Validation of quantitative method for determination of elemental impurities in pharmaceutical products following USP 232/233 on ICPMS-2030

Significance of the Topic

Elemental impurities in pharmaceutical products can undermine patient safety, impact drug stability and efficacy, and must be strictly controlled. The transition from colorimetric heavy metal tests to instrument-based quantification ensures accurate monitoring of 24 critical elements, aligning with modern regulatory requirements.

Objectives and Study Overview

This study validates a streamlined ICP-MS method for quantifying the 24 elemental impurities defined in USP<232> across three common dosage forms: capsules, tablets and liquids. It follows the sample preparation and validation protocols outlined in USP<233>, aiming to demonstrate reliable detection below Permitted Daily Exposure (PDE) limits while maximizing throughput.

Methodology and Instrumentation

The analysis employs closed-vessel microwave digestion to minimize loss of volatile elements, using a mixture of nitric acid, hydrochloric acid and hydrogen peroxide. Digested samples are diluted to matrix conditions of 2% HNO3 and 0.5% HCl, spiked with Sc, Y and Bi as internal standards.

Used Instrumentation

• ICP-MS: Shimadzu ICPMS-2030 with single He collision mode
• Microwave digestion: Milestone Ethos Easy
• Autosampler: Shimadzu AS-10

Main Results and Discussion

Calibration across all 24 elements yielded correlation coefficients ≥0.9994 over concentration ranges based on PDE calculations. Limits of detection and quantification were orders of magnitude below regulatory thresholds. In three tested drug samples:

• Most elements were not detected or fell well under calculated J values.
• Vanadium, nickel and antimony appeared at low µg/L levels but remained compliant.

Validation metrics showed:

• System suitability drift <5% for all analytes.
• Precision with repeatability and ruggedness RSD <2.5%.
• Accuracy with spike recoveries between 81% and 115%.
• Detectability ratios within USP<233> criteria.

Benefits and Practical Applications

This single-mode ICP-MS approach simplifies operation, reduces method development time, and enhances sample throughput for routine quality control in pharmaceutical manufacturing. Its low detection limits and robust validation support compliance with global regulatory standards.

Future Trends and Potential Applications

Advances in collision/reaction cell technology and high-throughput sample handling will further streamline impurity profiling. Integration with automated data processing and extended element panels could broaden applications in biologics, environmental monitoring and food safety.

Conclusion

The validated ICPMS-2030 method, paired with closed-vessel microwave digestion, offers a reliable, efficient solution for quantifying elemental impurities in pharmaceuticals. It meets USP<233> requirements and facilitates compliance with USP<232> limits, ensuring patient safety and product quality.

References

1. USP General Chapter <232> Elemental Impurities – Limits, USP 40-NF 35, 2017
2. USP General Chapter <233> Elemental Impurities – Procedures, USP 38-NF 33, 2015
3. Wang T.; Wu J.; Hartman R.; Jia X.; Egan R.S. A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials. J. Pharm. Biomed. Anal. 2000, 23(5):867-890