Mayeresse (GSK): Lyohilization has evolved a lot during the past 20 years. Years ago, lyophilization development mainly relied on the skills
of scientists who learned by a trial and error process. Today, analytical tools exist to assist the development of the freeze-drying
process. For instance, apparatus such as a cryomicroscope enable the determination of the glass transition temperature, which
is used to set up the temperature and pressure during the primary drying phase of a freeze-drying cycle. For a QbD approach,
it is quite easy to define at which step each tool will apply and what will its output will be on the process.
Yves Mayeresse (GSK Biologicals)
Nail (Baxter): At Baxter, the QbD approach to freeze-dry cycle development and optimization relies heavily on a process analytical technology
called tunable diode laser absorption spectroscopy (TDLAS). This is a near-infrared technology that measures the instantaneous
mass flow rate of water vapor from the chamber of the freeze-dryer to the condenser. We also use fairly standard methods for
characterizing the formulation, such as low temperature thermal analysis and freeze-dry microscopy, to determine the upper
product temperature limit during primary drying. We use a graphical approach to the design space that incorporates limitations
placed on the process that are based on both the characteristics of the product and the capability of the freeze-drying equipment.
TDLAS facilitates measurement of the vial heat transfer coefficient as a function of the pressure, measurement of the resistance
of the dried product layer to flow of water vapor, and the maximum sublimation rate supported by the equipment as a function
of pressure. All of these are needed to construct the design space.
Manfred Steiner (GEA Lyophil GmbH)
Page/Steiner (GEA): 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 behavior 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.
Steven Nail (Baxter Pharmaceutical Solutions)
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 (University of Connecticut): Nearly all lyophilized 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 lyophilized product;
otherwise, why lyophilize? 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 lyophilized products, it is not useful in the design of the primary drying
stage of lyophilization. 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.
Is lyophilization technology advancing fast enough to meet demands from manufacturers of increasingly sensitive biopharmaceutical