A scale-up test programme in the pilot plant for bulk solids aims to verify the intended mixing quality (target RSD) and the required discharge rates under conditions close to practice, before the process is transferred to the production scale.

Definition of objectives and acceptance criteria

At the outset, critical quality attributes (CQAs) and critical process parameters (CPPs) are defined, from which clear target values and limits are derived:

• Target RSD as a measure of mixing quality (for example distribution of active substance in formulations).
• Discharge rate as a measure of process efficiency, usually defined via the permissible residual quantity as a percentage of the batch mass.
• Limits for cross-contamination in multi-product plants.
• Secondary key figures such as cycle time, energy input and cleaning effort.

These criteria form the frame of reference for assessing the pilot-plant results and their release for the production scale.

Material characterisation as the basis

Robust planning requires detailed knowledge of the bulk solids properties, since they significantly influence mixing quality and discharge behaviour:

• Particle size, distribution and shape factor.
• Bulk and tapped density, compaction behaviour, Hausner ratio.
• Flow properties (for example ring shear tester, flow tester), cohesion and adhesion.
• Moisture content, hygroscopicity, electrostatic behaviour.
• Tendency to segregate and sensitivity to shear stress.

These data support the choice of process parameters, the interpretation of the RSD measurements and the assessment of wall adhesion and residue formation.

Trial design and scaling strategy

The pilot-plant programme is ideally structured via a statistical design of experiments (DoE):

• Factors: fill level, rotational speed or tip speed or Froude number, mixing time, order of loading, batch size ratio, temperature, pressure.
• Scaling rules: geometric similarity of the vessels, kinematic similarity (for example via the Froude number or circumferential speed) and, where applicable, dynamic similarity with cohesive powders.
• Types of design: screening designs (for example fractional factorial) to identify critical influencing variables, followed by response surface designs for optimisation and for defining a stable design space.
• Replicates and centre points: to estimate the process variance and to verify the repeatability of RSD and discharge rate.

The Froude number relates to rotating free-fall, drum and throw mixers as well as to systems with a horizontally mounted mixing tool. In vertical mixers with forced restratification it is not a design or scale-up criterion. What is decisive there is that the mixing principle remains the same across all sizes and that the restratification covers the entire mixing chamber independently of the fill level; transferability is secured in the pilot plant with the original product.

Combinations of parameters are thereby identified which ensure sufficient homogeneity and efficient discharge at the enlarged scale.

Sampling to verify the target RSD

The sampling strategy is decisive for the significance of the RSD determination:

• Samples from different zones of the vessel (core, wall, top/bottom, potential "dead zones") to assess homogeneity.
• A sufficient number of sampling points and repetitions, matched to volume and critical zones.
• Suitable sampling tools (for example thief sampler) or inline PAT systems, in order to avoid segregation during withdrawal.
• Definition of the sample size in relation to the single dose or to the analytical method.

The statistical evaluation provides the RSD as a key figure for mixing quality and shows whether the target RSD is reliably achieved at pilot-plant scale.

Determining and optimising the discharge rate

To verify the discharge rate, gravimetric and visual methods are combined:

• Mass balance by weighing the mass fed in and the mass withdrawn; the difference defines the residual quantity and thereby the discharge rate.
• Analysis of dead spaces, wall build-up and product accumulations in discharge fittings and pipework.
• Variation of discharge strategies (for example vibration, aeration, angle of inclination, discharge aids) in order to minimise bridging and hold-up.
• Visual or endoscopic inspection to identify critical zones and to derive constructional measures.

A high discharge rate reduces material losses, simplifies cleaning and lowers the risk of cross-contamination.

Influence of design and shear forces

In the scale-up, geometry, loads and shear conditions change:

• Changes in the ratio of surface area to volume influence wall effects and bulk pressure.
• Increased shear forces with larger rotors at unchanged rotational speed can cause particle breakage, a change in the particle size distribution and thus a deterioration in the RSD.
• Geometric particularities such as internals, baffles and outlet geometries influence flow patterns and discharge behaviour.

In the pilot-plant programme, the kinetic energy per unit volume and the resulting mixing intensity are therefore analysed in order to find a compromise between homogeneity and product integrity.

Evaluation, documentation and transferability

Finally, the pilot-plant trials are evaluated and documented systematically:

• Statistical analysis (for example ANOVA, regression models) to identify significant factors for RSD and discharge rate.
• Definition of a robust design space and of the proven acceptable range (PAR) for relevant CPPs.
• Derivation of a risk register (for example FMEA) for the transfer to the production scale.
• Documentation of the scale-up strategy, of the sampling and measurement methods and of the acceptance criteria as a basis for validation and routine production.