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, venkattg@wyeth.com
*To whom all correspondence should be addressed.
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