Page 332 - Chiral Separation Techniques

13.2 Requirements in the European Union 325

value for their assay determination. Care should be taken in the characterization of
such materials when they are required to support the stereochemical identification of
the drug substance. It is all too easy to fall into a circular argument when trying to
establish the absolute configuration of a compound based on mechanistic arguments
and/or the chirality of starting materials. Single crystal X-ray diffraction studies of
the final drug substance with methods appropriate for the determination of absolute
configuration provide the greatest confidence.
Stereoisomers may arise during synthesis of a drug substance, or they may arise
as degradation products on storage. The guideline on chiral active substances states
that when a chiral drug substance is presented as a single enantiomer, the unwanted
enantiomer is considered to be an impurity. The internationally harmonized guide-
line on impurities (see Section 13.5.3) applies in principle to substances containing
enantiomeric or diastereoisomeric impurities as it would to active ingredients con-
taining any other organic impurities. However, the limits normally expected do not
apply to chiral impurities. The limits for the control of enantiomers in drug sub-
stances are usually relaxed compared to tests using achiral methods because it is rec-
ognized that the chiral separation methods may not be able to achieve the same sen-
sitivity.
The use to which development and commercial scale batches were put must also
be detailed by the applicant so that each can be linked to a particular safety or clin-
ical study. This information assists in the qualification of impurities which is the pro-
cess by which the biological safety of an individual impurity, or an impurity profile,
is established at a specified level. If the new drug substance containing a particular
level of impurity has been adequately tested in safety and/or clinical studies then that
level is considered to be qualified. Metabolism studies with chiral drugs should
demonstrate whether or not chiral inversion occurs. Impurities that are also signifi-
cant human metabolites do not need further qualification, as exposure to them would
be automatic on administration of the drug in clinical trials. Together with the batch
analysis data, the qualification studies should be used to justify the specification lim-
its for individual known, unknown and total impurities. The applicant should demon-
strate that unacceptable changes in stereochemical purity or enantiomeric ratio do
not occur on storage of the active ingredient.
Chemical development: Proof of structure and configuration are required as part
of the information on chemical development. The methods used at batch release
should be validated to guarantee the identity and purity of the substance. It should
be established whether a drug produced as a racemate is a true racemate or a con-
glomerate by investigating physical parameters such as melting point, solubility and
crystal properties. The physicochemical properties of the drug substance should be
characterized, e.g. crystallinity, polymorphism and rate of dissolution.
Finished product: The applicant should show that the manufacturing process pro-
duces no unacceptable changes in the stereochemical purity of the active ingredient
and that such changes do not occur on storage for the proposed shelf-life.