Extractables & Leachables (E&L): Definition and importance in the Pharmaceutical industry
Last updated: 11. May 2026
Extractables are chemical substances that can be released from materials under forced conditions, such as elevated temperatures or solvents of different polarity. They show the overall release potential of a material and serve as a basis for risk assessment. Typical sources include plastics or elastomers in packaging such as vials or syringes.
A simple example: when a rubber stopper is heated in the laboratory and treated with a solvent, additives can be extracted – these are considered extractables.
Based on this, leachables are then considered. These are substances that actually migrate into the drug product under normal storage or usage conditions. Because they come into direct contact with the product, they are directly relevant for patient safety.
For example, during storage, small amounts of plasticizers from a plastic bag can end up in an infusion solution.
Main causes and risks of E&L
The formation of extractables and leachables depends mainly on the materials used and the storage conditions. In particular, plastics and elastomers contain additives such as plasticizers or stabilizers, as well as their degradation products (degradants), which can migrate under certain conditions. Interactions between the drug product and packaging also promote the migration of such substances. In addition, temperature, humidity, and storage time significantly influence this process. Process materials such as tubing or filtration systems can also introduce substances during manufacturing that later appear as leachables in the final product.
The risks can be seen in several areas:
- Patient safety: possible toxic effects, allergies, or long-term risks from substances like nitrosamines or PAHs
- Product quality: possible reactions with the active ingredient, reduced efficacy, formation of degradation products, and particulate contamination
- Regulatory aspects: delays in approval, product recalls, as well as legal and financial consequences
Importance and fundamentals of E&L studies
Extractables and leachables (E&L) studies are used to systematically identify and evaluate these substances. Two steps are distinguished: extractables studies show under extreme laboratory conditions which substances can be released from materials, representing a possible “worst-case” profile.
Based on this, leachables studies examine which of these substances actually occur in the drug product under real storage and usage conditions – often only in very small trace amounts. Reliable detection of very low levels is especially important.
E&L studies help to identify potential contamination sources such as plasticizers, antioxidants, or metal residues early. At the same time, they provide important information about material suitability and support compliance with regulatory requirements as well as ensuring product quality and patient safety.
Regulatory requirements for E&L studies
The conduct of extractables and leachables studies follows a clear regulatory framework set by international authorities and guidelines. The goal is the reliable assessment of potential chemical impurities from packaging and process materials and their impact on drug safety and product quality.
Key guidance is provided by the United States Pharmacopeia (USP), especially USP <1663> for extractables study design and scientific principles, and USP <1664> for leachables evaluation under real or simulated conditions. In addition, other relevant chapters such as USP <665> and <661> are considered, as well as future developments including the ICH guideline Q3E, which is expected to establish a globally harmonized standard for the assessment and control of E&L substances throughout the entire product lifecycle.
In addition, international frameworks further define methodological and regulatory expectations:
- Guidelines from FDA, EMA, and PQRI
- Requirements of ISO 10993 for biological evaluation of medical devices
- GMP/cGMP standards for manufacturing and testing
- Industry standards such as BPOG, ASTM, ISPE, and PDA
These requirements define the full E&L workflow – from risk assessment and material characterization to analytical testing and long-term stability studies under real storage conditions. Both organic and inorganic residues as well as additives from plastics and elastomers are considered.
Strategies and analytical methods for controlling Extractables and Leachables
Control of extractables and leachables is based on a risk-oriented approach combining material selection, process design, and modern analytical techniques. The goal is early identification of potential contamination sources and reliable assessment of possible substances in the drug product.
Important strategies include selecting low-E&L materials, optimizing manufacturing processes using inert components, and thorough cleaning procedures. Collaboration with suppliers also helps reduce material-related risks.
Established analytical methods include:
- HS-GC-MS: for detecting volatile organic compounds (VOCs)
- GC-MS: for semi-volatile organic compounds (SVOCs)
- LC-MS/UV: for identifying non-volatile organic compounds (NVOCs)
- ICP-MS: for measuring inorganic elemental impurities (e.g. metal residues)
Workflow of E&L studies
E&L studies follow a clear step-by-step process from initial assessment to final testing in the real product. The goal is a complete evaluation of potential migrating substances and their relevance for patient safety.
1. System and risk analysis
The entire packaging and contact system is evaluated. Focus is placed on interactions between the drug product, packaging, and process materials, as well as relevant regulatory requirements.
2. Extractables study (Worst-case analysis)
In the next step, the materials are extracted under forced conditions using extraction media of different polarity. This creates a complete release profile. Modern analytical methods detect organic and inorganic substances such as additives, degradation products, or metal residues.
3. Toxicological valuation
The identified substances are assessed toxicologically. The key question is which compounds are relevant for patient safety.
4. Leachables study (Real-Use conditions)
Finally, it is checked which substances actually appear in the product under real storage and use conditions. Quantification is typically performed during stability studies using validated GMP-compliant methods.