One common deficiency is related to a proposed overage of the active. The firm should identify and justify any formulation
overages that appear in the final product; and the overage should be further discussed with respect to the manufacturing process
in 3.2.P.3. Note that, in general, the only acceptable justification for an overage in the final drug product formulation
is if the ANDA sponsor demonstrates the same overage is also observed in the RLD. It is not acceptable to propose an overage
to increase the shelf-life of the drug product. Generic sponsors should justify the proposed overage as compared to the RLD.
Data that can be used to justify the overage may include comparative assay data on the test and reference products throughout
shelf-life and comparative impurity/degradant levels demonstrating similar behavior. Other reported overages such as the use
of excess coating solution in order to ensure uniform coating for product performance do require justification, and this information
should be reported in the 3.2.P.1 and 3.2.P.3 sections, as applicable.
Comparison to RLD.
Although questions with respect to comparability of the formulation to the RLD in certain dosage form are often addressed
during filing of the ANDA, with the justification for the allowed exceptions per the Code of Federal Regulations (CFR) is often times lacking. 21 CFR 314.94 (9) (iii through v) includes a list of "exception excipients" or inactive ingredient differences permitted in a generic
product when compared to the RLD (7). These regulations must be followed by the applicant in order to meet the requirements
of classification as a generic product. In cases where the applicant is using an exception excipient the sponsor must demonstrate
that the differences do not affect the safety or efficacy of the proposed drug product, as required by the CFR.
With respect to comparability of the active pharmaceutical ingredient (API) with the RLD product, this is outside the scope
if this article, however, good references can be found in the "Orange Book" with respect to pharmaceutical equivalence. (8)
There are a few commonly cited questions with respect to Q1/ Q2 formulations and the use of "exception excipients". For example,
the CFR allows substitution or addition of buffer, preservative or antioxidant in a parenteral dosage forms. However, the sponsor
needs to be cognizant of the impact of this substitution or addition on the overall product performance.
The QbR FAQ includes additional recommendations for other allowed differences in solution formulations and bioequivalence
impact (4). These include the amount of sorbitol or mannitol in an oral solution; the amount of penetration enhancer in a
topical product; any Q1 or Q2 differences in an ophthalmic solution; and any Q1 or Q2 difference in inhalation and nasal spray
Finally, if there is any additional risk introduced by a proposed generic formulation, comments may be provided to the firm
to justify that the use of the excipient will not introduce a higher risk product into the market. Examples may include the
use of aspartame, castor oil, peanut oil, colorants (e.g., FD&C yellow #5), or benzyl alcohol, when they are not present in
the new drug application (NDA) product.