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Extractables and Leachables (E&L): A Historical and Scientific Overview
Introduction
Extractables and leachables (E&L) are chemical compounds that can migrate from materials—such as packaging, medical devices, or manufacturing equipment—into pharmaceutical products. These compounds may affect drug safety, efficacy, and stability, making E&L studies a critical part of modern pharmaceutical development and regulation
Early Awareness (Pre-1970s)
Before formal terminology existed, concerns about contamination from packaging materials were already present. Early pharmaceutical products were often stored in glass containers, which were considered inert. However, issues such as alkali leaching from glass (e.g., sodium ions) highlighted that even “inert” materials could interact with drug products.
Early Awareness (Pre-1970s)
Before formal terminology existed, concerns about contamination from packaging materials were already present. Early pharmaceutical products were often stored in glass containers, which were considered inert. However, issues such as alkali leaching from glass (e.g., sodium ions) highlighted that even “inert” materials could interact with drug products.
Early Awareness (Pre-1970s)
Before formal terminology existed, concerns about contamination from packaging materials were already present. Early pharmaceutical products were often stored in glass containers, which were considered inert. However, issues such as alkali leaching from glass (e.g., sodium ions) highlighted that even “inert” materials could interact with drug products.
Regulatory Expansion (2000s–2010s)
Guidelines and expectations became more defined:
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The U.S. Food and Drug Administration (FDA) issued recommendations on container closure systems and drug-device combinations.
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The International Council for Harmonisation (ICH) introduced guidelines like Q3C (residual solvents) and Q3D (elemental impurities), indirectly supporting E&L assessments.
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The Product Quality Research Institute (PQRI) played a major role in defining safety thresholds and best practices, especially for orally inhaled and nasal drug products (OINDP).
During this time, analytical technologies such as GC-MS, LC-MS, and ICP-MS became standard tools for identifying and quantifying E&L compounds.
Modern Era (2020s–Present)
E&L studies are now a mandatory component of pharmaceutical development, particularly for:
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Biologics
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Combination products (drug-device)
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Single-use systems (SUS) in biomanufacturing
There is increasing focus on:
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Toxicological risk assessment (e.g., TTC—Threshold of Toxicological Concern)
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Lifecycle management of materials
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Sustainability and new packaging materials