Getting the most out of your Extractables and Leachables LC/MS Analysis with the Proposed US FDA CDRH CLAP Standard Set

Importance of the Topic

Non-targeted extractables and leachables (E&L) analysis by LC/MS is a cornerstone of safety risk assessments for medical devices and drug-delivery products. Regulatory bodies such as the US FDA CDRH require comprehensive chemical characterization to ensure patient safety and product performance.

Objectives and Study Overview

This study aimed to adapt and optimize the US FDA CDRH Chemicals List for Analytical Performance (CLAP) LC/MS method for the Agilent Revident LC/Q-TOF platform. Key goals included enhancing sensitivity, improving compound coverage at lower concentrations, and achieving robust, reproducible data for a diverse set of 82 standard compounds.

Methodology

Standard mixtures of 82 CLAP analytes were prepared at 0.2, 0.5, and 1 ppm. Chromatographic variables compared included mobile phase B solvents (methanol vs. acetonitrile), additives (formic acid, ammonium formate, ammonium fluoride) and the use of a solvent delay column to separate sample analytes from background contaminants.

Used Instrumentation

• Agilent 1290 Infinity III LC system
• Agilent Poroshell 120 Aq-C18 analytical column (2.1 × 150 mm, 2.7 μm)
• Agilent Poroshell 120 EC-C18 delay column (4.6 × 50 mm, 2.7 μm)
• Agilent Revident LC/Q-TOF with Dual AJS ESI source

Main Results and Discussion

Use of methanol-based mobile phase with ammonium formate and formic acid significantly improved signal responses, especially for ammonium adduct-forming analytes. Adding ammonium fluoride further enhanced sensitivity by reducing sodium adducts. The superficially porous Poroshell 120 Aq-C18 column improved retention of early-eluting polar compounds and resolved near-eluting isomers. Employing a solvent delay column effectively separated true sample peaks from solvent contaminants. Overall, 79 CLAP analytes were detected at 1 ppm on Revident LC/Q-TOF versus only 49 analytes at 10 ppm using the original FDA method.

Benefits and Practical Applications

• Enhanced detection limits and broader analyte coverage support more confident safety assessments
• Improved isomer separation and reduced background interference increase data quality
• Robust methodology suitable for regulatory submissions and QA/QC workflows

Future Trends and Potential Applications

Advances may include integration of Artificial Intelligence for spectral deconvolution, further exploration of novel column chemistries for challenging polar analytes, and harmonization of global regulatory standards. High-resolution platforms coupled with optimized workflows will continue to expand the detectable chemical space in E&L studies.

Conclusion

The optimized method on Agilent Revident LC/Q-TOF demonstrates marked improvements in sensitivity, specificity, and analyte coverage for non-targeted E&L profiling. Key innovations in solvent selection, column design, and use of a solvent delay column deliver a robust workflow suitable for stringent regulatory and research applications.

References

• United States Food and Drug Administration Center for Devices and Radiological Health. Chemicals List for Analytical Performance (CLAP), 2025.