The container that holds your peptide drug can add unwanted chemicals to your product. These chemicals come from the packaging materials (glass, rubber, plastic, coatings) and can affect drug safety and quality.
Extractable and leachable (E&L) testing identifies these chemicals and measures their levels.
Extractables are chemicals that can be pulled out of packaging materials under extreme laboratory conditions. Leachables are chemicals that actually migrate into the drug product under normal storage conditions.
E&L testing is required by the FDA for all parenteral (injectable) drug products. For peptide drugs, it is especially important because peptides can interact with leachable chemicals in ways that affect stability and safety.
Many companies outsource E&L testing because it requires specialized analytical chemistry expertise and advanced instrumentation.
- E&L testing identifies chemicals migrating from packaging into peptide drugs and is FDA-required for all injectable products.
- Extractable studies use extreme conditions to screen packaging materials before leachable studies assess real-world migration into the drug.
- Peptide injectables are high-concern because peptides readily interact with leachables through oxidation, aggregation, and potency loss.
- Glass vials, rubber stoppers, plastic components, coatings, and adhesives are all potential sources of leachable chemicals.
- Outsourcing E&L testing provides multi-method analytical capabilities and regulatory expertise most companies lack in-house.
- Begin E&L testing early during packaging selection to avoid costly material changes later in the regulatory process.
Why E&L Testing Matters
Leachable chemicals from packaging materials can cause several problems.
Patient Safety
Some leachables are toxic, carcinogenic, or allergenic. Patients should not be exposed to these chemicals through their medications.
Drug Stability
Leachables can react with peptides. For example, metal ions leaching from glass can catalyze oxidation. Organic compounds from rubber stoppers can react with peptide functional groups.
Drug Potency
Leachables can bind to peptides and reduce their biological activity. They can also cause aggregation or precipitation.
Regulatory Compliance
The FDA expects E&L data in every NDA and BLA for parenteral products. Without this data, your regulatory submission is incomplete.
According to the FDA Guidance on Container Closure Systems, the level of concern for potential E&L interactions is highest for injectable products, especially those that are aqueous-based and have long shelf lives. Peptide injectables fall squarely in this high-concern category.
The Difference Between Extractables and Leachables
Understanding the difference is important for study design.
| Feature | Extractables | Leachables |
|---|---|---|
| Definition | Chemicals removed under aggressive conditions | Chemicals that migrate during normal use |
| Conditions | Extreme solvents, temperatures, time | Actual product contact, normal storage |
| Purpose | Worst-case screening | Real-world assessment |
| Timing | Early development | Later development/stability |
| Sample type | Packaging materials only | Drug product in contact with packaging |
| Regulatory role | Identify potential leachables | Confirm safety of actual product |
Extractable studies come first. They cast a wide net to identify everything that could potentially leach. Leachable studies come second. They measure what actually does leach into the product.
A single rubber stopper can release over 100 distinct extractable compounds, many of which are not listed on the component manufacturer's data sheet.
Sources of Extractables and Leachables
Every component of the container closure system can contribute.
Glass Vials
- Metal oxides (silicon, boron, sodium, aluminum)
- Heavy metals (lead, arsenic)
- Delamination particles
Rubber Stoppers
- Vulcanization agents (sulfur compounds)
- Antioxidants (BHT)
- Plasticizers
- Processing aids
- Oligomers
Plastic Components
- Monomers and oligomers
- Plasticizers (phthalates)
- Antioxidants (Irganox)
- UV stabilizers
- Colorants
Coatings and Inks
- Solvents
- Pigments
- Binder degradation products
Adhesives and Labels
- Adhesive components
- Label printing chemicals
Analytical Methods for E&L Testing
E&L testing requires multiple analytical methods to cover the full range of potential chemicals.
| Method | Target Compounds | Detection |
|---|---|---|
| GC-MS | Volatile and semi-volatile organics | Low ppb |
| LC-MS | Non-volatile organics | Low ppb |
| ICP-MS | Elemental/metal impurities | Sub-ppb |
| HPLC-UV | Targeted organic compounds | Low ppm |
| IC (Ion Chromatography) | Inorganic anions and cations | Low ppm |
| NMR | Structure confirmation | Identification |
| FTIR | Polymer identification | Identification |
| TOC | Total organic carbon | Screening |
Why Multiple Methods Are Needed
No single analytical method can detect all potential extractables and leachables. Volatile compounds require GC-MS. Non-volatile compounds require LC-MS. Metals require ICP-MS. A comprehensive study uses all of these methods together.
The E&L Study Process
Phase 1: Extractable Study
- Identify all packaging components that contact the product or are within the container.
- Select extraction conditions (solvents, temperatures, times) that are more aggressive than normal use.
- Perform extractions using multiple solvents (aqueous, organic, acidic, basic).
- Analyze extracts using GC-MS, LC-MS, ICP-MS, and other methods.
