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"Preface According to the World Health Organization's International Agency for Research on Cancer (IARC) (Technical Publication No. 24, 1994), genotoxicity is defined as structural changes at the level of a gene. It is also defined as a broad term that refers to any deleterious change in the genetic material regardless of the mechanism by which the change is induced, as stated by ICH S2(R1), "Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use." Genotoxic compounds have the theoretical potential to damage DNA at any level of exposure, leading to tumor development. This makes the toxicological assessment and determination of acceptable limits of genotoxic impurities (GTIs) difficult. GTIs have become an intensely debated topic in the pharmaceutical industry in recent years. My experiences in the internal and external discussions in meetings and conferences indicate that there is a great deal of confusion and uncertainty over identification, assessment, and control of GTIs. GTIs require different rationale and strategies from "regular" or "ordinary" impurities. Proper management of GTIs entails appropriate guidance and strategies, effective communication between various disciplines, sharing information and results, and understanding of the overall implications. The goal of this book is to present the rationale, strategies, methods, interpretation, practices, and case studies in the pharmaceutical industry in order to facilitate scientific and systematic consensus establishment on GTIs"--
List of contents
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.
About the author
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.
