Implementation of real-time and in-line feedback control for a fluid bed granulation process.

The application of process analytical technologies (PAT) to monitor critical quality attributes (CQAs) provides an important approach to enhance process understanding and improve the reliability of pharmaceutical production processes. The present study focuses on the first PAT based feedback control system for a fluid bed granulation batch process. Real-time particle size measurement by in-line spatial filtering technique (SFT) using a modified time-based buffer system was applied to define a target particle size after spraying a specific amount of binder solution. After identifying an appropriate control variable, a suitable strategy for feedback control was established, followed by tuning of the control loop to obtain best performance of the integrated system. By adapting the final target particle size within a specified range good functionality of the system could be demonstrated. Investigations of the robustness further showed that the implemented system enables the production of a predefined target particle size also by varying process and formulation parameters. The effect of increasing spray rates and binder concentrations on the particle size could be compensated in a given range by feedback control ensuring a predefined product quality. The study provides an advanced approach for quality assurance of fluid bed granulation.

Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach.

The Process Analytical Technology (PAT) initiative published by the Food and Drug administration (FDA) describes PAT systems as important tools to optimize pharmaceutical processes in order to ensure the final product quality. Real-time particle size measurements provide a promising approach for process automation of fluid bed granulation processes. This work focuses on the introduction and evaluation of a new time-based buffer approach for in-line spatial filtering technique (SFT) in order to provide a minimum time delay of the real-time measurement. Comparing the new buffer system to the conventionally used number-based approach, a reduced influence of the particle rate and a constant response time was found. A performance qualification of the Parsum probe IPP 80 using this buffer approach according to the ICH guideline Q2 was performed to investigate whether common variations of process parameters influence the real-time particle size measurement. Focussing on the main requirements for process control, hereby a good precision and specificity as well as an adequate robustness was found. Summarized, this study identified the time-based buffer system as more suitable buffer system for process automation.