Page 275 - Chiral Separation Techniques

254 10 The Use of SMB for the Manufacture of Enantiopure Drug Substances: From …

the inhibition of terfenadine metabolism by drugs such as ketoconazole [13, 14]. The
result was later associated with significant toxicity [15].
In November 1997, the Department of Health and Human Services along with the
International Conference on Harmonisation (ICH) released a draft guidance for the
selection of test procedures, which included chiral drugs. For the development of an
enantiopure drug substance, acceptable criteria shall include, if possible, an enan-
tioselective assay. This assay should be part of the specification for the identification
of an enantiopure drug substance and related enantioenriched impurities [16].
These and other FDA policy decisions launched the pharmaceutical industry and
academia into a new era of developing stereoselective processes for the manufacture
of enantiopure active pharmaceutical ingredients (APIs).

10.1.1.1 Market Exclusivity: Newly Approved Drug Substances

The FDA had originally argued that the individual enantiomers for a previously
approved racemic drug should not be considered as a new chemical entity. In Jan-
uary 1997, following the proposal to remove Seldane, the FDA asked for public
comment on their proposal to grant 5-year marketing exclusivity to developers of
single-enantiomers of previously approved racemic drugs [17]. This would be a
change from FDA’s policy of treating chiral switches as a mere reformulation of
existing approved drugs, and therefore, entitled to only 3-year marketing exclusivity.
New drug applications (NDA) as defined in the Code of Federal Regulations
(CFR), was revised as of April 1, l998, by the FDA for approval to market a new drug
or an antibiotic drug [18]. The FDA’s final ruling defines new drug product exclu-
sivity for a drug product containing a new chemical entity that was approved after
September 24, 1984. The same active moiety cannot be resubmitted as a new chem-
ical entity for a period of 5 years from the date of approval of the first NDA [19].
These policy decisions by the FDA were the driving force for chiral switches and
the commercial development of chromatographic processes such as simulated mov-
ing bed (SMB) technology. Due to technological advances such as SMB and the
commercial availability of CSPs in bulk quantities for process-scale purification of
enantiopure drugs, the production of many single enantiomers now exists on a com-
mercial scale.

10.1.1.2 Fixed-Combination Dosage: Enantiopure Drug Substances

The FDA’s perspective with respect to the manufacturing of enantiopure drugs has
raised several issues. One issue is the acceptable control of a stereoselective synthe-
sis or purification of enantiopure drugs where discrepancy in pharmacological and
toxicological assessment during clinical evaluation is due to enantioenrichment of
one enantiomer in the presence of another. Other issues are when the properties of
enantiopure drugs have revealed instances in which both enantiomers exhibited sim-
ilar pharmacological activities, while others represented a combined pharmacologi-