Impact of Impurities on the Quality and Safety of Oligonucleotides as Drug Substances

The process of solid-phase oligonucleotide synthesis (SPOS) is well established and has been used in recent decades for the chemical synthesis of RNA therapeutics. With the growing understanding of RNA therapeutics, their overall structural design evolved to enhance efficacy, stability, or delivery by the introduction of various modifications. This had a direct impact on the impurities generated and their control. In parallel, the understanding of chemistry, manufacturing, and controls (CMC) was greatly enhanced by the advances in analytical techniques. Understanding of the manufacturing process and defined analytical checkpoints allow impurities to be traced back to the originating process step. This knowledge in turn can be used during process development to develop tight control strategies that enhance product quality. With the current speed of approvals of RNA therapeutics and the rapidly growing pipeline, regulations and guidelines are needed to ensure drug safety. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines ICH Q3A Impurities in New Drug Substances, Q3B Impurities in New Drug Products, and Q6A Specifications: New Chemical Drug Substances and Products exclude oligonucleotides as the guidance provided therein for small-molecule registration cannot be directly applied. In 2017, the Oligonucleotide Safety Working Group (OSWG) took a step forward to close this gap by publishing a White Paper on impurities in oligonucleotide drug substances and drug products. This chapter discusses regulations, suggestions, and opinions on the control of impurities formed during the manufacture of synthetic RNA therapeutics and related CMC strategies.