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NeSSI Analytical Applications
Brian Marquardt Ph.D. Charles Branham, Wes Thompson, Thomas Dearing, Michael Roberto, Lauren Hughs, Giacomo Guarrera* (Matric Europa) Applied Physics Laboratory University of Washington Seattle, WA 98105
Where Does NeSSI Fit in the Lab Instrument/Sensor Interfaces
Design standards make development simpler Reduced toolset to be mastered Reduced sample variability to account for
Calibration/validation built-in Consistent physical environment for measurement Stream switching and/or mixing allow generation of
standards to match analytical requirements
Reaction monitoring Microreactors and continuous flow reactors Batch reactors (with fast loop)
Sample Preparation Gas handling (mixing, generation, delivery) Liquid handling (mixing, dilution, conditioning, etc.)
NeSSI with an Array of Micro-Analytical Techniques will Impact Many Industries
• Process Control • Process Optimization • Product Development
Thermo/C2V Fast Micro-GC
http://www.c2v.nl/ as well as http://www.thermo.com
Applied Analytics Inc. Diode Array OMA-300 A Fiber-optics-diode-
array process analyzer For on-line concentration
monitoring
NeSSI Ballprobe - Raman/NIR/UV
Matrix Solutions: www.ballprobe.com
Ballprobe Specs. •Hastalloy c-276
Ti, SS, Monel •Sapphire optic •Std. temp range:
-40 – 350° C •Pressure:
0-350 Barr
Kaiser Airhead Raman Gas Probe
AirHeadTM Probe with compression mount
NeSSI interface
AirHeadTM Probe with
NPT- Threaded mount
NeSSI interface
H2Scan Adaptation to NeSSITM Platform • Hydrogen specific: 0.5% H2 to 100% H2 v/v
• Response time (T90) < 30 sec
• In-line, real-time measurements in process gas streams up to 100OC
• Unique models for CO, H2S, wet CL2
• 4-20mA, RS422 or RS232 serial connectivity
• Stable results
• On-site verification and calibration
• Approved for hazardous locations – Intrinsically safe design – ATEX certificate granted; UL pending
• Cost effective to buy / install / maintain
• Field verification and calibration kit available
http://www.h2scan.com/
Astute Sampling System
GAS TREATMENT
COLUMN
Sampling + Sensors & micro-analyzers
Astute System with C2V Micro GC and H2Scan hydrogen analyzer Process
www.eif-filters.com
Agilent NeSSI Dielectric Sensor Cable to Agilent
Network Analyzer
Swagelok 2-Port
Valve Base
Dielectric Probe
Inner Body
O-ring (inside)
Outer Body
Close up of Coaxial
Probe Tip
Teledyne: NeSSI Oxygen Sensor Fuel Cell or Zirconium Oxide Sensors Offer an SP76 compliant oxygen
sensor Available concentration ranges
0-10 ppm, 0-1000 ppm, 0-3%, 0-25%, 0-100% oxygen
Response time T90% < 45 seconds, Fuel Cell T90% < 10 seconds, Zirconium Oxide
Operating Temperature: 0-50˚C Signal output
4-20 mA and 0-10 VDC
http://www.teledyne-ai.com/
Mechatest Sampling Solutions
NeSSI Liquid Sampler Compliant with ANSI/ISA 76.00.02 38.2 mm
(1.5 in.) footprint. Three Port configuration: Sample Inlet,
Bypass and Vent. Quick and safe operation, low dead volume
design with bypass. Manual or Automatic sampling In-line Sampling Closed Loop and Emission Free Sampling Easy in operation
http://www.mechatest.nl/
Initial NeSSI Gas Blending System
NeSSI Gas/Vapor System
Aspectrics EPIR w/ glass cell
N2 Waste
NeSSI Flow Cell
ASI microFAST GC
Analog NeSSI Gas Mixture System
Features of Circor System obtained for UM: 1. 4 gasses line, able to produce and maintain gas mixtures 2. Fully automated system, set and forget capability
Automated NeSSI System
4 x Gasses
Mixed Gases
Mass Flow Controllers
Calibrated Analog Gas Mixer
- 3 stream calibrated mixing with fiber optic oxygen/temperature/humidity sensing
Digital Calib. Gas Generation System Features of NeSSI System : • Fully digital
• RS 485 • 4 Stage dilution,
able to produce and maintain gas concentrations in 1-5 ppm range
• Fully automated system, set and forget capability
• Integrated C2V NeSSI compat. GC
• Calib, platform for gas sensor dev.
