Ethylene Oxide ResidualsAn Alternative Testing

Method

Presented to:U.S. Technical Advisory Group for ISO/TC 198

April 24, 2007

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Drivers for Alternative MethodsDrivers for Alternative Methods

Meet new standard requirements for Meet new standard requirements for

1099310993--7 & 109937 & 10993--1818

Research alternative methodologies Research alternative methodologies

for Chemical Characterizationfor Chemical Characterization

Determine compliant, cost effective Determine compliant, cost effective

“One Shot Analysis”“One Shot Analysis”

Seek method that minimizes product Seek method that minimizes product

consumptionconsumption

ReviewReviewEquipment is QualifiedEquipment is Qualified

Validating test method for the analysis of Validating test method for the analysis of

EO/ECH/EGEO/ECH/EG

Publishing in scientific journal this yearPublishing in scientific journal this year

Evaluate & develop other applicationsEvaluate & develop other applications

�� Currently validating a method for the Currently validating a method for the

analysis of water content in polymers to analysis of water content in polymers to

assist with establishing manufacturing assist with establishing manufacturing

specificationsspecifications

Absorption of Infrared RadiationAbsorption of Infrared Radiation

FTIR TechnologiesFTIR Technologies

Absorbance / Wavenumber (cm-1) Y-Zoom CURSOR

File # 2 : 71_4H2O 3/23/2007 10:44 AM Res= 4.000

Water in G.5 N2, Cosameter 74.57 ppm -3.16 ppm BG= 71.41 ppm, 10m,0.981 atm, 121C,Avg files 34-36 BAL

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Gas Phase FTIR

Typical Bench Top FTIR

High Resolution vs. Low ResolutionHigh Resolution vs. Low Resolution

Absorbance / Wavenumber (cm-1) Y-Zoom CURSOR

File # 2 : 71_4H2O

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High Resolution (0.5 cm-1)

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Fourier Transform Fourier Transform

(Time Domain to Frequency)(Time Domain to Frequency)

Interferogram (Time Domain Spectrum)Interferogram (Time Domain Spectrum)

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Transformed InterferogramTransformed InterferogramFrequency DomainFrequency Domain

Photon intensity at the detector (YPhoton intensity at the detector (Y--axis) at each wavenumber cmaxis) at each wavenumber cm--1 (X1 (X--axis)axis)

�� Single beam spectrumSingle beam spectrum

Arbitrary Y / Wavenumber (cm-1) Y-Zoom CURSOR

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Water Absorbance (specific frequencies)

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Single Beam (SBBKG)

Single Beam (SBSample)

Transmission SpectrumTransmission Spectrum

Transmission Spectrum of Water Transmission Spectrum of Water �� Simple intensity ratio (SBSimple intensity ratio (SBsamplesample/SB/SBbg)bg)

�� Scales logarithmically with concentrationScales logarithmically with concentration

Transmittance / Wavenumber (cm-1) Y-Zoom CURSOR

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Transmittance:Transmittance:

oI

IT =

Absorbance SpectrumAbsorbance Spectrum

Absorbance of Spectrum of Water Absorbance of Spectrum of Water

�� Absorbance = Log 10 1/TransmissionAbsorbance = Log 10 1/Transmission

�� Scales linearly with concentrationScales linearly with concentration

Absorbance / Wavenumber (cm-1) Y-Zoom CURSOR

File # 5 : 23_9H2O 11/11/2006 8:45 PM Res=None

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Absorbance:Absorbance:

I

IlogA

o=

Beer’s Law SummaryBeer’s Law Summary

Ai = ai * b * ci

Ai = Absorption at a given frequency o the ith sample component

ai = Absorption coefficient (absorptivity) of the ith sample component

b = Pathlength of cellci = Concentration of ith sample

A = log10 (1/T) = -log10 TA = AbsorbanceT= Transmittance

Absorption CoefficientAbsorption Coefficient

& Pathlength& Pathlength

Certified gases are used to generate single Certified gases are used to generate single

component reference standardscomponent reference standards

The The absorption coefficientabsorption coefficient is a property of a is a property of a

material and it defines the extent to which a material and it defines the extent to which a

material absorbs energy material absorbs energy

�� Affected by TemperatureAffected by Temperature

�� Affected by PressureAffected by Pressure

Path length is fixed and calibratedPath length is fixed and calibrated

Innovative New Alternative toInnovative New Alternative to

Existing Technologies ….Existing Technologies ….

