Extractable and Leachable Studies in Pharmaceuticals: A Deep Dive into USP <1663>, <1664>, and AET
What Are Extractables and Leachables in Pharmaceuticals?
In the pharmaceutical industry, it’s vital to evaluate whether packaging materials interact with a drug product in a way that could compromise safety or quality. This evaluation is performed through extractable and leachable (E&L) studies, guided by USP <1663> and USP <1664>.
- Extractables: Compounds that can be drawn from packaging materials under aggressive conditions.
- Leachables: Compounds that migrate into the drug product during shelf life under actual conditions of use.
These studies are foundational for ensuring drug safety, stability, and regulatory compliance.
USP <1663>: Extractables Testing Guidelines
Key Objectives:
- Identify potential leachables early.
- Guide material selection and formulation design.
- Support the design of leachables testing (USP <1664>).
Study Process:
- Extraction with solvents like water, ethanol, hexane, acid/base under exaggerated conditions.
- Use of analytical technologies such as:
- GC-MS – Volatile and semi-volatile organics
- LC-MS – Non-volatile organics
- ICP-MS – Elemental impurities
Outcome: Identification of compounds that may leach and inform leachables study planning.
USP <1664>: Leachables Testing Guidelines
Key Objectives:
- Confirm actual patient exposure to potential migrants.
- Assess toxicological risk.
- Support product approval and post-approval compliance.
Study Process:
- Conducted on the final packaged drug product under long-term storage conditions.
- Performed over time points aligned with ICH stability guidelines.
- Uses validated analytical methods sensitive enough to detect low-level leachables.
Analytical Evaluation Threshold (AET): A Critical Concept in USP <1664>
The Analytical Evaluation Threshold (AET) defines the minimum concentration at which an individual leachable compound must be reported and evaluated during a leachables study.
Why AET Matters:
- Differentiates between compounds needing toxicological assessment and those that don’t.
- Ensures low-level impurities below safety concern thresholds aren’t over-evaluated.
How AET Is Calculated:
AET is derived from the Safety Concern Threshold (SCT) and depends on:
- Maximum daily dose of the drug product
- Analytical uncertainty factor
Example Formula:
AET = SCT / Maximum Daily Dose × Uncertainty Factor
Note: A typical SCT for most pharmaceuticals is 1.5 µg/day, but lower values may apply to inhalation, injectable, or pediatric products.
USP <1663> vs. USP <1664> and the Role of AET
| Feature | USP <1663> (Extractables) | USP <1664> (Leachables) |
|---|---|---|
| Study Type | Exaggerated lab conditions | Real-time, stability-based testing |
| Sample | Packaging or device materials | Final drug product |
| Output | Potential leachables profile | Actual leachables profile |
| Regulatory Relevance | Material screening and risk planning | Direct input to regulatory filing |
| AET Relevance | Not applicable | Defines reporting threshold for leachables |
Why Extractable and Leachable Studies—and AET—Are Essential
- Protect Patient Safety: Prevent exposure to toxic or carcinogenic substances.
- Ensure Regulatory Compliance: Meet expectations of FDA, EMA, and other authorities.
- Stabilize Product Development: Ensure compatibility of formulation and packaging.
- Streamline Risk Assessment: Use AET to focus on toxicologically relevant compounds.
- Enable Quality by Design (QbD): Use E&L data proactively in early stages.
Conclusion: Strengthening Safety Through E&L and AET Compliance
Extractable and leachable studies, supported by USP <1663>, USP <1664>, and the AET concept, are integral to modern pharmaceutical development. They form a comprehensive framework for risk mitigation, ensuring both regulatory compliance and patient safety.
Early investment in E&L analysis and scientifically justified AET calculations helps avoid regulatory delays and supports a robust product lifecycle.
Related Articles:
- Understanding ICH Q3D for Elemental Impurities
- Container Closure Integrity Testing (CCIT)
- Pharmaceutical Stability Studies Best Practices
- Pharmasciences.in