(451b) Impact of Material Properties and Process Parameters on Residence Time Distributions in Pilot Scale Continuous Powder Blending

The U.S. Food and Drug Administration (FDA) has taken multiple steps to support the implementation of the emerging technology continuous manufacturing (CM), including the release of a recent draft guidance regarding quality considerations for CM [1, 2]. Continuous processes are dynamic systems and knowledge of process dynamics is essential for identification and mitigation of risks to product quality. In this regard, residence time distributions (RTDs) offer powerful insight into flow processes. RTDs can be used to trace the flow and dispersion of material through a continuous process. Development of traceability algorithms for RTDs enables prediction of how disturbances will propagate through a process, allowing for isolation of out-of-specification material. For these reasons, interest in implementing and expanding the application of RTD models for powder flow processes in pharmaceutical industry is growing. Given the high impact of using RTD models for feed-forward process control, understanding how material properties and process parameters involved in the establishment of such models impacts their performance is critical to ensure product quality in continuous powder flow processes.

This work investigates the effects of material properties and process parameters on the RTD of active in continuous powder blending at the pilot scale (10–20 kg/hr). Indomethacin is used as the model active pharmaceutical ingredient (API), while the bulk material consists of a combination of two commonly used tablet fillers (lactose and microcrystalline cellulose). Material properties in the powder blend are manipulated via flow rate adjustment of the individual components fed into the blender. Separately, blending process parameters investigated include blender speed, screw element configuration, and total throughput. The effects of changing to another API with similar flow properties and switching to a different batch of the same API are also evaluated. In all cases, the composition of the exiting blend is monitored in-line via near infrared spectroscopy and confirmed via off-line measurement. These measurements are used to assess the RTD of API associated with each set of conditions, which are then compared to elucidate the major factors influencing the flow rate and degree of dispersion of API in continuous powder blending at pilot scale.

Disclaimer: This work reflects the views of the authors and should not be construed to represent FDA’s views or policies.

1. Lee, S.L., et al., Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. Journal of Pharmaceutical Innovation, 2015. 10(3): p. 191-199.
2. FDA, Quality Considerations for Continuous Manufacturing - Guidance for Industry. 2019.