deep uv raman & fluorescence spectroscopy for in situ ... · deep uv raman & fluorescence...
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1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Ray D. Reid, Quoc Nguyen, M. Reid, Kripa Sijapati, & William Hug
Photon Systems, Inc.
FACSS/SciX Palm Springs, CA October 15, 2019
DeepUVRaman&FluorescenceSpectroscopyforInSituProcessAnalysis
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Outline
q Detectiongoals&methodsforRCVandreal-timecontinuousmanufacturing
q AdvantagesofdeepUVRaman&fluorescencedetection
q Detectionexamplesforpharmaproducts
q DeepUVRaman&fluorescenceinstruments
q ChemicalprinterforNISTtraceablechemicalconcentrationcalibration
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
ThesolutionAminiaturedeepUVRamaninstrumentthatavoidsfluorescenceinterferenceorobscurationandprovidesahighlevelofsensitivityandspecificityfortheingredients
ThegoalProvideinstrumentationforreal-timedetectionofthekeyingredientsduringcontinuousflowmanufacturing
QualityControlinContinuousManufacturing
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
ThesolutionAhandhelddevicethatquantifiestraceamountsofAPIinrealtimeonmanufacturingsurfaces.Result:Significantlyreducingproductiondowntime.
ThegoalToaugmentorreplacethepresentswab&testmethodforequipmentcleaningverificationwithafasterandbettercontrolledanddocumentedmethod.
RapidCleaningVerification
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
AdvantagesofdeepUVRaman&fluorescencedetection
Advantages of Deep UV Detection vs Visible or IR?
q Non-contact,reagentless,nosamplehandlingorpreparation
q Excitationbelow250nmseparatesRaman&fluorescencespectralregionstoenable
ü ClearRamanspectrawithnoobscurationoralterationbynativefluorescence
ü NoalterationofthefluorescencespectrabymajorRamanbands
ü TheabilitytosimultaneouslydetectRamanandnativefluorescence
q MuchhigherRamansensitivityduetoRayleighlawandresonanceRamanenhancementeffects
q Fluorescencedetectionalonehasmuchhigherspecificitywhenexcitationisbelow250nm
q Detectionofconcentrationofpharmamaterialsinthelowng/cm2hasbeendemonstrated
q Detectionissolarblind,enablingdetectioninfulldaylightwithoutinterferences
7
Why Deep UV below 250nm?
When excitation < 250nm Raman and fluorescence spectral regions are separated
Fluorescenceregion
Ar+488
DPSSx2532nm
HeNe633nm
Semiconductor785nm
GaN365-405
DPSSx4263-266HeAg/NeCu
224/248
DPSS1064nm
1000
Sensitivity to Excitation Wavelength Raman Spectra with Excitation at 248 nm versus 262 nm
(Example is G Agents)
Adapted from Christesen, SD et al. Appl Spec. 2008 Oct; 62(10):1078-83
248 nm 262 nm
Deep UV Fluorescence Spectra of 52 Compounds with no baseline subtraction or compensation, Ex=248 nm
Raman Region Fluorescence Region
1-ring Biological 2-ring 3-ring 4-ring 5-ring
Chemical Differentiability Using Deep UV Excited Fluorescence Alone
A single deep UV laser pulse determines the location of an unknown substance in this chemometric space
A1
A2
C
(E) (F)
G
(H)
I
1 ring compounds incl. Tyr & Phe (A1 and A2)
2 ring aromatics (D)
nitrogen based heterocycles (E) including tryptophan
3 ring polyaromatic hydrocarbons (PAHs) (F)
4 ring PAHs (G)
>5 Ring PAHS (I)
vegetative bacterial cells (Gram + and Gram -) with cellular components (C),
bacterial spores (B)
“background” group (H), consisting of pollens, dust, minerals, and household materials (sugar, flour, corn starch, etc)
Combining the Sensitivity of Fluorescence & specificity of Raman
q Fluorescence is the most sensitive method of detection, over 106 to 108 times more sensitive than Raman, providing longer standoff distances and/or detection at lower concentrations
q Raman provides information about chemical bonds and functional groups, including those that do not fluoresce (aliphatics and simple compounds)
q Fluorescence data provides information about the overall electronic structure of target & substrate components (aromatics, ketones, aldehydes)
PETN VOCs
DetectionExamplesforPharmProducts
OTCBenylin:dextromethorphanhydrobromideC18H28BrNO2
Ex=1064 nm
Ex=785 nm
Ex=248 nm
Benylin (white) Sodium benzoate (green) Glycerol (red)
1585
987 2900
810
10/21/19 141512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
OTCChildren'sMotrin(ibuprofen)–BubblegumFlavorEx=248nm
Ex=248 nm
1585
1640
1170 990
Children’s Motrin-Bubblegum flavor Pure Ibuprofen
1585
1170
990 810
Ex=248 nm
1360 1260
AllInformationinthisslideisproprietary.WrittenpermissionisrequiredtofromPSI.
OTCChildren’sTylenol(acetaminophen)wVariousFlavorsEx=248.6nmRawresults.Nobaselinecompensation.
