ICH Q3E Guideline: Extractables & Leachables
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ICH Q3E Draft Framework for Extractables & Leachables
The ICH Q3E Guideline (draft) has been released on 01 August 2025 for public consultation. This marks a significant milestone in the global harmonization of impurity control, specifically addressing E&Ls in drug products and drug-device combination products. Furthermore, building on existing ICH guidance (i.e. Q3A–Q3D (impurities), M7 (mutagenic impurities), and Q9 (quality risk management)), the ICH Q3E guideline provides a comprehensive framework for assessing and controlling E&L risks across the entire product lifecycle. A visual overview of this framework is shown in Figure 1, illustrating the iterative nature.
Figure 1. ICH Q3E Framework for Extractables and Leachables
1) ICH Q3E Guideline: Risk-based E&L study design
Following the principles outlined in the ICH Q3E framework, extractables and leachables (E&L) studies are tailored to the risk profile of the drug product. As a result, this ensures that testing is both scientifically justified and tailored to the product’s intended use.
Key risk considerations
Safety aspects:
- Route of exposure (e.g. oral, dermal, inhalation, parenteral)
- Duration of exposure
- Patient population
Pharmaceutical quality aspects:
- Dosage form
- Storage conditions
- Manufacturing conditions
- Packaging complexity
Study designs:
- Extractables testing under exaggerated conditions to identify potential leachables
- Leachables testing under real-time or accelerated stability conditions to confirm actual migration into the drug product.
Extractables and Leachables correlation
A central concept in E&L risk assessment is the correlation between extractables and leachables
Figure 2. Correlation between Extractables and Leachables
Why correlation matters:
- Predictive value: extractables help anticipate potential leachables.
- Efficiency: enables targeted leachables testing, reducing unnecessary analysis.
- Safety focus: Toxicological qualification is limited to compounds with actual patient exposure.
Therefore, this correlation must be re-evaluated throughout the product lifecycle, especially when changes occur in formulation, packaging, or manufacturing.
2) Identification and selection of organic leachables
After completing E&L studies, laboratories should identify, quantify and select organic leachables exceeding the analytical evaluation threshold (AET) for toxicological risk assessment.
The AET is based on the Safety Concern Threshold (SCT). In turn, the SCT defines an exposure level below which a leachable is expected to pose a negligible risk, whether mutagenic or non-mutagenic.l
The Safety Concern Threshold (SCT)
Furthermore, the SCT is a route- and duration-specific threshold that incorporates the following toxicological principles:
- Threshold of toxicological concern (TTC) for mutagenic impurities
- Qualification threshold (QT) for non-mutagenic impurities
- Local toxicity thresholds
Moreover, these thresholds were derived from a review of approximately 330 potential leachable PDEs, providing a robust foundation for systemic safety evaluation (Table 1).
Table 1. Systemic and local toxicity thresholds
*Note: For ICH S9 (anti-cancer) products, the TTC is not applicable; the SCT is defined by the QT.
Consequently, only compounds exceeding the AET are selected for toxicological qualification. This ensures a focused safety evaluation, avoiding unnecessary qualification of compounds with low toxicological relevance.
3) ICH Q3E Guideline lifecycle-based re-evaluation
Another important aspect of the ICH Q3E Guideline is the emphasis on lifecycle-based re-evaluation of the leachables profile. ICH Q3E acknowledges that leachables may evolve over time due to a variety of factors, and therefore should not be assessed as a one-time exercise. Consequently, Q3E promotes ongoing risk management throughout the product’s lifecycle.
What are re-evaluation triggers?
- New (toxicological) information
- Changes in formulation, packaging or manufacturing
- Altered patient exposure (e.g. posology, treatment duration, exposure route, patient population)
- New indications of use affecting the benefit-risk balance
- Updates to storage conditions and shelf-life
What does lifecycle monitoring involve?
- Re-performing E&L studies and correlation
- Re-assessing AETs and SCTs
- Re-qualifying previously assessed leachables (new toxicological data
4) Establishment of acceptable exposure levels
Classes of leachables
To support risk prioritization, ICH Q3E introduces a classification system for leachables (Table 2). In practice, the system helps prioritize which compounds require in-depth evaluation and should be revisited during lifecycle-based re-evaluation, especially when new toxicological data or product changes arise.
Table 2. Leachable Classification System
Class |
Type |
Criteria |
Guidance |
|---|---|---|---|
|
Class 1 – Leachables to be avoided |
(Predicted) Mutagens/Non-Mutagens |
|
Avoid when feasible. Exposure must not exceed compound-specific acceptable exposure level |
|
Class 2 – Leachables to be limited |
(Predicted) Mutagens/Non-Mutagens |
|
Qualified up to the (less-than-lifetime) TTC or QT relevant to the drug product |
|
Class 3 – Leachables with low toxic potential |
Non-mutagens |
chronic PDE in excess of the levels at which leachables are typically observed |
Qualified up to 1.0 mg/day or compound-specific PDE without further safety justification |
AI = acceptable intake ; PDE = permitted daily exposure; QT = qualification threshold; TTC = threshold of toxicological concern
If a leachable exceeds the AET and is selected for qualification, a compound-specific toxicological risk assessment is performed. Specifically, this process integrates:
· Available toxicological data, including:
o Pharmacological/biological data
o Toxicokinetics
o Systemic toxicity
o Sensitisation potential and local irritation,
o Developmental and reproductive toxicity (DART)
o Genotoxicity and carcinogenicity
o Additional information
· Structure–activity relationships (SAR) and in silico predictions.
