Extractables and leachables: practical considerations

Alan Wood, E&L Technical Expert at RSSL, considers the need for extensive E&L testing to ensure that pharmaceutical products maintain their efficacy.


To ensure that pharmaceutical products maintain their efficacy, it is critical for extensive E&L testing to dismiss any chance of the products becoming toxic from its container closure system.

Pharmaceutical products interact with a variety of manufacturing and container closure system components during their shelf lives, which may migrate into the pharmaceutical product. Migratory species may be benign or toxic. They could also react with the active pharmaceutical ingredient (API) or excipients within the product.
This could affect product efficacy or, in a worst-case scenario, generate byproducts that render it unusable.

The FDA and European Medicines Agency (EMA) require an assessment of these component-product interactions to identify and assess any toxicological risks that consequently arise. These are addressed via extractables and leachables (E&L) studies.

Extractables are species migrating from manufacturing and packaging components during forced extraction. Leachables are species observed in the product under the gentler conditions of on-shelf storage and should have been observed in the preceding extractables study. In reality, unique leachable species are also observed, such that the two species subsets do not fully overlap.

Leachables migrating from manufacturing and packaging components must be identified and monitored over the shelf life of the pharmaceutical product. This permits toxicological assessments to be made, ensuring patient safety.

Key to this are safety concern thresholds (SCTs), which were introduced by the Product Quality Research Institute (PQRI) E&L working group. These are defined as the dose below which an individual leachable would not elicit effects, carcinogenic or otherwise, that could constitute a safety concern.

The route of administration and the degree of product-packaging contact help determine SCTs. To assign risk from leachable species to the product under investigation, the FDA have developed a matrix for this purpose.

The PQRI recommend that the high-risk SCT is set at 0.15µg/day for aerosols and injectables, while the low-risk SCT is set at 1.5µg/day for oral tablets and capsules, both having been justified from toxicological and safety perspectives. Where exposure is short term or a life-threatening condition is treated, SCTs can be raised substantially higher.

Originally published by Pharmaceutical Manufacturing and Packing Sourcer February 2020, pages 56-59. © Samedan Ltd.

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For further information or to discuss your E&L requirements, please contact the RSSL customer services team on +44 (0)118 918 4076 or email enquiries@rssl.com.