EMA publishes Comments on the ICH Q3E Draft Guideline for Extractables and Leachables
Introduction
Pharmaceutical products may come into contact with plastic materials during manufacturing, storage, and administration. As a result, organic substances can migrate from manufacturing components (for example, filters, tubing, and complex single-use assemblies), container-closure systems, or delivery devices. These impurities are assessed as extractables and leachables (E&L) and can affect product quality and patient safety. Extractables are chemical entities intentionally extracted from components under specified laboratory conditions and represent potential leachables. Leachables are substances that migrate into the drug product under actual manufacturing and storage conditions.
In 2020, the International Council for Harmonisation (ICH) started the work on the new guideline by publishing a concept paper to address the risk of E&L and convened an Expert Working Group (EWG) to develop a dedicated guideline that would complement existing impurity frameworks (ICH Q3A-D, M7). The resulting ICH Q3E draft guideline introduces a science- and risk-based framework grounded in quality-by-design principles, with a focus on critical aspects of E&L assessment and control for pharmaceutical products. The guideline seeks to standardize a safety assessment built on multiple qualification thresholds in the context of route of administration, drug indication, and patient exposure1.
Released for public consultation in August 2025, the step 2b document received extensive feedback across ICH regions, including EMA's compilation of 177 pages of comments2 and additional submissions to other authorities3. The targeted finalization by mid-2027 faces challenges given the volume and diversity of input. Nonetheless, the draft represents a significant step toward a holistic, risk-based E&L framework emphasizing ICH Q9 quality risk management (QRM) principles4.
The ICH Q3E draft guideline outlines the scope, risk considerations, chemical testing, and safety assessment (Figure 1). However, this article focuses only on the foundational elements of scope and risk assessment, which underpin the entire guideline.
Figure 1. Key Elements of the ICH Q3E Draft Guideline. The draft outlines a comprehensive, science- and risk-based strategy for managing extractables and leachables.
Scope and Applicability
The ICH Q3E guideline applies to the assessment and control of organic leachables migrating from polymeric manufacturing and packaging components, as well as delivery device components. However, the term "delivery device components" has raised concerns, as it may cause confusion regarding the inclusion of biological evaluation of medical devices, which are regulated separately under standards such as the ISO 10993 series. Clarification is requested to distinguish "delivery device components" from "drug-device combination products", which are outlined in the scope section. For clarity and readability, this article will exclude "delivery device components" from further discussion.
ICH Q3E primarily applies to new drug products and not retrospectively to approved ones, except when changes in formulation, manufacturing, dosing, or container closure systems may affect the leachable profile. While the guideline broadly calls for robust lifecycle management, commenters seek clearer, more concrete guidance - such as specific examples or decision trees - to determine when re-assessment is required.
Recommendation
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A common area of confusion is the guideline's exclusion of products in clinical research stages - unless a high patient risk necessitates early E&L evaluation. The term "clinical research stages" lacks clarity: does it refer to Phase I only, or does it also include Phase II? The accompanying ICH Q3E presentation instead refers to "clinical development products" as out of scope, raising questions about whether Phase III is excluded as well5. Explicitly specifying which clinical trial phases are out of scope would be straightforward, given their clear definitions by organizations such as the WHO6. Additionally, more precise guidance is needed on what constitutes "high risk cases," including examples of such scenarios during clinical development. Finally, defining minimum expectations for controls to ensure manufacturing and packaging components are fit for purpose during these phases would be helpful.
Several additional topics raised in the comments warrant clarification. Notably, the guideline excludes systems used solely in the manufacture or storage of excipients from its scope, prompting questions about the rationale behind this exclusion and how to cover such E&Ls in the final drug product assessment. Additionally, considerations related to active pharmaceutical ingredients (APIs) appear only in the "Special Considerations" chapter rather than within the formal scope. This chapter states that quality risk assessments and control strategies, when appropriate, should include potential leachables from containers used to store liquid or semi-solid drug substances. For biological and biotechnology-derived products, leachables are often removed during final purification steps; therefore, risk assessments typically focus on subsequent manufacturing processes where leachables may persist (Figure 2). Commenters have requested further details on what constitutes final purification steps and whether evidence is required to demonstrate the elimination of leachables through downstream processing.
