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 – 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 – 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) – 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.
FREEZE-DRYING
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 –
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
Melting
Freezing
Liquid
Evaporation
Triple point
Vapour
Sublimation
Solid
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 
W
at
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 v
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pr
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 (
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Temperature (°C)
-100 -80 -60 -40 -20 0 20 40 80 100
103
102
101
100
10-1
10-2
10-3
10-4
10-5
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. 
INDUSTRIAL DEVELOPMENT
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 – 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:
� The first steps involved optimisation of the 
process in terms of refrigeration systems,
components and control
� 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
� Increased requirements for aseptic conditions 
in the surrounding area led to the development 
of automated loading systems that minimised
human intervention
� Most recently, launch of the FDA’s Process
Analytical Technology (PAT) initiative has 
driven the development of process measurement
equipment that may also lead to optimisation 
of production yield
PREDICTING THE FUTURE
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’s 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’s 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, untilnow, the
industry seems to have lived up to it. The conceptual flaw
here is that we will never know how progress would have
been without this approach.
It is not easy to identify a similar approach for the
pharmaceutical industry – seeks to show the evolutionary
steps (see Figure 2). Whereas Moore used the number of
switch elements per unit area, we try a formula that
maximises the output per unit time related to the required
quality. An increase in the efficiency of the process can be
noticed here; this efficiency metric incorporates the
amount of resulting dry matter divided by the established
moisture level and the amount of process time. Note that
although automated loading systems are not maximising
the freeze-drying output, they do enable an increase in the
scale of operation in a GMP-acceptable manner.
If we look at the indicative points from 2000 onwards,
there are two elements that need some elaboration: PAT
tools and new freeze-drying methods (continuous freeze-
drying). Both elements represent a model for a family of
possibilities. PAT is a driver for better understanding of
pharmaceutical production processes. The flow of activities
under PAT is first to use scientific methods to understand
all steps and system elements from base materials until
effective disease treatment. With this knowledge the critical
parameters can be identified, and engineering can focus on
improvement of the control mechanisms to keep the values
67Innovations in Pharmaceutical Technology
Figure 2: Evolutionary steps in freeze-drying
Shackell Stokes
Edwards
Auto loaders
PAT tools
Continuous
Dr
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 e
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1900 1950 2000 2050
3.5
3
2.5
2
1.5
1
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Year
IPT 29 2009 11/6/09 10:18 Page 67
within a specified band. This control can only take place
when the appropriate measurement systems are applied;
this explains why the PAT initiative led to an intensified
development of measurement systems. 
An example of this is an optical method to determine the
rate of water vapour transport in the connecting tube
between chamber and condenser (Lyoflux®, see Figure 3).
Essentially, in an industrial freeze-dryer, the ‘process’ is the
transport of water vapour from the product to the
condenser where the vapour condenses to ice again. With
the Lyoflux® system, the near-infrared light beam crosses the
tube and the detector on the other side measures the
absorption, which is linearly dependent upon the
concentration of water vapour. As the beam is oblique to the
vapour flow, the absorption spectrum is shifted due to the
Doppler effect (see Figure 4). This information, combined
with the dimensions of the tube, results in the continuous
measurement of vapour flow. And this, in turn, forms a
continuous monitor of the state of the freeze-drying process.
The application opens the window to related possibilities
such as end-point detection of primary and secondary
drying, product temperature and parametric scale up.
Eventually, this will lead to a more efficient process with
more output per unit time and of the right quality.
Alternative methods are available to establish information
on the state of the freeze-drying process. One of the
founding fathers of the manometric temperature
measurement (MTM) application was Professor Michael
Pikal (3). By determining the pressure rise behaviour of
the vapour in the chamber, characteristic information on
product temperature can be determined using
thermodynamic balance equations. The downside to this
method is that it requires a temporary closure of the valve
between the chamber and condenser, thereby
fundamentally influencing the freeze-drying process.
Both methods – Lyoflux® and MTM – rely on measuring
the product temperature with respect to the heat transfer
characteristics of the various media. And this requires
adequate calibration, which may be complicated.
Equipment also exists to determine the moisture level in
the chamber in a continuous manner; this may be used to
determine the endpoint of primary drying, but it does not
provide adequate information on the instantaneous status
of the process, since during a large portion of the primary
drying (sublimation) phase, the humidity is close to 100
per cent without a lot of variation.
The most direct way to measure the temperature of a
product during freeze-drying is with thermocouples or
resistive methods. Non-contact, infrared measurements
cannot be used due to the glass being opaque for this
wavelength. A temperature mapping method using
thermo-elements is commonly used during engineering
and validation, but not in routine production operations.
GMP requirements dictate minimal human intervention,
and the placing of the sensors represents such an
intervention. Wireless measurement systems are therefore
under development.
THE FUTURE
Looking at current macroscopic trends, global warming is
forcing the industry of the developed world to devote more
attention to energy-efficient production. Freeze-drying, as
practiced nowadays, is extremely inefficient in terms of
energy use. Another trend in the pharmaceutical industry is
the need for flexibility and reduction of batch sizes. 
