Understanding Powder Behavior in Continuous Feeding: Powder Densification and Screw Layering

Introduction

Throughout history, continuous production has revolutionized industries, making goods quickly and efficiently. While initially embraced slowly, continuous manufacturing (CM) is steadily gaining momentum in the pharmaceutical industry, aided by FDA and other regulatory support and guidelines [1,2,3]. CM enables faster production with lower operating cost, modular manufacturing, and better monitoring and control over individual processes, and therefore more consistent product quality [4,5,6,7].

One significant advantage lies in CM’s integration with process analytical technology (PAT), enabling real-time release testing (RTRT) [8,9,10,11]. This allows products to be swiftly released on the market after production, a critical necessity to avoid drug product shortages [5], especially in catastrophic situations (i.e., the COVID-19 pandemic in 2020). Furthermore, CM provides enhanced scalability [5,12,13]. In view of these advantages, it is crucial to recognize that embracing CM technology is vital for maintaining competitiveness and efficiency in pharmaceutical manufacturing.
Adopting CM requires a comprehensive understanding of the critical material attributes (CMAs) or function-related characteristics (FRCs) of both the active pharmaceutical ingredient (API) and excipients at every unit operation. Knowledge and predictive capability regarding the scalability of materials, whether individual or in combination [14], tailored to the specific unit operation, are essential for establishing a robust production process.

In CM, the production is uninterrupted, with unit operations such as feeding, blending, granulation, and tableting or capsule filling all connected. Feeders play a critical role in continuous manufacturing lines, as they deliver the formulation components to the downstream process and finally to the final drug products. It is therefore important to maintain a steady state in the feeding process, as any variation or inconsistency in feeding can impact the quality of final drug products [15,16,17,18].

In continuous processes, blending unit operations are typically designed to reduce variability and create a uniform blend. However, if the feeders fail to provide a consistent flow, particularly with APIs, the blender may not be able to manage sudden fluctuations effectively. Several studies have indicated that variability and disruptions during the feeding operation can impact the performance of downstream unit operations and the quality of the final product [19,20]. The success of the feeder in regulating powder flow relies on the optimal setup of the feeder (type and tooling) and material properties such as particle size, shape, and flow characteristics [21,22,23,24,25].

Loss-in-weight (LIW) feeders are commonly used to feed pharmaceutical powders [18,26,27,28,29,30]. LIW feeders can operate in either volumetric or gravimetric mode [31,32]. In volumetric mode, material is fed based on a fixed volume by running the feeder at a constant screw speed. This mode is sensitive to changes in material density, which can lead to variations in mass flow rate at constant screw speed. In gravimetric mode, however, the feeder adjusts the screw speed to feed a constant mass of material, minimizing the impact of density changes. The control system continuously measures the material weight in the feeder over time during feeding in gravimetric mode. LIW feeders consist of a hopper for the powder, a weighing platform with a load cell to measure the loss of powder in the hopper for gravimetric control of the mass flow rate, and screws to transport the material out of the hopper to the next unit operation. In a continuous feeder, the hopper is regularly refilled with powder to maintain a suitable fill level for uninterrupted operation. The periodic refilling can lead to densification of the powder at the hopper–screw interface, increasing interparticle stress and causing overfeeding by forcing the powder into the screw flights [22,33,34].
Particle size distribution (PSD) significantly influences the precision of feeding processes. In materials with a wide PSD, smaller particles can fill the voids between larger ones, resulting in increased bulk density (referred to as densification) [14]. This packing effect alters flowability and mass flow rates, potentially leading to variations in material discharge from the LIW feeder, particularly in volumetric mode (where flowability plays a critical role in maintaining precise mass flow rates).

