Analytical Technologies Singapore

Knowledge

Knowledge, applications & more from our suppliers and experts.

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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What is Surface Work Function?

When a group of atoms or molecules are brought together to form a solid the highest occupied energy level, or Fermi level is termed the work function. The work function is continuous across the interior of the solid, however at the surface the electron energy is influenced by the exact state of the surface, e.g. type orientation and direction of the outer atoms and molecules. Thus different crystallographic orientations of the same solid may have different work functions. The work function of a surface can be modified by adsorbed layers, for instance in corrosion or oxidation of an iron surface, or by modification of composition or controlled contamination as in the case of polymer or inorganic semiconductors.

When two or more materials are brought together the Fermi levels equalise by a flow of electrons from the lower work function to the high. Detecting these electrons this in essence is the way all Kelvin probe systems work.

The work function is often described in introductory textbooks as ‘the energy required to remove an electron from a surface atom to infinity or equivalently the vacuum level’. Although this description appears easy, in surface analysis one has to ask further questions such as which type of electron, where is it taken from and where does it end up?

For example as an electron is removed a short distance ‘d’ from a conducting solid there is a so-called attractive image force (due to an imaginary positive charge a distance ‘d’ inside the solid). The force on the electron diminishes as ‘d’ gets larger and by approximately 30 – 50 nm it is exceedingly small. However some work function detection systems actually operate within this region thus the electron is not removed to infinity. This effect, coupled with the local electric fields in the vicinity of the tip, distort the work function data recorded.

In all KP Technology systems the Kelvin probe tip always operates at sufficiently large distances to produce the ‘true work function’ and further the mean spacing of the tip electrode above the sample is tightly controlled producing high-stability, repeatable measurements and allowing automatic system setup.

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What is a Kelvin Probe?

The Kelvin probe is a non-contact, non-destructive vibrating capacitor device used to measure the work function (wf) of conducting materials or surface potential (sp) of semiconductor or insulating surfaces. The wf of a surface is typically defined by the topmost 1 – 3 layers of atoms or molecules, so the Kelvin probe is one of the most sensitive surface analysis techniques available. KP Technology systems offer a very high wf resolution of 1 – 3 meV, currently the highest achieved by any commercial device.

The Kelvin probe does not actually touch the surface; rather an electrical contact is made to another part of the sample or sample holder. The probe tip is typically 0.2 – 2.0 mm away from the sample and it measures the ‘traditional work function’, i.e. that found in literature tables. Other techniques, using very sharp tips some 10’s of nanometres away from the sample, measure very reduced and distorted work functions due to the close separation of tip and sample.

The physical form of a Kelvin Probe is a head unit containing a voice coil driving system and integral amplifier suspended above a sample. The vibrating tip and the sample forms a capacitor, having ideal, or parallel-plate, geometry. As the tip vibrates electric charge is pushed around the external detection circuit. By careful control of the tip potential and automatic capture and analysis of the resulting waveform both the potential across the capacitor and the capacitor spacing can be calculated to very high resolution.

In scanning form the tip is steered across the sample surface using a high resolution 3-axis translator. The spatial resolution of the tip is approximately the tip diameter, we typically use tips of 2.00 mm and 0.05 mm as standard tips in air and anything from a sharp tip to 10.00 mm diameter in ultra-high vacuum. The resulting 3D surface work function images contain information about surface structures, surface composition, thin films, defects, etc. In time-varying mode artefacts such as oxidation (corrosion), defect relaxation, etc can be observed.

For semiconductor surfaces, both organic (polymer) and inorganic (Si, Ge, CdS, etc.) the Kelvin probe is the only way to directly measure the Fermi level. Changes in Fermi level, caused by illumination with white or monochromatic light, results in energy band shifts which can be used to characterise interface and bulk defect states. These techniques are termed Surface Photovoltage (SPV) and Surface Photovoltage Spectroscopy (SPS) for which KP Technology can supply both software and accessories for our systems.

The traditional Kelvin probe actually produces the work function difference between the tip and sample. The Kelvin method was first postulated by the renowned Scottish scientist Lord Kelvin, in 1861. Typically the tip is first calibrated against a reference surface, such as gold. However KP Technology is the only company to offer absolute Kelvin probes, which combine the Kelvin method and Einstein Photoelectric Effect to produce absolute work function values (in eV).

KP Technology has developed dedicated head units for ambient, controlled atmosphere, relative humidity and ultra-high vacuum environments. All of our systems share the off-null, height regulation (ONHR) method invented by Prof. Baikie and consequently produce stable high signal levels resulting in repeatable and high-resolution measurements. The rapid growth of the company since 2000 means the KP Technology systems are found in leading materials research laboratories worldwide. We pride ourselves on our rapid post-sales support and our ability to assist with technical and data interpretation queries.

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