Can Oligonucleotide Regulations Keep Up With Manufacturing Innovation?

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

Chemoenzymatic ligation.

Chemical Ligation.

Biocatalytic/fully enzymatic production.

Liquid-phase synthesis.

Continuous flow chemistry.

Novel solid supports.

Peptide and antibody conjugation for targeted delivery.

For an industry that has been around for a while, the oligo space sure knows how to change things up. Yes, we have 20 approved products and a “gold standard” manufacturing paradigm. But as the above list of manufacturing innovations should reveal, and as I explained in my previous takeaway article from TIDES, we’re also an industry realizing that what we’ve built will only take us so far. As such, this year’s TIDES felt like a merry gathering of process development aficionados, each of whom showcased their optimization strategies and/or the efficiencies unlocked by the integration of novel processes and technologies.

But all this manufacturing innovation signals another critical need for our field beyond the infrastructure: A more established and future-proof regulatory paradigm. We are certainly not in a regulatory guidance wasteland; oligos are in scope of a handful of ICH guidances, and EMA, FDA, China, and Japan have (predominantly draft) guidances/guidelines and/or Q&As centered around certain facets of oligo development. However, for an industry of our tenure, this landscape is patchwork, and as I’ve written before, there remains a great need for further scientific alignment across agencies.

This is why one of my favorite presentations at TIDES came from Katie Duncan, director of CMC policy and advocacy for GSK. Throughout her presentation, she walked us through points of convergence and, more importantly, divergence in the currently available draft guidances. In a future article, I’ll be unpacking several of the “hot topics” in the field that deserve a closer look through the regulatory lens. But before we get too deep in the weeds, it’s important to identify the current “knowns” of the RNA therapeutics regulations today. Here in part 2 of my TIDES takeaways, I’ll unpack which guidances we have at our disposal today in the oligo world, and what we can expect in the future.

The Current Oligo Regulatory Landscape, In Brief

It’s rare to find a resource putting all the regulatory guidelines/guidances in one place. So below, I put together a list of what’s available for us today (with links) to give us a better picture of what we’re working with — starting with ICH guidelines.  

1. Important to note right off the bat: There are no ICH guidelines dedicated solely to oligonucleotides. However…
2. There are currently several ICH guidelines that do apply broadly to oligo development. These include:
   1. ICH Q1: Guidelines on stability testing of drug substances and drug products
   2. ICH Q8 (R2): Pharmaceutical Development
   3. ICH Q9: Quality Risk Management
   4. ICH Q10: Pharmaceutical Quality System
   5. ICH Q11: Development and manufacture of drug substances (chemical & biological entities)
   6. ICH Q13: Continuous manufacturing of drug substances and drug products
3. Oligos are currently excluded from:
   1.  ICH Q3A/B: Impurities in new drug substances/drug products
   2.  ICH Q6A: Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances
   3.  ICH M7: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk
4. However, ICH Q1, Q6, and M7 are currently under revision, which, as Duncan pointed out, could have some big ramifications for the oligo space.

 “We’ve seen oligos be out of scope for a lot of the ICH guidances, but this is changing,” Duncan explained. “While we were previously ‘stepchildren’ off to the side, we’re now seeing revisions to ICH Q1 and Q6 where oligos are now in scope, and that’s really going to change things.”

Likewise, as she went on to add, questions remain around how ICH’s stance on oligo impurities and metabolites might push us to revisit our current control strategies and identification/qualification thresholds.

