Extractables and Leachables (E&L): Reviewing…

A Practical Perspective to Navigate Evolving Expectations

Extractables and Leachables (E&L) are no longer treated as a narrow packaging question. Today, they sit at the intersection of product quality, patient safety, and regulatory strategy.

In simple terms, extractables are compounds that can be pulled from packaging materials, manufacturing equipment, or delivery systems under exaggerated laboratory conditions. Leachables, by contrast, are compounds that actually migrate into the drug product during manufacture, storage, or use.

As pharmaceutical manufacturing systems become more complex, regulatory authorities increasingly expect companies to demonstrate a structured and scientifically justified approach to E&L assessment and control.

In this blog post, we explore:

How the regulatory framework for E&L has evolved
Draft ICH Q3E impact on global regulatory expectations
What the current regulatory landscape means for pharmaceutical companies
Practical actions Marketing Authorisation Holders (MAHs) can take to prepare

The Evolution of the E&L Regulatory Framework

In Europe, expectations for E&L have developed over many years without a single dedicated standalone guideline covering the topic in a fully integrated way across product types. However, this does not mean that E&L was previously unaddressed. Rather, companies had to build their strategies from broader principles related to impurities, product quality, packaging suitability, and risk management, together with product and material specific guidance. In particular, the EMA 2005 guideline on plastic immediate packaging materials already required extraction studies, migration studies, and toxicological information for certain non-compendial plastic materials, especially for inhalation, parenteral, and ophthalmic products.

Companies therefore had to build their strategies from broader principles related to impurities, product quality, and risk management. These approaches were further supported by FDA container-closure expectations, compendial practice, and evolving industry frameworks such as PQRI. FDA's 1999 container closure guidance already made clear that the type and extent of packaging information should depend on dosage form and route of administration, and that injectable and inhalation products generally require more detailed data than lower-risk dosage forms. It also framed packaging suitability in terms of protection, compatibility, and safety.

This context explains why the publication of draft ICH Q3E represents a significant regulatory milestone. Rather than creating the field from scratch, Q3E consolidates long-standing regional expectations into a more harmonized framework. According to EMA, Q3E presents a holistic framework and process for the assessment and control of E&L impurities, with the primary purpose of protecting patient safety and product quality through assessment and control of leachables in the drug product. The ICH draft itself was endorsed in August 2025 as a Step 2 guideline for public consultation, with finalization anticipated in 2027.

The European Medicines Agency (EMA) describes the guideline as the first holistic framework specifically addressing E&L impurities. It complements existing impurity-related ICH guidelines, including:

ICH Q3A: Impurities in new drug substances
ICH Q3B: Impurities in new drug products
ICH Q3C: Residual solvents
ICH Q3D: Elemental impurities
ICH M7: Mutagenic impurities

As can be seen, the E&L regulatory framework has evolved from fragmented, region-specific expectations toward a more integrated and risk-based model. Although E&L requirements were historically derived from multiple sources addressing packaging, impurities, and quality risk management, draft ICH Q3E is significant because it consolidates these principles into a single holistic framework.

Its alignment with ICH Q9 reinforces a science-based, proportionate approach to material selection, study design, analytical thresholds, toxicological qualification, and lifecycle control.

In the EU, robust E&L data have long been expected for higher-risk products, but the regulatory basis often had to be assembled from multiple guidelines rather than one overarching standard. In contrast, FDA expectations have become increasingly explicit through guidance, review practice, and structured submission tools. PQRI further advanced the field by translating broad regulatory principles into a practical, threshold-based methodology, including SCT, QT, and AET concepts.

Overall, ICH Q3E represents an important step toward global harmonization of E&L assessment and control across the product lifecycle.

Where E&L Regulation Stands Today

One of the most important recent developments is the progress of ICH Q3E through the regulatory consultation process.

The guideline was endorsed for public consultation on 1 August 2025, published by the EMA on 18 August 2025, and the consultation period closed on 18 December 2025.

The EMA website now includes an overview of the comments received, first published on 28 January 2026, confirming that extractables and leachables have moved from conceptual discussion to active regulatory convergence.

Substantively, the draft guideline is significant because it introduces a structured framework rather than repeating earlier impurity concepts.

