SCREENING FOR EXTRACTABLES AND LEACHABLES IN NASAL SPRAY DEVICES USING HIGH-RESOLUTION MASS SPECTROMETRY COMBINED WITH A DATA INDEPENDENT INFORMATICS STRATEGY

Importance of the Topic

Effective detection of extractables and leachables (E&L) in nasal spray devices is critical for patient safety and regulatory compliance. Chemical species migrating from container closure systems can pose health risks, and stringent screening protocols are required to meet global guidelines.

Goals and Study Overview

This study aimed to establish a unified workflow for comprehensive E&L screening in nasal spray container systems by combining ultra-performance liquid chromatography with high-resolution quadrupole time-of-flight mass spectrometry (UPLC-QTof HRMS) and a data-independent acquisition (DIA) informatics strategy. Three commercial nasal sprays were extracted under worst-case conditions and compared to procedural blanks to pinpoint migrating compounds.

Methodology and Used Instrumentation

Sample Preparation

1. Three nasal spray devices extracted with isopropanol at 40 °C for 72 h.
2. Procedural blank prepared and all samples injected in triplicate.

Chromatography
UPLC separation was performed on an ACQUITY Premier system with a CORTECS C18 column (2.1 × 100 mm, 1.6 µm) at 50 °C. A binary gradient of water with 1 mM ammonium acetate and 0.1 % formic acid (mobile phase A) versus methanol (mobile phase B) ran at 0.3 mL/min.
Mass Spectrometry
Analysis employed a Xevo G3 QTof with electrospray ionization in positive mode and MSE DIA acquisition. Source conditions included capillary voltage of 1.0 kV, desolvation temperature of 600 °C, and optimized gas flows. The UNIFI informatics platform managed data acquisition, system suitability testing, library screening, binary comparison, and structural elucidation within one customizable workflow.

Main Results and Discussion

• A tenfold increase in sensitivity and mass accuracies below 3 ppm enabled trace-level detection and confident compound identification.
• Simultaneous acquisition of precursor and fragment ions improved library matching and structural elucidation capabilities.
• Binary comparison against procedural blanks isolated sample-specific peaks above the analytical evaluation threshold (AET).
• The workflow tentatively identified a surfactant (m/z 368.4253) using accurate mass and fragment data, demonstrating its utility for unknown characterization.

Benefits and Practical Applications of the Method

• High sensitivity and mass accuracy satisfy regulatory screening levels for E&L studies.
• DIA acquisition consolidates screening and MS/MS characterization into a single run.
• An integrated informatics solution streamlines data processing, reduces analysis time, and minimizes false positives.

Future Trends and Potential Applications

Future developments may include integrating ion mobility for enhanced isomer separation and applying machine learning to predict E&L behaviors. The approach can be extended to other drug delivery systems and medical device materials, advancing patient safety and materials compliance.

Conclusion

The combined UPLC-QTof HRMS with DIA and a dedicated informatics workflow delivers a robust platform for comprehensive E&L screening in nasal spray devices. It provides high sensitivity, accurate mass measurement, and streamlined data analysis suitable for regulatory and quality assurance settings.

Reference

• United States Pharmacopeia. <1663> and <1664> Guidelines for Extractables and Leachables.
• ISO 10993-18:2020 Biological evaluation of medical devices – Chemical characterization.
• Norwood D., Paskiet D., Ruberto M., et al. Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products. Pharm Res. 2008;25:727–739.