DescriptionThis book examines genotoxic impurities and their impact on the pharmaceutical industry. Specific sections examine this from both a toxicological and analytical perspective. Within these sections, the book defines appropriate strategies to both assess and ultimately control genotoxic impurities, thus aiding the reader to develop effective control measures. An opening section covers the development of guidelines and the threshold of toxicological concern (TTC) and is followed by a section on safety aspects, including safety tests in vivo and vitro, and data interpretation. The second section addresses the risk posed by genotoxic impurities from outside sources and from mutagens within DNA. In the final section, the book deals with the quality perspective of genotoxic impurities focused on two critical aspects, the first being the analysis and the second how to practically evaluate the impurities.
Section I: Development of GI Guidelines and the TTC Concept.
Chapter 1. Historical Overview of the Development of Genotoxic Impurities Guidelines and their Impact (R. Ogilvie and A. Teasdale).
Chapter 2. Development of the Threshold of Toxicological Concern Concept (TTC) and its Relationship to Duration of Exposure (A. Brigo and L. Muller).
Section 2: Evaluation of Genotoxic Risk from a Pre-clinical Perspective.
Chapter 3. Genetic Toxicity Testing to Qualify Alerting Impurities (M. O’Donovan).
Chapter 4. Use of Structure Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation of the Genotoxic Potential of Impurities (S. Glowienke and C. Hasselgren).
Chapter 5. Compound-Specific Risk Assessments for Genotoxic Impurities: Examples and Issues (A. Teasdale and C. Humfrey).
Chapter 6. Human Genotoxic Metabolites: Identification and Risk (K. Dobo, D. Walker and A. Teasdale).
Section 3. Perspective on Risk Posed by Genotoxic Impurities.
Chapter 7. Genotoxic Thresholds (G. Jenkins, G. Johnson, J. Parry and S. Doak).
Chapter 8. Genotoxic Impurities a Risk in Perspective? (D. Elder).
Section 4. Assessment of Genotoxic Risk: Quality Perspective.
Chapter 9. Strategies for the Evaluation of Genotoxic Impurity Risk (A. Teasdale, S. Fenner and D. Elder).
Chapter 10. Analysis of Genotoxic Impurities: Review of Approaches (D. Elder).
Chapter 11. Development of a Strategy for Analysis of Genotoxic Impurities (Andrew Baker).
Chapter 12. Strategic Approaches to the Chromatograpic Analysis of Genotoxic Impurities (Frank David, Karine Jacq, Gerd Canhoenacker and Pat Sandra).
Chapter 13. Analysis of Genotoxic Impurities by Nuclear Resonance (NMR) Spectroscopy (Andrew Philips).
Chapter 14. Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters: Summary of the PQRI Studies – PQRI Working Group (Andrew Teasdale).
Chapter 15. Aspects to Consider when Devising a Strategy to Understand if Low Level API/DP Degradants have the Potential for Genotoxicity (Alan P. McKeown and Andrew Teasdale).
“This book is a valuable resource when dealing with genotoxic impurities. Its publication is timely considering the new ICH M7 guideline under discussion. I highly recommend the book to toxicology and CMC professionals and to anyone with a general interest in genotoxic impurities.” (Drug Information Journal, 1 March 2012)
"This is an unmatched resource for understanding current regulations that guide the development of pharmaceuticals with respect to genotoxic substances, including the foundational principles upon which these guidelines were established. Armed with this knowledge, readers will appreciate the assessment of analytical techniques to control genotoxic impurities to a level that preserves both drug safety and quality throughout the development process." (Doody's, 26 August 2011)
"This is a very good book and addresses the issue in a very sensible, dare I say it, pragmatic approach." (The British Toxicology Society Journal, 1 May 2011)
"Overall, a valuable addition to a pharmaceutical scientists' library. The topics covered are relevant and of interest to various ‘stake-holders' in the drug development arena, including chemists, analysts and programme managers. I can recommend it." (Journal of Organic Process Research & Development, 2011)
"The style throughout is easy to read and content readily digested, especially those chapters [on] chemical process development and early-phase API development ... From a more practical point of view, the contents are well set out, and indexing appeared appropriate. ... Overall, a valuable addition to a pharmaceutical scientist's library. The topics covered are relevant and of interest to various ‘stake-holders' in the drug development arena, including chemists, analysts, and programme managers. I can recommend it." (American Chemical Society, 2011)