CMC and regulatory aspects of oligonucleotide therapeutics

Oligonucleotide RNA therapeutics are manufactured by a controlled and well-established chemical process and their sizes typically reach from 5000 to 20,000 or more Daltons. They are viewed by regulatory agencies as "large small molecules" as they predominantly are manufactured like new chemical entities but also share properties with biologics and therefore fall in a regulatory gray area between small molecule drugs and biologics. Together with the fact that they are a recently introduced young therapeutic modality, some sections of the ICH (International Conference for Harmonization) guidelines, like Q3A/B and Q6B, have so far excluded oligonucleotide therapeutics in their preambles. Nevertheless, with the recent approval of over a dozen of oligonucleotide-based therapeutics, more guidance is needed. This publication makes an attempt to guide a CMC chemist or anyone interested in oligonucleotide therapeutic development to learn how to navigate their program and to be more prepared in answering CMC and in particular impurity-related questions by the regulatory agencies.