Examining the Growing Challenge of Extractables and Leachables

Experts share insight into extractables and leachables testing, including high-risk products, analytical testing, and regulatory requirements from FDA and EMA.
Nov 02, 2012
Volume 36, Issue 11

Extractables and leachables (E&L) are a growing area of concern for regulators, necessitating more oversight from pharmaceutical manufacturers. Pharmaceutical Technology conducted an industry roundtable to find out more about how extractables and leachables are being approached in the pharmaceutical industry. Participating in the roundtable were: Piet Christiaens, scientific director at Toxikon Europe; Andrew Feilden, chemistry operations director, at Smithers Rapra; Allen Kesselring, scientific director at EAG Life Sciences; Paul Killian, analytical technology R&D manager at EMD Millipore Corp.; and Wayland Rushing, senior scientific advisor at ABC Laboratories.

At-risk products

PharmTech: What are the most common causes and types of E&L? Are certain drug-delivery and packaging components or product types more at risk?

Feilden (Smithers Rapra): Leachables can come from any part of the supply chain or manufacturing process. Issues can arise from the container–closure system itself, the secondary packaging, the manufacturing process, and even the storage environment. Typically the longer the contact time and larger the contact surface area the higher the degree of risk of leachables. The drug-delivery systems most at risk are inhalation aerosols and injectable suspensions. As a rule of thumb, the container–closure systems for these types of products have a large elastomeric content that tends to produce more leachables. Another area of major concern for regulators is biological formulations. Even though a leachable in its own right may be safe, it may have a significant impact on the properties of a biological formulation, such as aggregation, particle formation, or other product quality issues.

Kesselring (EAG Life Sciences): E&L studies are traditionally associated with orally inhaled nasal drug products, ophthalmic products, and injectable products. The quick and efficient transport of material to the bloodstream, which make these drugdelivery routes highly effective, also makes them susceptible to impurities arising from the packaging (this neardirect exposure concern also extends to many topical, transdermal, and implantable products). In addition to route of delivery, exposure quantity, and length of use are other key considerations that must be evaluated during E&L testing.

Killian (EMD Millipore): I perform E&L studies on single-use processing equipment. The most common types of E&L are small-oxygenated compounds, such as ketones, aldehydes, and organic acids generated from the gammairradiation process. The compounds and concentration will vary based on the strength of the gamma irradiation; the higher the dose the greater the number and concentration of these compounds. Other common compounds may include breakdown products from antioxidants added to protect the plastics, siloxanes from silicone tubing, and residual solvents from filters.

Rushing (ABC Laboratories): Some drugdelivery systems are at higher risk for E&L issues. Liquid-based parenterals and inhalation products (specifically metered-dose inhalers and inhalation solutions) tend to attract the greatest regulatory scrutiny. Because of the nature of these formulations, it is not uncommon to observe leachables above the recommended safety concern thresholds set for the toxicological evaluation of leachables in final-drug products. A second common source of E&L problems we have seen at ABC Laboratories is the actual labels that are applied to the drug product bottles. The inks and glues used in labeling have been a common source of leachables in several drug-device configurations.

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