Design Space Calculation and Continuous Improvement Considering a Noise Parameter: A Case Study of Ethanol Precipitation Process Optimization for Carthami Flos Extract

Abstract

The optimization of process parameters in the pharmaceutical industry is often carried out according to the Quality by Design (QbD) concept. QbD also emphasizes that continuous improvement should be performed in life cycle management. Process parameters that are difficult to control in actual production can be regarded as noise parameters. In this study, based on the QbD concept, the ethanol precipitation process of Carthami Flos extract was optimized, considering a noise parameter. The density of the concentrated extract, ethanol concentration, the volume ratio of ethanol to concentrated extract, stirring time after ethanol addition, and refrigeration temperature were selected as critical process parameters (CPPs), using a definitive screening design. The mathematical models among CPPs and evaluation indicators were established. Considering that the refrigeration temperature of industrial ethanol precipitation is often difficult to control with seasonal changes, refrigeration temperature was treated as a noise parameter. A calculation method for the design space in the presence of the noise parameter was proposed. The design space was calculated according to the probability of reaching the standards of evaluation indicators. Controlling parameters within the design space was expected to reduce the influence of noise parameter fluctuations on the quality of the ethanol precipitation supernatant. With more data obtained, the design space was updated. In industry, it is also recommended to adopt a similar idea: that is, continuing to collect industrial data and regularly updating mathematical models, which can further update the design space and make it more stable and reliable.

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