Quick summary: Integrating extractables and leachables testing directly into pharmaceutical stability programmes offers a proactive strategy to accelerate drug development timelines and reduce regulatory approval risks by revealing unwanted packaging compounds that only emerge over extended storage periods. Industry specialist Paul Barr emphasizes that aligning toxicological objectives with analytical testing early in the cycle prevents costly reformulation delays and ensures comprehensive data package compliance with evolving global standards such as the International Council for Harmonisation guidelines. This unified approach carries profound implications for public healthcare practice and patient well being, directly safeguarding individuals from toxicological exposure by ensuring that high risk injectables, biologics, and inhalation therapies remain safe and effective throughout their entire lifecycle.
Extractables and leachables (E&L) testing is still frequently conducted in isolation from stability studies, introducing inefficiencies, increasing risk, and delaying regulatory approval. Integrating E&L testing directly into stability programmes offers a proactive route to de-risk development, accelerate timelines, and better meet the expectations of global regulators. Paul Barr, Senior Chemistry Consultant at testing and regulatory specialist Broughton, outlines why a unified approach is essential and increasingly expected.
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 unwanted or unknown substances that may compromise product quality, patient safety, or regulatory compliance.
A robust E&L strategy identifies potential migrating substances, characterises their toxicological impact, and quantifies patient exposure. This is particularly important given the wide range of materials used in pharmaceutical systems, from plastics in syringes and injector pens to polymers in primary packaging, all of which may contribute impurities that can interact with the drug product over time.
How stability studies factor in
Stability studies evaluate how drug substances and products perform over time under various environmental conditions. Often called shelf-life studies, they assess physicochemical and microbiological attributes to justify assigned shelf life and ensure that therapeutic efficacy is maintained throughout a product’s lifecycle.
Regulators including the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA) require stability studies for all drug product submissions. Harmonised guidance is provided by the International Council for Harmonisation (ICH) quality guidelines and the World Health Organization.
From an efficacy standpoint, any degradation of the active pharmaceutical ingredient (API) can reduce therapeutic effect. 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. Injectables, biologics, and inhalation products face greater scrutiny due to their increased vulnerability to leachables compared with oral solid-dose forms.
Key considerations for E&L programmes
Packaging and drug interactions evolve throughout a product’s shelf life. The extent of leaching is influenced by the pH of the formulation, the contact area between the formulation and the material, the surface area of powdered formulations, and the composition and susceptibility of packaging materials.
Drug degradation products or leachables may not appear until months or years into a stability programme. A meaningful toxicological risk assessment relies on safety control thresholds (SCTs), 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 capabilities at the outset helps avoid repeated evaluations, reformulation, and costly programme delays. Collaboration with experienced E&L specialists is recommended to ensure data are comprehensive, reliable, and aligned with regulatory expectations.
Packaging and 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. Relevant guidance includes ISO 10993-18:2020 for chemical characterisation, USP chapters on extractables and leachables, and ICH Q1A–Q1E for stability study design.
Recent developments, such as the ICH Q3E draft guideline on extractables and leachables, underscore the growing emphasis on holistic, risk-based approaches that align with stability data requirements. This evolving framework supports the integration of E&L assessments to strengthen submissions to regulatory authorities such as the FDA and (MHRA).
The case for a unified approach
Integrating toxicology, E&L testing, and stability studies under a single coordinated programme gives manufacturers 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.
Experts note that early integration helps address potential leachables that may only emerge over extended storage periods, ensuring patient safety across the full product lifecycle without unnecessary delays in approval processes. Working with a partner that actively contributes to shaping regulatory guidance further enhances confidence that development strategies are scientifically robust and future-proofed.