Setting impurity limits for endogenous substances: Recommendations for a harmonized procedure and an example using...

Area of Science:

• Pharmaceutical Chemistry
• Toxicology
• Drug Safety

Background:

• Endogenous substances (fatty acids, amino acids, nucleic acids) are common in parenteral pharmaceuticals but can act as impurities.
• Current regulatory guidance lacks consensus on setting impurity limits for these endogenous substances.
• Parenteral administration of endogenous substances presents unique toxicity risks due to non-physiological exposure.

Purpose of the Study:

• To propose a framework for developing health-based exposure limits (HBELs) for endogenous substances used as impurities in parenteral pharmaceuticals.
• To address the challenges in setting impurity limits due to limited toxicity data and non-physiological routes of administration.

Main Methods:

• Development and application of Risk Assessment Process Maps (RAPMAPs) to derive HBELs.
• Vetting of derived HBELs considering physiological serum levels, dose-rate, and intermittent dosing.
• Application of the framework to specific fatty acids commonly found in parenteral drugs.

Main Results:

• A framework for deriving parenteral HBELs for endogenous substances was established.
• Parenteral HBELs ranging from 100-500 mg/day were generated for several fatty acids.
• A proposed class-based limit of 50 mg/day was suggested for situations lacking chemical-specific data.

Conclusions:

• The RAPMAPs approach offers a systematic method for determining HBELs for endogenous impurities in parenteral drugs.
• The derived HBELs and proposed class-based limit provide valuable guidance for pharmaceutical impurity control.
• This framework supports enhanced drug safety by addressing the unique challenges of endogenous parenteral impurities.