Extractables and Leachables: An Overview of Emerging Challenges

Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies.
Aug 02, 2008

Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies. The development of unique packaging, novel formulations and delivery systems, and drug-coated medical devices has exacerbated this issue due to the growing possibilities of foreign materials coming into contact with drug products.

In the pharmaceutical industry, it is essential that a selected package adequately preserves the integrity of a product. But sometimes the packaging of pharmaceutical dosages forms can invalidate the most stable formulation. The selection of a package therefore begins with a determination of the product s physical and chemical characteristics, its protective needs and its marketing requirements (1, 2). Proper packaging maintains the integrity of a drug contents and preserves product ingredients at their listed concentrations until the expiration date, maintains the original purity of the drug, and delivers and dispenses the drug (3). Consequently, it is essential that the choice of the packaging materials for any particular product be made only after a thorough evaluation (2).

Primary container-closure systems, as well as other packaging components, have the potential to interact with the dosage form. Potential interaction between the drug product and the package has always been an important issue. It has never been more crucial than it is currently, as the US Food and Drug Administration demands more and more information about every packaging component and its potential to interact with the drug product. Interaction happens mainly in two ways: leachables from the package can get into the drug product, causing contamination, or the drug can be absorbed by the package, causing the package to compromise its barrier characteristics or the drug to lose some of its potency (4).

Packaging regulations and guidances

Table I: Regulation for extractables and leachables in materials and components
Factors that must be considered in evaluating container-closure systems are materials of construction of the systems, surface treatments and/or processing aids, dosage form active ingredients and excipients, sterilization and/or other related processing, and storage conditions (5). A number of regulatory guidances address the evaluations of packaging and delivery systems for pharmaceutical drug products (see Table I). These include those issued by FDA's Committee for Proprietary Medicinal Products (CPMP) and documents related to topics on the development of pharmaceutical packaging components (6).

The United States Pharmacopoeia (USP) and FDA have been and continue to be the driving force behind the safety evaluation of materials and container-closure systems in the US. An important step in such evaluations is characterizing the materials and the chemicals that can migrate or extract from container-closure system components to the drug product. Such basic information is critical to understanding the biological safety and suitability of a container.

A number of tests can be used to establish initial qualification of the container-closure system, and a quality-control plan can help ensure compatibility and safety. FDA's guidance document requires evaluation to establish suitability: protection, compatibility, safety, and performance/drug delivery. This document also provides a structured approach to ranking packaging concerns according to the route of drug administration and likelihood of packaging component-dosage form interaction. A container-closure system found acceptable for one drug product cannot be assumed to be appropriate for another. Each product should have sufficient information to establish that a primary container and its components are right for their intended use (7).