Chemistry Reference
In-Depth Information
tAble 7.3
Impurity reporting thresholds
maximum daily
dose
reporting
threshold
Identification
threshold
Qualification
threshold
a
≤2 g/day
0.05%
0.10% or 1.0 mg per day
(whichever is lower)
0.15% or 1.0 mg per day
(whichever is lower)
>2 g/day
0.03%
0.05%
0.05%
a
Qualification in this context refers to safety/toxicological testing.
cases, if an API batch intended for clinical use is acceptable. Impurities are classi-
fied in an HPLC impurity profile by retention time (or retention time relative to the
API) and structure (if known). Quantitative results should be presented numeri-
cally. Individual impurities and total impurity levels greater than 1% should be
reported to one decimal place (for example, 1.4%). On the other hand, impuri-
ties present at levels less than 1% should be reported to two decimal places (for
example, 0.23% and 0.07%). Results should be rounded using conventional rules
as described in the ICH and USP guidelines [6,10]. The ICH guidelines state that
all impurities at a level greater than the reporting threshold should be summed and
reported as total impurities [6]. Information on impurity-reporting thresholds is
shown in Table 7.3.
The specifications for APIs at the New Drug Application (NDA) stage should
include a list of impurities to be controlled, based on those observed in API batches
manufactured with the proposed commercial process. The structures of these impuri-
ties may be known or unknown. By NDA filing, a rationale for impurity limits based
on appropriate safety (toxicology) or human clinical studies should also be proposed.
7.2.3 S
PecIfIcIty
In
I
mPurIty
m
ethodS
Specificity testing is probably the most complex but also the most interesting part
of impurity method validation. The goal is to design an analytical method that
separates all impurities from each other and the API peak. Impurity methods must
be specific to ensure that levels of all impurities in the API are accurately mea-
sured. For an impurity method to be acceptable, impurity and API peaks should be
well resolved from each other. Because method specificity must be satisfied by the
conditions chosen in the separation, it makes the most sense to examine method
specificity first, before moving on to other validation criteria. If the current chosen
chromatographic conditions do not satisfy method specificity requirements, then the
analytical method will require further optimization. Only once the method has been
optimized to satisfy method specificity, can the remaining validation characteristics
be addressed with confidence.
During method development and prior to the Investigational New Drug
Application (IND) filing, the analytical researcher must first identify API samples
that contain impurities that are expected to be in the toxicology and clinical API
