title: The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product.
abstract: The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.
authors: Analytical Sciences Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. ldow@lilly.com
authors: Linda K
authors: LK
authors: Dow
authors: Marvin M
authors: MM
authors: Hansen
authors: Brian W
authors: BW
authors: Pack
authors: Todd J
authors: TJ
authors: Page
authors: Steven W
authors: SW
authors: Baertschi
mesh_terms: D004339:Drug Compounding; D004340:Drug Contamination / Q000331:legislation & jurisprudence / Q000517:prevention & control; D004355:Drug Stability; D004335:Drug and Narcotic Control / Q000331:legislation & jurisprudence / Q000379:methods; D006801:Humans; D009153:Mutagens / Q000032:analysis*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D018570:Risk Assessment; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D009153:Mutagens; D004364:Pharmaceutical Preparations