The Evolving Regulatory Expectations for Extractables and Leachables

Extractables and leachables (E&L) assessment has always been a key area of focus for the pharmaceutical and food sectors in order to ensure that there is no inadvertent toxicity related to packaging. However, for medical devices and nicotine products, it is a critical element due to the potential for leaching from the device/ product itself. Whether the product is an asthma inhaler or an e-cigarette, regulators expect manufacturers to demonstrate a clear, scientifically robust understanding of how materials behave under realistic conditions of use.

The new ICH Q3E Guideline, which is currently available as a draft for public consultation, not only provides a clear and overdue framework for managing extractables and leachables but also highlights the regulatory expectations for their systematic identification, qualification and safety assessment.

The recent FDA February 2026 PMTA Roundtable, reinforced the importance of E&L assessments. Previously, hazardous and potentially hazardous chemical (HPHC) assessments were considered to be the mainstay investigation to prove “Appropriate for the Protection of Public Health” (APPH) by comparing noncancer and cancer risks to that of combustible cigarettes and other ‘similar’ devices. FDA has emphasised that all chemical sources contributing to overall risk must be considered.

Particular attention is being paid to substances contributing to cumulative excess lifetime cancer risk (cELCR).

Extractables and leachables data should therefore be integrated into overall ingredient characterisation, rather than assessed in isolation.

The key parts of the E&L pathway are illustrated below, specifically as they apply to Toxicology.

While the evaluation of risk in the Toxicological Risk Assessment for both extractables and leachables are key deliverables, three key components also warrant further illustration:

• Materials Assessment. The chemicals that are used in the manufacture of the device/product may be of toxicological concern. They need identification and quantification.
• Selection of Analytical Evaluation Thresholds (AETs). The quantification levels for analytical methods need to be based on the Safety Concern Thresholds (SCTs) for each chemical of concern. The toxicologist identifies the toxicological risk, the level of the chemical that would not be expected to lead to that concern, and this determines the AET.
• Degradants. Aging or stressed chemicals (specifically under heat) are likely to result in degradation products that are hard to predict but may be of toxicological concern. Since these cannot easily be targeted, a likely lack of complete identification and quantitative risk assessment requires chemical prediction and often assumptions resulting in worst case scenario use. In aerosolised systems, such as inhalers and e-cigarettes, the regulatory question therefore shifts from theoretical presence within a formulation to actual inhalation exposure under defined use scenarios. Here, both known constituents and plausible degradation products therefore require systematic consideration.

Given all of these considerations, E&L assessments cannot be approached as standalone laboratory exercises. Study design must be based on how the product is used and must be scientifically justified. In addition, the calculation of AETs and the prediction of degradation pathways require transparent rationale.

Experience also plays a key role. Across polymers, elastomers, adhesives, heating elements and packaging components, recurring extractables patterns and material-specific degradation behaviours emerge. An accumulated understanding of these profiles allows potential issues to be anticipated and addressed during study design. Early identification of material risk reduces the likelihood of reformulation, delay or detailed regulatory questioning at a late stage.

Formulation science must also be considered. Flavour systems, excipients and other ingredients can behave differently under heated or aerosolised conditions. Interactions between materials and formulations may alter migration dynamics or generate secondary products. Evaluating materials and ingredients in isolation risks overlooking exposure pathways that only become evident when the system is assessed holistically.

Ultimately, extractables and leachables assessment is not solely about regulatory compliance, it should be a key responsibility during product design. Selection of high-quality materials, and early, scientifically rigorous evaluation reduces uncertainty, mitigates downstream risk and demonstrates that safety has been considered systematically from the outset.

In summary, the risk assessments for extractables and leachables, while requiring detailed knowledge of the human risk assessment framework and adherence to the new Q3E guideline, are a key part of the overall risk assessment of a device or product, and their complete evaluation in terms of risk are as important as the inherent risk of the ingredients and their bi-products. However, the role of the toxicologist must be realised earlier in the process, preferably when designing the product, but certainly when designing the studies that assess the product, evaluating the AETs for each chemical, and understanding the behaviour of each chemical under stressed conditions.

In an increasingly technically sophisticated regulatory landscape, Broughton has recognised that E&L is no longer peripheral. It is central to demonstrating that all parts of product safety have been assessed transparently, quantitatively, with appropriate scientific judgement, and at the right time. 

Find out more about Broughton's toxicology testing services.