Confident Identification of Leachable Impurities from Pharmaceutical Container Closure Materials using Orbitrap-Mass-Spectrometer-Based GC-MS

Significance of the Topic

Analysis of extractables and leachables in pharmaceutical packaging is vital for drug safety and regulatory compliance. Traceable, accurate identification of migrating impurities ensures patient protection and material selection.

Objectives and Study Overview

The study applied a full-scan orbitrap-based GC-MS workflow to identify leachable compounds from four types of O-ring materials (red, brown, white, black) under accelerated extraction conditions. The goal was to detect unique impurities by comparing sample extracts to a blank control and propose compound identities.

Methodology

O-ring sections were extracted in solvents (100% ethanol, 50% ethanol, water for injection, 5 M NaCl) at 40 °C for 30 days. A liquid–liquid extraction was used for aqueous extracts. Full-scan data were acquired in electron ionization (EI) and positive chemical ionization (PCI) modes at 60 000 resolving power, m/z 50–650.

Instrumentation

• Thermo Scientific Q Exactive GC Orbitrap GC-MS/MS
• Thermo Scientific TriPlus RSH autosampler
• Thermo Scientific TRACE 1310 GC with TraceGOLD TG-5SilMS capillary column

Main Results and Discussion

Binary comparison and accurate-mass deconvolution in TraceFinder isolated unique peaks in each O-ring extract. Sub-1-ppm mass accuracy enabled confident identification via spectral library matching (e.g., triphenylphosphine oxide, antioxidants, plasticizers) and formula assignment for unknowns (e.g., C20H20O4 isomers). Brown and black rings showed the highest extractable counts; white rings the fewest; red rings contained cyclic siloxanes from contamination.

Benefits and Practical Applications

This untargeted orbitrap GC-MS approach offers fast, sensitive, and comprehensive profiling of packaging leachables, supporting quality control, risk assessment, and material selection in pharmaceutical development.

Future Trends and Potential Applications

Advances in high-resolution MS, expanded MS/MS libraries, and automated data analytics will further streamline leachable identification. Integration with predictive modelling and real-time monitoring could enhance packaging design and safety evaluation.

Conclusion

The combination of orbitrap GC-MS and robust software workflows enables confident detection and identification of extractables and leachables with high mass accuracy, improving analytical efficiency and regulatory compliance.

References

1. Norwood DL. Understanding the challenges of extractables and leachables for the pharmaceutical industry–safety and regulatory environment for pharmaceuticals. Am Pharm Rev. 2007;10(2):32–39.
2. Ding W, Madsen G, Mahajan E, O’Connor S, Wong K. Standardized Extractables Testing Protocol for Single-Use Systems in Biomanufacturing. Pharm Eng. 2014;34(6).