"A Particular Set Of Skills:" Outsourcing Considerations For mRNA Therapeutics
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
In the mRNA space, we pride ourselves on our more efficient, cell-free manufacturing process in comparison to our viral-vector-based cell and gene therapy brethren. But despite the many technical differences that exist between the mRNA and CGT manufacturing paradigms, I’m starting to hear echoes of CGT conversations in the mRNA space today.
Look no further than my recent discussion on the mRNA outsourcing paradigm with Sujit Jain, senior director, CMC operations at SalioGen Therapeutics, a company utilizing both mRNA & DNA delivery technology to treat genetic disorders. During our conversation, I found myself gravitating back to an article from my previous four-part CGT outsourcing series entitled, “From Capacity To Comparability: The Shifting Onus In Cell & Gene Therapy Outsourcing.” As more CGT products move into mid-to late-stage clinical trials, biotechs need CDMO partners who — to quote Liam Neeson in the movie Taken — “have a very particular set of skills that have been acquired over a very long career.” Some of these skills include seamlessly handling tech transfer and analytical comparability for later stage CGT products.
Now, for those of us living and working within the predominantly pre-clinical mRNA space, such later-stage clinical considerations may seem like fires we fortunately don’t have to deal with in our outsourcing considerations — at least not today. But as Jain and I walked through the current state of the mRNA outsourcing paradigm, it became clear that we’re already having similar conversations today about the importance of finding partners with the technical and analytical capabilities to align with our increasingly complex mRNA products.
In the first of this two-part article series, Jain offers us his observations on the growth of the mRNA outsourcing sector, as well as the most important learnings he’s gleaned from engaging and contracting CDMOs in this space — particularly in these “earlier” days of the RNA therapeutics industry.
Celebrate mRNA’s Development Efficiencies — But Stay Level-Headed
Given Jain’s background in the biologics and viral vector gene therapy spaces, I was curious to get his perspective on what it’s been like to move into the cell-free mRNA world. Though we may be tempted to silo ourselves off by modality, I appreciated Jain’s reminder that mAb, AAV, or RNA modality aside, we’re all working within the parameters of the same foundational regulatory guidances that have come before.
“The agency expectations for product safety, integrity, identity, potency, and quality (SISPQ) are still the same in the RNA space,” Jain explained. “They will ask you to share your control strategy and demonstrate that the product is safe and provides a functional benefit in nonclinical models prior to moving into the clinic. Once the product is in the clinic, you must demonstrate that your process is reproducible and that your product quality remains consistent.”
Now, to be clear, we’re still living within a regulatory “grey zone” in the mRNA space. As such, we remain unclear about the specific quality thresholds and the extent of the data packages we will need for our wide range of therapeutic approaches (i.e., vaccines, gene editing, protein replacement, etc.). Whether regulators consider mRNA technology scientifically akin to that of biologics/mammalian cell culture or to that of viral vectors (or somewhere in the middle) remains unclear today but is a topic on which the industry has many opinions.
Regardless of the potential for regulatory ambiguity for RNA products today, I appreciated Jain’s reminder of the importance of “going back to basics” and evaluating an mRNA product through the lens of ICH guidance. “As sponsors, we need to be the subject matter experts about the chemistry and biology of our proposed molecules/therapies and — in partnership with regulators — advise and lead accordingly.”
Though Jain acknowledged that regulations are a critical piece of the mRNA production/quality puzzle we can’t gloss over, there are still high-level “wins” we can celebrate about the mRNA manufacturing paradigm. For one, the platform technologies we rely on are familiar members of the biologics or viral vector manufacturing paradigms, meaning it’s not a heavy lift — equipment or cost-wise — for existing or new CDMOs to establish an mRNA production line. As Jain explained, a new viral vector facility could cost upwards of hundreds of millions of dollars. Comparatively, the construction of a new, state-of-the-art mRNA facility falls within a range of tens to hundreds of millions of dollars, thanks to mRNA’s small scale manufacturing footprint.
Likewise, our synthetic manufacturing paradigm has enabled us to achieve an enviable level of productivity, at least compared to the cell-based modalities that have come before us. Today, some mRNA companies are already boasting production of 10 grams per liter of mRNA. Achieving the same level of productivity took the mAb industry decades — and it was still not reliably achieving such titers in 2014-2015 when Jain himself was working on mAbs. Similarly, though there has been vast improvement in the AAV manufacturing paradigm, the industry still find itself bumping into issues achieving the scale and quality needed today, especially as companies transition from adherent to suspension processes.
Despite the relative “ease” with which we can make larger quantities of mRNA, Jain’s focus on the current knowledge gaps we have — particularly around mRNA quality — underscores a critical point that we cannot ignore as an industry. Much of the industry’s production expertise to-date has been in linear mRNA production for prophylactic vaccines, the dose for which is much smaller compared to that of an mRNA therapeutic; think 30 micrograms (mcg) for a vaccine. Depending on the indication, the dose of a linear mRNA therapeutic is likely to be 10 to 20 times more than that of a vaccine.
Though the raw material needs and manufacturing scale to achieve higher doses of mRNA therapeutics is much smaller compared to mAb or viral vector production, going from 30 mcg to 300 mcg is “a big leap” for the industry, Jain admitted. The larger the dose of mRNA needed for a (likely chronically dosed) therapeutic, the greater our scrutiny must be on the overall purity of the mRNA constructs we’re producing.
Overall, it’s still early days in the grand scheme of things for our IVT manufacturing paradigm — a fact that demands a certain amount of humility about the known-unknowns and the unknown-unknowns.
“The mRNA industry, including the CDMO sector, has done a good job so far of understanding IVT reaction kinetics as well as identifying some of the knowledge gaps we need to fill,” Jain explained. For example, “We know we can achieve 90-plus percent purity of our mRNA drug substances, but can we match the antibody world with its 99 percent purity? Additionally, we know that double stranded RNA impurities remain a gap we don’t yet fully understand — especially as we set our sights on mRNA therapeutics beyond prophylactic vaccines. It’s going to take the industry time to understand and mitigate dsRNA production, but at least we know this is a critical area in which we need to improve.”
Stay tuned for part 2 in which Jain shares the capabilities and contracting “must-haves” mRNA therapeutics companies should be considering when selecting their outsourcing partners.