Question-Based Review: An FDA Reviewer's Perspective

The Office of Generic Drugs (OGD) fully implemented Question-based Review (QbR) in 2007 with the broad goal of encouraging sponsors to include quality-by-design (QbD) principles in their product and process development and to communicate this knowledge in their submissions. In light of this goal, OGD outlined the following four major benefits that the QbR platform would bring to the chemistry, manufacturing, and controls (CMC) review process (1, 2):

• Ensure product quality through product design and performance-based specifications

• Facilitate continuous improvement and reduce CMC supplements through risk assessment

• Enhance the quality, transparency, and consistency of reviews through standardized review questions

• Reduce CMC review time when applicants submit a quality overall summary (QOS) that adequately addresses the QbR questions.

This article will provide a CMC reviewer's assessment of how QbR has contributed to achieving these benefits. The author will identify the current approach's strengths and areas for improvement within OGD and for sponsors of abbreviated new drug applications (ANDAs). The assessment and recommendations are based on the author's experience reviewing more than 20 QbR applications submitted during the past two years. The applications covered various dosage forms, including numerous modified-release drug products.

Table I: Key Question-based Review questions for process and product understanding (listed by section).

Ensuring product quality

Of the 37 questions in the current QbR QOS template, about 14 critical questions, most of which come from Section 3.2.P.2, are designed to encourage the sharing of product design and development information not typically included under the old CMC review paradigm. These questions incorporate QbD principles into the CMC review process and result in the most significant changes in the approach to product development and documentation suggested in a QbR ANDA for the sponsor and the reviewer. That is not to say that some information in these areas was not provided by sponsors and evaluated by CMC reviewers under the old review format. This information, however, was often provided only in response to agency queries or to correct deficiencies. Also, under the old paradigm, submissions and reviews in these areas were highly variable, thus no consistent basis for assessing process and product understanding was established. The QbR format has provided the necessary framework for sponsors to provide this information consistently and for CMC reviewers to assess this information critically.

Typically, the product development information that answers the critical QbR questions is incorporated into the ANDA as a Pharmaceutical Development Report (PDR). Incorporating the PDR into the ANDA review process is the most significant change brought about by the QbR approach because this information was almost entirely excluded under the old approach. The PDR provides the means for a sponsor to demonstrate to the reviewer its level of process and product understanding and provide the crucial link between the process, control testing, and specification choices in the final product to the data obtained during development on experimental and pilot-scale lots. Without a high-quality PDR that addresses these key questions in a meaningful way, the QbR amounts to little more than format change rather than the mechanism for communicating process and product understanding it was intended to be.

As previously pointed out, some QbR applications are accompanied by answers to these critical questions and PDRs that lack substantive information (3). Contrary to the intent of the critical QbR questions, some submissions demonstrate that QbD principles did not guide product and process development from the beginning and that sponsors have continued to test rather than design quality into their products. On the other hand, many high-quality submissions have incorporated QbD principles and thus benefited both the reviewer and the sponsor.

To realize the full extent of possible benefits for review quality and efficiency, it is imperative that sponsors provide meaningful answers to all of the relevant critical questions and submit PDRs that give a full scientific basis for them. The best product-development reports currently provided by sponsors possess the following common attributes:

• Clearly support the sponsor's choices of critical quality attributes (CQAs) and critical process parameters (CPPs) with relevant experimental data.

• Clearly present experimental design and clearly link it to the corresponding CQAs or CPPs with scientific rationales.

• Present data to demonstrate why individual unit operations, specifications, or process parameters are or are not critical.

• Present data from pilot batches of failing or suboptimal formulations or processes, offer an analysis of the issues and problems, and explain how this knowledge led to the optimized formulation or process. This information is especially useful for evaluating complicated products such as modified-release dosage forms.

Most QbR submissions stop short of using a design-of-experiments approach, often associated with QbD, to perform an extensive, systematic exploration of process parameters. However, a small number of experiments on laboratory-or pilot-scale lots in which carefully chosen critical variables are explored across a limited range is extremely useful in demonstrating process and product understanding. The experience gained by sponsors preparing high-quality PDRs will be helpful as OGD prepares to incorporate full QbD elements in the future (3–5). This transition will be much easier for sponsors who consistently provide high-quality PDRs with meaningful information.

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.

Conclusion

Based on the original vision of QbR, FDA and sponsors have made significant progress. Gains in review quality, consistency, and efficiency have been realized as a result, but progress can still be made in several areas. Some important elements originally identified as critical at the outset of QbR have not yet been addressed. OGD can improve the QbR process by using increases in product and process knowledge to enhance efficiency by implementing a supplement-reduction strategy described in the original QbR vision and by developing an abbreviated review format for low-risk products. Sponsors should continue to improve the content and quality of their responses to the QbR questions and of the supporting information in the PDRs. This strategy will facilitate gains in review efficiency for OGD and aid sponsors as the transition to a formal QbD approach takes shape in the future.

Acknowledgments

The author wishes to thank Lawrence Yu, PhD, director for science, and Andre Raw, PhD, a senior chemist, both at FDA's Office of Generic Drugs, for their valuable insights.

David J. Skanchy, PhD, is a review chemist with the US Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, tel. 240.276.8552, fax 240.276.8582, david.skanchy@fda.hhs.gov

References

1. L.X. Yu et al., "US FDA Question-Based Review for Generic Drugs: A New Pharmaceutical Quality Assessment System," J. Generic Med. 4 (4), 239–248 (2007).

2. FDA, "White Paper: Question Based Review (QbR) for Generic Drugs: An Enhanced Pharmaceutical Quality Assessment System" (FDA, Rockville, MD, Apr. 2009).

3. A. Srinivasan and R. Iser, "FDA Office of Generic Drugs Question-Based Review Initiative: An Update—Past, Present, and Next Steps," J. Valid. Technol. 15 (2), 10–12 (2009).

4. L.X. Yu, "Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control," Pharm. Res. 25 (4), 781–791 (2008).

5. R. Lionberger et al., "Quality by Design: Concepts for ANDAs," AAPSJ. 10 (2), 268–276 (2008).

6. L.X. Yu et al., "FDA Office of Generic Drugs' Pharmaceutical Quality Initiative: Progress and Feedback on Question-Based Review," Pharm. Eng. 27 (6), 52–61 (2007).

7. FDA, "Example Quality Overall Summary ER Product," (FDA, Rockville, MD).

8. FDA, "Example Quality Overall Summary IR Product," (FDA, Rockville, MD).

9. FDA, "QbR Frequently Asked Questions," (FDA, Rockville, MD, June 2007).

See the related generic-drug story by FDA and generic-drug industry representatives.