As part of the US Food and Drug Administration's Office of Generic Drugs (OGD) ongoing effort to streamline the review process
and reduce the number of deficiencies cited for applications, a series of articles are being published to provide transparency
and clarity to the sponsors submitting applications in the Question-based Review (QbR) format. The articles highlight the
need and significance of science-based justification in establishing drug substance (DS) and drug product (DP) specifications,
in-process controls for both DS/DP, choice of formulation, selection of a product design, and selection of the manufacturing
processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in
January 2010 (1).
The current article is a continuation of this series, with the focus on providing clarification with respect to intent and
criticality of some common deficiencies cited in the description and composition (3.2.P.1) and excipient (3.2.P.4) portions
of abbreviated new drug application (ANDA) submissions using the Common Technical Document (CTD) and Question-based Review–Quality
Overall Summary (QbR-QOS) format as a guide. Also included are other issues related to section P.1 and P.4. These P.1 and
P.4 issues are not part of routine deficiency letters, however are considered critical to the quality of the drug product;
if not addressed these may have regulatory as well as quality impact. Please refer to the sidebar, "Examples of commonly cited
deficiences and comments." This list is not all-inclusive but does include frequently cited comments and deficiencies pertaining
to composition and excipients.
Examples of commonly cited Description, Composition, and Excipient deficiencies and comments*
2.3.P.1 Description and composition of the drug product
There are three sets of QbR-QOS questions with respect to composition of the drug product. They are as follows:
1. What are the components and composition of the final product? What is the function of each excipient?
2. Does any excipient exceed the Inactive Ingredients Database (IID or IIG) limit for this
route of administration?
3. Do the differences between this formulation and the reference listed drug (RLD) present potential concerns with respect
to therapeutic equivalence?
The description and composition information is satisfactory in the majority of ANDAs submitted to OGD. Usually there is no
need to issue deficiencies or comments to ANDA sponsors. However, when deficiencies are cited, they typically fall into four
main categories. The first category is with respect to issues with the composition information. This information is typically
presented in a tabular format in 2.3.P.1 and 3.2.P.1. When deficiencies are provided to sponsors they are, in many cases,
related to insufficient clarity in the answers to the first set of QbR-QOS questions noted above. Second, there are common
deficiencies cited with respect to proposed overages. The third category is related to the qualitative (Q1) or quantitative
(Q2) formulation including the comparison to the reference listed drug (RLD) or the IIG (2). These are related to the second
and third QbR-QOS questions above. The final category of composition related deficiencies is related to the make-up of ingredients
(e.g., iron oxide in coatings).