Pharmaceutical Industry Practices on Genotoxic Impurities

Heewon Lee is Senior Associate Director of the Chemical Development Department at Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA. She is also leader of the Analytical Research Group, an active participant in the Genotoxic Impurity Council, and a member of the Pharmaceutical IQ Consortium Working Group. She holds a BS and a MS from Seoul National University, South Korea, as well as a Ph.D from the University of Michigan, Ann Arbor, USA. Previously, she worked at ArQule, a biotechnology company located in Woburn, Massachusetts, USA. After ArQule, she joined the Medicinal Chemistry Department at Boehringer-Ingelheim before moving to her current position.

A great deal of confusion and uncertainty over genotoxic impurity (GTI) identification, assessment, and control exists. This book strives to facilitate scientific and systematic consensus on GTI management by presenting rationales, strategies, practices, and case studies from the pharmaceutical industry. Exploring the safety, quality, and regulatory aspects of GTIs, the text explains the how and why of various GTI control tactics and practices, including GTI control examples in drug substance and drug product development processes from large and small pharmaceutical firms in multiple geographical regions.

Overview of Regulatory Guidelines on Impurities and Genotoxic Impurities. Structural Alerts for Genotoxicity and Carcinogenicity. Acceptable Exposure Calculations for Impurities and Selected Compounds from the Carcinogenic Potency Database. Genotoxic Impurities from Toxicology Perspectives Including Cancer Risk Assessment, In Silico, In Vitro/In Vivo Testings, and Regulatory Aspects. In Silico/Computational Assessment for the Evaluation of Genotoxic Impurities. Preclinical Assessment of Genotoxic Impurities: An Overview of Current Regulatory Guidance, Available Assays, and Data Interpretation. Purification of Lead Compounds for Early Toxicology Profiling such as Ames and Short-Term Nongood Laboratory Practice Toxicology Tests. Analysis of Genotoxic Impurities in Pharmaceuticals by Gas Chromatography-Mass Spectrometry. Control of Chloroethane in Raw Materials and Drug Substances Using Headspace/Gas Chromatography Analysis. Quantification of Genotoxic Impurities in Active Pharmaceutical Ingredients. Analytical Testing and Control for Genotoxic Impurities in Drug Substances. Approaches to Assess, Analyze, and Control Genotoxic Impurities in Drug Substance Development. Control and Analysis of Genotoxic Impurities in Drug Substance Development. Salt Formation of Pharmaceutical Compounds and Associated Genotoxic Risks. Identification and Control of Genotoxic Degradation Products. Identification and Qualification of Genotoxic Impurities as Leachables in Drug Products. Pharmaceutical Industry Survey on Genotoxic Impurities and Related Topics.