Analytical Technologies Singapore

photon system

Virological Analysis

Traditional virological analysis techniques such as molecular methods based on PCR, RT-PCR and qRT-PCR are expensive and time consuming.

 

Deep UV laser induced fluorescence offers the ability to perform the analysis in a few minutes or near real time without the use of expensive assays or reagents. With deep UV (248nm) excitation, the complete emission spectra of the virus from the deep UV to visible range may be detected. This fluorescence spectrum is a function of the specific molecules in the microorganisms. Although this technique has commonly been used in bacterial detection and analysis it has recently been shown to also be applicable to quickly detecting novel strains of viruses. Due to differences in the amount and composition of fluorescent molecules, different viruses have been shown to have variations in spectra which allows them to be classified.

 

Instruments such as the Photon Systems DUV Raman PL 200 have the ability to excite virus samples with deep UV (248nm) laser based illumination and collect a high resolution (1.2nm) fluorescence spectra over the range of 250nm to 620nm. When combined with principal component analysis and classification algorithms, this allows sensitive virological detection and analysis.

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Pharmaceutical Cleaning Validation

Detecting and quantifying trace residue concentrations of active pharmaceutical ingredients (API), excipients, and washes during cleaning validation procedures on pharmaceutical manufacturing equipment is one of the single largest costs associated with the manufacture of pharmaceutical drugs. Current cleaning validation cost are dominated by high labor cost of swabbing and ~90 hours of manufacturing equipment down time due to exhaustive lab (HPLC) analysis throughput limitations.

Presently, pharmaceutical companies pill process manufacturing require about 12 hours to blend and press a tablet, the machines are then broken down and washed (4 hours). The swabbing, 25cm2 area at 100 to 300 locations within each piece of manufacturing equipment, extracting residual contamination picked up by each swab, and running each sample through an HPLC instrument, which takes at least 30 minutes per sample accounts for (90 hours) 4 days after manufacturing a single batch of pills to validate that they have adequately cleaned the equipment, within internal and FDA regulations, in preparation for manufacturing a new batch of pills. This is a very laborious process and combined with the idle time of the manufacturing equipment is a very expensive part of pharmaceutical manufacturing cost.

The Photon Systems’ deep UV TraC instrument can reduce the time to validate the cleaning process to less than 4 hours and virtually eliminate equipment down time and eliminate the need for sample collection, extraction and testing with HPLC reducing cost associated with cleaning and turnaround by 1000 times or more.

Photon Systems has already demonstrated to a leading global pharmaceutical manufacturer that we can reduce the cleaning validation process to a few hours. We have currently tested several active pharmaceutical ingredients such as antidepressants of the serotonin-norepinephrine reuptake inhibitor (SNRI) class and beta blockers, cleaning washes such as SumaStar, Diver Wash, and CIP-200, as well as excipients such as microcrystalline cellulose, ethyl cellulose, magnesium stearate, and starch. We accomplished this with a demonstrated ability to detect and quantify APIs down to less than 0.2 mg/cm2. The system and method we have demonstrated has the ability to virtually eliminate the extensive labor cost by eliminating the need for sample collection, extraction, and testing with HPLC and the vastly reduced and materials and time cost associated with machine down time. The cleaning validation cost savings to pharmaceutical manufacturers is still under study, but it is massive.

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Optical Scattering using DUV

Photon Systems has developed a unique instrument to measure the deep UV non-specular scatter properties of optical elements, including gratings, mirrors, filters, etc. Extraneous scattering may adversely affect the performance of spectrometers and other deep UV instruments, even with a grating separator on the laser beam to clean-up  laser lines and various plasma lines from the laser.

Until now it has been expensive or difficult to measure optical scattering in the deep UV, as commercial instruments do not exist in the deep UV, and other deep UV lasers are expensive.  To better understand the scatter performance of the optical elements used in our spectrometers, we have created a deep UV scatterometer that is based on our compact and cost effective 248.6nm hollow cathode laser and our single channel boxcar integrator and averager with combined PMT.

The graph to the right shows the photon count average of 20 laser pulses using a Photon Systems single channel boxcar integrator and averager. This instrument enables photon counting down to about 2 to 3 photons during a single laser pulse and has a dynamic range from about 50 million, or over 7 orders or magnitude. This is accomplished in the combined PMT with PSI’s gated boxcar integrator, synchronized with a Photon Systems’ 248.6 nm laser.

To enable detection over this wide a dynamic range we employed a series of filters over the gated PMT detector including a Semrock 248.6 nm laser line filter, an Edmund Optics bandpass filter 248/10, and three UV neutral density filter in series, including an OD7, OD1, and OD1.9. This enabled the gated PMT detector to directly observe the laser output during a pulse, and to automatically adjust the sensitivity when the scatter angle was off-axis. They dynamic range is provided by the Photon Systems single channel gated boxcar integrator, which has 3 orders of magnitude in integration capacitor range, and over 6 orders of magnitude range in gain of the PMT.

