Predictive Model-Based Process Start-Up in Pharmaceutical Continuous Granulation and Drying

Abstract

Continuous manufacturing (CM) is a promising strategy to achieve various benefits in the context of quality, flexibility, safety and cost in pharmaceutical production. One of the main technical challenges of CM is that the process needs to handle transient conditions such as the start-up phase before state of control operation is reached, which can potentially cause out-of-specification (OOS) material. In this context, the presented paper aims to demonstrate that suitable process control strategies during start-up of a continuous granulation and drying operation can limit or even avoid OOS material production and hence can ensure that the provided benefits of CM are not compromised by poor production yields. In detail, heat-up of the drying chamber prior the start of production can lead to thermal energy being stored inside of the stainless-steel housing, acting as an energy buffer that is known to cause over-dried granules in the first few minutes of the drying process. To compensate this issue, an automatic ramping procedure of dryer rotation speed (and hence drying time) was introduced into the plant’s process control system, which counteracts the excessive drying capacity during start-up. As a result, dry granules exiting the dryer complied with the targeted intermediate critical quality attribute loss-on-drying (LOD) from the very beginning of production.

Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

“…When the CM process is operated at a small scale (short run time), for example, if CM is being used during development or for a niche product, the diversion of material during start-up can be significant and expensive. A variable control strategy has been suggested to minimise waste [ 58 ]. This has been applied to a semi-continuous segmented fluid bed dryer to adjust the drying time during the initial warm-up of the equipment.…”

“…Their continuous fluid bed dryer (GPCG 2) has 10 chambers and can be coupled to a Thermo Fisher Pharma 16 twin-screw granulator. This set-up has been studied in detail and has been shown to achieve a very narrow RTD [ 58 , 79 ].…”

Evaluation of Binders in Twin-Screw Wet Granulation

“…The latter affords the opportunity to use 24 h automatic product lines, a reduction of development time caused by lack of challenging upscaling procedures, as well as a decrease in labor costs, device costs, and processing time [ 2 , 3 , 4 ]. Moreover, continuous manufacturing features advantages with regard to quality, flexibility, and safety [ 5 ]. Twin-screw wet granulation is a granulation method, which enables continuous manufacturing and thereby is an auspicious manufacturing technique.…”

End-Point Prediction of Granule Moisture in a ConsiGmaTM-25 Segmented Fluid Bed Dryer

“…Although a technique is introduced to approximately model dynamic changes of the dryer parameters, e.g., dryer rotation speed or inlet material mass flow, a more rigorous mechanistic modeling approach would be needed to predict the impact of these dynamic parameter changes accurately. The potential of applying a process model for optimizing the startup procedure of pharmaceutical drying units is demonstrated in [ 6 , 7 ]. The process model used in these studies is not based on first principles but on statistically obtained factor–response relationships.…”