ICH Q3E: The First Global Guideline for Extractables and Leachables
Until now, extractables and leachables were governed by pharmacopoeial chapters and industry recommendations. ICH Q3E is the first attempt to give them a harmonized, impurity-style framework, and it is moving through the approval process now.
01Why this guideline matters now
The earlier post in this series on extractables and leachables was built on USP chapters and the PQRI threshold concepts. Q3E is the layer that is now being added on top, and it changes who has to be at the table.
ICH describes Q3E as a holistic framework for assessing and controlling leachable impurities, expanding the existing impurity guidelines for drug substances (Q3A), drug products (Q3B), residual solvents (Q3C) and elemental impurities (Q3D), alongside the M7 guideline on DNA-reactive impurities.2,3 It covers leachables from manufacturing systems, container closure systems and delivery device components, and it adds a standardized safety assessment based on qualification thresholds that take route of administration and patient exposure into account.1
Two features stand out. First, leachables are sorted into potency classes, so the level of toxicological effort scales with concern. Second, it ties E&L directly to the nitrosamine topic covered earlier: N-nitroso compounds sit in the ICH M7 cohort of concern and land in the strictest class.4
Extractables and Leachables — Dennis Jenke
The current Wiley reference on chemical characterization and safety assessment of extractables and leachables, the discipline Q3E is now formalizing. It is the same book recommended in the earlier E&L post and remains the best background for reading the draft.
Find it on Amazon →02The regulatory landscape
| Document | Body | Status and role |
|---|---|---|
| ICH Q3E — Guideline for Extractables and Leachables | International Council for Harmonisation | Step 2 draft released Aug 2025, with Step 4 adoption anticipated around June 20271,5 |
| Q3E draft guidance and Class 3 leachable monographs | U.S. FDA (CDER/CBER) | Draft published Nov 2025, non-binding, not for implementation3 |
| Supporting Documentation: Class 3 Leachable Monographs | ICH / EMA | Companion document for low-concern leachables, such as common fatty acids7 |
| USP <1663> and <1664> | United States Pharmacopeia | Existing compendial approach that Q3E aims to align with and harmonize across regions1 |
The draft includes six appendices, covering typical E&L workflows and, in Appendix 4, the potency classes for leachables.2 One commentary notes that it is the first guideline in the ICH Quality portfolio to explicitly incorporate new approach methodologies, such as in silico toxicology tools, into its safety assessment.6
03The Q3E assessment workflow
Q3E lays out a staged workflow that starts with extractables and works toward leachables and safety assessment. Click each stage to expand it.
An adequate extractables study uses solvents and extraction conditions relevant to the product and component. Observed extractables are quantified against appropriate standard compounds and compared with the analytical evaluation threshold (AET).4
- Quantitative extractables work focuses on compounds above the AET
- Manufacturing components with short contact time and large volume-to-surface ratios are treated as lower risk1
Where extractables data cannot be used to qualify a component, the drug product is studied for the leachables that actually migrate, targeted using the extractables profile as a guide.1,4
- Targeted leachables are identified and quantified in the real product
- Timepoints should align with the stability program covered earlier in this series
Organic leachables above the AET are identified, quantified and classified by hazard. Each class has its own expectation, from avoidance to qualification at a general level.5
- Mutagenicity is predicted or tested using the M7 approach
- Where needed, a compound-specific limit is derived toxicologically
Mutagenic Impurities: Strategies for Identification and Control — Andrew Teasdale
Q3E's classes lean directly on the ICH M7 cohort of concern and its Class 1 to 3 categories. This book covers how those are assigned, including in silico assessment, which is the skill the new classification demands.
Find it on Amazon →04The leachable classes
The draft sorts leachables by potency. Switch tabs to compare the classes and how manufacturing components are treated.
