Elemental Impurity Analysis in Cutaneous and Transcutaneous Drug Products Using ICP-MS Based on ICHQ3D (R2)

Significance of the Topic

Topical and transcutaneous drug products can introduce elemental impurities through excipients such as oils and petrolatum. Adherence to ICH Q3D (R2) guidelines is crucial to ensure patient safety by controlling Permitted Daily Exposures (PDE) and cutaneous concentration limits (CTCL).

Objectives and Study Overview

This study evaluates the Shimadzu ICPMS-2030 system for quantifying class 1 and 2A elemental impurities (Cd, Pb, As, Hg, Co, V, Ni) in white petrolatum and heparinoid oil-based cream. The aim was to demonstrate compliance with Japanese Pharmacopoeia 18th Edition and ICH Q3D (R2), using a target concentration set at 10 % of the PDE.

Methodology

• Pretreatment: Samples (0.2 g) were digested with 5 mL HNO₃, 0.25 mL HCl, and 2 mL ultrapure water in an Anton Paar Multiwave 5000 microwave system, then diluted to 50 mL.
• Calibration Standards: Prepared at 0.5, 1.0, and 1.5 J (target concentration units) plus blank, with matrix-matched acidity.
• Spike Tests: Accuracy and precision verified by adding 0.5 J and 1.0 J spikes to samples.
• Internal Standards: Ga, Te, Y, Tl automatically added at 1:9 ratio via Shimadzu Automatic Internal Standard Addition Kit to correct for signal drift.

Used Instrumentation

• Anton Paar Multiwave 5000 Microwave Digestion Platform.
• Shimadzu ICPMS-2030: RF power 1.2 kW; plasma gas 9.0 L/min; auxiliary gas 1.1 L/min; carrier gas 0.7 L/min; Nebulizer 07UES; electronically cooled cyclone chamber; mini-torch; collision gas He.

Main Results and Discussion

• Unspiked samples: All target elements were below detection limits (<1.0 J), indicating low background contamination.
• Spike recoveries at 0.5 J and 1.0 J levels: 98–106 % (accuracy) with ≤2.6 % RSD (precision), meeting Japanese Pharmacopoeia acceptance criteria (70–150 % recovery, ≤20 % RSD).
• The detection limits remained well below the 10 % PDE target, confirming the system’s sensitivity for topical product analysis.

Benefits and Practical Applications

• Provides a sensitive, reliable workflow for controlling elemental impurities in topical and transdermal formulations.
• Facilitates regulatory compliance with ICH Q3D (R2) and Japanese Pharmacopoeia requirements in QA/QC laboratories.
• Enables efficient risk assessment and routine monitoring during formulation development and manufacturing.

Future Trends and Potential Uses

• Extension of the method to additional dosage forms and new impurity classes under evolving regulatory frameworks.
• Automation of sample preparation and data handling to increase throughput and reproducibility.
• Integration with advanced data analytics and real-time monitoring for proactive quality control in pharmaceutical production.

Conclusion

The Shimadzu ICPMS-2030 combined with microwave digestion and automated internal standard addition delivers robust elemental impurity analysis in topical drug products. The method achieves necessary sensitivity, accuracy, and precision to meet stringent regulatory limits, supporting patient safety and compliance.

References

1. Japanese Pharmacopoeia, 18th Edition, Ministry of Health, Labour and Welfare Notification No. 220 (2021).
2. ICH Q3D Guideline for Elemental Impurities (R2) Draft Version.