T E C H N O T E

Basic Principles Of Freeze-Drying

Author: John Barley

Portfolio Manager, SP VirTis, SP Industries, Inc.

Overview
Freeze-drying is the removal of ice or other frozen solvents from
a material through the process of sublimation and the removal of
bound water molecules through the process of desorption.
Lyophilization and freeze-drying are terms that are used
interchangeably depending on the industry and location where
the drying is taking place. Controlled freeze-drying keeps the
Figure 1 Phase Diagram of Water
product temperature low enough during the process to avoid
changes in the dried product appearance and characteristics.
It is an excellent method for preserving a wide variety of heat- • Secondary Drying (desorption) under vacuum
sensitive materials such as proteins, microbes, pharmaceuticals, • Backfill & Stoppering (for product in vials) under partial vacuum
tissues & plasma. • Removal of dried product from freeze dryer
Sublimation In addition to providing an extended shelf-life, successful freeze-
drying should yield a product that has a short reconstitution time
Sublimation is when a solid (ice) changes directly to a vapor with acceptable potency levels. The process should be repeatable
without first going through a liquid (water) phase. Thoroughly with well defined temperature, pressure and time parameters
understanding the concept of sublimation is a key building block for each step. Visual and functional characteristics of the dried
to gaining knowledge of freeze-drying. product are also important for many applications.
Sublimation is a phase change and heat energy must be added
to the frozen product for it to occur. Sublimation in the freeze-
drying process can be described simply as:
1. FREEZE - The product is completely frozen, usually in a vial,
flask or tray
2. VACUUM - The product is then placed under a deep vacuum,
well below the triple point of water
3. DRY – Heat energy is then added to the product causing the
ice to sublime
Lyophilization Process Overview
The steps required to lyophilize a product in a batch process can
be summarized as follows:
• Pretreatment / formulation
• Loading / container (bulk, flask, vials)
• Freezing (thermal treatment) at atmospheric pressure
• Primary Drying (sublimation) under vacuum Figure 2 Typical Freeze-Dried Products

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Basic Principles Of Freeze-Drying

Freeze-Drying Equipment pumps can be oil-lubricated (rotary-vane) style, or they can be

“dry” scroll in design. Rotary-vane vacuum pumps require the
The main components of freeze-drying equipment are:
use of an oil mist eliminator (OME) to capture oil particles in the
• Refrigeration system exhaust stream, or the exhaust can be vented to outside. They
• Vacuum system require frequent oil changes based on usage conditions.
• Control system Dry scroll vacuum pump designs have become more robust
• Product chamber/shelves or manifold and are now frequently used in freeze-drying equipment. They
• Ice condenser can reach the low vacuum levels needed for freeze-drying, even
with their gas ballast set to open, which makes them ideal for
Refrigeration Systems processing products with solvents/acids. Although they provide
The refrigeration system cools the (ice) condenser located inside the benefit of not needing oil changes, the tip seals on dry scroll
the freeze dryer, with refrigerant routed through a coil in the pumps do require periodic replacement to enable reaching
condenser. This is known as “direct expansion” (DX) refrigerant lower vacuums.
cooling. DX refrigeration is uncontrolled by design, and when
running continuously, the system will eventually reach its coldest For the best control of vacuum to the desired set point, the
“bottom out” temperature in the condenser. vacuum pump will run continuously and then a small gas bleed
valve will be used to intermittently allow a small amount of gas/
The refrigeration system is also employed to cool the shelves in air into the system to balance out the vacuum level
the product chamber for both freezing of the product and for
maintaining temperature during drying. For tighter control of Control Systems
shelf surface uniformity, an indirect method of cooling is used. Control systems vary in complexity and will usually include
The refrigerant is sent to a heat exchanger where it cools silicone several features such as:
heat transfer fluid. This fluid is continuously circulated through • Temperature (shelf, condenser & product probes) and pressure
the inside of the shelves. A resistive electric heater is added to sensing
the heat transfer fluid loop to provide shelf heating. The heater • Control of system vacuum and shelf (fluid) temperature
and refrigeration system work together to maintain precise shelf
• Ability to program a complete “recipe” for freeze-drying
temperature control.
• A recipe manager to save multiple recipes for future use
On advanced freeze dryers, a shared refrigeration system is used
• Process alarms
to cool both the shelves and the condenser. All of the cooling
load is at the shelf stack during freezing. Then, during drying,
• HMI (Human-Machine Interface)
most of the cooling load is at the condenser. Shared refrigeration • Data trending and data export
systems have less components and are more reliable, they are • Manual mode operation
more energy efficient and generate less waste heat. Older freeze • Synoptic screen showing which systems are active
dryer designs may have two separate refrigeration systems, one Advanced control systems can also include the following
for the shelf and on for the condenser, with each system having additional options:
its own compressors.
• SCADA (Supervisory Control And Data Acquisition) system to
Refrigeration systems on laboratory and pilot freeze dryers are record data
typically cascade in design, where there are two refrigerant
• Data historian with secure encryption
circuits working in series. The cold side of the warmer “high-
stage” intersects with the warm side of the colder “low-stage”. This
• Secure user ID/Login & Password
provides for system temperatures colder than -80 °C. On production • Multiple user groups with different permission levels
freeze dryers, the larger compressors are compound/multi-stage in • Audit trail for change control of who made what recipe change,
design, and they can reach -75 °C with a single refrigeration loop. when & why (FDA 21 CFR Part 11 requirement).
Vacuum Systems • PAT (Process Analytical Technology) tools to monitor how the
The vacuum system consists of a separate vacuum pump connected freeze-drying process is progressing
to an airtight condenser and attached product chamber. Vacuum • Automatic system performance tests

