What are Extractables and Leachables?
When preparing to release a pharmaceutical product to the general public, 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 inorganic and organic 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. Extractables may be generated by manufacturing equipment, packing components, and labels, including inks and adhesives.
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 may form under ambient conditions over the duration of the product’s shelf life. In addition to the sources listed above, leachables may also be formed from product stabilizers, antioxidants, coatings, emulsifiers, lubricants, and dyes. While leachables are often classified as a subset of extractables, leachables studies frequently reveal the identities of species that are not observed in preceding extractables studies. Furthermore, the leachable may further interact with the drug product or packaging materials to form additional components, known as secondary leachables.
Analytical Testing Techniques
Both classes of compounds pose safety and efficacy concerns within the drug product and are required to be assessed by the FDA. Such assessments are carried out through controlled extraction studies followed by leachables stability studies designed according to preceding experiments. Controlled extraction studies involve the employment of multiple extraction techniques done with multiple solvents of varying polarity to identify as many impurities as possible. A variety of analysis techniques are used depending on the compound.
Subsequent leachables stability tests are then performed to identify if the extractants identified will leach out of the closed container system and into the drug product formulation. In these studies, samples of the drug product are aged in the final closed container system and evaluated for leachables at multiple time points.
At Emery Pharma, we have the capability to perform extractions via Soxhlet, reflux, and sonication with a range of solvents of varying polarity. With our Thermo Scientific Trace 1310 GC/MS, we can confidently identify volatile and semi-volatile organic compounds through either head space or direct injection. Non-volatile organic compounds can be identified using our Thermo Scientific Exploris 240 Orbitrap mass spectrometer. In addition to traditional E&L testing, we are capable of further structural elucidation of critical compounds with our on-site 400 MHz NMR.