This data in the graph to the right shows that mirrors are typically 100X lower in scatter than gratings with the Newport mirror having nearly 5x less scattering than the Lambda XHR. To be fair, the Newport mirror is a simple UV enhanced aluminum mirror and the Lambda is a much higher efficiency narrow band mirror centered around 248 nm. Among the gratings, the Newport/Richardson 3600 g/mm SSI grating has highest scatter, followed by the Edmund 3600 g/mm grating, followed by the SSI 1200 g/mm and SSI 3600 g/mm grating.

You will note that at high scattering angles, the mirrors approach the dark signal of the detector, which is near 5 photons. This simple Photon Systems deep UV scatterometer capability is only available in one other organization worldwide, to the best of our knowledge. This is at the Fraunhofer Institute for Applied Optics and Precision Engineering in Jena, Germany.

Optical schematic and photo of deep UV reflectometer and scatterometer setup operating at 248.6 nm for use with gratings, dichroic filters, mirrors, and other optical surfaces. Theata1 is fixed at 10 deg. The only moving element is the optic, which is rotated around the vertical axis only. For gratings, the grating is mounted in a vertical Littrow so that the rotation of the grating is in a “conical” mount configuration.

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Fingerprint Detection using DUV Fluorescence imaging

Fingerprint detection and ridge morphology analysis traditionally requires the use of additives and taggants such as Ninhydrin or DFO to enhance the contrast between a fingerprint and the background substrate and enable imaging of defining ridge details. Once captured and scanned digitally, these can be processed and further enhanced to match to existing databases.

However use of these additives or taggants require the addition of a contaminant to a forensic scene. In additional, the processing eliminates, or seriously degrades, the use of post chemical analyses that could provide insight into any illicit chemicals that may be present associated with the fingerprint.

Therefore a major challenge in the fingerprint analysis community is to address the use of a non-contact, non-invasive, non-destructive method. This challenge does not assume the latent fingerprint is well preserved. In a real-world scenario, the fingerprint will degrade by exposure to heat, sunlight, oxidation, or other environmental attributed effects. While the chemistry may change and adversely effect current methods, deep UV fluorescence imaging is not tied to a specific chemical compound and is significantly more tolerant to these environmental influences.

Since the fundamental nature of fingerprints, either fresh or latent, is an organic residue on a surface, deep UV autofluorescence imaging translates well to fingerprint detection and morphological analysis. As with environmental samples, deep UV autofluorescence alone provides a wealth of information. In addition, with the deep UV laser excitation, deep UV Raman can be used for additional chemical-specific characterization of the fingerprint; providing an orthogonal dimension of profiling and analysis of what an individual may have come in contact with.

Deep UV autofluorescence is most sensitive to aromatic structures such as aromatic amino acids (tryptophan, tyrosine, phenylalanine) found in the majority of proteins and as free amino acids in eukaryotic and prokaryotic cells. In addition it is highly sensitive to single and polyaromatic hydrocarbons (benzene, naphthalene, anthracene, etc) and various thermally altered forms of carbon (coals, diesel soot, etc).

Detection of this range of materials is what makes deep UV fluorescence tolerant to environmental effects. A fresh fingerprint may have a significant amount aromatic amino acids, however, if heated, these can thermally degrade to bituminous carbon; an organic that is still detectable by the deep UV autofluorescence methods. In addition to detecting these materials, the use of the deep UV also provides a signature that enables differentiation between these materials.

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Trace Contamination Detection

Detecting and quantifying trace surface contamination is an important step in many manufacturing processes.  Organic compounds such as oil, grease, cleaning agents may be present on surfaces in low concentrations.  This needs to be detected before a sensitive processing step such as bonding, coating or welding.  Or, the final cleaning may need to be verified before an item is delivered to customers.

Other technologies used for trace surface contamination detection may include total organic carbon, optical imaging, FTIR, optical emission spectroscopy, reflectance hyperspectral imaging and solvent extraction/swabbing.  All of these techniques have limitations such as lack of sensitivity or signal response, operator training issues, inability to work on curved surfaces, limitations on material types or not feasible for in-line processes.

Deep UV fluorescence detection offers significant advantages for organic trace surface contamination detection.  With laser based detection, the limit of detection can be well under 1 nanogram per square cm and the working distance can be up to 1m.  This can allow the surface contamination detection on parts with unusual shapes. The detection is real time and can be quantified through the generation of calibration samples (using the ChemCal) and fluorescence response calibration curves.  Therefore,  the deep UV fluorescence signal is correlated to a known contamination concentration.  Also, through the use of multiple detection bands, multiple contaminants can be detected.

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