Robust Oligonucleotide Impurity Profiling in a GMP Setting Using the Waters SQ Detector 2 Mass Detector

By
  • Lara Nercessian
  • Claire Butré
  • Damien Mouvet
  • Cristian I. Cojocariu (Waters Corporation)
  • Jonathan Fox (Waters Corporation)
  • Arnaud Delobel
Date
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Therapeutic oligonucleotides are increasingly used to modulate gene expression, but their chemical complexity and synthesis process generate a wide range of impurities that must be accurately monitored. Ensuring precise impurity profiling is essential to guarantee product safety, efficacy, and regulatory compliance in GMP environments. Traditional approaches using UV or high-resolution mass spectrometry can present limitations in routine QC settings due to complexity or cost.

This application note introduces a practical LC-MS method using the Waters SQ Detector 2 to simplify workflows while maintaining analytical performance. The approach combines robustness, sensitivity, and ease of implementation for routine use. The full technical details and results are available in the complete application note written in collaboration with Waters.

KEY HIGHLIGHTS OF THE METHOD

  • Accurate quantification of truncated oligonucleotide impurities down to 0.1% with good linearity (R² > 0.99)
  • High-sensitivity mass detection
  • Precision below 6% RSD for repeatability at low concentration and below 3% at higher levels
  • Robust performance demonstrated across instruments, columns, and days

HOW THIS SUPPORTS YOUR QC PROGRAMME?

This method provides a practical solution for QC laboratories seeking reliable oligonucleotide impurity profiling while maintaining operational simplicity and regulatory compliance.

  • Enables routine impurity quantification using a single quadrupole MS system, reducing complexity compared to HRMS
  • Supports GMP compliance with full control via Empower Software and 21 CFR Part 11 alignment
  • Improves workflow efficiency through streamlined LC-MS setup and simplified data processing
  • Ensures reproducible results across different systems and analytical conditions
  • Balances sensitivity, cost-effectiveness, and ease of use for routine QC environments

APPLICATIONS

  • Routine impurity analysis of synthetic oligonucleotides in QC laboratories
  • Quantification of truncated oligonucleotide species (e.g. N-1, shortmers, failure sequences)
  • GMP-compliant analytical workflows for pharmaceutical quality control
  • LC-MS method implementation in laboratories seeking simplified MS-based impurity profiling

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