WCPS: Analytical Workflow for Elemental Extractables and Leachables in reference to USP and ICH Guidelines: Intravenous Bag Case Study

Significance of the Topic

Elemental extractables and leachables from pharmaceutical packaging can compromise drug safety by introducing trace metal contaminants into formulations. Intravenous bags, which directly contact parenteral solutions, present a critical case for screening elemental impurities to ensure compliance with regulatory exposure limits and protect patient health.

Objectives and Study Overview

This case study establishes a comprehensive workflow for profiling 70 elemental impurities in IV bag materials according to United States Pharmacopeia (USP) and International Council for Harmonization (ICH) guidelines. The goals include optimizing extraction conditions, analytical instrumentation, and data processing to deliver accurate, reliable quantitation across trace and major element ranges.

Instrumentation

• Agilent 7800 ICP-MS with Ultra High Matrix Introduction (UHMI) system to tolerate up to 25% total dissolved solids.
• Octopole Reaction System in helium mode to reduce common polyatomic interferences.
• Agilent MassHunter software featuring automated USP-ICH preset methods and Excel interfacing for streamlined data handling.

Methodology

Extraction Protocol
The IV bag components (bag film, tubing, filter) were separately subjected to aqueous and saline extractions at 50 °C with 50 rpm shaking for 72 hours to simulate worst-case leaching conditions.

Standards and Quality Control

• Prepared calibration stocks for 70 elements in 5% nitric acid, covering 0.1–10 ppb with extensions to 100–1000 ppb for high-abundance species like sodium.
• Employed independently sourced QC standards at 0.5 and 5 ng/g and sample spikes at 0.1 and 1 µg/kg to validate accuracy and precision.
• Diluted extracts 1:10 in 5% nitric acid and analyzed each sample in triplicate.

Data Acquisition and Analysis
MassHunter automated the ICP-MS setup, autotune, and USP-ICH method execution. Results were imported into Agilent Mass Profiler Professional for statistical evaluation, including principal component analysis to compare solvent effects.

Key Results and Discussion

All 70 elements were detected within regulatory limits, confirming method sensitivity and dynamic range. However, over ten toxic metals—including arsenic, cadmium, mercury, lead, cobalt, nickel, chromium, molybdenum, antimony, and barium—migrated into extraction solvents at trace levels. Multivariate analysis revealed distinct elemental profiles between saline and water extracts, with zinc notably elevated in saline, underscoring matrix-dependent leaching behavior.

Practical Implications and Benefits

• A single-run ICP-MS approach accelerates sample throughput by combining trace and major element detection over ten orders of magnitude.
• UHMI and helium-mode collision cell technologies ensure robust performance in high-salt matrices.
• Automated software workflows reduce development time and support compliance with USP and ICH validation criteria.

Future Trends and Opportunities

Advancements in high-throughput ICP-MS, coupled with data-driven software and AI-enhanced analytics, will further streamline E&L testing. Emerging packaging materials and stricter regulatory thresholds will drive method innovations, while integration with orthogonal techniques such as time-of-flight MS may offer broader contaminant coverage.

Conclusion

This study demonstrates a robust, reproducible workflow for profiling elemental extractables and leachables in IV bags, meeting USP-ICH requirements and providing critical safety data. The approach supports risk assessment and quality assurance in pharmaceutical packaging.

References

• Solomon P. E., Nelson J., Jordi M. Analytical Workflow for Elemental Extractables and Leachables in Reference to USP and ICH Guidelines: Intravenous Bag Case Study. Poster #73, EWCPS 2017.
• Khera S., Jordi M., Arnaud C. Analysis of Extractables and Leachables: Methodologies, Regulations, Best Practices Series. Chemical & Engineering News, 2016.