Page/Steiner: In any QbD process, it is important to first define the required performance of the finished product. In other words, what
are the critical quality attributes of the product? For a freeze-dried product these are typically things like reconstitution
time, appearance, shrinkage, collapse, viability of product and shelf life.
The next step is to use analytical methods to determine the behaviour of the product during the freezing and drying process.
A risk assessment technique, such as failure modes and effects analysis, determines which factors in the process can be expected
to impact the quality of the final product.
The basis of QBD is to make sure the level of knowledge regarding product and how product quality varies with changes in raw
materials or variability in process conditions ensures that the process is fully capable of producing a product that meets
Pikal: Nearly all lyophilised products must be sterile, which imposes a critical quality attribute that is not relevant to oral
products. Also, while stability is often an issue with oral products, it is nearly always an issue with a lyophilised product;
otherwise, why lyophilise? In addition, Design of Experiments (DOE) is often a critical part of QbD. Although QbD can be useful
for the design of formulations and processes for lyophilised products, it is not useful in the design of the primary drying
stage of lyophilisation. This is a result of the fact that the physics of primary drying are well understood. Designing processes
based on physics is better and more efficient than designing them based on statistics.
Michael J. Pikal (University of Connecticut)
Q. What key factors must be considered when determining design space?
Gieseler: Design space should be defined for both 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. 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.
Recent studies have suggested that determination of the primary drying design space alone seems insufficient to draw a representative
picture of product behaviour 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
then that the originally defined process design space might not perfectly match the process design space in manufacturing.
Mayeresse: 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