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Basic Principles Of Freeze-Drying

Product Chamber Freeze dryers can be informally classified by the type of product
Product chambers are typically a large chamber with a system of chamber: (1) Manifold dryers where the product is typically pre-
shelves on which to place the product. The standard material of frozen & in flasks (2) Shelf dryers where the product is placed in a
construction is 316L Stainless Steel for both the chamber and the tray or directly on a shelf.
shelves. In simpler form, a manifold with attached flasks functions
as the product chamber.
Product chambers are designed to withstand pressure differentials
for full vacuum conditions. They can be either square/rectangular
or round/cylindrical in design.
Product shelves can be either fixed in place or moveable.
Moveable shelves can have a hydraulic or pneumatic ram added
for the ability to stoppering vials at the end of the process.
Ice Condenser
The purpose of the condenser is to attract the vapors being
sublimed off of the product and protect the vacuum pump. 1) Manifold Dryer 2) Shelf Freeze Dryers
Because the condenser is maintained at a lower energy level
relative to the product ice, the vapors condense and turn Freeze dryers can also be grouped by size & use: (1) laboratory
back into solid form (ice) in the condenser. The sublimated ice bench-top units for R&D (2) pilot units for process development
accumulates in the condenser and is subsequently removed at and scale-up studies, and (3) larger production-sized units. It
the end of the freeze-drying cycle, after the product has been should be noted that in addition to process scale-up work, pilot-
unloaded. This defrost step is facilitated by the refrigeration sized freeze dryers are often also used for product R&D as well as
system on laboratory/pilot units (known as “hot-gas defrost”). On for small volume production applications.
larger production units, hot water or steam can be used to speed
up the defrost process, together with an automatic drain valve.
The condenser temperature required for a specific product is
dictated by the freezing point and collapse temperature of that
product. The refrigeration system must be able to maintain
the temperature of the condenser substantially below the
temperature of the product while it is being freeze-dried.
In shelf freeze dryers, the condenser can be located inside the
product chamber (internal condenser) or in a separate chamber
(external condenser) connected to the product chamber by a 1) Bench-Top R&D 3) Production
Freeze Dryer 2) Pilot Freeze Dryer Freeze Dryer
vapor port. This vapor port can have a normally open isolation
valve, which can be closed when desired for product unloading,
defrost, or for process control end-of-drying measurements Choosing a freeze dryer depends on the product characteristics
know as a pressure-rise test. as well as many other application-based variables including
the container that the product will be dried in, the shelf area or
The refrigerant coil can be wrapped around the outside of the
number of ports required to accommodate the quantity to be
condenser chamber, providing a “smooth wall” design for the ice
dried in each batch, the total volume of ice to be condensed and
to collect on. Alternately, the coil can be placed internally. There
whether there are any organic solvents. The type and shape of
are different advantages to both designs. Smooth-wall designs
product being dried and its end-use also need to be considered.
are easier to clean manually and will melt/defrost large ice loads
much more quickly if hot-gas defrost is used. Internal coils on
pilot units better approximate most production freeze dryer
designs and may provide better process scale up data.

