Drug product composition information.
Very few deficiencies and comments are cited with regard to the information presented in the composition tables. If cited,
these include not providing the percent of each excipient (e.g., w/w %) in the formulation. The intent of this question is
to clearly provide the reviewer the intended function of the multifunctional excipients in the formulation at the proposed
w/w % level. This information is critical to the assessment of the formulation as it is well documented that changing the
w/w % of multifunctional excipient in the formulation can potentially change the function. In cases of multistrength products,
it also provides the information on the dose proportionality over the range of strengths.
An applicant should provide a list, for each product strength where applicable, the quantitative composition, function of
excipient, grade (e.g., Avicel PH 101 etc.), the standard (e.g., US Pharmcopeia, National Formulary, Food Chemicals Codex,
etc.), and origin as applicable (e.g., vegetable or animal source) of each component. This list should include all materials
that are used throughout the process including organic and aqueous solvents and processing aids used in the manufacturing
process and are removed during the process (e.g., water, alcohol, nitrogen, etc.). Information for all ingredients including
specifications and certificates of analysis should be provided in 3.2.P.4. The quantitative information for unit dose must
specify a unit of measure for all other ingredients contained in the product.
Another issue that may need to be addressed is with regard to the justification of the excipient function in the formulation.
The reported function should be based on documented evidence and the design of the product. For multifunctional excipients,
the sponsor should provide the basis of the function intended in the proposed formulation. Based on the intended function,
specific controls should be included in the excipient specifications. The assigned excipient function in the original filing
will have regulatory implications with respect to post-approval changes depending on the function of the excipient (i.e.,
recommendations found is SUPAC-IR) (3). An example of a common multifunctional excipient is starch which may be used for multiple
purposes (binder, disintegrant, etc.).
Additionally, for complex products (e.g., modified-release products, etc.) with multiple processing steps, it is recommended
that the composition of the "intermediates" (e.g. granules, tablet cores or beads) be separated out to reflect each major
process step in the composition table for ease of review. Also, it should be clear which ingredients will be added intragranularly
or extragranularly. The QbR Frequently Asked Questions (FAQ) document and the Guidance for Industry on Submitting Documentation for the Manufacturing of and Controls for Drug Products provide additional insight (4, 5).
A topic that should also be addressed is related to the chosen dosage form. To be a generic, the dosage form must be the same
as the approved RLD unless under an approved suitability petition, and this is clearly one of the main Quality Target Product
Profile (QTPP) tenets. With this being said if the RLD is a capsule, the generic must also be a capsule, and also meet the
definition in CDER Data Standards Manual (6). Similarly, a formulation may not be called a cream unless it meets the Data
Standards Manual (monograph) definition of a cream (6).