Global Regulatory Submissions for QbD: Wyeth's Experience in the CMC Pilot - Pharmaceutical Technology

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Global Regulatory Submissions for QbD: Wyeth's Experience in the CMC Pilot
Representatives of one pilot program participant, Wyeth, outline the experiences and lessons learned for implementing a science- and risk-based approach to drug-development and manufacturing.


Pharmaceutical Technology
Volume 33, Issue 10, pp. 96-102

Global experiences

Wyeth submitted MAs for Products X and Y to the regulatory authorities of the European Union, Australia, South Africa, Canada, and several other markets outside the United States. The company requested a meeting with the European Medicines Agency (EMEA) PAT working group to discuss its planned QbD approach before submitting the MA for Product X. Members of the EMEA PAT working group and rapporteurs were present at the meeting, which led to a common understanding of the developmental approach using QbD principles. Besides these discussions, there were no formal opportunities for scientific interchange during the review process. A similar approach was taken with the Canadian submission. Wyeth's QbD strategy was discussed at a pre-new drug submission meeting.

In a majority of the other markets, formal processes for scientific interactions before the submission or during review may not exist. Therefore, clarifications of the QbD strategy were provided in writing upon receipt of Board of Health queries. Global understanding of applications of QbD by all reviewers is, at times, variable.

The MAs submitted to regions outside the US required a traditional Quality Overall Summary (QOS), as opposed to the comprehensive QOS that was required by the FDA CMC Pilot Program. In addition, because a framework for the comparability protocol does not exist in other regions, Wyeth did not include its RTR proposal in international MAs.

The review of the MAs and the interactions with regulators were beneficial to Wyeth despite the traditional approach. A majority of the agencies posed primarily science-based questions. In a few cases, however, the review was very traditional and the expectations of the agencies were sometimes inconsistent with ICH Q8, Q9, and Q10. In such cases, the application had to be modified to incorporate traditional control strategies.

Lessons learned

Wyeth learned several lessons during the submission and review process for its Products X and Y applications for the CMC Pilot Program and for international MAs, as outlined below.

Comprehensive QOS. The feedback received during the NDA review indicated that the contents of the comprehensive QOS were important. The QOS ultimately served as the roadmap and launching point for the review of the dossier. Clear presentations, including tables and pictures that showed results, allowed the reviewer to reach the fostered conclusions. Wyeth found that the QOS document should be concise, emphasizing the data and providing conclusions based on data analysis. The document also should highlight the process used for the identification of CPPs, CMAs, and so forth.

Wyeth's experiences with the CMC Pilot Program and the submission and review of MAs in other regions of the world indicate that a traditional QOS as described in ICH M4Q (R1) on the common technical document (9) may be needed for some markets, while others may accept the comprehensive QOS, the contents of which may exceed the requirements specified in the harmonized guideline.

Development report. The primary goal of QbD is to adopt a structured approach to yield a deeper product and process understanding. Regulatory flexibility may be an outcome. Wyeth found that this goal of understanding needs to be driven home in development reports. To increase the reviewer's confidence in the application and facilitate a smoother review, the expanded Pharmaceutical Development Report (3.2.P.2) section for the drug product and an expanded drug-substance manufacturing process module (3.2.S.2.6) should demonstrate the enhanced product and process understanding by including the following information for various experiments: rationale, data summaries, analysis of data, and conclusions drawn from all experiments. Expanded development reports increase the reviewer's confidence in the applicant's ability to reliably and consistently manufacture quality drug substances and drug products.


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