Physical Sciences Inc. VG15-012 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. 20 New England Business Center Andover, MA 01810
Outline VG15-012 -1 Background & Motivation H 2 O 2 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
Sterile Processing in Barrier Isolators Pharmaceutical products manufactured in sterile (aseptic) conditions to prevent contamination and maintain quality VG15-012 -2 Incomplete sterilization of manufacturing facilities causes pharmaceutical product recalls, leading to financial loss and compromised patient health
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 VG15-012 -3
Typical Sterilization Cycle (from Bioquell) VG15-012 -4
New Challenge: Lower VPHP Detection Limit VG15-012 -5 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)
Spectroscopic Modeling VG15-012 -6 Goal: Use spectroscopic modeling to determine system parameters suitable for detecting 10 ppb VPHP in 10,000 ppm water vapor HITRAN database used to calculate spectra Parameters / criteria: Laser wavelength Absorption line strength Non-overlapping spectral features Use CH 4 as calibration gas Identified conditions ideally suited to VPHP detection application
Quantum Cascade Laser to Probe VPHP Absorption Line VG15-012 -7 Robust semiconductor laser Compact High power, hits target wavelength Room temperature operation Compatible with field-deployment/productization
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 VG15-012 -8
PAS Figures of Merit (to Maximize Sensitivity) PAS signal amplitude is quantity to maximize Microphone converts pressure signal (A n ) to voltage A C ( ) W α : gas absorption coefficient (cm 1 ) W L : light power n n n L PAS signal is linearly proportional to light power and cell constant (C n ) C n ( 1) LFnQ n V cell n Q : resonator quality factor, V : volume : adiabatic ratio F : scaling factor VG15-012 -9 Best resonator shape is long and skinny (like a flute or clarinet!)
PAS Major Drawback VG15-012 -10 Detection of 1 ppmv CH 4 corresponds to ~0.5 ppmv H 2 O 2 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 H 2 O 2 with <±10 ppbv precision When μ σ, background noise offset interferes Challenging to detect 10 ppbv H 2 O 2
Acoustic Modeling to Optimize Resonator Design Optimize cylindrical acoustic resonator design for trace-detection Measure longitudinal standing wave Increase photoacoustic signal Minimize background noise VG15-012 -11 A. Miklo s, P. Hess, and Z. Bozo ki, Application of acoustic resonators in photoacoustic trace gas analysis and metrology, Rev. Sci. Instrum., vol. 72, no. 4, p. 1937, 2001.
Simulation Results: Resonator Properties vs. Length VG15-012 -12 Intensity Map (A.U.) P= 1 atm R = 2.5 mm T = 45 C Cell constant increase is sub-linear Resonator transmission drops exponentially Leads to reduced background noise Q decreases because surface losses increasingly dominate
Noise Transmission vs. Buffer & Resonator Dimensions VG15-012 -13 Choose buffer dimensions for minimal noise
Curves of Growth (CH 4 ) for Different Resonator Dimensions VG15-012 -14 Experimental curves of growth validate theoretical model
Allan Deviation (CH 4 ) VG15-012 -15 Implies ~3 ppb detection limit after 60 s averaging
COG and Experimental Detection Limit w/ Methane VG15-012 -16 Microphone Noise: ~100 nv Hz 1/2 Lock-in: t=2 sec. f BW =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 C 5ppbv Implies 2.5 ppbv H 2 O 2 LOD 30
VPHP Experimental Setup to Validate CH 4 Results VG15-012 -17 Sigma-Aldrich H 2 O 2 and reagent grade H 2 O 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
PAS Comparison to Commercial VPHP Sensor (Drager) PAS vs. Drager VG15-012 -18 Compare Drager to Raoult s Law PAS Cell & Drager measurements agree within measurement range, precision of Drager
Optimized Resonator H 2 O 2 COG at 760 Torr Has Baseline VG15-012 -19 Limit of Detection (LOD) is governed by ambient water vapor concentration For 10,000 ppmv H 2 O, LOD is 0.1 ppmv For 7,000 ppmv H 2 O, LOD is ~ 80 ppbv For dry air/n 2 only LOD would be (based on CH 4 results) 4.5 ppbv
Measured Absorption Spectra at Different Pressures Ambient Pressure Reduced Pressure VG15-012 -20 Minimum noise with 10,000 ppmv of water present is ~7.3 mv Indicates the LOD is: 0.0073V 2.2 ppmv 90 ppbv 0.17V Minimum noise with 10,000 ppmv of water present is ~0.5 mv Indicates the LOD is: 0.0005V 1ppmv 32 ppbv 0.016V
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 VG15-012 -21
Summary VG15-012 -22 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 CH 4
Questions?