Historical Background - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 5

2000 units of human blood plasma. With the help of several US
companies, a peak production of 100,000 units per week was eventually
achieved. At about the same time, R.I.N. Greaves, working at the
University of Cambridge, began the development of more advanced
equipment, which was later employed in the first commercial production
of antibiotics. During the 1950s, freeze-drying began to be routinely
used by the food and drug industries. The rapid development of the
technology can best be judged by the number of publications in the field,
which grew from 10 in pre-1930, to 350 over the period 1930-1945.
When freeze-drying first became an important process technology in the
pharmaceutical industry, the number of publications began to climb
rapidly, reaching ca. 600 in the year 2000. The first patent was issued in
1934, and the number of US-granted patents during the period 1945-
2003 exceeds 400; although references to freeze-drying, as a manufac-
turing process, feature in many more food and pharmaceutical patents,
although not always as the inventive step.
It is interesting to chart the importance attached to the various aspects
of the technology at different periods. Thus, during the 1970s, emphasis
was placed on modelling the process in terms of heat transfer through
frozen layers, and the problems of ''collapse'' received intensive study.
During the following decade, emphasis shifted to the development of
electronic devices to control the process. Investigations also commenced
on additives and ''bound water''. The freeze-drying of blood derivatives
(oxyhaemoglobin, albumin and clotting factors) became of commercial
importance. The decade also witnessed the publication of numerous
studies by M.J. Pikal (sometimes referred to, and rightly so, as ''the king
of freeze-drying''), dealing with more advanced and realistic models of
heat and mass transfer. A particular strength of Pikal's contributions
derives from his often-expressed philosophy that experimental tests need
to be applied to validate all theoretical results. During the 1990s, several
reports appeared analysing the economics of large-scale batch freeze-
drying. This is a subject to which we shall return later. Product formu-
lation issues also received attention, and the significance of amorphous
states vis-a` -vis crystalline states began to dawn on the pharmaceutical
industry, especially when related to biopharmaceutical products that
cannot be crystallised. At the same time, regulatory hurdles became of
importance, reining back the more adventurous product developers.
Although freeze-drying of foods had declined during the second half of
the 20th century, the appearance of probiotics and other ''nutroceutical''
products regenerated interest in the freeze-drying of bacterial cultures,
particularly lactic acid bacteria, where it soon became apparent that
isolated molecules are easier to stabilise against deterioration than living