Freeze Drying: The Experts' View - Pharmaceutical Technology

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Freeze Drying: The Experts' View
Lyophilisation is often necessary for pharmaceutical products to improve stability or shelf-life. However, the process can present difficulties, particularly when scaling up from the laboratory to commercial production. We bring experts together to discuss best practices for developing a lyophilisation process, including quality by design (QbD) and design space.

Pharmaceutical Technology Europe

Manfred Steiner (GEA Lyophil GmbH)
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.

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.


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