The derivation of design space can be applied practically via product specific scientific knowledge gained during development, data-mining across similar products, and/or statistically
designed experiments based to define operating parameters. Once adequately defined, the design space has the potential to
be expanded, based on additional knowledge, across similar products and operating platforms or unit operations such as chromatography
columns. The final list of those items critical to drug product quality is part of process development; once complete, the
data can be used to identify CPQAs and CPPs. Given the scientific basis for design space, much of the additional postdevelopment,
technology transfer, and validation effort will be significantly reduced, if not eliminated.
A quality system (covered in ICH Q10) is an essential umbrella for all development, facility, equipment, technology transfer,
and production activities. The quality system also creates and governs planning, protocol development, test requirements,
data generation, and data-assessment structure.
The power of QbD is in the partnership between FDA and industry to streamline the process of product development and regulatory
approval. Such a transformation will require an unparalleled level of communication and trust between the parties. The most
important communications will be contained in a firm's development summary report. This report includes: a definition of the
product's CPQAs and the rationale for their criticality; risk-assessment summaries for all facilities, utilities, equipment,
raw materials and processing conditions; and scientific data in support of the identification of CPPs. CPQAs should be incorporated
in the development section of the regulatory submissions and CPPs should be incorporated in the manufacturing section.
The practical application of QbD principles will be the upfront agreement between FDA and industry to establish a well-defined
design space approach, including an agreed-upon definition and examples, a pilot program for biotechnology products that can
build on the success of the CMC pilot, an assessment of the use of comparability protocols as an interim approach, and QbD
submission expectations for a preapproval inspection both from FDA reviewers as well as Team Bio in the Center for Biologic
Evaluation and Research, and inspectors in the Office of Regulatory Affairs.
The hopeful outcome of the QbD initiative and industry investment is better product and process understanding and a smoother,
if not faster, path to product approval. The real payoff will be safe and efficacious drugs that are reliably supplied to
the patients we serve.
Process control and postapproval product life-cycle considerations.
Application of a comprehensive, scientifically sound approach to product design and process development should result in an
efficient and well-controlled manufacturing process that facilitates postapproval changes and product improvements. The inherent
diversity and complexity of biotech and biological products present challenges in the development and implementation of QbD
approaches. Nevertheless, for many products, leveraging existing knowledge and experiences operating in defined design space,
in conjunction with risk-assessment and risk-management tools could result in the implementation of manufacturing changes
in a timely fashion with minimal burden on resources.
An overview of the relationship between the ability to establish an understanding of biopharmaceutical drug substance and
drug product, mechanism of action and toxicity, and product interaction related to medical indication (efficacy and safety)
with QbD was presented at a high level during this breakout session. It is clear that establishing these relationships may
be easier where there is greater understanding. Session participants addressed issues and potential impacts of QbD on the
implementation of postapproval process changes for biological and biotech products. These issues are described below.
As a living document, design space should be periodically reviewed as part of industry's quality system. Risk assessment and
growing knowledge (e.g., failures and investigations) should be used to reassess and update the design space.
Operations can be adjusted within the design space. For example, design space may be expanded with continued experience and
FDA approval. A nested relationship was envisaged among design space, normal operating ranges, and control ranges. Participants
suggested that operations outside the normal operating ranges but within design space should be investigated, but need not
be reported. Based on additional knowledge for a robust design space, tests may be eliminated and specifications modified
with FDA agreement. New control parameters may also be found. Industry was comfortable periodically reporting (e.g., annual
report) changes within a design space to FDA.