Some Practical Aspects - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 123

overseals after stoppering), are carried out manually. When moving to a
larger scale, many of these operations are carried out automatically, and
this leads to further engineering considerations, e.g. the partial insertion
of 50,000 stoppers.
In the pharmaceutical industry, the objective of the formulation scien-
tist will typically be the manufacture of the three ICH stability test lots, as
required for a regulatory filing. The rules of the ICH (International
Conference on Harmonisation of Technical Requirements for Registra-
tion of Pharmaceuticals for Human Use) are shown in Table 1. Essentially
they require the manufacture of three batches at a scale representative of
the intended commercial scale, which are then subject to formal stability
and quality trials, typically for a period of 12 months. With other dosage
forms (e.g. oral tablets), this is usually taken as 10% of the proposed
commercial production scale, but the interpretation for lyophilised prod-
uct, e.g. intravenous parenterals, is not so clear, especially as the volume
of water to be removed may impact upon the performance of the drying
equipment. For example, would filling only one shelf of a 10-shelf drier be
representative of the heat and mass transfer characteristics of a fully
loaded drier? A more conservative approach is therefore taken, and in
many cases commercial-scale lots are prepared for ICH stability trials.
Apart from the inevitable delay that an ICH failure would introduce to
the filing date, there is also a very real direct cost. Three ICH lots of a
sterile product, carried out at a contract-manufacturing site, could easily
run to $2 million. A full programme for scale-up and ICH manufacture of
a sterile parenteral product could then easily amount to $4-6 million.
Table 1 contains a typical list of operations that need to be carried out in
order to complete such a programme.
10.2 Economics
Several economic analyses of freeze-drying are on record (e.g. Millman
et al. 122 ). They do, however, consider the process, as applied by the food
industry. The conclusion is that the operation regime with the shortest
drying cycle also gives the lowest production cost and the highest
capacity. The recommendation has therefore been for large volumes.
In view of the nature of the products and their robustness to the drying
stresses, this seems a sensible strategy.
In pharmaceutical freeze-drying, on the other hand, importance is
placed not on mass, but on activity/unit mass, and the parameters that
govern survival of some biological activity in small volumes are totally
different and more subtle than they are for a simple dewatering process.