QBD IMPLEMENTATION FOR BIOPHARMACEUTICALS
According to the Q8 guidance, quality by design means:
Designing and developing a product and associated manufacturing processes that will be used during product development to
ensure that the product consistently attains a predefined quality at the end of the manufacturing process.
The concept of design space as defined in ICH Q8, is gaining popularity as a platform for communicating QbD principles for pharmaceutical products. ICH
Q8 defines design space as:
The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that
have been demonstrated to provide assurance of quality.
and goes on to say:
Working within the design space is not considered as a change. Movement out of the design space is considered to be a change
and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject
to regulatory assessment and approval.
Design space is a well-developed concept in the pharmaceutical industry.6,7 This paper focuses on presenting a stepwise approach to defining the design space for both biotech and traditional small-molecule
Figure 1 illustrates the key phases of process development: early development, commercialization, and post-launch. The early
development phase includes the first-in-human milestone and typically encompasses work up to the decision made at the end
of Phase 2 about whether or not to continue developing the product. Most pharmaceutical candidates are eliminated at the end
of Phase 2 because of concerns related to safety or clinical efficacy. Because of the high rate of product attrition, the
objective in early development is to produce the drug substance and drug product in the amounts required to meet clinical
needs. Limited process development is performed at this stage, and the use of platforms is quite prevalent for both biologics
and traditional oral dosage form products. The focus is on ensuring product safety and efficacy by minimizing process variability
and maximizing product quality. As a result, at this early stage, it is typical for the process to be defined by narrow operating
ranges and a narrow design space.
Figure 1. An illustration of the phases of process development: early process development, commercialization, and post-launch.
Process understanding continues to grow post launch through process monitoring, and information gained may be used to make
the process more robust or to make process improvements.
However, once the decision is reached to further commercialize a pharmaceutical product, the purpose of process development
becomes creating a robust process, identifying critical process steps, identifying critical raw materials and their attributes,
and controlling the environmental factors that may affect process variability. At this later stage of development, the scope
of process development work may include obtaining an empirical understanding, a mechanistic understanding, and knowledge of
first principles, as appropriate. Steps in the commercialization process as illustrated in Figure 1 include: commercial process
development, process characterization, process validation, and regulatory filing.
No matter how well a pharmaceutical product has been characterized, however, process understanding grows throughout the lifecycle
of the product. It is common practice to continue to invest in learning efforts post-launch through a process-monitoring program.
The objectives of the program may include: to confirm that the process continues to perform within the approved design space;
to seek opportunities to make the process more robust and eliminate additional sources of process variability; and to make
process improvements geared toward improving productivity or product quality. As illustrated in Figure 1, these opportunities
may drive re-initiation of the commercial process development or process characterization step.
In the following sections, case studies from both biotech and small-molecule pharmaceutical manufacturing are presented to
illustrate key steps in establishing a design space.