STEPHEN P. RAILLARD
XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA

Abstract

An overview is presented covering the last ten years of evolving regulations relating to genotoxic impurities (GTIs) in Active Pharmaceutical Ingredients (APIs) and some of the major corresponding pharmaceutical industry responses. Several conceptual and practical approaches for GTI control will be presented. Special cases that warrant additional attention such as API starting materials and degradation products will be discussed. Finally an attempt will be made to highlight potential future regulatory developments.

INTRODUCTION

The chemical processes that are used to produce APIs inherently make use of reactive starting materials, intermediates and reagents. Some of these are known or potential genotoxins. It can therefore be expected that APIs may contain low levels of such potential GTIs. This has been increasingly recognized by both industry and the regulatory bodies in the last decade. To support the need to manage the risk from potential GTIs, both during development and post-approval, the regulatory bodies have issued several guidelines in the last few years.

HISTORY OF REGULATIONS UNTIL 2004
While it was recognized by regulatory authorities in the late 90s and early 2000s that genotoxic and carcinogenic impurities can pose a special risk, they were regulated mostly on a case by case basis. The field had not advanced enough to allow for a unified regulatory view on what levels of GTIs might be acceptable or technically achievable. This was reflected in the ICH impurity guideline ICH Q3A “Impurities in New Drug Substances” which was issued in 1996. This guideline lacked a specific recommendation on how to address mutagenic ...