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Misconceptions in Freeze Drying

by biopharma-admin in BTL News Cat 1

Freeze drying can be a complex process to handle effectively but despite improvements in analytical and process science a number of misconceptions persist that prevent practitioners from achieving the best results. In this article we look at some of the misunderstandings we encounter most often.
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1. Colder condenser temperature mean faster freeze drying
2. “One size fits all” cycle development
3. Vials can be filled to any depth
4. It doesn’t matter how a product is frozen—it’s the drying that’s important
5. Drier (lower final moisture content) is always better
6. Lower chamber pressure means faster freeze drying
7. Condenser overloads
8. Shelf spacing requirements
9. Vacuum pumps are all the same
10. Freeze drying equipment doesn’t need maintenance

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1. Colder condenser temperatures mean faster freeze drying

It is often thought that a colder condenser will improve freeze drying and “suck the water out faster”. However it is the difference in vapour pressure between product and condenser that drives the process, not the condenser temperature alone.

Increasing the pressure differential between product and condenser will speed up the process. However lowering the temperature of the condenser is less efficient than raising the temperature of the product. If we consider table 1 below we can see that the pressure differential decreases as temperature drops; for example the pressure difference between -40°C and -80°C is just 0.1283mbar, whereas the difference between 0°C and -10°C is 3.505mbar.

Vapour Pressure of Ice Table

Table 1: Vapour Pressure of Ice

Of course, the product temperature cannot be forced above its collapse point during primary drying. However a more favourable thermal profile might be generated via reformulation, which would then allow the freeze drying process to be driven more quickly.

Colder condensers are designed to process non-aqueous solvents which have a low freezing point. Unnecessarily cold condensers will increase the cost and complexity of the equipment and also increase running costs.

2. “One size fits all” cycle development

In both manufacturing and development it’s not uncommon to find one cycle borrowed for other applications. We have seen one instance where one cycle was used for over 200 different products! The reality is, a freeze drying cycle needs to be optimized for a specific product, batch parameters and freeze dryer. An unsuitable cycle will be inefficient at best and can even risk process failure.

Even seemingly small changes can have significant effects. For example, if the container size is changed the product may dry more quickly (requiring additional thermal energy from the shelf to counteract sublimation cooling) or more slowly (requiring less heat energy and extended primary drying). Formulation changes including the type or amount of active ingredient will affect the thermal characteristics of the product overall. A small change in fill volume could increase the overall vapour load of the batch, decreasing the drying rate or even overloading the condenser.

Freeze Drying Cycle Graph

Figure 1: An example of a freeze drying cycle

Scaling up from development to production is particularly important as production equipment tends to have different process capabilities. For example, laboratory freeze dryers often feature lower condenser temperatures than those in production systems. When changing equipment proper consideration should be given to the implications and testing carried out.


3: Vials can be filled to any depth >>