Methods for Measuring

Shelf Temperature Uniformity in a Lyophilizer
by Timothy Dutill and Wendy Sunderland

Introduction

When considering the pharmaceutical application of freeze drying, of utmost concern is the
ability to manufacture a consistent product with the required critical quality attributes. In
order to do so, process uniformity must be ensured. A common and expected approach is
to conduct process qualification (PQ), for the freeze drying process. Prior to a product
specific PQ, the lyophilizer performance should be verified at the factory, once installed at
the site as part of commissioning, and again for operation qualification (OQ). The studies
should ensure the critical process parameters are functioning as intended and within a
specified allowable range. In addition to tests qualifying the independent and controllable
variables of the lyophilizer, including shelf inlet temperature, chamber pressure, and time, it
is beneficial to also assess certain dependent variables directly impacting product
uniformity. One such important measurement is shelf temperature uniformity, sometimes
referred to as shelf temperature mapping.

Shelf temperature is typically controlled and monitored by a resistance temperature

detector (RTD) immersed in a thermal well at the heat transfer fluid inlet to the shelves and
is often known as the shelf inlet temperature (Shelf Inlet). As heat transfer from the
lyophilizer to the product occurs at the shelf surface to vial interface, measuring the actual
temperature of the shelf surface is critical for assessing lyophilizer function. The shelf
temperature distribution of these measurements should then be compared relative to the
control point and the Shelf Inlet to ensure an acceptable range and uniformity.

One of the greatest challenges during such studies is the ability to measure the actual shelf
surface temperature without the influence of environmental conditions. Temperature
measurement devices can be divided into two distinct groups: direct measurements and
indirect measurements. The direct measurement is a device which secures the temperature
sensor, usually a thermocouple, directly to the shelf surface. The drawbacks of the direct
measurement method are that the temperature sensors are difficult to place, difficult to
keep in place at low and high temperature ranges, and typically require extensive cleaning
due to residual adhesives or paste. The main advantage of this method is that, when
executed correctly, it provides a measurement of the actual surface temperature in a
specific location. The indirect measurement is a device with the temperature sensor
embedded in a heat conductive material resting on the shelf surface. There are a number

© 2014 Lyophilization Technology, Inc.

 
Methods for Measuring Shelf Temperature Uniformity   Page 2 of 6
 
of commercially available devices employing the indirect method of temperature
measurement. The main drawback of this type of device is that temperature measurement
is more likely to be influenced by the chamber environment; however, these influences can
be addressed by the test method. The main advantages of the indirect measurement are
the ability to consistently place the devices and the elimination of any potential residues.

Methods

Studies were conducted at Lyophilization Technology, Inc (LTI) evaluating the ease of use
and effectiveness of a number of different temperature measuring devices on measuring
shelf temperature uniformity. Studies were run in a 2ft2 single shelf lyophilizer and a 24ft2
four shelf lyophilizer. Although other methods were investigated, only the most viable
methods will be discussed here including direct measurement with thermocouples
(thermocouple setup) and indirect measurement with Aluminum discs, Copper discs, and
the Kaye 1 ValProbe® (ValProbe) (P/N X2534). Figure 1 is a photograph of the
thermocouple setup, Copper disc and ValProbe.

Thermocouple setups are often considered the

“gold standard” in shelf temperature mapping since
the measurement is made directly at the shelf to
sensor interface. The method used here to attach
the thermocouples to the shelf included two 4”
sections of duct tape formed as a cross with the
thermocouple and heat conductive paste placed in
the center under a 1” x 1” section of refrigeration
tape. A variation on this method uses a plastic tube
with a spring to hold the thermocouple in place. As
described above, the thermocouples are very difficult
to place, in particular in the back of the lyophilizer.
The pilot scale lyophilizer used for the studies at LTI
had a 3 foot depth; using this method for a
commercial lyophilizer would only add additional
challenge.

Discs or ‘pucks’ of varying conductive material are a

simple way to employ the indirect method and are
often used in the industry in varying arrangements. Figure 1: Temperature measurement
A thermocouple or RTD is inserted into, or adhered devices – Copper disc (back left),
onto, a flat disc of some heat conductive material ValProbe (back right), thermocouple setup
(front)
such as aluminum or copper which then rests on the
shelf surface. The disc can then be easily slid to its
proper place on the shelf. This method requires no cleaning of residual paste or tape on the
shelves. Studies here used 2 inch diameter cylinders of Aluminum and Copper cut into
0.25” thick discs. Sections of insulation tape secured a thermocouple tip coated in heat
conductive paste to the top of the disc.

