Page 329 - Chiral Separation Techniques

322 13 International Regulation of Chiral Drugs

cal Evaluation Report (PER) scheme which was initiated by the EFTA countries but
now has world-wide membership. The publication of guidance by the various regu-
latory authorities has itself in turn further stimulated the development of single enan-
tiomers by the pharmaceutical industry and thus ensured the continued introduction
of new enantioselective methods of synthesis and analysis.
The progress made in this area has been such that, in retrospect, it is difficult to
see why the biological significance of chirality was not initially more widely appre-
ciated and why there was so much controversy when the concept of regulating chi-
ral drugs was first aired. Nowadays, it is widely accepted that enantiomers should be
treated as separate compounds from the point of view of their pharmacological
action, although there are still lessons to be learned with respect to drug safety [12].
The presentation of a drug as a racemate now requires full justification before a mar-
keting authorization can be granted, which means that studies with individual enan-
tiomers using chiral analytical procedures are a necessity during product develop-
ment even if it is the racemate that is finally marketed. The issue of chirality has been
reviewed with respect to classes of drugs such as nonsteroidal anti-inflammatory
agents [13] and antimicrobials [14].
The remainder of this chapter outlines the regulatory requirements for investiga-
tion of chiral drugs in the three regions of Europe, the US and Japan. These coun-
tries provide the sponsoring bodies for the International Conference on Harmoniza-
tion which aims to unify the process of drug registration globally (see Section 13.5).
The requirements are discussed with particular emphasis on their pharmaceutical
and chemical (quality) aspects: enantiopurity is a significant factor to be considered
when seeking approval of a chiral drug.

13.2 Requirements in the European Union

13.2.1 Introduction

Common legislation governs the criteria for the approval of human medicines
throughout the countries of the EU whether applications for marketing authoriza-
tions are made through the centralized or national routes. There are several volumes
of the Rules Governing Medicinal Products in the European Community [15] which
include the relevant Directives and also provide interpretation of the pharmaceutical
legislation. The Rules are available on the Internet web-site for Directorate General
III of the European Commission which is responsible for pharmaceuticals
(http://dg3.eudra.org). Recommendations on the studies to be conducted in support
of an application for a marketing authorization are made in Guidelines on Quality,
Safety and Efficacy of Medicinal Products for Human Use contained in Volume III
of the Rules. These notes for guidance begin life under the auspices of the various
working parties of the Committee of Proprietary Medicinal Products (CPMP) and
include guidelines which are the result of international harmonization (see Section