If the product is an Orally Disintegrating Tablet (ODT), it is recommended that, in most cases, a criterion of NMT 30 seconds
is proposed based on the current guidance (11). However, a higher criterion may be allowed for disintegration time if justified
based on comparison to the RLD.
It is generally required that the scoring configuration of generic tablets be the "same as" that of the reference listed
drug. For more information regarding scoring requirement, please refer to the CDER MAPP 5223.2, Scoring Configuration of Generic
Drug Products (12). Other sources of information regarding scoring may be obtained in British Pharmacopeia (BP) (13) and a
recent USP stimuli article (14).
Applicants have frequently been asked questions based on the fact that the tablets are scored. In order to ensure the quality
of the split tablets, information regarding uniformity of dosage based on content uniformity or weight variation on each half
of the tablet is generally requested, based on drug load. Regarding the breakability of the drug product, applicants are often
requested to provide the mass loss after splitting. In certain cases, where breakability is in question based on the shape
and size of the tablet, the reviewer may also request the applicant to provide the score depth as a fraction of the tablet
thickness. For modified release tablets with score, a one time demonstration of the comparability of the dissolution on whole
vs. split tablets is recommended. The aforementioned studies on split tablets should be performed during product and process
development. As the dosage form becomes more complex, the necessity of routine testing during drug product release and stability
analysis is more critical to the overall control strategy.
In many cases a control for water content is either not proposed or is poorly justified. An appropriate limit for water content
takes into consideration contributions from the formulation components, the manufacturing process (e.g., a wet or dry process)
and the product stability. The proposed limit should be reasonable based on the observed data for the exhibit batch(es). The
criticality of the limit is heightened for products that contain API or excipients that are sensitive to residual moisture,
which may lead to degradation or product performance issues.
Microbiological controls–nonsterile products.
A common comment that may come from the Agency during the review is with respect to microbiological control for non-sterile
products. Based on the formulation components (e.g., lactose, other sugars) and product's water content, it may be prudent
to include standard microbiological tests including aerobic microbial count, total yeasts and molds or specific pathogens.
In some cases data on water activity of the product can be used to justify not performing microbial limits testing. The term
'water activity' (aw) describes the (equilibrium) amount of water available for hydration of materials (15). Published literature
shows that absolute limit of microbial growth is about aw = 0.6. Thus, pharmaceutical development studies showing the water
activity of the formulation is below this level during typical storage may justify not including microbiological controls
for non-sterile, solid oral dosage forms. Additional references for microbial testing for non-sterile products and water activity
may be found in ICH Q6A and USP <1111> (3, 16); and USP <1112> (16), respectively.
For injectables (especially intravenous products) comparison of osmolality/osmolarity to RLD should be provided. If the results
differ, then justification may be needed. As buffer systems may be different based on 21 CFR 314.94(a)(9)(iii) (17), differences in the osmolality/osmolarity compared to the reference product may be observed. The applicant
needs to address this difference, as noted in the CFR, which states that the difference in formulation should not affect the
safety of the proposed product. If the acceptance criterion for osmolarity/osmolality is listed in the RLD labeling, it is
recommended that it be included in the product specification.