Non-targeted screening of extractables from vial septa using high-resolution Orbitrap GC-MS

Importance of the Topic

Advanced analysis of extractable chemicals from vial septa is essential for ensuring the safety and efficacy of pharmaceutical products. Undetected impurities transferring from packaging into drug formulations pose significant health risks. High-resolution gas chromatography–mass spectrometry allows comprehensive, non-targeted detection of both known and unexpected leachables.

Goals and Overview of the Study

This work demonstrates the capability of the Thermo Scientific™ Orbitrap Exploris™ GC mass spectrometer for confident, untargeted screening of extractables from various septa types. Complementary flame ionization detection validates chromatographic performance and extends detection coverage.

Used Methodology and Instrumentation

Sample Preparation:

• Twenty-one septa from multiple suppliers (PTFE/silicone blends and rubber variants) were sectioned and extracted in a 1:1:1 methanol/dichloromethane/hexane mixture for approximately 18 hours.

Instrument Configuration:

• TRACE 1310 GC with splitless injection, TraceGOLD TG-5SilMS column (30 m × 0.25 mm × 0.25 μm), and standard temperature ramp to 320 °C.
• Orbitrap Exploris GC mass spectrometer operated in electron ionization (EI) and positive chemical ionization (PCI) modes, mass range 50–650 Da, resolving power 60 000 FWHM, mass accuracy <1 ppm.
• Flame ionization detection (FID) for complementary profiling at 300 °C.

Data Processing:

• TraceFinder software for accurate mass deconvolution and library searching.
• Compound Discoverer for spectral deconvolution, statistical analysis (PCA, volcano plots), and streamlined identification workflows.
• Mass Frontier for in silico fragmentation and structural elucidation.

Main Results and Discussion

High-resolution full-scan EI data and automated deconvolution revealed numerous extractable compounds, notably cyclic siloxanes and hindered phenolic antioxidants. Key findings include:

• Identification of tetradecamethyl-cycloheptasiloxane with >90% library match and high-resolution filter validation.
• Characterization of a bis(tert-butylated) phenol antioxidant by elemental composition analysis and fragment matching using Mass Frontier.

Principal component analysis (PCA) clearly separated septa by composition, while volcano plots highlighted statistically significant differences in extractable profiles between sample groups.

Benefits and Practical Applications of the Method

The integrated high-resolution GC-MS and FID workflow delivers:

• Unambiguous detection of both trace and abundant extractables across a broad volatility range.
• Elimination of isobaric interferences through sub-ppm mass accuracy and high resolving power.
• Streamlined data analysis for risk assessment, material selection, and quality control in pharmaceutical packaging and other regulated industries.

Future Trends and Possibilities

Emerging developments poised to enhance extractables screening include:

• Expansion of accurate mass spectral libraries and advanced in silico fragmentation tools.
• Integration of machine-learning algorithms for automated unknown identification and classification.
• Real-time monitoring and regulatory compliance platforms coupling non-targeted screening with predictive toxicology.

Conclusion

The Orbitrap Exploris GC-MS platform, combined with GC-FID and specialized software, offers a robust, comprehensive solution for non-targeted screening of vial septa extractables. High mass accuracy, resolving power, and intuitive data workflows enable confident compound identification, supporting safer packaging choices and regulatory compliance.