Moving Beyond Solid-Phase Synthesis: The Momentum of Oligonucleotide Manufacturing

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

Being a writer in pharma can be a humbling profession.

“Pretend you’re explaining what you do to a five-year old,” has become a regularly uttered phrase during my interviews over the past 11 years of my career — especially when embarking into a new industry.

As you likely expected, this, dear reader, is exactly how I started my conversation about ASO manufacturing with Satya Kuchimanchi, SVP, tech ops for CAMP4. Not only was Kuchimanchi willing to embark upon a two-hour-long conversational journey with me, but he also gets hero points for undertaking the (not insignificant) task of educating me from the ground up (or, perhaps, from the solid support up?) on the how-and-why of the RNAi industry’s current state and where it’s headed.

Though solid-phase organic synthesis (SPOS) is the “backbone” of the oligo sector, my discussion with Kuchimanchi painted a much more nuanced portrait of the state of manufacturing in an industry that — at least on the surface — may seem relatively clear-cut. Overall, there were three main takeaways I gleaned from our conversation that suggest the oligo sector, though more established than its mRNA cousins, is not comfortable with the status quo and is actively trying to grow beyond the limits of its current manufacturing paradigms.

Here in part 1, we’ll start with my number one takeaway, which also comes equipped with a bit of history as to how we find ourselves at our current juncture. Part two will home in on how the industry is currently working within — and challenged by — what Kuchimanchi refers to as the continuum of growth in the world of oligo CMC.

For a “well-established industry,” the manufacturing paradigm is still dynamic

I daresay, I don’t need to go too long on the merits of SPOS — the fact that it has long been regulatorily derisked being a benefit we certainly cannot underestimate. (Altogether, there are  more than 20 FDA-approved ASOs and siRNAs.) Such derisking, along with the growth of our knowledge and experience over the past ~ two decades has naturally translated into a robust supportive infrastructure. Not only are we seeing more suppliers, vendors, and available manufacturing sites for production, global regulators — namely FDA, EMA, and PMDA — also have a much clearer understanding of the safety profiles and “must-watch” areas when a new oligo comes to them for review and approval, Kuchimancki went on to explain.

We also can’t sell short the efficiency such a platform promises.

“The beauty of the ASO field — or any synthetic molecule including siRNA — is that the process doesn’t change based on the molecule or the sequence you’re making,” Kuchimanchi added. “You take one method, one procedure, and tweak your parameters based on your sequence.” In turn, GMP production — regardless of the quantity you may be making, be it grams or kilograms — takes roughly three months. And despite the occasional failure, the manufacturing success rate is upward of 90 percent, a factor which Kuchimanchi credits to the industry’s willingness to share its learnings and the changes being made to processes and platforms overtime.  

Like any established manufacturing paradigm, however, we didn’t go from one approved drug to 20 overnight, and we’re not moving upward from 20 without continued improvements. As my conversation with Kuchimanchi explored, our road to the present has been paved with a variety of key improvements — perhaps the biggest being a key alteration to the solid support itself. In the “beginning,” controlled pore glass (CPG) beads were the base from which we built our oligonucleotide molecules. However, as we faced necessary increases in scale from the bench, CPG beads — no matter how large the chosen dimensions — became a limiting factor.

Enter the polymer bead, a switch that resulted in a 10x improvement in scale. In fact, as Kuchimanchi went on to explain, there are now five different kinds of polymer beads (e.g., polystyrene; polystyrene-divinyl benzene; swellable and rigid supports, etc.), each of which have their own individual attributes that have helped improve therapeutic oligo production over the past decade. (“Some people have even started to forget we ever used CPG beads,” he joked.)

But we are an ambitious industry, and our hopes of broadening access to oligos across a diverse array of therapeutic indications necessitates even more dramatic changes to our manufacturing paradigm. Though our transition from CPG to polymer beads helped us overcome constraints due to column packing limitations and reagent pumping capacity issues at larger scales, this improvement has only taken us so far.

“It’s a continuum,” Kuchimanchi said. “For a paradigm that hasn’t changed for three decades, we’re now seeing changes every five years.”

As most of us are more than aware, we’re on the cusp of several big changes. As we start moving beyond rare disease into more common indications like diabetes or hypertension, we’re starting down the (albeit arduous) path away from solid-phase synthesis in its entirety. As Kuchimanchi explained, large scale synthesis can be accomplished by relying on two alternate manufacturing paradigms — solutions phase synthesis or enzymatic synthesis. (Or, as my previous article from TIDES showcases, a hybrid of both known as enzymatic ligation in the siRNA world.)

“In the next couple of years, I anticipate we’ll be seeing a lot of investment in solutions phase and enzymatic synthesis, whether it’s simply the industry talking/sharing more research in this area; firms actually establishing the manufacturing capacity for such a process; or a company actually converting their manufacturing process from SPOS to solution-phase synthesis,” Kuchimanchi explained.

Stay tuned for part 2, forthcoming!