Development and Scale-Up of Diversion Strategy for Twin Screw Granulation in Continuous Manufacturing

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.

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The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation

Pharmaceutics ◽

10.3390/pharmaceutics13020293 ◽

2021 ◽

Vol 13 (2) ◽

pp. 293

Author(s):

Alexander Ryckaert ◽

Michael Ghijs ◽

Christoph Portier ◽

Dejan Djuric ◽

Adrian Funke ◽

...

Keyword(s):

Process Development ◽

Wet Granulation ◽

Major Goal ◽

Drying Time ◽

Process Step ◽

Manufacturing Line ◽

Fluid Bed ◽

Twin Screw ◽

Filling Phase ◽

Twin Screw Granulation

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25.

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Mechanistic understanding of the effects of process and design parameters on the mixing dynamics in continuous twin-screw granulation

Powder Technology ◽

10.1016/j.powtec.2021.05.071 ◽

2021 ◽

Author(s):

Lalith Kotamarthy ◽

Rohit Ramachandran

Keyword(s):

Design Parameters ◽

Mixing Dynamics ◽

Twin Screw ◽

Mechanistic Understanding ◽

Twin Screw Granulation

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Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process

Pharmaceutics ◽

10.3390/pharmaceutics13020210 ◽

2021 ◽

Vol 13 (2) ◽

pp. 210

Author(s):

Lise Vandevivere ◽

Maxine Vangampelaere ◽

Christoph Portier ◽

Cedrine de Backere ◽

Olaf Häusler ◽

...

Keyword(s):

Dissolution Kinetics ◽

Wet Granulation ◽

Continuous Manufacturing ◽

Formulation Development ◽

Granulation Process ◽

Low Viscosity ◽

Twin Screw ◽

Poorly Soluble ◽

Selection For ◽

The Impact

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.

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Effect of Aspect Ratio on the Mixing Performance in the Kenics Static Mixer

Processes ◽

10.3390/pr9030464 ◽

2021 ◽

Vol 9 (3) ◽

pp. 464

Author(s):

Xingren Jiang ◽

Ning Yang ◽

Rijie Wang

Keyword(s):

Pharmaceutical Industry ◽

Aspect Ratio ◽

Flow Reactor ◽

Mixing Time ◽

Continuous Process ◽

Scale Up ◽

Influence Factors ◽

Continuous Manufacturing ◽

Static Mixer ◽

Mixing Performance

Continuous manufacturing has received increasing interest because of the advantages of intrinsic safety and enhanced mass transfer in the pharmaceutical industry. However, the difficulty for scale-up has limited the application of continuous manufacturing for a long time. Recently, the tubular flow reactor equipped with the Kenics static mixer appears to be a solution for the continuous process scale-up. Although many influence factors on the mixing performance in the Kenics static mixer have been investigated, little research has been carried out on the aspect ratio. In this study, we used the coefficient of variation as the mixing evaluation index to investigate the effect of the aspect ratio (0.2–2) on the Kenics static mixer’s mixing performance. The results indicate that a low aspect ratio helps obtain a shorter mixing time and mixer length. This study suggests that adjusting the aspect ratio of the Kenics static mixer can be a new strategy for the scale-up of a continuous process in the pharmaceutical industry.

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Definition of a JA-2 Equivalent Propellant to be Produced by Continuous Solventless Extrusion

Journal of Applied Mechanics ◽

10.1115/1.4023315 ◽

2013 ◽

Vol 80 (3) ◽

Cited By ~ 1

Author(s):

Thelma G. Manning ◽

Joseph Leone ◽

Martijn Zebregs ◽

Dinesh R. Ramlal ◽

Chris A. van Driel

Keyword(s):

Extrusion Process ◽

Continuous Manufacturing ◽

Twin Screw Extrusion ◽

Extrusion Processing ◽

Roll Mill ◽

Screw Extrusion ◽

Twin Screw ◽

Ballistic Properties ◽

Definition Of ◽

Double Base

In order to eliminate residual solvents in ammunition and to reduce the emissions of volatile organic compounds to the atmosphere, the U.S. Army ARDEC has teamed with TNO in developing a new process for the production of solventless propellant for tank ammunition. To reduce the costs of solventless propellants production, shear roll mill and continuous extrusion processing was investigated. As described in this paper JA-2 a double base propellant cannot be processed without solvent by the extrusion process. An alternative JA-2 equivalent propellant was defined. The aim of this work is to demonstrate the manufacturing of this propellant by solventless continuous twin screw extrusion processing while maintaining gun performance characteristics of conventional JA-2 propellant. This is elucidated by explicitly researching the relationship between interior ballistic properties of the gun propellant and utilizing a continuous manufacturing process. Processing conditions were established, and the propellant was manufactured accordingly. The extruded propellant has the desired properties, which resulted in a comparable gun performance as the conventional JA-2 propellant.

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Scale-Up of twin screw extruders application and verification with the example of PVC

Advances in Polymer Technology ◽

10.1002/adv.1984.060040204 ◽

1984 ◽

Vol 4 (2) ◽

pp. 123-129 ◽

Cited By ~ 1

Author(s):

G. Menges ◽

W. Feistkorn

Keyword(s):

Scale Up ◽

Twin Screw Extruders ◽

Twin Screw ◽

Screw Extruders

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Metamorphosis of Twin Screw Extruder-Based Granulation Technology: Applications Focusing on Its Impact on Conventional Granulation Technology

AAPS PharmSciTech ◽

10.1208/s12249-021-02173-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Rajat Radhakrishna Rao ◽

Abhijeet Pandey ◽

Aswathi R. Hegde ◽

Vijay Induvadan Kulkarni ◽

Chetan Chincholi ◽

...

Keyword(s):

Process Analytical Technology ◽

Twin Screw Extruder ◽

Continuous Manufacturing ◽

Screw Extruder ◽

Solid Dosage ◽

Regulatory Standards ◽

Technology Applications ◽

Twin Screw ◽

Extrusion Technology ◽

Granulation Technology

AbstractIn order to be at pace with the market requirements of solid dosage forms and regulatory standards, a transformation towards systematic processing using continuous manufacturing (CM) and automated model-based control is being thought through for its fundamental advantages over conventional batch manufacturing. CM eliminates the key gaps through the integration of various processes while preserving quality attributes via the use of process analytical technology (PAT). The twin screw extruder (TSE) is one such equipment adopted by the pharmaceutical industry as a substitute for the traditional batch granulation process. Various types of granulation techniques using twin screw extrusion technology have been explored in the article. Furthermore, individual components of a TSE and their conjugation with PAT tools and the advancements and applications in the field of nutraceuticals and nanotechnology have also been discussed. Thus, the future of granulation lies on the shoulders of continuous TSE, where it can be coupled with computational mathematical studies to mitigate its complications.

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