CDMO experts lavished on the trials and tribulations of analytical platform development. As one executive explained, CDMOs have been beta testing a lot of different analytical technologies to determine their strengths and limitations in analyzing different molecules. Not to mention our ongoing interactions with regulatory agencies continue to provide greater definition and/or evolutions in the recommended testing.

“Every few months, companies are asking for a different assay,” one expert explained. “So what worked six months ago has all of a sudden changed in the last six weeks. As CDMOs, we’ve been on the edge of our seats, regularly testing out new methodologies and integrating a large array of processes into the mix to establish our quality systems.”

As we perhaps could predict/expect, the conversation also drifted to impurities, with double-stranded RNA (dsRNA) earning a special shout-out as the current and future “bane of our existence.” Obviously, we can attribute this moniker to our present lack of standards around how best to measure dsRNA, as well as our insufficient knowledge of dsRNA’s clinical impact. However, as we were also reminded, we still haven’t aligned as an industry around acceptable limits for other impurities either, whether they be residual enzymes, protein levels, or byproducts. Though each expert on the panel acknowledged that the goal is to achieve an “undetectable” reading for each impurity, the performance variabilities we often see demonstrated across commercial kits reinforce our ongoing need for standards.

Likewise, the transition from vaccines to therapeutics continues to augment the intensity of these analytical growing pains. We’ve always made an educated guess we’d see increased regulatory scrutiny on impurities as we transition to higher-dose/repeatedly dosed therapeutics from vaccines. This hypothesis was anecdotally confirmed by one speaker who referenced the FDA’s recommendation for sub-nanogram levels of residual DNA in gene editing products compared to the nanograms accepted for the first commercialized vaccines.

As one expert cogently summarized: “Sometimes, we’re challenged in our ability to measure certain attributes. But I’d take it a step farther; the bigger overarching challenge at hand is really our ability to make meaningful measurements.”

“Genie, I wish for my mRNA therapeutic to have been completed and FDA-approved, like, yesterday…”

Automation has been a popular topic for years in the advanced therapies space, and not surprisingly, it was also a topic of discussion following a conversation on time-to-market and the (still high) COGS plaguing mRNA development. While the IVT process is hailed for its timeliness compared to cell-based manufacturing, construct optimization and analytical development post-manufacturing are the often-forgotten “time sucks” in mRNA development. We’ve already heard — and celebrated — the FDA grant which was awarded to MIT and ReciBioPharm to work on a continuous mRNA manufacturing platform — a central goal of which is to make process development and analytical development/quality control more efficient. Though the work is ongoing, this remains a long-term goal for the industry to reduce overall development time.

In the more immediate present/near-term future, the panel touched upon the rise of robotic arm technologies and constant fluidic systems that would help reduce the inconsistencies that come with human operators. Given how central the topic of automation has been in the autologous cell therapy space, it goes without saying that automation would be an exceptionally important development for the mRNA industry to achieve its desired six-week turn-around-time for personalized mRNA cancer immunotherapies.

However, I appreciated one speaker’s important clarification that the efficiency automation brings is a somewhat “nuanced” term. Automation may not necessarily translate into “faster” manufacturing, per se, but given that it promotes fewer lot-to-lot variations, it is a more “direct” approach to a product.

Likewise, as another panelist reminded us in conclusion, we’re on an “incremental journey” toward automation. As facilities plan their roadmaps toward automation, there are other equally important incremental improvements in the works to reduce mRNA development times and COGS. Some of these advancements of note include utilizing synthetic plasmid DNA, exploring novel raw materials like mutant T7 polymerase, and reducing QA/QC review times.