Page 343 - Chiral Separation Techniques

336 13 International Regulation of Chiral Drugs

13.5.3 Impurities

There are two ICH guidelines on impurities: Topics Q3A makes recommendations
on Impurities in new drug substances and Topic Q3B on Impurities in new medici-
nal products. In Europe, the guidelines are published respectively as
CPMP/ICH/142/95 and its Annex CPMP/ICH/282/95. Revisions to these to guide-
lines are at Step 2 of the ICH process (regulatory consultation in the three regions)
and affect the way rounding of analytical results is related to the limits for impuri-
ties denoted in the texts. As previously stated, enantiomeric impurities are excluded
from the guideline, but the principles expressed are expected to apply. There are two
aspects of control of impurities: firstly, their chemical classification and identifica-
tion; and secondly, assessment of their safety at the level imposed by the drug sub-
stance specification. The latter is the process of qualification already mentioned in
Section 13.2.3.2, Quality of the active substance.
The guidance on impurities in new drug substances state that the sources of actual
and potential impurities, whether arising from synthesis, purification or degradation,
should be discussed. Analytical data are required that show the level of individual
and total impurities in development and commercial scale batches. The impurity pro-
files, e.g. chromatograms, must be available if requested. Samples should be inten-
tionally degraded so that potential impurities arising from storage can be identified.
Such studies would reveal whether racemization of single enantiomers was likely to
occur. In normal application of the guideline, identification of organic impurities is
required above certain specified thresholds, usually by isolation and spectroscopic
characterization, or if this has not been possible, the unsuccessful laboratory studies
described. Below these thresholds, identification is not required but it is useful to
present this data if available and identification should be attempted in any case for
compounds expected to be unusually potent or toxic. Chiral analysis would enable
the identification of enantiomeric impurities.
The guideline gives thresholds depending on the maximum daily dose of the drug
above which qualification studies are required. Lower or higher qualification thresh-
olds may be appropriate for certain classes of drugs. Where the qualification thresh-
old is exceeded, additional safety studies may be required according to a decision
tree provided in the guideline. Similar qualification of enantiomeric impurities by
their presence in batches of drug substance used in safety and/or clinical studies
would be expected, although they are not strictly covered by the guideline. The revi-
sions to the guideline currently under consultation include the designation of report-
ing thresholds for impurities.
The guideline on impurities in new medicinal products parallels the drug sub-
stance text, but the designated thresholds concern only degradation products. The
thresholds should be applied to the product at the end of its shelf-life, as that is when
the greatest level of degradation is expected to have occurred.