Facilitating continuous improvement and reducing CMC supplements
Unfortunately for both reviewers and sponsors, the benefit of a reduced supplement burden facilitated by the increased process
and product understanding has not yet materialized.
Record numbers of original and supplemental applications continue to tax available review resources, and the need for relief
has never been greater. The reduction in the number of supplements was a major element in the original QbR initiative. Unlike
the overall positive effects on the knowledge base included in submissions and the increased quality and consistency in CMC
reviews, substantial progress has not been made in this area. Progress and implementation by the agency of this key aspect
of QbR should be a priority in the future.
That being said, the goal of supplement relief is inextricably linked to the demonstration of a high level of process understanding
by the sponsor (i.e., a low-risk application). Presently, only a small number of applications for nonsimple dosage forms would
qualify as low-risk because most lack demonstrable product and process understanding. Sponsors should continue to incorporate
QbD principles in their product and process development and improve the quality of their PDRs in the hope that a supplement
relief mechanism will become a reality in the near future.
Enhancing the quality, transparency, and consistency of reviews
Transparency in the review process has increased substantially for both the agency and industry under QbR. Agency communications,
workshops, QOS examples, and guidance in the form of lists of frequently asked questions demonstrate the high level of open
communication and transparency incorporated into QbR from the outset (1, 2, 6–8). OGD's expectations for documentation and
the primary focus of the reviews on "quality designed into the product" have been clearly and consistently communicated to
industry. QbR has increased transparency in the submissions as well. The development information, which was previously a black
box in most submissions before QbR, is now fully integrated into the submissions. From a reviewer's perspective, the more
information included in ANDA submissions in this regard, the better.
QbR questions have increased the quality of CMC reviews by shifting the focus of the review to areas that are most likely
to affect product quality for a particular drug product. By incorporating QbD into the submission, reviews are now knowledge-based
rather than requirement-based. The increase in product and process knowledge allows reviewers to identify deficiencies that
are directly linked to critical product-quality issues, the resolution of which should yield a better product at the time
of approval. Approving better products is really the goal of a quality-review process.
The clear format of the QOS and the corresponding review template have provided a framework that has increased review consistency.
Review content and focus previously varied according to the drug product, submission quality, and the individual reviewer,
team, and division assigned to the application. Variability in the content of reviews was sometimes substantial. Consistency
of reviews is of particular importance for OGD because the receipt of 20 or more applications for a given product is common
and can of necessity involve multiple reviewers at several review divisions. The specificity incorporated into the standardized
format of the QbR ensures that critical areas remain the central focus in every review.
Reducing CMC review time
The QbR has significantly increased the amount of material covered in the CMC review, and thus, the time for the initial CMC
review is marginally longer. The positive effect of QbR on review efficiency is seen in the reduced number of review cycles
when the sponsor demonstrates process and product understanding. Because the critical QbR questions are designed to focus
the submission on product quality and understanding, reviewers naturally spend more time focused on high-impact issues for
a particular product. This focus has allowed deficiency letters to concentrate on issues of primary importance to product
quality and enables the reviewer to be much more specific. When the sponsor provides a high-quality product-development report
that provides a clear scientific rationale for the process and testing decisions in the submission, many of the common issues
and questions previously raised by reviewers are already answered, and the deficiency letters often contain fewer items. Highly
focused and short deficiency letters, coupled with an increased comfort level with the sponsor's knowledge base, increases
teleconferences and allows issues to be resolved more quickly.
For OGD, the CMC review serves as an informative document that summarizes the important information about the drug product
and, more importantly, as a critical evaluation of product quality. In terms of the informative aspect of the CMC review,
the QOS has significantly decreased the time spent transcribing and summarizing information, thus leaving more time for the
evaluation. QbR has also stimulated an increase in the number of fully electronic submissions, which save OGD time in processing
the applications and increase efficiency for the reviewer by facilitating access to the information.