Extractables and Leachables Analysis of IV Bag Systems

Importance of the Topic

The safety and efficacy of intravenous drug delivery can be compromised by chemical compounds migrating from packaging materials into the drug product. Monitoring extractables and leachables from IV bag systems is essential to identify potential toxicants, meet regulatory requirements, and protect patient health.

Objectives and Study Overview

This study aimed to characterize both extractables from bag components under exaggerated conditions and leachables in an aqueous simulant stored in the same IV bag type. Results from direct thermal desorption coupled to GC/MS were compared with stir bar sorptive extraction (SBSE) followed by GC/MS and high-resolution GC/Q-TOF confirmation.

Methodology

• Extractables: Small pieces of bag, tubing, and valve materials (3–15 mg) were thermally desorbed at 80 °C, 140 °C or 200 °C in a thermal desorption unit (TDU) and analyzed via GC/MS with splitless and split inlets.
• Leachables: Empty IV bags filled with water were incubated at 40 °C for 48 h. Ten-milliliter aliquots were extracted by SBSE using PDMS-coated stir bars, then thermally desorbed and analyzed by GC/MS.
• Confirmation: Selected trace analytes were interrogated by GC/Q-TOF high-resolution mass spectrometry to confirm or refute library identifications.

Instrumentation

• Agilent 7890B GC with 5977A MSD, Gerstel CIS 4 PTV inlet and TDU, MPS autosampler
• Gerstel Twister SBSE stir bars (24 µL PDMS) for aqueous extraction
• Agilent 7890B GC coupled to 7200 Q-TOF for accurate mass confirmation

Results and Discussion

Thermal desorption at 80 °C revealed cyclohexanone, 2-ethylhexanol and antioxidant-related compounds. Raising to 200 °C increased recovery of both volatile and semi-volatile species. Printed areas contributed methyl methacrylate and toluenesulfonamides. PVC tubing and valves showed high DEHP peaks overloaded at 200 °C, yet no carryover due to inert flow path and post-run bake-out. SBSE of aqueous simulant captured leached cyclohexanone, phthalates, antioxidants and trace benzothiazole. Q-TOF ruled out sulfur in unknowns and confirmed benzothiazole with <3 ppm mass error.

Benefits and Practical Applications

This combined workflow rapidly generates a comprehensive target compound list, links extractables to their polymer sources, and provides ultra-trace leachable profiling. The inert thermal desorption path prevents carryover even with heavily overloaded samples, ensuring reliable results. High-resolution MS adds confidence in identification, guiding risk assessment and quality control.

Future Trends and Applications

Advances in sample preparation, such as microextraction and enhanced SBSE coatings, will expand sensitivity and selectivity. Integration of two-dimensional GC and tandem MS will improve separation of complex extractables. Data analytics and predictive modeling may anticipate leachable profiles based on polymer composition. Adoption of real-time monitoring and automation will streamline regulatory compliance and accelerate investigations.

Conclusion

The study demonstrates that direct thermal desorption GC/MS and SBSE-GC/MS, complemented by high-resolution Q-TOF confirmation, form a robust, efficient, and comprehensive strategy for profiling extractables and leachables in IV bag systems. This approach meets stringent regulatory requirements, prevents carryover, and enhances contaminant identification at trace levels.

References

1. FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. FDA; 1999.
2. United States Pharmacopeia (USP) 1664: Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems. USP; 2013.
3. J.-T. Huang et al. Stir Bar Sorptive Extraction and GC-MS/MS Determination of Halogenated Impurities in Drug Products. J. Chromatogr. A. 2012.
4. B. L. Armstrong et al. SBSE-GC-MS/MS for Low-Level Leachables from Medical Devices. J. Pharm. Biomed. Anal. 2013.
5. E. Baltussen et al. Stir Bar Sorptive Extraction of Aqueous Samples: Theory and Principle. J. Microcolumn Sep. 1999.
6. C. Zweiben, A. J. Shaw. Thermal Desorption GC-MS to Characterize Packaging Materials. J. Pharm. Sci. Technol. 2009.
7. C. S. Thompson-Torgerson et al. Cyclohexanone Contamination Impairs Cardiovascular Function. Am. J. Physiol. Heart Circ. Physiol. 2009.