Lyophilisation 1

Is it an Intelligent Decision to Import the Lyophilisers ?
Lyophilisation is a process in which liquid material is slowly frozen in a vacuum, thereby

removing water by maintaining the water vapour pressure. This technology appears to
be very simple, but when the techniques are practiced and developed, the processes
are deceptively complex, therefore, lyophilisation is treated as an art rather than
science.
Refrigeration system for lyophilisation
Lyophilisation consists of three separate unique and interdependent processes--

freezing, primary drying (sublimation), and secondary drying (desorption).
The freezing step utilises maximum power. Lyophiliser manufacturers in India are few,
which is why most of the time they are imported from Europe or China, and the
problem with imports is that sometimes the specifications do not meet with the
requirements of Indian climatic conditions, due to which the system does not operate
properly, leading to more number of breakdowns in the refrigeration system. The
principle function of lyophilisation is to slow down the kinetic clock while freezing.
Figure 1: Normal lyophilisation equipment
Natrajan Iyer- Engineer

natrajan.iyer@vhbgroup.com
Pallavi Hanwante- Pharmacist
pallavi.hanwante@gmail.com
Ice Condensor
Heat transfer ∆
medium eg. Shelf
Compressor
Silicon Oil
Figure 2: Refrigerant flow in a lyophiliser
In figure 2 the indirect cooling takes place in the shelf and direct cooling takes place in
the ice condenser.The whole system in the figure can be taken as a low temperature
reservoir in the figure below.

Ice Condensor
Heat transfer
medium eg.
Silicon Oil
Shelf
Compressor
High temperature reservoir consists of

refrigeration condenser and cooling tower
In figure 3, the condenser named in the lyophilisation equipment is a misnormer

because this part of the equipment contains the coil, which maintains the lowest
temperature in lyophilisation during the freezing cycle, thereby, propagating water
vapour from product to coil due to the difference in temperature, and converting the
vapour phase into solid phase (ice).
The thermal energy moves from left to right through five loops of heat transfer to
lyophilisation (see figure 4).

Shelf Evaporator Condenser Cooling Atmosphere
Tower
Figure 4: Refrigerant transfering the heat
The refrigeration system used in lyophilisation--the vapour compression refrigeration

(VCR)--uses mechanical and electrical energy.
The compression refrigeration cycles take advantage of the fact that highly
compressed fluids at a certain temperature tend to get colder when they are allowed to
expand. If the pressure change is high enough, then the compressed gas will be hotter
than the source of cooling (outside air, for instance) and the expanded gas will be
cooler than the desired cold temperature. In this case, fluid is used to cool a low
temperature environment and reject the heat to a high temperature environment.
Vapour compression refrigeration cycle has two advantages—first one being that a the
large amount of thermal energy is required to change liquid to vapour, and therefore, a
lot of heat can be removed from the shelf and the ice condenser. Secondly, tThe
isothermal nature of vapourisation allows extraction of heat without rising the
temperature of the working fluid to the temperature of whatever is cold i.e. heat
transfer rate remains high.

High Pressure side Low pressure

Expansion Device Compressor side
Figure 5: Schematic Diagram Of Refrigerant System
As explained in figure 5, low pressure liquid refrigerant transfers the heat directly in
case of ice condenser and indirectly through heat transfer medium silicon oil in case of
shelf. During this process, it changes its state from liquid to gas as the exit of the ice
condenser and silicon oil tank is slightly superheated. The superheated vapour enters
the compressor where its pressure is raised and the temperature is also increased
because the portion of the energy put into the compression process is transferred to
the refrigerant. The high pressure superheated gas passes from compressor to the
condenser and the initial part of the cooling process de-superheats the gas before it is
turned back into liquid. The cooling for this process is usually achieved by using air or
water. The high pressure sub cooled liquid passes through an expansion device, which
reduces its pressure, and controls the flow into the evaporator. The condenser is
capable of rejecting the combine heat input of the evaporator and compressor.

The high pressure superheated gas will be converted into liquid at a particular
temperature known as saturated temperature. In countries where there is not much of
a seasonal variation the atmospheric temperature variation is also minimum when we
import lyophilisation equipment from these countries and try to operate them in India.
This may not work upto our satisfaction because in our country the summer is as high
as 40o C at some of the places and winter is as low as 8-10 o C. The difference between
these temperatures is almost 30o.The selection of the condenser and the compressor
has to be done properly to be fully efficient. If this is not done during the peak of
summer, the lyophilisation equipment goes on high pressure, trips, leading to leakages.
Normally, in such situations the condenser can be cleaned, having no impact on the
operation. So while making the user required specification, the operational parameters,
and the condition of the place the equipment is imported from need to be mentioned. It
is generally preferred that condenser should be bought from the same manufacturers
as that of compressors.
A variety of refrigerants are used in vapour compression systems which require the
cooling temperature largely depending on the choice of fluid. Nowadays CFC free
refrigerants are used. The specific power consumption KW/TR is a useful indicator of
the refrigeration system’s performance. By measuring refrigeration duty performed in
TR and the KW input, KW/TR is used as an energy performance indicator while making
the specification for a lyophiliser. By comparing KW /TR for two different systems, the
one with a narrow gap should be chosen.
The theoretical coefficient of performance (Carnot), (COP Carnot, a standard measure

of refrigeration efficiency of an ideal refrigeration system) depends on two key system
temperatures--evaporator and condenser temperature.
COPCarnot = Condenser Temperature
C. T- E T
Where as, C T is condenser temperature and E T is evaporator temperature

The theoretical equation is only a ratio of temperature and does not take into account
the type of compressor being used. Hence, the practical equation for coefficient of
performance is
COP = Cooling Effect (KW) .

