Scale-up of freeze-drying cycles, the use of process analytical technology (PAT), and statistical analysis

Chapter 10Traditionally, the quality of pharmaceutical drugs is tested on the final freeze-dried product following a regulatory framework known as Quality-by-Testing (QbT) (Yu, Pharm Res 25: 781–91, 2008). In this system, product quality and performance are ensured by performing extensive tests on the final product, and by using a fixed formulation and manufacturing process. In contrast, the US Food and Drug Administration (FDA) proposed the Quality by Design (QbD) initiative with the idea that quality cannot be “tested into” the product, but it should be built into it (FDA, Guidance for industry, Q8(R2) pharmaceutical development. Dept. of Health and Human Services, Center for Drug Evaluation and Research. Rockville, MD, 2009). Quality by Design consists of a systematic approach to pharmaceutical product development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management (FDA, Guidance for industry, Q8(R2) pharmaceutical development. Dept. of Health and Human Services, Center for Drug Evaluation and Research. Rockville, MD, 2009; Mockus et al, Pharm Dev Technol 16: 549–76, 2011; Yu, Pharm Res 25: 781–91, 2008). In this chapter, a statistical model for the sublimation step in freeze-drying was used to construct the design space for the cycle development and to select adequate parameters for scaling up from pilot to commercial scale. Three critical operating variables of the process were tested: freezing rate, shelf temperature, and chamber pressure in primary drying. The model was used to predict the sublimation rate and the product temperature, since their selection is of paramount importance to obtain a product of high quality. The obtained results were then used to define the design space of the product at pilot scale