From The Editor | May 13, 2024

2 "Must-Haves" In mRNA CDMO Outsourcing Partnerships

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

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In any high-level discussion about mRNA, it’s not unusual to tout the manufacturing benefits of working with cell-free technology. In fact, if we had to create a list of mRNA’s “Greatest [Slogan] Hits,” we would probably include mRNA’s manufacturing efficiency, as well as its overall lower cost of goods thanks to its smaller and quicker cell-free manufacturing footprint.

But here at Advancing RNA, we pride ourselves on going a little deeper than the marketing slogans. After all, if it were that easy, everyone would do it and would instinctively know what “high quality” means for an mRNA therapeutic — and achieve it — from the start. Though we may prefer this utopic version of reality, I was particularly excited to meet Sujit Jain, senior director, CMC operations at SalioGen Therapeutics, to get the inside scoop of where outsourcing the development and manufacturing of mRNA gets a little trickier than our slogans may reveal.  

In the first of this two-part article, Jain gave us the lay of the land on the benefits and “grey areas” of working with and outsourcing mRNA/RNA modalities today. Here in the final installment of this two-part series, he continues to share his assessment of the partnering landscape for mRNA therapeutic candidates. Though capacity has been a hot-button topic/need for other modalities in the ATMP space, his tips for evaluating CDMOs for mRNA therapeutics keep us aligned around the importance of capability and flexibility in outsourcing partnerships, especially when working with a nascent therapeutic modality.    

Capacity Is Plentiful: Keep Quality & Capability Your First Priorities

For those of us who remember the great capacity crunch and unreturned phone calls of 2020 (and onwards) in the CGT space, you’ll probably be relieved to know that the efficiency of mRNA production can translate into more seamless partnering — even for small biotechs. So far, both large and small CDMOs have been willing to enter partnership discussions, even as early as research scale development, Jain acknowledged. This was not often the case for small CGT biotechs striving to get on larger CDMOs’ radars for viral vector development in the past.

But as Jain (and many others) have emphasized, CDMO availability/capacity is only one part of this equation. A potential partner’s capability and experience working with encoding RNA modalities, as well as the CDMO’s master & quality service agreements terms demand a special level of scrutiny today given the novelty of mRNA production.

“There are a lot of CDMOs willing to entertain partnerships, but the maturity of their capabilities for developing RNA is not always there,” Jain said.

As he continued, some of the more mature and established CDMOs are advancing to higher productivity and offering better purification techniques, especially to confront dsRNA. In many cases, these CDMOs have commercial experience thanks to COVID development and/or have employed long-term RNA “veterans.” There is still plenty of room across the outsourcing sector to establish and/or improve upon early research and/or process development capabilities for RNA therapeutics. Research-scale production of high-quality mRNA remains elusive and it’s not often until scale-up that the desired product quality is achieved.

It’s also important to emphasize that, with the rise of new CDMOs, we cannot forget to go back to “the basics,” particularly as it relates to a potential partner’s GMP compliance.

“It’s not just a partner’s scientific expertise with RNA that is important,” Jain added. “Their GMP expertise is another important indication of their overall experience and will be critical for RNA players interested in developing and commercializing RNA therapeutics.”

Don’t Overlook These Two Critical Aspects Before Contracting A CDMO Partner

It should come as no surprise that Jain first emphasized the importance of a partner’s analytical capabilities when I asked about his “make-or-break” outsourcing partnership needs. Having the necessary manufacturing equipment/platform established is only a benefit if it is accompanied by a strong analytical team. In fact, he went on to reiterate what I’ve heard many times before — one of the greatest areas for innovation and leadership in the RNA space today will be analytical development.

“Process development and analytical development go hand in hand, especially with this modality,” Jain furthered. “That’s perhaps one of the most challenging aspects of development today for RNA: Making informed decisions about our processes based on our analytical data.”

In particular, he homed in on the unique sequencing needs for RNA compared to other modalities. Though I’ve sat through quite a few discussions on the current & future potential of next-gen long-read sequencing for mRNA, sequencing capabilities across the industry remain unreliable, especially when investigating the more “niche” aspects of our molecules — for example, our poly-A tails. Though some labs have stronger sequencing capabilities today, Jain reminded us that these capabilities were not developed overnight. As such, having the technology available internally at a CDMO does not necessarily translate into method capability or reproducibility.

In turn, Jain reiterated the importance of relying on orthogonal methods where appropriate.  “Orthogonal measurements ultimately help you compare data and the performance/reliability of different assays,” he said. “If two different methods arrive at the same conclusion, it’s a good sign that a partner’s analytical capabilities are strong.” 

We also turned our attention to his “must-haves” when negotiating “watertight” quality technical and master services agreements. Though books could no doubt be written about the most important and/or overlooked factors in crafting these agreements (some of which are catalogued here), Jain emphasized the importance of process portability at this time in the mRNA space. Small biotechs on tight clinical timelines are always looking to protect their product (mRNA or otherwise) from any manufacturing site-related issues. But he also pointed particularly to the IP-related considerations biotechs and CDMOs are navigating in the mRNA space today.

Given the nascence of mRNA development, it’s only natural we all — biotechs and CDMOs alike — have the desire to hold our technical know-how close to our chests. However, in the mRNA space in particular, Jain could see a future in which companies with more established product pipelines choose to bring their manufacturing in-house — a choice that may prove to be more manageable for mRNA than other modalities given its smaller, more cost-effective footprint. In turn, process portability may be a hotter-button issue and could cause contracting stalemates between biotechs and CDMOs.

“I can see both sides of this,” Jain admitted. “Biotechs want to protect their product development know-how and timelines, and CDMOs want to ensure long-term demand for their capacity and capabilities.”

At the end of the day, Jain urged us all to start portability discussions as early as possible. Even for a product as established as a monoclonal antibody, it can take upwards of 9 months to negotiate the MSA alone, with a few additional months added on for the QTA. These contracting discussions become increasingly nuanced the more complex and novel the modality.

Though these conversations may be lengthy and require some (often financial) give and take, Jain urged companies to stay the course and arrive at a partnership agreement with which both the biotech and CDMO are comfortable.

“We have to think about the patient here,” he concluded. “Continuing the development and supply of the product is the biotech’s and CDMO’s mutual goal.” 

Miss part 1? Check it out here!