During biopharmaceutical manufacturing, it’s critical that container systems for drug products not release any chemicals that can build up in quantities that could create a risk of toxicity or impact the stability or efficacy of the drug. Extractables and leachables (E&L) refer to compounds which can be either extracted or leached from the container into a drug formulation as a result of direct contact with the drug.
- What are extractables? Extractables are chemicals which can be extracted or “pulled out” from a container when in contact with a solvent as part of a laboratory study. In order to study the risk of materials extraction, experiments are performed, generally using aggressive solvent conditions including acidic, basic, organic and aqueous solvents and sohxlet or accelerated solvent extraction. It’s important that the extraction process does not degrade or deform the material of interest. Compounds present in the resulting extracts are called “extractables.”
- What are leachables? Leachables are chemical substances that leach or “come out” and make their way into the product under normal product, application or storage conditions. There is generally an overlap in that the leachables involved may be classified as a subset of the extractables. Forced or accelerated leachable studies can be performed to assess leachables that migrate under simulated environmental conditions by analyzing the drug formulation after exposure to elevated temperature. However, if the leachable interacts with the drug product or packaging materials, new components can be present. These are termed secondary leachables. Drug formulations often contain buffers, surfactants, fillers and other excipients. This complexity means that there are sometimes secondary leachables that can only be identified after long stability studies over the typical drug shelf life.
- What are extractables and leachables (E&L) studies? E&L studies are in-depth analytical investigations of the chemical interactions between:
- a container closure and a drug product or pharmaceutical formulation
- a drug delivery system and a drug product or pharmaceutical formulation
- an implantable medical device and the human body
- different materials comprising a medical device
- manufacturing components and finished products
- other component interactions relevant in the pharmaceutical or medical device industries
- Why are E&L studies done? These studies are typically performed to create a “worst case scenario” and assist in materials selection and early risk assessment.
- How are extractables and leachables detected? E&L studies can identify key components using a range of analytical technologies:
Quantification of these compounds is performed using relative reference standards, in which a qualified toxicologist calculates the analytical evaluation threshold (AET), above which an extractable or leachable needs to be reported for toxicological assessment. Analytical data for these impurity classes is meant to provide information to help customers determine what further studies are needed to mitigate risks associated with the final product.
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