Extractables & Leachables (E&L) - FAQs
This page has a few questions and answers that I hope will find useful
Questions
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Why are leachables not typically covered by regulatory guidance for impurities such as ICH Q3A or B, despite being impurities themselves?
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What factors influence the probability of leachables migrating from source materials into a drug product?
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Explain the primary purpose of an extractable study.
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List three examples of substances that can be classified as extractables.
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How does the design of extractable studies aim to achieve their purpose, and what effect does this have on the detected substances?
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Identify three key experimental variables that can significantly influence the results of an extractable study.
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Describe a scenario where a leachable might not be considered an extractable, despite the general relationship between the two.
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What is the significance of using extractables as a "worst-case" surrogate for predicting leachables?
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What is the fundamental difference between how leachables and extractables are "created" or observed?
Answer 1:
Leachables are substances that migrate from packaging or manufacturing materials into a pharmaceutical formulation due to the action of the formulation itself. Extractables, on the other hand, are substances that can be removed from these materials through deliberately designed, accelerated experimental procedures.
Answer 2:
Leachables are not covered by normal impurity expectations like ICH Q3A or B because their source is not the Active Pharmaceutical Ingredient (API) or its synthesis. Instead, they originate from the materials used in the packaging or manufacturing system of the pharmaceutical.
Answer 3:
The probability of leachables migrating is influenced by their concentration and type in the source materials, and the likelihood of their removal by the formulation. Factors such as time, temperature, and the contact area between the source and the drug product fluid also play crucial roles.
Answer 4:
The primary purpose of an extractable study is to understand what substances are contained within packaging or manufacturing materials. These studies involve solvent extractions designed to accelerate and exaggerate the removal of substances, making them easier to detect and identify.
Answer 5:
Examples of substances that can be classified as extractables include additives used to improve material properties (e.g., antioxidants, plasticizers, fillers), or residues and degradation products (e.g., manufacturing solvents, unreacted monomers, peroxide reaction products).
Answer 6
Extractable studies are designed to accelerate and exaggerate the removal of substances from materials, often using harsh conditions. This ensures that a wider range of potential impurities are detected, representing a "worst-case" scenario for what might potentially leach into the drug product.
Answer 7:
Three key experimental variables that can significantly influence the results of an extractable study are the type of solvent used, the temperature at which the extraction takes place, and the length of time the experiment is conducted for.
Answer 8:
A leachable might not be considered an extractable if it is a reaction product formed when a substance from the material interacts with an element of the formulation, and the extractable study failed to exactly reproduce these specific conditions. Another reason could be poor experimental design in the extractable study failing to predict it.
Answer 9:
Using extractables as a "worst-case" surrogate helps to predict what leachables may be present and in what quantities they might be leached into the drug product. This allows for proactive assessment of potential patient exposure and safety risks, even before actual leaching occurs under real-world conditions.
Answer 10:
Leachables are "created" or observed through the natural, often slow, interaction of a pharmaceutical formulation with its container or manufacturing system. Extractables, conversely, are observed as a result of active, controlled, and often aggressive experiments designed by investigators to purposefully remove and identify substances from materials.