GC/MS Approach for Analysis of Extractables and Leachables (E&L) in Complex Matrices Using Spectral Deconvolution and Retention Indices

Importance of the Topic

Extraction and leaching from drug delivery components can introduce contaminants that affect patient safety and drug efficacy. A sensitive and comprehensive analytical strategy is essential to detect and identify extractables and leachables (E&L) in complex matrices. Gas chromatography coupled with mass spectrometry (GC/MS) provides robust analysis for volatile and semi-volatile compounds. Enhancing spectral deconvolution and leveraging retention indices, together with accurate mass measurements from high-resolution GC/Q-TOF, significantly improves confidence in compound identification and structural elucidation.

Objectives and Study Overview

This work aimed to develop and demonstrate an integrated GC/MSD and GC/Q-TOF workflow for characterizing E&L compounds from rubber syringe gaskets. The study focused on optimizing chromatographic separation, enhancing sensitivity for both low- and high-boiling analytes, and applying spectral deconvolution, retention index matching, and accurate mass confirmation to expand compound coverage in a single compliance-enabled environment.

Methodology and Instrumentation

• Sample preparation: Rubber gaskets were extracted in tetrahydrofuran (THF) at room temperature over six months.
• Chromatography: Agilent 8890 GC with Agilent J&W DB-5Q and DB-5ms Ultra Inert columns; pulsed splitless injection and retention time locking ensured reproducible retention indices.
• Mass spectrometry: Agilent 5977C GC/MSD (unit resolution) and Agilent 7250 GC/Q-TOF (high resolution) operated under 70 eV and low-energy EI (15, 12, 10 eV) to enhance molecular ion signals.
• Data analysis: Agilent MassHunter Unknowns Analysis 12.1 with NIST23 library for spectral deconvolution and initial ID; ExactMass tool and Molecular Structure Correlator 8.2 for accurate mass confirmation and structural proposal.

Key Results and Discussion

Spectral deconvolution combined with retention index filtering enabled the reliable identification of over 80 compounds by both GC/MSD and GC/Q-TOF. The novel low-bleed DB-5Q column reduced background noise by an order of magnitude, enhancing detection of late-eluting analytes. High-resolution MS resolved coelutions and identified more than 60 additional compounds uniquely, while accurate mass data confirmed true positives and rejected false positives. Low-energy EI improved molecular ion detection, and targeted MS/MS experiments with MSC provided structure proposals for unknown peaks.

Benefits and Practical Applications

• Comprehensive profiling of extractables and leachables in pharmaceutical packaging and delivery systems.
• Improved sensitivity and selectivity via optimized chromatography and ultra-low bleed column technology.
• Enhanced identification confidence through combined library matching, retention index filtering, and accurate mass confirmation.
• Capability for structural elucidation of unknowns to support risk assessment and regulatory compliance.

Future Trends and Applications

Ongoing advancements in spectral deconvolution algorithms, expanded high-resolution mass spectral libraries, and integrated software workflows will streamline non-targeted E&L screening. Emerging ionization techniques and multidimensional GC methods may further improve detection of polar or thermally labile compounds. Integration of automation and machine learning is expected to accelerate data processing, enabling near real-time quality control and more comprehensive safety evaluations.

Conclusion

The combined GC/MSD and GC/Q-TOF approach presented here offers a robust, high-confidence workflow for analyzing extractables and leachables in complex matrices. By integrating spectral deconvolution, retention index time filtering, and accurate mass confirmation, this methodology significantly extends compound coverage and identification confidence, facilitating regulatory compliance and ensuring product safety.