2026 年 57 巻 4 号 p. 334-364
The number of oligonucleotide therapeutics approved in the U. S., Europe, and/or Japan has been steadily increasing, and a clear trend toward increased structural complexity is apparent. For example, various chemically modified nucleotides have been incorporated to enhance in vivo stability, and organ-specific drug delivery system ligands have been introduced into oligonucleotides targeting specific genes. Efficacy and safety are both critical issues for chemically synthesized oligonucleotides, and controlling impurities generated during production is essential for maintaining consistent product quality, minimizing batch-to-batch variation, and ensuring stable therapeutic effects. It is thus imperative to identify and manage impurities, such as products with incomplete sequences and synthetic by-products, necessitating the establishment of more precise quality-control methods.
Here, we aim to deepen understanding of impurities actually or potentially formed during oligonucleotide manufacturing by reviewing the oligonucleotide synthesis workflow and the separation modes used for purification, based on published reports and patents. The structures and formation mechanisms are described, as well as the manufacturing stages with which they are likely to be associated.
