Rapid prototyping of miniaturized powder mixing geometries

Continuous manufacturing is an important element of future manufacturing solutions enabling for both high product quality and streamlined development process. The increasing possibilities with computer simulations allow for innovating novel mixing principles applicable for continuous manufacturing. However, these innovative ideas based on simulations need experimental validation. The use of rapid prototyping based on additive manufacturing opens a possibility to evaluate these ideas at a low cost. In this study, a novel powder mixing geometry was prototyped using additive manufacturing and further, interfaced with an in-line near-IR spectrometer allowing for investigating the residence time distribution (RTD) in this geometry.


Continuous manufacturing has recently gained more interest as an alternative to conventional batch manufacturing due to, e.g., the ability to perform straightforward scale up, to achieve a more constant quality product and a possibility for reducing the cost of production.In addition, this approach is supported by regulatory initiatives including a risk-based approach with implementation of Quality by Design (QbD) and Process Analytical Technologies (PAT),as well as an initiative for a guideline from The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH (ICH Q13 Continuous Manufacturing for Drug Substances and Drug Products).

The mixing of powders is a ubiquitous step in the manufacturing of pharmaceuticals and has traditionally been carried out as a batch process. The performance of continuous powder mixing is of major importance when developing a continuous manufacturing line.The performance of a continuous mixer can be evaluated by the residence time distribution (RTD), which is a well-established practice in many areas of chemical engineering.The RTD will describe the behavior of powder within the mixing unit and thus, address the challenge of material traceability within continuous manufacturing lines. RTD was originally used for describing flow in liquid-phase processes, but is also used to describe the flow of particles in solid-phase processes. A common approach for investigating RTD is based on an empirical model, which includes three considerations; material (tracer) added to the system, mean residence time (MRT), and the number of continuously stirred tank reactors (CSTR) in series. The number of CSTR provides a model for defining the statistical moments of the RTD.

For the detection and measurement of powder within a mixing unit, in-line process interfacing would be ideal for continuous manufacturing processes. A well-established in-line process analytical method is near infrared spectroscopy (NIR) that is suitable for continuous manufacturing due to the speed of analysis and size of the analytical equipment. Moreover, NIR is suitable for in-line measurements as the method is non-destructive and the accessibility of specifically optic fiber probes for diffuse reflectance measurements creates the possibility of cheap implementation in continuous manufacturing lines.

Additive manufacturing (AM) or “3D printing” has gained interest broadly within the pharmaceutical area, as it serves as a platform for rapid prototyping at low cost. Examples cover, e.g., analytical method development, production in microfluidics-based geometries and design of innovative drug delivery systems. AM coupled with in-line analysis is suitable for producing prototypes of pharmaceutical powder handling processes to assist in process development. At the same time, there is a growing interest to use process modeling and simulation to support pharmaceutical product and process design. This has been demonstrated with several examples with pharmaceuticals allowing for, e.g., in silico optimization of operating conditions and virtual ‘design of experiments’. However, it is necessary to experimentally validate the in silico work, and the use of AM for rapid prototyping of the optimized processing geometries is an attractive alternative testing innovative process solutions.

The aim of this study was to demonstrate the use of 3D printing for rapid prototyping of continuous manufacturing equipment. A miniaturized powder blending unit coupled with an NIR spectroscopy was used as a model of a continuous process and the estimation of RTD in this geometry.


Three common excipients and one active compound were used in the model powder mixture system: lactose monohydrate (FlowLac 100 SD, Meggle Pharma; Wasserburg, Germany) was used as carrier and mannitol (Pearlitol 100 SD, Roquette; Lestrem, France), galenIQ (Isomalt DC 101, Beneo; Mannheim, Germany), calcium carbonate (Scora SA; Caffiers, France) and paracetamol (Fagron; Barcelona, Spain) were used as tracers.

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Rasmus Svane, Troels Pedersen, Cosima Hirschberg, Jukka Rantanen,
Rapid prototyping of miniaturized powder mixing geometries,
Journal of Pharmaceutical Sciences, 2021,

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