Trends In Oligo Scale-Up & Delivery & How They're Impacting Manufacturing
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
As I’ve said many times before, the RNA space is far from straightforward. That “simple” heading of RNA spans two drastically different manufacturing paradigms, as well as differing mechanisms of action and regulatory classifications/designations (i.e., small molecules, biologics, & ATMPs).
But every so often, I encounter a discussion that bridges the gap between the coding and noncoding RNA sectors, and one of those discussions happened to take place at the 2025 RNA Leaders conference. The topic was oligo scaling — which, to be clear, the panel delved into beautifully. That said, don’t let the oligo-centric headline fool you; despite their notable differences, the coding and noncoding sectors are both facing similar complexities in achieving the scale we need with our current technologies/manufacturing approaches. We also are equally challenged to deliver our molecules to the appropriate organs/tissues/cells. In turn, as our molecules get more structurally and biologically complicated, our quest to attain the necessary scale and quality also intensifies.
Here, a panel comprising experts from Codexis, Novo Nordisk, Arrowhead Pharmaceuticals, and Alnylam give a fantastic overview of where we are today and why, as one expert so nicely put it, “This is one of the most fun times to be an oligo scientist or chemist.”
Solid Phase to Enzymatic Ligation: The Fragmented Path to Large-Scale Oligo Production
Just because oligos may be tagged as a burgeoning/emerging class of medicines certainly doesn’t mean they were “born” yesterday. In fact, we’ve been talking about how we can efficiently achieve mid- to large-scale manufacturing for 20-plus years. However, as the Alnylam expert explained, it took making it to Phase 3 clinical trials to really push the dial towards “figuring it all out.”
“Twenty years ago, we had conversations with investors and boards about how to make siRNA efficiently while reducing our footprint and increasing our scale. We always would arrive at the conclusion that we’d have the money to be able to figure it all out once we reached Phase 3. Of course, 20 years ago, nothing much made it to Phase 3, so we never really had to figure it out. Now we’re figuring it out.”
As each member of the panel went on to reaffirm, the industry has certainly come a long way in the past 20 years. Solid-phase synthesis serves us quite well in the rare disease segment today. There are currently CDMOs with technologies capable of producing metric tons to meet mid-sized market indications (i.e., a few million patients) — though, to be clear, these processes are non-aqueous and come with an “ugly” environmental footprint. Likewise, the speed at which we’re able to move from concept to IND (~18 months) for an oligo is unheard of for other modalities.
However, we’ve also realized that making full-length oligos will not be feasible when targeting large patient populations (i.e., tens of millions of patients). Enter: oligo fragments. In our current day and age, these fragments can be made the most efficiently using solid phase synthesis. There’s also liquid phase, but “as anybody working on liquid phase and/or who has followed the literature for the last 30 years knows, the problems of 25-30 years ago — particularly solubility — are still there,” one speaker qualified.
In the long term, our goal is to figure out how to make these fragments enzymatically. In the meantime, we’ve been relying on a mix of solid-phase synthesis followed by an enzymatic ligation step to stitch the fragments together. (Check out one of my previous articles on enzymatic ligation.)
Learning from Biologics: The Push for Modular, Intensified Oligo Manufacturing
Of course, we can’t talk about improving oligo scale-up without focusing on the current state of manufacturing — namely, how efficiently we’re able to produce products today. As you can imagine, this verged into a discussion on the current build vs. buy dynamics in the oligo space.
While we may have a strong reliance on outsourcing, there are natural caveats to this — with time of development being a potential pain point. As one speaker pointed out, it can take upwards of a year to get a batch synthesized. While this doesn’t jive with sponsors’ goals of getting into the clinic “yesterday,” the conversation reminded us that maintaining/operating an oligo manufacturing facility is a complicated ordeal for CDMOs.
“These are incredibly expensive facilities to run, and they have to keep them full,” one speaker who has worked for both CDMOs and sponsor companies clarified. “You can lose your shirt very quickly when your facility is empty. So, you must stay booked out well in advance and move as quickly as possible. That’s a challenge; I think that’s a part of the industry which isn’t particularly rapid right now.”
Naturally, there are a few ways in which we can respond to these challenges. Smaller companies looking to get their products into the clinic as quickly as possible may need to partner with a smaller CDMO for earlier development and transition to a larger CDMO as clinical development progresses. Likewise, as one speaker also pointed out, for companies with the means, building a small facility has also become a more common occurrence.
However, if we have learned anything from our past in biologics, it’s that anything is possible if the appropriate investments are made in process intensification. While it used to be a significant investment to build and run a 20,000-liter plant, process intensification opened the door to smaller, modular equipment and, in turn, greater flexibility for facility utilization.
“An important transition would be one where we use equipment that can be more flexible, suited to smaller suites, and can be brought online or taken offline quickly,” one speaker explained. “This way you also escape the crippling ongoing operating expenses if that equipment isn’t fully utilized.”
Beyond GalNAc: Reconfiguring Facilities for Next-Gen Oligo Conjugates
Given our lofty but still achievable goals for revolutionizing the manufacturing paradigm, there’s hope we will arrive at a future in which our manufacturing is nimbler. But we also can’t ignore the fact that there is an interesting tension arising within our goals. While we are striving to simplify and make our manufacturing processes more efficient, we also are trying to overcome significant biological challenges, like targeted delivery. And some of the solutions we’re exploring today may necessitate much more biologically and structurally complicated drug products, which ultimately translates into more complex CMC and longer timelines.
As one speaker clarified, we’re exploring several different linkers or conjugates to get our molecules to the right tissues, including antibodies, peptides, and/or small molecules. But transitioning these molecules into CMC takes our current timelines from a Phase 1 initiation in 18 months to as long as 2-4 years.
As the Alnylam speaker went on to explain, “How do we make these complex conjugated molecules that have a whole variety of different flavors to them, and how do we have a facility that can handle that? If you think about our facility in Norwich, we have two trains: One train makes galNac and the other makes lipid conjugates. As an industry, we’re not set up to integrate peptides and antibodies into the mix. So, I think that’s going to be a big challenge moving forward.”
In every industry, there are evergreen pieces of advice, and I was delighted to be reminded of one I’d written several years ago at the start of my tenure in the CGT space: For those of us in CMC, our R&D colleagues ≠ aliens. (And, of course, vice versa for those of us who live in R&D…)
As our constructs get more complicated, the relationship between R&D and CMC teams needs to become more collaborative. There will inevitably be disagreements; after all, “both sides want to do it their own way,” a speaker added. But when communication remains sparing, it’s common to find ourselves facing molecule constructs that, while great in theory, are ultimately not manufacturable. In turn, the panel emphasized the importance of establishing a feedback loop between research and CMC teams to ensure manufacturability is kept in mind from the beginning.
“This may take a few rounds of going back and forth,” one expert admitted. “But once you get that healthy feedback loop going, you start receiving molecules that are much more manufacturable, and we can start moving a hell of a lot quicker.”