Specific studies or tests on stability samples.
Per ICH Q1A(R2) (23), it is recommended that aqueous-based products packaged in semi-permeable containers should be evaluated
for potential water loss during stability studies. Deficiencies have been cited with respect to applicants using semi-permeable
containers with no evaluation of potential water loss. It is recommended that the ICH Q1A guidance approach be used with respect
to performing studies under low relative humidity conditions. Alternative approaches to determine water loss based on differing
stability conditions can also be used, per the guidance.
The responsibility of reviewing the adequacy of the dissolution specification rests with the Division of Bioequivalence (DBE).
However, a frequent deficiency provided to the applicants is to update the drug product release and stability specification
based on DBE recommendations. It is also imperative that the applicants conduct the dissolution test by using the DBE recommended
method on retained 3rd month accelerated stability samples for all packaging configurations and ensure that the exhibit batch
meets the proposed specification. If accelerated stability samples are not available, testing should be conducted on samples
placed in controlled room temperature. In this case, typically, the age of the samples at the time of testing will be the
tentative expiration dating period that OGD will grant to the drug product. As such, updated stability protocols should be
provided reflecting the reduced tentative expiration date. To avoid the reduction of shelf life, it is recommended that samples,
which have already been taken out from the accelerated stability study chamber be retained until approval of the ANDA.
The information regarding photostability studies for the drug product is often absent from the application. As ICH Q1B (24)
states, the studies on the photostability of drug product need to be done in a sequential manner, starting with the fully
exposed product and proceeding, if necessary to the immediate pack and then to the marketing pack, until results demonstrate
that the drug product is adequately protected from exposure to light. In some cases, the ANDA holder justifies not performing
photostability studies for the drug product based on the fact that the drug substance did not show photo-degradation during
the forced degradation studies. However, this is may not be acceptable, in some cases, since the excipients or impurities
there in, may catalyze photo-degradation of the API in the drug product. In these cases the applicant will need to scientifically
justify why photostability studies are not necessary.
Alternatively, if the applicant demonstrates that the generic product packaging provides a comparable level of protection
to the RLD packaging, photostability studies may be exempted.
Thermal cycling studies or freeze-thaw cycling studies are recommended for certain dosage forms such as solutions, suspensions
and emulsions to ascertain the effect of extreme temperature fluctuations during shipping through various climatic zones,
seasonal fluctuation in temperature and mode of transport on the physical stability of the drug products. These studies are
generally desirable for those drug products which may undergo phase separation, loss of viscosity, precipitation, and change
in particle size distribution. However, we frequently see deficiencies cited in the ANDA due to lack of thermal cycling studies.
It is desirable that the ANDA holders carry out thermal cycling studies during product development to assure a robust formulation.
Also, a one time thermal cycling stability study needs to be conducted on the exhibit lot of the drug product to verify its
physical stability, when applicable.
Diluent studies. Stability testing of the pharmaceutical product after constitution or dilution, where applicable, should
be conducted based on the information in the labeling of the RLD. This testing should be performed on the constituted or diluted
product through the proposed in-use period on exhibit batches as part of the ANDA submission.
Usually, satisfactory results of three months accelerated studies justify a tentative expiration date of 24 months. However,
based on trends observed in the accelerated stability data, the expiry date for some products may be based solely on the accumulated
full long-term stability data.
There are drug products, due to their inherent nature show a significant change during the accelerated stability studies.
In these cases, the expiration date is based on the long term stability data, though the ANDA holder may demonstrate that
the RLD exhibits similar behavior under accelerated stability conditions. In cases were significant changes occur in accelerated
conditions, applicants may also need to demonstrate (e.g., intermediate storage conditions) that excursions in temperature
during routine shipping and storage have no detrimental impact on the product quality.