Page/Steiner: 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.
Manfred Steiner (GEA Lyophil GmbH)
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: 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. Secondly, 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.
Q. Changes in formulation and manufacturing processes during development and lifecycle management should be seen as opportunities
to gain additional knowledge. Could you please give examples of how this principle can be applied?
Gieseler: One of the best methods of gaining additional knowledge about the product and process is to implement robustness testing
protocols during cycle development in the laboratory. Here, one would use the desired final formulation composition and desired
(optimised) freeze-drying recipe and then develop protocols that challenge the cycle and the formulation. The shelf temperature
is elevated in predefined steps to obtain higher product temperatures during primary drying. The same principle can be applied
to the chamber pressure set point. After the cycle, the product-quality attributes are inspected and correlated to the observed
process-performance attributes. The same robustness testing concept may be applied to the formulation stage. A change in excipient
concentration or even exchange of single excipients typically results in a significant change of the formulation performance,
and thus design space. The use of statistical methods, such as a Design-of-Experiments (DoE), helps us during formulation
development to identify relevant factors. In general, DoEs are much more helpful during the formulation stage than during
process development because of the number of experiments required.
Overall, a gain of additional knowledge is certainly a desire for most formulation scientists or process engineers, but stringent
timelines in the routine day-to-day work don't usually provide enough time to look deeper into the science.
Mayeresse: The role of stabilisers such as sugar, buffer, polymers and surfactant are now better understood. Nevertheless, depending
on the complexity of the molecules, some surprises can occur during development that will need to be corrected. The knowledge
gleamed from this will be remembered when developing new molecules. It is necessary to detect all the specificities of the
molecule during the early stage of the development because at this stage it can easily be corrected without impacting results
of clinical studies. Formulation changes in the late stage of a project can be a major concern.
Nail: We don't consider changes in the formulation in the context of life cycle management; that is, once the formulation is established,
we don't make changes. However, during product development, making systematic changes in composition is part of the development
of the formulation design space. This might be a plot of Tg' versus pH, for example. The idea is to get a good sense of how
changes in composition affect the behaviour of the product. For examining stability, we generally rely on short term testing
under stressed conditions.