Identification and Risk-Assessment of Extractables and Leachables

Feb 01, 2006

Lancaster Laboratories
Drug manufacturers invest a tremendous amount of time and money to identify, quantify, and minimize impurities related to their drug products so that the US Food and Drug Administration can make informed decisions regarding drug product purity and safety. An area of increasing concern and scrutiny for FDA's Center for Drug Evaluation and Research (CDER) is the potential adulteration of drug products by extractable and leachable compounds that enter a drug from a container, closure system, disposable, or device.

Addressing this concern, 21 CFR 211.94 a) states that:

Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements (1).

FDA provides guidance for protection against extractables and leachables in various documents (2, 3).

Therefore, the qualification and quality control of all components coming into contact with the drug formulation is an integral part of any FDA application process.

Extractables and leachables issues often are not addressed up front and ultimately can cause regulatory delays for the drug manufacturer. The development of unique packaging, novel formulations and delivery systems, and drug-coated medical devices has exacerbated this issue because of the increasing opportunities for foreign materials to come into contact with drug products. In addition, the increasing popularity of single-use disposables such as filters, tubing, and bags for biopharmaceuticals can introduce unwanted extractables into the final product. (For the rest of the article, the word components will refer to container closures, labels, drug delivery systems, packaging materials, devices, disposables, and so forth).

The development, validation, and testing of these components must be carried out under International Conference on Harmonization and United States Pharmacopeia guidelines in a laboratory that complies with current good manufacturing practices. These activities may be time consuming and require expertise and a wide array of analytical techniques. Drug manufacturers may not have the resources available or may want to keep these resources focused on development of new products. Therefore, it is common for drug manufacturers to outsource these activities to contract laboratories.

What are extractables and leachables?

Extractables are compounds that can be extracted from a component under extreme conditions such as the presence of harsh solvents or elevated temperatures. These compounds can contaminate the drug product. Leachables are compounds that leach into the drug product formulation from the component as a result of direct contact with the formulation under normal conditions. Leachables are typically a subset of extractables. Sources of these compounds include plastic components, elastomers, coatings, accelerants, antioxidants, inks, and vulcanizing agents. Phthalates are one specific example. These carcinogens are 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, and, therefore, phthalates, PAHs, or nitrosamines could potentially come into contact with the drug product and be passed on to the patient. Metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and nebulizers can be complex because they may be constructed from a myriad of plastic, rubber, and stainless steel components. Nevertheless, these devices have many advantages (e.g., rapid absorption and onset of activity and reduced dosing) for effective drug delivery.