As part of FDA's Office of Generic Drugs' (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies
cited for abbreviated new drug applications (ANDAs), a series of articles is being published to provide transparency and clarity
to applicants 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,
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). Part 2 of the series
regarding drug product composition and excipients and Part 3, regarding the control of the drug product and stability, were
published in August 2010 (2) and February 2011 (3), respectively.
The current article is the last of this series, with the focus on providing clarification regarding some common deficiencies
cited in the drug product manufacturing (3.2.P.3) and the container closure system (3.2.P.7) portions of ANDA submissions
using the Common Technical Document (CTD) and Question-based Review–Quality Overall Summary (QbR-QOS) format as a guide. See
the sidebar for a list of some of the deficiencies and comments related to these sections. This is not an all-inclusive list
of comments and deficiencies pertaining to the drug product manufacturing and container closure controls and information;
but includes some questions that are cited frequently.
There are a myriad of manufacturing processes related to dosage forms available in the market. It is beyond the realm of this
article to cover all this information. Thus, the focus will be chiefly on the deficiencies and other comments raised while
reviewing the in-process data and controls. In-process controls (IPCs) and manufacturing data for the exhibit batches represent
sections of ANDA submissions where a majority of manufacturing deficiencies are cited.
Examples of Commonly Cited Manufacturing (3.2.P.3) and Container Closure System (3.2.P.7) Deficiencies and Comments*
Before delving into IPCs, we would be remiss without noting a common deficiency with regard to proposed batch formula. A deficiency
is often cited when the information regarding the actual manufacturing formula for the exhibit lot and the proposed commercial
lots is not provided. It is preferable that the quantities of all the raw materials used in the formulation including those,
which do not appear in the final formulation, be provided in a clear tabular format for ease of comparison. Any overages should
be indicated clearly and justified. Overages and their acceptability have been discussed in detail in Part 2 of this series