Proposed new ICH and USP methods for elemental impurities: The application of ICP-MS and ICP-OES for pharmaceutical analysis

Significance of the Topic

Modern pharmaceutical products must meet ever-stricter safety standards for elemental impurities, due to their potential toxicity, impact on drug stability, and patient health. The existing USP<231> “heavy metals limit test”, a colorimetric sulfide precipitation assay over 100 years old, has well-documented shortcomings, including lack of specificity, high variability, poor sensitivity, and inability to quantify individual elements. To address these issues, ICH Q3D and USP General Chapters <232> (Limits) and <233> (Procedures) introduce updated limits based on toxicological data, closed-vessel digestion, and advanced multi-element analysis using ICP-OES and ICP-MS, ensuring accurate, reproducible control of a broader list of analytes across different routes of administration.

Study Objectives and Overview

This white paper from Agilent Technologies examines:

• The rationale behind replacing USP<231> with ICH Q3D and USP<232>/<233>.
• The selection of ICP-MS (Agilent 7900) and ICP-OES (Agilent 5100) systems for routine pharmaceutical testing.
• Method development to meet new Permitted Daily Exposure (PDE) limits for oral, parenteral, and inhalation products.
• Validation and compliance strategies aligned with regulatory requirements (FDA 21 CFR Part 11, EU Annex 11, PIC/S).

Methodology and Instrumentation

Sample preparation under USP<233> emphasizes closed-vessel microwave digestion to prevent loss of volatile elements (e.g., Hg) and uses dilute HNO₃/HCl matrices to stabilize target analytes. Alternative approaches for soluble samples include controlled dilution in aqueous or organic solvents with appropriate stabilizers. Pharmaceutical matrices often require:

• Complete acid digestion in sealed vessels to achieve homogeneity and eliminate particulate interferences.
• Addition of HCl (~1%) or gold(III) chloride for stabilization of Hg and platinum group elements (PGEs).
• Careful control of dilution factors to translate PDE limits into concentration thresholds (J-values) in the final solution.

Instrumentation choices:

• Agilent 7900 ICP-MS: Offers ultralow detection limits (<0.001 µg/L), extended linear dynamic range (11 orders of magnitude), and robust collision-cell He-mode to remove Cl-based polyatomic interferences—critical for digests containing HCl. Secondary isotopes enable analyte confirmation. Optional organic solvent introduction and HPLC coupling facilitate speciation of As and Hg.
• Agilent 5100 ICP-OES: Provides high throughput, stable plasma for >4 hr analysis in high-TDS matrices, dual axial–radial viewing, and CCD detection to verify concentrations at primary and confirmation wavelengths. Ideal for routine screening of oral dosage forms where detection limits meet USP<232> component limits.

Key Results and Discussion

Interference removal in the 7900 ICP-MS He-mode reduces background equivalent concentrations of V and As from ~2.5 µg/L to <0.01 µg/L, enabling reliable quantification at stringent PDE-derived limits after digestion. The 5100 ICP-OES demonstrated <2.5% RSD over 4 hr for As, Cd, Pb, Se in 25% NaCl digests, and consistent Cd determination at two emission lines in an oil matrix. Both techniques meet or exceed method performance requirements for specificity, precision, and sensitivity under USP<233> and ICH Q3D.

Benefits and Practical Applications

Adopting ICP-MS and ICP-OES methods delivers:

• Individual quantification of up to 24 elements including toxic “Big 4” (As, Cd, Hg, Pb) and PGEs.
• Lower detection capability than required PDE thresholds for oral, parenteral, and inhalation products.
• Robust, automated sample introduction and collision-cell interference removal for high matrix tolerance.
• Regulatory compliance via integrated software solutions (Agilent OpenLAB, SDA, MassHunter UAC) supporting 21 CFR Part 11/EU Annex 11, audit trails, electronic signatures, and secure data management.

Future Trends and Opportunities

Emerging directions include:

• Wider adoption of speciation analysis (e.g., methyl vs. inorganic forms) for complex APIs and excipients.
• Integration of real-time process monitoring with rapid screening ICP-MS modes for in-line quality control.
• Application of Quality by Design (QbD) principles to optimize digestion protocols and instrument parameters for diverse sample types.
• Advances in automated sample handling and data analytics to further enhance throughput and traceability in multi-site pharmaceutical operations.

Conclusion

The upcoming ICH Q3D and USP <232>/<233> standards drive a transition from subjective heavy-metal tests to precise, multi-element analysis using ICP-MS and ICP-OES. Agilent’s 7900 ICP-MS and 5100 ICP-OES platforms provide the sensitivity, robustness, and compliance tools needed for accurate control of elemental impurities across pharmaceutical raw materials, APIs, and finished products. Implementing these technologies ensures alignment with global regulatory guidelines, enhances laboratory productivity, and safeguards patient safety.

References

1. USP <231> Heavy Metals Limit Test; 2. USP <232> Elemental Impurities—Limits; 3. USP <233> Elemental Impurities—Procedures; 4. ICH Q3D Guideline for Elemental Impurities; 5. CHMP/SWP/4446/2000 EMA Guideline on Inorganic Impurities; 6. Liba A., McCurdy E., Ashdown R., Agilent White Paper, 2014.