The growing need for oligonucleotide therapeutics aimed at larger patient populations has driven the demand for high-quality nucleoside phosphoramidites – the building blocks for oligonucleotide therapeutics. To support the emergence of synthetic oligonucleotide therapeutics, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have recently provided more clarity in regulatory expectations. In 2024, the FDA published a guidance that described the clinical pharmacology requirements while the EMA’s guidance focused on manufacturing and control of synthetic oligonucleotides. The recent EMA guidance reiterated the principles per International Conference on Harmonisation (ICH). This guidance reinforces the regulatory expectations of analytical rigor and process robustness needed for starting material by highlighting ICH Q9 Quality risk management and ICH Q11 Guideline on development and manufacture of drug substances. ICH Q11 is referenced in the context of starting materials selection, and Q9 is referenced to highlight how the benchmarking of certain impurities (referred to as “critical impurities” in the guidance) impacts process development. The guida ...