USP <1663>: Materials and Conditions Used in Extractables Testing
Extractables and leachables (E&L) testing is essential to ensure the safety and compatibility of pharmaceutical packaging and delivery systems. According to USP <1663>, extractables studies are performed under exaggerated conditions to identify compounds that could potentially migrate into drug products. Below, we explore the different types of materials tested and the conditions applied to simulate worst-case scenarios.
Types of Materials Used in Extractables Testing
The materials tested are categorized based on their proximity to the drug product and their functional role in the packaging system.
1. Primary Packaging Components
These come into direct contact with the drug and are the highest priority in testing.
- Rubber stoppers and seals
- Glass or plastic vials and ampoules
- Syringe barrels and plungers
- Blister pack films (PVC, PVDC, aluminum foil)
2. Secondary Packaging Components
These materials do not touch the drug product directly but may pose a risk through indirect interaction (e.g., vapor migration).
- Cartons with adhesives or coatings
- Outer wraps
- Labels and printed inks
3. Drug Delivery Devices and Components
Includes materials from inhalers, injectors, and ophthalmic applicators, where frequent or direct patient exposure is possible.
- Metered-dose inhalers (actuators, containers)
- Auto-injector pens
- Ophthalmic droppers
- Catheters and tubing sets
4. Manufacturing Contact Surfaces
Materials that contact the drug during manufacturing are tested when there’s potential carryover into the final product.
- Silicone or PVC tubing
- Mixing tanks (stainless steel, lined materials)
- Gaskets, hoses, and filters
5. Specialized Dosage Forms
Packaging for sensitive dosage forms like injectables or inhalables undergo additional scrutiny.
- Pre-filled syringes
- IV bags and connectors
- Nasal sprays
- Single-use cartridges
Conditions Applied During Extractables Testing
USP <1663> recommends using aggressive conditions that simulate or exaggerate the real-world scenarios to release as many potential extractables as possible.
1. Solvent Selection
A range of solvents is used to target compounds of various chemical properties:
| Solvent Type | Example | Purpose |
|---|---|---|
| Polar | Water, saline | Extracts hydrophilic compounds |
| Semi-polar | 50% ethanol-water, isopropanol | Extracts alcohol-soluble organics |
| Non-polar | Hexane, heptane | Extracts hydrophobic and oily residues |
| Acidic | 0.1 N HCl | Releases acid-sensitive compounds |
| Basic | 0.1 N NaOH | Targets base-sensitive leachables |
| Surfactant-based | Polysorbate 80, SDS | Extracts silicone oils, surfactants |
2. Temperature Conditions
- Room Temperature (25–30°C): Control or baseline condition
- Elevated (40–70°C): Accelerated extraction to simulate stress
- Autoclave (121°C): Mimics sterilization for parenteral products
3. Extraction Time
- Short (24 hours): Initial screening
- Medium (3–7 days): Common for typical extractables testing
- Long (up to 30 days): Simulates extended exposure
4. Surface Area-to-Volume Ratio
This ratio determines the amount of packaging material exposed to the solvent:
- Standard: ~6 cm²/mL for most materials
- Exaggerated: 10–20 cm²/mL for worst-case risk analysis
5. Agitation and Mixing
To enhance solvent-material interaction:
- Static soaking (simple immersion)
- Shaking or stirring (accelerated contact)
- Sonication (for difficult-to-release compounds)
6. Optional Stress Conditions
Applied as needed based on product type:
- Light Exposure: Tests UV-sensitive inks or plastics
- Vacuum or Pressure: Simulates special delivery systems
- Humidity: For packaging stored in tropical zones
Conclusion
Understanding the types of materials and testing conditions outlined in USP <1663> is critical for designing an effective extractables study. By applying exaggerated solvent conditions, temperatures, and durations, scientists can identify potential leachables early and prevent safety risks in the final drug product.
In a future blog, we’ll discuss how the results of extractables testing under USP <1663> are used to design leachables studies according to USP <1664>, including the application of the Analytical Evaluation Threshold (AET).