The P.8 sections of the QbR–QOS and the body of data in submitted ANDAs include information with respect to stability studies
used to determine the shelf-life of the product. As stated previously, much of the information provided in the P.5 section
is relevant to both release testing (P.5) and stability testing (P.8).
There are three QbR–QOS questions noted in P.8. These are as follows:
- What are the specifications for stability studies, including justification of acceptance criteria that differ from the drug
product release specification?
- What drug product stability studies support the proposed shelf life and storage conditions?
- What is the post-approval stability protocol?
This article will focus on the first two questions with respect to common deficiencies and comments cited in ANDA submissions.
Based on ICH Q1A(R2) (23) stability studies should include testing of attributes of the drug product that are susceptible
to change during storage and may influence quality, safety, and/or efficacy of the drug product. The testing should cover
the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial
preservative), and functionality tests (e.g., for a dose delivery system). Analytical procedures should be fully validated
and stability indicating.
Modification of limits for stability.
In some cases, the relaxation of the limits of certain quality attributes in stability is necessary based on the nature of
the drug product. Applicants should take great care in using realistic, as well as, scientific and regulatory approaches to
setting acceptance criteria for the stability studies.
For example, when the API or one of the excipients is hygroscopic, the water content may increase during shelf life for solid
oral dosage forms. Similarly, if a hydrolytic degradation pathway related to an API is well documented in literature, the
resultant degradant may be controlled at a higher level in stability. This may also be the case with an impurity, which arises
due to reaction of the API with one or more of the excipients in the dosage form. However, deficiencies are cited when the
relaxation of the specification is not well justified.
In case of water content, in the example noted above, it needs to be demonstrated that the proposed relaxation is not detrimental
to the product quality in any way, leading to change in appearance, physical attributes or impurity levels. In case of degradants,
the relaxed limit is acceptable as long as it is within the ICH Q3B (R2) qualification threshold (QT) and the impurity is
not a structural alert for genotoxicity. However, if a limit higher that the QT is proposed, it needs to be justified by comparison
with several lots of RLD, close to or at expiration date. In case of artifacts arising due to interaction of the API with
the excipients, the levels need to be at ICH Q3B (R2) proposed QT or adequately justified based on safety data.
Accelerated stability data on RLD samples.
Deficiencies are often cited when the relaxation of specifications of impurities in stability is justified by comparison with
RLD, which has been subjected to degradation under accelerated stability conditions. Since accelerated storage conditions
are not the normal storage condition of the drug product, it is recommended that the comparative batch analysis is conducted
at controlled room temperature conditions to demonstrate similarity of behavior between the RLD and the generic.