Mitigating the Risk from Rubber Closures
Fluorocarbon film coatings provide the best combination of protection from extractables from the stopper material while providing a high level of barrier protection for the drug product, therefore minimizing leachables.
When applied to stoppers, fluorocarbon films reduce adsorption of the drug onto the stopper, which is critical for maintaining the product's potency and shelf life. In addition, fluorocarbon films provide extra lubricity for proper vial seating, without the need for silicone oil. Fluoroelastomer films, which are made from inert materials, also reduce the possibility of extractables migrating from the rubber stopper into the biopharmaceutical product.
Since the cost of specifying the wrong closure components and materials is so high, biopharmaceutical manufacturers need to devise a separate development plan for primary packaging, just as they do for molecule and clinical development.
Normally this separate activity is contracted out to firms that specialize in packaging components by Phase I when sponsors and regulators get serious about product and package. During Phase I a package component expert company will begin screening for closure designs and materials.
Screening involves assessing packaging alternatives, generating preliminary data on leachables, and choosing one or several alternatives that provide the highest degree of product compatibility and the lowest level of leachables. By Phase II, earlier if possible, sponsors need to begin to develop precise, validated methods for determining extractables and leachables. For products that get this far, methods development becomes almost a separate phase of stability testing.
It is difficult to overestimate the importance of carrying out these studies for the full testing period. Some product-package combinations that showed little or no degradation over the first few months may lead to significant inactivity, due to adsorption onto the glass vial prior to expiration of a two-year shelf life. Similarly, leachables that do not appear for the first several weeks may emerge later on, well within the products specified shelf life.