Class 1: leachables to be avoided. Compounds in the ICH M7 cohort of concern, such as aflatoxin-like, N-nitroso and alkyl-azoxy structures, that meet M7 Class 1 criteria with an acceptable intake below 1.5 µg/day. The draft says they should be avoided when practically feasible.4,5
Class 2: leachables to be limited. Leachables that are mutagenic or predicted mutagens with a higher acceptable intake, and other compounds that call for a defined limit. These need a compound-specific or threshold-based justification rather than avoidance.4,5
Class 3: leachables with low toxic potential. Non-mutagenic compounds of relatively low concern. As summarized from the draft, they can be qualified up to a general level of 1.0 mg/day, or a compound-specific limit, without further safety justification. A companion document supplies monographs for common examples.5,7
Manufacturing components. Equipment and systems with short contact time and a large volume-to-surface ratio are treated as lower risk, and the draft expects fewer extractables above the AET from them than from long-term packaging contact.1
05Leachable exposure checker
Whatever the class, the practical question is the same: how much of a leachable does a patient receive each day, and how does that compare with the applicable limit? This tool does that arithmetic.
Daily exposure vs. class limit interactive
Daily exposure (µg/day) = leachable per unit (µg) × units per day. For Class 3 the limit defaults to the 1.0 mg/day (1000 µg/day) level as summarized from the draft. For Class 1 and 2, enter the compound-specific limit from your toxicological assessment.
This is a simplified illustration based on a draft guideline. Real assessments depend on classifying each compound, the route of administration, treatment duration and patient population, and on the final Q3E text. Never rely on this tool alone for a safety conclusion.
Casarett & Doull's Toxicology: The Basic Science of Poisons
Class 2 leachables and anything needing a compound-specific limit end in a toxicological risk assessment. This standard toxicology reference supports reading and challenging the dose-response and uncertainty-factor logic behind those limits.
Find it on Amazon →06Q3E readiness self-check
Readiness checklist
07Where programs will be challenged
- Assuming existing studies will carry over unchanged. Studies designed around USP chapters may lack the quantification and classification detail the draft expects.
- Missing a cohort-of-concern leachable. N-nitroso structures in a packaging extract put a compound into the strictest class, so the nitrosamine risk assessment and the E&L program need to talk to each other.
- Treating Class 3 as a free pass. The general qualification level applies to non-mutagens of low concern, so a compound still has to be correctly classified first.
- Waiting for the final text before preparing. The draft is stable enough to show the direction, and gap assessments take months.
08Specimen quality forms
A Q3E gap assessment worksheet and a leachable classification and exposure record, to adapt to your own E&L procedure.
Form QE-01 — Q3E Gap Assessment Worksheet
Specimen only — not a controlled document.
| Q3E element | Existing evidence | Gap? | Action |
|---|---|---|---|
| Extractables study (solvents, conditions, quantification) | |||
| AET derivation | |||
| Leachables study | |||
| Mutagenicity assessment / class assignment |
Form QE-02 — Leachable Classification & Exposure Record
Specimen only — one row per identified leachable above the AET.
| Leachable | Class (1/2/3) | Daily exposure (µg/day) | Applicable limit | Conclusion |
|---|---|---|---|---|
These specimen forms illustrate typical content only. Your quality system's document control procedure takes precedence over this format.
Leachables and Extractables Handbook — Douglas J. Ball (Ed.)
Written with PQRI working group contributors, it documents the threshold concepts that Q3E now builds on, which makes it useful for seeing how the draft differs from earlier practice.
Find it on Amazon →09References
- International Council for Harmonisation. "ICH Q3E: Guideline for Extractables and Leachables — Step 2" (presentation). database.ich.org
- Regulatory Focus (RAPS). "ICH releases Q3E guideline on controlling extractables and leachables in drugs." raps.org
- U.S. Food and Drug Administration. Q3E Guideline for Extractables and Leachables — Draft Guidance, November 2025 (Docket FDA-2025-D-4678). fda.gov
- U.S. Food and Drug Administration. "Q3E Guideline for Extractables and Leachables" (draft text). fda.gov
- Agirad. "Understanding the ICH Q3E Draft Guideline: A New Framework for Extractables & Leachables Risk Assessment." agirad.com
- PMC. "Extractables and Leachables in Pharmaceutical Products: Potential Adverse Effects and Toxicological Risk Assessment." pmc.ncbi.nlm.nih.gov
- European Medicines Agency. ICH Q3E Guideline for Extractables and Leachables — Supporting Documentation: Class 3 Leachable Monographs (Step 2b). ema.europa.eu
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