Page 335 - Chiral Separation Techniques

328 13 International Regulation of Chiral Drugs

edges that the development of racemates may continue to be appropriate, but identi-
fies two areas which should be considered in product development.
The first is the manufacture and control of a product to assure its stereoisomeric
composition with respect to identity, strength, quality and purity. The quantitative
composition of the material used in the pharmacological, toxicological and clinical
studies conducted during development must be known.
The second point of consideration is the pharmacokinetic evaluation of a chiral
drug. Results from such studies will be misleading if the disposition of the enan-
tiomers is different, unless a chiral assay is used. Such an assay would have to be
established for in vivo use early in the drug development process as results from ini-
tial pharmacokinetic measurements, including information on interconversion of
enantiomer in vivo, will inform the decision as to whether the individual enantiomer
or racemate should be developed. If the drug product is to contain a racemate and the
pharmacokinetic profiles of the individual isomers are different, appropriate studies
should be conducted to measure characteristics such as the dose linearity, the effects
of altered metabolism and excretion and drug–drug interactions for the individual
enantiomers. An achiral assay or monitoring of only one enantiomer is acceptable if
the pharmacokinetics of the optical isomers is the same or in a fixed ratio in the tar-
get population. The in vivo measurement of individual enantiomers would be of
assistance in assessing the results of toxicological studies, but if this is not possible
then human pharmacokinetic studies would be sufficient.
The pharmacological activities of the isomers should be compared in vitro and in
vivo in both animals and humans. Separate toxicological evaluation of the enan-
tiomers would not usually be required when the profile of the racemate was rela-
tively benign but unexpected effects – especially if unusual or near-effective doses
in animals or near planned human exposure – would warrant further studies with the
individual isomers.
The guideline notes that the FDA invites discussion with sponsors on whether to
pursue development of the racemate or single enantiomer. This reflects the some-
what different regulatory approach in the US where there is greater interaction
between the FDA and sponsor during the drug development process than occurs in
Europe. All information obtained by the sponsor or available in published literature
relating to the chemistry, pharmacology, toxicology or clinical actions of the
stereoisomers should be included in the investigational new drug (IND) or new drug
(NDA) submissions.

13.3.3 Chemistry, manufacturing and controls

The policy gives further recommendations on the information which should be pro-
vided on chemistry, manufacturing and controls (CMC) in addition to that found in
other guidance (see Section 13.3.6).