A better understanding emerged regarding the purpose of including extensive pharmaceutical development information in QbD-based
application and the possible regulatory flexibility as a result of sharing this information. Participants reached consensus
on several topics as outlined below.
In terms of the type of regulatory flexibility proposed or envisioned in a QbD-based application, participants suggested:
- No postapproval filings for:
- Manufacturing site change, alternate packaging or packaging sites, alternate analytical methods and testing sites, scale-up
- Movement within the design space and/or proven acceptance ranges
- Replacement of end-product testing with in-process testing
- Flexibility would be dependent on what is submitted.
Participants deemed a "regulatory agreement" as both necessary and useful, because it can:
- Capture the commitments of industry and FDA
- Help avoid possible loss of knowledge due to staffing changes
- Document the relationship between quality attributes and design space
- Facilitate life-cycle management.
The scope of a regulatory agreement might include original NDAs (i.e., NDAs with QbD information, traditional NDAs) and legacy
products (i.e., previously approved NDAs). The agreement's content, including possible product life-cycle management, might
include identification of critical quality attributes, agreement on the design space, a regulatory reporting mechanism for
postapproval changes, product life cycle changes envisioned for the future, and change control strategy (i.e., the plan and
Several apparent challenges to industry and FDA concerning a regulatory agreement came up as well. For example, how will a
company anticipate all the changes envisioned from a life-cycle viewpoint? Industry does not have any current guidance or
case studies to use as a model and would have to think differently. Finally, industry may be concerned about delayed approval
time and maintaining a living document. On the FDA side, there might be more upfront work, although it could be balanced by
fewer supplements. In addition, there may be additional burden for field investigators, and it was brought up that if there
is no information on commercial-scale design space, it may be a leap of faith for a reviewer to agree to design space based
only on lab- or pilot-scale experiments.
Biological and biotech product breakout reports
Product and process development design.
QbD refers to a product and process that consistently delivers a product with the desired product quality attributes. A well-designed
product and process requires extensive knowledge of a product's quality attributes, how these attributes impact clinical performance,
and how the process impacts the critical product-quality attributes (CPQAs). Product- and process-development design can be
streamlined by using existing data and knowledge in conjunction with risk-management tools and statistically valid designed
experiments to define acceptable operating ranges for both critical and noncritical parameters. This breakout session explored
the development of a robust quality system and its role in documenting data and knowledge to facilitate the definition of
design space and the impact of QbD on validation, product approval, and postapproval process changes.
QbD provides a more structured approach to the identification of critical product quality attributes and how the process parameters
(both critical and noncritical), which define the design space, affect them. Firms should understand and control variability
in this design space using risk-based process development as defined in ICH Q8, Q9, and Q10. By using QbD concepts, industry
may obtain postmarketing regulatory submission relief.
Cross-functional teams select molecules based on the potential therapeutic efficacy of specific protein structures. The essential
elements that are responsible for the protein's safety and efficacy are defined as CPQAs. The design space is based on the
combination and interaction of process parameters, which consistently produce product that meets CPQAs. Design space must
account for the inherent variability of raw materials, facilities, equipment, utilities, and processing conditions in manufacturing
operations, which all can influence product. The company's development team should conduct a formal risk assessment (covered
in ICH Q9) that will determine the critical process parameters (CPPs), that have a significant impact on the drug product.
These CPPs are defined by well-controlled experiments, preferably a statistically valid design of experiments (DOE).