Main Conference Day 2Wednesday, 4 November 2026 - Europe/Amsterdam

This presentation will review the recent evolution of global regulatory guidance for synthetic oligonucleotides, assess areas of convergence and divergence, and explore future opportunities for harmonisation and efficiency.

CMC regulatory strategies and health authority interactions for oligonucleotide programs will be discussed, with a focus on recent ASO commercial applications in the US and ex-US regions. Similarities and differences in submission content, filing strategies, regulatory expectations, and health authority requests will be highlighted, supported by recent filing experiences and case studies. Perspectives on emerging hot topics and practical learnings from recent submissions will be discussed, along with potential future areas for regulatory engagement.

The presentation will provide an update on the main principles and current status of guidelines and the expected timelines for implementation. It will summarise key feedback received during the public consultation of two draft guidelines, with a focus on the main scientific and regulatory challenges for stakeholders. The presentation will also provide an overview of the most common issues encountered during Marketing Authorisation Application procedures in recent years.

Regulators increasing expect terminal sterilization for ASO drug products by steam/autoclave as a process that offers high sterility assurance levels (≤10^-6). Aseptic processing is only allowed if steam sterilization is not feasible. Published ASO data to date (DeCollibus et al 2023) largely focus on molecule-centric, concentration-based chemical degradation, such as depurination and backbone cleavage/hydrolysis, with limited evaluation of the formulation aspects. EMA draft guidance (EMA/CHMP/CVMP/QWP/262313/2024) states that moderate degradation, even above qualification limits, is not enough to reject terminal sterilization. Instead, the guideline encourages optimizing formulation factors (pH, buffer system, and osmolality), and container-closure to enable its use. With advancements in ASO chemical modifications and molecule designs, formulation composition may emerge as a potentially limiting factor. This presentation will illustrate some case studies under such circumstances to help make informed decisions on feasibility of steam sterilization during early phases of ASO drug product development.

Enzymatic ligation has continued to gain traction as a way to augment traditional SPOS processes. However, the manufacturing process challenges with enzymatic processes shift with the introduction of more aqueous-based processes and conditions that favor microbial growth. This talk will examine a typical enzymatic ligation process and focus on the decision points around these unit operations with regard to microbial and bioburden control and the potential implications for gmp manufacturing that arise, comparing them to analogous traditional SPOS considerations.

As the therapeutic landscape for small interfering RNAs (siRNAs) continues to rapidly expand, the demand for the fast development of scalable, sustainable, and highly efficient manufacturing methodologies has never been more critical. Traditional solid-phase chemical synthesis is limited by its high environmental footprint while fully enzymatic approaches are restricted by poor chemical compatibility. This stimulated the emergence of chemo-enzymatic technologies as a disruptive alternative that combines biocatalysis sustainability with chemical synthesis flexibility. However, the identification of fragmentation designs resulting in successful and complete ligation conversion requires navigating a vast multi-variable space that changes from sequence to sequence. In this presentation, we detail the implementation of a robust high-throughput screening (HTS) platform designed to rapidly evaluate different cutting sites to identify the best ligation approach. By leveraging automated workflows, we screened various ligation strategies and fragment combinations, drastically accelerating early-stage process development. Moving beyond small-scale screening, we successfully implemented the ligation strategy into a successful, upscaled ligation process. Our data shows that chemo-enzymatic approaches result in increased yield, improved purity profiles, and reduced process mass intensity (PMI). From this scale-up example we demonstrate that chemo-enzymatic workflows are fully primed as the future for therapeutic siRNA supplies.

As oligonucleotide therapeutics advance toward commercialization, analytical methods must support the entire product lifecycle—from critical raw materials and components to final drug substance release. This presentation will share practical strategies from a CDMO perspective on validating robust analytical methods that are fit for purpose and transfer-ready. Topics include method maturity, impurity characterization, robustness, lifecycle management, and strategies for avoiding common validation pitfalls while maintaining development speed and regulatory compliance.