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Basic Principles Of Freeze-Drying

Product Containers & Containment Systems

A suitable container system must be chosen for the product.
The most common product containers are flasks, vials and trays.
If possible, it is advisable to pick a container that keeps the
maximum thickness of the product to less than 2 cm (3/4 inch).
Special containers made of Gore-Tex* & Tyvek* are also available for
specific applications where product contamination is a concern.
Product trays with removable bottoms are available when
Product Not Fully Frozen Before Starting Vacuum & Drying!
working with vials. The tray is loaded with vials, placed on a shelf
in the freeze dryer and then the bottom part of the tray is slid out. With simple manifold freeze dryers, the product is placed in a
This allows the vials to rest directly on the shelf and increases the vial or flask depending on quantity, and then frozen in a separate
heat transfer to the product. piece of equipment. Options include standard laboratory freezers,
shell baths and direct immersion in liquid nitrogen.
Special containment systems such as isolators and glove boxes
are required for freeze-drying certain products, especially when Shelf freeze dryers have cooling capability built into the product
cytotoxic materials are present. shelf which allows the product freezing to be accomplished
inside the freeze dryer. Product is either pre-loaded into vials
Physical Properties of Materials & Formulation
which are then transferred to the shelf, or it is loaded in bulk form
Understanding the physical properties of materials that are directly onto a product tray.
freeze-dried is a key part in developing a successful lyophilization
Shelf freeze dryers allow the precise control of cooling rates
process. Although a few products are simple crystalline materials,
which affects product freezing rates and crystal size. Larger ice
the vast majority of products that are lyophilized are amorphous
crystals improve the speed of the freeze-drying process because
and form glassy states when frozen.
of the larger vapor pathways left behind in the dried portion of
Processing and formulation development are important steps often the product as the ice crystals are sublimated.
taken to make a product ready for freeze-drying and usable for its
Slower shelf cooling rates do not necessarily yield larger ice
specific application. The choice of excipients added to a formulation
crystals because of the effects of super-cooling. When the
can severely affect the thermal characteristics of the product and its
super-cooled liquid finally freezes, it happens extremely quickly,
ability to be freeze-dried in a reasonable amount of time.
resulting in smaller ice crystals. In a clean room environment with
Recipe For Freeze-Drying very few particulates for ice nucleation, there is a significantly
Lyophilization in a shelf freeze dryer requires the design of a greater amount of super-cooling.
working process or cycle which is sometimes referred to as a Newer technologies such as ControLyo® Nucleation are available
“recipe”. Typically, there are multiple steps involved for both to control ice crystal growth to minimize the effects of super-
freezing and drying of the product. Individual temperature, cooling and provide larger crystal sizes.
pressure and time settings need to be determined for each step.
Each specific product or formulation that is lyophilized requires
the development of a freeze-drying process that is based on the
unique characteristics of the product, the amount of product
and the container used. There is no universal “safe” recipe that will
work with every product.
Freezing Forced Normal
nucleation process
It is extremely important that the sample be fully and completely
frozen prior to pulling a vacuum and starting the drying process.
Unfrozen product may expand outside of the container when
placed under a vacuum.

