ISCC 2016: Identification of Leachable Impurities from Pharmaceutical Container Closure Materials using Orbitrap based GC-MS

Significance of the topic

In pharmaceutical manufacturing, controlling impurities that migrate from packaging materials into drug products is essential for patient safety and regulatory compliance. Extractables and leachables studies help to identify, quantify and minimize chemical contaminants released from container closure systems under accelerated and real-world conditions.

Objectives and study overview

This study aimed to develop and demonstrate a fully untargeted workflow for detecting and identifying known and unknown compounds leaching from polymer O-ring gaskets. Using high-resolution Orbitrap gas chromatography-mass spectrometry, the work evaluated the system’s ability to isolate unique features, perform accurate mass deconvolution and assign confident identifications in a complex sample matrix.

Methodology

Samples of red, brown, white and black O-ring gaskets were sectioned and subjected to an accelerated leachable protocol over 30 days at 40 °C in sealed vials containing 100 % ethanol, 50 % ethanol, water for injection and saline. Solvent blanks underwent the same treatment. Full-scan chromatograms (50–600 m/z) were acquired in electron impact mode at 60 000 FWHM resolving power with internal lock mass calibration. Data were processed using Thermo Fisher TraceFinder software to perform accurate mass deconvolution and binary comparisons between test samples and blanks.

Instrumentation used

• Thermo Scientific TRACE 1310 gas chromatograph with TRACEGOLD TG-5SILMS column (30 m×0.25 mm×0.25 μm)
• Thermo Scientific Q Exactive GC Orbitrap mass spectrometer (EI mode, 60 000 FWHM)
• Thermo Scientific TriPlus RSH autosampler
• TraceFinder software for deconvolution, library searching and high resolution filtering

Main results and discussion

Binary comparison highlighted peaks significantly elevated in gasket leachates relative to blanks. Deconvoluted spectra were searched against nominal mass libraries (e.g. NIST 2014) and scored by search index and high resolution filtering. Ethyl octanoate and triphenylphosphine oxide were identified with sub-1 ppm mass accuracy and >98 % spectral explanation. Routine resolving power of 60 000 FWHM eliminated isobaric interferences and enabled confident assignment of unknowns even at low abundance.

Benefits and practical applications

• Fast, untargeted screening of volatile and semi-volatile impurities in packaging materials
• High confidence identifications through coupling of accurate mass deconvolution and spectral library matching
• Robust chromatographic separation and data acquisition suitable for QA/QC and regulatory extractables studies

Future trends and applications

Advancements in real-time data acquisition, automation and expanded high-resolution spectral libraries will further streamline untargeted leachables screening. Integration with complementary techniques such as LC-HRMS and machine learning-driven data analysis promises deeper chemical characterization and faster decision-making in pharmaceutical packaging safety.

Conclusion

The combination of Orbitrap GC-MS and advanced software tools provides a powerful platform for comprehensive extractables and leachables studies. Exceptional mass resolving power, accurate mass stability and robust data processing deliver rapid, reliable identification of potential packaging-related impurities.