Detection of Acids, Bases, and VolatilesDetection of Acids, Bases, and Volatiles

Identification and QuantitationIdentification and Quantitation

Fast collection and analysis time Fast collection and analysis time –– Get Product Get Product

to Market Fasterto Market Faster

Provides Low Limits of Detection required by Provides Low Limits of Detection required by

GuidelinesGuidelines

Static Headspace FTIRStatic Headspace FTIR

FTIR Static Headspace (SHS):Outgassing Profile

FITR Spectra

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Ab

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Unit

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Time

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

SAMPLE

IR Source

IR Detector

FTIR Static Headspace (SHS):Outgassing Profile

FITR Spectra

Co

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ntr

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sorb

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Unit

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Time

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

SAMPLE

IR Source

IR Detector

FTIR Static Headspace (SHS):Outgassing Profile

Co

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ntr

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Unit

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Time

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

IR Source

IR Detector

FTIR Static Headspace (SHS):Outgassing Profile

FITR Spectra

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ntr

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sorb

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Unit

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Time

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

SAMPLE

IR Source

IR Detector

FTIR Static Headspace (SHS):Outgassing Profile

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

FITR Spectra

Co

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ntr

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Ab

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Unit

s

Time

SAMPLE

IR Source

IR Detector

FTIR Static Headspace (SHS):Outgassing Profile

FTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

FITR Spectra

Co

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ntr

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sorb

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Unit

s

Time

SAMPLE

IR Source

IR Detector

Multiple Regions for AnalysisMultiple Regions for Analysis

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Ethylene Oxide Reference Spectrum

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Pag ed Z-Zoom CU RSOR

Reference Spectra of Reference Spectra of EOEO//ECHECH//EGEG

EO Reference

Spectrum

ECH Reference

Spectrum

EG Reference

Spectrum

Calibration Reference SpectraCalibration Reference Spectra(Prediction Model)(Prediction Model)

-2.2720.0353.52654.7755EO_H

0026.2926.2926EO_H

-4.4550.01213.70114.3414EO_H

8.3160.0128.6768.018EO_H

2.1430.0125.3835.275EO_HSPC

Prediction %Error (ppm)

SEC (ppm)

Predicted Conc (ppm)

Actual Conc (ppm)Filename

CLS Prediction Model LinearityCLS Prediction Model Linearity

Linearity of EO at 121 oC

y = 0.9821x

R2 = 0.9993

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Actual Concentration (PPMv)

Pre

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Co

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PP

Mv)

AnalysisAnalysisReference spectra Reference spectra

�� Prepared on the instrument used for analysis but can be transferPrepared on the instrument used for analysis but can be transferred to red to other instrumentsother instruments

�� Recorded at the experimental temperature / conditionsRecorded at the experimental temperature / conditions

�� Concentration is measured using second technique or certified Concentration is measured using second technique or certified standardstandard

�� Multiple concentrations are prepared to bracket the experiment rMultiple concentrations are prepared to bracket the experiment range ange

Reference spectra are implemented into a Classical Least SquaresReference spectra are implemented into a Classical Least Squares (CLS) (CLS) fit routinefit routine

Sample Spectra are quantified by comparison to Single Component Sample Spectra are quantified by comparison to Single Component Reference spectra using CLSReference spectra using CLS

Multiple Species can be quantified simultaneouslyMultiple Species can be quantified simultaneously

�� Analysis regions can be chosen to avoid interferences Analysis regions can be chosen to avoid interferences

�� Multiple regions can be chosen to circumvent saturated absorbancMultiple regions can be chosen to circumvent saturated absorbance e bands that may deviate from Beer’s Law bands that may deviate from Beer’s Law

IDEAL GAS LAWIDEAL GAS LAW

PV = nRTPV = nRT

Cell Volume = 5.7 LCell Volume = 5.7 L

Pressure = 1 atmPressure = 1 atm

Molecular Weight = 44 g/molMolecular Weight = 44 g/mol

Cell Temperature = 121 Cell Temperature = 121 ooCC

Mass(g) Sample))CoTemp( Cell(273

Kmol

atmL 0.08206

ol)Weight(g/mMolecular tm)Pressure(aVolume(L) Cellion(PPMv)Concentrat

g

g

••

•••

+

=

µ

•

•

Recovery of EO SpikesRecovery of EO Spikes

7.4% RSD

100.6Average Recovery

92.68.7

116.711.2

96.69.8

99.110.6

103.029.5

103.030.3

102.029.9

101.131.3

100.020.9

99.719.3

107.319.1

86.115.7

% RecoveryMeasured Concentration

(PPMv)

