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

Raw-material characterization. The characterization of raw materials and their functionality affects product performance, manufacturability, and quality; this information is critical for complete process and product understanding. Although there has been a considerable effort to further understand excipient functionality, sponsors still tend to rely on compendial specifications for raw-material testing and release. Further emphasis on the functionality testing, raw materials with greater variability in design of experiments, and an understanding of the limitations of the process and product development studies is also needed. When appropriate, enhanced controls beyond the compendial specifications should be applied to the excipient to ensure the product's performance. In the absence of the necessary understanding, further downstream controls may be needed to ensure product quality.

Implementation of QbD. A multidisciplinary and cross-functional team is an important element of incorporating QbD. The team should comprise individuals from quality, regulatory affairs, manufacturing, and development departments so that multiple viewpoints can be considered in the decision-making process. Although the level of involvement may vary during the stages of development, a team approach facilitates a transfer of knowledge and ensures that the team considers the development of the supportive systems needed to implement QbD. Wyeth recognized that the skill sets of individuals required to develop and implement QbD may be slightly different. More control engineers and chemometricians, for example, may be needed to support the concept. In addition, quality and CMC personnel may need to be more familiar with the intricacies of design space and its application. Such training will enable them to understand the uncertainties involved in design space and thereby facilitate a science- and risk-based approach for evaluating changes.

The change of mindset from a reactive approach to a proactive approach is one of the challenges of implementing QbD. The development of a science- and risk-based approach to quality necessitates this change and it is important to incorporate this mindset throughout the organization to make QbD implementation successul.

Quality risk assessment. Quality risk assessments submitted in a sponsor's application should be clear and concise. The basis for the identification of process parameters as either critical or noncritical should be provided. Terminology used by the manufacturing firm should be clarified and facilitate review. Quality risk-assessments should be part of the firm's quality systems, and a process to review and maintain risk assessments based on current knowledge should exist within the manufacturing site.

Process scale-up. During the review and implementation of the design space for Product X, scale-up equations based on engineering principles were used to develop the commercial-scale design space. Although this approach was successful and accurate, development of design space based on scale-independent CQAs such as ribbon porosity for roller compaction has the potential to enable even greater regulatory flexibility.

Conclusion

The global regulatory submission and review process for Products X and Y provided Wyeth with enhanced understanding of the current regulatory landscape in various markets. The process helped crystallize the strategy for the development and submission of future QbD-based applications.

FDA's CMC Pilot Program provided a framework for pharmaceutical companies to gain experience in the submission, review, and inspectional aspects of a pharmaceutical quality- assessment system. This experience was positive and educational, and provided opportunities for scientific interactions and discussions. Similar experiences were gained from submissions to the international markets.

To ensure the success of the QbD initiative, Wyeth suggests that harmonized QbD concepts be applied globally. Consistent inspection practices among the regions of the world, common understanding of risk-management concepts and terminology throughout the industry and respective Boards of Health, and finalization of the FDA postapproval management plan (10) will further accelerate the QbD implementation.

Acknowledgments

The authors would like to acknowledge the assistance of the following scientists within Wyeth for their contributions: Dominic Ventura, PhD, Parimal Desai, PhD, Richard Saunders, PhD, Subodh Deshmukh, PhD, Michael O'Brien, PhD, Shailesh Singh, PhD, Arwinder Nagi, PhD, Carl Longfellow, PhD, and Loren Wrisley.

Thirunellai G. Venkateshwaran, PhD*, is senior director of new product quality and process knowledge (NPQPK), Stephen P. Simmons, PhD, is vice-president of NPQPK, Nirdosh Jagota, PhD, is vice-president of global regulatory affairs (GRA)–CMC, Donald G. Esherick is director of GRA–CMC, and Patricia Foti Mann is senior director of GRA for Asia Pacific and Latin America, all at Wyeth,

*To whom all correspondence should be addressed.


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