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

Significance of the topic

Pharmaceutical products must meet strict safety standards, including limits on elemental (inorganic) impurities. Regulatory bodies such as the US Pharmacopeia (USP), ICH Q3D, and major global pharmacopoeias have harmonized requirements to replace older wet chemical tests with modern instrumental methods that offer specific, quantitative determination of individual elements in drug substances and products.

Objectives and study overview

This white paper outlines the requirements of USP <232>/<233> and ICH Q3D for elemental impurity analysis and presents the Agilent ICP-OES solution as a complete workflow. It covers risk assessment guidelines, permittable daily exposures (PDEs), sample preparation techniques, instrument selection criteria, and qualification strategies to ensure regulatory compliance.

Methodology and instrumentation

Sample preparation methods recommended in USP <233> include:

• Direct analysis or simple dilution/solubilization in aqueous or organic solvents.
• Closed-vessel microwave digestion using nitric and hydrochloric acids to stabilize all analytes, including volatile elements like mercury.

Key Agilent instrumentation and software:

• ICP-OES systems (5800 VDV and 5900 SVDV) featuring a vertical plasma torch for high matrix tolerance (up to 25% total dissolved solids).
• ICP-MS (7850) with Ultra High Matrix Introduction (UHMI) for lower detection limits and handling complex matrices.
• LC-ICP-MS for speciation analysis of arsenic and mercury species.
• ICP Expert software with Vista Chip III CCD detector, integrated 21 CFR Part 11/Annex 11 compliance modules, and automated J-value and QC calculations.
• Spectroscopy Database Administrator (SDA) and Configuration Manager (SCM) for secure data storage and user management.

Main results and discussion

The paper introduces the concept of the J-value, a target concentration derived from the PDE, sample dilution, and maximum daily dosage. Example calculations for Class 1 elements (Cd, Pb, As, Hg) demonstrate achievable ICP-OES detection limits relative to regulatory thresholds. A comparison of ICP-OES and ICP-MS highlights:

• Detection limits: ICP-MS offers ppt-level sensitivity, while ICP-OES benefits from greater matrix tolerance, reducing dilution needs.
• Throughput: ICP-OES can analyze up to ~2500 samples/day, approximately twice the rate of ICP-MS.
• Cost and ease of operation: Lower capital and maintenance costs for ICP-OES, with simplified method setup; ICP-MS provides flexibility for more demanding matrices.

Additional performance features such as in-method confirmation using multiple emission lines and the stability of the vertical torch are discussed, illustrating robust long-term precision in high-matrix samples.

Benefits and practical applications

Implementing the Agilent ICP-OES solution enables pharmaceutical laboratories to:

• Meet ICH Q3D and USP <232>/<233> requirements with validated workflows.
• Perform comprehensive risk assessment supported by direct analysis, component testing, or supplier risk data.
• Reduce sample preparation time using robust dilution and digestion protocols.
• Maintain instrument performance and compliance through automated IQ/OQ services and real-time system health monitoring.
• Ensure data integrity and traceability with certified reference materials (CRMs) traceable to NIST and 21 CFR Part 11 compliant software.

Future trends and potential applications

Advances in elemental impurities testing are likely to include:

• Greater automation of sample preparation and data analysis workflows.
• Expanded use of UHMI and high-matrix-tolerant ICP-MS for challenging excipients and complex formulations.
• Integration with laboratory information management systems (LIMS) and AI-driven quality control.
• Development of additional certified multielement standards tailored to various dosage forms.
• Enhanced speciation techniques for emerging contaminants and nanoparticle characterization.

Conclusion

The Agilent ICP-OES solution, combined with microwave digestion, certified reference standards, and compliance-focused software, provides a turnkey approach for elemental impurity analysis. It meets the sensitivity, robustness, and regulatory requirements of USP <232>/<233> and ICH Q3D, supporting pharmaceutical manufacturers in ensuring product safety and quality.

References

1. USP General Chapter <232>, “Elemental Impurities—Limits,” Pharmacopeial Forum, 2016.
2. USP General Chapter <233>, “Elemental Impurities—Procedures,” Pharmacopeial Forum, 2014.
3. ICH Guideline Q3D on Elemental Impurities, EMA/CHMP/ICH/353369/2013, July 2016.
4. L. Whitecotton, G. Gilleland, E. Kulikov, A. Liba, “Elemental Impurities in Aspirin: USP <232>/<233> and ICH Q3D Methods Using ICP-OES,” Agilent Technologies, Publication 5991-8337EN.