Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products:...

Area of Science:

• Pharmaceutical Science
• Toxicology
• Regulatory Science

Background:

• Leachables from pharmaceutical packaging are impurities that can affect drug safety and quality.
• Evaluating extractables and leachables (E&Ls) is crucial for impurity control strategies.
• Lack of specific regulatory guidance for E&L risk assessment leads to industry inconsistency.

Purpose of the Study:

• To provide clarity and detail on conducting risk assessments for E&Ls.
• To promote consistency in the industry for deriving compound-specific safety limits.
• To address the need for standardized approaches in pharmaceutical impurity control.

Main Methods:

• Collaborative effort by the Extractables and Leachables Safety Information Exchange (ELSIE) consortium.
• Calculation of health-based exposure limits, termed Permitted Daily Exposure (PDE), where sufficient data exist.
• Case studies detailing the risk assessment of four common E&Ls: bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010.

Main Results:

• Demonstrated the calculation of PDEs for common E&L substances.
• Explored the utility of extractable data in risk assessments.
• Provided guidance on route-to-route extrapolations and handling degradation products.

Conclusions:

• Establishing PDEs for E&Ls aids in consistent risk assessment.
• Standardized approaches for E&L safety evaluations are essential for patient safety and product quality.
• This work supports the development of harmonized industry practices for managing pharmaceutical impurities.