Validating performance of an Agilent ICP‑MS for USP <232>/<233> & ICH Q3D(R2)/Q2(R1)

Significance of the topic

Elemental impurities in pharmaceuticals pose potential health risks and must be controlled under modern regulatory standards. The ICH Q3D(R2) and USP<232>/<233> guidelines define stringent permitted daily exposure limits for multiple elements. Validated ICP-MS methods can streamline compliance, reduce development time and cost, and improve data reliability.

Objectives and overview of the study

This study evaluates the performance of Agilent 7800 and 7850 ICP-MS systems against USP<232>/<233> and ICH Q3D(R2) requirements. It demonstrates that a predefined helium collision cell protocol can deliver the sensitivity, specificity, accuracy and precision needed for elemental impurity testing across diverse pharmaceutical matrices.

Methodology and instrumentation

Pharmaceutical grade hypromellose and sodium carbonate samples were prepared by acid digestion or room temperature solubilization. Samples were spiked at parenteral PDE levels (0.5 J, 0.8 J, 1.0 J, 1.5 J) and analyzed after addition of internal standards. Calibrations covered Class 1, Class 2A, Class 2B and Class 3 elements. System suitability and validation tests for limit and quantitative procedures were conducted according to ICH Q2(R1) and USP<233>. 

Instrumentation used

An Agilent 7800 ICP-MS with standard glass concentric nebulizer, quartz spray chamber and ORS4 octopole collision cell in helium mode was employed. Method parameters were predefined in the Agilent ICP-MS MassHunter software. Additional tests used Agilent 7850 and 7900 instruments to confirm intermediate precision.

Main results and discussion

Method detection limits for all 24 target elements were in the low ppt range, well below required PDE concentrations after dilution. Helium mode efficiently removed chloride-based polyatomic interferences, enabling HCl sample stabilization. System drift remained under the 20 percent limit across nine-hour runs. Limit procedures at 0.8 J and 1.0 J spikes achieved recoveries within ±15 percent and RSDs below 2 percent. Quantitative tests over 0.5 J to 1.5 J spikes yielded recoveries between 70 percent and 150 percent and linear calibrations with ng/L limits of quantification. Repeatability and ruggedness RSDs were well under the 20 percent and 25 percent acceptance criteria, confirming robustness across operators and instruments.

Benefits and practical applications

Agilent ICP-MS predefined workflows accelerate method setup, reduce validation burden and ensure compliance with USP/ICH standards. Helium collision cell technology simplifies interference management and allows use of standard acids. High matrix tolerance and wide dynamic range enable analysis of complex matrices and seamless coupling with HPLC for arsenic and mercury speciation. Laboratories benefit from faster turnaround, lower cost and high confidence in impurity data.

Future trends and potential applications

Advances in collision cell design and sample introduction are expected to further enhance sensitivity, precision and matrix tolerance. Integration with automated sample preparation and on-line separation will increase throughput and support speciation analysis. Emerging high-resolution ICP-MS and multi-collector techniques may further improve isotope confirmation in challenging pharmaceutical matrices.

Conclusion

The Agilent 7800 and 7850 ICP-MS platforms fully meet ICH Q3D(R2) and USP<232>/<233> requirements for elemental impurity testing. Helium collision mode, robust plasma and workflow software streamline validation and routine analysis. These systems deliver reproducible low-level detection, accurate quantification and consistent performance across extended runs and varied operators.

References

1. International Council for Harmonisation Guideline Q3D R2 April 2022
2. USP General Chapter 232 Revision Pharmacopoeial Forum 2016
3. USP General Chapter 233 Revision Pharmacopoeial Forum 2014
4. ICH Q2 R1 Validation of Analytical Procedures November 2005
5. Hussain Liba and McCurdy Agilent 7700x ICP-MS validation 2011