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13.4 Requirements in Japan 331

structure of a chiral drug molecule should include determination of its configuration.
This analytical information should be supplemented by an knowledge of the synthe-
sis and the way in which the chiral center is produced (e.g. from a starting material,
stereospecific reaction or by resolution of intermediates). Optically active starting
materials may require additional testing compared to those without asymmetric cen-
ters if their chirality is of significance in the manufacture of the drug substance, e.g.
they are used in a resolution step. The policy notes that enantiomers may be consid-
ered as impurities (even in racemates) and as such require proper control during
manufacture and in the final drug substance. The guidance specifically addresses the
issue of key intermediates, those compounds in which the essential molecular char-
acteristics necessary for the desired pharmacological activity are first introduced into
the structure. Key intermediates will often be those where a chiral center of the cor-
rect stereochemistry is introduced, and as such they should be subjected to quantita-
tive tests to limit the content of undesired isomers. The control of drug substances is
discussed in the policy, but specifications and tests are now addressed by the inter-
nationally harmonized guideline discussed in Section 13.5.2. The need for stereo-
chemical characterization of reference materials used during analytical procedures is
noted.
The FDA’s Reviewer guidance on the validation of chromatographic methods
issued in November 1994 also refers to chiral methods. The guidance incorporates
the ICH analytical terms (see Section 13.5.4). It is noted that separation of enan-
tiomers can be achieved by HPLC with chiral stationary phases or with achiral sta-
tionary phases by formation of diastereoisomers using derivatizing agents or by the
use of mobile phase additives. When the chromatographic method is used in an
impurity test, the sensitivity is enhanced if the enantiomeric impurity elutes before
the enantiomeric drug (to avoid the tail of the main peak).

13.4 Requirements in Japan

The Japanese regulatory authority is the Ministry of Health and Welfare (MHW) and
the Pharmaceutical and Medical Safety Bureau (PSMB) is responsible for the pro-
mulgation of national and international guidelines in the form of Notifications.
Guidelines are available on the Internet web-site of the National Institute of Health
and Science (http://www.nihs.go.jp). The MHW has not issued specific guidance on
the development of chiral drugs, but has nonetheless responded to the “enantiomer-
versus-racemate” scientific debate. The attitude of the MHW and its advisory body,
the Central Pharmaceutical Affairs Council (CPAC) is discussed in two articles by
Shindo and Caldwell published in 1991 and 1995 [17, 18]. The latter paper analyzes
the results of a survey of the Japanese pharmaceutical industry which sought
responses on chirality issues.
Shindo and Caldwell reported that specific reference was made to chiral drugs in
only two places in the Japanese Requirements for Drug Manufacturing Approval.