Extractables and Leachables Analysis of IV Bag Systems using Direct Thermal Extraction of the Materials and Stir Bar Sorptive Extraction of Aqueous Solutions coupled with Thermal Desorption Gas-Chromatography with Unit Mass and High Resolution MSD

Importance of the Topic

Intravenous (IV) bag systems can release chemical compounds from packaging materials into drug formulations, posing potential safety and efficacy risks. A thorough analysis of both extractables (compounds released under accelerated conditions) and leachables (compounds migrating into aqueous products under normal use) is critical for regulatory compliance and ensuring patient safety.

Study Objectives and Overview

• Develop a comprehensive workflow to identify extractables from individual IV bag components by direct thermal extraction.
• Simulate leachables by applying Stir Bar Sorptive Extraction (SBSE) to an aqueous simulant stored in identical IV bags.
• Use high-resolution GC-QTOF-MS to confirm or refute compound identities and assign sources within the packaging system.

Methodology and Instrumentation

• Direct thermal desorption GC/MS of bag film, tubing, and valve components heated at 80 °C, 140 °C, and 200 °C.
• SBSE using PDMS-coated stir bars (Twisters) to extract leachables from 10 mL aliquots of water stored in IV bags at 40 °C for 48 h.
• Confirmatory analysis on an Agilent 7890B GC coupled to a 7200 QTOF MS for accurate mass measurement and high resolving power.

Instrumentation Used

• Agilent 7890B GC with 5977A MSD, Gerstel CIS 4 PTV inlet, Thermal Desorption Unit, and MPS autosampler.
• Agilent 7890B GC with 7200 QTOF MS for high-resolution confirmation of extractables and leachables.

Main Results and Discussion

• Thermal extraction revealed residual solvents (cyclohexanone, acetone, hexane), plasticizers (DEHP, DEP), antioxidants (BHT, BHA), and printing-ink additives (methyl methacrylate, toluenesulfonamides) in bag materials.
• Elevated extraction temperatures (200 °C) liberated volatile residues not observed at 80 °C, emphasizing the value of multiple temperature steps.
• SBSE of the aqueous simulant confirmed leaching of key compounds—cyclohexanone, phenolic antioxidants, benzothiazole—into water under near-normal storage conditions.
• High-resolution QTOF-MS verified compound identities and excluded false positives, such as suspected sulfur-containing analytes that were not present.

Benefits and Practical Applications

• Combined thermal extraction and SBSE workflows streamline sample preparation and minimize solvent artifacts.
• High sensitivity and trace-level detection support risk assessments for IV packaging systems.
• Source-specific profiling allows attribution of extractables to individual components, guiding material selection and design.
• Accurate mass spectrometry reduces uncertainty in compound identification and enhances regulatory confidence.

Future Trends and Opportunities

Advances in automated thermal extraction and coupling with high-resolution MS will further improve throughput and analytical depth. Predictive modeling of leachable migration and expanded use of LC-HRMS for polar analytes are emerging areas. Updates to USP chapters and ICH guidelines will drive standardization and adoption of these techniques.

Conclusion

The integrated use of direct thermal desorption, SBSE, and GC-QTOF-MS provides a robust, efficient approach for comprehensive extractables and leachables analysis of IV bag systems. This methodology enhances compound identification, supports regulatory compliance, and ultimately protects patient health.

References

1. FDA Guidance for Industry: Container–Closure Systems for Packaging Human Drugs and Biologics; U.S. Food and Drug Administration, 1999.
2. United States Pharmacopeia, General Chapter <1664>: Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems; USP, 2013.
3. Baltussen E, Sandra P, David F, Cramers C. Stir Bar Sorptive Extraction (SBSE), a Novel Extraction Technique for Aqueous Samples: Theory and Principle. Journal of Microcolumn Separations. 1999;11(11):737–747.