Reference Temperature degC

1.00E+09

1.00E+08

1.00E+07

1.00E+06 O

1.00E+04

1.00E+03

1.00E+02

Figure 20.4 Thermal analysis of a monoclonal antibody-containing tissue culture supernatant. (a) Conductivity showing a transition at —32 °C. (b) DTA profile showing a change in the gradient of delta T at —38 °C. Runs performed on Lyotherm (Biopharma Technology Limited, Winchester, UK).

Figure 20.4 Thermal analysis of a monoclonal antibody-containing tissue culture supernatant. (a) Conductivity showing a transition at —32 °C. (b) DTA profile showing a change in the gradient of delta T at —38 °C. Runs performed on Lyotherm (Biopharma Technology Limited, Winchester, UK).

Figure 20.5 Freeze drying microscopy of 0.2 % trehalose, 0.5 % human albumin, 0.9 % sodium chloride. (a) Frozen at —23 °C, no vacuum applied; (b) Freeze drying front advancing through sample, below Tcollapse (—26 °C); 132 |bar vacuum, ramping at 20 °C/min. (c) Collapse of freeze dried cake occurring above rcollapse (—17 °C); 132 |bar vacuum ramping at 20 °C/min. Images courtesy of Julie Fleming and Dr Roland Fleck, Cell Biology & Imaging Division, NIBSC.

Figure 20.5 Freeze drying microscopy of 0.2 % trehalose, 0.5 % human albumin, 0.9 % sodium chloride. (a) Frozen at —23 °C, no vacuum applied; (b) Freeze drying front advancing through sample, below Tcollapse (—26 °C); 132 |bar vacuum, ramping at 20 °C/min. (c) Collapse of freeze dried cake occurring above rcollapse (—17 °C); 132 |bar vacuum ramping at 20 °C/min. Images courtesy of Julie Fleming and Dr Roland Fleck, Cell Biology & Imaging Division, NIBSC.

20.4.1.4 Freeze drying microscopy

Freeze drying microscopy allows for the modelling of the lyophilization process in an ultra-thin layer of sample enclosed in a modified microscope slide mounted upon a cryostage, capable of evacuation to partial or full vacuum. Although the technology was described many years ago (MacKenzie 1964), commercially available equipment has recently become available. Freeze drying microscopy can add valuable insights into suitable freeze drying parameters for a given formulation (Zhai et al. 2003; Fleck et al. 2003).

The technique is different from those previously discussed in that it can be used to determine the temperature at which a thin film of frozen matrix undergoes collapse and so provides a visual record of the freeze drying process, albeit on a micro-scale. The temperature at which freezing occurs can be identified. On application of vacuum the freeze-drying commences and the rate at which the freeze drying front proceeds can be monitored at given temperatures. Finally as the sample is warmed the point at which collapse of the freeze dried matrix occurs can be identified (see Figure 20.5 for an example of the images obtainable from freeze-drying microscopy).

Although generally applicable across all formulations, the results from this methodology are obtained at micrometre depths and must be extrapolated to a lyophilized cake of one or more centimetres depth in the product; the data on collapse temperature and freeze drying rates must therefore be viewed with some caution and margins of error of several degrees centigrade are recommended.

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