BMSS: ADDRESSING THE CHALLENGES OF EXTRACTABLES AND LEACHABLES SCREENING USING HIGH-RESOLUTION QUADRUPOLE TIME OF FLIGHT

Significance of the Topic

Monitoring extractables and leachables released from pharmaceutical packaging and medical devices is essential to ensure patient safety and regulatory compliance. These low-level migrants, including polymer additives, impurities and degradation by-products, can pose toxicological risks if undetected. High-resolution mass spectrometry combined with optimized data workflows addresses the need for sensitive, comprehensive screening and quantitation in a single analytical platform.

Objectives and Study Overview

The study aimed to demonstrate an integrated screening and quantitation strategy for extractables and leachables using liquid chromatography–quadrupole time-of-flight high-resolution mass spectrometry. By applying a customized UNIFI E&L workflow, the method was evaluated on commercial nasal spray devices to identify potential migrants, perform structural elucidation and quantify selected analytes alongside effective library matching.

Methodology

Sample preparation involved extraction of nasal spray container closure components with isopropanol at 40 °C for 72 hours alongside neat solutions and procedural blanks. Extracts were spiked with an internal standard (metafluzimone) and analyzed in triplicate. System suitability tests using a standard E&L mix verified sensitivity, reproducibility and mass accuracy. Data processing employed an E&L-specific workflow in UNIFI with analytical evaluation threshold (AET) filtering, binary comparison and structural elucidation tools to streamline feature selection and compound identification.

Instrumentation

• Liquid Chromatography: ACQUITY Premier System with CORTECS C18 column (2.1 × 100 mm, 1.6 μm); gradient from 2% to 99% methanol over 13 min at 0.3 mL/min; column temperature 50 °C; injection volume 1 μL.
• Mass Spectrometry: Xevo G3 QTof MS operated in positive and negative electrospray ionization with MSE acquisition (m/z 50–2000); low-energy 6 eV and high-energy ramps (20–40 V for ESI+; 30–70 V for ESI-); source at 120 °C; desolvation at 600 °C.
• Data System: UNIFI Application within waters_connect platform for acquisition, system suitability, library search, AET filtering, binary comparison and structural elucidation.

Key Results and Discussion

Optimized ion optics and detector achieved a tenfold sensitivity increase with retention time repeatability of 0.01% RSD. Mass errors for all detected compounds were below 3 ppm, enhancing library matching and elemental composition calculations. A unique surfactant at m/z 368.4253 was tentatively identified via the UNIFI elucidation toolkit. Hexadecylamine was detected exclusively in extracted samples and neat solutions above the procedural blank. Quantitative workflows using metafluzimone yielded a calibration range from 5 to 1000 ng/mL (R²=0.999) and internal standard levels within 8% of true values. Semi-quantitation of Irganox 1010 using response factors delivered under 5% deviation. MSE acquisition provided concurrent precursor and fragment ion data, improving confidence in structural assignments.

Benefits and Practical Applications

• Single-platform screening and quantitation reduce analysis time and complexity.
• High sensitivity meets regulatory E&L thresholds for trace-level detection.
• MSE data acquisition and UNIFI workflows streamline unknown identification and structural elucidation.
• Customizable reporting and AET filtering support diverse regulatory requirements.

Future Trends and Applications

Anticipated advances include integration of machine learning for automated feature prioritization, expanded compound libraries for wider coverage, and real-time risk assessment through data analytics. Broader adoption of HRMS platforms across pharmaceutical and device industries will drive enhanced safety evaluations and more rapid regulatory submissions.

Conclusion

The LC-QToF HRMS approach coupled with a unified E&L workflow delivers robust, sensitive and accurate screening plus quantitation of extractables and leachables. High resolution, precise mass measurement and comprehensive data processing enable confident identification and quantitation in complex matrices, supporting regulatory compliance and patient safety.

Reference

• Food and Drug Administration. Analytical Procedures and Methods Validation for Drugs and Biologics Guidance for Industry. 2015.
• Product Quality Research Institute. Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products. 2021.
• ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process.
• Waters Corporation. Elucidation Toolkit in the UNIFI Scientific Information System for Identifying Unknown Compounds. 2014.
• Engel, J. What Is a Response Factor? Chromatography Today.