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Basic Principles Of Freeze-Drying

Eutectic / Collapse Temperature

Determination of the critical collapse temperature of a product
is an important step in establishing and optimizing a freeze-
drying process. This critical temperature determines the
maximum temperature that the product can withstand during
primary drying without it melting or collapsing. Thermal analysis
(Differential Scanning Calorimetry & Freeze Dry Microscopy) and
Dielectric Resistance analysis and are common methods used to Collapsed Product –
determine this critical temperature of the product. Critical Temperature
Was Exceeded

Annealing
Some amorphous products (such as mannitol or glycine) form
a metastable glass with incomplete crystallization when first
frozen. These products can benefit from a thermal treatment
process, which is also called annealing. During annealing, the
product temperature is cycled (for example: from -40 °C to -20 °C
for a few hours and then back to -40 °C) to obtain more complete
crystallization. Annealing has the added advantage of larger
crystal growth and corresponding shorter drying times.
Freeze Dry Microscope Differential Scanning Calorimeter Organic Solvents
The use of organic solvents requires more attention in the freeze-
Frozen products can be categorized as either crystalline or drying process. Lower temperatures are required to freeze and
amorphous glass in structure. Crystalline products have a well condense solvents and they can easily bypass the condenser
defined “eutectic” freezing/melting point that is its collapse and end up causing damage to the vacuum pump. Freeze dryer
temperature. Amorphous products have a corresponding “glass refrigeration designs are available to provide the lower shelf and
transition” temperature and they are much more difficult to freeze- condenser temperatures needed to freeze and then condense
dry. The collapse temperature of amorphous products is typically some organic solvents.
a few degrees warmer than its glass transition temperature.
Special filter cartridges or liquid nitrogen (LN2) traps may be
Although most materials that are freeze-dried are actually
required to catch/condense certain solvents with very low
amorphous, the term “eutectic” is often used (erroneously) to
freezing temperatures. Safety considerations must be made
describe the freezing/melting point of any product.
when handling volatile and/or potentially harmful materials
The US FDA Guide To Inspections Of Lyophilization Of Parenterals
states that the manufacturer should know the eutectic point
(critical collapse temperature) of the product. It is good practice
to characterize the collapse temperature for all new injectable or
ingestible drug formulations to be freeze-dried.
Without knowing the critical temperature of the product, a
trial-and-error approach is required to determine appropriate
primary drying temperatures. A slow conservative cycle with low
temperatures and pressures can be used initially. The temperature
and pressure can then be raised on subsequent cycles until LN2 Trap Filter Cartridge
evidence of collapse or melt-back is seen – indicating that the The bulk of organic solvents will typically be removed early
product was too warm. during the freeze-drying process.

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Basic Principles Of Freeze-Drying

