Integrated heat flux measurements as a non invasive monitoring technique for freeze drying

Freeze drying is a well established technique to improve the stability of biopharmaceuticals, specifically proteins, if a liquid formulation is not sufficiently stable. Freeze drying is a complex process, where the product temperature (Tp) during primary drying is a highly critical parameter, because a loss of product quality can occur if Tp exceeds the glass transition temperature (Tg) or the collapse temperature (Tc) resp.. Thus, monitoring of this critical parameter in combination with a good process and product understanding is of utmost importance. A common method for temperature monitoring is the usage of thermocouples, which are placed in some product containers of a batch. A major drawback of thermocouples is their contact with the product, the difficult handling to assure their optimal and reproducible positioning in the vial center close to the bottom and their limitation in usage in aseptic manufacturing. The aim of this study was to evaluate heat flux measurements using LyoPATTM (AccufluxTM and FreezeBoosterTM) as a new, non invasive monitoring technique during freeze drying. The heat flux sensor is mounted on the shelf and analyzes the heat transfer from shelf to product.