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The VERISEQ™ Ice Fog Nucleation process cuts production time by up to 30%, increases process control, and improves finished product attributes.
Freeze drying has a long history as a viable technology, dating back to the days of the Inca, who used it to preserve potatoes, and to the turn of the 20th century, when it was used during industrial coffee production in the United States.
More recently, in the days of World War II, high overseas demand for serum drove Americans to freeze dry serum in granular form for transportation. This marked the beginning of modern-day freeze drying, with the pharmaceutical sector the biggest driver.

The freeze drying method consists of three phases; freezing, sublimation, and desorption.  The critical role of the freezing step has for years been overlooked.  The freezing process determines the fundamental crystal structure that influences the drying rate for each unit.

Freezing of the pharmaceutical product in itself entails several steps.  First, the free solvent (usually water) must be frozen.  This occurs after supercooling, where the solution temperature is reduced to below the equilibrium freezing point of the solution.  Supercooled solution then undergoes nucleation, where a single seed crystal or nuclei forms somewhere in the solution.  Ice crystals propagate rapidly from the nucleation site. Nucleated units are then solidified, and finally , the solute components are crystalized or solidified into glassy states.
In nature, ice crystals form around suspended particles or container defects, while in pure systems, nuclei form from water, but only after significant super cooling.



The degree of supercooling is critical because this temperature determines the minimum size of the crystals formed.  More supercooling equals smaller crystals.  Small crystals are resistant to vapor flow during subsequent drying steps, and during reconstitution. 

In the past, there has been no means of controlling the amount of supercooling, so individual units would nucleate at variable times.  This leads to inconsistent drying and longer cycles.
When applied to industrial processes, traditional freeze drying methods do not allow for great efficiency, since large quantities of vials tend to cool inconsistently depending on their placement, and supercooling at significantly low temperatures produces smaller ice crystals that are more resistant to vapor flow.
All this leads to longer production cycles.

One solution for this problem is a process that induces nucleation through the introduction of seed crystals in the form of ice fog, yielding four significant results:

  • Shorter processing time
  • Less vial-to-vial variance
  • Greater control of the lyophilization process
  • Shorter reconstitution time

Ice fog is produced in an apparatus that uses liquid nitrogen to vaporize sterile water within a lyophilizer chamber.

While the mechanized system designed by IMA Life and Linde is not the only one being developed for the pharmaceutical market, it does feature the following particular benefits:

• Compact size
• Sanitary, easily sterilizable design
• System easily retro-fitted to any lyophilizer
• Product exposed only to sterile nitrogen and trace amounts of WFI 
• System requires small amounts of liquid nitrogen (a Dewar will suffice)
• System compatible with pre-existing access ports on chamber
• No need to pressurize the product chamber
• Software easily integrates with existing control systems
• System features stand-alone control for non/semi-automated systems

The preliminary tests performed on this apparatus with water, Mannitol Solution and Sucrose Solution, followed by a test with Vancomycin HCl, produced excellent results which led to the following conclusions:

• Ice Fog is capable of inducing nucleation consistently and quickly throughout a vial pack
• Induced vials exhibit larger and more consistent crystal structures than those created via natural nucleation
• Mass flow (sublimation rate) is increased thanks to the use of ice fog
• Vial-to-vial temperature profiles appear to be more consistent when nucleation is induced
• Product attributes are significantly improved

The tests revealed significantly reduced processing times – as much as 30% shorter than traditional methods.

Before these new methods can be applied to pharmaceutical production lines, various types of adjustments will undoubtedly need to be made – not the least of which requires adherence to the standards set by an area’s regulatory entities – which could cause delays in implementation.

There is no doubt, however, that the future of freeze drying is in ice fog nucleation.
Increasing competition and the need for quicker and safer production processes will lead to an ever stronger push for the adoption of this new technology.