Development of a Controlled Continuous Low-Dose Feeding Process

Sara Fathollahi,M. Sebastian Escotet-Espinoza,Julia Kruisz,Stephan Sacher,Benjamin J. Glasser,James DiNunzio,Johannes G. Khinast,Jakob Rehrl

doi:10.1208/s12249-021-02104-9

Abstract

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 μm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.

Highlights

Tablets and capsules are the most common forms of drug products [1] and comprise in total more than 70% of oral dosage forms [2]
Powder feeders play an important role in the continuous manufacturing (CM) process: they maintain the steady state of the process and deliver the pharmaceutical ingredients to the downstream process[6, 8], e.g., continuous granulation, tableting, and coating
Di-calcium phosphate, croscarmellose sodium, and barium sulfate were used for evaluating the performance of the feed-forward control strategy

Summary

Introduction

Tablets and capsules are the most common forms of drug products [1] and comprise in total more than 70% of oral dosage forms [2]. Many factors, such as the variability in raw material’s physical properties (e.g., bulk properties) and manufacturing process disturbances [3], can affect the quality of final drug products. Continuous powder feeding is a common unit operation for all continuous manufacturing (CM) processes for both active pharmaceutical ingredients (APIs) and excipients [7]. Control of the feeding operation is a primary component of a system’s control strategy since the input of the continuous process directly affects the output, and the critical quality attributes of a drug product, such as assay and content uniformity [6]

Methods

Results

Conclusion