Innovations at INTERPHEX Guide 2022 - 18

Commercial Applications of a Residual
Gas Analyzer for Lyophilization
Vaibhav Kshirsagar,1
and Francis DeMarco2
1Technical Product Manager, IMA Life, Tonawanda, NY
2Technology Manager, IMA Life, Tonawanda, NY
Introduction
Process monitoring and sterility assurance are critical
for ensuring batch quality and eventual product release
for freeze-dried or lyophilized drug products. In freeze
drying or lyophilization, drug products are susceptible
to certain infrequent occurrences of contamination that
can pose a significant risk to product quality. In addition,
the use of process analytical technologies in maintaining
the assured state of a validated process is important
for continued process verification. FDA's guideline
UCM074909 on the freeze drying process also refers to
the necessity of monitoring the leak rate of a system
periodically to maintain its integrity and to investigate
and determine the actual leak site for the purposes of
repair should the leak rate exceed the specified limits.
It further goes to emphasize that the leakage into a
lyophilizer may originate from various sources. It may
be a leakage occurring from the atmosphere or outside
environment into the vessel itself or from other media
sources employed throughout the system. One of these
is silicone oil used as a thermal fluid for heat transfer in
the shelves of a lyophilizer. Proposed revisions to Annex
1 also indicate a regulatory proposal to include the
detection of contaminants such as silicone oils and other
hydraulic fluids in lyophilizer leak testing protocols.
In this paper, we discuss experimental approaches
aimed at effective sterility assurance with respect to
contaminant detection using mass spectrometers.
Materials and Methods
A mass spectrometer, Quantum, developed and
manufactured by Atonarp, CA in collaboration with
IMA Life, NY is used in this study. The Quantum mass
spectrometer has a sampling range of 0-100 amu and
is commonly intended for freeze drying applications. To
establish a sensitivity curve that tests the effectiveness
of the mass spectrometer under consideration, some
experiments were conducted using gas permeators by
Atonarp in Fremont, CA. These experiments used a PD-1B
gas permeator from Gastec Corp, which allows a measured
quantity of vaporized contaminant such as silicone oil to be
injected into the Quantum mass spectrometer along with a
nitrogen carrier gas. This method is highly reliable because
the concentration of the silicone oil gas is determined by
calculating the decrease in weight of the permeation tube
and the quantity of dilution gas. Thus, a measured PPM
quantity of silicone oil was injected into the Quantum mass
spectrometer and the ion current response was measured.
To test the limits of detection in pilot and production
lyophilizers, the mass spectrometer was connected to
two freeze dryers, Lyofast3 and Lyomax40 manufactured
by IMA Life in Tonawanda, NY. 100mm Fisherbrand petri
dishes from Fisher Scientific were used for containing
measured quantities of a 5cSt
silicone heat
transfer
oil from Dow Chemicals. The quantity of silicone oil
in each petri dish was limited to 400mg to allow for
a thin even layer. The schematic in Figure 1 shows a
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