Tracking raw material flow through a continuous direct compression line. Part II of II: Predicting dynamic changes in quality attributes of tablets due to disturbances in raw material properties using an independent residence time distribution model

Abstract

Continuous manufacturing of pharmaceuticals promises many advantages regarding economics and quality. However, tracing deviating material in such processes is much more challenging than in batch processes due to axial back-mixing. The literature has proven the traceability of disturbances in the active pharmaceutical ingredient (API) by residence time distribution (RTD) models. Nevertheless, pharmaceutical quality attributes (QAs) and disturbances are not limited to the API content. The present study investigates different disturbances affecting the particle size in a direct compression by recording various QAs. The application of a tracer-based model demonstrates the generalizability of RTD models regarding tracing the propagation of nonconforming material. The model applied may predict the appearance of deviating material in the tablets accurately up to 60 s. However, nonlinear and dynamic effects complicate predicting values of the QAs. Due to dynamic effects, tablet masses deviate up to 2.5 percentage points from values measured in steady-state, at an acceptable total deviation of 7.5 %. Consequently, if other QAs are critical, the transfer of control concepts developed for the API content will be challenging due to such effects different from API-based disturbances. Additionally, higher tolerances for errors will be required considering those deviations.

Keywords: Continuous manufacturing; Critical quality attribute; Direct compression; Material traceability; Residence time distribution.