Setting Specifications and Investigating Out-of-Specification Results - Analytical Validation - page 105

such as differential scanning calorimetry and thermogravimetric analysis), Raman
spectroscopy, and solid-state NMR are often used to determine if multiple forms
exist.
6.5.4 c hIrAl -d rug S ubStAnce
When a new drug substance is developed as one enantiomer, the other enantiomer is
generally treated in the same way as other impurities. However, sometimes technical
limitations prevent the same limits of quantitation from being applied. Nevertheless,
an assay for the enantioselective determination of the drug substance should be a
part of the specification [11]. The determination can be achieved either by a chiral
assay procedure or by the combination of an achiral assay together with an appropri-
ate method to control the enantiomeric purity. For a drug substance developed as a
single enantiomer, criteria should be included in the specification when the specific
test has an impact on quality for batch control. Identity tests should be capable of
distinguishing both enantiomers and the racemic mixture. In general, there are two
cases where a stereospecific test is appropriate for release/acceptance testing: where
there is a significant possibility that the enantiomer might be substituted for the race-
mate; and where there is evidence crystallization might lead to unintentional produc-
tion of a nonracemic mixture.
6.5.5 c hIrAl -d rug P roduct
Unless racemization has been shown to be insignificant during manufacture of
the dosage form and on storage, stereospecific control for the analysis of degrada-
tion products is necessary. On assay, where there is no racemization, an achiral
assay may be sufficient. Otherwise a chiral assay should be used, or alternatively
the combination of an achiral assay plus a validated procedure to control stereo-
specificity. For identification, a stereospecific test is not generally employed unless
racemization is a concern. Then it is more appropriately covered at the drug sub-
stance stage.
6.5.6 w Ater c ontent
When the new drug substance is known to be hydroscopic, a test for water content
is important. Justification of the specification should include data on the effects of
hydration and moisture absorption. A detection procedure specific for water (e.g.,
Karl Fischer titration) is preferred, but in some cases a loss on drying procedure may
be sufficient.
6.5.7 I norgAnIc I mPurItIeS
Inorganic impurities commonly arise from catalysts used in the manufacturing pro-
cess. The need for tests and acceptance criteria is usually determined during develop-
ment based on knowledge of the process. Pharmacopeial procedures and acceptance
criteria exist for sulfated ash/residue on ignition; other appropriate techniques, such