The RNA Synthesis Spectrum: Between Solid-Phase Roots & A Hybrid Enzymatic Future
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Some requests are easier to handle than others. Asking how to spell “phosphoramidite,” for example, is one thing; to ask for a cogent but detailed history of solid-phase synthesis in both its past, present, and future forms is another.
Naturally, my request of Satya Kuchimanchi, SVP tech ops, CAMP4, fell more in the latter camp. Having spent most of my time on the coding side of the RNA industry, Kuchimanchi and I had a lot to catch up on, starting with the basics of solid phase synthesis and which improvements to the manufacturing paradigm have been — or will be — the most impactful in the long run. As my previous article explained, we’ve come a long way with solid-phase synthesis. It’s thanks to this manufacturing paradigm that we can boast more than 20 FDA approvals for antisense oligonucleotides and siRNA products.
However, just because something is established doesn’t necessarily mean that there isn’t still work to be done. Much like self-improvement, advancements in CMC are also iterative. As Kuchimanchi nicely summarized, all improvements are on a “continuum,” and our previous conversation explored some of the history and advancements that have brought us to where we are today — on the cusp of great change in the world of oligo manufacturing. But there were two additional takeaways I had following my conversation with Kuchimanchi, each of which depicts where there still exists quite a bit of dynamism for an industry which can claim an “established” manufacturing paradigm.
One “scale” does not fit all in the oligo world
There has never been an industry more deserving of the phrase “one size does not fit all” than the RNA space — especially with its variety of modalities and therapeutic applications, each of which demands its own scale/dosing considerations. In general, these varied needs have and continue to influence the pace at which innovation moves forward in the oligo manufacturing space. This was made clear throughout my conversation with Kuchimanchi as we discussed the industry’s overall transition to solution-phase, hybrid approaches, and eventually, enzymatic synthesis.
As Kuchimanchi explained, solutions phase synthesis has been in the works for the past decade-plus. Much of this work has been inside the walls of Big Pharma — with GSK being one of the companies at the forefront. However, much of this innovation has remained proprietary to each company. To this day, there are only a small number of CDMOs that currently offer solid and solution phase synthesis capabilities.
“A decade ago, there was no broader industry demand for this platform,” Kuchimanchi clarified. “But as we see more oligo development for chronic diseases and larger patient populations, this area of innovation has started to become of interest. So, while we started working on solution-phase synthesis and enzymatic approaches roughly 10 to 15 years ago, it has only just become a focus area again in the last 5 years” to confront the limitations to large scale synthesis posed by solid-phase equipment capability, flow chemistries, solid support costs, and excessive organic solvent usage.
That said, however, I also appreciated his reminder that in this space, one “scale” does not fit all. Much of the attention being lavished on solution-phase and enzymatic manufacturing is with the goal of achieving larger batches of ASOs and/or siRNAs (i.e., 10-20 kg per batch) while reducing COGS and shortening cycle times.
For companies like CAMP4 that are focused on rare diseases, however, solid-phase synthesis remains the gold-standard.
“I liken solution-phase synthesis to a really large car,” he explained. “I don’t need that large of a car.” However, as he went on to clarify, this certainly doesn’t render the work being done on solution-phase synthesis null-and-void. As advancements continue to be made — particularly around quality and scale — he could see such an innovation turning heads in the smaller rare disease oligo treatment space, as well.
“By the time one of CAMP4’s products is on the commercial market in 5-plus years, if solution-phase synthesis can achieve high-quality small-scale manufacturing, I would not hesitate to make that leap to such a platform,” he added. “But for now, the COGS and manufacturing capabilities for solid-phase synthesis are more reasonable for small-scale ASO programs.”
Outsourcing requires stringent gap and risk assessments
On the surface, the outsourcing paradigm for solid-phase synthesis is well established. As Kuchimanchi emphasized in part 1, the beauty of oligo manufacturing is that the solid phase process, along with the equipment, is relatively straightforward today. Not only does this mean that CDMOs follow the same order of manufacturing steps, Kuchimanchi also pointed to the fact that there isn’t a great amount of diversity on the equipment front today either, thanks to a limited number of equipment providers. (Though, to be clear, production trains can cover a broad range of scales. For example, a CDMO may have multiple trains ranging in production scale from 10-500 grams; 500 grams to two kgs; or 1 kg to 5 kgs, for example.)
Though costs are, of course, a critical consideration, he also emphasized that production costs per gram tend to be comparable across CDMOs.
As such, for Kuchimanchi, the choice of CDMO is centered predominantly around timelines. This requires a close look, firstly, at the size of a CDMO’s facilities — namely the number of trains available for production.
But we also can’t ignore quality, and this is where some of the biggest and most dynamic discussions with potential and current outsourcing partners continue to occur. As Kuchimanchi went on to explain, a common area of discussion between biotechs and CDMOs is often over achievable quality thresholds and what types of testing are necessary at the start of a new development program.
“We want 90% purity for a first batch of product,” Kuchimanchi clarified. “But we can be met with pushback from CDMOs, especially if they’re making the batch for the first time. They may say they can only guarantee 85% quality. So, we must arrive at a middle ground because whatever we agree to also must be explained and justified to regulators.” Not to mention, any quality issues or human errors are key ingredients in development delays.
When I asked how biotech sponsors can and should handle such push back and/or compromises, Kuchimanchi pointed to some of our best-known tools for managing uncertainty and risk.
“We do a lot of gap assessments,” he said. “We also do a lot of risk assessments. We identify what we don’t know. We also identify where the big gaps exist in terms of meeting regulators’ expectations. There will be gray areas, which is where you take some risks. But you cannot leave big gaps.”
As he went on to explain, this is where interaction with the agencies and the trusty “phase-appropriate” approach come in. Naturally, one of the biggest challenges facing early-stage development companies can be a lack of scientific alignment between regulatory agencies about when it’s the appropriate time for a biotech to develop a specific method to demonstrate control over a certain impurity. But in Kuchimanchi’s experience, working hand-in-hand with the regulatory agencies has been critical for establishing concrete expectations and timelines for method development both internally and with CDMO partners.
“The agencies want to work with you,” he concluded. “They’re not trying to stop your development from moving forward. They just want to ensure each drug is safe. So, by the time you reach Phase 3, all the agencies are well aligned on what your final data package should look like.”
Missed part 1? Check it out!
For more on oligo outsourcing considerations, I’d direct you to my colleague Louis Garguilo’s discussion here.