Some Practical Aspects - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 122

CHAPTER 10
Some Practical Aspects
10.1 Scale-Up and ICH Manufacture
The removal of 99 þ % of water, at subfreezing temperatures, from the
solution of a product that is potentially chemically and mechanically
labile is a complex, stressful and costly operation. Once the physico-
chemical parameters (e.g. T g and residual water content) have been
established, the process optimisation is governed by the coupled heat
and mass transfer rates, the operating scale and the particular equip-
ment available. For small-scale formulation and process development,
engineering considerations are rarely of consequence. As the operating
scale and the associated level of automation (e.g. filling and stoppering)
increase, these factors will become of ever-increasing importance.
The ultimate aim in the development of every freeze-dried product is
full-scale manufacture, in line with market requirements. For many
products, this can be in the range of 50,000-100,000 vials per batch. At
this scale, many of the operations are automated, and consideration
must be given to the practicalities of working at this scale. Also, as a
product approaches the time when it will be administered to animals
and, eventually, humans, health and safety factors enter the equation.
The demands of the regulatory authorities will then have to be met.
During the initial development of a freeze-dried product, it is quite
typical to work on a laboratory scale with batch sizes of about 200 vials.
Before committing to full-scale manufacture, process refinement and the
production of sufficient samples for informal stability trials are carried
out at an intermediate scale; it is simply a balance of sufficient produc-
tion capacity, the cost in time and materials cost of ''failed'' batches.
Pilot-scale refinement is conveniently carried in a drier of approximately
1m 2 shelf area, equivalent to ca. 1200-1500 vials per batch. At this scale
most ancillary operations, filling, capping (the application of aluminium
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