(51a) Scale Independent Approach for Drug Product Development by High Shear Granulation Process

Pharmaceutical drug product development is driven through empirical experimentation.  Factorial experimental design methodologies are utilized to improve the efficiency of this approach.  A key unit operation in the manufacture of many immediate release tablets is high shear wet granulation.  High shear wet granulation is a time-dependent process with many simultaneous physical mechanisms occurring and therefore development work is often focused on the impact of this unit operation on final product quality attributes.  During process development, experimental designs will include typical factors such as impeller speed (rpm) or spray rate (g/min), which tend to be scale-dependent.  Analysis of such an experimental design provides important process knowledge and understanding and often includes empirical models relating process parameters to product properties.  However, as the input factors are scale-dependent, it remains unclear how to quantitatively transfer the empirical models and understanding to different equipment scales.

Historically, scale-independent parameters such as tip speed and Froude number have been developed for the high shear granulation process, many based on the principles of dimensionless numbers.  These scale-independent parameters are typically focused on different mechanisms of the wet granulation process and therefore can provide conflicting scale-up relationships.  The challenge remains in terms of how to utilize factorial experimental design data across manufacturing scales, and how to identify the most appropriate scale-up relationships.

A methodology is presented whereby experimental data is analysed in the context of a range of scale-independent parameters from the literature.  Statistical techniques are used to identify the sub-set of parameters that provide the best description of the product attributes.  These scale-independent parameters are then used as a basis for developing a scale-independent understanding of the manufacturing of a particular formulation. 

A case study is presented where this methodology was retrospectively applied to a product that had been manufactured over scales ranging from 2.5 to 180 kg.  Throughout development, the method of water addition had been qualitatively identified as important for the product intermediate quality.  Based on this observation, the dimensionless spray flux was included as part of retrospective analysis using scale independent parameters.  The dimensionless spray flux definition of Litster et al. (Pow. Tech. 114, pp32-39, 2001) is based on carefully controlled experimental studies examining droplet spray on the exposed powder surface of a spinning riffler.  The approach has been extended in order to provide a consistent definition that only depends on easily measurable and controllable wet granulation process parameters.  The key process parameters that are included in the definition are shown in Figure 1.

Figure 1  Key parameters included in dimensionless spray flux calculation

Retrospective analysis identified that the scale-independent parameter of dimensionless spray flux had been maintained within a consistent range of 0.2 to 1.4 leading to consistent intermediate granule attributes and end product quality.  It is not possible to directly compare the numeric range with the regimes proposed by Litster et al. (Pow. Tech. 114, pp32-39, 2001) due to the changes in the method of calculation.  Nevertheless, the approach appears relevant in this case, whereby the majority of product experience has been generated within a relatively narrow regime and resulted in controlled granule growth and consistent product quality attributes.  The extension of the dimensionless spray flux calculation therefore allows future changes in granulation scale and process parameters to be constrained multivariately, such that the high shear wet granulation process will remain in a spray controlled regime consistent with demonstrated experience and assuring product quality attributes.