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

The US Food and Drug Administration launched the Chemistry, Manufacturing, and Controls (CMC) Pilot Program in the Federal Register in 2005 (1), as part of its Pharmaceutical CGMPs for the 21st Century initiative (2). The purpose of the CMC Pilot Program was twofold: to provide pharmaceutical companies the opportunity to demonstrate enhanced process and product understanding by submitting critical CMC information in a new drug application (NDA), and to collect feedback from the industry that could enable the agency to develop a guideline on the new FDA quality-assessment system.

The quality-assessment system aims to promote innovation throughout the product life cycle and provide regulatory flexibility. The fundamental principles behind the development of a risk-based scientific approach to the development of quality systems are described in the International Conference on Harmonization (ICH) Q8(R2), Q9 , and Q10 guidelines (3–5) as well as in the FDA guidance for industry on process analytical technology (PAT) (6). These guidances are intended to provide regulatory pathways for the modernization of the pharmaceutical industry and to facilitate the incorporation of quality into the design of drug products (i.e., quality by design [QbD]).


Table I: Unique aspects of dossiers.
Two small-molecule developmental compounds were submitted to FDA under the CMC Pilot Program. Wyeth (Madison, NJ) submitted marketing applications (MAs) for these compounds in other regions of the world during the same timeframe. Table I provides a summary of the unique aspects of the dossiers for the two compounds, labeled Product X and Product Y throughout this article.

Product X was being developed for two separate indications and, therefore, had two associated NDAs, both of which were accepted into the CMC Pilot Program. FDA agreed to assign one team to review both NDA CMC sections for Product X.

Product X and Product Y were in Phase 3 development. A combination of retrospective and prospective approaches, therefore, were included in the application to the pilot program. Scientific interactions between CMC Pilot Program reviewers and Wyeth subject-matter experts facilitated NDA approval for both products.

This article summarizes Wyeth's experiences in the CMC Pilot Program as well as lessons learned for implementing QbD in drug development and manufacturing. In addition, this article highlights the review of global regulatory submissions for Products X and Y. Because the experiences of the two programs were similar, the authors emphasize Product X and point out how the interactions regarding Product Y differed.

Regulatory submission experiences

CMC Pilot Program: Wyeth had several interactions (either via teleconferences or face-to-face meetings) with FDA to discuss the scientific content of its NDA submissions. For Product X, Wyeth also interacted with the agency during a preapproval inspection (PAI) and a preoperational visit (POV) at the product manufacturing sites. Wyeth requested the POV to gain the agency's feedback and suggestions on the implementation of real-time release (RTR), or in-process tests, for the extended-release drug product through a comparability protocol (7). Before FDA accepted the company's applications into the pilot program, Wyeth discussed with the agency its development approach for both compounds during Type B and C meetings. These interactions gave Wyeth insight into the approach that would be used during the NDA review.

Early in the review process for the NDA for Product X, Wyeth and FDA agreed that certain changes needed to be submitted as amendments, and that similar changes needed to be made to the NDA for Product Y. This agreement was a key factor in simplifying the review process. During the review of the Product X NDA, most discussions focused on QbD concepts. Reviewers emphasized the demonstration of the mechanistic understanding and the process and product understanding. Topics discussed included:

  • Terminology used in the application to describe various QbD concepts (e.g., control space, design space)
  • Identification of critical process parameters (CPPs), critical quality attributes (CQAs), and the establishment of acceptance criteria for CQAs
  • The use of quality risk management (QRM) and the approach that Wyeth used to identify high-risk process parameters and unit operations for further studies
  • Design-space development, scale-up, and implementation
  • Development of design space and the use of scale-up factors for predicting commercial-scale design space
  • Confirmation of design space at commercial scale
  • Operationalization of design space and control space
  • Impact of the equipment type and design on the design space and control space
  • Sampling plans and in-process controls
  • Regulatory strategies for managing changes (e.g., expansion of design space, movement within design space, equipment, scale changes).


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