Calculating qualified non-mutagenic impurity levels: Harmonization of approaches

The presence of impurities in drugs is unavoidable. As impurities offer no direct benefit to the patient, it is critical that impurities do not compromise patient safety. Current guidelines on the derivation of acceptable impurity levels leave aspects of calculations open for interpretation, resulting in inconsistencies across industry and regulators. To understand current impurity qualification practices from a safety standpoint, regulatory expectations and the safety risk that impurities pose, the IQ DruSafe Impurities Working Group (WG) conducted a pharmaceutical industry-wide survey. Survey results highlighted areas that could benefit from harmonization, including nonclinical species/sex selection and the application of adjustment factors (i.e., body surface area). Recommendations for alignment on these topics is included in this publication. Additionally, the WG collated repeat-dose toxicity information for 181 starting materials and intermediates, reflective of pharmaceutical impurities, to understand the toxicological risks they generally pose in relation to the drug substance (DS) and the assumptions surrounding the calculation of qualified impurity levels. An evaluation of this dataset and the survey were used to harmonize how to calculate a safe limit for an impurity based on toxicology testing of the impurity when present within the DS. • IQ DruSafe WG survey results on industry practices regarding the calculation of qualified impurity levels. • Presentation of a harmonized approach to calculate qualified impurity levels from a safety perspective. • Body surface area conversion is not necessary from a safety perspective. • Recommendations on NOAEL selection to qualify impurity levels and dosing schedule conversion. • Impurity and correlated DS toxicity data support the safety of 1 mg non-mutagenic impurity/day.