Page 339 - Chiral Separation Techniques

332 13 International Regulation of Chiral Drugs

The first was an amendment to the original document on Points to consider when
preparing data published in 1989 in the section on ‘Data concerning physicochem-
ical properties and standards and test methods’. It stated that, for mixtures of optical
isomers, it was recommended that chromatographic tests were performed in addition
to optical rotatory tests and indicated the MHW’s response to the growing develop-
ment of chiral stationary phases in HPLC. The second reference was added in 1985
and appeared in the section on ‘Test data concerning absorption, distribution,
metabolism and excretion’. It stated that when the drug concerned was a racemate,
investigation of the absorption, distribution, metabolism and excretion (ADME) of
each optical isomer was recommended.
Further references to chiral drugs have been found in the Japanese guidelines on
establishing specifications for new active substances issued in 1994. These indicate
firstly that consideration should be given to the solvent used in a test for optical rota-
tion and its effect on the result explained, and secondly that where the active ingre-
dient is an optical isomer, a method of discriminating between enantiomers should
be investigated and the ratio of enantiomers determined. The ICH guideline on spec-
ifications and tests (Section 13.5.2) now applies in Japan.
While the official requirements offer limited guidance on investigation of chiral
drugs, there is considerable correspondence on individual cases either with individ-
ual applicants or pharmaceutical industry associations. Shindo and Caldwell [17]
report that in 1986 this led to a distinction by the MHW between racemates, where
the ADME patterns of each enantiomer should be investigated together with the pos-
sibility of interconversion in vivo, and mixtures of diastereoisomers, where the
kinetics and contribution of each isomer to the efficacy of the drug should be estab-
lished. The CPAC also publishes an annual review of answers to industry questions.
These comments allow an insight into the drug approval process in Japan and offer
interpretations of the official guidelines. Shindo and Caldwell [18] provide examples
of some responses from the CPAC which show that the approval of a racemate is not
precluded, but that the selection of the optical form for marketing should be based
on a consideration of the efficacy and toxicity of each isomer. Investigations should
be performed on enantiomeric composition, pharmacological effect, metabolism,
toxicity, in vivo interconversion, etc. for the racemate and different isomers. In this
respect, the Japanese authorities operate on the same principles as other regulatory
authorities. However, it is also true that the requirements for drug registration in
Japan are more stringent than elsewhere, for example, in the battery of preclinical
tests required preapproval.
Thus, although there is a lack of formal guidance in Japan, it is apparent that there
is a considerable degree of concordance with the regulatory principles established
elsewhere. Approval is not proscriptive, is based on the data for individual cases and
the applicant is required to justify their reasons for developing a racemate if that is
the case.