PharmTech: According to ICH guidelines, determining the "edge of failure" is nonessential when establishing design space but
can is onbe informative. How much consideration should be given to determining the edge of failure in lyophilization process
development and why?
Gieseler (University of Erlangen-Nuremberg):
In my opinion, the 'edge of failure' is important to both know and understand in freeze-drying science. Although processes
or formulations should not be designed at the 'edge,' you can't estimate an appropriate 'safety margin' that is required.
In cases where the 'edge of failure' has not been investigated, a safety margin might be too conservative, or defined on a
trial-and-error basis. More importantly, for some critical process or product parameters, "edge of failure" conditions do
not exist, which is then quite relevant. For example, a product that can be processed in primary drying at shelf temperatures
well above ambient, the limiting parameter is not the product anymore, but the design of the equipment. Again, we should work
with a safety margin in the established design space, but we need to rationally set the safety margin, based on the knowledge
of the 'edge of failure.'
Mayeresse (GSK Biologicals):
It's interesting to know where the edge of failure is, even if it's nonessential data because it provides knowledge about
the total robustness of the formulation. In a QbD approach, the extent of your design space comes from the risk analysis you
used to determine the necessary margin. Let's imagine that for shelf temperature we define a 5 °C range around the target.
For some formulation, 5 °C is near the edge of failure, but for others we have five more degrees. From this value, different
formulation can be ranked in term of robustness against collapse.
Nail (Baxter Pharmaceutical Solutions):
We give this a great deal of consideration for the development of freeze-dried products. Our understanding of the idea
of a design space is to know all of the combinations of, for example shelf temperature and chamber pressure, that result in
a pharmaceutically acceptable product. We like for this design space to be as large as possible, so the boundaries of the
design space are the upper product temperature limit during primary drying (i.e., the edge of failure of the product) and
the equipment capability, which is the edge of failure of the equipment. Therefore, we think the 'edge of failure' is a key
component in design space development.
Page/Steiner (GEA Pharma Systems):
The value of knowing where the process may fail is important. Determining the design space depends on the level of confidence
in the rate of change of the relevant parameters in the region between the limit of the design space and the edge of failure.
If a process is very predictable and linear, then risk of failure can be reasonably predicted. However, in a freeze-drying
process the impact of the process condition on the product quality may be non-linear and prediction of the proximity to the
failure edge less easily defined. In this case, it may be better to explore the edge of failure explicitly.
Pikal (University of Connecticut):
In general, I agree with this philosophy. However, I maintain that with regards to the impact of collapse, it is advisable
to freeze dry a product well above the collapse temperature to observe the impact on product quality. The reason is that collapse
temperatures are determined using techniques that do not always quantitatively predict collapse in a product that is being
freeze dried in a vial. Sometimes you can freeze dry 5 °C or more above the collapse temperature measured by freeze-drying
microscopy without observable collapse in the vial. There are theoretical reasons and several observations that provide documentation
for this statement. Second, even if collapse does occur in the vial, there is a question on whether or not any critical quality
attribute is compromised. Often, the answer is no, and sometimes product quality (stability) is better in a collapsed product.
The application of this information is the knowledge on assessing the risk of collapse. The measure of risk is really the
product of the probability of the event and the severity of the occurrence of the event. Running above the collapse temperature
addresses the 'severity' of the occurrence of the event.
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