Primary Drying
The drying portion of freeze-drying is actually a two-part process
consisting of Primary Drying and Secondary Drying. The bulk
of water removed from the product during freeze-drying is via
sublimation of all of the free ice crystals during the primary drying
step. Organic solvents are also removed during primary drying.
Primary drying (sublimation) is a slow process conducted at
cooler temperatures, safely below the product’s critical collapse
temperature. Sublimation requires heat energy to drive the
phase change process from solid to gas. All three methods of
heat transfer - conduction, convection and radiation, must be
considered when freeze-drying a product.
In a simple manifold dryer, heat is transferred to the flask/product
primarily through convection and radiation from the surrounding Heat Transfer in a Shelf Freeze Dryer
environment. With little control over heat flow into the product,
Primary drying is a top-down process with a well-defined
it is more difficult to control the process. When working with
sublimation front moving through the product as it dries.
products with low collapse temperatures, it may be necessary to
Above the ice surface interface is dried product, or “cake”; below
wrap or insulate the flask to slow down the rate of heat transfer
the interface is product with ice crystals still remaining to be
and avoid collapse.
sublimed. At the end of primary drying when all of the free ice
In a shelf freeze dryer, it is important to maximize the surface crystals have been sublimed, the product will appear to be dried.
contact of the product/container/tray with the shelf for good However, the moisture content can still be in the 5-10 % range
conductive heat transfer. However, the effects of radiation and due to the presence of “sorbed” water molecules attached to the
convection also need to be considered for product uniformity product.
and process control purposes.
Pressure & Temperature During Primary Drying
Radiant heat from the inside walls of the product chamber will
As mentioned earlier, each frozen product has a unique critical
cause product/vials on the perimeter of the shelf to dry more
temperature. It is necessary to keep the product temperature
quickly than product in the center of the shelf (known in freeze-
safely below this critical temperature during primary drying to
drying as the “edge effect”). Radiation coming through the acrylic
avoid collapse. The product temperature is dependant on the
doors commonly used on pilot and R&D freeze dryers has an even
vapor pressure at the ice interface and in turn, this vapor pressure
greater effect and product located in the front of these dryers will
is dependant on both the rate of heat transfer into the product
typically dry the fastest of all. For this reason, production freeze
(which is controlled by adjusting the shelf temperature) and the
dryers are designed with metal doors and small view ports. A
system vacuum level set point.
piece of aluminum foil can be hung in front of the product on
the inside of a pilot freeze dryer as a shield – of course this will Once a target product temperature is identified (typically several
block the view of the product and not allow observation during degrees safely colder than the critical temperature), the only two
the process. variables left to determine/control are the shelf temperature and
system vacuum level. During primary drying, the system pressure
Because shelf contact is often inconsistent, convective heat
and the shelf temperature are set and controlled in combination
transfer can help promote uniform product drying. System
to yield the appropriate product temperature.
pressures in the 100 mTorr to 300 mTorr range will usually
promote an adequate amount of convection. At very low system A recommended approach is to first set the system pressure using
pressures less than 50 mTorr, there are fewer gas molecules the vapor pressure over ice table (below). The product temperature
present to provide convection and uneven / slower drying is is monitored using thermocouples and then the shelf temperature
likely and maintaining vacuum control can become an issue. set point is slowly increased until the product reaches its target

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Basic Principles Of Freeze-Drying

temperature. When the target product temperature is obtained, With the temperature and pressure parameters set, primary
the shelf temperature is held constant for the balance of primary drying is then continued for a length of time sufficient for all of
drying. Certain products with high resistance to vapor flow in the the ice crystals to be sublimed.
dried portion of the cake may require that the shelf temperature As can be seen in the table below, temperature and pressure
be reduced towards the end of primary drying to keep the product have a direct relationship, the lower the temperature of the ice,
temperature at its target and to avoid collapse. the lower the saturated vapor pressure over it.
It is not recommended to increase the shelf temperature Because most commercial freeze dryers can not consistently
arbitrarily and repetitively during primary drying, as is seen on control vacuum much below 30mTorr, at very cold product
some older legacy cycles. temperatures (less than -40 °C), it becomes impossible to have
Using the vapor pressure of ice table is a scientific way to a system pressure set point that is 20 % to 30 % of the vapor
determine an appropriate pressure for freeze-drying. A general pressure of ice. Freeze-drying occurs extremely slowly at these
guideline is to choose a system pressure that is 20 % to 30 % cold product temperatures and process times may extend for 5
of the vapor pressure of ice at the target product temperature. to 7 days or longer.
When the vacuum level set point is deeper than the vapor With manifold freeze-drying, the process is driven by the system
pressure of ice at the current product temperature, sublimation pressure set point and the ambient temperature in the room.
can take place. Typically, vacuum levels for freeze-drying are Because of the lack of control over the rate of heat transfer into
between 50mTorr and 300mTorr with 100mTorr to 200mTorr the product, most manifold dryers are operated conservatively
being the most common range. at lower pressures to help keep the product temperature lower.

