Abstract

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.

摘要

冻干循环的开发、技术转让和循环放大，特别是初级干燥，是制药公司工程师常见且具有挑战性的任务。在这份手稿中，我们分享了我们将先前测试的循环从中试规模扩大到生产规模，然后优化初级干燥的经验。我们描述了一个用于数学模型可调参数的直接顺序和无偏计算的工作流程：传热系数和孔隙的平均半径（传质系数）。中试规模的校准模型随后可用于模拟该规模的不同场景，以及将循环放大到生产规模。在生产规模中，建议进行水升华研究，以确定该尺度下的传热系数。在中试规模确定的平均孔隙半径可用于生产规模。然后可以使用针对生产规模的校准模型在生产中达到最佳和稳健的溶胶循环。案例研究的最后一个例子说明了使用开发的模型和软件进行初步干燥优化（起酥油），最初在更高的温度下运行。总之，可以得出结论，开发的数学模型、有针对性的实验和建议的工作流程可以显着加速初级干燥的开发、技术转移和优化。然后可以使用针对生产规模的校准模型在生产中达到最佳和稳健的溶胶循环。案例研究的最后一个例子说明了使用开发的模型和软件进行初步干燥优化（起酥油），最初在更高的温度下运行。总之，可以得出结论，开发的数学模型、有针对性的实验和建议的工作流程可以显着加速初级干燥的开发、技术转移和优化。然后可以使用针对生产规模的校准模型在生产中达到最佳和稳健的溶胶循环。案例研究的最后一个例子说明了使用开发的模型和软件进行初步干燥优化（起酥油），最初在更高的温度下运行。总之，可以得出结论，开发的数学模型、有针对性的实验和建议的工作流程可以显着加速初级干燥的开发、技术转移和优化。