Physical Sciences Inc. developed a compact hydrogen peroxide sensor using photoacoustic spectroscopy to monitor sterilization cycles. Strict limits on residual vapor phase hydrogen peroxide require detection down to 10 parts per billion, challenging with current technology. Through spectroscopic modeling and acoustic resonator optimization, the sensor achieves a detection limit of approximately 32 parts per billion of hydrogen peroxide in 10,000 parts per million of water vapor interference. Experimental results validate the sensor performance compared to an industry standard. The low-cost, field-deployable sensor will aid pharmaceutical manufacturing in ensuring sterile conditions.

1. Physical Sciences Inc. 20 New England Business Center Andover, MA 01810
Physical
Sciences Inc.
Compact Hydrogen Peroxide Sensor for
Sterilization Cycle Monitoring
January 26, 2015
Krishnan R. Parameswaran, Clinton J. Smith,
Kristin L. Galbally-Kinney, William J. Kessler
krp@psicorp.com
Acknowledgement of Support
The project described was supported by Award Number 4R44EB013517 02 from the National Institute of Biomedical Imaging and Bioengineering. The content is
solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institute of Biomedical Imaging and Bioengineering or
the National Institutes of Health.
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2. Physical Sciences Inc.
Outline
 Background & Motivation
– H2O2 facilitates sterile processing in pharmaceutical manufacturing
– Difficult to measure extremely low (part-per billion) concentrations
 Solution: Photoacoustic Spectroscopy – Less (cost, size) is More
 Sensor Development Results
 Summary
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Sterile Processing in Barrier Isolators
 Pharmaceutical products manufactured in sterile (aseptic)
conditions to prevent contamination and maintain quality
 Incomplete sterilization of manufacturing facilities causes
pharmaceutical product recalls, leading to financial loss and
compromised patient health
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4. Physical Sciences Inc.
Vapor Phase Hydrogen Peroxide (VPHP) Sterilization
 Liquid hydrogen peroxide solution vaporized and sent into
isolator to sterilize
 Sterilant must be removed to very low levels prior to
pharmaceutical filling operations
– Low VPHP concentration measurement is difficult due to water vapor
interference
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5. Physical Sciences Inc.
Typical Sterilization Cycle (from Bioquell)
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New Challenge: Lower VPHP Detection Limit
 New biologic drugs more sensitive to VPHP
– Must reduce concentration to 10 ppb before manufacturing
 Current state of the art not able to reach 10 ppb (0.01 ppm)
detection limit
 Goal:
Develop (robust) commercial sensor capable of measuring
10 ppb VPHP in presence of 10,000 ppm water vapor
 PSI Approach:
Mid-Infrared Laser-Based Photoacoustic Spectroscopy
(MIR PAS)
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Spectroscopic Modeling
 Goal: Use spectroscopic modeling to determine system parameters
suitable for detecting 10 ppb VPHP in 10,000 ppm water vapor
 Identified conditions ideally suited to VPHP detection application
 HITRAN database used to
calculate spectra
 Parameters / criteria:
– Laser wavelength
– Absorption line strength
– Non-overlapping spectral
features
 Use CH4 as calibration gas
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8. Physical Sciences Inc.
Quantum Cascade Laser to Probe VPHP Absorption Line
 Robust semiconductor laser
– Compact
– High power, hits target wavelength
– Room temperature operation
– Compatible with field-deployment/productization
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VPHP Measurement Method:
Photoacoustic Spectroscopy (PAS)
 As in optical spectroscopy, mid-infrared laser probes fundamental
ro-vibrational absorption lines
– Produces strong absorption
– High sensitivity
 Absorbed light creates heat  increases pressure
– Modulating laser beam creates acoustic wave detected by microphone
 Acoustic detection eliminates expensive optical mirrors and detector
– Low cost
– Compact size
– Long-term measurement stability
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10. Physical Sciences Inc.
PAS Figures of Merit (to Maximize Sensitivity)
 PAS signal amplitude is quantity to maximize
– Microphone converts pressure signal (An) to voltage
– PAS signal is linearly proportional to light power and cell constant (Cn)
– Best resonator shape is long and skinny (like a flute or clarinet!)
( )n n n LA C W  α : gas absorption coefficient (cm−1)
WL : light power
( 1) n n
n
cell n
LF Q
C
V



