Extractables Analysis of Elements in Plastic Pharmaceutical Packaging

Importance of the Topic

This study addresses the critical need to monitor elemental impurities that can migrate from pharmaceutical packaging into drug products. Understanding extractables and leachables (E&L) is essential for patient safety, regulatory compliance with ICH Q3D and related guidelines, and for ensuring drug quality throughout shelf life.

Study Objectives and Overview

The primary goal was to evaluate and quantify elemental extractables from three types of single-use infusion bags (PVC, PE and EVA) using an inductively coupled plasma mass spectrometer (ICP-MS). The focus elements were those listed in ICH Q3D (Classes 1–3), supplemented by Fe and Zn. A risk assessment approach determined which impurities could leach under worst-case extraction conditions.

Methodology and Instrumentation

The study employed three extraction solvents to simulate a range of pharmaceutical formulations:

• pH 2.5 solution (0.01 M KCl adjusted with HCl)
• pH 9.5 solution (phosphate buffer)
• 50 % isopropanol (IPA) in water

Sample preparation included:

• Cutting unprinted bag sections to ~100 cm2, washing and finely cutting.
• Extraction in 30 mL solvent at 70 °C for 24 h (n = 6), with parallel extraction blanks (n = 3).
• Ten-fold dilution of extracts with water, acidification (1 % HNO3 and 0.5 % HCl), and spiking for recovery tests.
• Calibration using multiple mixed standards (XSTC-22, XSTC-2071A) and single-element solutions, matched in acid and IPA content.

Quality control included spike recovery (95–108 %) and calculation of packaging-adjusted limits of quantitation (LOQs) relative to parenteral PDEs.

Used Instrumentation

The Shimadzu ICPMS-2030 was employed with the following key parameters:

• RF Power: 1.2 kW
• Gas flows: plasma 9.0 L/min, auxiliary 1.1 L/min, carrier 0.7 L/min (He collision gas)
• Nebulizer 07 UES, cyclone spray chamber, mini torch
• Internal standards: Be, Sc, Ga, Y, In, Te, Bi via automatic addition (1:9 ratio)

Main Results and Discussion

PVC bags released trace levels of Ti and Zn under all conditions. Pb and Ba leached notably under acidic and 50 % IPA conditions. All measured values were below packaging-adjusted PDE limits, confirming method sensitivity. PE extracts showed consistent Sb release and detectable Zn in basic and IPA solutions. EVA extracts released Fe under acidic conditions. LOQs were sufficient to quantify elements down to the ng/cm2 level.

Benefits and Practical Applications

• Simultaneous multi-element detection with high sensitivity and low detection limits.
• Reduced operating costs thanks to lower argon consumption and compatibility with low-purity gas.
• Comprehensive E&L risk assessment tools for pharmaceutical packaging qualification.

Future Trends and Opportunities

Ongoing developments will likely include:

• Standardization and harmonization of E&L protocols (ICH Q3E).
• Expansion to new packaging materials and biologics.
• Integration with data analytics and AI for predictive leachables modeling.
• Further miniaturization and automation of ICP-MS workflows.

Conclusion

The validated ICPMS-2030 method demonstrates robust, sensitive quantitation of elemental extractables in pharmaceutical packaging. It meets ICH Q3D requirements and supports regulatory filings by providing reliable impurity profiles for a range of polymeric bag materials.

References

• FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, January 2023.
• PQRI, Experimental Protocol for Controlled Extraction Studies on PFS and SVP Container Closure Systems, 2015.
• BioPhorum, Best Practices Guide for Extractables Testing of Single-Use Components, April 2020.
• ICH, Q3E Concept Paper: Guideline for Extractables and Leachables, July 2020.
• ICH, Q3D(R2): Guideline for Elemental Impurities, March 2022.