(191u) Experimental Approach to Determine K-Value Impact on Critical Quality Attributes (CQAs) in Diffusive Batch Blending

Batch blending is an important operation in pharmaceutical drug product manufacturing to prepare a formulation for processing into the final dosage form. It is necessary to assess solid oral drug products for critical quality attributes (CQAs) to ensure a quality dosage form is delivered to the patient from the process. One tablet design consideration required by the description CQA is achievement of adequate mechanical strength for doses to withstand downstream processing for the tablet to maintain its appearance. Mechanical strength can be influenced by formulation choices and processing methods, namely lubricant concentration and blending process shear. To design for blending impact to tablet tensile strength, a model exists to determine K-value, a scale independent latent variable, used to describe extent of blend lubrication resulting from blending shear (Kushner 2012; Nassar et al., 2021). The K-value model has been used extensively to ensure tablet tensile strength remains acceptable during scale up of pharmaceutical batch blending processes (Kushner & Schlack, 2014).

To understand if K-value could be further leveraged as a design tool applicable to scale up of other drug product CQAs, namely content uniformity of a tablet, experimentation was conducted using the K-value to scale up a batch blending/tableting process.

Lab-scale blending studies were initially conducted to identify a K-value range of interest, ensuring robust tablet tensile strength and acceptable dissolution profiles. Constrained by the acceptable K-value range, equipment control capabilities, and allowable variation in material properties, an optimization problem was formulated and solved to identify maximal operating condition ranges – blend speed, blend time, and fractional head space – for commercial scale bin blenders. Then, pilot and commercial scale studies were conducted to further validate the K-value model predictions and selected K-value range. Operating within the K-value range ensures that the tablet CQAs, including content uniformity, description, and release, are met. Following this workflow, a multivariate design space for the blending process was defined including acceptable operating ranges across multiple equipment scales.

The findings highlight the importance of the K-value in achieving consistent blend uniformity and maintaining CQAs across different scales, providing a reliable framework for the manufacturing process of tablets.

References:

Kushner, J. (2012). Incorporating Turbula mixers into a blending scale-up model for evaluating the effect of magnesium stearate on tablet tensile strength and bulk specific volume. International Journal of Pharmaceutics, 429(1), 1-11. https://doi.org/https://doi.org/10.1016/j.ijpharm.2012.02.040

Kushner, J., & Schlack, H. (2014). Commercial scale validation of a process scale-up model for lubricant blending of pharmaceutical powders. International Journal of Pharmaceutics, 475(1), 147-155. https://doi.org/https://doi.org/10.1016/j.ijpharm.2014.08.036

Nassar, J., Williams, B., Davies, C., Lief, K., & Elkes, R. (2021). Lubrication empirical model to predict tensile strength of directly compressed powder blends. International Journal of Pharmaceutics, 592, 119980. https://doi.org/https://doi.org/10.1016/j.ijpharm.2020.119980