Compact Hydrogen Peroxide Sensor for Sterilization Cycle Monitoring

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

[email protected]

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.

VG15-012

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

VG15-012 -1 -1


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

VG15-012 -2 -2


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 -3


Typical Sterilization Cycle (from Bioquell)

VG15-012 -4 -4


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)

VG15-012 -5 -5


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

VG15-012 -6 -6


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

VG15-012 -7 -7


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 -8


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 nn

cell n

LF QC

V

Q : resonator quality factor,

V : volume

: adiabatic ratio

F : scaling factor

VG15-012 -9 -9


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

VG15-012 -10 -10


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. Miklos, P. Hess, and Z. Bozoki, “Application of acoustic resonators in photoacoustic trace gas analysis and metrology,” Rev. Sci. Instrum., vol. 72, no. 4, p. 1937, 2001.

VG15-012 -11 -11


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

VG15-012 -12 -12


Noise Transmission vs. Buffer & Resonator Dimensions

Choose buffer

dimensions for

minimal noise

VG15-012 -13 -13


Curves of Growth (CH4) for Different

Resonator Dimensions

Experimental curves of growth validate theoretical model

VG15-012 -14 -14


Allan Deviation (CH4)

Implies ~3 ppb detection limit after 60 s averaging

VG15-012 -15 -15


• 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

Cppbv

COG and Experimental Detection Limit w/ Methane

VG15-012 -16 -16


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

VG15-012 -17 -17


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

VG15-012 -18 -18


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

VG15-012 -19 -19


0.00051 32

0.016

Vppmv 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:

0.00732.2 90

0.17

Vppmv ppbv

V

Ambient Pressure Reduced Pressure VG15-012 -20 -20


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 -21


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

VG15-012 -22 -22


Questions?

Healthcare

Compact Hydrogen Peroxide Sensor for Sterilization Cycle Monitoring