This paper is focused on the development of a new methodology to determine the design space of a drug freeze-drying process through a risk-based approach, compliant with the ICH Q8, Q9, and Q10 Guidelines. The risk related to the selected operating conditions for the freeze-drying process is calculated using mathematical modeling, focusing on product temperature, that should be kept below a limit value, as a critical quality attribute, with the goal of minimizing potential negative effects on patients. An observer is used to identify, in few experimental tests, the values of model parameters, as well as their uncertainty. A target value of the risk is identified, and its effect on the design space is assessed by means of process simulation, thus allowing for the identification of the most suitable operating conditions.