The Process Sequence in Summary - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 15

The vacuum system must be able to maintain the chamber pressure at
below the saturation vapour pressure (SVP) of ice at the chosen process
temperature. Although it is not universally recognised, freeze-drying can
also be performed without the need of a vacuum system. The ''laundry
model'' in which, even on the coldest of days, frozen laundry on a
washing line can be air dried, albeit at a low rate, has been cited as an
example.
A condenser system, fitted with its own compressor and heat exchange
system, serves to remove the water vapour liberated by the subliming ice
from the chamber. The system must be able to operate efficiently well
below the chosen sublimation temperature and up to high temperatures,
so that the accumulated ice can be efficiently removed. It must also be of
a capacity sufficient to prevent redeposition of water onto the surface of
the drying product.
Modern equipment will also contain computer-based control and
monitoring systems by means of which a desired drying cycle pro-
gramme can be preset. Finally, for pharmaceutical applications, it is
essential to prevent cross-contamination between consecutive batches. A
''clean-in-place'' (CIP) system and a ''sterilise-in-place'' system are
therefore provided by means of which the chamber can be cleaned
between successive production cycles.
The whole process can thus be divided into five distinct stages:
(i) The solution, suitably formulated,

is frozen on refrigerated

shelves.
(ii) The chamber pressure is reduced to the desired value (not nec-
essarily the lowest value that can be achieved) and ice is sublimed
by the supply of heat to the product, and the water vapour
is removed from the chamber and condensed as ice (primary
drying).
(iii) The remaining unfrozen water trapped in the product is removed
by further warming at a controlled rate (secondary drying).
(iv) The containers are sealed and removed from the drier.
(v) The condenser is heated to melt and remove the collected ice.

Once formulation and container details have been decided, the entire
process cycle can essentially be controlled by only three parameters -
temperature, pressure and time. It is important to remember also that
freeze-drying in practice is always a compromise between competing
demands and often leads to variable or unpredictable results. The
standard industry view used to be, and still is in some quarters, that
acceptable freeze-drying conditions can only be determined by trial and