IMSC: ENSURING CONFIDENT ANALYSIS OF EXTRACTABLES AND LEACHABLES USING HIGH-RESOLUTION QUADRUPOLE TIME OF FLIGHT TECHNOLOGY

Importance of the Topic

Extractables and leachables (E&L) are chemical substances migrating from pharmaceutical packaging and medical devices into drug products, posing potential safety risks. High-resolution analytical methods are essential to detect trace-level E&L compounds to ensure patient safety and regulatory compliance.

Objectives and Study Overview

This study demonstrates a streamlined workflow using liquid chromatography coupled to a high-resolution quadrupole time-of-flight mass spectrometer (LC-QToF HRMS) for simultaneous screening and quantitation of E&L in nasal spray products.

Methodology and Used Instrumentation

Sample preparation involved extracting container closure systems with isopropanol at 40 °C for 72 hours, alongside analysis of neat solutions and procedural blanks. An internal standard (metafluzimone) was spiked for quantitation.

• Liquid chromatography: ACQUITY Premier UPLC system with CORTECS C18 column (2.1×100 mm, 1.6 μm), gradient of water and methanol with ammonium acetate and formic acid, flow rate 0.3 mL/min.
• Mass spectrometry: Xevo G3 QTof operated in MSE mode with ESI in positive and negative ionization, acquisition range m/z 50–2000, accurate mass < 3 ppm error.
• Data processing: UNIFI Application tailored for E&L workflows, including system suitability testing, automated screening against libraries, trend plots, and quantitation using calibration curves and response factors.

Main Results and Discussion

System suitability testing showed a tenfold increase in sensitivity and retention time precision (RSD 0.01%). Screening identified unique E&L compounds such as surfactants at m/z 368.4253 using structural elucidation tools. Calibration curves for the internal standard were linear over four orders of magnitude (R² 0.999), enabling quantitation within 8% accuracy. Semi-quantitative analysis of antioxidants like Irganox 1010 achieved within 5% of expected values.

Benefits and Practical Applications

• High sensitivity and mass accuracy facilitate confident identification of trace-level E&L components.
• Combined screening and quantitation on a single platform streamlines E&L analysis workflows.
• Customizable E&L workflows in UNIFI enable compliance with regulatory thresholds and efficient data interpretation.

Future Trends and Opportunities

Advancements in ion optics and data processing are expected to further improve sensitivity and throughput. Integration of predictive libraries and machine learning may enhance structural elucidation and semi-quantitative estimations. The platform’s flexibility suggests broader adoption for diverse polymer materials and biocompatibility studies.

Conclusion

The LC-QToF HRMS workflow coupled with UNIFI software provides a robust solution for confident, high-throughput screening and quantitation of extractables and leachables, meeting regulatory requirements and ensuring product safety.

Reference

1. FDA Guidance for Analytical Procedures and Methods Validation for Drugs and Biologics, 2015.
2. PQRI Safety Thresholds and Best Practices for E&L in Parenteral Products, 2021.
3. ISO 10993-18:2020 – Chemical Characterization of Medical Device Materials.