Scale-up of high shear wet granulation: developing high protein products supported by down scale characterization and modeling of powder properties

Abstract

Granulation converts fine powders into granules with desired physical properties, minimising dustiness, ingredient segregation, and handling hazards. Within Novonesis solid enzyme products, granulation enables higher enzyme activity and stability while preventing dust release. This thesis focused on high shear wet granulation, a complex process associated with high variability, influenced by equipment, process parameters, and formulation. The objectives were to develop a
placebo formulation mimicking high protein load enzyme products, optimise high shear wet granulation at small-scale (5 L) and pilot-scale (50 L) by investigating the effects of the impeller speed, chopper speed, and fill level and evaluate scale-up criteria related to these process parameters. Granule attributes including particle size distribution (PSD) and shape, density, porosity, and colour were characterised, and a friability test was developed.
At 5 L scale, a narrow operational optimum for the impeller speed was observed at 240 rpm, while increasing the chopper speed improved the amount of granules of the target size range, but resulted in a broader PSD and lower convexity. Simultaneously decreasing fill level and impeller speed produced more granules within the desired size range and more convex granules. At pilot-scale, lowering the impeller speed improved target fraction, PSD, and porosity. Similarly to small scale, the chopper was found to be the dominant parameter, strongly influencing PSD, shape and overall granulation behaviour. The chopper effect was dependent on the granulation stage.
During scale-up, maintaining a constant chopper Froude number resulted in the most
comparable granule attributes across scales among the criteria tested. In contrast, maintaining constant chopper tip speed, impeller-based criteria or fill-level did not result in consistent scale-up behaviour. However, the independent effects of impeller speed and fill level could not be fully assessed due to unmatched chopper operating conditions between scales. These results indicate that chopper-based similarity is the most relevant scale-up criterion for the system studied and therefore it should be fixed to accurately study other process parameter’s effects.
Granules produced at pilot-scale exhibited higher bulk density, lower porosity, and improved reproducibility compared to those produced at small-scale. The friability test requires further development to improve accuracy and sensitivity, but the results allowed correlation between more porous granules from the 5 L scale and higher friability. Overall, the 50 L mixer produced more robust and reproducible granules, suggesting improved binder distribution, mixing efficiency and drying performance at this scale.

Popular Abstract

Novonesis provides solutions for real-world challenges through biology. These biosolutions are based on enzymes, which can be formulated as liquids or solids. While enzymes have the potential to improve many processes, for instance by efficiently removing difficult stains from clothes at lower temperatures, inhaling enzyme powders can trigger allergy reactions, and therefore enzyme products should not be handled as fine powders.
Granulation is a process that converts fine powders into enlarged particles named granules with desired physical properties, thereby minimising dust release, improving ingredient uniformity, and reducing the hazards associated with handling powder products. This technique has been widely used in industries to produce pharmaceuticals, enzyme products, detergents, etc. The focus of this thesis was high shear wet granulation (HSWG), which is performed using a granulating liquid such as water in a bowl containing an impeller and a chopper (knife). The impeller provides powder agitation, while the chopper breaks the wet lumps. This process is associated with high variability due to the complex influence of the equipment, formulation, and process parameters, and therefore it is relevant to study its optimisation.
The objectives of this study were to develop a placebo formulation that mimics enzyme products with a high protein concentration and is suitable for HSWG, optimise HSWG conditions at small-scale (5 L) and pilot-scale (50 L) by investigating impeller speed, chopper speed, and fill level and evaluate scale-up strategies related to these process parameters. Granule attributes including particle size and shape, density, porosity, and colour were characterised using established methods. The tendency of the granules to fragment into smaller particles under mechanical stress is referred to as friability, and a test was developed to assess this property.
At 5 L scale, varying the impeller speed produced better results at 240 rpm (revolutions per min), whereas deviations from this speed resulted in a higher proportion of oversized granules. Increasing the chopper speed led to more granules within the desired size range (target fraction), but the particle size distribution (PSD) and shape (convexity) were negatively affected. Ideally, granules should have similar sizes and be as convex (rounded) as possible. Simultaneously decreasing fill level and impeller speed improved target fraction and granule convexity.
At pilot-scale, lowering the impeller speed improved target fraction, PSD, and porosity. Similarly to the 5 L scale, the chopper speed showed a strong influence on granulation behaviour and was identified as the dominant factor controlling particle size and shape, although the effect seemed to depend on the granulation stage. Compared with the 5 L mixer, the 50 L mixer produced more robust and reproducible granules, with lower tendency to break and more consistent product quality across batches
Different strategies were tested to understand how to produce similar granules in the 5 L and in the 50 L mixer. Keeping the chopper Froud number constant, which compares the energy needed to move the powder to the gravitational forces, gave the most comparable granules between the two scales. Other factors, such as the impeller speed and fill level, did not show consistent scale-up behaviour. Overall, the results showed the importance of controlling the chopper operating conditions during scale-up.
The friability test required further development to improve accuracy. Nevertheless, this study demonstrated the potential and importance of assessing this attribute, especially for evaluating granule robustness during handling and transport.
The objectives of the project were achieved, providing a better understanding of HSWG and of its scale-up using different strategies.

• author: Gomes Carvalhão, Mariana
• supervisor: Carl Grey; Pär Tufvesson
• organization: Biotechnology (MSc); Biotechnology (M.Sc.Eng.)
• course: KBTM01 20261
• year: 2026
• type: H2 - Master's Degree (Two Years)
• subject: Science General
• keywords: high shear wet granulation, placebo, optimisation, scale-up, chopper Froude number, biotechnology
• language: English
• additional info: Supervisor from Novonesis: Pär Tufvesson
• id: 9241693
• date added to LUP: 2026-06-22 09:48:16
• date last changed: 2026-06-22 09:48:16