Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2

Area of Science:

• Pharmaceutical manufacturing
• Toxicology
• Drug safety

Background:

• Pharmaceutical facilities require cleaning criteria for multipurpose manufacturing.
• Health Based Exposure Limits (HBELs), also known as permitted daily exposures (PDEs), are crucial for ensuring drug safety.
• HBELs are derived from toxicological and pharmacological data of active pharmaceutical ingredients (APIs).

Purpose of the Study:

• To demonstrate diverse approaches for evaluating a generic drug, paracetamol, in deriving PDEs.
• To discuss the relevance of nonclinical studies in PDE calculations.
• To establish example PDE values for paracetamol across different administration routes.

Main Methods:

• Toxicological and pharmacological evaluation of paracetamol.
• Analysis of nonclinical study data for PDE derivation.
• Comparison of different company approaches to PDE calculation.

Main Results:

• Established PDE limits for paracetamol: 25 mg/day (oral), 20 mg/day (intravenous), and 20 mg/day (inhalation).
• Acknowledged acceptable variations in PDE calculations due to data access, company policies, and expert judgment, potentially causing up to 3-fold differences.
• Highlighted that overly conservative PDE values increase cleaning and manufacturing costs.

Conclusions:

• The derived PDE values for paracetamol are protective against adverse and pharmacological effects.
• Variability in PDE calculations is acceptable and influenced by multiple factors.
• Optimizing PDE derivation balances safety with manufacturing efficiency and cost-effectiveness.