Temp Vapor Pressure Temp Vapor Pressure

[°C] [milliTorr] [milliBar] [pascal] [°C] [milliTorr] [milliBar] [pascal]
0 4,584.000 6.1115 611.148 -46 48.000 0.0640 6.399
-2 3,883.000 5.1769 517.689 -48 37.700 0.0503 5.026
-4 3,281.000 4.3743 437.429 -50 29.500 0.0393 3.933
-6 2,765.000 3.6864 368.635 -52 23.000 0.0307 3.066
-8 2,325.000 3.0997 309.974 -54 17.900 0.0239 2.386
-10 1,949.000 2.5984 259.845 -56 13.800 0.0184 1.840
-12 1,630.000 2.1731 217.315 -58 10.600 0.0141 1.413
-14 1,359.000 1.8118 181.185 -60 8.100 0.0108 1.080
-16 1,130.000 1.5065 150.654 -62 6.160 0.0082 0.821
-18 936.800 1.2490 124.896 -64 4.660 0.0062 0.621
-20 774.400 1.0324 103.245 -66 3.510 0.0047 0.468
-22 638.200 0.8509 85.086 -68 2.630 0.0035 0.351
-24 524.300 0.6990 69.901 -70 1.960 0.0026 0.261
-26 429.400 0.5725 57.248 -72 1.450 0.0019 0.193
-28 350.500 0.4673 46.729 -74 1.060 0.0014 0.141
-30 285.100 0.3801 38.010 -76 0.780 0.0010 0.104
-32 231.200 0.3082 30.824 -78 0.570 0.0008 0.076
-34 186.800 0.2490 24.905 -80 0.410 0.0005 0.055
-36 150.300 0.2004 20.038 -82 0.290 0.0004 0.039
-38 120.600 0.1608 16.079 -84 0.210 0.0003 0.028
-40 96.300 0.1284 12.839 -86 0.150 0.0002 0.020
-42 76.700 0.1023 10.226 -88 0.100 0.0001 0.013
-44 60.800 0.0811 8.106 -90 0.072 0.0001 0.010
Vapor Pressure Over Ice Chart

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Basic Principles Of Freeze-Drying

Determination of the End of Primary Drying capacitance manometer. A capacitance manometer always
gives a true pressure reading in the product chamber. The Pirani
Several analytical methods are available for determining that
gauge, however, will give a false high reading in the presence
primary drying is complete. The most basic method is to monitor
of water vapor. When the Pirani pressure reading decreases
the product temperature with a thermocouple probe. The
and approaches the true pressure reading of the capacitance
measured product temperature will be colder than the shelf
manometer, little or no water vapor is present, and it can be
temperature set point during active primary drying because
concluded that primary drying is complete.
the heat from the shelf is being used for the sublimation phase
change. When sublimation of ice crystals is complete, the product Another tool is available with freeze dryer designs that have
temperature will increase and approach the shelf temperature. external condensers. An isolation valve can be added to the vapor
When the product temperature equals the shelf temperature, it port that connects the product chamber to the condenser. This
can be inferred that primary drying is complete. valve can be closed for a short period of time and the subsequent
Note: the specific vial that contains the thermocouple wire will rise in pressure in the product chamber can be measured. When
typically dry faster than the other vials on the shelf because this pressure rise approaches zero, no more water vapor is being
the wire will conduct more heat into that specific vial. Similarly, generated via sublimation.
if bulk drying, the area around the thermocouple wire will dry LyoFlux* TDLAS (Tunable Diode Laser Absorption Spectroscopy)
more quickly than other areas in the product tray. It is important is an advanced tool which measures the amount of water vapor
to allow a modest amount of additional drying time (30 min to 2 flowing through the vapor port between the product chamber
hrs, depending on the product characteristics) after the product and condenser.
thermocouple temperature increases to ensure that all of the ice
in the entire batch of product has been completely sublimated.
Secondary Drying

