(466b) Experimental and CFD Study of Mixing Two Fluids of Different Properties and Its Application in Biological Drug Product Manufacture

During biological drug product manufacture (solution in syringe or vial), concentrated drug substance in solution, typically with high viscosity, is either used as is or diluted with buffer to desired concentration. The high viscosity drug substance is amenable for subcutaneous administration but is difficult to administrator through intravenous injection (IV) without dilution. While subcutaneous administration can be conducted at home by a non-healthcare professional, intravenous injection must be administrated by a healthcare professional. Therefore, highly concentrated drug substance with high viscosity is desired at the starting point of drug product process to allow flexibility between subcutaneous administration (used as is) and intravenous injection (used after dilution). Efficient dilution of highly concentrated drug substance can be achieved at an appropriate mixing speed in a given mixer. However, the max mixing speed is set by the sensitivity of the biological molecules to shear and interfacial stress. A speed too fast may raise stability concerns. Hence, an optimal mixing condition balances between efficiency and product stability.

In this study, sucrose solution of various concentrations is mixed with water or water like liquid to mimic the two-fluid mixing system in biological drug product formulation process(Sucrose solution: drug substance, water: buffer). The impacts of initial concentration of sucrose and impeller speed on the mixing time are investigated using both experiments and computational fluid dynamic (CFD) simulation at three different scale (impeller bottom driven) mixing tanks, 250ml, 10L and 400L respectively. The experimental results in 250ml and 10L tank show that there exists a minimum mixing speed at which two fluids homogenous mixing occurs. It is also found that the impact of the initial concentration of sucrose solution on mixing time decreases at the mixing speed increases. To scale up two fluids mixing system using the traditional dimensionless number like Reynold number or tip speed is challenging due to the complexity of two-fluid mixing. A CFD two-fluid mixing model recognizing the difference of viscosity and density between the two fluids is developed for scale up. The model captures the characteristics of two-fluid mixing as described in experiments. After validated by the experimental at 250ml and 10L tanks, the model is applied at a 400L mixing tank. The model suggests key mixing operation parameters based on the liquid volume in the tank. The suggested parameters work as expected from the model.

* Presenter.