Figure 2. The ICH Q3E chapter "Special Considerations" addresses biotechnology-derived products. Leachables may accumulate during upstream processing but are often removed during purification. Consequently, risk assessment primarily focuses on manufacturing steps following the final purification.
While the primary focus of ICH Q3E is the safety assessment of leachables and their direct potential adverse effects on patients, the guideline also acknowledges the importance of evaluating interactions between reactive leachables and formulation components that could adversely affect product quality, safety, or efficacy for biological and biotechnology-derived products. Appendix 1 of the draft guideline provides typical workflows for E&L risk assessment and control, requiring product quality impact assessments for packaging components but generally not for manufacturing components.
The current language leaves ambiguity regarding chemically produced liquid or semi-liquid APIs, as it does not explicitly address risk assessment for leachables associated with APIs that serve as precursors to non-biopharmaceutical drug products. In contrast, the guideline's scope specifically calls out its applicability to new drug products including cell and gene therapy products, without clarifying why these modalities are called out separately.
Risk Assessment
A cornerstone of the ICH Q3E guideline is the integration of quality risk management (QRM) principles as established in ICH Q9. The guideline requires initiating a QRM process for every product, leveraging prior knowledge of critical attributes related to manufacturing and packaging components, drug product characteristics, and manufacturing and storage conditions. However, these considerations are not explicitly detailed in ICH Q3E's overview of the Risk Management Process.
The typical QRM framework from ICH Q9 has been adapted within ICH Q3E to specifically address risk management for E&L. While ICH Q9's hazard identification step as part of the risk assessment broadly addresses the question "What might go wrong?", ICH Q3E's hazard identification begins more narrowly with the requirement to identify specific E&L of concern. Although the guideline introduces a "multifactorial concept risk matrix", this matrix is not formally integrated into the hazard identification step, and the connection between this multidimensional risk matrix and the typical E&L risk assessment workflow remains unclear.
The multidimensional risk matrix considers critical pharmaceutical quality factors such as the potential for interaction between components and the drug product, physico-chemical properties of materials, manufacturing and storage conditions (including surface area to volume ratio, temperature, and contact duration), and formulation-specific leaching propensity factors such as pH and solvent content. These considerations align closely with established frameworks like USP <1665>7 and the BioPhorum E&L risk assessment template8 (Table 1). However, unlike these references, ICH Q3E does not provide a standardized risk categorization template (e.g., low, moderate, high risk), which would allow manufacturers flexibility to apply existing risk matrices or develop tailored approaches.
| ICH Q3E | USP <1665> | BioPhorum* |
| Leaching propensity (e.g., API, pH, organic co-solvents, surfactant/chelating agents, etc.) | The chemical composition of the process stream | Process fluid interaction |
| Manufacturing/storage conditions (e.g., surface:volume ratio, temperature, duration of contact, etc.) | The temperature of contact The duration of contact (no dilution ratio considerations) | Exposure temperature Exposure duration Dilution ratio |
| Physico-chemical properties of components, including any pre-treatment | The nature of the component's materials of construction | -/- |
| Potential for interaction between component and DP | Mitigation factors allowed, e.g., leachables removal during purification steps | Distance along the production stream |
Table 1: Comparison of Multifactorial Risk Considerations. USP <1665> and BioPhorum offer risk assessment matrices that categorize risk as low, moderate, or high, whereas ICH Q3E provides general considerations without a formal risk categorization framework.
*BioPhorum's Best practice guide for evaluating leachables risk from polymeric SUS, 20218
Ultimately, manufacturers are responsible for incorporating multifactorial considerations and prior knowledge into the initial hazard identification phase. This flexibility supports product-specific adaptation, but commenters have requested clearer guidance on linking multidimensional risk factors with the overall E&L risk management process to ensure consistent evaluation.