Power input to Compressor (KW)
This is also an important parameter in selecting the refrigeration system for

lyophilisers. The power consumption is maximum during refrigeration in the
lyophilisation process. To reduce the power consumption and to keep all the other
parameter constant, COP of one needs to be greater than the other, making the system
efficient.
Vacuum requirement in lyophilisation
To create vacuum in system a pump is required to remove mass or gas from the
system. The more mass is removed; lower is the pressure that exists inside the system.
Various vacuum levels are defined depending on the ultimate absolute pressure, in Torr
or mm/Hg. The pressure is directly proportional to boiling point i.e as the pressure
reduces, the boiling point also reduces. In lyophilisation, we freeze and sublimate the
product which is thermally sensitive and unstable in solution.
The vacuum is divided as:

• Coarse vacuum 10-760 Torr
• Medium Vacuum 0.001-10 Torr
• Fine vacuum 10-3 – 10-7 Torr
• Ultra High vacuum <10-7 Torr

The performance of the vacuum process largely depends on the right vacuum pumping
system. Lyophilisation takes place only when partial pressure of the vapour in the
drying chamber is lower than water vapour pressure above the product. Going by this,
the required vacuum is not essential as sublimation can take place at atmospheric
pressure by passing dehydrated air above the product. Lowering the pressure through
a vacuum pump can reduce the drying time drastically, which is why vacuum systems
are used in lyophilisers.
For example, a product sublimates at –20o at a given vapour pressure of 0.8 Torr. As
soon as the vacuum in the chamber reaches below 0.8 Torr the ice begins to sublimate.
There is a general misunderstanding that as we keep decreasing the pressure,
evaporation increases (but the rate of evaporation is not without a limit) and reaches
maximum limit when the pressure in the chamber has a value equal to 50 percent of
the vapour pressure above the product, so it is not necessary to always go for very low
vacuum during sublimation.
With the product maintained at constant temperature, it will be necessary to supply

energy of sublimation, which is a combination of latent heat of fusion (to convert water
into the ice) and the sublimation energy which is about 700 cal/g of evaporated ice.
Here the frozen product is brought to the highest temperature, which is compatible to
the frozen step. If you exceed this temperature, irreversible production of foam melt
back and product can deteriorate. On the other hand, if the heat energy supplied is
insufficient, the product will sublime at very low temperature and the length of the
lyophilisation cycle becomes abnormally long.
Application of vacuum in combination with rise in temperature plays a critical role in
sublimation.
Vacuum plays a major role during primary drying and secondary drying in
lyophilisation. By application of vacuum the vapour pressure of the solid can be

lowered by reducing the vapour pressure in the water, which crystallises as solid starts
evaporating. This vapour pressure drives the reaction in forward direction as vacuum is
applied, which reduces the time requirement for lyophilisation. If the pressure is
lowered more than the required amount, then the product can also be transferred to
the ice condenser. The lowering of vapour pressure is a very critical parameter and
depends on the product which is getting lyophilised.
After freezing, the pressure in the chamber reduces to a value that would allow the
sublimation of ice. Normally dry vacuum pump or oil ring vacuum pump is used. When
you use oil ring vacuum pump, which uses synthetic oil this vapour can get migrated
into the chamber while in operation this is a serious concern for inspectors from
regulatory authorities while ordering the lyophilser equipment make sure to validate
the presence of vapour in the chamber while in case of oil ring vacuum pump.
In order to minimise oil vapour migration, some lyophilisers are designed with a
tortuous path between the vacuum pump and the chamber. For example, one
fabricator installed an oil trap in the line between the vacuum pump and chamber in a
lyophiliser with an internal condenser. Leakage can also be identified by sampling
surfaces for contaminants in the chamber after lyophilisation is done. One could
conclude that if contamination is found on a chamber surface after lyophilisation, then
dosage units in the chamber could also be contaminated. It is a good practice to
sample the surfaces both before and after cleaning as far as validating of cleaning of
the lyophilisation chamber is concerned.

