Chemistry Reference
In-Depth Information
Because quantitation is not required, it is sufficient to measure the LOD and dem-
onstrate specificity and robustness. For a Category II limit test, it is only necessary
to show that a compound of interest is either present or not; that is, above or below
a certain concentration. Methods used in support of stability studies (referred to as
SIMs; Section 7.3) are an example of a quantitative Category II test. A SIM is used to
quantify the presence of impurities generated through a forced degradation of the API;
it is assumed that this test will enable measurement of any impurities generated during
normal or accelerated shelf-life testing of a drug substance or product. Methods in sup-
port of cleaning validation and environmental EPA methods often fit into this category,
as well as residual solvent testing [3]. Although, as seen in Table 7.1, it is never neces-
sary to measure both LOD and LOQ for any given Category II method, it is common
during validation to evaluate both characteristics (more out of tradition than necessity)
because often methods are used to fulfill requirements of more than one category.
7.1.3 c
Ategory
III m
ethodS
The parameters that must be documented for methods in USP-assay Category III
(specific tests or methods for performance characteristics) are dependent on the
nature of the test. Dissolution testing (Section 7.4) is an example of a Category III
method. A
dissolution
assay measures the concentration of API in a solution designed
to simulate release of the drug from a formulation under the conditions of admin-
istration of the drug (e.g., in simulated stomach fluids). Because it is a quantitative
test optimized for the determination of the API in a drug product, the validation
parameters evaluated are similar to a Category I test for a formulation designed for
immediate release. However, for an extended-release formulation, where it might be
necessary to confirm that none of the active ingredient has been released from the
formulation until after a certain time point, the parameters to be investigated would
be more like a quantitative Category II test that includes LOQ. Because the analyti-
cal goals may differ, the Category III evaluation parameters are very dependent on
the actual method, as indicated in Table 7.1.
7.1.4 c
Ategory
Iv m
ethodS
Category IV identification tests are qualitative in nature, so only specificity is
required. Identification can be performed, for example, by comparing the retention
time or a spectrum to that of a known reference standard. Freedom from interfer-
ences is all that is necessary in terms of chromatographic separation.
7.2 vAlIdAtIon oF ImpurIty metHods
To ensure that the data from impurity methods are reliable (precise and accurate),
regulated laboratories are expected to validate impurity methods for the API and
latter stage key synthetic intermediates. As outlined in Table 7.1, accuracy, preci-
sion, linearity/range, specificity, and robustness should all be considered. In addition
to these parameters, it is also recommended that sample solution stability should
be examined and an appropriate system suitability test established to verify the
