Scale-up of fluid bed granulation of an active formulation with a scale independent parameter and a process model

A practice based approach for the scale-up of fluid bed granulation in the context of drug product development is presented and evaluated in this work in the context of clinical drug product manufacturing development. The approach is based on using a scale independent parameter, the evaporation energy to drying capacity ratio (EE/DC), and a process model. An example of application is presented, where the fluid bed granulation process of two formulations, one placebo and one active, was scaled-up from laboratory to pilot scales.

Right-first-time scale-up in accelerated and lean development

With the current trend of portfolio projects acceleration and the aim to efficient development, often process experience collected with the active formulation at the conclusion of the formulation development phase is little and limited to the laboratory scale [1]. Depending on the clinical needs, it can be required to scale up a process from a laboratory scale
(0.5-1 kg batch size) to the pilot scale (15-20 kg). API for technical experiments aimed at assessing scale-up effects is often not available and therefore scale-up must be done right-first-time. In this work, an approach based on process engineering and process modelling was applied to scale-up fluid bed granulation for the Phase 2 clinical manufacture of a portfolio project, where limited experience had been collected at laboratory scale during the formulation development.

Fluid bed granulation scale-up

Few key response variables affect more directly the granulation process [2]. Two were used here and kept the same across scales:

Gas surface velocity to achieve similar bed hydrodynamic behavior

Evaporation energy to drying capacity ratio to achieve similar product bed moisture

Method

Scale-up approach to pilot scale:

• Air flow rate calculated with Eq. 1.

• Spray rate 𝑚̇ calculated by keeping constant EE/DC ratio (Eq. 2) across scales.

• A process model (gFormulate, Siemens PSE, London, UK) was used to predict when to switch spraying phase (objective: granules moisture between 10 and 12%).

Results of experiments at laboratory scale

Process optimization experiments were planned by targeting wet and dry conditions by choosing a high and a low EE/DC for the initial granulation phase. In the second granulation phase an EE/DC close to 100 was chosen and no granules moisture increase was expected: indeed granule moisture increases more slowly.

Similar granules moisture was achieved with the active formulation.