PharmTech: What are the key challenges and potential factors to consider when planning to scale up a lyophilization process?
Gieseler (University of ErlangenNuremberg): Examples of challenges include differences in environmental factors (e.g., non-cGMP versus sterile environment) and the different freezing behavior of the product solution in manufacturing. Other challenges are differences
in equipment design and performance, such as emissivity of the surfaces, condenser performance, shelf cooling/control performance,
vacuum control capabilities and choked-flow conditions, and a lack of appropriate tools to monitor the freeze-drying cycle.
However, the above-mentioned challenges can be overcome if operational qualification testing is performed on pilot–production
equipment during a factory test or installation at the customer site. Performance testing can be conducted using a predefined
freeze-dryer load (i.e., water or excipient solution) at various shelf temperature and pressureovertime profiles.
Mayeresse (GSK Biologicals): During the early development of a new product, the final facility is not necessarily defined and a product may also be transferred
to another factory or CMO. For good scale up, it's important to know the final freeze dryers in which the product will be
lyophilized. However, as this is not always possible, the best method is to define a design space that is large enough to
transfer towards in the worst-case scenario, such as an in-house industrial freeze-dryer.
Nail (Baxter Pharmaceutical Solutions): Perhaps the biggest mistake development scientists make when developing freeze-drying cycle conditions is to conduct trial
cycles using too few vials, in which most, or all, of the vials are in the "edge effect," where vials close to the edge dry
at a faster rate than vials in the center of the array. We always use at least one full shelf of product for trial cycles.
If there is not enough drug available for this, we use placebo for most of the vials, and put the vials containing active
in the center of the vial array.
In addition to this, we consider differences in equipment capability between laboratory- and production-scale equipment, such
as lowest attainable shelf temperature, fastest attainable shelf temperature, ramp rate under load, lowest attainable vacuum,
and so forth.
Page/Steiner (GEA Pharma Systems): Science and risk management must form the basis of the scale-up process. The impact of changes in heat and mass transfer with
scale and equipment design can be measured and predicted by applying basic process engineering techniques. If the process
equipment is not properly characterized and understood, then scale-up will be a trial and error process. Where the equipment
has been properly characterized, however, there is no reason why the scale effects should not be reasonably estimated and
Pikal (University of Connecticut): There are differences in heat and mass transfer that may constitute scale-up problems. These issues need to be addressed by
doing operational qualification testing under conditions of defined thermal and masstransfer load, perhaps using TDLAS, so
that the capabilities of each dryer are known. Thus, a process can be designed with this constraint in mind. However, the
major scale-up issue is the bias in ice nucleation temperature between freezing in a standard laboratory or pilot laboratory,
and that characteristic of the Class 100 environment of a production facility. An easy way to circumvent this issue is to
use controlled ice nucleation. In fact, even with the extensive knowledge we have now, good freeze-drying practice must include
controlled ice nucleation.
PharmTech: What recent advances are being made in heat and mass transfer theory? How might breakthroughs in this area be applied to more
effective scale-up using a QbD approach?
Mayeresse (GSK Biologicals): There are several good mathematical models that can be used, and some have been applied to freeze dryers to facilitate cycle
development. One of the benefits of mathematical models is that they can support the thinking behind the physical aspect of
the freeze-drying process. These models are a simplification of the reality and allow for better understanding of the underlying
rules. In the future, more specific models based on other mathematical theories may arise that will offer more accurate insight
into process development. Such models will surely improve the scale-up process in freeze drying.
Nail (Baxter Pharmaceutical Solutions): I don't think any real advances are being made in heat and mass transfer theory, because both disciplines are already very
mature, but there are advances being made in application of this theory to freeze drying. In particular, the industry has
realized the relative importance of thermal radiation as a heattransfer mechanism. This understanding could result in changes
in equipment design and construction that take better advantage of thermal radiation, resulting in a more efficient process.
Pikal (University of Connecticut): I would maintain that the physics of heat and mass transfer, which is quite relevant to the design and control of primary
drying, is relatively well understood. There may well be advances in applications, including using heat and mass transfer
theory to assess in a quantitative fashion the impact of natural variation in key freeze-drying parameters (i.e., heat transfer
coefficient, ice nucleation temperature, fill volume, and shelf temperature variation) on product quality (i.e., thermal history,
collapse, and degradation). Indeed, some efforts in this area have started. Use of theory in scale-up is also underutilized,
and application guidelines are needed.