Technology Overview

Sartorius Stedim Biotech offers Controlled Freeze-Thaw Technologies with more than a decade long track record of success. Nearly all approaches to large-scale freezing of liquid formulated biopharmaceuticals suffer from negative effects of uncontrolled solidification and melting. Approaches such as freezing in bags and bottles have been repeatedly shown to result in cryoconcentration and non-uniform temperature profiles within containers. Inadequate control of phase change has been shown to result in product losses due to aggregation, precipitation, oxidation and denaturation. Additionally, it is especially problematic to validate the uncontrolled freezing and thawing processes.

Cryoconcentration

Insufficient heat flux results in concentrations of solutes as pure water freezes first, followed by other components according to individual solidification temperatures.

Cryocentration often results in product loss due to protein aggregation and precipitation.

Controlled Rate Dendritic Ice Growth

Sartorius Stedim Biotech's proprietary controlled rate dentritic ice growth virtually eliminates the protein degradation effects of cryoconcentration as solutes are quickly embedded between dendrites. The formation and growth of dendritic ice crystals is reliant on precisely controlled directional heat flux. Sartorius Stedim Biotech's technology utilizes high efficiency heat exchange systems that maximize the contact surface optimizing the heat transference.

Factors Affecting Freezing and Thawing

Macro Factors

  • Distances the freeze fronts must travel to complete freezing.
  • Heat removal surface area and local overall heat removal.
  • The temperature difference between the liquid phase and the heat transfer surface temperature.
  • Freeze front velocity - overall freezing time.

Micro Factors

  • Pattern of ice crystal growth.
  • Solute distribution in frozen mass.
  • Solute composition and concentration may affect the first two points.

Molecular Level Factors

  • Formulation composition and the concentration of solutes - final solidification temperature.
  • Presence of stabilizers.
  • Protein characteristics (stability, unfolding/refolding, aggregation).