(274c) Investigating Continuous Powder Blending at Different Scales Using Residence Time Distribution Studies

O'Mahony, M., Vertex Pharmaceuticals
Bunchatheeravate, P., Vertex Pharmaceuticals
Dale, S., Vertex Pharmaceuticals
Connelly, G., Vertex Pharmaceuticals
Bullard, J. W., Vertex Pharmaceuticals
Powder mixing or blending is an essential unit operation required to achieve the homogenization of excipients (fillers, disintegrates, lubricants, etc.) and active pharmaceutical ingredient(s). Pioneering developments in continuous drug product manufacturing have facilitated the adoption of continuous powder blending platforms.1-3 The residence time distribution (RTD) is a probability function that describes the amount of time that a fraction of material spends within any continuous processing system. The RTD is a critical tool in continuous processing equipment and rig design, in pharmaceutical process understand and is also used to ensure the quality of the manufactured product. 4

In this work, continuous powder lubrication performance was compared using continuous dry powder blenders at both lab scale and production scale by varying total mass flow rate and blender blade speed with a view to translating the lubrication performance between blender systems. At steady state, the RTD and residence mass hold-up in the blender were measured. The tensile strength of tablets compacted from the blend at steady state were also measured in order to characterize the lubrication response.5 Three different regimes of blending were observed with increasing blade speed – ‘mixing’, ‘transitioning’ followed by ‘conveying’. Peclet number (Pe# - ratio of axial transport to axial dispersion) was determined by fitting RTD curves using the axial dispersion model. A slower line rate was required at the lab scale in order to achieve the same Pe# at production scale. The mean residence time, τ, was found to be the key predictor of lubrication performance, independent of blender scale. For both blender systems, τ decreases with increasing mass flow rate and increasing blade speed and, where blender speed was increased, changes in τ were minimized by selecting higher mass flow rates. Longer τ produced greater variation and skewness of the RTD across each blending system which has implications for material tracking and product yield within any continuous manufacturing process. Significantly, we show that the mean residence time, τ can be calculated directly from knowledge of the residence mass hold-up and mass flow rate for both systems.


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2. Teżyk, M., Milanowski, B., Ernst, A. & Lulek, J. Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review. Drug Development and Industrial Pharmacy 42, 1195-1214, doi:10.3109/03639045.2015.1122607 (2016).

3. Gao, Y., Vanarase, A., Muzzio, F. & Ierapetritou, M. Characterizing continuous powder mixing using residence time distribution. Chemical Engineering Science 66, 417-425, doi:http://dx.doi.org/10.1016/j.ces.2010.10.045 (2011).

4. Engisch, W. & Muzzio, F. Using Residence Time Distributions (RTDs) to Address the Traceability of Raw Materials in Continuous Pharmaceutical Manufacturing. Journal of Pharmaceutical Innovation 11, 64-81, doi:10.1007/s12247-015-9238-1 (2016).

5. Kushner Iv, J. & Moore, F. Scale-up model describing the impact of lubrication on tablet tensile strength. International Journal of Pharmaceutics 399, 19-30, doi:http://dx.doi.org/10.1016/j.ijpharm.2010.07.033 (2010).