Gas Calib. System LabView Control Program • Perform automated DoE calibration runs • Input and log sensor, reference, temperature and pressure feeds • System designed for full digital (plug and play) performance as h/w matures
Modular NeSSI Oxygen Gas Sensor
Exploded View
1/16 in bifurcated fiber optic fiber
1/16 to 1/8 in Swagelok union
Agilent NeSSI Mount
Sensor Body
Close up of Outer Body Tip
Vapochromic Tip
Fiber optic ferrule with plastic housing
Sensor response to O2 Gas
Pre
dict
ed O
2 %
Calculated O2 %
R2 = 0.990, 3 PC RMSEC = 1.0744
20 replicates at each concentration Concentration range: 0 -100% Oxygen 16 ms reversible response full range
Inte
nsity
(cou
nts)
Wavelength (nm)
100 %
0%
120
100
80
60
40
20
0 100 90 80 70 60 50 40 30 20 10 0
0 10 20 30 40 50 600
10
20
30
40
50
60
Measured Oxygen Concentration(micromol/liter)
Pred
icte
d O
xyge
n C
once
ntra
tion(
mic
rom
ol/li
ter)
R2 = 0.9982 Latent VariablesRMSEC = 0.90163Bias = -7.1054e-015
Sensor Response for O2 in Solution
5 replicates at each concentration Concentration range: 1 μmol/L - 55 μmol/L 3.2 sec reversible response – full range
1 μmol/L = 32.5 ppb
500 550 600 650 700 7500
0.2
0.4
0.6
0.8
1
Wavelength(nm)
Rea
lativ
e In
tens
ity
55 μmol/L
1 μmol/L
Initial NeSSI Permeation System
NeSSI Gas/Vapor System
Permeation Tower
Aspectrics EPIR w/ glass cell
N2 Waste
NeSSI Flow Cell
ASI microFAST GC
Permeation Apparatus – ver. 2
- CPAC inspired and Parker built prototype permeation apparatus - Currently, used to generate calibrated organic vapor samples for sensor testing - Vapor calibration NeSSI system with Kaiser Airhead gas probe for analysis
Advanced NeSSI Perm. System Ver. 3
MFC 1
MFC
2
MFC 3
Perm
eatio
n Ap
para
tus
Vapor
Balance Gas
Sample to IR
Heater Set Temp. 65˚C Permeation App. Temp. 48˚C
Permeation System – Ver 4
Heater Set Temp. 65˚C Permeation App. Temp. 48˚C
Parker NeSSI Permeation Apparatus
Aspectric EP-IR
4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000-2
-1
0
1
2
3
4
5x 10-3
Wavenumber (cm-1)
Abs
orba
nce
(Arb
itrar
y U
nits
)
Temperature Results: IR Spectra
H2O
Ethanol CO2 As Temp Decreases the Signal Decreases 85˚C
65˚C
NeSSI Continuous Flow NMR System
Pump
Sampling System
Reactor
NMR
• Challenges with steel – polymer NeSSI system being manufactured to perform this measurement
Goal: to improve reaction monitoring and optimization through the use of continuous glass flow reactors, NeSSI and analytics
Funded by the FDA to demonstrate the benefits of improved reactor design, effective sampling and online analytics to increase process understanding (QbD)
Demonstrating Quality by Design
CF Reactor and Raman Analyzer
4 channel, 785 nm Kaiser Optical Systems Rxn2 probes placed at different reactor zones
Raman Analysis of CF Reactor
3 4
1
2
• Monitor reaction with 4 channel 785 nm Raman system • NeSSI sampling systems (1-4) equipped with Raman ballprobes • Online GC also used as post quench online analyzer (4)
Continuous Chemical Synthesis
- NeSSI flow management system (P, T, flow sensors, backpressure, filter) - NeSSI analytic sampling system (mulit probe Raman, IR, NIR, RI, Density, …)
Analytical Control System Design
Feedback & Control
Process Modeling
Data Fusion
Analytics and Data Handling
Hardware Control and Monitoring (Software)
Hardware – NeSSI, Raman, Other PAT, Reactor
Optimization
39
Interface with continuous flow reactor Mechanisms to ensure safe reactor
conditions Combined waste outlets from safety mechanisms
On-line analytics Temperature, flow, pressure
Product / Waste stream mechanism downstream of analytics
Open ports to allow for new analytics
Continuous Flow System Targets
HPLC Pump (Flow Rate)
Back Pressure Regulator Flow Meter Pressure
Gauge
•Reactant 1
Thermocouple Raman Other PAT