According to EMA, Q3E provides:

A holistic framework for assessing and controlling extractables and leachables
A lifecycle approach to risk assessment, risk control, and risk review
A clear link between analytical assessment and toxicological evaluation

The guideline is supported by technical annexes addressing key methodological elements, including:

Study types for E&L assessment
Analytical Evaluation Threshold (AET) calculations
Potency-based classification of leachables
Exposure-limit derivation
Class-specific monographs

Taken together, these elements move the industry toward a more structured and traceable regulatory framework.

FDA communications in recent years point in a similar direction, emphasizing structured E&L summaries, improved review efficiency, and data-driven assessment of potential deficiencies.

What to Expect Over the Medium Term

One of the most important recent developments is the advancement of ICH Q3E into formal regulatory consultation. The draft guideline was endorsed on 1 August 2025, adopted by CHMP on 4 August 2025, released by EMA for public consultation on 18 August 2025, and the EU consultation period closed on 18 December 2025.

EMA subsequently published an overview of comments received, and the EMA Q3E page was updated on 28 January 2026. At the broader ICH level, Q3E remains in Step 3 while consultation comments are being considered.

Substantively, the draft guideline is significant because it establishes a structured framework for the assessment and control of E&Ls rather than addressing them only indirectly through existing impurity guidance. According to EMA, Q3E provides a holistic framework and process for E&L assessment and control. The draft guideline is further supported by appendices covering typical workflows for E&L risk assessment and risk control, types of studies, AET calculations, potency classes for leachables, methods for establishing exposure limits, and Class 1 leachable monographs; separate supporting documentation was also released for Class 3 leachable monographs.

Taken together, these elements show a clear move toward a more explicit and traceable regulatory framework for E&L. In practical terms, companies should increasingly adopt:

A lifecycle-based approach
More robust scientific justification for study design
Clearer threshold-based decision-making
Greater traceability of analytical and toxicological assessments

Over the medium term, ICH Q3E has the potential to reduce the fragmentation that has historically existed across regions and product categories by providing a more consistent framework for the assessment and control of E&L. The practical value of the guideline is likely to extend beyond regulatory harmonization, particularly by supporting more predictable approaches to submissions, material and supplier qualification, and lifecycle management.

This is likely to be particularly relevant for complex modalities, high-risk routes of administration, and manufacturing settings involving multiple process-contact materials. In such cases, leachables associated with manufacturing equipment and material interactions are receiving increasing regulatory attention, as reflected in the Q3E draft's emphasis on materials characterization, process understanding, and manufacturing and storage conditions.

How MAHs Can Prepare for Emerging E&L Requirements

Review Your Current E&L Strategy

Make sure your current E&L strategy reflects emerging ICH Q3E principles and is not based only on legacy expectations or disconnected guidance.

Strengthen Documentation and Traceability

Ensure that analytical methods, AET calculations, toxicological assessments, and the rationale behind key decisions are clearly documented and easy to defend.

Validate Your Risk-Based Approach

Check that study design, analytical testing plans, and any waivers are scientifically justified, proportionate to risk, and applied consistently.

Assess High-Risk Areas Proactively

Take a fresh look at packaging systems, process contact materials, and manufacturing equipment where leachable risk may be higher.

Align Internal Processes and Suppliers

Update internal procedures and confirm that suppliers can support evolving E&L expectations with suitable data and technical documentation.

Adopt a Lifecycle Mindset

Manage E&L as a lifecycle activity so you remain prepared for post-approval changes, regulatory questions, and future guideline updates.

Closing Remarks: Preparing for a More Structured Global E&L Framework

E&L requirements are entering a more mature and structured phase of regulatory development.

While companies have historically worked within a fragmented landscape of regional guidance and established practice, draft ICH Q3E signals a transition toward a more harmonized framework for E&L assessment and control.

Organizations that begin aligning their E&L strategies with these emerging expectations now will be better positioned to support regulatory submissions, address authority questions efficiently, and manage lifecycle changes with greater confidence.

Strengthening Your Extractables and Leachables Strategy

Effective E&L management increasingly requires close coordination across analytical science, toxicology, manufacturing, and regulatory functions.

QbD Group supports pharmaceutical companies in developing science- and risk-based E&L strategies, preparing robust regulatory submissions, and aligning internal processes with emerging ICH Q3E expectations.

Talk to an E&L Expert →