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).
2.3.P.1 Description and composition of the drug product 1There 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).