The identified hazards form the basis for further risk analysis, which evaluates the likelihood of leachables to be present in the final drug product and the potential severity of harm. For example, a risk-based approach may consider it highly unlikely that leachables originating upstream of the last purification step in the manufacturing process will remain in the final product. However, the ICH Q3E draft describes the risk analysis step as "quantitate the potential of leachables in the drug product and assess patient exposure," which has caused some confusion over the term "quantitate" versus alternatives like "determine" or "estimate." According to ICH Q9, risk analysis is defined as the "estimation of the risk associated with the identified hazards," and risk evaluation can yield either a quantitative risk estimate or a qualitative description of risk levels Revisiting the E&L risk assessment framework to align more explicitly with ICH Q9, or providing additional explanation – particularly on how manufacturing components fit into the risk framework – would enhance clarity.
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Conclusion
The increasing complexity of pharmaceutical products, particularly biopharmaceuticals, has heightened the risk of impurities, including organic leachables from polymeric manufacturing and packaging components. The ICH Q3E guideline seeks to address this critical gap left by existing ICH impurity frameworks by providing a dedicated, science- and risk-based approach to E&L assessment and control.
Extensive public consultation has revealed areas needing further clarity and refinement. Ambiguities persist regarding the guideline's scope - especially the inclusion of delivery device components - and its applicability to clinical research stages, chemically produced APIs, and retrospective assessments triggered by lifecycle changes. Stakeholders emphasize the need for concrete examples, decision trees, and practical tools to support lifecycle management.
While the risk assessment framework aligns with ICH Q9 principles, it would benefit from clearer integration of multifactorial risk matrices, particularly in differentiating manufacturing components from packaging. Some stakeholders suggest excluding manufacturing components at all, due to insufficient distinction. Despite these challenges, the draft guideline marks a significant step forward in harmonizing global regulatory expectations and reinforcing quality risk management. A general question remains: given widespread industry adoption of ICH Q9, is the detailed QRM content in ICH Q3E necessary, or would referencing ICH Q9 suffice? This tension reflects the balance between detailed guidance sought by stakeholders and practical risk management practices.
Ultimately, the finalization of ICH Q3E will require balancing scientific rigor with pragmatic flexibility to support innovation, regulatory consistency, and, above all, patient safety.
About the Author
Dr Simone Biel is Senior Regulatory Consultant at Merck Life Science KGaA
References
1 International Council for Harmonisation (2025), Guideline for Extractables and Leachables Q3E, https://database.ich.org/sites/default/files/ICH_Q3E_EWG_Step2_DraftGuideline_2025_0704.pdf. Accessed 13 April 2026
2 European Medicines Agency, (2026) Overview of comments received on ICH Q3Eguideline (EMA/CHMP/ICH/236669/2025), https://www.ema.europa.eu/en/documents/comments/overview-comments-received-ich-q3e-guideline-supporting-documentation-extractables-leachables-ema-chmp-ich-236669-2025-ema-chmp-ich-236668-2025_en.pdf. Accessed 13 April 2026
3 Food and Drug Administration (2026), https://www.regulations.gov/document/FDA-2025-D-4678-0002/comment. Accessed 13 April 2026
4 International Council for Harmonisation (2023), Quality Risk Management Q9(R1), https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2025_0115_0.pdf. Accessed 13 April 2026
5 International Council for Harmonisation (2025), Q3E Training presentation, https://database.ich.org/sites/default/files/ICH_Q3E_Step2_Presentation_2025_0826.pdf. Accessed 13 April 2026
6 World Health Organization, Clinical Trials, https://www.who.int/health-topics/clinical-trials#tab=tab_1. Accessed 13 April 2026
7 United States Pharmacopeia (2022), USP <1665> Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Durg Products and Biopharmaceutical Drug Substances and Products
8 BioPhorum (2021), Best Practices Guide for Evaluating Leachables Risk from Polymeric Single-Use Systems Used in Biopharmaceutical Manufacturing
