The oligonucleotide therapeutics field is entering a new phase of clinical and commercial maturity, driven by increasing approvals, expanding pharma investment, and growing complexity across ASOs, siRNA, gRNA and conjugates. However, as momentum builds, oligonucleotide analytical development and CMC are emerging as the primary limiting factors impacting timelines, regulatory success, and scalability.
This page explores the six biggest oligonucleotide CMC and analytical development challenges impacting drug developers today, spanning impurity profiling, regulatory uncertainty, analytical complexity, manufacturing scale-up, comparability, and cross-functional alignment. Each bottleneck is mapped to practical, solution-focused sessions at the 5th Oligonucleotide Analytical Development & CMC Summit.
Impurity Profiling Challenges in Oligonucleotide Development
Impurity profiling remains one of the most significant bottlenecks in oligonucleotide analytical development. Due to increasing chemical complexity, oligonucleotides generate large numbers of closely related impurities, including truncated sequences, mismatches, and modified linkages. As modalities evolve into conjugates and highly modified chemistries, impurity profiles are becoming more complex and less predictable.
Regulatory expectations for impurity characterisation in oligonucleotide CMC are increasing, with agencies expecting a deep understanding of impurity origin, structure, and impact. However, global guidance remains unclear, leaving teams uncertain about what constitutes acceptable impurity control strategies. In practice, this can delay IND submissions, create approval risk, and complicate scale-up.
Sessions Addressing This Bottleneck: