PharmTech: What types of unique approaches and product knowledge are required when using a QbD approach for lyophilization?
Gieseler (University of Erlangen-Nuremberg):
We need to find a more profound translation for experiments conducted in different scales of equipment. Successful freeze
drying requires a sound understanding of both product and process related attributes, as well as the corresponding analytical
tools used during product and process development to representatively measure them. When we look at the desired final quality
characteristics of a freeze-dried product, the term 'quality' is, in the first instance, unrelated to the stability of an
API, but targets other characteristics, such as cake elegancy, reconstitution time, moisture content and other parameters.
A vial with a collapsed cake is routinely rejected from the batch during optical inspection, even though API stability may
be perfectly acceptable from a pharmaceutical point of view. Optical inspection is one of the first tests to be performed
on a freeze-dried product, not API stability.
(IMAGE: DIAMOND SKY IMAGES/DIGITAL VISION/GETTY IMAGES)
The connecting link between 'quality attributes' and 'product/process attributes' is often grounded in the physicochemical
behavior of the formulation, which is a function of temperature and time. Physicochemical properties, such as the critical
formulation temperature (the glass transition temperature of the freeze concentrated solute [Tg'] for amorphous products or
the eutectic temperature [Teu] for crystalline materials) are important parameters that must be determined prior to cycle
development. Then, the goal is to control product temperature at the ice sublimation interface below this critical temperature
during the cycle to avoid elevated mobility in the system and morphological changes, such as shrinkage, collapse and melt.
In industry, differential scanning calorimetry (DSC) has been used for decades to assess the thermal fingerprint of a material.
DSC is a powerful tool, but not perfectly representative for the real freeze-drying situation of a product. A more representative
procedure is the determination of the collapse temperature (Tc) by freeze-dry microscopy (FDM). The technical set-up of an
FDM experiment is currently the best way to simulate freeze-drying in microscale, but still presents obstacles in data interpretation.
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 often cannot 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 (GSK Biologicals):
Lyophilization has evolved a lot during the past 20 years. Years ago, lyophilization development mainly relied on the skills
of scientists who learned through trial-and-error. 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
Nail (Baxter Pharmaceutical Solutions):
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.
Page/Steiner (GEA Pharma Systems):
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, can determine which factors in the process may impact
the final-product quality.
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.