Analysis of pharmaceutical products for their elemental impurities with the Thermo Scientific iCAP RQ ICP-MS

Significance of the Topic

The control of elemental impurities in pharmaceutical products is critical to patient safety and drug stability. Recent revisions to United States Pharmacopeia General Chapters <232> (Limits) and <233> (Procedures) mandate more specific, sensitive tests for 15 regulated elements. Reliable analytical methods are needed to ensure compliance, maintain product quality, and support regulatory audits under FDA 21 CFR Part 11.

Objectives and Study Overview

This application note demonstrates the use of the Thermo Scientific iCAP RQ single quadrupole ICP-MS to accurately measure trace levels of elemental impurities in three pharmaceutical products. Goals included:

• Preparing samples via closed-vessel microwave digestion.
• Adhering to USP <232> limit criteria and USP <233> procedural requirements.
• Implementing FDA 21 CFR Part 11–compliant data acquisition and management.

Methodology

Samples of a phytotherapeutic, a cardiovascular medication, and an antianxiety drug (0.5 g each) were digested in an UltraWAVE closed vessel system under 40 bar N₂ at 200 °C using nitric acid (and sulfuric acid for one matrix). Digests were cooled, diluted to 50 mL, then further diluted 1:5 into a 1.2 % HNO₃/0.5 % HCl solution containing 200 μg·L⁻¹ gold, yielding a total sample dilution of 500. Calibration standards at blank, 0.5 J and 2 J (where J = target limit) were prepared in the same matrix. Internal standards (Ga, In, Tl) were introduced online.

Instrumentation

Thermo Scientific iCAP RQ single quadrupole ICP-MS with Qtegra Intelligent Scientific Data Solution software provided:

• High-sensitivity detection in single-mode and helium KED for interference removal.
• Comprehensive audit trails and electronic signature support for FDA 21 CFR Part 11 compliance.
• Automated calibration, drift correction, and reporting workflows.

Main Results and Discussion

Calibration curves for all elements were linear at sub-ng·g⁻¹ levels. Instrument detection limits were in the single-digit pg·g⁻¹ range, and method detection limits (MDLs) were at least 50-times below USP target limits. Analysis of six replicates per drug showed no element exceeding its limit; several were below MDL. Drift tests over three hours yielded relative differences below 20 %.

Validation according to USP <233> included:

• Accuracy: Spike recoveries at 0.5 J and 1.5 J ranged from 92 % to 128 % (acceptance 70–150 %).
• Precision: Six replicates at target limits showed RSDs < 20 %.
• Ruggedness: Triplicate runs on separate days gave RSDs < 25 % across all elements.

Benefits and Practical Applications

The iCAP RQ ICP-MS workflow offers:

• Exceptional sensitivity to quantify impurities well below regulatory thresholds.
• Universal sample digestion preserving volatile elements (e.g., mercury).
• Streamlined data integrity features supporting secure, auditable results.

These capabilities enable pharmaceutical laboratories to reliably enforce elemental impurity control throughout development and manufacturing.

Future Trends and Possibilities for Utilization

Advancements likely to shape elemental impurity testing include:

• Integration of high-resolution and tandem ICP-MS for speciation and complex matrices.
• Automation and miniaturization of sample digestion and introduction.
• Enhanced data analytics and machine learning for predictive quality control.
• Global harmonization of impurity thresholds and expanded element panels.

Conclusion

This study confirms that the Thermo Scientific iCAP RQ ICP-MS, combined with closed-vessel microwave digestion, exceeds USP <232>/<233> requirements. The method achieves low MDLs, robust validation performance, and full data integrity under FDA 21 CFR Part 11. Pharmaceutical labs can invest in this platform to future-proof their elemental impurity testing.

References

• United States Pharmacopeia. General Chapter <232> Elemental Impurities – Limits.
• United States Pharmacopeia. General Chapter <233> Elemental Impurities – Procedures.
• U.S. Food and Drug Administration. 21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule.