Determination of Extractable and Leachable Elements Using ICP-MS

Significance of the Topic

The assessment of extractable and leachable (E&L) elemental impurities from ophthalmic plastic containers under extreme and real-world conditions is essential to safeguard patient health. Metallic contaminants may compromise drug stability, efficacy, and pose direct toxicity risks, especially in sensitive applications such as eye drops.

Study Objectives and Overview

This application note presents a systematic study of elemental impurities released from low-density polyethylene (LDPE) eye drop bottles. The goals were to:

• Quantify extractable elements under harsh extraction conditions (acidic, basic, and organic solvents, with and without heat or sonication)
• Measure leachable metals in actual eye drop solutions following storage and stress simulating extended shelf life
• Demonstrate compliance with global pharmacopeial guidelines (USP<232>/233 and ICH Q3D)

Methodology and Instrumentation

Extractions:

• Acidic: 0.01 M KCl + 0.003 M HCl, pH 2.29
• Basic: phosphate buffer, pH 9.47
• Organic: 50:50 isopropyl alcohol/water
• Stress conditions: heating to 120 °C and sonication at 55 °C for three days

Sample preparation and QC:

• Calibration standards (0.01–10 ppb) and internal standards (6Li, 45Sc, 72Ge, 89Y, 115In, 159Tb, 209Bi)
• Continuing calibration blanks and verifications every ten samples
• Spike recoveries and low/mid-level QC to verify accuracy and precision

Instrumentation:

• Agilent 7900 ICP-MS with ORS4 collision/reaction cell in He KED mode
• Glass concentric nebulizer, quartz double-pass spray chamber, UHMI system, Ni cones
• Autosampler SPS 4 and automated MassHunter tuning

Main Results and Discussion

Method performance:

• Calibration linearity with R=1.0000 for key elements (As, Cd, Hg, Pb)
• Instrument detection limits at sub-ppt levels; LOQs down to 0.0001 µg/L
• QC and spike recoveries within ±20 %

Leachables in eye drop solution:

• Most elements remained below LOQ in as-supplied and stressed samples
• Minor increases in Li, Fe, Mn, Sr, Cs under heat or sonication, but all below parenteral J values

Extractables from empty bottles:

• Significant release of Zn and Fe under acidic and basic heated conditions (up to 106 µg/kg Zn)
• Trace levels of Ni, Rb, Zr, Nb, Ba, W, U under specific solvent/temperature combinations
• Extraction profiles varied markedly with pH, solvent polarity, and stress

Benefits and Practical Applications

The Agilent 7900 ICP-MS method delivers rapid, sensitive, multi-element analysis suitable for routine E&L monitoring in pharmaceutical packaging. It supports:

• Regulatory compliance with USP<232>/233 and ICH Q3D requirements
• Risk assessment of container-closure systems for ophthalmic and parenteral formulations
• High-throughput workflows with robust QC controls

Future Trends and Potential Uses

Advances in collision/reaction cell technology and high-matrix introduction aim to further improve detection limits and reduce sample preparation. Emerging directions include:

• Automated E&L screening across diverse single-use systems
• Integration with non-targeted organic impurity analysis for a comprehensive safety profile
• Data analytics and machine learning to predict extractable profiles based on container material properties

Conclusion

The study confirms the Agilent 7900 ICP-MS as a reliable platform for low-level elemental impurity analysis in ophthalmic packaging. While all detected levels were within safe exposure limits, stress-induced release of Fe and Zn highlights the need for thorough E&L evaluation under simulated worst-case conditions.

Reference

1. US FDA Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics
2. USP Chemical Tests Elemental Impurities—Limits (USP<232>) and Procedures (USP<233>)
3. ICH Q3D Guideline on Elemental Impurities
4. PQRI Leachables and Extractables Working Group
5. Sanderson J., Whitecotton L. Elemental Impurity Analysis of Sterile Artificial Tear Eye Drops on Agilent 7900 ICP-MS