Analysis of Extractable/Leachable Compounds From Plastic Intravenous Bag Sets Using GC/MSD Systems

Importance of the Topic

Polymeric materials such as PVC are widely used in intravenous (IV) bag sets for drug storage and administration, offering advantages in durability, cost, and functionality. However, additives like phthalate plasticizers can migrate (extractables and leachables) from packaging into drug solutions, posing potential health risks. Regulatory authorities including FDA, USP, PQRI and ISO provide guidelines but demand detailed analytical profiling to ensure patient safety.

Study Objectives and Overview

This study evaluated extractable and leachable compounds in two plastic IV bag types—a long-expired 150 mL dextrose bag and a heated 1 L sodium chloride bag—along with associated tubing. A combination of headspace sampling and large-volume solvent injection on GC/MSD systems aimed to identify potentially toxic additives under worst-case and simulated-use conditions.

Used Instrumentation

• Agilent 7697A Headspace Sampler coupled to a 7890A GC and 5977A MSD for high-temperature extractables analysis
• Agilent 7890A GC with Multimode Inlet (MMI) and 5977A MSD for large-volume solvent extracts and trace leachables
• Solvents: Dichloromethane (DCM) and Hexane; Surfactant: Kolliphor EL

Applied Methodology

Headspace GC/MS analysis was performed on 10 mL vials containing bag fragments or tubing at temperatures from 85 °C to 275 °C, enabling detection of volatile and semi-volatile extractables. Solvent extraction of bag materials and infusion solutions (dextrose, saline, saline with Kolliphor EL) was achieved by sonication followed by room-temperature equilibration. Large-volume injections in solvent-vent mode with the MMI allowed sensitive identification of low-level leachables using scan and single-ion monitoring (SIM).

Main Results and Discussion

• Headspace analysis detected plasticizers (DEHP, DBP, isobutyl nonyl phthalate), UV stabilizers (benzophenone), antioxidants (BHT, Metilox, Irgafos 168), fatty acids (palmitic, stearic) and other additives in IV bags and tubing.
• Solvent extracts confirmed migration of DEHP and DEHA into expired dextrose solution, exceeding detection levels and highlighting storage impact.
• Heated saline and saline with Kolliphor EL showed enhanced migration of phthalate esters and alkyl phthalates, demonstrating surfactant-facilitated leaching.
• Complementary use of headspace and MMI GC/MSD provided a broad profile of extractable/leachable compounds across volatility and concentration ranges.

Benefits and Practical Applications

Combining headspace GC/MS with large-volume solvent GC/MS offers a comprehensive workflow for screening both high-volatility extractables and trace-level leachables in pharmaceutical packaging. This approach supports risk assessment, quality control, and compliance with industry guidelines by enabling robust identification of additives and potential contaminants.

Future Trends and Possibilities

Advancements in quantification strategies using representative response factors, integration of high-resolution MS (e.g., GC/QTOF) for isomer differentiation, and development of standardized reference materials will improve accuracy and reliability. Emerging alternative plasticizers and automation in sample preparation and data analysis will further enhance extractables and leachables investigations.

Conclusion

The dual GC/MSD approach detailed herein demonstrates effective identification of extractable and leachable compounds from plastic IV bag sets under worst-case and simulated-use conditions. The methodology facilitates thorough safety evaluations and informs packaging design and regulatory compliance efforts.

References

1. Pearson SD, Trissel LA. Leaching of diethylhexyl phthalate from polyvinyl chloride containers by selected drugs and formulation components. Am J Health Syst Pharm. 1993;50:1405–1409.
2. Tickner JA, Schettler T, Guidotti TL, McCally M, Rossi M. Health risks posed by use of Di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: A critical review. Am J Ind Med. 2001;39:100–111.
3. Demoré B, Couture M, Doelker E. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous etoposide solution. J Clin Pharm Ther. 2002;27:139–142.
4. Gotardo MA, Monteiro M. Migration of diethylhexyl phthalate from PVC bags into intravenous cyclosporine solutions. J Pharm Biomed Anal. 2005;38:709–713.
5. Venkataramanan R, et al. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm. 1986;43:2800–2802.
6. Jaeger RJ, Rubin RJ. Migration of a phthalate ester plasticizer from polyvinyl chloride blood bags into stored human blood and its localization in human tissues. N Engl J Med. 1972;287:1114–1118.
7. Maas B, Huber C, Kramer I. Plasticizer extraction of Taxol-infusion solution from various infusion devices. Pharm World Sci. 1996;18:78–82.
8. Nishioka D, Yamamoto N, Fujii S, et al. Activity related to the carcinogenicity of plastic additives in the benzophenone group. J UOEH. 2006;28:143–156.
9. Rhodes MC, Wartenberg D, Reid L. Carcinogenesis studies of benzophenone in rats and mice. Food Chem Toxicol. 2007;45:843–851.
10. Branen AL. Toxicology and biochemistry of butylated hydroxyanisole and butylated hydroxytoluene. J Am Oil Chem Soc. 1975;52:59–63.
11. Taylor LJ, Tobias JW. Degradable plastics containing dual-function additive system. US Patent 3,941,759. 1973.
12. Askwith TC, Cameron A, Crouch RF. Chain length of additives in relation to lubricants in thin film and boundary lubrication. Proc R Soc Lond Math Phys Eng Sci. 1966;291:500–519.
13. Hornbach KH, et al. Storage-stable aqueous emulsions and liquid blends with low viscosity as stabilizers. US Patent 2011/0196082 A1. 2011.
14. Goulas AE, Koutsoumpelis KL, Saravacos GD. Migration of di-(2-ethylhexyl) adipate plasticizer from food-grade polyvinyl chloride film into hard and soft cheeses. J Dairy Sci. 2000;83:1712–1718.
15. Rahman M, Brazel CS. The plasticizer market: an assessment of traditional plasticizers and research trends to meet new challenges. Prog Polym Sci. 2004;29:1223–1248.