Page 331 - Chiral Separation Techniques

324 13 International Regulation of Chiral Drugs

with respect to identity, related substances and other impurities as for any other drug
substance, but with the additional requirement of establishing stereochemical purity.
Several synthetic strategies are possible and demand that different types of infor-
mation be provided. In cases where the starting material, whether a racemate or
enantiomer, already contains the required chiral center, full characterization of that
substance is required, including stereochemical purity and validation of chiral ana-
lytical procedures. Where a racemate or other intended enantiomeric mixture is
required, evidence should be provided that these are the result unless obvious from
the synthetic route employed. Where the preferred enantiomer is obtained by isola-
tion, the resolution step is considered part of the overall manufacturing process and
the usual details of the procedure should be given together with the number of cycles
used. If a nonequimolar mixture of enantiomers is needed, then the manufacturing
process must be validated to ensure consistent composition of the active ingredient.
There are circumstances in which it is not possible to obtain the required enan-
tiomer at manufacturing scale either by synthesis or isolation, e.g. because of diffi-
culties with scale-up or failure to obtain material in a suitable physical form for phar-
maceutical manufacture. In such cases, all the experimental results available should
be described and the reason for the failure given. Likewise, if enantiomeric material
could not be obtained for preclinical and clinical studies (see below), this should also
be discussed. Advances in preparative techniques should eventually make this sce-
nario less common.

13.2.3.2 Quality of the Active Substance

The quality of a drug substance is controlled by its specification. An internationally
harmonized guideline on specifications and tests for chemical substances as active
ingredients and in drug products makes reference to chiral compounds. This has
recently been finalized and is discussed in Section 13.5.2.
The guideline on chiral active substances states that particular attention should be
paid to identity and stereochemical purity. It states that specifications for a racemate
should include a test to show that the substance is indeed a racemate and this is a
position supported by the requirements of the European Pharmacopoeia for drug
substance monographs [16].
The chiral drugs guideline lists examples of methods that may be used for the con-
trol of drug substances, ranging from the simpler ones such as optical rotation, melt-
ing point, chiral HPLC to the more sophisticated techniques including optical rota-
tory dispersion, circular dichroism, or NMR with chiral shift reagents. It is not
expected that this list would preclude the adoption of other methods or those that
may be introduced in the future. It is the responsibility of applicants to decide on the
techniques that are appropriate for the satisfactory control of each drug substance
and to ensure that they are fully validated. The guidelines on analytical validation
have been internationally harmonized and are discussed below (Section 13.5.4).
Stereoisomeric reference substances may be required for test procedures for chiral
drugs. The stereochemical purity of reference materials must be stated by giving a