A harmonization effort for acceptable daily exposure application to pharmaceutical manufacturing - Operational...

Area of Science:

• Pharmaceutical Regulatory Science
• Toxicology
• Drug Safety

Background:

• European Union (EU) regulatory guidelines for pharmaceutical products became effective in 2015.
• These guidelines focus on the implementation of Acceptable Daily Exposure (ADE), also known as Permitted Daily Exposure (PDE).
• The guidelines apply to new and existing pharmaceutical products, impacting active pharmaceutical ingredients (APIs) and other substances.

Purpose of the Study:

• To outline operational considerations for implementing EU regulatory guidelines on ADE/PDE.
• To address challenges in establishing ADEs for substances with limited toxicological data.
• To discuss strategies for risk management in pharmaceutical manufacturing facilities.

Main Methods:

• Review of EU regulatory guidelines concerning ADE/PDE.
• Exploration of methodologies for setting ADEs, including occupational exposure limits/bands (OELs/OEBs) and threshold of toxicological concern (TTC).
• Discussion of the use of maximum daily dose (MDD) for cross-contamination limits and maximum allowable/safe concentration (MAC/MSC) calculations.

Main Results:

• The guidelines require ADEs for all APIs, with potential benefits for starting materials, intermediates, and cleaning agents.
• Established methodologies like OELs/OEBs and TTC can serve as interim ADEs for data-poor substances.
• Operational considerations include updating ADE documents, communicating changes, defining MDD, and managing risks in shared facilities.

Conclusions:

• Formal ADE derivation is crucial, but interim solutions using toxicological data limitations are necessary.
• Effective implementation requires clear definitions, routine updates, stakeholder communication, and robust risk management.
• The guidelines necessitate careful consideration of various factors, including pediatrics, large molecules, and shared facility operations.