Extractables Analysis of Nasal Spray Devices Using Gas Chromatography and High- Resolution Mass Spectrometry With Soft Ionization

Importance of the Topic

Ensuring the safety of pharmaceutical packaging and medical devices requires comprehensive screening of extractables and leachables. Volatile and semi-volatile compounds can migrate from plastics into drug products, posing potential health risks. Traditional GC-EI techniques often fragment molecules extensively and may miss compounds not present in reference libraries or those with low sensitivity. A softer ionization approach coupled with high-resolution detection addresses these challenges by preserving molecular ions and enabling accurate mass measurement.

Objectives and Study Overview

This study evaluates a workflow for extractables analysis of nasal spray devices using gas chromatography combined with a quadrupole time-of-flight high-resolution mass spectrometer equipped with an atmospheric pressure gas chromatography source. The aim is to enhance compound coverage and identification confidence through soft ionization and data independent acquisition strategies.

Methodology and Instrumentation

• Sample preparation: Isopropanol extraction of commercial nasal spray assemblies at 40 °C for 72 h, with procedural blanks and system suitability mix injected in triplicate.
• GC conditions: Agilent 8890 GC, PAL RSI autosampler, splitless inlet at 300 °C, Rtx-5MS column, helium carrier at 1 mL/min, temperature ramp from 40 °C to 330 °C.
• MS conditions: Waters APGC source with mixed charge transfer and protonation, Xevo G3 QTof, source at 150 °C, mass range m/z 50–1200, MSE acquisition with low energy 6 V and high energy 15–45 V.
• Software: MassLynx 4.2 for data acquisition, UNIFI within waters_connect for screening, library matching, and structural elucidation.

Key Results and Discussion

GC-APGC-QTof analysis demonstrated high sensitivity and reproducibility in system suitability tests (<0.01 % RSD for retention time). Screening against a dedicated extractables library identified antioxidants and other process aid residues not detected by LC-QTof. The soft ionization preserved intact molecular ions, facilitating elemental composition assignment. MSE spectra provided simultaneous precursor and fragment data, enhancing confidence in identifications and reducing false positives. An unknown compound at m/z 284.2703 was tentatively assigned as N-(2-(1-piperazinyl)ethyl)decanamide using UNIFI discovery tools and accurate mass fragmentation.

Benefits and Practical Applications

• Orthogonal coverage complementing LC-HRMS and traditional EI-GC-MS for broader extractables profiling.
• Improved sensitivity and preservation of molecular ions for more reliable library matching.
• Data independent MSE acquisition streamlines compound confirmation and unknown elucidation.
• Integrated UNIFI workflows enable efficient filtering by analytical evaluation thresholds and direct comparison to blanks for targeted unknown discovery.

Future Trends and Applications

Advances in ion mobility-enhanced libraries, expanded high-resolution spectral databases, and machine learning-driven annotation are expected to further accelerate extractables screening. Integration of risk-based thresholds and real-time data processing will support dynamic quality control in pharmaceutical and medical device manufacture.

Conclusion

Combining GC-APGC soft ionization with QTof high-resolution detection and MSE acquisition delivers a powerful orthogonal approach for extractables analysis of nasal spray devices. The workflow enhances compound coverage, yields reliable molecular ion data, and supports confident identification and structural elucidation of both known and unknown components.

References

1. USP NF Appendix 1664 Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems
2. USP NF Appendix 1663 Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems
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10. ISO 10993-18 Biological Evaluation of Medical Devices Part 18 Chemical Characterization of Medical Device Materials 2020
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