The optimization and scale-up of wet granulation processes is often an essential step in the commercialization of oral solid dosage (OSD) products. Granulation enables the preparation of an optimized blend for tableting in which small quantities of highly potent active ingredients (APIs) are stably and homogeneously distributed. Furthermore, granule properties can be manipulated to control, for example, the flowability of the blend and its compressibility. In these ways granulation underpins the manufacture of high-quality tablets with consistent dose uniformity.
Wet granulation, and in particular high shear wet granulation, is the technology of choice for many OSD production processes. Compared with alternative methods, high shear granulation produces good quality, high bulk density granules, quickly and efficiently. However, batch high shear granulation processes are notoriously difficult to control because of their sensitivity to small changes in the formulation or mixing regime. Batch-to-batch variability is frequently high and process scale-up can be challenging, primarily because of the potential for mixing regimes to change as a function of scale. Learning how to control the relatively few processing variables that can be manipulated to achieve successful high shear granulation is essential for process optimization and for successful scale-up.
Teva, a global leader in the manufacture of generic products, adopts a Quality by Design (QbD) approach to develop the knowledge required to minimize and control the risk associated with moving high shear granulation from R&D through to commercialization. This involves a systematic approach to screening for the optimal combination of material attributes (formulation) and critical process parameters that give rise to a product, in this case a tablet, with defined clinical efficacy. Real-time Process Analytical Technology (PAT) is deployed to facilitate this process. Here the authors discuss the application of this analytical approach and present a case study demonstrating the value of in-line particle size analysis, within this context.
APPLYING HIGH SHEAR GRANULATION
The first step in producing optimized granules for tableting is the wet granulation itself which produces agglomerates that range from a few hundred microns to several millimeters in diameter (see Figure 1). These are typically wet milled (de-lumping) prior to drying in a fluidized bed dryer. Subsequent milling of the dried particles produces a closely specified granular feed for the tablet press.
Focusing on the wet granulation step, this can be further broken down into a number of stages. The first, pre-mixing, involves dry mixing of the components of the blend where the API is often present as a micronized powder and excipients are in the form of powders with a larger (typically 50-200um) average size. Once pre-mixing is complete, granulation liquid is sprayed into the mixer to promote cohesion of the powder particles. This liquid may be either water or a solution containing a dissolved binder. A second stage of liquid addition promotes further granule growth, to an acceptable finished granule size, as the mass is mixed to completion of the granulation process.
The performance of the high shear granulation process and the properties of the resulting granules, are controlled by the following variables:
• The composition of the blend;
• The amount of binder liquid added;
• The rate at which the granulation liquid is added;
• The design and operating conditions of the granulator such as speed of rotation of the mixing blade, and
• Mixing time.
When applying QbD, the aim is to control the manufacturing process to ensure that the critical quality attributes (CQAs) of the pharmaceutical product are consistently met. Typically the CQAs for tablets are properties such as hardness, dissolution profile and content uniformity. Fully scoping the design space for the wet granulation step therefore involves investigating how the processing variables listed above change the trajectory of the granulation, its outcome — the properties of the finished granules — and ultimately the CQAs of completed tablets. Continuous particle size analysis allows real-time tracking of the particle size of the granules during processing, and therefore has the potential to accelerate such studies. The following case study demonstrates its application.