Accurate Determination of IV Bag Extractables and Leachables

The Food and Drug Administration is concerned with a number of leachables and extractables in a range of drug products, particularly inhalation aerosols and sprays, injections and injectable solutions, inhalation solutions, and transdermal ointments and patches. Regulations and USP 1664 require rigorous testing for extractables and leachables, at very low concentration levels.

Extractables and leachables are of special concern in IV bags, which contain aqueous solutions of drug products. Unfortunately, the standard techniques typically used to determine these compounds (LC/MS and GC/MS) have difficulty with the analysis of these solutions. LC/MS has difficulty detecting compounds in the non-polar to slightly polar range and GC/MS does not perform well for aqueous matrices. In both cases, detection limits are difficult to obtain, and low concentrations or novel compounds make identification using unit mass-based spectral libraries difficult.

To demonstrate a simple, efficient way to analyze pharmaceutical packaging for unwanted compounds, scientists from GERSTEL and Agilent Technologies performed direct thermal desorption of IV bag components at elevated (80, 140 and 200°C) temperatures, using GERSTEL Thermal Desorption Unit (TDU) tubes, and a GERSTEL CIS4 PTV inlet. GC/MS analysis was then performed. In a second step to test for leachables, a Twister SBSE stir bar was used to extract deionized water that had been contained in an IV bag for 48 hours at 40 °C. After stirring for 60 minutes at room temperature, the Twister bar was removed and placed into a thermal desorption tube for GC/MS analysis.

The SBSE technique revealed a number of extractable compounds, including cyclohexane, 2-ethyl hexanol, 1,3-di-tert-butyl benzene, and diphenyl ether, and acetone. Because thermal extraction was performed on the bag components it was possible to trace each contaminant back to a specific part of the IV bag.

While this procedure was only for demonstration (FDA and other regulations would require more replicates and quantitative estimates of extractables and leachables), it showed how efficiently a target list of leachable and extractable compounds could be assembled for more detailed analysis. The procedure also illustrated the usefulness for GC-QTOF-MS in cases where higher resolving power is required.

In addition, the technique was superior to solvent extraction, which requires more sample preparation steps, more analyst time, risks sample contamination from solvents, and depends more on solvent polarity than on mobility.

You can learn more details about how the procedure for analyzing leachable and extractable compounds from IV bags was set up, and the researchers’ results by reading the application note here. After reading the paper, we would be happy to talk with you about how you may incorporate this new method into your laboratory.