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LYOPHILIZATION
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Practical Considerations for Freeze-Drying Process Design, Development and Scale-Up
Sajal Manubhai Patel, Ph.D., Brian Lobo, Ph.D. and Ambarish Shah, Ph.D.
Department of Formulation Sciences, Biopharmaceutical Development, MedImmune
Introduction
Biopharmaceuticals are routinely freeze-dried to improve product stability and, thereby, achieve acceptable commercial shelf life. However, freeze-drying is a unit operation coupled in formulation and process. While selection of excipients is primarily focused on improving product stability, for a freeze-dried product an additional consideration is the compatibility of the formulation with the freeze-drying process. The rational selection of excipients for freeze-dried product has been reviewed extensively [1-3]. This article will focus on freeze-drying process development after formulation selection. Understanding the impact of formulation and process parameters on drug product quality is critical to application of quality by design (QbD) principles, which aim to build quality within the process rather than monitoring it off-line at the end of the process. This article will lay out the approach and the significance for systematic formulation and process characterization for successfully designing and developing a robust freeze-drying process with acceptable product quality attributes. Also, an overview is provided of tools and techniques available to monitor and control the key freeze-drying process parameters during design, development, and scale-up. Lastly, the critical elements of QbD—Process Analytical Technology (PAT) and design space—are discussed for the primary drying step of the freeze-drying process.
Considerations for Freeze-Drying Process Design, Development and Scale-Up
The four steps outlined in Table 1 are key to successfully designing, developing, and scaling up the freeze-drying process.
Step 1: Pre-lyophilization Formulation Characterization
Thermal characterization of the formulation, using differential scanning calorimetry (DSC) and freeze-drying microscopy (FDM), is critical for defining the maximum allowable product temperature during the primary drying step of the freeze-drying process because
78 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
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