Increased Identification Confidence for Extractables Screening Using the Xevo™ MRT Mass Spectrometer

Significance of the Topic

Screening for extractable compounds in pharmaceutical packaging and medical devices is essential to ensure patient safety and regulatory compliance. Trace levels of polymer additives and their degradation products can migrate into drug products, requiring confident identification and reporting when concentrations exceed analytical evaluation thresholds.

Objectives and Study Overview

This study evaluates the performance of the Xevo MRT Mass Spectrometer in a data-independent acquisition (DIA) workflow for extractables screening. It aims to demonstrate how sub-ppm mass accuracy for precursor and fragment ions enhances identification confidence and streamlines structural elucidation in complex sample matrices.

Methodology

Samples of plastic and foil packaging from antihistamine tablets were extracted in isopropanol at 50 °C for 24 hours and spiked with a standard extractables mixture. Separations were carried out on an ACQUITY Premier C18 column using a water/methanol gradient. The Xevo MRT Mass Spectrometer operated in positive ESI mode with alternating low- and high-energy scans (MSE) over m/z 50–1200. Data acquisition and processing employed the waters_connect Software with the UNIFI application; multivariate analyses were performed in EZInfo 3.0.

Employed Instrumentation

• LC system: ACQUITY Premier with CORTECS C18 column (2.1 × 100 mm, 1.6 μm) at 50 °C, 0.3 mL/min flow.
• Mass spectrometer: Xevo MRT with quadrupole-multi-reflecting TOF, achieving up to 100 000 FWHM at 50–100 Hz scan rates.
• Ionization: ESI positive, source 120 °C, desolvation 550 °C, cone voltage 40 V, collision energy 6 eV (low) and 20–40 eV (high).
• Software: waters_connect with UNIFI for automated workflows; EZInfo for PCA and OPLS-DA.

Main Results and Discussion

System suitability checks with the extractables standard showed an RMS mass error of 0.81 ppm across injections. The MSE approach aligned precursor and fragment ions precisely by retention time, reducing false positives and narrowing candidate lists. Screening against an E&L library using accurate mass, retention time, and fragment matching further improved confidence. The Binary Compare tool highlighted sample-specific features versus blanks, and custom filters (fragment count, mass error, elevation above control) reduced candidate matches by up to 80 % at ±5 ppm and a further 60 % at ±1 ppm. Trend plots tracked compound levels across packaging types. Multivariate analyses (PCA and OPLS-DA) distinguished extraction profiles and identified differential markers. The UNIFI Discovery Tool combined elemental composition scoring, database searching, and in silico fragmentation to propose structures—e.g., diethyl phthalate and N,N′-1,12-dodecanediyldidodecanamide with mass errors below 1 ppm.

Benefits and Practical Applications

• Consistent low- to sub-ppm mass accuracy across a broad m/z range.
• DIA/MSE acquisition delivers both precursor and fragment data for confident identifications and structural elucidation.
• Automated UNIFI workflows and filtering tools reduce analyst workload and false positives.
• Statistical and trend-plot modules enable robust QA/QC monitoring of packaging materials.

Future Trends and Potential Applications

Advances may include integration of artificial-intelligence-driven spectral interpretation, expansion of curated extractables libraries, coupling with ion mobility separations for multidimensional characterization, and real-time monitoring of leachables during manufacturing and storage.

Conclusion

The combination of the Xevo MRT Mass Spectrometer’s high-resolution, sub-ppm mass accuracy and the DIA/MSE acquisition strategy provides a powerful, streamlined workflow for extractables screening. When paired with the UNIFI application and multivariate tools, it delivers rapid, reliable compound identification and structural elucidation, significantly reducing false positives and analytical burden.

Reference

1. USP-NF/PF. Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, Chapter 1664.
2. USP-NF/PF. Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, Chapter 1663.
3. Norwood D. et al. Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products, Pharm. Res. 25, 727–739 (2008).
4. ISO 10993-18:2020 Biological evaluation of medical devices – Part 18: Chemical Characterization of Medical Device Materials.
5. Plumb R. S. et al. UPLC/MSE; Rapid Commun. Mass Spectrom. 20(13), 1989–1994 (2006).