Prediction of the Optimum Primary Drying Temperature from a Stepwise Temperature Increased Lyophilization Cycle

Prediction of the Optimum Primary Drying Temperature from a Stepwise Temperature Increased Lyophilization Cycle
November/December 2004
Wei Liu, Ph.D., Amol S. Ketkar, Ph.D., and Ping Y. Yeh, Ph.D., GlaxoSmithKline
APR
Introduction
Lyophilization is a widely used process in the pharmaceutical industry because of the increased product stability it affords, especially to biological products. Unfortunately, lyophilization can be both time-consuming and costly to manufacture. Therefore, the development of a short lyo-cycle is of great interest from the business and manufacturing perspectives of pharmaceutical and biotech companies. Among the three steps involved in lyophilization - freezing, primary drying, and secondary drying - primary drying is the most time-consuming process and its reduction would have a significant economic impact on the development and commercialization of lyophilized products.
The primary drying temperature is often set below or close to the glass transition temperature (Tg') or the eutectic temperature (Teu) to prevent product collapse for amorphous or crystalline material-dominated formulations, respectively. Given that the product temperature is lower than the shelf temperature prior to the end of ice sublimation during primary drying, the shelf temperature can be set higher to increase the drying speed as long as the product temperatures remain below the Tg' or Teu. It is a difficult and lengthy task to determine the optimum primary drying temperature without fully understanding the relationship between the shelf and product temperatures. Therefore, random testing of lyo-cycles in search of optimum drying temperatures is usually unsuccessful.
A general approach for estimating the shelf temperature as a function of product temperature can be calculated based on limited formulation data [1]. Although crude, the calculated shelf temperature for a target product temperature could serve as a guideline for primary drying temperature selection. However, the calculation method involves multiple variables that have to be calculated individually and is therefore a bit cumbersome from a practical standpoint.
The purpose of this study is to propose and evaluate a simple and practical method for predicting the optimum primary drying temperature using temperature data generated from a stepwise temperature increased lyo-cycle.
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