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

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.

Yves Mayeresse (GSK Biologicals)
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.

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.


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