Amy Miller & Jennifer Riter

Analytical Lab Services

February 17, 2012

The Effect of a Barrier Film on Elastomeric Extractables in a Parenteral Packaging System

Amy Miller and Jennifer Riter

Extractables from elastomeric components become an issue even before a pharmaceutical drug makes contact with the elastomeric component. The suitability of the elastomer and the drug product needs to be taken into consideration at the development stage of the packaging and delivery system for the drug product. The potential for an extractable to leach into the drug product and the impact that leachable will have on the drug’s stability, efficacy and toxicity needs to be scientifically evaluated.

 A way to reduce the amount of extractables that could potentially leach into a drug product from an elastomeric closure is to utilize a fluoropolymer film on the closure. The fluoropolymer film reduces the closure-drug interaction there-by reducing the amount of leachables in the drug product. To demonstrate the effectiveness of the fluoropolymer film, multiple closures, some laminated with fluoropolymer film and some without, were sealed onto vials containing various solvents representing typical drug product solvent vehicles. To stimulate a worst-case scenario the vials were inverted and stored at 40°C/75% RH (± 2°C/5% RH). Each set of vials/solvents was tested at time 0, 3 months and 6 months. The analytical techniques used to identify any leachables included Ion Chromatography (IC), Inductively Coupled Plasma Spectroscopy (ICP), and High Performance Liquid Chromatography utilizing Photodiode Array and Mass Spectrometry (LC/PDA/MS) and Gas Chromatography with Mass Spectrometry (GC/MS). The results from this study confirmed that inclusion of a fluoropolymer film reduced leachables from the elastomeric closures.

The results of this study show that the potential for extractables leaching into drug product solvent vehicles from closures is a reality. The LC and GC results show that antioxidants and other formulation-related compounds leached from the closures without fluoropolymer film into 50% ethanol/water and 50% propylene glycol/water solutions. These antioxidants and other formula-related compounds were either not detected or were only seen at reduced levels with the closures coated with fluoropolymer film.

The ICP analysis showed quantifiable levels of calcium leached into the pH 3 and 0.03% Polysorbate 80 solutions from the closures without fluoropolymer film, while over the same period of time, no quantifiable level of calcium leached from the closures with the fluoropolymer film. The IC results show that chloride was detected from closures without the fluoropolymer film but not from the closures with fluoropolymer film after 3 and 6 month of storage at accelerated conditions.

The study revealed that even over a period of 6 months, leachables can be detected and there is a potential for those leachables to increase over time. It is important to not only look at what can leach from the closure but how much of that leachable can be detected and its effect on the drug product.

The methods used in this study are screening methods. Now that extractables have been identified, the next step is to develop and validate test methods in drug product. The leachables can then be quantified over the shelf life of the drug product. Three key points to take from this study are that the use of a fluoropolymer film can greatly reduce the risk of leachables in a drug product, leachables can increase over even a short time period at accelerated conditions, and choosing the correct methods for analysis of leachables is critical.