Analysis of Artificial Tear Eye Drops For Elemental Impurities

Significance of the Topic

Trace elemental impurities in pharmaceutical formulations pose significant risks to patient safety and product quality. Regulatory authorities including USP, ICH, Ph. Eur., CHP and JP require quantitation of 24 specific elements with defined permitted daily exposure (PDE) limits. Although ophthalmic solutions typically exhibit minimal systemic absorption, applying parenteral PDEs ensures a stringent safety margin for artificial tear products.

Objectives and Study Overview

This study evaluates a validated inductively coupled plasma mass spectrometry procedure for quantifying elemental impurities in sterile artificial tear eye drops. Key aims include demonstrating compliance with USP <232>/<233> and ICH Q3D(R2)/Q2(R1) performance criteria and assessing whether simple dilution negates the need for microwave digestion in this matrix.

Methodology and Instrumentation

Sample preparation employed both direct 200× dilution and microwave acid digestion (CEM Mars6) using a 9:1 HNO3–HCl matrix. Spikes at 0.5, 1.0 and 1.5 J levels (based on a 5 g/day dose) facilitated accuracy, precision and detectability studies. Calibration standards were prepared from a USP 232 parenteral kit combining 24 elements into three mixes for ease of use. Instrumentation comprised the Agilent 7900 ICP−MS with ORS4 octopole He collision cell, standard glass concentric nebulizer, quartz spray chamber and SPS 4 autosampler. Agilent ICP−MS MassHunter software provided preset USP/ICH methods and automated QC reporting.

Results and Discussion

• Accuracy: Recoveries for all elements at three spike levels fell within 93–102% of target.
• Precision: Repeatability RSDs were below 3%, ruggedness RSDs stayed below 2.7% across 12 independent replicates.
• Linearity and LOQ: Calibration coefficients (R2) exceeded 0.999 for all analytes; background equivalent concentrations were in low parts-per-trillion.
• Specificity: He collision mode effectively removed chlorine-based polyatomic interferences, and secondary isotopes served as qualifiers.
• Sample analysis: Undigested dilution provided concentrations at least two orders of magnitude below 0.5 J, indicating digestion is optional for this matrix.

Benefits and Practical Applications

The validated workflow offers a single-source solution from sample introduction through report generation, streamlining elemental impurity analysis in QA/QC laboratories. Use of standardized parenteral kits and preset software methods reduces setup time and potential for user error.

Future Trends and Opportunities

• Integration of automated sample preparation and online dilution for higher throughput.
• Coupling ICP-MS with high-resolution detectors to further improve specificity in complex matrices.
• Miniaturized and portable ICP-MS platforms for in-line process monitoring.
• Advanced chemometric tools and AI-driven data analysis for real-time compliance assessment.

Conclusion

The Agilent 7900 ICP-MS method demonstrated robust performance in accordance with USP and ICH guidelines for artificial tear formulations. Exceptional accuracy, precision, linearity and specificity were achieved with minimal sample preparation, supporting routine implementation in pharmaceutical laboratories.

References

• International Council for Harmonisation Q3D(R2) Guideline, April 2022.
• USP Elemental Impurities–Limits Chapter <232>, Pharmacopeial Forum 2016.
• ICH Validation of Analytical Procedures Q2(R1), Step 4, November 2005.
• USP Elemental Impurities–Procedures Chapter <233>, Pharmacopeial Forum 2014.
• Whitecotton L et al. Validation of Agilent 7800 ICP-MS for USP <232>/<233> and ICH Q3D/Q2(R2), Agilent Application Note 5991-8335EN, 2017.
• Wilbur S, McCurdy E. Using qualifier ions to validate multi-element ICP-MS data, Spectroscopy 25(5), 2010.