The International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) endorsed a new draft guidance on extractables and leachables in August 2025 that the FDA has since published for review and comment. The version published by the FDA is accessible at Q3E Guideline for Extractables and Leachables and includes Supporting Documentation: Class 3 Leachable Monographs. The guideline and its supporting documentation provide a comprehensive and harmonized view of risk assessment and control of extractables and leachables in drug products, but let’s take a step back for a moment to orient to the subject matter, extractables and leachables.
Often extractables and leachables, or E&L for short, are discussed in the same breath, as though they are the same entity, but they are very different and should be evaluated and discussed in different ways. Extractables are chemical entities that, as the guideline notes, are intentionally extracted from manufacturing components, packaging, or delivery device components under specified laboratory test conditions. Leachables, as noted in the guideline, are chemical entities that may migrate from manufacturing components, packaging, or delivery device components under the established manufacturing and labeled storage conditions. Thinking of them in another way, extractables are anything that can be extracted from a component under the laboratory conditions, often very harsh or extreme, explored during the extraction. The extractables can be a long list of chemicals, some of which are inert or aren’t a concern, but some extractables do pose a threat to patients, and an assessment of safety should be performed to identify the materials of concern that should be tested for in a leachable study.
Leachables are chemical entities that may be present in the drug product under normal manufacturing and storage conditions. They migrate from the manufacturing or packaging equipment, or from the container-closure system, into the drug product and can expose a patient to unsafe levels of chemicals. Extractables represent what may possibly be present in a drug product, while leachables represent what has actually been identified in a drug product. Not every chemical that can be extracted will go on to leach into a drug product. Leachables represent the actual conditions of manufacturing and labeled storage; while you may be able to extract something in the lab under harsh conditions, when the product is manufactured, stored, and used, the leachables may not be identified or may be detected at very low levels that are below the threshold of concern for safe use.
Additionally, as noted in the guideline, not every drug product needs to be tested for leachables. Evaluation of E&L should be risk-based, and the assessment should leverage anticipated risk and prior knowledge of the product under development as well as periodically throughout the product’s lifecycle to ensure safe use. The conditions of manufacture, the materials that contact the drug during manufacturing and packaging, and the drug-contact components of the container and drug delivery device are examples of information to be evaluated. Some products may not trigger testing as the initial risk may be acceptable; for other drug products, the risk may need to be mitigated through additional study and documentation. For example, a solid oral dosage form, used in adults for short duration or acute use, that is manufactured under mild conditions is a low-risk product that might be successfully evaluated and supported using existing food-contact safety statements and regulatory compliance of the drug’s product-contact components. Conversely, a parenteral product for chronic use that has high-temperature or pressure manufacturing steps and an extractable profile that includes chemicals of concern poses a higher risk; it might be necessary to have the chemicals of concern monitored on stability to ensure that they do not leach into the drug product and the chemicals do not exceed safety thresholds.
The draft guideline provides a framework for the risk assessment process and the information to be provided in an application more clearly than it had been available previously in a single document. The guideline also includes flow charts, example scenarios, and calculations for the Analytical Evaluation Threshold (AET) and, in the supplemental documents, provides some classification and acceptable-exposure-level information for potentially leachable compounds to support the assessment process. Additionally, the guideline provides clearer guidance on when to reassess risk as well as examples of new information that might trigger the need for a new assessment and generation of additional documentation to support the change in risk profile.
The guideline is open for comments under Docket FDA-2025-D-4678. The docket may be accessed here, and comments may be submitted electronically at Regulations.gov. Now is the time to give your opinion and let the FDA know whether the guideline provides too much detail or not enough detail and which parts need further clarification. The comment period is open now through January 30th. Happy commenting!
If you have questions on extractables or leachables, need help with a risk assessment regarding a drug product, or have questions on other regulatory guidances, please reach out to us for a consultation at LCS@LachmanConsultants.com.
