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13.2 Requirements in the European Union 323

13.5). Such guidelines are not legally binding, but the applicant would be expected
to provide a satisfactory (scientifically based) justification in cases where the rec-
ommendations had not been followed. European guidelines are available at their
draft consultation stages and in their final form on the Eudranet web-site of the Euro-
pean Medicines Evaluation Agency (EMEA) at http://www.eudra.org/emea.html.
The note for guidance of primary interest for drugs which may exist as optical iso-
mers is called Investigation of Chiral Active Substances (CPMP/III/3501/91). Dis-
cussion on this guideline started in 1991, it was adopted in October 1993 and came
into force in April 1994. Its requirements are discussed below together with relevant
aspects of other notes for guidance concerning quality issues.

13.2.2 Note for Guidance on Investigation of Chiral Active Substances

The contents of this guideline are additional to other guidelines relating to the qual-
ity, safety and efficacy of medicinal products licensed in the EU. Manufacturers
must decide whether to market a drug as a single enantiomer or a racemate. They
should provide sufficient justification of their decision so that the licensing author-
ity can assess the risk:benefit ratio. The key to a successful outcome for an applica-
tion for a marketing authorization is proper justification of the decisions made con-
cerning a product during development. The guideline sets out requirements for stud-
ies to justify the chosen strategy in the areas corresponding to the three technical
parts of the dossier accompanying the application.

13.2.3 Chemistry and pharmacy aspects

Chemical aspects of the information required to support an application for a medic-
inal product containing a new drug were set out in the original guideline Chemistry
of Active Ingredients (Eudra/Q/87/011) published in Volume III of the Rules. This
guidance has since been updated in the draft note for guidance on the Chemistry of
new active substances (CPMP/QWP/130/96). The guideline on chiral active sub-
stances supplements these texts.

13.2.3.1 Synthesis of the Active Substance

In addition to providing the usual information concerning the manufacturing proce-
dure, the step where the chiral center is formed must be described in detail, and the
measures taken to maintain the desired configuration during subsequent stages of
synthesis must be shown. The ability of the process to provide adequate stereo-
chemical control must be validated and thus analytical methods for determination of
chiral compounds are of fundamental importance in the control and regulation of
medicines containing such drugs. The synthetic product must be fully characterized