Development of a Continuous Blending Process through Mechanistic Understanding of the Shear Effect
AJie Ren1*, Anthony Tantuccio2, Billy Blincoe3, Jasdeep Mandur3, Brandye Smith-Goettler3, Justin Moser1, and James DiNunzio1
1 Formulation Sciences, MRL, Merck & Co., Inc., Kenilworth, NJ, USA
2 Pharmaceutical Commercialization Technology, MMD, Merck & Co., Inc., Kenilworth, NJ, USA
3 Process Analytical Technologies, MMD, Merck & Co., Inc., Kenilworth, NJ, USA
* Presenting author
Continuous blending, as a critical step in continuous manufacturing of solid dosage drug products, has a drastically different powder mixing mechanism from that of batch blenders. In this work, an experimental framework is presented to compare performances of batch and continuous blending through mechanistic understanding of the shear effect. Specifically, the effect of shear on a formulation during blending was characterized with two orthogonal shear-sensitive measures: a compaction analysis tracking the effect of extended lubrication caused by MgSt, and a color measurement tracking the color of the powder blend caused by a shear-sensitive color tracer. It was demonstrated that both methods were sensitive enough to pick up shear-induced formulation responses in the pocessing range tested: with increased amount of shear, the blend showed a drop in tensile strength due to over-lubrication, as well as a change in color appearance caused by the dispersion/de-agglomeration of the colorant. By comparing such measures between a Gericke continuous blender and the traditional Turbula and Bohle blenders, a potential processing advantage of continuous blending was identified: it can offer better dispersion & de-agglomeration for very fine particles (like red iron oxide), while reducing the risk of over-lubrication of MgSt, compared to batch blending. Such advantage can potentially be leveraged in formulation design to create unique process-performance relationships using continuous blending. In addition, the results of this work also allowed for the development of bridging tools between process modes, as well as material-sparring methods for at-scale blending performance predictions.
Jie Ren is a scientist in the Formulation Sciences department at Merck. In this role, Jie has lead various efforts for the formulation and process development of multiple Merck products, and has devised development guidelines for many processes including compression, roller compaction, and spray drying. Currently, Jie works on Merck’s development of Continuous Manufacturing framework, with a focus on early-development strategies. Jie graduated from Duke University with a PhD in soft matter physics. Coming from such background, Jie is passionate about utilizing advanced characterization techniques to gain fundamental understandings of formulations as complex soft materials, and use these understandings to guide the development of formulations and processes.