Powder densification in the hopper–screw zone poses challenges by altering material flowability [35] and consistency in the continuous feeding process [22]. As powders compact, their bulk density increases, disrupting uniform material feeding and causing fluctuations in mass flow rates. This necessitates frequent screw speed adjustments to maintain accuracy and can extend startup times, reducing overall process efficiency. Densification is typically not a concern in gravimetric mode feeding, as the control system adjusts screw speed to maintain the target mass flow rate. However, in volumetric mode feeding, such as during refills, the screws operate at a constant speed, so changes in bulk density lead to changes in mass flow rate.
Hopper and screw design [36,37,38,39] can significantly influence the solids stress profile within a feeder, affecting bulk density due to powder compressibility [40]. To ensure smooth feeding operation, it is crucial to use tooling, including optimal screw design and size, and appropriate hopper design to mitigate densification effects, facilitating consistent material flow and minimizing disruptions in the feeding process.

Another challenge in LIW feeders is screw layering, when layers of powder accumulate along the length of the screw conveyor in an LIW feeder [30,31]. This can occur when the mass flow rate is too low and/or when the powder has poor flow properties with high affinity to the feeder’s screws, e.g., cohesive powder and/or a powder with a high degree of electrostatic charge [41]. Over time, as the screws rotate, the layers of powder can become thicker and more compact, which can lead to disruptions in the feeding process. Screw layering can also cause blockages in the screw zone of the feeder, which can lead to disruptions in the feeding process and therefore potentially impact the quality of the final drug product. Additionally, even a thin layer forming on the screws can reduce the interaction and friction between the screws and powder, altering surface friction and influencing how effectively the screws can transport the powder compared to the friction between the powder and the feeder walls. This in turn can diminish the conveying potential of the feeder. If more and more material sticks to the screw, the desired mass flow rate might not be achieved due to the feeder’s motor speed limit. Understanding this feeding challenge is crucial for predicting the CM runtime without interruptions for cleaning material adhered to the screws and halting the feeding unit operation.

To prevent or delay screw layering, it is essential to optimize the mass flow rate and select appropriate tooling, such as screws and screens, tailored to the specific properties of the powder being fed. Additionally, the choice of excipient should be considered. While the API is usually fixed in the formulation, the excipient, such as the type of lactose, can be selected. In the case of preblending of APIs and excipients or excipients alone, choosing an excipient that helps prevent or delay screw layering can improve feeding process.

In this study, we explored powder behavior in continuous feeding, specifically focusing on the degree of powder densification and screw layering among various excipients. While previous research has delved into screw layering within feeders [31], it is noteworthy that (to our knowledge) this study represents the first comprehensive investigation into densification and screw layering with such a diverse collection of excipient types. Additionally, this study introduces a methodology to quantify these effects.

The excipients investigated, spray-dried lactose, anhydrous lactose, granulated lactose, and microcrystalline cellulose, are widely used in the pharmaceutical industry as fillers and binders. Additionally, a preblend and a co-processed excipient were investigated to assess their feeding performance. Traditionally, blends are created to minimize the number of feeders, thereby simplifying the CM process. Recently, co-processed excipients have been introduced by suppliers as an innovative solution for reducing the number of feeders in CM. This rationale underlies the investigation of both an MCC–lactose preblend and a co-processed excipient (lactose–lactitol) feeding in this study.

It is recognized that controlling LIW feeder performance necessitates aligning feeder tooling with material properties and implementing tailored feeder control strategies [15] to minimize variability in fed material concentration. The findings from this study offer valuable insights into the feeding performance of various excipients. Given that excipients are inactive ingredients (that can be present in high volume in the formulation or tablet), they can be selected based on the manufacturing process to optimize API performance. The results of this study support selecting the most suitable excipients to ensure solid CM and scalability. The significance of this study lies in its potential to provide guidance to practitioners in the pharmaceutical manufacturing sector.

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Table 1. Overview of the investigated materials: excipient name, manufacturer, material type, and abbreviation.

Fathollahi, S.; Janssen, P.H.M.; Bekaert, B.; Vanderroost, D.; Vanhoorne, V.; Dickhoff, B.H.J. Understanding Powder Behavior in Continuous Feeding: Powder Densification and Screw Layering. Powders 2024, 3, 482-499. https://doi.org/10.3390/powders3040026