Nail: The key factors are the upper product temperature limit during primary drying (either a collapse temperature or a eutectic
melting temperature) and the capability of the equipment. In addition to this, we need to know the relationship between the
variables we control, such as shelf temperature and chamber pressure, and the variable we are most interested in, which is
the product temperature. This is done using well-established equations for heat and mass transfer in conjunction with the
vial heat transfer coefficient and the resistance of the dried product layer to flow of water vapour.
At my company, we have directed most of our attention to design space development for primary drying, since it is generally
the most time-consuming part of the process, and is generally associated with the highest risk to product quality. We also
need to direct our attention to the freezing and the secondary drying phases of the cycle.
Page/Steiner: The design space defines the acceptable processing conditions that have been shown to result in an on-spec product. Frequently,
the concept is considered in terms of the allowable range of setting of the critical process parameters. However, it is also
useful to use it to consider the range of process conditions that naturally occur inside a freeze dryer.
The main paradigm shift that occurs currently within the lyophilisation world is to admit that each container has its own
individual process, which is determined by influencing factors such as the position on the shelf or nucleation sources. This
applies for all kinds of containers including vials, syringes or trays.
Pikal: Normally there are three types of constraints. First, you want to restrict the temperature of the product during primary drying
to a value less than some maximum allowable temperature, which is frequently (but not always) the collapse temperature. Selecting
the proper combination of shelf temperature and chamber pressure will ensure this goal is met, but the process should also
at least close to the minimum time as possible to achieve the best process efficiency. Secondly, the time spent in primary
drying needs to be sufficiently long enough such that all of the product will be devoid of ice before the shelf temperature
is increased for secondary drying. Premature increase of shelf temperature may cause product collapse. Finally, the process
needs to be run at a sublimation rate that is within the capabilities of mass and heat transfer for the system. Running under
conditions that are excessively aggressive may, for example, result in choked flow, meaning loss of chamber pressure control
and perhaps leading to loss of the entire batch.
Q. How much consideration should be given to determining the edge of failure in lyophilisation process development and why?
Gieseler: In my opinion, the 'edge of failure' is important to both know and understand in freeze-drying science. While 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: 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 degree. From this value, different
formulation can be ranked in term of robustness against collapse.
Yves Mayeresse (GSK Biologicals)
Nail: 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 (that is, 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.