Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes—Part 1 - How to use multivariate experiments to define acceptable ranges. - BioP


Quality by Design: Industrial Case Studies on Defining and Implementing Design Space for Pharmaceutical Processes—Part 1
How to use multivariate experiments to define acceptable ranges.

BioPharm International
Volume 21, Issue 12


Overall approach
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. 1

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 pharmaceutical products.

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.
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.

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.

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