The ever increasing workload at the Office of Generic Drugs (OGD) within the US Food and Drug Administration's Center for
Drug Evaluation and Research (CDER) has led the office to develop a number of strategies to streamline the review process.
One such strategy was the introduction of Question-Based Review–Quality Overall Summary (QbR–QOS). Another strategy involves
asking sponsors of abbreviated new drug applications (ANDAs) to provide a Pharmaceutical Development Report with their application.
The QbR is a platform for implementation of CDER's Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach and a
springboard to quality by design (QbD). It also provides the sponsors with an opportunity to discuss the development of their
product. The summary report in QbR-QOS can be referenced by the reviewers as a snapshot of the ANDA before they review the
entire application (i.e., the body of data). Adequate information provided in the QbR–QOS and the Pharmaceutical Development
Report reduces the application assessment time, minimizes transcriptional errors, and helps the review process at all levels
(primary, secondary, and tertiary).
Also, by seeking sponsors' responses to critical questions regarding the quality of their drug product, the QbR has helped
to reduce the number of deficiencies cited for an application. This process of knowledge sharing has improved the overall
review quality. However, it has not met the expectation of the Office of Generic Drugs (OGD) because applications are being
submitted with minimal justification in establishing product quality. Despite OGD's efforts, the number of amendments submitted
in response to FDA's deficiency letters, have still been staggering.
Examples of commonly cited drug-substance related deficiencies in ANDAs (as paraphrased by the authors)
With this as prologue, a series of articles are forthcoming in an effort to be more transparent and to assist sponsors to
submit applications with adequate justification for drug substance and drug product (DS and DP) specifications, in-process
controls, choice of formulation, product design, and manufacturing processes. Our experience shows that having justification
in the original submission reduces the number of deficiencies and provides assurance to the agency in the sponsors' ability
to manufacture high quality drug products.
These articles will attempt to clarify the intent and criticality of some of the common deficiencies cited throughout the
Chemistry, Manufacturing, and Controls (CMC) portion of ANDA submissions. Sponsors may use this information to build quality
into their submissions. As background for this work, the authors have surveyed a representative sample of deficiency letters
issued by each chemistry team within OGD over the past six months. The surveyed deficiencies were cited for ANDAs submitted
in the QbR–QOS format. However, this article is not intended to be a discussion of all common deficiencies in ANDAs. The article
focuses exclusively on the drug substance portions of the ANDA submissions using the Common Technical Document (CTD) and QbR
format as a guide. For a partial list of some common drug substance related deficiencies, see the sidebar "Examples of commonly
cited drug-substance related deficiencies."
One area that will not be expanded on in this article is the common deficiency that the referenced Drug Master File (DMF)
is inadequate and, as such, the ANDA sponsor should not respond until they have been informed that the DMF deficiencies have
been addressed. The deficiency in itself is rather clear and its criticality is obvious as the drug substance is the key ingredient
in the product. However a recommendation to ANDA sponsors is that they "do their homework" when selecting a DMF partner and
be aware of the information available to them with regard to drug-substance characterization, properties, purity, and methodology
as well as the regulatory history of the DMF holder. The upcoming International Conference on Harmonization (ICH) Q11 guideline
on drug substances should provide clarity for both DMF holders and ANDA sponsors with respect to the critical aspects of the
drug substance. Schwartz provides another helpful resource with respect to critical information to be gleaned from the referenced
A second topic not discussed in this article is the issue of polymorphism. It is again a frequently cited deficiency where
the ANDA sponsor has been requested to include information and a control for polymorphic identity and its impact on the performance
of the drug product. The sponsors are highly recommended to address criticality of controls of polymorphism in the drug substance
and/or the drug product based on an evaluation of drug substance characteristics, proposed formulation, proposed manufacturing
process, and its impact on the product performance. For more details on the significance of polymorphism in ANDAs, please
refer to the following publications (2, 3).