Extractables and leachables and stability studies: The overlooked link

~ Integrating testing can help satisfy regulators ~

Extractables and leachables testing is well established within the pharmaceutical sector, yet it is still frequently conducted in isolation from stability studies. Treating these activities as separate, sequential exercises can introduce inefficiencies, increase risk, and delay regulatory approval. Instead, integrating E&L testing directly into stability programmes offers a proactive route to de-risk development, accelerate timelines, and better satisfy global regulators. Here, Paul Barr, Senior Chemistry Consultant at testing and regulatory specialist Broughton, outlines why a unified approach is essential and increasingly expected.

Why Extractables and Leachables Matter

Extractables are compounds that emerge from container closure systems or delivery devices under exaggerated conditions, while leachables are compounds that migrate into the drug product under its normal storage and use conditions. Both categories represent unknown or unwanted species that may compromise product quality, patient safety or regulatory compliance.

A robust extractables and leachables (E&L) strategy identifies all potential migrating substances, characterises their toxicology, and quantifies patient exposure. This is particularly important given the wide range of materials in pharmaceutical systems from plastics in syringes and injector pens to the polymers in primary packaging all of which may contribute impurities that interact with the drug product over time.

Stability studies evaluate how drug substances and drug products perform over time under various environmental conditions. Often referred to as shelf-life studies, they assess both physicochemical and microbiological attributes to justify the assigned shelf life and ensure that therapeutic efficacy is maintained throughout the product’s lifecycle.

Regulators including the Food and Drug Administration (FDA) and Medicines and Healthcare products Regulatory Agency (MHRA), require stability studies for every drug product submission. Degradation processes such as hydrolysis, oxidation, isomerisation, photochemical decomposition, and polymerisation, may reduce the efficacy of the active pharmaceutical ingredient (API) or generate new degradation products requiring toxicological assessment.

Harmonised guidance for designing and evaluating stability studies is provided by the International Committee of Harmonisation (ICH) quality guidelines (ICH, 1996A; ICH, 1996B; ICH, 2002; ICH, 2003A; ICH, 2003B) and the World Health Organisation (WHO, 2018).

From an effectiveness standpoint, drug products must maintain their clinical efficacy throughout their assigned shelf life. Any degradation of the active pharmaceutical ingredient (API) can reduce therapeutic effects.

From a toxicological perspective, any new compounds generated through degradation pathways or arising as leachables from packaging components must be quantified and assessed for potential patient impact. Certain dosage forms, such as injectables, biologics, and inhalation products, are scrutinised more heavily due to their increased vulnerability to leachables compared with oral solid dose forms.

Leachables and shelf life

Packaging drug interactions evolve throughout a product’s shelf life, influencing the leachable profile. Liquid formulations, in particular, present a higher risk because of their continuous contact with the container closure system. The extent of leaching is influenced by several factors, including pH of the formulation, contact area between the formulation and the material, surface area of powdered formulations, composition and susceptibility of materials used in packaging.

Leachables studies are therefore commonly integrated into long-term stability programmes to monitor the migration of species over time. However, the complexity of the product matrix can make leachables analysis more challenging than extractables testing, requiring sophisticated sample preparation and targeted analytical methods.

Toxicological considerations

Drug degradation products or leachables may appear months or years into a stability programme. A meaningful toxicological risk assessment relies on Safety Control Thresholds (SCTs) to ensure analytical sensitivity, Analytical Evaluation Thresholds (AETs) calibrated for each relevant chemical, and effective collaboration between toxicologists and analytical scientists.

Aligning toxicological objectives with analytical capability early in development helps avoid repeated evaluations, reformulation, and costly programme delays.

Because registration-ready leachables assessments can take up to 18 months to prepare, extractables testing should begin early in development. Early evaluation also enables manufacturers to replace problematic materials, react to unexpected findings, and accelerate their route to market. This aligns closely with the Quality by Design (QbD) principles promoted by the FDA and EMA.

For certain products, such as pressurised metered dose inhalers (pMDIs), early method development and material assessment are well-established best practices. Ensuring effective API clean-up during sample preparation is particularly important for achieving accurate trace analysis free from interference. Partnering with E&L specialists can significantly improve turnaround time and analytical robustness.

Once the container closure system design has been finalised, stability studies can commence. These integrate targeted leachables assessments to determine whether identified extractables migrate into the product and at what levels; non-targeted screening to detect unanticipated compounds, including leachables not previously observed, degradants of known leachables, and secondary reaction products formed through API–packaging interactions.

Given the complexity of designing and executing these multi-stage studies, collaboration with experienced E&L specialists is recommended to ensure that the data generated is comprehensive, reliable, and aligned with regulatory expectations.

Regulatory expectations

Packaging-drug interactions are under increasing regulatory scrutiny. The U.S. Food and Drug Administration (FDA) provides safety thresholds based on route and duration of exposure and emphasises extraction studies using solvents compatible with the dosage form or more aggressive alternatives (e.g., HPLC or fluorocarbon solvents) to support packaging component qualification.

In Europe, the European Medicines Agency (EMA) is consulting on ICH Q3E, which introduces a risk-based framework for E&L assessments aligned with ICH Q9 on quality risk management. This initiative aims to complement existing impurity guidelines and further strengthen patient safety requirements. Updates are expected before the end of 2025.

Existing guidance includes ISO 10993-18:2020 for chemical characterisation, relevant USP chapters for extractables and leachables and ICH Q1A-Q1E for stability study design.

Given the complexity of these assessments, bespoke E&L programmes involving multidisciplinary expertise, manufacturing, analytical chemistry, toxicology, and regulatory affairs are increasingly necessary to meet regulatory expectations.

Integrating toxicology, E&L testing, and stability studies under a single, coordinated programme provides manufacturers with faster turnaround and reduced duplication, better-aligned thresholds and risk assessments, improved visibility of material-related risks, stronger regulatory data packages and fewer reformulation delays.

Working with a partner who actively contributes to shaping regulatory guidance further enhances confidence that development strategies are scientifically robust and future-proofed.

Ultimately, E&L analysis should not be viewed as a supplementary activity. It is fundamental to understanding material interactions, informing stability studies, and ensuring product quality and safety throughout the product lifecycle. A holistic, integrated approach is therefore an essential component of pharmaceutical development and regulatory submission.

Therefore, working with a partner that offers toxicology, stability testing and E&L testing together can help manufacturers quicken their testing and approvals process. This aids faster turnaround, provides you with aligned thresholds and fewer tests. Coupled with a partner that closely scrutinises and contributes to the regulatory space, this provides manufacturers with the confidence they need to help design and implement an effective E&L strategy. This strategy therefore is an integral element to inform stability studies. Ensuring both are scientifically robust is an integral part of the pharmaceutical development and submission process. To find out more about Broughton’s testing capabilities, visit our pharmaceutical testing page.