Genotoxic Impurities (eBook)

ANDREW TEASDALE, PhD, is a senior QA executive with AstraZeneca and chairs the company's internal genotoxic impurities advisory group. With over fifteen years of experience in analytical chemistry and quality assurance, Dr. Teasdale has published a number of papers relating to GIs and has been a speaker on genotoxic impurities at a number of conferences. Dr. Teasdale has also led two expert groups working in the field of genotoxic impurities, including an analytical group in the UK and a Project Quality Research Institute (PQRI) working group, which focused on the critical area of sulfonate ester formation and control.

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

"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)