PharmTech: What key factors must be considered when determining a design space for a lyophilized product?
Gieseler (University of Erlangen-Nuremberg):
Design space should be defined for critical formulation and process factors. Considering formulation, such factors could
include the critical formulation temperature (i.e., the collapse temperature), moisture content, API stability parameters,
appearance, and morphological parameters (e.g., specific surface of the cake inner structure that influences, among other
things, reconstitution time). Most scientists, however, focus on the process design space, or more precisely the primary drying
design space. Here, the most important factor is the product interface temperature, which, in turn, is a result of the applied
shelf temperature, chamber pressure, and heat and mass transfer characteristics of the applied container system.
Recent studies have suggested that determination of the primary drying design space alone seems insufficient to draw a representative
picture of product behavior during the process. At the very least, the freezing step must be considered as well because it
determines the pore size distribution and, therefore, affects mass flow resistance during primary drying. Moreover, the freezing
step may cause API instability due to occurring freeze concentration or ice/water induced surface denaturation (proteins).
A product morphology that has formed at different nucleation temperatures during the freezing step might also provide a different
degree of stability to the cake structure during primary drying. For example, warmer nucleation temperatures form bigger pores.
Some product cakes have shown a higher structural firmness during the sublimation phase when bigger pores were present. The
product morphology formed during the freezing phase even influences the secondary drying performance of the drug product.
The biggest obstacle is to representatively determine the formulation and process design space. While the process design space
is typically defined in laboratory-scale equipment, such information must then be scaled to manufacturing. The challenge is
that the originally defined process design space might not perfectly match the process design space in manufacturing.
Mayeresse (GSK Biologicals):
The key factors to determine a freeze-drying process are temperature of the shelves, pressure in the chamber, and time.
The value of these parameters is influenced by the equipment, which means the design space should be as large as possible.
For the output parameters of the process, the key factors are cake elegance, moisture content and potency. Depending on the
product, some specific parameters can be added. For example, if the active ingredient is prone to oxidation, a specific test
can be developed.
Nail (Baxter Pharmaceutical Solutions):
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 vapor.
At my company, we have directed most of our attention to design space development for primary drying, because 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 (GEA Pharma Systems):
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 lyophilization 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 (University of Connecticut):
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 that this goal is met, but the process
should also at least close to the minimum time as possible to achieve the best process efficiency. Second, 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.