Charting A New Course: Extractable and Leachable Testing

Derek Wood, an associate director for PPD^® Laboratories GMP Lab, discusses the growth of extractables and leachables in the required testing for pharmaceutical products.

Extractable/leachable (E&L) testing includes the evaluation of potential or actual impurity compounds that may migrate into a drug product from various sources, including the final container/closure components, peripheral packaging, manufacturing or product administration components. Discussions of E&L testing have shifted significantly from where they were just a decade ago. Prior to 2010, the emphasis was on inhaled products (metered dose inhalers [MDI], dry powder inhalers [DPI], etc.), and the final container/closure. Today, the focus is on parenteral products, including biologics or other large molecule products, and the latest E&L topics highlight manufacturing process evaluations. Parenteral products are defined in this case as products administered through the skin, and often refer to injectables (from pre-filled syringes, or vialed products that are administered by an injection, or IV administration) or transdermals.

Ten and more years ago, E&L professionals were looking for ways to arrive at a better-defined experimental approach for conducting E&L studies for inhaled products, and to answer the question “How low do you go?” in reporting thresholds. That put the emphasis on inhaled products, which were of greatest interest due to: 1) the high potential risk based on the route of administration (directly to the lungs and systemic circulation); 2) the number and type of potentially leaching components that are part of the MDI metering valve system; and 3) the high extracting properties of the propellants used in MDI products.

Joint efforts in clinical trials

The industry came together and generated a “points to consider” document that in turn helped usher in the formation of the Orally Inhaled and Nasal Drug Product (OINDP) working group of the Product Quality Research Institute (PQRI). The PQRI OINDP working group included representation from industry, academia and the U.S. Food and Drug Administration (FDA). The group included laboratories that generated data in support of the approach recommendations, as well as toxicologists who evaluated database information that resulted in established safety concern thresholds for E&L reporting. PPD was one of the member organizations of the PQRI OINDP. We also contributed laboratory data and participated in sessions that culminated in the PQRI working group 2006 publication, “Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products.”

In the 10 years since, the industry largely applied a similar approach for other types of dosage forms, such as parenteral products. Parenteral products pose unique challenges; however, such as their typical need for much larger dosage volumes compared to inhaled products. The evaluation of parenteral products often includes a review not only of the long-term storage container/closure, but also the components used for administration of the product, such as IV bags or administration sets. An exposure of the product to an IV bag may be for a day or less, so the use of simulation-type studies was introduced, where the actual exposure duration and conditions are simulated in the laboratory to evaluate E&L. A new PQRI working group was formed for Parenteral and Ophthalmic Drug Products (PODP) shortly after the OINDP recommendation was published, and that group’s guidance is expected to be finalized and published later this year.

The importance of E&L

A significant portion of the growing, innovative treatment options and therapies being developed for patients today falls under the realm of biologic medicines. These types of products are most often parenterally administered, so they are a high risk for E&L based on route of administration, but they also pose unique properties that make E&L even more critical. Especially for biopharmaceutical products, leachables pose not only a potential hazard for direct patient safety, but also a potential concern for product integrity. Leachables may interact with the drug product to cause product quality or efficacy issues and could indirectly cause patient safety concerns, for example, by causing an immunologic response.

Large protein molecules and biologic products are more likely to directly interact with certain leachable compounds due to the chemical nature and complex folding of the protein. In addition, proteins are often amphiphilic, meaning they present both water soluble and water insoluble chemical properties, and the solubilizing effect of certain formulation constituents common to biopharmaceuticals, can hasten leachable migration. Another key aspect of biologic products in particular, and which is a current topic of debate in industry, is the evaluation of components used in the manufacture of large molecule products.

Due to the nature of biologics, the manufacturing process often is made up of disposable, single-use system components. These components in general tend to be made of materials that can be more likely to contribute leachables. Different industry groups have proposed approaches or discussions on this topic, including the BioPhorum Operations Group (BPOG), which has published a protocol for the evaluation of single-use systems. This protocol, intended for the suppliers of components used by pharmaceutical manufacturers, has been adopted by some suppliers and in other cases certain pharmaceutical companies are using this protocol, often in modified format, as a basis for conducting their own E&L process evaluations for their specific products.

More enhancements underway

As the E&L testing arena continues to mature, more standardized approaches are being undertaken. This is evidenced by the previously mentioned PQRI working group recommendations: first, for OINDP and soon to be issued for PODP, but also in the form of complementary, updated USP (United States Pharmacopeia) chapters. New chapters will be available for public comment likely this year, which will include risk assessment ranking and a recommended standard extraction protocol for testing of high-risk process components.

Although E&L testing is becoming more standardized, the approach taken requires careful evaluation and scientific rationale or justification for such a breadth of products that require evaluation. Since inhaled and parenteral products are considered higher risk for E&L, they all require an E&L assessment as part of the regulatory submission package. As such, E&L testing remains a large and growing aspect to the required testing for pharmaceutical products, especially for the growing biologics industry.

Derek Wood is an associate director for PPD® Laboratories GMP Lab in development and validation.