Paul Barr, senior chemistry consultant at testing and regulatory specialist Broughton, outlines why a unified approach is essential and increasingly expected.
Broughton
Despite it introducing inefficiencies, increasing risks and delaying regulatory approval, extractables and leachables (E&L) are still frequently tested in isolation from stability studies. However, integrating E&L testing directly into stability programmes offers a proactive route to de-risk development, accelerates timelines and better satisfies global regulators.
Extractables are compounds that emerge from container closure systems or delivery devices under exaggerated conditions, while leachables are compounds that migrate into drug products under normal storage and use conditions. Both categories represent unknown or unwanted species that may compromise product quality, patient safety or regulatory compliance.
A robust 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. 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.
Key E&L considerations
Packaging drug interactions evolve throughout a product’s shelf life, influencing the leachable profile. 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.
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.
Because registration-ready leachables assessments can take up to 18 months to prepare, extractables testing should begin early in development. Aligning toxicological objectives with analytical capability early in development helps avoid repeated evaluations, reformulation and costly programme delays.
Given the complexity of designing and executing 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 compliance
Packaging-drug interactions are under increasing regulatory scrutiny. The 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 to support packaging component qualification.
Related 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.