Measuring Elemental Impurities in Pharmaceutical Materials

Significance of the Topic

The presence of elemental impurities in pharmaceutical materials poses significant health risks if left uncontrolled. Regulatory bodies worldwide have updated their guidelines to limit toxic metals in drug substances and finished products. Accurate measurement of trace and ultra-trace metals is therefore essential for ensuring patient safety, meeting compliance requirements, and maintaining product quality.

Objectives and Study Overview

This whitepaper outlines how modern atomic spectroscopy techniques and robust compliance workflows can be implemented to satisfy USP <232>/<233> and ICH Q3D(R2)/Q2(R1) requirements. It presents a complete solution for risk assessment and analytical testing of 24 regulated elements across all administration routes. The goal is to guide laboratories in selecting appropriate sample preparation, instrumentation, and software to achieve reliable, reproducible results.

Methodology and Instrumentation

Sample Preparation and Digestion

• Closed-vessel microwave digestion with strong acids for solid matrices, ensuring complete solubilization of excipients and raw materials.
• Appropriate dilution schemes to accommodate high matrix loads and variable concentrations.

Instrumentation

• Agilent 5800/5900 VDV ICP-OES for rapid, multi-element screening at parts-per-billion levels, handling up to 25 % dissolved solids.
• Agilent 7850 ICP-MS equipped with Ultra High Matrix Introduction (UHMI) for low-level determination (down to sub-ppt) and single-cell helium collision/reaction mode to eliminate polyatomic interferences.
• Supportive atomic absorption systems for elements not requiring the lowest detection limits.

Software and Compliance

• Preconfigured USP <232>/<233> and ICH Q3D method templates, including optimized wavelengths and quality control checks.
• CrossLab Automated Compliance Engine (ACE) for installation and operational qualification (IQ/OQ) and 21 CFR Part 11/EU Annex 11 software solutions to manage electronic records and signatures.

Main Results and Discussion

Agilent’s solutions enable consistent detection of all regulated Class 1, 2A, 2B, and 3 elements at permitted daily exposure (PDE) levels for oral, parenteral, inhalational, and cutaneous routes. The ICP-OES systems deliver high throughput with minimal downtime, while the ICP-MS system achieves robust performance across diverse matrices and broad dynamic ranges. Method verification and suitability tests demonstrate compliance with sensitivity, accuracy, and precision criteria. Automated software features reduce method development time and lower the risk of operator errors.

Benefits and Practical Applications

• Comprehensive coverage of all USP/ICH-listed elements in final drug products or individual components to support risk-based assessments.
• Streamlined workflows combining sample prep, instrumentation, and software to accelerate implementation and maintain regulatory compliance.
• Scalable solutions suitable for contract testing laboratories, QC labs in pharmaceutical manufacturing, and academic research facilities.
• Global support network offering training, preventive maintenance, qualification services, and certified reference materials for ongoing quality assurance.

Future Trends and Possibilities

Advancements in high-resolution mass spectrometry and collision/reaction cell chemistries are expected to further lower detection limits and expand interference removal capabilities. Increased automation, artificial intelligence–driven data analysis, and cloud-based compliance tools will enhance method robustness and traceability. Emerging nano- and biologic pharmaceuticals will drive demand for specialized sample introduction systems and speciation analyses to address novel impurity profiles.

Conclusion

Implementing a fully integrated elemental impurities testing program requires careful selection of digestion protocols, analytical instrumentation, and compliance software. Agilent’s portfolio of ICP-OES, ICP-MS, certified reference materials, and qualification services offers a proven pathway to satisfy USP <232>/<233> and ICH Q3D(R2)/Q2(R1) requirements. By adopting these solutions, laboratories can ensure patient safety, product quality, and regulatory confidence.

References

• USP General Chapters <232> and <233> on Elemental Impurities
• ICH Q3D(R2)/Q2(R1) Guideline for Elemental Impurities in Pharmaceuticals