(184d) Empirical Calculations for Reliable Batch Blending Operation Scale-up in Pharmaceutical Manufacturing

Batch blending is an important step in pharmaceutical drug product manufacturing for preparing the final formulation blend that goes into the drug product dosage form. A batch process is initially explored and developed at a small (lab) scale and then scaled up to the intended commercial scale. Currently, there is a gap in the availability of rigorous scale-up criteria for batch blending. A commonly used scale-up factor for blending is ‘K-value’ that is a scale-independent parameter to quantify the effect of lubrication on the tablet physical properties [1, 2]. Kushner [3] proposed empirical formulas, derived through experimental knowledge, to calculate the K-value.

Given the straightforward nature of the empirical formula [3], we adopted the K-value approach to scale-up a batch blending operation. We assume that K-value can be used to ensure both comparable lubrication and blend content uniformity across different scales. In this work, two case studies are presented from different stages of process development to explore the applicability of K-value to facilitate reliable scale-up of the blending operation for specific formulations.

The first application is at a later stage of process development when the expected variability in the material properties and the operating parameters relevant to blending are known. An extensive sensitivity analysis was used to identify the range of K-value expected over the range of variabilities in the blending parameters. Experiments were then designed at the extreme corners to confirm the K-value range.

The second application is from an early stage of process development, where an optimization routine was setup to design the blending process at the pilot and commercial scales based on the lab scale data to obtain maximum flexibility for process scale-up.

References:

[1] 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(1-2), 147-155.

[2] 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.

[3] Kushner IV, 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(1-2), 1-11.