(463d) Rapid Manufacturing Route Conversion Based on the Role of Shear and the Effect of Shear on the Formulation

The current practice, when transferring between batch manufacturing and continuous manufacturing, is to perform multiple designed experiments and perform statistical analysis on the results. While scientifically beneficial, practically this leads to significant waste in material with little to no actionable items. When we take a step back and start comparing between continuous and batch manufacturing, the tablet presses are the same for both manufacturing platforms. Thus, we can assume the table press will impart the same amount of conditioning (shear) to the powder blend in order to create the tablets. Therefore, if the material entering the tablet press has the same properties (bulk packing and flow) for both batch and continuous manufacturing, similar tablet properties should be obtained for both processes. If this is true, the focus of the work should be to identify if the bulk properties of the intermediate blend from one process is essentially equivalent to another process.

Formulations will inevitably end up in two categories. The first is a blend that is insensitive to the conditions at which it is produced, i.e. shear insensitive. The second category are blends that will undergo property changes due to the conditions at which they are made, i.e. shear sensitive. Within the second category, formulations can fall within subcategories, i.e. shear sensitive blends that do not effect the final product, shear sensitive blends that can be manipulated so that the final products can be matched, and shear sensitive blends that will always result in a different final product.

In this project multiple formulations were used to study how the bulk properties of each formulation would change based on increasing levels of shear. Since shear can effect API agglomerate size, lubrication, and granule size, the formulations utilized in this work varied each of these mechanisms and was able to identify shear sensitive and shear insensitive formulations. Next shear sensitive formulations were generated using different manufacturing routes and critical process parameters to identify if the blend can be manipulated enough to generate blends with similar bulk properties. For the batch manufacturing route, a V-blender was utilized to mix the blend at 50, 250, and 500 total revolutions. Next each of the blend was passed through a feedframe at 20, 60, or 100 RPM. Two continuous manufacturing routes were utilized LIW Feeders to dispense the individual components into a continuous blender, at three levels of RPM, and then into a feedframe with three levels of RPM. Two different continuous blenders and feedframes were utilized to represent two distinct manufacturing lines. The three manufacturing routes are identified in Figure 1. All the blends were characterized and blends were identified with the same bulk properties while being produced by different manufacturing routes. Tablets were generated and characterized to show the final products were in-fact equivalent. The results indicate that the critical process parameters of the manufacturing route can be optimized in order for the bulk blend properties can be matched independent of manufacturing route. No extensive designed experimental plan would be required to operate the manufacturing route at conditions that are unlikely to ever be utilized at the manufacturing facility. By matching blend properties, time, material, and money can be saved when converting formulations between manufacturing routes.