· Read-across approaches, using data from structurally/metabolically similar compounds.
Overall, the assessment should follow a weight-of-evidence approach, integrating all available data.
Moreover, to establish a PDE, a Point of Departure (PoD) is selected from the most sensitive and relevant toxicological endpoint, such as
- NOAEL – No Observed Adverse Effect Level
- LOAEL – Lowest Observed Adverse Effect Level
- BMDL – Benchmark Dose Lower Confidence Limit
To account for uncertainties in the data and extrapolation across species and populations, toxicologists apply uncertainty factors (UFs). These factors help ensure that the derived PDE is protective of all patient groups, even in the presence of data gaps or variability. In addition, while F1–F5 uncertainty factors were already covered in ICH Q3C, Q3E expands the scope by introducing:
- F6: route-to-route extrapolation: used when toxicological data are available for one route (e.g., oral) but the drug product is administered via another (e.g., parenteral or dermal).
- F7: read-across: applied when using surrogate data from structurally similar compounds, to account for uncertainty in the extrapolation.
Finally, these additional factors support the derivation of robust, scientifically justified PDEs, tailored to the product’s route of administration, duration of use, and patient population.
5) Key takeaways from the ICH Q3E Guideline
ICH Q3E guideline offers a clear, iterative roadmap for managing extractables and leachables throughout the product lifecycle. Overall, by combining risk-based study design, toxicological classification, and ongoing re-evaluation, the ICH Q3E Guideline prioritizes patient safety throughout impurity control.
Frequently
Asked Questions
The ICH Q3E Guideline is a draft guideline developed by the International Council for Harmonisation (ICH) to establish a harmonized framework for assessing and controlling extractables and leachables (E&L) in drug products and drug-device combination products. It provides a lifecycle-based, risk-driven approach covering E&L study design, toxicological assessment, acceptable exposure levels, and ongoing re-evaluation.
The ICH Q3E Guideline is developed to address the need for a consistent global approach to managing extractables and leachables risks. It builds on existing ICH quality and impurity guidance, including ICH Q3A–Q3D, ICH M7, and ICH Q9, while specifically focusing on potential chemical substances that may migrate from packaging, manufacturing components, or device materials into drug products.
Extractables are chemical compounds that can be released from a packaging material, manufacturing component, or device under exaggerated laboratory conditions. Leachables are compounds that actually migrate into a drug product during storage or use and may result in patient exposure.
The relationship between extractables and leachables helps predict potential risks and supports a targeted approach to safety evaluation.
The ICH Q3E Guideline applies a risk-based approach. The extent of E&L testing depends on factors such as the route of administration, duration of exposure, patient population, dosage form, storage conditions, manufacturing process, and packaging complexity.
This approach ensures that studies are scientifically justified and focus on compounds with potential patient exposure.
The Analytical Evaluation Threshold (AET) is a level used to determine which leachables require identification, quantification, and further toxicological assessment. It is derived from the Safety Concern Threshold (SCT) and helps focus evaluation efforts on compounds with potential safety relevance.
The Safety Concern Threshold (SCT) is an exposure-based threshold below which a leachable is considered to have negligible safety concern, considering both mutagenic and non-mutagenic effects. The SCT is route- and duration-specific and supports the selection of compounds requiring toxicological qualification.
No. The ICH Q3E Guideline does not replace existing scientific practices or standards. Instead, it provides a harmonized framework that complements existing regulatory expectations and integrates principles from other ICH guidelines, including impurity control, mutagenic risk assessment, and quality risk management.
The ICH Q3E Guideline promotes lifecycle-based monitoring rather than a one-time assessment. Re-evaluation may be needed when there are changes in formulation, packaging, manufacturing processes, storage conditions, shelf-life, patient exposure, or when new toxicological information becomes available.
The ICH Q3E framework introduces three general categories of leachables:
- Class 1: Leachables to be avoided due to higher toxicological concern.
- Class 2: Leachables that require limitation and qualification within defined exposure limits.
- Class 3: Leachables with low toxic potential that may be qualified using established exposure limits.
This classification supports prioritization during toxicological evaluation.
Acceptable exposure levels, such as permitted daily exposures (PDEs), are established through a compound-specific toxicological assessment. This assessment considers available data from multiple toxicological endpoints, including acute toxicity, skin and eye irritation, skin sensitisation, repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and absorption, distribution, metabolism, and excretion (ADME) data.
The available data are evaluated using a weight-of-evidence approach to determine the dose–response relationship and identify the most relevant critical effect. A Point of Departure (PoD), such as a NOAEL, LOAEL, or BMDL, is then selected. Finally, uncertainty factors are applied to account for data gaps and differences in species, patient populations, exposure routes, and other sources of variability, resulting in a scientifically justified PDE.
The ICH Q3E Guideline is relevant for pharmaceutical manufacturers, packaging developers, analytical laboratories, toxicologists, regulatory professionals, and companies developing drug-device combination products where extractables and leachables may affect product quality or patient safety.
The ICH Q3E Guideline was released as a draft guideline for public consultation on 1 August 2025. Following the consultation process, the guideline may be revised before reaching final adoption.