A Contribution to Disturbance Prediction in Continuous Manufacturing of Solid Oral Dosage Forms

Beschreibung

The continuous manufacturing of pharmaceuticals offers several advantages compared to common batch manufacturing. Material affected by disturbances may be back-mixed with adjacent material in such processes. At strong disturbances, this leads to the contamination of the adjacent material and to higher yield losses. Back-mixing may also smoothen out minor disturbances and reduce the amount of nonconforming material. The present work deals with balancing those opposite effects to reduce yield losses due to disturbances. Residence time distribution theory (RTD) is applied to quantify the degree of back-mixing and trace disturbance propagation. The framework developed on this basis defines a minimal degree of back-mixing. This degree just smoothens out all non-detectable disturbances. Further back-mixing is considered detrimental due to the contamination of adjacent material. In a case study, the framework is applied to a direct compression line using a placebo formulation. The influence of different operational parameters on the overall RTD is quantified by performing RTD measurements. The study demonstrates that yield losses due to back-mixing can be reduced by up to 30 % if those parameters are set advantageously. Additional model validation demonstrates that the propagation of deviating raw material through such lines can be predicted, although the models applied are not dedicated to a specific disturbance. Models for feeding units are further developed based on preliminary investigations. Next to general uncertainties in measuring and modeling, the work discusses further challenges for predicting disturbance propagation and how these challenges affect the framework. These challenges are dead zones, non-steady mode of operation, non-monotonous changes in material properties, and dynamic effects. However, more experience with disturbances in practical operation should be gathered in the future.

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Moritz Peterwitz

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