There are no two completely identical units in operation anywhere. Even if the difference is only in the version of the operating
software, we are always dealing with a unique piece of equipment. Lyophilisers are also one of the few equipment items that
are constantly undergoing continuous, and often significant, design changes as manufacturers respond to the evolving needs
of customers. In general, there is a global shortage of freeze-drying capacity, which has led to many companies outsourcing
this activity. It is not unusual for small-scale production (development to clinical phase II) to be performed at one contract
manufacturer, while large-scale (clinical phase III and commercial product) manufacture takes place at another.
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One of the principal issues facing manufacturers is the significant differences that often occur in lyophilisation equipment
performance and operation at the development and production stages. Because of this, it is difficult to develop models for
process controls linking critical quality attributes with critical process parameter that scale easily, or that can be transposed
from one site to another. Quality by Design (QbD) is an initiative that is gaining much attention in the industry. However,
so far there isn't much proof of concept for QbD in freeze drying. In the pharmaceutical industry, there have been several
QbD submissions, but lyophilisation predominantly applies to biological products and by the end of 2011 there had been no
submissions that included a design space for biological compounds, according to a personal communication I had with the FDA's
Lucinda Buhse in March 2012
The fact that freeze drying is mostly used for biological products also creates further challenges. Biologics tend to cost
more and there are usually limited amounts of product available. Experiments with the freeze-drying process tend only to be
used in early development, and even then they are performed on small scales. One key parameter that must be known is the eutectic
point of the formulation, so that the melting point of the frozen product is known. Without this information, the manufacturer
will not know when melt back could occur and develop a cycle that has enough safety margin to prevent melt back from occurring.
Siegfried Schmitt is Principal Consultant at PAREXEL.