Looking first at the energy aspects, Figure 5 (see page 70)
shows the energy consumption of a range of five freeze
dryers. (The numbers 1, 10, 20, 30 and 40 refer to the
effective area of the shelves.) The theoretical required
energy (Process) for temperature changes and phase
transitions is compared with the electromechanical
properties of the components (process and equipment).
The graph illustrates how energy is wasted during freeze-
drying; it also shows that larger freeze dryers are more
efficient than small ones. The latent heat dissipation and
absorption is achieved in a very inefficient way. Also, the
68 Innovations in Pharmaceutical Technology
Figure 3: The practical implementation of Lyoflux®
Figure 4: Doppler shift of absorption spectrum. A laser beam is obliquely fed
through the channel between the chamber and ice-condenser. The absorption
spectrum is then shifted due to the Doppler effect
Diagnostic duct assembled in IMA
Edwards Miniast® freeze-dryer
Fibre-optic
cable from
laser
Detector
Frequency shift
D
Relative frequency (cm-1)
q
Laser
Detector
Vapour flow
1.2
1.0
0.8
0.6
0.4
0.2
0
N
or
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 a
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-0.4 -0.2 0 0.2 0.4
IPT 29 2009 11/6/09 10:18 Page 68
sub-optimal use of compressors is a big contributor to the
waste. Scenarios are being developed to link heat sources
and sinks in a more efficient way.
Advances in freeze-drying rarely occur in step-changes –
hence, use of the word ‘evolution’ for the title of this
article. Another example of evolutionary improvement is
the novel design of hollow shelves flushed with diathermal
fluid to provide the source or sink of heat for the product
to be treated. Instead of welding the top and bottom plate
together with bars forming the channels, as widely
practiced previously, the new design is based upon a well-
engineered vacuum brazing process. This results in a
significantly reduced amount of stainless steel and a
reduced volume for the diathermal fluid, and so the energy
needed to achieve the required temperatures is reduced.
An additional advantage is an improvement in the thermal
homogeneity and mechanical strength of the shelves.
A schematic outline of the brazed shelf system is shown in
Figure 6. Note also the specific improvement in the
bottom of the shelves (the PLUS option), designed to
provide an uninterrupted release of rubber stoppers
during automated stoppering. The rubber stoppers will
no longer stick to the bottom of the shelves after the
automated stoppering process – increasing the yield of the
batch and therefore the efficiency of the process.Personalised medicine can be seen as having significant
implications for the pharmaceutical industry, whereby there
will be a growing need for flexibility (fewer ‘blockbuster’
products) and the size of the batches will decrease. It is not
yet clear where this trend will lead. One possibility would be
smaller but more numerous freeze-dryers, and consequently
more flexible loading systems. Conceptual thinking might
also lead to continuous solutions, but the ramifications of
this for the pharmaceutical industry are still unclear.
CONCLUSION
Although the use of pharmaceutical freeze-drying is
relatively young, the process has been in practical
existence for ages. The development of pharmaceutical
freeze-drying has been slow, and has proceeded in an
evolutionary manner. For the future, macro-trends such
as ‘global warming’ and ‘personalised medicine’ are likely
to have a significant impact on freeze-drying within the
context of the pharmaceutical industry.
Acknowledgement
The author wishes to thank Alexander Schaepman and Frank
De Marco for their contributions on Lyoflux® and the energy
aspects of freeze-drying. ‘Edwards’ is a registered trademark
of Edwards Ltd and is used by IMA Group under licence.
References
1. Altmann R, Die Elementarenorganismen Und 
Ihre Bezeihungen Zu Den Zellen, Veit, Leipzig,
Germany, 1890
2. Shackell LF, Am J Physiol xxiv, 325, 1909
3. Tang Xiaolin, Nail Steven L and Pikal Michael J,
Evaluation of manometric temperature measurement, 
a process analytical technology tool for freeze-drying:
Part I, product temperature measurement, AAPS
PharmSciTech Vol 7, No 1, March 2006
70 Innovations in Pharmaceutical Technology
Jos Corver has a background in Aero- and Hydro-dynamics and
Applied Physics; he graduated from Delft University of Technology
(Delft, Netherlands) in 1981. After a research project at Eindhoven
University of Technology (Eindhoven, Netherlands) on early
detection of atherosclerosis, he joined Océ Technologies (Venlo,
Netherlands), where he developed new colour printing processes,
managed the industrialisation of a novel photoconductor and was
eventually responsible for the engineering and release of wide format printers. He
joined IMA Edwards in 1999 to develop new products related to primary packaging
with a focus on freeze-drying, filling processes and loading systems. He acquired
patents on measurement systems and some improvement on freeze-dryers. 
Email: jos.corver@imaedwards.com
Process and equipment
Process
Efficiency
Figure 5: Energy consumption of freeze-drying and freeze-dryers
Figure 6: Improved shelf design
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