Extractables and Leachables

Extractable and leachable studies have become a hot topic within the Pharmaceutical industry.  Some individuals consider Extractables and Leachables as one entity, but they are really considered two different studies.  Extractables are compounds that can theortically be extracted from the container closure system (CCS), which are assessed in the presence of solvent(s).  Leachables are compounds that seep into the drug product formulation from the container closure system as a result of direct contact with the formulation.

As per 21 CFR 211.94 a), “Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of a the drug beyond the official or established requirements(1).”  The FDA provides guidance documents to assist companies in their assessment of extractables and leachables.  During the drug application process, the FDA will assess the qualification and quality control of all components coming in contact with the drug product.   It has now become imperative that E&L studies be addressed as early as the drug and package development stages.  The studies should take into account patient population, route of administration, and potential for interaction between the drug product formulation and the container closure system.

Extractable studies are typically performed to qualify the container closure system components.  They are done to screen or monitor any toxic materials that could be removed from any component within the container closure system.  Methods like USP <661> Containers- Plastics, could be used to qualify plastic components within the container closure system, however, some companies may develop more enhanced methods depending on their container closure system.  These extractable methods can later be used for quality control for acceptance of CCS components. Extractable methods can later be used as guidelines in the development of analytical methods for Leachable studies.

On the other hand, Leachable studies monitor and control container closure system-derived impurities in the drug product during stability and/or as part of the container qualification testing.  In a leachable study, compounds found in the drug product can come directly from the primary packaging components, migrate from secondary packaging components or labels, or be present as byproducts of reactions between the the drug formulation and CCS.   Undesirable compounds can be found in plastic components, elastomers, coatings, accelerants, antioxidants, inks, and vulcanizing agents. An example of this are phthalates, which are carcinogens added to plastics to make them more flexible and can be found throughout the manufacturing process and in packaging materials. Other examples are nitrosamines and polynuclear aromatic hydrocarbons (PAHs), which are classes of carcinogenic compounds found in rubber.  Many drug products are distributed or administered in packages made of plastic and rubber components, therefore, the above carcinogens could potentially come in contact with the drug product and be passed on to the end user.

The development, validation, and testing of these components should be carried out under the International Conference on Harmonization (ICH) in conjunction with the United States Pharmacopeia (USP) guidelines in a laboratory that conforms to current good manufacturing  practices (cGMP).  E&L studies are time consuming and could require a wide array of analytical techniques and expertise, so drug manufactures may outsource to contract laboratories.