🧬Day 7| Oligonucleotide Raw Materials: More Than a Quality Issue

After years of hands-on experience in solid-phase oligonucleotide synthesis and scale-up manufacturing, one thing has become very clear to me:
Raw material purity, moisture control, and lot-to-lot consistency are not just quality parameters — they directly determine process robustness and project risk and ultimately commercial cost.
These factors impact not only coupling efficiency during synthesis, but also final product quality, clinical performance, and regulatory compliance.
These factors strongly influence:
1️⃣Coupling efficiency during solid-phase synthesis, target compound yield
2️⃣Batch-to-batch reproducibility
3️⃣Downstream purification performance
However, in the early stages of development, solid-phase synthesis process optimization is often prioritized, while raw materials are still treated as a secondary factor.

The starting materials commonly used in oligonucleotide synthesis include standard nucleoside phosphoramidites (A, C, G, T, U, and 5-Me-C), as well as a range of widely used sugar modifications such as 2′-O-Me, 2′-F, and 2′-MOE.
As oligonucleotide therapeutics become increasingly complex in structure, the use of non-traditional or customized modified starting materials has grown significantly. These include, but are not limited to, GalNAc conjugation reagents, specialized linkers, and LNA monomers. Such materials present higher challenges in terms of impurity profiles, stability, and lot-to-lot consistency, thereby placing greater demands on quality control strategies.

👉 In the next post, I’ll share a real manufacturing pitfall involving GalNAc-conjugated reagents.