Page 274 - Chiral Separation Techniques

Chiral Separation Techniques: A Practical Approach, Second, completely revised and updated edition
Edited by G. Subramanian
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29875-4 (Hardcover); 3-527-60036-1 (Electronic)
10 The Use of SMB for the Manufacture

of Enantiopure Drug Substances:

From Principle to cGMP Compliance

S.R. Perrin and R.M. Nicoud

10.1 Introduction

10.1.1 FDA as the Driving Force: Enantiopure Drugs and Compliance

In May 1992, the U.S. Food and Drug Administration (FDA) issued a policy state-
ment for the development of stereoisomeric drugs [1]. The statement focused on the
study and pharmaceutical development of single enantiomers (enantiopure) and
racemic drugs. The policy stated: “Now that technological advances (large scale chi-
ral separation procedures or asymmetric syntheses) permit production of many sin-
gle enantiomers on a commercial scale, it is appropriate to consider what FDA’s pol-
icy with respect to stereoisomeric mixture should be”. Furthermore, the manufac-
turer should develop quantitative assays for stereoisomeric drugs in the early stages
of drug development to assess the efficacy of the drug. The message from the FDA
was clear and urged the pharmaceutical industry to evaluate enantiopure drugs
alongside racemic drugs as new candidates for the future [2, 3]. Consequently,
worldwide scientific and regulatory agencies (European Union, Canada, and Japan)
soon released guidelines for the development and manufacture of enantiopure drugs
[4–7].
It was apparent that the FDA recognized the ability of the pharmaceutical indus-
try to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the
early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus
enabling the researcher the ability to quantify, characterize, and identify stereoiso-
mers. Given these tools, the researcher can assess the pharmacology or toxicology
and pharmacokinetic properties of enantiopure drugs for potential interconversion,
absorption, distribution, and excretion of the individual enantiomers.
Despite widespread adherence to the 1992 guidelines, the FDA soon toughened
its stance in January 1997 by first proposing and then removing the drug Seldane
(terfenadine), manufactured by Hoechst Marion Roussel [10–12]. The rule change
by the FDA regarding extended market exclusivity and new chemical entities were
based on pharmacological data, and resulted in a new interpretation of fixed combi-
nation dosages. The example of Seldane was due to the rapid metabolism of terfe-
nadine to a pharmacologically active carboxylic acid metabolite (fexofenadine) and