evolution freeze drying
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evolution freeze drying

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Ingredients, Formulation & Finishing
In ancient Egypt, the culture of mummification as the
key to immortality was developed to a high level. The
whole process of quickly removing the organs and
embalming a body could take weeks \u2013 but the result was
that the remains of the deceased were almost completely
deprived of humidity. The final encapsulation of the
mummy in resin provided a perfect isolation against
rehydration. As well as this culture of mummification
that has been practiced all around the world, natural
mummies have also been found. Some were conserved
thanks to the removal and absence of water, others to
the complete absence of oxygen \u2013 both of which are
necessary for the natural reduction process to develop.
The removal of water for conservation purposes has been
extensively developed for the preservation of food. The
Inuit use the cold dry atmosphere to dry fish and then seal
it for use during their long hikes; the Sami people of
northern Europe are also known to use this conservation
method. Even today, the native people of the high Andes
dry their potatoes using the low temperatures of the night
and the low humidity of the day.
The essence of these examples is that the removal of water
is the key to reducing material degradation, leading to a
prolonged shelf life. There are a couple of ways that water
removal can be achieved. Water can be removed with
chemicals, such as those the Egyptians used during
mummification, or by supplying heat (boiling out) \u2013 but
the best way to remove water without harm to the structure
is freeze-drying. Reconstitution by adding water results in a
product with the same functionality as before, whereas with
other dehydration methods this is not the case.
The freeze-drying process (to the primary drying stage) is
illustrated in Figure 1. The essence of the process is the
removal of water while keeping the chemical and physical
structures of the material intact; therefore, the first step is
to stabilise the structure of the material by freezing. This
freezing is a complicated step where ice crystals are grown
intertwined with crystalline or amorphous components of
the active product and excipients. The composition of the
material determines the freezing curve, and even
annealing steps are introduced to generate favourable
crystal structures.
The second step is to introduce a vacuum until the state is
below the triple point of water. In this state, the water can
convert from ice to vapour without melting, which would
destroy the physical structure that is to be achieved. In the
vicinity of the frozen product is located an ice-condenser \u2013
a structure of metal pipes, cooled to temperatures well below
that of the frozen product. Therefore the partial water-
vapour pressure near the condenser is significantly lower
than near the frozen product, and this leads to transport of
water to the condenser, followed by condensation.
For this sublimation process (primary drying) to continue,
it is necessary to supply energy to the sublimation front to
compensate for the latent heat of evaporation. This energy
is commonly supplied by heat, and the shelves on which
the vials of pharmaceutical product are standing are
brought to higher temperatures. In all cases, however, care
has to be taken that all the product contained in the vial
stays in a frozen state, and even glass transition
temperatures or eutectic temperatures have to be respected.
Collapse of the product would lead to rejection. 
Once the crystalline water has sublimed, the product is
usually not sufficiently dried. The remains of absorbed or
interstitial water lead to moisture concentrations of above
five per cent, which is usually too high for adequate
Advances in freeze-drying have evolved on a gradual basis, rather than by step-
changes; for the future, macro-trends such as global warming and personalised
medicine will drive further advances in the pharmaceutical sector.
66 Innovations in Pharmaceutical Technology
By Jos Corver 
at IMA Edwards
The Evolution of Freeze-Drying
Triple point
The product is first cooled down until freezing starts. After further
cooling down, the pressure is reduced until below the triple point
of water. The supply of heat results in vaporisation of the ice. 
This vapour is removed by a device with the surface held at a very
low temperature where the vapour condenses: the ice-condenser.
Figure 1: Phase diagram of water with reference to freeze-drying 
Temperature (°C)
-100 -80 -60 -40 -20 0 20 40 80 100
IPT 29 2009 11/6/09 10:18 Page 66
prolonged shelf life. Therefore, an additional drying step
(secondary drying) is performed where the temperature of
the product is further increased. Since the free water is
already sublimed, this can be done safely provided that
the maximum allowable temperature for the product is
not reached. 
A methodical approach to freeze-drying was first
published by Altmann in 1890 for the preparation of
biological tissues for research (1). After several variations
of creating a vacuum or lowering water vapour
concentrations, it was Shackell who used an electrically
driven electrical pump for establishing the vacuum (2).
Tival (1927) and later Elser (1934) patented systems for
freeze-drying, and established improvements on the
freezing and condenser concepts.
The industrial importance of freeze-drying became
apparent in World War II, when large quantities of
blood plasma and penicillin were needed in the field. In
the 1950s and 60s, there was much optimism for the
broad use of freeze-drying for pharmaceutical and food
purposes. But since, with freeze-drying, process times
are long and energy efficiency is low, the food industry
adopted different methods such as spray drying. This
method is suitable for production in bulk \u2013 but for
pharmaceutical applications, this approach is not
suitable because, on the one hand, the spraying results in
relatively high shear stresses, and on the other, the 
small and accurate dosages required per vial are difficult
to achieve with powder filling. Therefore, for
pharmaceutical purposes, freeze-drying takes place in
containers fitted with accurate fluid filling systems.
Over the years, freeze-drying has evolved in a number 
of ways:
\ufffd The first steps involved optimisation of the 
process in terms of refrigeration systems,
components and control
\ufffd The demands of drug regulatory authorities
subsequently prompted a drive for predictive process
operation. This meant more reliable equipment,
support for aseptic processing and process validation
\ufffd Increased requirements for aseptic conditions 
in the surrounding area led to the development 
of automated loading systems that minimised
human intervention
\ufffd Most recently, launch of the FDA\u2019s Process
Analytical Technology (PAT) initiative has 
driven the development of process measurement
equipment that may also lead to optimisation 
of production yield
Trying to predict future developments in freeze-drying
represents a major challenge; it might thus be useful to
first make a little excursion into the semicon industry.
In the semicon industry, developments can be identified
with roadmaps. The so-called Moore\u2019s law plays an
important role since it points out the key element of
industrial achievement: either pursue the miniaturisation
of patterns or increase the number of active elements per
unit area. Moore\u2019s law was established by retrospective
analysis of the growth of the microelectronics industry.
After publication of this relationship, the industry
adopted it as a roadmap standard and, until