Driven by greater global competition and the growing impact of information technology, the pharmaceutical industry faces a need to improve its performance. Speed to market, product quality, regulatory compliance, cost reduction, waste, and cycle time are among the concerns that must be addressed in a systematic, focused, and sustainable manner. Quality by design (QbD), an approach offered by the US Food and Drug Administration, provides an effective tool for addressing these concerns. This article discusses the key steps for implementing QbD by providing a focus on how to develop the process understanding that leads to a useful design space, process-control methods, and characterization of process risk. Product and process life-cycle model validation is also addressed. Integrating these concepts provides a holistic approach for effectively designing and improving products and processes from the development of an active pharmaceutical ingredient to its manufacture and for other pharmaceutical processes.
Origins of QbD
Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, defined the desired state of pharmaceutical manufacturing as "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight" (1). QbD has been suggested as the route to achieving Woodcock s vision. ICH Q8(R1) Step 2 defines QbD as a systematic approach to development that begins with predefined objectives, emphasizes product and process understanding and process control, and is based on sound science and quality risk management (2). QbD is not new. Its roots are in the work on design of experiments (DOEs) by R. Fisher, who did seminal work on design of experiments at the Rothamsted Experiment Station in England in the 1920s and 1930s, and by G. Box, professor at the University of Wisconsin, and his colleagues in the 1950s and 1960s (3,4). QbD was popularized in the 1990s by quality guru J. Juran, founder and chairman of the Juran Institute (5).
From an operational perspective, QbD is a systematic and scientific approach to product and process design and development that uses the following:
- Multivariate data acquisition and modeling to identify and understand the critical sources of variability
- Process-control techniques to ensure product quality and accurate and reliable prediction of patient safety and product efficacy
- Product and process design space established for raw-material properties, process parameters, machine parameters, environmental factors, and other conditions to enable risk management
- Control space for formulation and process factors that affect product performance.
QbD is useful for improving existing products, developing and improving analytical methods, and developing new products. The crux is implementing QbD in a cost-effective manner. The following issues are critical in that assessment:
- The recognition that the end result of successful implementation of QbD is the design space, process-control methodology and quantitative and qualitative estimates of risk level
- A strategy for identifying the critical process parameters that define the design space
- The creation of robust products and processes that sustain the performance of the product and process over time
- The use of change-management techniques to enable the cultural change required for success and long-term sustainability.
Building blocks of QbD
A lack of understanding of QbD in its entirety is a large stumbling block to its use. Stephen Covey, chairman of the Covery Leadership Center, points out that a successful strategy for any endeavor is to "begin with the end in mind" (6). Following Covey's advice, the first step of QbD is to understand the critical outputs of QbD and then identify the critical building blocks of QbD, namely, improving process understanding and control to reduce risk. The outputs of design space, process-control procedures, and the risk level (both quantitative and qualitative risk assessment) are consistent with this approach (2). Before results can be realized, however, the building blocks of QbD need to be assembled (see Figure 1 and Table I) as outlined below:
Figure 1: Building blocks of quality by design. Xs are critical process parameters. Ys are critical quality attributes. (FIGURE IS COURTESEY OF THE AUTHOR)
- Identify critical quality attributes (CQAs)
- Characterize raw-material variation
- Identify critical process parameters (CPPs)
- Characterize design space
- Ensure process capability, control, and robustness
- Identify analytical method capability, control, and robustness
- Creates process-model monitoring and maintenance
- Offers risk analysis and management (7).
Attention must be paid to the product formulation, manufacturing process, and analytical methods. Measurement is a process that needs to be designed, improved, and controlled just as any other process. The QbD building blocks provide a picture of the critical elements of the roadmap.
Table I: Building blocks of quality by design. (TABLE IS COURTESEY OF THE AUTHOR)