Because product will dry from the top down, the tip of the In addition to the free ice that is sublimed during primary
thermocouple should always be placed at the very bottom and drying, there remains a substantial amount of water molecules
center of the container. It is OK if the thermocouple touches the that are bound to the product. This is the water that is removed
bottom of the container. If drying in vials, it is good practice to (desorbed) during secondary drying. Since all of the free ice
insert the thermocouple in a vial located in the middle of the has been removed in primary drying, the product temperature
shelf. Radiant heating effects will cause vials/product on the can now be increased considerably without fear of melting or
perimeter of the shelf to dry more quickly. collapse.
Secondary drying actually starts during the primary phase, but
at elevated temperatures (typically in the 30 °C to 50 °C range),
desorption proceeds much more quickly. Secondary drying rates
are dependant on the product temperature. System vacuum
may be continued at the same level used during primary drying;
lower vacuum levels will not improve secondary drying times.
Amorphous products may require that the temperature increase
from primary to secondary drying be controlled at a slow ramp
rate to avoid collapse.
Secondary drying is continued until the product has acceptable
moisture content for long term storage. Depending on the
Thermocouple Placement –
application, moisture content in fully dried products is typically
Special MVP Stopper
between 0.5 % and 3 %. In most cases, the drier the product, the
Additional primary drying endpoint determination tools are longer its shelf life will be. However, certain complex biological
available on larger freeze dryers equipped with advanced products may actually become too dry for optimum storage
process control systems. One such method entails comparison results and the secondary drying process should be controlled
of parallel pressure readings between a Pirani gauge and a accordingly.

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Basic Principles Of Freeze-Drying

During secondary drying, a “sample thief” mechanism may Process Scale-Up to Production Considerations
be used to periodically remove vials from the freeze dryer for
Laboratory pilot-sized shelf freeze dryers are often used to
residual moisture content determination.
develop a cycle to be used for process scale-up to a larger
production sized unit. Similarity in heat transfer characteristics
and shelf temperature uniformity is important to ensure that a
lyophilization process developed in the lab can be successfully
transferred to a production freeze dryer.
One of the most important factors to consider is the difference
between the cleanroom environment typical of a production
freeze dryer and the lab environment that most pilot units are
operated in. The difference in particulates can greatly affect
product freezing and ice crystal size.
Production freeze dryers are usually configured for operation
in a cleanroom environment and can have the ability for clean-
Sample Thief - For Removal of Vials During Secondary Drying in-place (CIP) and steam sterilization (SIP). Another production
Cycle Optimization consideration is process compliance to US FDA regulation 21 CFR
Part 11, if required. This regulation requires certain standards of
In addition to designing a recipe that successfully dries a product, electronic data security.
it is also extremely valuable to optimize (shorten) the length of
the cycle, especially if there is potential for process repetition Storage of Dried Product
or scale-up for production. Freeze-drying can be a multi-day Lyophilized products are extremely hydroscopic, and they must
process. The cycle time can often be substantially reduced by be sealed in airtight containers following freeze-drying to prevent
investigating several factors: rehydration from atmospheric exposure. Freeze dryers can be
• Freezing and annealing – maximize crystal size and crystallization configured with a “stoppering” capability to seal the product
to increase drying rates while it is still under partial vacuum inside the unit. Typically,
stoppering is done on vials with partially inserted stoppers.
• Thickness of product – water vapor molecules experience
The shelves are collapsed so that each shelf pushes down the
resistance as they exit from the dried portion of the product;
vials/stoppers located on the adjacent shelf. It is also common
thinner samples yield less resistance to vapor flow and lead to
to backfill with an inert gas such as dry nitrogen before sealing/
faster drying
stoppering the product.
• Critical collapse temperature – this is the most important
piece of information for cycle optimization; the ability to run
primary drying at higher product temperatures greatly reduces
drying time by creating a larger pressure differential between
the vapor pressure over ice in the product and the pressure at
the condenser; each 1 °C increase in product temperature can
decrease primary drying time by 13 %
Cycle optimization using eutectic/collapse temperature
information requires an iterative approach of taking real-time
measurements of the product temperature during primary
drying and then making corresponding adjustments to the
shelf temperature settings. This can be accomplished manually
using product thermocouples or, if drying in vials, an automated
SMART* system can be used. Stoppering Mechanism in a Production Freeze Dryer

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