Tools for Process Development

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Chapter: Pharmaceutical Engineering: Quality by Design

Thorough documentation of all potential variables in a process is essential to defining the objectives of any experiments.


Thorough documentation of all potential variables in a process is essential to defining the objectives of any experiments. It is rarely the case that a single individual has the capacity to create the database necessary to support this activity. Consequently, a variety of brainstorming tools intended to facilitate identification of all variables by a group of people involved in the process development have been designed. These include, but are not limited to, mind mapping and fishbone (Ishikawa) diagrams. It is important to use a tool that is most convenient and facilitates the thought process of the group. A mind map considers the way in which paths from an outer region of ignorance to a central well-defined process are characterized by the impinging variables as shown in Figure 17.2. A fishbone diagram defines a process as a linear phenomenon in which variable impinge on a line leading to a clearly defined output as shown in Figure 17.3. Depending on the stage of assessment and the intent of the review either of these approaches might be expected to give a thorough pre-liminary understanding of the process under consideration.

It is important to the process that all opinions are welcome, no judgment is placed on the priority of the input variable or that premature blocking (analysis) of the variables occurs. In this manner all parties who might be able to con-tribute to the discussion are encouraged and any dominant personalities are set aside for the purpose of the initial review. Only when all opinions have been rendered and a list of potential variables has been collected is the second step of blocking the variables, in terms of their dependency or their proximity, or dis-tance from, the final output, undertaken. Again this should be reviewed by the group for general agreement on the framework of relationships of the variables under consideration.

FIGURE 17.2 Schematic illus-trating the approach to mind mapping.

FIGURE 17.3 Schematic illustrating the fishbone approach to capturing input variables and their relationship to output properties.

Once a framework has been constructed, a judgment is made regarding the potential significance of each input variable to place emphasis in the experimental design on the potentially most significant variables. All minor variables are then controlled within defined limits to mitigate their contribution to the overall outcome of the subsequent experiments.

This approach has several valuable implications as follows for the process development:

1. It maximizes the potential of identifying all relevant variables.

2. It builds confidence in the group that all factors have been considered.

3. It allows a range of expertise to be brought to bear, which minimizes the potential to overlook factors.

4. Involves several opportunities to review and reevaluate before conducting time-consuming and sometimes expensive experiments.

5. Allows a rational experimental design that will lead to definition of process space.

To achieve these objectives appropriate statistical methods (chap. 18) and methods of obtaining data on the process are required, preferably with an ability for real-time monitoring and control through process analytical technology (chap. 19).

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