- Identify and quantify all detected extractables.
- Perform toxicological risk assessment on identified extractables.
- Create a target leachable list of compounds that need monitoring.
Phase 2: Leachable Study
- Store the drug product in the actual container closure system under ICH stability conditions.
- Sample at defined time points (initial, 3, 6, 12, 24, 36 months).
- Analyze samples for target leachables using validated methods.
- Compare leachable levels to safety thresholds.
- Report results as part of the stability program.
Request extractable profiles from your packaging component suppliers before finalizing container closure selection. Comparing profiles across vendors early can eliminate high-risk materials and save months of reformulation work downstream.
Safety Assessment of E&L
Not all extractables and leachables are dangerous. A toxicological risk assessment determines whether detected compounds pose a safety risk.
The assessment typically uses the Safety Concern Threshold (SCT) and the Qualification Threshold (QT) from the Product Quality Research Institute (PQRI).
- SCT: Below this threshold, a compound is considered safe without further evaluation (typically 0.15 micrograms/day for parenterals).
- QT: Above this threshold, the compound must be identified and its safety justified.
"E&L testing is not just about finding chemicals. It is about understanding which chemicals matter. A thorough toxicological risk assessment turns raw analytical data into actionable safety information."
Why Outsource E&L Testing?
Multi-Method Analytical Capability
Few labs have all the needed instruments (GC-MS, LC-MS, ICP-MS) in one place. E&L-specialized labs do.
Regulatory Experience
E&L studies must be designed to meet FDA and EMA expectations. Labs that specialize in E&L know what regulators look for.
Toxicological Assessment
E&L testing is incomplete without a safety assessment. Specialized labs have toxicologists who can evaluate the data and prepare the risk assessment.
Method Development and Validation
Leachable methods must be validated for the specific drug product matrix. This requires method development expertise.
Cost of Outsourcing E&L Testing
| Service | Estimated Cost |
|---|---|
| Extractable study (full, multi-method) | $50,000 - $150,000 |
| Leachable method development and validation | $30,000 - $80,000 |
| Leachable testing (per time point) | $5,000 - $20,000 |
| Toxicological risk assessment | $15,000 - $40,000 |
| Complete E&L package | $100,000 - $300,000 |
Choosing an E&L Testing Partner
Look for these qualities.
- Multi-technique analytical capability (GC-MS, LC-MS, ICP-MS minimum)
- E&L-specific experience with pharmaceutical packaging
- Toxicological assessment expertise including PQRI/BPOG guidelines
- Regulatory submission support for FDA and EMA filings
- Method development and validation for leachable testing
- Familiarity with peptide products and their unique sensitivities
For a complete packaging quality program, explore our guide on container closure integrity testing.
You can also learn about peptide stability testing best practices where E&L data plays a supporting role.
Starting E&L testing during packaging selection, not after, prevents costly material changes that can delay regulatory submissions by a year or more.
People Also Ask
When should E&L testing be done during peptide development?
Extractable studies should be done during Phase 1 or Phase 2 clinical development, when you are selecting your commercial container closure system. Leachable studies should run throughout stability testing, starting with registration stability batches. Starting early avoids surprises late in development.
How long does an E&L study take?
An extractable study takes 3 to 6 months, including method development, extraction, analysis, and risk assessment. Leachable studies run for the duration of the stability program (typically 12 to 36 months). The initial leachable method development and validation takes 2 to 4 months.
What is the difference between E&L testing and compatibility testing?
E&L testing identifies chemicals that migrate from the packaging into the product. Compatibility testing evaluates whether the drug product changes when stored in the packaging (loss of potency, pH changes, appearance changes). Both are needed. E&L focuses on the packaging, while compatibility focuses on the product.
Are E&L studies required for all peptide products?
E&L studies are required for all parenteral (injectable) drug products, which includes most peptide drugs. The level of testing depends on the route of administration, the dosage form, and the packaging materials. High-risk products (aqueous injectables with long shelf lives) require the most extensive testing.
What materials pose the highest E&L risk?
Rubber stoppers are generally the highest-risk component because they contain many processing additives. Uncoated glass can leach metals and silicates. Plastic components (syringes, cartridges) can release monomers and plasticizers. Coated or treated components generally have lower E&L risk.
Can E&L testing be done on the same samples as stability testing?
Yes, and this is the most efficient approach. Leachable testing is typically performed on stability samples at each time point. This integrates the leachable study into the existing stability program and ensures that leachable data is obtained under the same conditions as stability data.
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Robert Kim
Outsourcing Strategy Consultant
MBA, Operations Management | 10 years in healthcare business outsourcing
Advises peptide companies on building scalable virtual assistant and outsourcing programs. Specializes in vendor selection, SLA design, and cost optimization for life-science businesses.
Reviewed by Robert Kim, MBA, April 2026