With evolving regulatory frameworks and increasingly sophisticated therapeutic formats, a product-specific, risk-based approach to E&L is no longer optional.
Drug products inevitably come into contact with numerous components and systems throughout the development and manufacturing processes. As a result of this contact, there is a risk of impurities — extractables and leachables (E&L) — entering the drug product during production, testing, storage, and use, that can impact the quality, safety, and efficacy of the product (1).
Given the risks associated with the presence of these impurities, comprehensive evaluation of these impurities is of the utmost importance for drug developers and regulatory authorities. Recent efforts by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the matter have included the release of new guidelines aimed at establishing a globally harmonized, science-driven, and risk-based framework for the toxicological evaluation and control of E&L (2).
However, these guidelines are not without limitations and as drug development pipelines evolve to more complex modalities, new challenges are arising. “The shift toward more complex dosage forms, particularly biologics, sterile injectables, and inhalation products, has expanded both the number and the types of materials that interact with a drug throughout its lifecycle,” observes Chris Williams, Executive Director of Development Services at Alcami. “At the same time, the growth of parenteral and other non-oral routes of administration has introduced heightened sterility and compatibility requirements.”
Overcoming Matrix Interference
Screening for potential leachables within complex drug formulations presents significant analytical hurdles. Highly concentrated biologic payloads, lipid nanoparticles, surfactant systems, and API degradation products often generate severe matrix suppression or signal overlap, masking subtle trace-level impurities.
According to Williams, achieving analytical clarity requires a combination of complementary instrumentation and deliberate study design. “Extractables work typically includes testing for non-volatile organic compounds, semi-volatiles, volatiles, and elemental impurities using a suite of complementary analytical techniques,” he explains. “Study design matters as much as instrumentation, though.”
To circumvent matrix suppression caused by complex excipients or APIs during early testing, technical teams frequently rely on simulated extraction models, Williams reveals. “In simulated or probable leachables studies, components are exposed to a formulation-mimicking solvent system rather than the actual drug product. This [exposure] reflects the product more realistically while avoiding much of the analytical interference caused by active ingredients, excipients, and degradation products,” he notes.
“When testing the drug product itself, leachables data should be interpreted against an appropriate control, typically bulk or unpackaged product held in an inert container, so that formulation-related peaks are not mistaken for packaging-derived compounds,” Williams stresses. “Without a suitable control, teams may spend time investigating compounds that have nothing to do with packaging or process contact materials.”
De-Risking Late-Stage Changes
Component substitution late in a program’s lifecycle, such as those driven by single-use supplier shortages, vendor material alterations, or secondary source qualification, can introduce severe regulatory and timeline risks to a project. If a substitute elastomer, tubing, or container system alters the leachables profile, sponsors may be forced to re-execute extended stability and toxicology studies.
“The best way to handle a late change is to avoid needing one,” affirms Williams. “In E&L, poor early choices are expensive because changing a critical component late in development often means repeating not just E&L work but delaying filing for months or years to obtain the data needed to support the change.”
To establish a resilient supply chain strategy early in development, sponsors and CDMOs must exercise strict due diligence regarding vendor documentation and material compatibility, Williams explains. “Material selection is key,” he emphasizes. “Well-characterized components with a strong quality history are preferable to poorly documented alternatives. Early review of supplier extractables packages, construction details, and compatibility information can help teams avoid selecting materials that later force redesign, repeat studies, or regulatory explanations.”
Furthermore, synchronization between packaging lock and stability testing protocols is essential to ensure regulatory submissions contain necessary real-time support data. “Stability samples should also be placed as soon as the packaging configuration is locked,” Williams advises. “Otherwise, teams may reach filing or review milestones without the aged material needed to answer predictable regulatory questions.”
Evolving Regulatory Expectations and Complex Modalities
Looking toward the future of bio/pharmaceutical manufacturing, the rapid growth of non-oral delivery formats, targeted bioconjugates, and advanced parenteral therapies is driving fundamental shifts in E&L risk management. As drug delivery systems become more intricate, the surface-area-to-volume exposure ratio increases, heightening the probability of chemical migration.
As regulatory agencies globally align on safety concern thresholds and analytical evaluation thresholds, drug developers must embed E&L considerations into the earliest phases of quality-by-design frameworks. “In an era of increasingly sophisticated therapies and tightening regulatory scrutiny, a product-specific, risk-based approach is no longer optional,” Williams concludes. “E&L has become part of the architecture of development itself.”
References
1. Kuzmič, S.; Zlobec, T.; Dolenc, M.S.; Roškar, R.; Lušin, T.T. Extractables and Leachables in Pharmaceutical Products: Potential Adverse Effects and Toxicological Risk Assessment. Toxics 2026, 14 (1), 92.
2. ICH. ICH Q3E Guidelines for Extractables and Leachables. Draft Guidance Document, Endorsed on Aug. 1, 2025.
Image Credit: © Quality Stock Arts – stock.adobe.com
