5 Critical Regulatory Topics To Watch In The Oligo Sector
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
I love writing about regulatory paradigms. Having attended TIDES a few months ago, I was privy to several fantastic conversations that centered around this topic and the regulatory challenges facing us in the oligo sector.
Whether it be ICH guidelines or draft guidance from regulators, the oligonucleotide space is certainly not flying blind. But as I wrote in my previous article on this topic, there are still several big discrepancies between regulatory guidances. We’re also awaiting changes to a handful of ICH guidelines that will bring oligos into scope — a change that raises significant questions about the future of our industry as we continue to innovate on our manufacturing paradigm.
Though our guidances have helped us achieve upwards of 20 commercially approved oligo products, as I listened to GSK’s director of CMC policy and advocacy, Katie Duncan, present at TIDES, it struck me just how far we have yet to come. Here, I single out a few of the biggest topics of regulatory discussion shaping the oligo therapeutics market. As you can no doubt ascertain, these are not small topics of conversation. How we and regulators engage with them in the future will go on to influence everything from how we source our raw materials, evaluate impurities, and optimize, improve, or innovate with our manufacturing processes.
Regulatory Starting Materials
EMA, PMDA, and NMPA each have sections dedicated to regulatory starting materials (RSMs). But the extent to which this topic is discussed varies, with PMDA guidance being the most sparing of the three in detailing expectations for starting materials. As Duncan went on to explain, EMA & NMPA both recognize phosphoramidites as typical RSMs. However, when it comes to the widely used GalNAc, for example, we start to see some variability in approaches. EMA, for example, articulates that it will address such non-nucleoside starting materials on a case-by-case basis, while NMPA guidance isolates out “some innovative GalNAc” products as “unsuitable to control as starting materials.”
As we all know our push toward larger scale manufacturing also necessitates a much larger supply chain, and an increasing number of suppliers leads to a wider spectrum of material quality. It would seem this growth has not been lost on regulators. As Duncan explained:
“One area of divergence we’re seeing across agencies is how much information we should provide about our starting materials. Generally, more information is required for your EMA submission than for FDA, but we’re also seeing a wide difference in the information expected about our starting materials. Additional justification may be required, and we may need to add additional tests to control other attributes.”
Chemoenzymatic Ligation
As Duncan pointed out in a previous article, our current regulatory guidance caters to oligos made using legacy SPOS — a distinction that gives her pause considering how much innovation we’re exploring. For example, of current guidance, only the NMPA touches on innovative manufacturing paradigms like liquid-phase manufacturing, enzymatic ligation, and/or biocatalytic approaches.
As you might have expected, a big topic of conversation throughout TIDES was the growing use of chemoenzymatic ligation. Everything was coming up fragments. But one of the biggest questions remains whether regulators will approach these blockmers/shortmers as regulatory starting materials — a factor that will ultimately impact our GMP principles. (FYI, an expert from Alnylam did share that FDA and EMA regulators were open to the company’s justification of blockmers being categorized as regulatory starting materials. NMPA considers them an intermediate.)
As Duncan went on to explain, successfully doing so will require education to familiarize regulators with the concept — much like the peptide industry has had to do to justify its own use of dipeptides/short fragments as RSMs. This also necessitates ongoing dialogue across the industry around minimum and maximum fragment lengths.
“Is a dimer ok?” Duncan posed. “Are we only arguing for 7-mers? What are we asking for? Dimer is a much more solvable issue, but does that get us where we want to go? Probably not. So where is our line?”
Stereochemistry
If you read my previous articles from TIDES this year, you’ll know that stereochemistry was front and center of conversations about the future of oligo quality. It’s universally understood that stereochemistry is important, but big questions remain about what truly matters in terms of stereochemical composition. Should we be striving for stereopure, and will regulators one day push for this? The jury is still out. But the EMA guidance and recently finalized guidance from NMPA both lavish attention on the biological impacts of stereochemical composition.
Broadly speaking, regulators do acknowledge the difficulties facing the industry when measuring diastereomers. Of the available guidances, only NMPA outlines methods for evaluating stereochemistry, and, fortunately, there are no recommendations for release tests to demonstrate stereochemistry.
That said, however, regulations around stereochemistry are in a state of flux. Not only are we waiting to see what, if anything, ICH Q6 might say about stereochemistry, but the NMPA did outline recommendations for a bioassay in demonstrating comparability. As Duncan clarified, this (difficult to develop) assay is expected to help us evaluate the impact of changes on stereochemical composition. But this recommendation has given the industry pause, predominantly because of how difficult it is to develop an assay that has the discriminatory power to tell us what does and doesn’t matter.
“It’s a challenge for the whole field to figure out what matters when it comes to stereochemical composition,” Duncan explained. “Is there a difference between 60/40, 50/50, and 40/60? I don’t know. Let’s try and figure out what matters.”
And speaking of comparability…
Comparability
There are a lot of reasons as to why this is going to be a big topic to watch for the oligo space moving forward. Duncan put it best:
“If we don’t have a clear pathway for making changes, it becomes that much harder to justify making a change, and delaying implementing changes can be really bad.”
As we already know, there are a lot of changes being made, particularly to our supply chains and manufacturing processes, as we strive to move from rare to larger indications — whether it be reducing solvent usage to improve sustainability or bringing on a new process. Likewise, our pursuit of targeted delivery — particularly conjugations with biologics — also has the potential to shake things up from a comparability standpoint.
Despite the importance of comparability for our future development, it’s important to note that regulatory guidance addresses comparability in a relatively patchwork way. The only guidance to have a section dedicated to oligo comparability is the NMPA, and as we already know, they’ve broken free from the rest of the pack with their recommendation of a bioassay for demonstrating comparability.
Now, it’s important to note that each regulator is aligned around the criticality of evaluating the impact that any changes have on impurity profiles pre- and post-change. However, only PMDA and NMPA address comparability for manufacturing process changes. The EMA guidance only discusses comparability in terms of generics development.
Given the amount of innovation happening in the oligo space, this remains an area that could stand for more added clarity. Fortunately, as Duncan revealed, there will be a paper on comparability forthcoming from the European Pharma Oligonucleotide Consortium (EPOC) — so please stay tuned!
Impurities
The Capaldi identification and qualification thresholds are both recognized by EMA and NMPA guidance. As Duncan acknowledged, the FDA was also receptive to these limits; however, as she went on to qualify, this alignment with EMA’s guidance is case-by-case depending on the indication and dose and requires the appropriate justifications.
“The FDA is not necessarily going to blindly follow the EMA’s lead,” she said.
In particular, she went on to single out class three impurities, indicating that the Chinese regulators seem to be taking a more cautious stance with these in particular — perhaps out of concern about off-target effects.
“I would be cautious with any class 3 impurity, even if it doesn’t fall above these typical levels,” Duncan advised. “It’ll also be interesting to see what ICH Q6 and ICH S13 say about these because that’s a big unknown right now.”