OutgassingOutgassing rates @ rates @

121121ooC (Exhaustive) and C (Exhaustive) and

37C (Simulated use)37C (Simulated use)

EO Release from Medical Device 121oC

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Elapsed Time (Hours)

PP

Mv

121C EO

37C EO

Exhaustive Outgassing of Exhaustive Outgassing of

1 Medical Device1 Medical Device

Outgassing of EO @ 121C

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Elapsed Time (Hours)

EO

PP

Mv

Nitrogen purge

Max PPMv @ ~ 13 hours

1.5 hrs static after purge max PPMv = 0.6 ppmv

EO Spike in Biodegradable EO Spike in Biodegradable

Polymer MatrixPolymer Matrix

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Absorbance / Wavenumber (cm-1)

Water

absorbance

Carbon Dioxide

absorbance

CH4 Stretch of Polymer

Fingerprint absorbance of

Polymer

Spectrum of Biodegradable Polymer OutgassingSpectrum of Biodegradable Polymer Outgassing

EO Spike in Biodegradable EO Spike in Biodegradable

Polymer MatrixPolymer Matrix

Polymer outgassing spiked with EO Polymer outgassing spiked with EO

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Absorbance / Wavenumber (cm-1)

EO Spike in Biodegradable EO Spike in Biodegradable

Polymer MatrixPolymer Matrix

ResidualResidual Spectrum after Subtraction of Polymer Spectrum after Subtraction of Polymer

absorbanceabsorbance

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Absorbance / Wavenumber (cm-1)

EO absorbance bands

suitable for quantitation

EO Spike in Biodegradable EO Spike in Biodegradable

Polymer MatrixPolymer MatrixFingerprint overlay of Fingerprint overlay of Residual Spiked Polymer Residual Spiked Polymer spectrumspectrum and and EO Reference spectrumEO Reference spectrum

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Absorbance / Wavenumber (cm-1)

EO Spike in Biodegradable EO Spike in Biodegradable

Polymer MatrixPolymer MatrixResidual spectrumResidual spectrum after subtraction of after subtraction of Reference EOReference EO

Absorbance / Wavenumber (cm-1)

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Spiked EO Concentration (barometrically delivered) Spiked EO Concentration (barometrically delivered) -- 10.95 10.95 ppmvppmv

FTIR Indicated Concentration (CLS analysis) FTIR Indicated Concentration (CLS analysis) -- 11.46 11.46 ppmvppmv

105 % Recovery105 % Recovery

EO Matrix Spike on Outgassing Medical EO Matrix Spike on Outgassing Medical

DeviceDevice

Simulated Use

EO Release @ 37oC

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Elapsed Time (Hours)

PP

Mv

EO

EOEO Spike 103% Recovery

EO Spike 114% Recovery

24 Hour outgas

= 4.8 ppmv

= 38 ug EO

Recovery of EO Matrix SpikesRecovery of EO Matrix Spikes

at 121 at 121 ooCC

3 %Percent RSD

107Average Spike

1062.862.708

1035.555.387

1104.444.036

1094.434.055

1094.594.034

11014.8313.423

10511.4610.952

1017.797.711

Average Recovery (%)

Average Indicated PPM

Average Prepared PPM

Spike

Method AdvantagesMethod Advantages

RealReal--time data collection allows time data collection allows

calculation of release rates, calculation of release rates,

formation of compounds, & formation of compounds, &

outgassing endpoints outgassing endpoints

FTIR method allows simultaneous FTIR method allows simultaneous

data collection for materials data collection for materials

characterization (ISO 10993characterization (ISO 10993--18 )18 )

Method AdvantagesMethod Advantages

FTIR is additive, interferences can FTIR is additive, interferences can

be subtractedbe subtracted

Multiple compounds can be Multiple compounds can be

detected in a single test using fewer detected in a single test using fewer

devices for testingdevices for testing

Limits of Detection can be lower Limits of Detection can be lower

than GC methodsthan GC methods

Method AdvantagesMethod AdvantagesBroad range of selectivity for Broad range of selectivity for

detection of compounds (organic detection of compounds (organic

and inorganic)and inorganic)

Multiple spectral regions can be Multiple spectral regions can be

used to quantify compoundsused to quantify compounds

Recent ASTM, NIOSH & EPA Recent ASTM, NIOSH & EPA

approvalsapprovals

--Methods have been validatedMethods have been validated