Figure 6: The transformation of phases for lyophilisation
At the end of the sublimation phase (primary drying), all the ice will have disappeared.
The product will begin to rise in temperature, and will tend to approach the control
temperature of the shelf. However, the product is not sufficiently dry for long term
storage. For most products, the residual moisture is in the region of five to seven
percent.
The product now enters the desorption phase, during which the last traces of water
vapour are removed, along with traces of the ‘bound’ water within the product matrix.
This phase is identified as secondary drying. The aim of this final phase is to reduce the
product to the acceptable moisture levels needed for long term storage (three to one
oercent).
The reasons for drying the product to these levels are desirable for several benefits--
when water content is higher than these levels, the product will denature; when the

residual moisture is forced lower than these levels, many products may undergo
chemical or enzymatic changes; residual moisture in the product depends on the
product matrix (both in frozen and sublimation mode) and the vacuum in the drying
chamber.
In the secondary stage the bound water (water that did not freeze) is due to physical
adsorption and crystallisation of water. Since the amount of the non-frozen water is
about 10-35 percent of the total moisture contents, its effect on the drying rate and
overall drying time is very significant.
Bound water is removed by desorption which takes place by heating the product under
vacuum. Moisture may move by vapour diffusion through the solid under a vapour
pressure gradient. Usually, the pressure is also lowered in this stage to encourage
sublimation. However, there are products that benefit from increased pressure as well.
After the freeze drying process is complete, the vacuum is usually broken with an inert
gas, such as nitrogen, before the material is sealed.
Shelf
Condenser
Butterfly Or Mushroom Valve

The process designed to remove water from materials generally faces pumping
problems that are traceable to the gas laws--it is necessary to compress the vapour in
order to pump it away. Compressing a condensable gas causes it to liquefy whenever it
is compressed beyond the critical point. In some cases, steam jet or water ring pumps
that are able to easily deal with condensation are used, but are limited in terms of the
ultimate vacuum levels they are able to produce. If the drying process requires that
lower ultimate vacuums be achieved at the end of the process, positive displacement-
type oil-sealed rotary piston pumps are usually used. If the process is hydrocarbon
sensitive, the oil-sealed pumps are replaced with oil-free pumps such as roots, screw,
hook-and-claw, or scroll pumps. All positive displacement pumps will respond to water
vapour by loading up with liquid water which reduces their pumping efficiency to an
unacceptable extent. In some cases, a refrigerated trap, often dry ice-cooled, is
interposed between the chamber and the pump to freeze and hold the water before it
reaches the pump. In other cases, it is necessary to gas-ballast the pump by bleeding a
dry gas through it to remove the condensate as it forms. Although these are difficult
problems, the real complexity occurs when the process requires that a low partial
pressure of water vapour within the chamber be achieved before initiating the actual
process.
When a chamber is pumped to a pressure of 10 -3 Torr or below, most of the chamber’s

volume gas has been pumped away and water vapour becomes the predominant gas
within the chamber. The source of the water vapour at these pressures is not from
humidity in the volume gas, but from internal surfaces of the chamber, elastomer O-
rings, and process work load materials. At this point in the pumpdown process, the rate
of pressure reduction is controlled by the rate of water desorption from the surfaces
instead of the amount of gas within the chamber’s volume. The highly polar water
molecules are sorbed on the surface with relatively weaker bonds, and the molecules

will only desorb as fast as they can absorb enough energy to exceed the bonding force.
In a simple and common pumpdown scenario, the required energy comes from the slow
flow heat from the room temperature chamber walls to the sorbed molecules. The
desorption rate will then be proportional to both the bond strength and the total
number of sorbed molecules. This, then, means that the chamber’s total desorption
rate will be proportional to the internal surface area. The only way to increase the
pumpdown rate is to increase the desorption rate temporarily by supplying additional
energy to the molecules. The two most common methods of energy transfer are
heating the chamber or by UV bombardment from an internal source. As desorbed
water molecules are pumped away, the rate of total desorption drops and so does the
pressure.


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Is it an Intelligent Decision to Import the Lyophilisers ?

Lyophilisation is a process in which liquid material is slowly frozen in a vacuum, thereby

Refrigeration system for lyophilisation

Lyophilisation consists of three separate unique and interdependent processes--

Figure 1: Normal lyophilisation equipment

Natrajan Iyer- Engineer

Figure 2: Refrigerant flow in a lyophiliser

Natrajan Iyer- Engineer

High temperature reservoir consists of

In figure 3, the condenser named in the lyophilisation equipment is a misnormer

Natrajan Iyer- Engineer

Shelf Evaporator Condenser Cooling Atmosphere

Figure 4: Refrigerant transfering the heat

The refrigeration system used in lyophilisation--the vapour compression refrigeration

Natrajan Iyer- Engineer

High Pressure side Low pressure

Figure 5: Schematic Diagram Of Refrigerant System

Natrajan Iyer- Engineer

The theoretical coefficient of performance (Carnot), (COP Carnot, a standard measure

Natrajan Iyer- Engineer

COP = Cooling Effect (KW) .

This is also an important parameter in selecting the refrigeration system for

Vacuum requirement in lyophilisation

The vacuum is divided as:

Natrajan Iyer- Engineer

With the product maintained at constant temperature, it will be necessary to supply

Natrajan Iyer- Engineer

Natrajan Iyer- Engineer

Figure 6: The transformation of phases for lyophilisation

Natrajan Iyer- Engineer

Butterfly Or Mushroom Valve

Natrajan Iyer- Engineer

When a chamber is pumped to a pressure of 10 -3 Torr or below, most of the chamber’s

Natrajan Iyer- Engineer

Natrajan Iyer- Engineer

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