Case Study: How to Assess and Control DNA Reactive (Mutagenic) Impurities in the Pharmaceutical Industry (CE8-5)

The lecture will describe a real world small molecule example of how the risk assessment of potential genotoxic impurities is conducted in the pharmaceutical industry in a practical sense. The presentation will draw on what has been presented by earlier speakers and will provide the audience with an understanding of the challenges and best practice solutions. In 2007, a contamination of Viracept (nelfinavir) tablets with the mutagenic DNA-ethylating agent ethyl methanesulfonate (EMS) occurred because of a production incident. Patients could have been exposed for 3 months to daily doses of up to 2.75 mg EMS. The description of this case will explain how the license holder managed the incident and how regulatory agencies handled it. The toxicological information available at the time on EMS had to be complemented by a number of additional experiments and studies to further refine the risk assessment. Extensive studies on the genotoxicity showed threshold-like dose responses for both chromosome damage (bone marrow micronucleus test) and gene mutation (lacZ transgenic MutaMouse test) in various organs of mice treated for up to 4 weeks. This represented a paradigm shift in the area of genotoxicity, showing that even DNA alkylating agents can have a threshold-based mechanism to induce genetic toxicity. Consequently, using a threshold risk assessment based on estimated Cmax and exposure values of EMS, allowed the derivation of significant safety factors (of 370 and 28) for the maximum doses ingested by patients treated with Viracept.