The importance of the Design Space (DS) definition lies in the assurance of quality, a key goal of Quality by Design, and in the broadening from a single acceptable operating point, to a collection of feasible operating regions. Therefore, properly defining the limits of the design space is vital to provide manufacturing flexibility and quality assurance. In this work, we propose new MINLP reformulations to the extended flexibility analysis, where we distinguish between process and model parameters, to efficiently calculate a new flexibility index for process parameters. This index defines a hyperrectangular operating region within a design space of a pharmaceutical process in terms of the process parameters and accounts for the uncertainty in the model parameters, described by hyperrectangle and ellipsoidal sets. We illustrate the application of these novel techniques on several examples.

设计空间（DS）定义的重要性在于保证质量，按设计质量的关键目标以及从单一可接受的工作点扩展到可行的工作区域集合。因此，正确定义设计空间的限制对于提供制造灵活性和质量保证至关重要。在这项工作中，我们为扩展的灵活性分析提出了新的MINLP公式，我们在其中区分了过程参数和模型参数，以有效地计算过程参数的新灵活性指标。该指数根据过程参数在制药过程的设计空间内定义了一个超矩形操作区域，并说明了模型参数的不确定性，用超矩形和椭圆集描述。