Q. What types of unique approaches and product knowledge are required when using a QbD approach?
Bearing these critical temperatures in mind, freeze-drying demands reliable and representative control of the product temperatures at the ice sublimation interface during primary drying to obtain a high-quality product. Many commercially available PAT tools (e.g., manometric temperature measurement, TDLAS and others) help during the developmental stage to determine product interface temperatures, but such tools can often not be used in a production environment. As a result, the biggest obstacle and challenge for the future when establishing a reliable QbD concept for freeze drying is to determine (relevant) critical product and process parameters that are also scaleable.
Mayeresse: Lyohilisation has evolved a lot during the last twenty years. Years ago, lyophilisation 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.
Today, the development of a new process is more systematic, which gives developers more time to concentrate on the product's specificity.
Nail: At Baxter, the QbD approach to freeze dry cycle development and optimisation 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 vapour from the chamber of the freeze-dryer to the condenser. We also use fairly standard methods for characterising 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 vapour, and the maximum sublimation rate supported by the equipment as a function of pressure. All of these are needed to construct the design space.