1615
2332
1258
1168
2900
3200
600 780
Increasing fluorescence
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
DeepUVRaman&FluorescenceInstrumentsq Raman PL 200: Fully self-contained deep UV Raman & fluorescence instrument
q TraC: Handheld trace surface contamination detector for RCV
q STANDOFF 200: Fully self contained, handheld standoff chemical & biological sensor
q ChemCal: NIST traceable chemical printer & calibration instrument for surface detectors
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Deep UV Raman PL 200 with manual or computer-controlled stage or liquid flow cell
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
q AdeepUVRamanandfluorescencespectrometerq Witheithercomputer-controlledstageformappingorliquidflowcellforcontinuous
manufacturingqualitycontrolq IntendedforOEMapplicationswithdramaticallysmallerSWAP/CthanotherdeepUV
instrumentsonthemarketq AvoidsfluorescenceinterferenceorobscurationofRamanspectraq EnablesdetectionandquantificationofRamanbandsforawiderangeofpharma
ingredientsnotpossiblewith785nmor1064nmRamansystemsduetofluorescenceq SWAP:18x20x42cm,10kg,60Wmax(100-260VAC)
Features of the Deep UV Raman PL 200
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Raman PL 200 with various types of flow cells or cuvette holders
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Deep UV Trace Chemical (TraC) Sensor LODs < 1 µg/cm2 Wt. 1.5 lbs
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
q Fullyself-containedRCVsensorwithembeddedmicroprocessorforinstrumentcontrol,dataprocessing,real-timedatastorage,anddisplay
q Abletomeasuretraceconcentrationsoncurvedsurfaces,corners,crevices,screens,gratesq Samplerate>10samples/swithtime-stampedreal-timerecordingq Hisensitivity:abletodetectconcentrationsofAPIs<1µg/cm2
q Largeworkingdistance:0to2cmq Samplingarea:0.25cm2
q Non-contactsensingwithlargeworkingdistance(0to2cm)q Hand-Held:<0.7kg(1.5lbs)q Small:7.6x8.9x19cmq Longbatterylifetime:>40hoursfullpower;>120hoursstandbyq Startuptime<10sq GMP&Intrinsicallysafe
Features of Deep UV TraC RCV Sensor
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Typical Concentration Calibration Curve & Time Stability
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
STANDOFF 200 CB Surface Analyzer
FeaturesFullyintegrateddeepUVRaman&fluorescencesurfacedetectionanalyzerSinglehandedoperation:4-buttonplustriggercontrolWarm-up:<10sfromcoldstart,3sfromstandbymodeBuilt-in-test:fullfunctionaltestofallcomponentsonstartupSpectralCalibration:Auto-calibratedonanalyzerstartupTwoCoaxialContextCameras:75owideangleimage,20mmmicroimagearoundlaserspotAutofocusedStandoff:0.6mto5+mMaterialsDetected:ChemicalandBiologicalCBELibraries:Builtinunclassifiedlibrary+SDcardlibrariesStandoffDistance:0.5mto5+minfulldaylightconditionsSpectralRange: Raman:250cm-1to3500cm-1
Fluorescence:270nmto320nmContextInfowithSpectralData:Date/timestamps,GPS,azimuth,distanceandtwocontextualphotosPowerSupply:Userreplaceable24VLiPObatterypack(UN/DOT38.3rated)or24VwalladapterCommunication:WiFiplusWiredUSB3.0Weight:12poundsDimensions:7”Wx11”Hx16”LIngressProtection:IP67Robotcompatible:¼-20camerathreadordove-tailmount
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Whydoyouneedachemicalprinter?
q Test/calibrate/validatefutureRCVtoolsusingNISTtraceablemethodq Test/calibrate/validateCURRENTcleaningtools&methods
ü Createconcentrationcurvesforswabbing.ü Test/trainswabbingpersonnelwithaccuratearealconcentrations.ü Testrecoveryfromvarioussurfaces/topologieswithdifferentswabbingmedia.
q Createcouponsforvisual/hotspotdetectionofAPI.ü Hotspotdetection.ü Trainpersonnelonvisualinspectionlimits.
q Performallofthesewithsingleormultiplechemicalsonasinglecouponorcoupons.ü Detergent+API.ü Excipient+API.ü Detergent+API+Excipient.
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Chemical Calibration Printing
Inkjet Printing
Manual Deposition
ChemCal-Printer
Ultrasonic Piezo Printing Spray Coating Speed Uniformity
Known Quantity (Pre determined)
Spin Coating
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
NISTTraceableChemicalConcentrationCalibrationChemCal:Achemicalprinter,mapper,&calibrator
TraC sensor
Operational Scenario: ü Load APIs, etc in Eppendorf rack. Up to 21. ü Load coupons onto tray. ü Press Start. ü The system prints, scans, & outputs a full
calibration curve in under 3 hours. (Prints and scans 16 coupons.)
ChemPrint head
q Createsupto16couponswithaprioriknown,NISTtraceable,concentrationsofmanydifferentchemicals,includingAPIs,detergents,excipients,etc.onPharma-typesurfacesorquartzcrystalmicrobalanceelementsforthepurposeofperformingcalibrationofhand-heldtracechemicalsensorsforrapidcleaningvalidation.
q Printsanddetectsoncurvedorflatsurfaces,corners,grates,screens,etc.
Coupons
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
Summary
q Several opportunities exist for pharma and other chemical manufacturing RCV and continuous flow manufacturing instrumentation using deep UV excitation below 250 nm.
q Excitation below 250 nm provides fluorescence-free Raman and Raman-free fluorescence detection simultaneously, enabling both modes of detection to provide more accurate information about a trace substance on a surface or in a liquid.
q Combined Raman & fluorescence detection method enhance both sensitivity and specificity in identifying unknown targets
q Detection of Raman & fluorescence in the deep UV can be accomplished using low energy lasers without major alteration or damage/ignition of targets.
q Surface detectors need a method of accurate chemical concentration calibration, common to all methods of surface detection. We call this instrument is called ChemCal.
1512 Industrial Park St., Covina, CA 91722 T: 626 967-6431 F: 626 967-5813 www.photonsystems.com
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