10-step systemic safety assessment of extractables and leachables associated with drug products integrating topline, traditional, and next generation risk assessment.

New approach methodologies (NAM)-based next generation risk assessment (NGRA) has been investigated for toxicological risk assessment (TRA) mainly for cosmetic ingredients in recent years. With more knowledge and understanding of its application, NAM-based NGRA is anticipated to be practiced by more industry sectors. Although its regulatory acceptance is not a reality yet, practice of NGRA in drug impurity safety assessment community would benefit drug development. Extractables and leachables (E&Ls) are important part of lifecycle of drug products. Their safety must be evaluated to ensure patient safety. Due to their typically large profiles and wide chemical structural domains and often rarely encountered structures, safety assessment of E&Ls is challenging. The recently published ICH Q3E draft guideline lays out the principle, approach, and process of how to qualify E&Ls associated with drug products. To provide a holistic approach of performing E&L systemic safety assessment, a framework for E&L safety assessment is developed by integrating exposure-led topline risk assessment, animal data-based traditional risk assessment, and NAM-based NGRA. This framework can be used for other types of drug impurities and industry sectors such as medical devices and represents an initial effort for NAM-based NGRA in drug impurity safety assessment.