Chemistry Reference
In-Depth Information
batches. The impurity challenge depends, in part, upon the chemical process utilized
to synthesize the API. By working closely with colleagues in the process chemistry
department, representative samples containing impurities to be expected in the API
can usually be obtained. Degradants can be obtained from forced degradation stud-
ies or from actual stability samples [11,12].
Two main challenges exist at this first stage: resolving impurities from each other
and resolving impurities from the API. Peak resolution is verified by inspecting the
chromatograms. Resolution from the API is verified by inspecting the chromato-
grams (to ensure the peaks are Gaussian), analyzing peaks for homogeneity by pho-
todiode array (PDA) detection, liquid chromatography/mass spectrometry (LC/MS),
and by chromatographic methods of alternate selectivity. For additional information
on the use of PDA and MS detection in impurity analysis, see Section 7.3.1.4.
7.2.4 A
ccurAcy
In
I
mPurIty
m
ethodS
Guidelines recommend that accuracy be assessed on samples spiked with known
amounts of impurities [1,2,6]. In ideal cases, increasing amounts of known impuri-
ties are simply spiked into the API test sample, and the closeness of the obtained
result to that of the known amount of each impurity in the sample plus the added
amount are measured. This determination takes place individually for each
i mpu r it y.
However, early in the drug development process, impurity and degradant stan-
dards are not always available. In such cases, it is acceptable to compare impurity
values from the procedure under validation to an alternative impurity assay, such as
an alternative impurity assay designed during the method specificity testing. In this
instance, the impurity content value for each impurity from one procedure is com-
pared to those obtained from a second, well-characterized procedure.
When authentic impurity standards are not available, it is acceptable to use the
API response factor when measuring impurity levels. In these cases, the accuracy of
the impurity measurement relies on the closeness of the impurity response factor to
that of the API. Finally, the method should specify how the individual or total impu-
rities should be determined, for example, by wt./wt. assay (versus external, authentic
impurity standards, or the API diluted to a concentration close to that of the expected
individual impurity levels), or by area-%. In all cases, impurity levels should be
expressed with respect to the major analyte.
7.3 stAbIlIty IndIcAtIng metHod
Stability testing is performed during drug development to provide evidence of how
the quality of a drug substance or drug product changes over time in response to a
variety of environmental factors. Factors such as temperature, humidity, and light
are studied to establish shelf life for the drug product and recommended storage
conditions or packaging [11,12]. But before stability studies can be initiated, a SIM
must be developed and validated to quantitatively measure potency and impurity lev-
els, to provide the type of information ultimately used for the validation of impurity/
degradant methods (Section 7.2).
