Analysis of the Effects of Process Parameters on Start-Up Operation in Continuous Wet Granulation

Abstract

Toward further implementation of continuous tablet manufacturing, one key issue is the time needed for start-up operation because it could lead to lower product yield and reduced economic performance. The behavior of the start-up operation is not well understood; moreover, the definition of the start-up time is still unclear. This work investigates the effects of process parameters on the start-up operation in continuous wet granulation, which is a critical unit operation in solid drug manufacturing. The profiles of torque and granule size distribution were monitored and measured for the first hour of operation, including the start-up phase. We analyzed the impact of process parameters based on design of experiments and performed an economic assessment to see the effects of the start-up operation. The torque profiles indicated that liquid-to-solid ratio and screw speed would affect the start-up operation, whereas different start-up behavior resulted in different granule size. Depending on the indicator used to define the start-up operation, the economic optimal point was significantly different. The results of this study stress that the start-up time differs according to the process parameters and used definition, e.g., indicators and criteria. This aspect should be considered for the further study and regulation of continuous manufacturing.

Linking material properties to 1D-PBM parameters towards a generic model for twin-screw wet granulation

“…A central composite circumscribed Design of Experiments (CCC DoE) with three factors of L/S, SS, and MFR (for API 2, 3, and 4), 2) CCC DoE with two factors of L/S and MFR (for API 1), and 3) DoE only with L/S (for API [5][6][7][8][9][10][11]. In the first step, all three process parameters were varied to confirm the lower impacts of SS and MFR for both hydrophilic (API 2 and 3) and hydrophobic (API 4) materials.…”

“…Among the unit operations, twin-screw wet granulation (TSWG) plays a key role in the utilization of continuous manufacturing because of the significant differences compared to the conventional batch wet granulation. Numerous experimental investigations of TSWG have been performed to analyze the impacts of process parameters, equipment specifications, and material properties on granule properties [3,4,5,6,7,8,9,10,11,12,13]. Most of the works have been done within the framework of Quality-by-Design (QbD), which is a systematic pharmaceutical process design concept and encouraged by the regulatory authorities [14].…”

Digital Twins for Continuous mRNA Production

“…QbD-based process development can be used to establish causality between process parameters and the relevant quality attributes of the product. The holistic QbD approach can ensure consistent product quality from development through piloting to production, and is also applied in other pharmaceutical manufacturing applications [15,35]. Process models can be used for the real-time prediction of quality attributes and their development during the process.…”

Process Design and Optimization towards Digital Twins for HIV-Gag VLP Production in HEK293 Cells, including Purification

“…QbD-based process development can be used to establish causality between process parameters and relevant product quality characteristics. The holistic QbD approach can ensure consistent product quality from development to piloting to production [27,28]. QbD is based on a validated design space in which consistent quality can be ensured to avoid out-of-specification (OOS) batches [27,29].…”