 Q : resonator quality factor,
V : volume
 : adiabatic ratio
F : scaling factor
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PAS Major Drawback
• Isolate microphone from background “noise”
• Reduces trace sensitivity and drifts over time
• Very precise (small σ) when average signal (μ) is greater than σ
• e.g. “Can measure 1 ppmv H2O2 with <±10 ppbv precision”
• When μ≈σ, background noise offset interferes
• Challenging to detect 10 ppbv H2O2
Detection of 1 ppmv CH4 corresponds to ~0.5 ppmv H2O2
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12. Physical Sciences Inc.
Acoustic Modeling to Optimize Resonator Design
 Optimize cylindrical acoustic resonator
design for trace-detection
– Measure longitudinal standing wave
– Increase photoacoustic signal
– Minimize background noise
A. Miklós, P. Hess, and Z. Bozóki, “Application of acoustic
resonators in photoacoustic trace gas analysis and
metrology,” Rev. Sci. Instrum., vol. 72, no. 4, p. 1937, 2001.
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Simulation Results: Resonator Properties vs. Length
 Cell constant increase is sub-linear
 Resonator transmission drops exponentially
– Leads to reduced background noise
 Q decreases because surface losses increasingly dominate
Intensity Map (A.U.)
P= 1 atm
R = 2.5 mm
T = 45 °C
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Noise Transmission vs. Buffer & Resonator Dimensions
 Choose buffer
dimensions for
minimal noise
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Curves of Growth (CH4) for Different
Resonator Dimensions
 Experimental curves of growth validate theoretical model
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Allan Deviation (CH4)
 Implies ~3 ppb detection limit after 60 s averaging
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• Microphone Noise: ~100 nv Hz−1/2
• Lock-in: t=2 sec.  fBW=0.08 Hz
• Lock-in output (with microphone noise) = 28.2 nV
• From slope of 7cm curve
• 1 [nV/ppbv] C [ppb] = 28.2 nV
• With 2 sec. time constant, microphone noise limited detection limit is: C = 28 ppbv
• 1 minute averaging brings it down to
 Implies 2.5 ppbv H2O2 LOD
5
30
C
ppbv
COG and Experimental Detection Limit w/ Methane
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18. Physical Sciences Inc.
VPHP Experimental Setup to Validate CH4 Results
 Sigma-Aldrich H2O2 and reagent grade H2O
 Cooled to <10 °C to avoid condensation on tubing
 Flow at < 300 sccm to reduce noise from turbulence
 Drager in-line for near-simultaneous comparison
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PAS vs. Drager
PAS Comparison to Commercial VPHP Sensor (Drager)
● Compare Drager to Raoult’s Law
● PAS Cell & Drager measurements agree within measurement
range, precision of Drager
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20. Physical Sciences Inc.
Optimized Resonator H2O2 COG at 760 Torr Has Baseline
 Limit of Detection (LOD) is governed by ambient water vapor
concentration
 For 10,000 ppmv H2O, LOD is 0.1 ppmv
 For 7,000 ppmv H2O, LOD is ~ 80 ppbv
 For dry air/N2 only LOD would be (based on CH4 results) 4.5 ppbv
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0.0005
1 32
0.016
V
ppmv ppbv
V
 
• Minimum noise with 10,000 ppmv
of water present is ~0.5 mV
• Indicates the LOD is:
Measured Absorption Spectra at Different Pressures
• Minimum noise with 10,000 ppmv
of water present is ~7.3 mV
• Indicates the LOD is:
0.0073
2.2 90
0.17
V
ppmv ppbv
V
 
Ambient Pressure Reduced Pressure
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PSI VPHP Sensor User Interface Details
• Fits in 19" rack drawer, including control electronics
• Touch screen user interface
• Swagelok gas connections
• Product release expected mid-2015
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Summary
 New biologic drugs more sensitive to VPHP than small
molecules
 Must reduce concentration to as little as 10 ppbv before
manufacturing
 Current state of the art spectrometers have ~ 0.1 ppmv
detection limit
 Demonstrated photoacoustic VPHP detection in compact,
low-cost platform
– High dynamic range (> 4 orders of magnitude)
– Detection limit of ~32 ppbv
– Easily calibrated with CH4
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Questions?