                                                            
1
 Kaye is an Amphenol advanced sensors brand 
Methods for Measuring Shelf Temperature Uniformity   Page 3 of 6
 
ValProbes are a wireless device with a stainless steel base and a RTD secured into it. The
device is supplemented with a thermal pad that adheres to the base. The thermal pad
diminishes the time required to reach steady state and ensures a more accurate
measurement especially under vacuum conditions. Similar to the discs, the devices are
easily placed in the proper location on the shelves. There is slight inconvenience in
comparison to other methods with having to program the ValProbes, ensuring there is
adequate battery life, and for some versions, not having real time data and uploading the
data into analysis software.

Results

Figure 2 shows the difference between the average shelf inlet temperature and the average
measured surface temperature over a 5 hour interval at -55°C, 5°C, and 50°C. The
Aluminum disc showed minimal difference compared to the thermocouple method at -55°C
and 5°C. At 50°C, the Aluminum disc was closer to the shelf inlet temperature than the
thermocouple which is most likely due to the thermocouple not remaining firmly adhered to
the shelf.

3.5

3.0
Temperature Difference (°C)

2.5

2.0

1.5 Aluminum Disc
TC taped to shelf
1.0

0.5

0.0
‐55°C 5°C 50°C
Target Shelf Temperature

Figure 2: Difference between the average shelf inlet temperature and the
average measured surface temperature for Aluminum disc versus
thermocouple (TC) taped to shelf.

Figure 3 shows the difference between the average shelf inlet temperature over a 1 hour
interval at -50°C, 0°C, and 50°C and the average measured surface temperature of three
thermocouples taped to a Copper disc or three thermocouples taped directly to the shelf.
The Copper disc performed as well or better than the thermocouple taped directly to the
shelf when the system was at or near atmospheric pressure. However, when the pressure
in the chamber was decreased to 200 microns the temperature measurements with the
Copper discs were skewed relative to the thermocouples.
Methods for Measuring Shelf Temperature Uniformity   Page 4 of 6
 

1.2
Temperature Difference (°C)
1.0
Copper Disc ‐
0.8 atmosphere

0.6 TC taped to shelf ‐
atmosphere
0.4 Copper Disc ‐
vacuum
0.2 TC taped to shelf ‐
vacuum
0.0
‐50°C 0°C 50°C
Target Shelf Temperature

Figure 3: Difference between the average shelf inlet temperature and the
average measured surface temperature for Copper disc versus thermocouple
(TC) taped to shelf.

Figure 4 shows the difference between the average shelf inlet temperature over a 1 hour
interval at -50°C, 0°C and 50°C and the average measured surface temperature of 20
ValProbes or thermocouples. The ValProbes, in general, performed as well as or better than
the thermocouples both at atmospheric pressure and under vacuum. The measured shelf
temperatures for the thermocouples and ValProbes were closer to the shelf inlet
temperature when the system was under vacuum.

4.0

3.5
Temperature Difference (°C)

3.0 ValProbes ‐
atmosphere
2.5
TC taped to shelf ‐
2.0 atmosphere
1.5 ValProbes ‐
vacuum
1.0
TC taped to shelf ‐
0.5 vacuum

0.0
‐50°C 0°C 50°C
Target Shelf Temperature
Figure 4: Difference between the average shelf inlet temperature and the
average measured surface temperature for ValProbes versus thermocouple
(TC) taped to shelf.
Methods for Measuring Shelf Temperature Uniformity   Page 5 of 6
 

‐40
‐41
‐42
Temperature (°C)

‐43
‐44
‐45
‐46
‐47
‐48
‐49
‐50
2 2.5 3 3.5 4 4.5 5
Elapsed Time (hours)
Shelf Inlet Thermocouple ValProbe

Figure 5: Average thermocouple and ValProbe temperatures at the end of a

ramp to -50°C.

