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Detection of Silicone Oil Leakages in Freeze Dryers

U. Meissner, Harald Stahl and D. Steinkellner

PDA J Pharm Sci and Tech 2011, 65 481-485

Access the most recent version at doi:10.5731/pdajpst.2011.00748
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Tech Report

Detection of Silicone Oil Leakages in Freeze Dryers

U. MEISSNER1, HARALD STAHL2,*, and D. STEINKELLNER2
1
MKS, Munich, Germany and 2GEA Lyophil GmbH, Huerth, Germany ©PDA, Inc. 2011

ABSTRACT: As a small leakage from the silicone oil tubes in pharmaceutical freeze dryers may go undetected for
several cycles, it provides a major threat to both product safety and the economic performance of such installations.
A properly mounted mass spectrometer offers a non-invasive method of detecting the smallest amounts of silicone
oil down to 1 ppm. Additionally the system will improve leak testing procedures and can also be used as a process
analytical technology tool to improve process control.

LAY ABSTRACT: Drugs, and in particular parenterals, need to have a very high level of purity. A production process
such as freeze drying carries the inherent risk of contamination by process fluids. This should not happen during
routine production, but in the event of a malfunction small amounts of these fluids may contaminate the drug product.
The purpose of this paper is to introduce a method which is able to detect such malfunctions before they can develop
into a risk for drug purity and ultimately patient safety.

KEYWORDS: Freeze drying, Leak detection, Lyophilisation, Mass spectroscopy, Silicone oil

Introduction areas and introduces a system for the detection of

small amounts of silicone oil in the system.
Freeze drying has been used for many years in the
production of parenterals to stabilize thermo labile Silicone oil is heated to the required temperature using
molecules. With the increasing number of large mol- heat exchangers in the technical area, from where it is
ecules, the spread of freeze drying will further con- circulated into the system. A typical setup is shown in
tinue because it offers the gentlest way of converting Figure 1. One of the most important aspects of freeze
a liquid formulation into a more stable solid. drying processes is the heating and cooling of this oil
in the shelves. From an engineering perspective, the
From an engineering point of view the preparation and shelves need to be as lightweight as possible while
ensuring a uniform surface temperature and planarity.
process of a freeze dryer places very high physical
The shelves are moved up and down during the load-
demands on the hardware. After washing, all potential
ing and unloading cycles as well as during stoppering
product contact parts are exposed to saturated steam at
and subsequent CIP/SIP at the end of the process. This
121 °C, which relates to an overpressure of ⬃1.5 bar.
means that the tubes supplying the silicone oil to the
After vial loading, the dryer is evacuated down to
shelves need to be constructed and guided in a way
0.05 mbar while the shelves and the ice condenser are
that reduces stress that could increase the risk of
cooled down to as low as ⫺85 °C (1). Various types of
cracks in the tubes.
silicone oils are used to transfer the required heat
energy in and out of the dryer. Following multiple Older freeze dryers in particular have been known to
cycles under extreme conditions it has been seen that develop small cracks as a result of numerous cycles
micro leaks can occur in the silicone oil circulation and movements. It is through these cracks that silicone
system. This article identifies the most likely leak oil can escape into the drying chamber. In the begin-
ning these leaks are relatively small and will not cause
malfunctions of the system. This means there is the
risk that several batches might be produced before
* Corresponding author: Dr. Harald Stahl,
Quality Control (QC) identifies the problem. The QC
Kalscheurener Strasse 92, D-50354 Huerth, Germany;
unit would then have to decide at what moment in time
⫹49 172 620 6864; harald.stahl@geagroup.com
(from what batch onwards) the problem initially

Vol. 65, No. 5, September–October 2011 481

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Figure 1 Figure 3

Typical setup of a freeze dryer. MKS Instruments Inc. Vision 2000-P.

started. For these reasons it would be helpful to have ionization, the separation of the formed ions in an
a method allowing the detection of traces of silicone electromagnetic field, and their detection.
oil from the moment the first leak occurs.
Early trials proved the principle eligibility of the
Feasibility Trials: The Detection of Silicone Oil method and allowed the determination of its sensitiv-
Traces ity. An MKS Vision 2000-P mass spectrometer, as
shown in Figure 3, was connected via a standard
Mass spectroscopy (principle shown in Figure 2) was flange with an FCM-2 freeze dryer (Figure 4) installed
chosen as a method of detection because of its sensi- in the test centre at GEA Lyophil in Hürth (Germany).
tivity. Quadrupole mass spectrometer systems are
widely used for the monitoring of critical processes When silicone oil is introduced into the mass spec-
and the detection of residual contamination. The prin- trometer the molecule is broken into several frag-
ciple of the operation is based on electron impact ments. By detecting characteristic fragments, traces of

Figure 2

Function of a quadrupole mass spectrometer.

482 PDA Journal of Pharmaceutical Science and Technology

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peak at 73 AMU (atomic mass units) was found.

Additionally, other types of silicone oil that may be
present in a freeze dryer were tested. While the oil
typically used for the siliconisation of stoppers gave a
characteristic peak at 56 AMU, silicone oil-based
maintenance spray—typically used for lubrication of
moving parts in loading and unloading systems— gave
a characteristic peak at 58 AMU. As the characteristic
peak at the mass of 73 AMU represents the type of oils
used in the temperature circuits of a freeze dryer, this
signal was used for the subsequent measurements.