Meanwhile, global regulatory agencies have been publishing a variety of different guidances illuminating various aspects of oligo development. In particular:

• EMA published its “Draft Guidance on the Development and Manufacture of Oligonucleotides” in 2024. Since then, the agency has been chipping away at addressing nearly 700 industry comments, with (rumored) goals of releasing final guidance in Q3/Q4 of this year.  
  • Please note, if you are working on a targeted delivery strategy, oligos conjugated to antibodies or peptides are in scope of this guidance.
• PMDA (Japan) released its “Points to Consider for Quality Assurance and Evaluation of Oligonucleotide Therapeutics” in 2018. The agency then followed up with a “Questions and Answers” document on its “Points to Consider” guidance in 2022.
  • Please note, antibody/peptide conjugated oligos are not in scope of this guidance.
  • Likewise, unlike EMA and NMPA, this guidance does not address the all-important concepts of “platforming” and/or utilizing “prior knowledge.”
• NMPA/China made waves in February 2026 with the release of its final “Technical Guidelines for Pharmaceutical Research of Chemically Synthesized Oligonucleotide Drugs (Innovative Drugs).”
  • Please note, antibody/peptide conjugated oligos are not currently in scope of this guidance.
  • Likewise, if there was one differentiating feature to call out about this guidance, it would be the agency’s recommendation for a bioassay to demonstrate comparability. As Duncan neatly summarized, this recommendation is going to be “tricky.” (More on this in part 3!)
• ANVISA/Brazil included a section on oligo-related impurities in its “Guide for submission of Qualification Studies of Impurities and Degradation Products in Medicines.” The consultation period for this guidance just concluded at the end of June.
• To date, the FDA does not have any CMC-specific guidance for oligonucleotide therapeutics development. That said, the FDA has released a handful of oligo-specific guidances on the preclinical or clinical aspects of development, including:
  • “Nonclinical Safety Assessment of Oligonucleotide-based Therapeutics” (Draft)
  • “IND Submissions for Individualized ASO Drug Products for Severely Debilitating or Life-Threatening Diseases: Clinical Recommendations” (Draft)
  • “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics” (Final)
• Korea does not currently have publicly available oligo guidance. But as Duncan indicated in her presentation, the agency is working on a draft that looks to be closely in line with EMA’s recommendations.
• In fact, it’s worth noting that each of the CMC guidances mentioned above — though from different regulatory agencies — are generally in alignment with EMA’s draft recommendations.

Additional Regulatory Considerations: Current Challenges & Questions

During the past few years in the ATMP space, we’ve grown used to the concept of phase-appropriate development. However, we’ve also had to familiarize ourselves with the notion that certain marketing/post-approval concepts have become much more relevant to/applicable to earlier clinical development (e.g., comparability).

Though oligos are regulated as small molecules as opposed to advanced therapies, it would seem the industry is also starting to feel a similar level of pressure to apply certain marketing principles to clinical development.

As Duncan explained, “While these guidelines are meant to be applied to the marketing application, we are often seeing regions apply the marketing application expectations to our clinical trial submissions and therein lies a big problem. The bar for a phase one study should, in theory, be lower than a phase 3 study. This is playing out in a lot of the health authority questions we receive and is something that the European Pharma Oligonucleotide Consortium [EPOC] continues to monitor closely.”

Beyond feeling the pressure of increasingly sophisticated regulatory expectations/recommendations in early development, our space is facing the evergreen struggle between achieving maximum clarity from regulatory agencies and maintaining regulatory flexibility. Arguably one of the biggest questions Duncan posed was whether our space needed a dedicated, oligo-specific ICH guideline. While, on the one hand this could answer many of our questions and provide a clearer path forward for us, she also pointed to the fact that such a guideline could “put us in a box” — and it’s difficult to streamline development from inside a box. But a lack of oligo-specific guidelines could also lead to a proliferation of smaller regulatory agencies putting forth their own guidance that stymie attempts at reliance and/or global harmonization efforts.

Overall, as Duncan nicely articulated, there is a real concern that our regulatory infrastructure will be a limitation for us, especially as we continue to pursue innovative manufacturing efforts — particularly enzymatic ligation.   

“Guidelines were written to make recommendations for solid-phase synthesis,” she explained. “Obviously, SPOS has been our bread and butter for the past couple of decades of innovation. But it’s a big concern that these guidelines are being written in a way that may not be future proof as we continue to innovate and think of new and better ways to make our molecules.”

Stay tuned for part 3, which will be a deeper dive into the regulatory paradigm!

If you missed part 1, read it here: “Stay Stereocurious”: What the Future Holds for Oligo Quality”