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Genotoxic Impurities
Strategies for Identification and Control

Andrew Teasdale (Edited by), A Teasdale (Author)

9780470499191, Wiley

Hardback, published 15 February 2011

448 pages
24.1 x 16.3 x 2.8 cm, 0.758 kg

“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)

 

This 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.

Foreword ix

Preface xi

Contributors xiii

Part 1 Development of Genotoxic Impurities Guidelines and the Threshold of Toxicological Concern Concept

Chapter 1 Historical Overview of the Development of Genotoxic Impurities Guidelines and TheirImpact 3
Ron Ogilvie and Andrew Teasdale

Chapter 2 Development of the Threshold of Toxicological Concern Concept and Its Relationship toDuration of Exposure 27
Alessandro Brigo and Lutz Müller

Part 2 Evaluation of Genotoxic Risk from a Preclinical Perspective

Chapter 3 Genetic Toxicity Testing to Qualify Alerting Impurities 67
Mike O’Donovan

Chapter 4 Use of Structure Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation ofthe Genotoxic Potential of Impurities 97
Susanne Glowienke and Catrin Hasselgren

Chapter 5 Compound-specific Risk Assessments for Genotoxic Impurities: Examples and Issues 121
Andrew Teasdale and Charles Humfrey

Chapter 6 Human Genotoxic Metabolites: Identification and Risk Management 151
Krista Dobo, Don Walker, and Andrew Teasdale

Part 3 Perspective on Risk Posed by Genotoxic Impurities

Chapter 7 Genotoxic Thresholds 171
Gareth J.S. Jenkins, George E. Johnson, James M. Parry, and Shareen H. Doak

Chapter 8 Genotoxic Impurities: A Risk in Perspective 193
Dave Elder and Jim Harvey

Part 4 Assessment of Genotoxic Risk: Quality Perspective

Chapter 9 Strategies for the Evaluation of Genotoxic Impurity Risk 221
Andrew Teasdale, Dave Elder, and Simon Fenner

Chapter 10 Analysis of Genotoxic Impurities: Review of Approaches 249
Dave Elder

Chapter 11 Development of a Strategy for Analysis of Genotoxic Impurities 281
Andrew Baker

Chapter 12 Strategic Approaches to the Chromatographic Analysis of Genotoxic Impurities 305
Frank David, Karine Jacq, Gerd Vanhoenacker, and Pat Sandra

Chapter 13 Analysis of Genotoxic Impurities by Nuclear Magnetic Resonance Spectroscopy 351
Andrew Phillips

Chapter 14 Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters:Summary of the Product Quality Research Institute Studies 385
Andrew Teasdale

Chapter 15 Aspects to Consider When Low-level Active Pharmaceutical Ingredient/Drug ProductDegradants Have the Potential for Genotoxicity 409
Alan P. McKeown and Andrew Teasdale

Index 423

Subject Areas: Chemistry [PN]

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