Abstract
Process development, especially in regulated industries, where quality-by-design approaches have become a prerequisite, is cost intensive and time consuming. A main factor is the large number of experiments needed. Process modelling can reduce this number significantly by replacing experiments with simulations. However, this requires a validated model. In this paper, a process and model development workflow is presented, which focuses on implementing, parameterizing, and validating the model in four steps. The presented methods are laid out to gain, create, or generate the maximum information and process knowledge needed for successful process development. This includes design of experiments and statistical evaluations showing process robustness, sensitivity of target values to process parameters, and correlations between process and target values. Two case studies are presented. An ion exchange capture step for monoclonal antibodies focusing on high accuracy and low feed consumption; and one case study for small molecules focusing on rapid process development, emphasizing speed of parameter determination.
Highlights
Chromatography is a widely-used unit operation in chemical and pharmaceutical engineering with broad fields of application from low-cost bulk chemicals to high potential pharmaceuticals.Regardless of the area of application, process development always targets specific product quality and process performance attributes
The first case study is set as an example of modelling chromatography for detail engineering for monoclonal antibody separation on cation exchange media
Adding the results from the fractions next to it creates the other points. The feed for this ion exchange separation was cell free culture after harvest only diafiltrated without any further purification, the overall purity is relatively low compared to the classical ion exchange chromatography that follows protein A chromatography in the platform process [91]
Summary
Chromatography is a widely-used unit operation in chemical and pharmaceutical engineering with broad fields of application from low-cost bulk chemicals to high potential pharmaceuticals. The second case study shows a slightly faster approach for rapid process evaluation and design based on a relatively simple separation of cyclopentanone and cycloheptanone and normal phase media [32] In this case, feed is less expensive and available in a larger amount, so that the focus is set more on speed of parameter determination. Process development can proceed with optimizing the working point with the help of the model and with focus on the relevant parameters, as learned from steps 2 and 4 This approach was already used for solid–liquid (phyto-) extraction [33], upstream fermentation of monoclonal antibodies [38], and aqueous two-phase liquid–liquid extraction of monoclonal antibodies [17]
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