Flow Meter Pressure Gauge Thermocouple
•Product
Raman Infrared Needle Valve
Temperature Control
Control Analytics
Target System
HPLC Pump (Flow Rate)
Back Pressure Regulator Flow Meter Pressure
Gauge
•Reactant 2
Thermocouple Raman Other PAT
41
Current Reactor Iterative design
process, with multiple redesigns New analytics brought
to bear on system New safety and valve
mechanisms NeSSI allows for this
iterative process to proceed rapidly at practical costs
Analytical Hardware
Corning CF Reactor Kaiser 4-channel
Raman system Mettler Toledo IR On-line analytics
Pressure Temperature Flow
Esterification of benzoic acid
Straight-forward, pharmaceutically relevant
Strong dependence on temperature, flow rates
Chemical Reaction
Wiles, C., Watts, P. 2009
PLS Raman Calibration Model
0 20 40 60 80 1000
10
20
30
40
50
60
70
80
90
100
Yield Measured by HPLC (%)
Yiel
d Pr
edic
ted
by R
aman
(%)
PLS Model - Raman Prediction vs. HPLCHigh Concentration Factorial Calibration
R^2 = 0.9992 Latent VariablesRMSEC = 0.91141Bias = 0
Real-time Analysis of a Simulated Batch Fermentation Process
Simulated Fermentation liquor 900 mL of synthetic sugar water was
fermented with yeast for 8 hours The solution of sugar was held at 30˚C
and pH 6 for the duration of experiment. Glucose additions were added when
ethanol peak equilibrated. The final total sugar concentration in the reactor was 25 g/L glucose
NeSSI Fast-Loop Kaiser Optical Systems Raman
½” ballprobe with sapphire optic, 250mW power at probe tip
Average of six, 5 second exposures Mettler React-IR
MCT Detector Silver Halide Immersion Probe Diamond ATR
Fiber Optic O2 Sensor Cassini O2 Sensor
NeSSI Ferm. Fast-loop Design
• Custom designed NeSSI interfaces for all process analyzers in my lab • Plug and play analytics for any flowing system (liquid, slurry or gas)
Ethanol HPLC and Raman PC1
0 50 100 150 200 250 300 350 400 0
2
4
6
8
10
12
Time (Min)
Etha
nol (
mg/
mL)
-8
-6
-4
-2
0
2
4
6
8
Scor
es P
C1
HPLC Concentration Scores of Raman Data
After validating the loadings with the standard spectra, we can compare the scores plots (change in Raman spectra with time) with the reference method (change in concentration with time)
Glucose HPLC and Raman PC2
0 50 100 200 250 300 350 400 0
1
2
3
4
5
6
Glu
cose
(mg/
mL)
150 -3
-2
-1
0
1
2
3
4
Time (Min)
Scor
es P
C2
HPLC Concentration Scores of Raman Data
Sterilization of NeSSI Fast Loop? Concerns for sterilization
The flow path for a single NeSSI block has potential eddy points that can hold organisms
O-rings, seams and seals can allow holdup of biological material
Potential sterilization methods 10% bleach solution, initially
flowed through system, then held static to allow diffusion
Steam sterilization, heats entire block to 120°C
Autoclave
Substrate
Top Mount Component
Bleach Sterilization Method Rinsed 10% Bleach Solution for 1 hour Sterile Water Rinse
Filled Sterile Growth Media
Incubated 37°C for 72 hours
Swabbed
Culture plates
1. End piece (Start Flow) 2. Valve substrate 3. Top mount 3 4. Substrate 3 5. Top mount 4
6. Substrate 4 7. Top mount 5 8. Substrate 5 9. Valve substrate 10.End piece (End Flow)
1 2
3 5 7
9 4 6 8 10
contaminated
Conclusions and Challenges Demonstrated sterilization of NeSSI
components Possibly contaminated by residual cells
trapped in valve seat Pre autoclaving worked to remove
majority of possible contamination points O-rings and tubing
Next step – Sterile pumps and tubing Food grade diaphragm pump Stainless steel tubing Diaphragm valves to replace ball valves
More Dev. in Steam sterilization 120°C for 15 minutes (15 psi)
More work to be done!
LinkedIn NeSSI Group www.linkedin.com - search in groups tab for NeSSI and join!!!
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