Page 336 - Chiral Separation Techniques

13.3 Requirements in the United States 329

13.3.3.1 Methods and Specifications

For drug substances and drug products, applications for enantiomers and racemates
should include a stereochemically specific identity test and/or a stereochemically
selective assay. The choice of control tests should be based on the method of manu-
facture and stability characteristics and, in the case of the finished product, its com-
position.

13.3.3.2 Stability

Methods of assessing the stereochemical integrity of enantiomeric drug substances
and drug products should be included in the stability protocols for both, but stereos-
elective tests may not be required once it has been shown that racemization does not
occur.

13.3.3.3 Impurity Limits

It is essential to determine the concentration of each isomer and define limits for all
isomeric components, impurities, and contaminants of the compound tested preclin-
ically that is intended for use in clinical trials. The maximum level of impurities in
a stereoisomeric product used in clinical studies should not exceed that in the mate-
rial evaluated in nonclinical toxicity studies. This point is expanded in the ICH
impurities guideline (Section 13.5.3).

13.3.4 Pharmacology/Toxicology

The activity of the individual enantiomers should be characterized according to the
principal and any other important pharmacological effects with respect to the usual
parameters including potency, specificity and maximum effect. The pharmacokinetic
profile of each isomer should be established in animals and later compared to the
human pharmacokinetic profile found in Phase I studies which are conducted in
healthy volunteers. It is normally sufficient to carry out toxicity studies on the race-
mate. If the drug causes toxic effects other than that predicted from its pharmacol-
ogy at relatively low exposure in comparison with planned clinical trials, then the
studies should be repeated with the individual isomers to ascertain whether a single
enantiomer is responsible for the effect. If this is the case, then it would be desirable
to eliminate the toxicity by developing the appropriate single enantiomer with only
the desired effect.