Identification of Leachable Impurities from Pharmaceutical Container Closure Materials Using Orbitrap based GC-MS

Importance of the Topic

Extractables and leachables analysis evaluates chemical impurities migrating from packaging components into pharmaceutical products. Ensuring container closure integrity and patient safety while meeting regulatory requirements is critical in drug development and quality control.

Goals and Study Overview

This study presents an untargeted workflow for identifying leachable impurities from polymer O-ring gaskets using Orbitrap-based GC-MS. Four different O-ring materials (red, brown, white, black) were subjected to accelerated leaching in various solvents. The aim was to isolate unique extractable features, perform library searches, and propose elemental formulas for unknown compounds.

Methodology and Instrumentation

• Sample Preparation: O-rings were cut into 20 × 20 mm sections and leached for 30 days at 40 °C in 100% ethanol, 50% ethanol, water for injection, and 5 M NaCl.
• Chromatography–Mass Spectrometry: 1 µL splitless injections on a TRACE 1310 GC with a TG-5SILMS column; separation achieved with a 30 m × 0.25 mm × 0.25 µm film thickness.
• Mass Spectrometry: Q Exactive GC Orbitrap operated at 60 000 FWHM resolution, 50–600 m/z range, full-scan electron ionization (EI) and positive chemical ionization (PCI), internal mass lock for sub-ppm accuracy.
• Data Processing: TraceFinder software performed deconvolution, differential analysis against blanks, library matching (NIST spectra), high resolution filtering, and elemental composition assignment for unknowns.

Instrumental Setup

• Thermo Scientific TRACE 1310 Gas Chromatograph
• Thermo Scientific TriPlus RSH Autosampler
• Thermo Scientific Q Exactive GC Orbitrap Mass Spectrometer
• TraceFinder Software for deconvolution and compound identification

Main Results and Discussion

• TIC profiles revealed sample-specific peaks elevated relative to blanks, with brown and black O-rings showing the highest extractable load.
• NIST library matching of deconvoluted EI spectra identified ethyl octanoate and triphenylphosphine oxide with >98% high resolution filtering (HRF) and <1 ppm mass error.
• Unknown peaks lacking library hits were characterized using PCI adducts ([M+H]+, [M+C₂H₅]+), leading to an unambiguous formula C₂₀H₂₀O₄.
• Red O-rings exhibited dominant cyclic siloxane contamination; white rings yielded the fewest unique extractables.

Benefits and Practical Application

• Fast chromatographic separation and high-speed acquisition support high-throughput screening of extractables in quality control workflows.
• Consistent sub-ppm mass accuracy and 60 000 FWHM resolution reduce isobaric interferences for confident compound assignments.
• Combined EI and PCI strategies enhance identification reliability for both library-matched and novel impurities.

Future Trends and Opportunities

• Expansion of high-resolution spectral libraries and deployment of AI-driven untargeted identification tools.
• Coupling orthogonal separation techniques (e.g., GC×GC, LC-HRMS) to broaden extractable coverage.
• Development of real-time in-line mass spectrometry monitoring for container closure integrity and accelerated stability testing.
• Standardization of data processing pipelines to harmonize regulatory submissions and improve reproducibility.

Conclusion

The Q Exactive GC Orbitrap MS, integrated with TraceFinder software, offers a powerful untargeted platform for comprehensive profiling of extractables and leachables from pharmaceutical container materials. High resolution, accurate mass capabilities and combined EI/PCI workflows enable confident identification of both known and previously unreported impurities.