Extractables & Leachables

ICH Q3E has been published in draft form and presents a holistic framework and process for the assessment and control of extractable and leachable impurities to further expand the existing ICH guidelines on impurities. The guideline applies to the risk assessment and control of these potential impurities arising from the manufacture and packaging of new drug products, including cell and gene therapy products.

Modern products use polymers, single-use manufacturing systems, and delivery devices that raise E&L hazards and new drug products such as biologics and gene/cell therapies are potentially more susceptible to those hazards.

Global harmonisation of the standard should increase regulatory efficiency and adopts the lifecycle concept used in other ICH quality guidelines.

It is a continuous, risk-based process that follows the product from development through its entire commercial lifespan.

Focusing on the safety aspects of the new guideline, experts at ApconiX will provide strategic advice:

  • Helping you understand what is new about the draft ICH guideline and how it interacts with existing guidance such as USP 665 and EMEA/CVCMP/205/04
  • Explaining what is not yet decided in the draft ICH guideline and may be subject to further change
  • Helping you determine what to implement now and which aspects to consider later as the guidance develops
  • And how best to risk assess individual extractables above a qualification threshold.

“Extractables are chemical entities that are intentionally extracted from manufacturing components/systems, packaging or delivery device components”

ich | ApconiX

“Leachables are chemical entities that migrate from manufacturing components/systems, packaging or delivery device components into a drug product under the established manufacturing and labelled storage conditions”

ICH Q3E Key Milestones and Timeline

Milestone Target/Actual Date Description
Step 2a/2b: Draft guideline endorsed and released for consultation 1 August 2025 Draft Q3E published by ICH; regulators (e.g., EMA, FDA, PMDA, Swissmedic) launched national consultation periods.
Public consultation period Aug – Dec 2025 Open for stakeholder feedback; Europe’s window closes 18 December 2025.
Step 3: Revision and sign-off of final text Mid-2026 to early 2027 EWG will review global comments and prepare the final guideline.
Step 4: Adoption by ICH Assembly (final guideline) June 2027 (planned) Global harmonised Q3E guideline officially adopted and published.
Step 5: Regional implementation Late 2027 – 2028 EMA, FDA, PMDA, etc., integrate Q3E into regional regulatory frameworks.

FAQ’s

Sponsors need to consider L&E at the point where sourcing decisions are made regarding primary contact materials during manufacture, and for the primary packaging/ dose delivery system. This is likely to be several years before approval of the product, by which time Q3E may have reached step 4.

As a safety consultancy company, ApconiX can help you plan for the safety aspects of your L&E programme, and help you navigate the interface between safety and pharmaceutical quality. Advice can be provided for a specific program, but ApconiX can also help facilitate discussions around the strategic approach to be taken on L&E.

The step 2 guideline is open for public consultation, and the ICH website explains how to make commentary using a specific Excel spreadsheet https://www.ich.org/page/public-consultations.  Note the closing date for the public consultation is 18th December.

Regional implementation is expected late 2027 and into 2028.

Apconix is currently offering safety-focused advice on L&E.  This could be advice on the approach to be taken for a specific program or it could be more strategic advice on the implementation of a company-wide L&E program. Advice will need to be taken in partnership with pharmaceutical quality experts within the client’s company, as there is a complex interface between quality and safety, and efforts need to be “joined-up”.

A key sticking point in the Step 2 guideline concerns the qualification thresholds to be applied to extractables. These are currently not harmonsed globally, and individual sponsors may well be applying different thresholds- for example those from ELSIE. Thresholds are still under active discussion in the ICH EWG, and may well change. Another unresolved issue is that the guideline requires companies to identify and manage “Class 1 extractables” (those of the highest concern), but in order to do this, an analytical evaluation threshold (AET) would need to be lower than that recommended for the general evaluation of extractables. This is not explored in the current draft.

The support we give is very  flexible and bespoke.  The investment of time needed, the geographic location and the mode of support will all be factors. For us it is important the support fits your needs in a timely fashion.

Advice on a specific product/program could be provided virtually.  However if a company is requesting advice of a strategic nature (such as how understand and best integrate Q3E into current work), then a face to face meeting is recommended. Although ApconiX would focus on the safety aspects of guidance, the presence of Pharmaceutical Sciences colleagues would be recommended, as there are very important interfaces between quality and safety on topics such as setting the correct Analytical Evaluation Threshold (AET).

Our Experts

Andrew Fleetwod Cropped scaled | ApconiX

Andrew Fleetwood

B.Vet.Med., C.Biol., MRSB, M.Topra, MRCVS

Andrew is a Regulatory toxicologist, and has had a long career in industry supporting the registration of new products through the FDA and EMA and Rest of World processes. This has included the management of a regulatory toxicology group, where Andrew represented the company at the EFPIA Preclinical Development Group (PDEG) and co- chaired an Impurities Safety Council which oversaw all specification setting in terms of ICH Q3A, Q3B and M7.

Andrew has continued working on regulatory toxicology deliverables as a consultant, and this now includes the support of Leachables and Extractables for pharmaceutical products, helping plan the L&E strategy, and risk assessing the extractable and leachable profiles generated on manufacturing equipment and primary packaging.

simon | ApconiX

Simon Craige

MSc, ERT, DABT, FRCPath

Simon has over 20 years’ nonclinical and toxicology experience working in contract research, medical and pharmaceutical organisations across multiple disciplines. These include small molecules, vaccines, biologics, and medical devices. He has experience of a diverse range of therapeutic areas (including oncology, CNS, ocular and dermal) and across various phases of drug discovery and development.

As well as a Master’s degree in toxicology from the University of Birmingham, professional credentials include European Registered Toxicologist (ERT) since 2012, American Board Registered Toxicologist (DABT) since 2014 and a Fellow of the Royal College of Pathologists in Toxicology (FRCPath) in 2025. He’s currently a member of the Society of Toxicology (SOT), American College of Toxicology (ACT), British Society of Toxicology (BTS) and European Teratology Society (ETS).

Angela Stokes 8by6 scaled 1 | ApconiX

Angela Stokes

MSc CSci CChem FRSC FTOPRA

Angela has a strong scientific background in chemistry, pharmacology and toxicology and over 30 years of regulatory affairs experience in medicinal product and medical device development.   She has extensive experience of ICH, FDA and Committee for Medicinal Products for Human Use (CHMP) guidelines for a wide range of pharmaceutical products, and the International Organization for Standardization (ISO) standards for medical devices, in vitro diagnostics and quality systems. She has been influential in regulatory affairs training and mentoring and is a Fellow of The Organisation for Professionals in Regulatory Affairs (TOPRA) and a Fellow of the Royal Society of Chemistry. Angela was the winner of the 2015 TOPRA Award for Contribution and 2020 TOPRA Award for Inspiration.  Angela’s knowledge, breadth of experience in regulatory affairs, toxicology and pharmacology abilities and strategic approach aligns with and supports the toxicology group in ApconiX.

We also support our clients in the biological safety evaluation of medical devices under ISO 10993-1:2018 soon to be replaced by ISO 10993-1.

Want to find out more?

To discuss the best approach for your drug project, please get in touch.
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