Organic Impurities: New Draft ICH Q3E Guidance For Leachables And Extractables

By Tim Sandle, Ph.D.

Extractables and leachables refer to various chemical compounds that can potentially migrate from packaging, devices, or manufacturing equipment into pharmaceutical products, posing safety risks. These are forms of impurity and can be organic impurities (process- and drug-related), inorganic impurities, or residual solvents. Different classifications for leachables and extractables exist, based on the potential harm they can cause to a patient (with mutagenic compounds in the highest class). Toxicological assessments need to consider both short- and long-term exposure.

A new draft guidance document from ICH, issued jointly with the European Medicines Agency,¹ adopts the position that the assessment of these entities requires a holistic framework for risk evaluation, where risk concern should be foremost with patient safety and product quality. The ICH Q3E guidance focuses primarily on organic impurities, reserving elemental impurities for the companion document, ICH Q3D.²

Organic impurity is a general term for any unwanted carbon-based compound in a substance, such as pharmaceuticals. This can originate from raw materials, by-products, or degradation. In drugs, these also include intermediate compounds and isomers.

This article assesses the key points and requirements stemming from the guidance.

Leachables And Extractables

Where drug products come into contact with components of single-use systems, it is important to evaluate foreign impurities — leachables and extractables — that can arise due to that contact. In terms of differentiating between leachables and extractables:³

• Extractables refer to a profile of extracted compounds observed in studies under harsh conditions. Hence, these have potential compound migration. 
• Leachables refer to those impurities that leach from the materials under real-world use conditions and may be present in final drug products. Hence, these have actual compound migration.

Therefore, all leachables are extractables, but not all extractables become leachables. To evaluate these impurities, the assessment for extractables uses harsh conditions, whereas the assessment of leachables occurs under real-world conditions.

These impurities can affect both drug substances (defined in ICH Q3A)⁴ and new drug products (ICH Q3B).⁵ Related areas of concern are residual solvents (ICH Q3C) and elemental impurities (ICH Q3D),² as well as DNA-reactive (mutagenic) impurities (ICH M7).⁶

Even where a robust framework is established within a pharmaceutical company, the process of leachable and extractable evaluation is continuous, reflecting rapid advances in materials engineering, device innovations, new manufacturing paradigms, and the emergence of novel therapeutic modalities.

Risk Assessment

The basis for assessing leachables and extractables as organic impurities begins by adopting a risk-based approach as recommended by the ICH document. This commences with assessing material risk, followed by extraction studies, then long-term stability studies to track leachables, often involving three batches of drug product. 

When constructing the risk assessment, the ICH document recommends this is structured around “dimensions.” These are:

• the potential for interaction between manufacturing equipment or packaging components and the formulation
• the chemical and physical properties of the equipment or component that contribute to leachables and pretreatment of components prior to use
• the manufacturing and storage conditions, including surface area to solution volume ratio, temperature, duration of contact, and proximity of the downstream removal steps and their capacity to deplete potential leachables
• the leaching propensity of the formulation, including but not limited to API, pH, organic co-solvents, and surfactant/chelating agents.

There are different conditions that can elevate or lower the risks in relation to the dimensions:

1. Liquid products are at a higher risk than solid dosage forms.
2. Storage at room temperature presents a higher risk than cold storage.
3. Longer manufacturing processes present a higher risk than shorter processes.
4. Harsher process conditions, such as where high pressure is applied, present a higher-risk scenario.
5. Higher process temperatures increase the risk compared with lower operational temperatures.
6. The greater the quantities of surfactants used, the higher the risk.
7. Processes operating at a higher pH are under greater risk compared with processes operating at a lower pH.
8. Lipophilic substances are at a higher risk compared with hydrophilic substances.

Risk assessments must additionally take account of:

• the route of administration (with oral products presenting a lower patient risk compared with injectable or inhalation products)
• duration of the treatment (where risk will increase with treatment duration)
• the presence of leachables, which raises the risk as the dose increases
• patient population, with neonates and the elderly being at a greater risk compared with the general population.

The guidance recommends adopting a risk matrix approach and then putting in place appropriate risk mitigation steps. These include a sampling plan for components using a suitable analytical method and establishing quality agreements with component vendors so that materials likely to have an adverse impact are excluded. A change agreement process must be established with the vendor so that any alterations to the composition or fabrication process can be evaluated in terms of their extractable profiles.

