Extractables and Leachables (E&L) Studies

What are Extractables and Leachables?

In the development of biopharmaceutical products and in some cases, medical devices, the FDA requires an impurity profile to make an ultimate assessment of the product’s safety. Beyond consideration of the drug itself, impurities generated by the manufacturing and storage conditions of the product must also be evaluated. These impurities are separated into two classifications: extractables and leachables.

Extractables are defined by the FDA as “compounds that can be extracted from the closed-container system when in the presence of a solvent.” Simply put, these are impurities that can arise from the surface of compounds used to manufacture and store the pharmaceutical product under exaggerated temperatures or when met with a solvent or other form of surface contact. The identification of extractables under these more extreme conditions aids in the identification of leachables, which are collected under milder, more ambient conditions, and are typically present in lower concentrations.

Leachables are defined by the FDA as “compounds that leach into the drug product formulation from the container closure as a result of direct contact with the formulation.” Differing from extractables, leachables are collected under ambient conditions and thus more accurately reflect impurities that can be present over the duration of the product’s shelf life. Leachables may or may not have detrimental effects on a product’s efficacy and/or safety, therefore their identification and quantitation are critical in the development of a safe product.

Analytical Testing Techniques

Ensuring the safety and efficacy of drug products is imperative, prompting thorough assessments by the FDA. These evaluations involve controlled extraction studies and subsequent leachables stability studies.

Controlled Extraction Studies:

In these studies, various extraction techniques employing solvents of different polarities are utilized to identify impurities. Diverse analysis techniques, tailored to the compound, are then applied to enhance accuracy.

Leachables Stability Studies:

Following controlled extraction, leachables stability tests determine whether identified extractants will leach into the drug product formulation from the closed container system. Samples are aged in the final container and evaluated at multiple time points.

At Emery Pharma, we adhere to ISO/IEC 17025 guidelines, ensuring quality in our processes. Our capabilities include:

Extraction Techniques:

  • Soxlet, reflux, sonication, and incubation with solvents based on ISO 10993-18 guidance.

Analytical Techniques:

  • Semi-quantitative screening with LC-MS, GC-MS, HS/GC-MS, LC-UV, and ICP-MS.
    • Thermo Scientific Trace 1310 GC/MS for volatile and semi-volatile compounds.
    • Thermo Scientific Exploris 240 Orbitrap mass spectrometer for non-volatile compounds.
    • ICP-MS for elemental impurities detection.
    • Thermo Vanquish Flex UPLC for ionic species analysis.
    • 400 MHz NMR for structural elucidation.
  • We also offer the development of quantitative methods when needed, ensuring a comprehensive approach to safety and efficacy assessments.