Current CMC challenges in oligonucleotide API development: from IND to NDA

IF 3.1 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2026-04-25 DOI:10.1007/s00044-026-03569-8

Daoqian Chen, Xiaobing Zhang, Songgen Xu, Deming Liu

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Abstract

Oligonucleotide therapeutics are becoming representatives of the “Third Wave” of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a “regulatory grey area” between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).

AbstractSection Graphical Abstract

The alternative text for this image may have been generated using AI.

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当前CMC在寡核苷酸原料药开发中的挑战：从IND到NDA

继小分子和蛋白质之后，寡核苷酸疗法正在成为“第三波”药物创新的代表，从最初的罕见疾病扩展到肿瘤和慢性适应症。在全球范围内，除了已经批准的26种寡核苷酸药物外，目前正在进行数百项临床试验。尽管自最初批准Fomivirsen以来已经过去了近30年，但寡核苷酸疗法仍然面临着与小分子不同的独特CMC（化学、制造和控制）挑战。此外，缺乏专门针对寡核苷酸的统一ICH指南迫使开发人员在新分子实体（NMEs）和生物制剂之间的“监管灰色地带”中导航。本观点侧重于API（活性药物成分）CMC开发的技术和监管障碍，涵盖合成（包括与递送系统的偶联策略），分析和监管方面，特别强调从研究新药（IND）申请到新药申请（NDA）的阶段适当要求。此图像的替代文本可能是使用AI生成的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.