USP <232>/<233> and ICH Q3D Elemental Impurities Analysis: The Agilent ICP-MS Solution

Significance of the Topic

Worldwide regulatory updates have replaced traditional wet chemistry heavy metal tests with quantitative instrumental methods. Ensuring compliance with ICH Q3D and USP <232>/<233> standards for elemental impurities is essential to assess drug safety, manage patient exposure, and meet global pharmaceutical regulations.

Objectives and Study Overview

This white paper describes an integrated workflow for elemental impurity analysis in pharmaceuticals according to ICH Q3D and USP <232>/<233> guidelines. It highlights how Agilent ICP-MS and ICP-OES instruments, sample preparation techniques, software tools, and certified reference materials streamline method implementation and regulatory compliance.

Methodology and Instrumentation

• Regulatory framework: ICH Q3D and USP <232>/<233> define Permitted Daily Exposure limits based on toxicity and administration route (oral, parenteral, inhalational).
• Sample preparation: direct analysis; aqueous and organic solvent dilutions; closed-vessel microwave digestion with nitric and hydrochloric acids to stabilize volatile mercury and platinum group elements.
• Instrumentation: Agilent 7850/7900 ICP-MS featuring robust low-oxide plasma; Ultra High Matrix Introduction tolerating up to 25% dissolved solids; ORS4 helium collision cell for interference removal; 10+ order dynamic range. Agilent 5800 ICP-OES offers high throughput and matrix tolerance. LC-ICP-MS enables arsenic and mercury speciation.
• Software: ICP-MS MassHunter with pre-set methods for ICH/USP/ChP, automated system optimization, QC checks against J-values, and report templates for performance qualification and statistical validation.
• Standards and compliance: Agilent ICH/USP certified reference materials traceable to NIST covering Class 1–3 elements; User Access Control and OpenLab Shared Services for FDA 21 CFR Part 11 compliance; Agilent CrossLab services for installation, qualification, and maintenance.

Main Results and Discussion

The Agilent workflow enables accurate quantitation of elemental impurities at or below required PDE limits. Instrument detection limits reach low parts per trillion, supporting high dilution factors and small sample sizes. ICP-MS delivers lower detection limits and broad applicability across dosage forms; ICP-OES offers higher sample throughput when detection requirements allow. Integrated speciation for inorganic arsenic and mercury ensures compliance. Software automation and qualification packages simplify method validation, routine QC, and GMP data integrity.

Benefits and Practical Applications

• Rapid implementation of ICH/USP and ChP elemental impurity methods in pharmaceutical QC labs.
• Flexible sample preparation and instrument configurations to handle diverse matrices and dosage forms.
• High sensitivity and wide dynamic range enable simultaneous analysis of major and trace elements.
• Automated workflows and pre-configured methods reduce training requirements and risk of operator error.
• Comprehensive compliance tools ensure electronic record integrity and audit readiness under 21 CFR Part 11.
• Agilent CrossLab services support installation, qualification, and ongoing maintenance for sustained performance.

Future Trends and Potential Applications

Advances in triple quadrupole ICP-MS technology will enhance interference removal and lower detection limits for challenging elements. Increased automation and connectivity will support real-time monitoring of manufacturing processes. Expanded speciation capabilities will enable deeper understanding of bioavailability and toxicity of trace elements, while integration with data analytics and AI will improve risk assessment and regulatory compliance workflows.

Conclusion

The Agilent ICP-MS and ICP-OES solution offers a complete, compliant workflow for elemental impurity testing in pharmaceuticals. Combining robust sample preparation, high-performance instrumentation, certified standards, software automation, and qualification services accelerates method deployment and ensures reliable, regulatory-compliant results across all dosage forms.

References

1. Pharmacopeial Forum. Elemental Impurities—Limits, General Chapter <232>, revision 42(2), 2016.
2. Pharmacopeial Forum. Elemental Impurities—Procedures, General Chapter <233>, revision 40(2), 2014.
3. ICH Guideline Q3D on Elemental Impurities, EMA/CHMP/ICH/353369/2013, July 2016.
4. Dhuria RS, Jain V, Kapadnis G, Vyas S. Determining Elemental Impurities using USP/ICH and ICP-MS. Agilent Technologies, 5991-7674EN, 2017.
5. Whitecotton L et al. Validating Agilent 7800 ICP-MS for USP <232>/<233> and ICH Q3D/Q2(R1) Elemental Impurity Analysis. Agilent Technologies AN 5991-8335EN, 2017.
6. Sanderson J, Whitecotton L. Elemental Impurity Analysis of Artificial Tear Eye Drops on Agilent 7900 ICP-MS. AN 5994-1561EN, 2019.