The risk process also needs to consider compound risk, where multiple components are used across distinct stages. Hence, the cumulative leachables risk should also be assessed. Attention must also be paid to the life cycle of the product, such as if new patient or regulatory information becomes known, which warrants a revisit of the risk assessment.

Evaluation Studies

Although knowledge and prior test results are key components of the risk evaluation, in many cases studies will be required to assess the likelihood of impurities entering the product stream. Extractable studies require the application of chemical or physical processes to transfer constituents of a test article into an extraction medium (for which the selection of a suitable extraction medium is essential).⁷ Leachable studies need to represent actual manufacturing conditions and intended storage conditions. Where products are of similar formulation or different strengths of the same formulation, a matrix approach can be adopted, provided there is a suitable scientific justification.⁸

Such studies are reliant on analytical instruments and real-world situations, where simulations are run and designed to represent the worst-case scenario of the manufacturing conditions (e.g., smallest scale with longest contact durations, highest temperature and pressure). Studies should further consider whether leachables introduced upstream can be removed downstream; the closer the process is to the drug substance and drug product, the greater the risk, since the opportunities for impurity removal decrease.

Analytical Assessment

There are different methods suitable for assessing leachables and extractables, depending on the compounds being screened for. The test objective includes the identification and quantification of compounds above the analytical evaluation threshold (AET). The AET is the concentration level at or above which extractable/leachable compounds in a drug product or medical device must be identified and quantified for toxicological safety assessment. Setting the AET begins with a safety concern threshold (SCT), the exposure level below which an impurity presents negligible risk. The SCT varies according to the route of administration. The AET is a conversion of the SCT to a drug-specific analytical threshold.⁹ This requires a determination of the uncertainty of measurement for each analytical method/technique that produces a particular leachables/extractables profile. An alternative method is to divide the AET by two to give the final assessment. This involves less laboratory work and provides an equally appropriate uncertainty estimate.

Achieving AET quantification is performed using techniques like gas chromatography mass spectrometry (which separates compounds based on volatility and identifies molecules by mass‑to‑charge ratio), liquid chromatography mass spectrometry (which separates molecules by polarity and interaction with a liquid mobile phase), and headspace gas chromatography (used to analyze volatile compounds in the gas phase above a solid or liquid sample). The method selected needs to be robust and meet the standard analytical instrument criteria, including an understanding of the limit of detection and limit of quantification.

Regulatory Submission

The importance of leachable and extractable studies is not only a core part of understanding day-to-day manufacturing risks; the output of such evaluations needs to be provided in new drug applications. Submissions need to contain a list of extractables and leachables studies conducted, which should be included together with details of the analytical method, extraction condition, solvents, temperature, duration, and surface/volume ratio.

References

1. ICH Q3E Guideline for extractables and leachables, Step 2b at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-q3e-guideline-extractables-leachables_en.pdf
2. ICH Q3D (R2) Elemental impurities - Scientific guideline, Step 5, 2022, at: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-q3d-elemental-impurities-step-5-revision-2_en.pdf
3. Sandle, T. (2025). Evaluating single-use systems for extractables and leachables, Life Science Insights, 9^th December 2025: https://www.rssl.com/insights/life-science-pharmaceuticals/evaluating-single-use-systems-for-extractables-and-leachables/
4. ICH Q3A(R2) Impurities in new drug substances, Step 4, 2006: https://database.ich.org/sites/default/files/Q3A%28R2%29%20Guideline.pdf
5. ICH Q3B(R2) Impurities in new drug products, Step 4, 2006: https://database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdf
6. ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk - Scientific guideline, 2023: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-m7r2-guideline-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential-carcinogenic-risk-step-5_en.pdf
7. ISO 10993-18:2020 Biological evaluation of medical devices, Part 18: Chemical characterization of medical device materials within a risk management process
8. Parris P, Martin EA, Stanard B, Glowienke S, Dolan DG, Li K, et al. Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies. Regul Toxicol Pharmacol. 2020; 118:104802
9. Parris P, Whelan G, Burild A, Whritenour J, Bruen U, Bercu J, et al. Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis. PDA J Pharm Sci Technol. 2024;78(4):399-444.

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.