As a next step an amount of 2 mg of KT5 was

introduced into a vial, which was closed by a stopper
Figure 4 and held in position by the upper shelf. After the
desired vacuum level was reached, the upper shelf was
GEA Lyophil Lab Scale Freeze Dryer Type FCM-2. lifted. As a result, the stopper popped off and the oil
evaporated into the freeze dryer. After just a few
silicone oil can be found. During the tests different seconds a signal was detected.
types of silicone oils were used. As KT5 (Bayer AG,
Leverkusen, Germany) has the lowest vapour pressure During an additional simulation 100 mg—less than 10
of common oils for freeze drying, it was used for all droplets—KT5 was introduced over a small buffer
measurements. After the first trials a characteristic volume into the drying chamber with a shelf size of 40

Figure 5

Test with 100 mL Baysilone KT5 on a freeze dryer with 40 m2 shelf size.

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TABLE I For the determination of sensitivity it was decided that

Detection Limit as a Function of Dryer Size the signal would be measured after the chamber was
contaminated with a known amount of silicone oil that
Shelf Chamber
should be at least 5 times higher than the average
Area Volume
background noise level detected. The time until this
Unit [m2] [m3] [mg]
condition was reached is given as “Max time” in Table
FCM-2 0.1 0.08 0,4 II. After 12 h of evacuation the noise level was slightly
GT-10 0.8 0.21 1 below 0.2 ppm, resulting in the ability to safely detect
GT-300-D 24.8 9.1 45 silicone oil contamination down to 1 ppm. This trans-
FCM-400-D 20 6.1 30 lates in absolute numbers to 1 mg for a GT/FCM 10,
FCM-500-D 44 12.2 60 and 60 mg for a FCM 500-D. An average drop of
silicone oil generated by a pipette has a weight of 10
mg.
m2. While the drying chamber was evacuated to the A summary of the results obtained is given in Table II.
desired vacuum level, the vial containing the silicone
oil was stored in an attached small compartment sep- Evaluation of Further Possibilities
arated by a valve. After the desired vacuum level had
been reached in the main drying chamber, the sepa- Performing a leak test is a standard procedure when
rating valve was opened. As a result the pressure of the assuring the integrity of a freeze drying chamber. The
small compartment (now connected with the main test requires the chamber and condenser to be evacu-
chamber) dropped, which resulted in the vaporization ated to a pre-defined pressure, all valves closed, and
of the silicone oil. This test confirmed again the char- the rise in pressure monitored. To assure a meaningful
acteristic signal pattern of silicone oil (Figure 5). measurement this is often done for between 2 and 4 h.
A mounted mass spectrometer offers a much faster
Measurements on Production Units way. Tests proved that a total measurement time of 20
min is sufficient if a mass spectrometer is used. Before
The detection system was mounted onto production evacuation the chamber is flushed with nitrogen. After
size freeze driers. Drier sizes tested are shown in the desired vacuum level has been reached all valves
Table I. While two of these driers were installed at are closed and the composition of the remaining gas
GEA Lyophil, the other three are manufacturing units (⬎99% nitrogen) is monitored. As a result of small
installed at European production sites of two multina- leaks (which can be found in every industrial freeze
tional pharmaceutical companies. dryer), air flows into the chamber can be detected by
monitoring the rise in concentration of oxygen.
Dynamic effects have to be taken into consideration as
a result of the larger dimensions of production-scale Summary and Outlook
driers. To achieve an enhanced sensitivity, the mea-
surement is done when the mushroom valve between A model for the quantitative analysis of the oxygen
the product chamber and condenser chamber is closed. signals has been developed. Due to the sensitivity

TABLE II
Measurements in Chambers of Different Sizes

Unit Max
Test Size Amount Time Peak
No. Unit Type [m2] [mg] AMU [sec] [ppm]
1 FCM-2 0.5 2 73, 71, 75 0 ⬎10
2 GT 10 0.8 2 73, 71, 75 5 5
3 GT 300-D 24.8 49 73, 71, 75 20 2.9
4 FCM 400-D 20 51 73, 71, 75 42 3.3
5 FCM 500-D 44 100 73, 71, 75 89 3.1

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and fast response of the instrument, it can addition- Declaration of Interest

ally be used to determine the location of leaks in the
chamber. The authors declare that they have no competing in-
terests.
In addition, the spectrometer can also detect the con-
centration of water in the freeze drying chamber. This References
means that it can be used as a process analytical
technology tool for monitoring the drying cycle and 1. Handbook of Vaccuum Technology, 1st ed.;
the safe and non-invasive detection of the end points Jousten, J., Ed.; Wiley-VCH Verlag GmbH & Co.
of primary and secondary drying. KGaA,Weinheim, Germany, 2008.

The system is currently retrofitted to two production- 2. NIST Chemistry WebBook; NIST (National Insti-
scale freeze driers owned by multinational pharmaceu- tute of Standards and Technology) Standard Ref-
tical companies, with additional companies currently erence Database Number 69, http://webbook.nist.
evaluating the potential of the method. (1, 2) gov/chemistry.

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