Integrated use of mechanistic models and targeted experiments for development, scale-up and optimization of lyophilization cycles: A single vial approach for primary drying

Development of lyophilization cycles, tech transfer and scale-up of the cycles, particularly of the primary drying, are common and challenging tasks for engineers in pharmaceutical companies. In this manuscript we share our experience with the scale-up of a previously tested cycle from pilot scale to production scale and then with optimization of the primary drying. We describe a workflow for a straightforward sequential and unbiased calculation of the mathematical model adjustable parameters: heat transfer coefficients and average radii of the pores (mass transfer coefficients). The calibrated model for the pilot scale can be then used for simulations of different scenarios at this scale, and for scale-up of the cycle to production scale. In production scale it is recommended to run water sublimation studies, to determine the heat transfer coefficients at this scale. The average radii of pores determined at the pilot scale can be used at the production scale. The calibrated model for the production scale can then be used to arrive at an optimum and robust lyo cycle at production. The final example of the case study illustrates the use of the developed model and software for primary drying optimization (shortening) by initially running it at a higher temperature. In summary, it can be concluded that the developed mathematical models, targeted experiments, and proposed workflow can significantly accelerate development, tech transfer and optimization of the primary drying.