The Next Frontier In Extractable Screening Analyses: Increased Identification Confidence Provided by a Benchtop Multi-Reflecting Time-of-Flight Mass Spectrometer

Importance of the Topic

With growing concerns about potential extractables from plastic packaging and medical devices migrating into pharmaceutical products, reliable screening methodologies are essential to ensure patient safety and meet regulatory thresholds for toxicological assessment.

Objectives and Study Overview

This study evaluates the performance of a benchtop multi-reflecting time-of-flight mass spectrometer in extractables screening. It aims to demonstrate how high mass accuracy and resolution for both precursor and fragment ions enhance identification confidence and reduce false positives.

Methodology

Sample preparation involved thermal extraction of three types of plastic packaging in isopropanol at 50 °C for 24 hours, with negative controls and pooled quality controls spiked with a standard extractables mixture. Data were acquired in MSE mode, allowing simultaneous collection of precursor and fragment ion information. Statistical analyses using PCA and OPLS-DA were conducted to highlight significant markers and reduce candidate lists.

Instrumentation

The analytical platform comprised an ACQUITY Premier UPLC with a CORTECS C18 column and a Waters Xevo MRT time-of-flight mass spectrometer operated in positive electrospray ionization. Key settings included 0.3 mL/min flow rate, column temperature at 50 °C, acquisition range m/z 50–1200, and high-energy ramp collision energy of 20–40 eV. Data processing utilized the waters_connect platform, UNIFI Application, and EZInfo software.

Main Results and Discussion

The method delivered excellent reproducibility and mass accuracy with RMS errors below 1 ppm for both precursor and fragment ions. Statistical filtering and high-resolution data enabled clear discrimination of extractables, such as diethyl phthalate and bis(2-ethylhexyl) adipate, with significantly reduced false positives and enhanced confidence in compound identifications.

Benefits and Practical Applications

This approach streamlines extractables screening by combining accurate mass fragmentation data with statistical and software-driven filtering, reducing potential candidate matches and analysis time. It is particularly valuable for quality control in pharmaceutical packaging and medical device evaluation.

Future Trends and Opportunities

Advancements may include integration of ion mobility separation, expansion of high-confidence spectral libraries, enhanced in-silico fragmentation tools, and greater automation via artificial intelligence to further increase throughput and identification certainty.

Conclusion

The benchtop multi-reflecting TOF mass spectrometer demonstrates superior mass accuracy and resolution in extractables screening, improving identification confidence and operational efficiency in compliance-driven analytical workflows.

References

• USP-NF/PF <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems.
• USP-NF/PF <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems.
• Stevens D., Cabovska B., Bailey A. Detection and Identification of Extractable Compounds from Polymers. Waters Application Note 720004211 (2012).
• ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterization.
• McCullagh M. et al. Ion Mobility-Enhanced Mass Spectrometry Libraries. Application Note 720007655 (2022).
• Cabovska B. Screening Workflow for Extractable Testing Using UNIFI. Technical Note 720005688 (2016).