ESTABLISHING BOUNDARIES OF THE DESIGN SPACE
Identify Product Failure Modes
Probably the most common approach to development of a freeze-dry cycle for a given product is to identify, through trial and
error, a set of process conditions (shelf temperature profile, chamber pressures, and time) that produce a pharmaceutically
acceptable product. Typically, upper and lower limits are placed around these temperatures, pressures, and times; the process
is validated and is thus frozen in terms of the inability to make improvements to the process without prior FDA approval.
In the Quality by Design approach, the development scientist must gain a superior understanding of a larger map of process
conditions that produce an acceptable product. This understanding requires preparing trial batches under increasingly aggressive
conditions until the product is unacceptable. Most commonly, the product will fail because of collapse. Collapse is characteristic
of predominantly amorphous formulations where the upper limit of product temperature (the collapse temperature) is exceeded
during primary drying (removal of water by direct sublimation of ice). As the sublimation front recedes, the partially dried
solids undergo viscous flow, resulting in the loss of the microstructure that was established by freezing. The collapsed material
is characterized by a pharmaceutically unacceptable appearance, high residual water content, and poor reconstitution characteristics.
For predominantly crystalline formulations, the upper product temperature limit during primary drying is the eutectic melting
temperature. A eutectic mixture is an intimate physical mixture of two or more crystalline solids that has a sharp melting
point. Exceeding this melting point during primary drying causes puffing of the vial contents and loss of pharmaceutical acceptability.
At least one other product-related failure mode is less common than the two mentioned above. For some formulations having
a relatively low concentration of total dissolved solids, and particularly for formulations that use a co-solvent system consisting
of water and an organic solvent (most commonly t-butanol), solids may be ejected from the vial. This is, of course, unacceptable
because of the risk of subpotent product as well as the possibility of compromising the container or closure integrity by
the presence of product between the sealing surfaces of the vial and rubber closure.
Identify Product-Imposed Boundary on the Design Space
The upper product temperature limit during primary drying should be determined during characterization of formulations intended
for freeze-drying, using low temperature thermal analysis, freeze-dry microscopy, or both. As an example, suppose that characterization
of the formulation shows an upper product temperature limit during primary drying of –25 °C. This upper temperature limit
is shown by the broken blue line in Figure 1, and it represents the boundary of the design space imposed by the characteristics
of the formulation.
For a failure mode involving ejection of solids from vials, the product-imposed boundary on the design space would be a horizontal
line corresponding to the sublimation rate above which significant solids ejection takes place.
Identify Equipment-Imposed Boundaries on the Design Space
In the current culture of increased reliance on third-party organizations for formulation development, manufacture of clinical
supplies, and manufacture of commercial product, it is essential to understand the limitations of the performance of laboratory-scale,
pilot-scale, and production-scale freeze-drying equipment. To illustrate the potential pitfalls associated with multi-organizational
and multi-site product development, consider the following scenario:
A small biotech company enters a joint venture with a large pharmaceutical company. Development scientists in the small biotech
company characterize their formulation and determine that it will withstand very aggressive cycle conditions. They develop
a freeze-dry cycle accordingly, using laboratory-scale equipment. The development scientists do not take into account the
potential performance limitations of equipment at a separate company contracted to manufacture clinical supplies. The first
clinical supply lot is manufactured using the cycle developed at the small biotech company, and the batch is rejected because
of a failed freeze-dry cycle, resulting in a significant delay in the project.
This scenario is all-too-common. It illustrates the necessity of knowing the capability of equipment at the site where a product
will be manufactured, and the need to take into account equipment limitations during initial cycle development.
Equipment limitations can take many forms. For example, the condenser has a limit as to the flow rate of water vapor that
can be condensed while keeping the surface temperature of the condenser adequately low. This condition may occur because of
limitations in refrigeration capacity at the condenser, because of limited surface area of the condenser, or perhaps because
restrictions in water vapor flow around the condenser make some surfaces relatively inaccessible for condensation.