But as we also pointed out previously, one of the biggest obstacles to adopting QbD is the industry's inconsistent understanding and application of the tools and methods that are essential for accurately determining Design Space. In this article, we show how those tools are typically used in describing the relationships between the manufacturing process inputs and the critical quality attributes (CQAs). Used correctly, these tools help make it possible to map the multidimensional Design Space in which quality is ensured, and to carve out an efficient operating space in the center of that Design Space where process robustness resides.
THE OBJECTIVE: PROCESS UNDERSTANDINGThe CQAs are the desired outputs of the manufacturing process. In mapping out Design Space, the goal is to understand the relative impact on CQAs of input variables—process steps, process parameters, and raw materials. For example, in a large-scale mammalian cell culture bioreactor, there are any number of potential CQAs, which could include buffer components, media components, supplements (e.g., nutrients), dissolved gases, etc. One surrogate measure for these CQAs in a biologic operation is yield, and the case study detailed below focuses on this surrogate measure. The Design Space encompasses numerous permutations of the input variables in relation to each other that still produce the desired outputs. In other words, the goal is to achieve a profound and comprehensive understanding of the process and then carefully monitor and control those critical elements.
APPLYING THE STATISTICAL TOOLS TO HISTORICAL DATA
The first step in achieving process understanding is to make sure that you have gathered in one place all of the historical data about the development of the product. Ideally, a database and all development reports to date will already exist. But if the data are lacking or spotty, it's necessary to compile the data before trying to map the Design Space. Once all of the historical data is on hand, you can then apply and sequence the appropriate tools.