Figure 5 shows the average of 20 thermocouples and 20 ValProbes at the end of a ramp
to -50°C and the beginning of a hold at -50°C. The thermocouples level off after about 0.75
to 1 hour into the hold at -50°C while the ValProbes take between 1.5 and 2 hours to reach
steady state. This difference does not significantly change the final readings as the average
values are between 0.4°C and 0.6°C different in the last half hour of the hold.

Conclusions
Shelf temperature mapping using thermocouples taped directly to the shelf surface has
historically been the most effective means of measuring shelf surface temperatures because
it provides a direct measurement of the temperature. The direct measurement has typically
been more accurate and precise when a good measurement was obtained. However, the
main disadvantage of using thermocouples has been the difficulty in obtaining consistently
good measurements. This can be seen graphically in Figure 2 where the thermocouple
performed much worse at 50°C when compared to the same thermocouple at -55°C and
5°C. The adhesive used did not hold as well at 50°C and the thermocouple rose off the
shelf surface slightly causing a shift in the temperature reading.

The alternate methods investigated represent alternative techniques. The Aluminum and
Copper discs are easily manufactured, cheap, and require little if any maintenance. The
techniques of attaching the thermocouple to the surface or embedding it inside the disc do
not alter the resulting temperature measurements. These methods make placing the
thermocouples much easier than taping the thermocouple to the shelf; however the wires
continue to add difficulty to the method.

The main disadvantage of using discs is that when the system is placed under vacuum, they
present an impedance to heat transfer due to the imperfect contact with the shelf surface.
In order to get around this limitation, most shelf temperature mapping experiments are run
with the system at or near atmospheric pressure. However as the data presented shows,
Methods for Measuring Shelf Temperature Uniformity   Page 6 of 6
 
the measurements made under vacuum are more representative of the shelf surface
temperature and the actual processing conditions of the shelf.

Kaye ValProbes® (ValProbes) present a viable alternative to both the disc method and to
thermocouples being taped directly to the shelf. They are easy to place and do not have
any interference from wires. They also perform as well or better than thermocouples when
the system is under vacuum, providing a more representative picture of the actual shelf
temperature uniformity during processing. The main disadvantage of the ValProbes is the
need to program them for each run. In addition, the upfront investment may be considered
prohibitive; however, it is a minimal investment when compared to the cost of repeating a
single qualification study due to poor measurements from non-adhered thermocouples. Due
to the extended equilibration time with the ValProbes, it may be necessary to extend the
hold at each target temperature. Future shelf temperature mapping studies at LTI will be
conducted using the ValProbes as they are consistent from run to run and set up and clean
up time for these studies is much less than when using thermocouples.

Timothy S. Dutill, Associate Scientist

Tim has been a part of Lyophilization Technology since January 2011. He is involved in
managing client projects including product and process development, clinical manufacturing,
validation, and troubleshooting. Focused activities include equipment qualification and
thermal analysis, including freeze drying microscopy, electrical resistance measurements,
differential scanning calorimetry, and thermogravimetric analysis. His career began in 2006,
in the vaccine field, as a Product Development Scientist at the Infectious Disease Research
Institute. Tim’s educational background consists of a B.S. in Chemical Engineering from
Pennsylvania State University. He has been published in the Journal of Colloids and
Surfaces B: Biointerfaces, Pharmaceutical Development and Technology and Biopharm
International. His professional memberships include the American Association of
Pharmaceutical Scientists (AAPS), the International Society of Lyophilization - Freeze-Drying
(ISL-FD) and the Parenteral Drug Association (PDA).

Wendy B. Sunderland, Director, Development Sciences

Wendy has been part of LTI since January 2001 and is currently responsible for the
Research and Development laboratories, including management of Development
Technicians. She is also involved in managing client projects including product and process
development, clinical and toxicological material preparation, technical support, validation,
and troubleshooting. In her role as Director, she reviews all development work from both a
scientific and quality perspective. Wendy has a B.S. degree in Materials Engineering from
Drexel University and an M.B.A. from LaSalle University. Starting her career in 1997 in the
orthopedic medical device field, she has authored papers in the Journal of Spine and Journal
of Pharmaceutical Engineering, and has presented podium presentations in the US and
Europe. Wendy is a member of the AAPS, International Society for Pharmaceutical
Engineers, ISL-FD, and the PDA.