Genotoxicity evaluation of a valsartan-related complex N-nitroso-impurity.

Recently, the formation of genotoxic and carcinogenic N-nitrosamines impurities during drug manufacturing of tetrazole-containing angiotensin-II blockers has been described. However, drug-related (complex) nitrosamines may also be generated under certain conditions, i.e., through nitrosation of vulnerable amines in drug substances in the presence of nitrite. An investigation of valsartan drug substance showed that a complex API-related N-nitrosamine chemically designated as (S)-2-(((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)(nitroso)amino)-3-methylbutanoic acid (named 181-14) may be generated. 181-14 was shown to be devoid of a mutagenic potential in the Non-GLP Ames test. According to ICH M7 (R1) (2018), impurities that are not mutagenic in the Ames test would be considered Class 5 impurities and limited according to ICH Q3A (R2) and B (R2) (2006) guidelines. However, certain regulatory authorities raised the concern that the Ames test may not be sufficiently sensitive to detect a mutagenic potential of nitrosamines and requested a confirmatory in vivo study using a transgenic animal genotoxicity model. Our data show that 181-14 was not mutagenic in the transgenic gene mutation assay in MutaTMMice. The data support the conclusion that the Ames test is an adequate and sensitive test system to assess a mutagenic potential of nitrosamines.

Environmental Metrics to Drive a Cultural Change: Our Green Eco-Label.

A novel Green Chemistry Process Scorecard was developed to assess the environmental impact of chemical production processes to manufacture the Active Pharmaceutical Ingredients (API) within our portfolio. These new metrics not only cover the resource consumption from the overall chemical synthesis, but also consider the use of Substances of Concern and the number of chemical transformations. The Process Mass Intensity (PMI), i.e. the ratio of accumulated kilogram quantities of materials per kilogram of API, is used to quantify the resource consumption. An 'eco-label' for specific APIs is used to visualize the environmental impact from their chemical synthesis. For an overview of the environmental impact of a complete product portfolio, a diagram of PMI or total waste quantity vs. the number of synthetic steps can also be used as a visualization tool to identify chemical syntheses with a high need for process improvements. Implementation of this process led to a dramatic change of mindset within the organization. It now supports and drives the decision making at Chemical and Analytical Development, and helps to trigger new projects more readily for sustainability reasons.