In the pharmaceutical industry, ensuring the quality and safety of drug products is paramount. One critical aspect of this is controlling impurities, which are unintended substances that may arise during the manufacturing process, from raw materials, or through storage. When an impurity exceeds the established specification limit, it is classified as an Out-of-Specification (OOS) impurity. Such instances demand prompt and robust investigations including (but not limited to) toxicological risk evaluation to determine the impact on product quality, safety and compliance. This blog intends to explore the toxicological approaches and risk assessments that can be utilized to address OOS impurities effectively.Understanding Out-of-Specification (OOS) ImpuritiesThe OOS impurities can be broadly categorized into:Process-related impurities: These arise from raw materials, intermediates, or by-products of the manufacturing process.Degradation products: These result from the chemical breakdown of the drug substance during production, packaging, or storage.Excipients or leachables: Contaminants introduced through packaging materials or excipients.The International Council for Harmonisation (ICH) guidelines (ICH Q3A, Q3B, and Q3D) provide guidance for control and management of impurities in drug substances (DS) and drug products (DP). Similarly, various pharmacopoeias (for example, USP, BP, IP) provides information on standards and quality specifications for medicines used in that country or region. However, when any impurity surpasses the specific levels or thresholds, the impurity(ies) are subjected to investigation including evaluation of its safety (health-hazard assessment) by performing a thorough toxicological risk assessment.