WO2015128635A1 - Procédé et dispositif de surveillance de substances - Google Patents

Procédé et dispositif de surveillance de substances Download PDF

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Publication number
WO2015128635A1
WO2015128635A1 PCT/GB2015/050536 GB2015050536W WO2015128635A1 WO 2015128635 A1 WO2015128635 A1 WO 2015128635A1 GB 2015050536 W GB2015050536 W GB 2015050536W WO 2015128635 A1 WO2015128635 A1 WO 2015128635A1
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WIPO (PCT)
Prior art keywords
substance
product
analysis
changes
server
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PCT/GB2015/050536
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English (en)
Inventor
Mohammad Farid KHAN
Awan MUZAMMAL
Original Assignee
Protein Technologies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Protein Technologies Ltd filed Critical Protein Technologies Ltd
Priority to GB1614493.3A priority Critical patent/GB2537787A/en
Publication of WO2015128635A1 publication Critical patent/WO2015128635A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3563—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light for analysing solids; Preparation of samples therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering

Definitions

  • the present invention relates to a method for monitoring substances, products and materials.
  • the invention relates to using spectroscopic analysis to authenticate, track and monitor events subsequent to the manufacture of such substances, products and materials at various points in time and at various locations as they pass through the supply chain.
  • Applied DNA Sciences, Inc. (USA) has developed a system using plant DNA, used as markers, which are alleged to be non-removable from packaging, even with aggressive industrial solvents, and it is claimed that readings are not obscured by false positives.
  • the CSEM SA (Centre Canal d'Electronique et de Microtechnique) has produced zero-order diffractive pigments (ZOPs) which provide packages with very pronounced, iridescent colours that are extremely difficult to duplicate.
  • ZOPs diffractive pigments
  • Tru-Tag Technologies Inc. USA manufactures spectrally coded silica microtags which are edible and can thus be incorporated into the drug preparations themselves as forensic markers.
  • the fundamental challenge is not strictly speaking one of duplicating plant DNA, zero-order diffractive pigments or spectrally coded tags etc., but rather of providing the computerized systems employed to scan those compounds with the digital data set that equates to the relevant identifying pattern.
  • Radio frequency identification tags are an extremely effective means of tracking high- value products such as pharmaceutical preparations, but are very costly.
  • the United Kingdom Office of Fair- Trading estimates initial set-up costs for RFID implementation at around $500,000 per product. Further ongoing costs must then be incurred in the form of the tags themselves which, being electronic circuits, are difficult to manufacture below a cost $0.50 each and more advanced tags can cost up to $200 each.
  • RFID are also quite bulky and therefore difficult to attach to individual packages or vials.
  • a method of monitoring a first substance comprising the steps of:
  • step (ii) performing spectroscopic analysis on the second substance at multiple time points; and (iii) evaluating the measurements of step (ii) to determine cumulative information on the state of the first substance by reference to changes to at least one known parameter of the second substance.
  • the term physical and/or chemical state is intended to include, but is not limited to, whether the substance has a solid or fluid like form, the chemical or physical composition of the substance, its morphology, age or crystallinity, temporal or physical location for example. It should be understood that the method may be used to analyse any one or more physical and/or chemical property or properties which is/are indicative of the state in which the substance is in and/or its temporal or physical location. By performing spectroscopic analysis on the second substance at multiple time points and evaluating the measurements, such as by comparing the measurements to known parameters, the cumulative physical and/or chemical state of the second substance can be determined and correlated to the physical and/or chemical state of the first substance and/or its temporal or physical location.
  • the method may further comprise performing spectroscopic analysis on the first substance preferably at multiple time points; and comparing the results of such an analysis with expected values to obtain further information on the physical and/or chemical state of the first substance and/or its temporal or physical location.
  • the spectroscopic analysis of the first substance may be performed during step (ii) of the method and may be performed at one or more time points.
  • the spectroscopic analysis is preferably non-visible spectroscopic analysis.
  • the method may comprise monitoring a product which comprises the first substance.
  • the product or first substance may comprise a solid, colloidal, nanoparticles or fluid form. Fluid form may include liquid, gel or gas, or any form which is flowable.
  • the product or first substance comprises a pharmaceutical product such as a medicine or a vaccine, for example.
  • the second substance may comprise a label or marker connected to or inserted into the first substance.
  • the second substance may be directly connected to the first substance, or intimately mixed with the first substance, such as a homogeneous mix, suspension or solution for example, and the combined first and second substances may comprise a composite substance.
  • the second substance may be indirectly connected to the first substance, such as by way of an intermediate barrier substance or where the first substance is coated.
  • the second substance may comprise a label or marker applied to packaging in which or on which the first substance is located.
  • the second substance may be located on the outside of the packaging, may form an integral part of the packaging or may be located within the packaging.
  • the second substance does not affect the physical and/or chemical state of the first substance.
  • the second substance does not affect, reduce or alter the therapeutic benefits of the product.
  • the second substance is preferably not harmful to the patient using the pharmaceutical product.
  • the second substance may be provided on a surface of the first substance or product.
  • the first and second substances may be mixed to form a solid composite substance.
  • the first and second substances may be mixed to form a fluid composite substance which may be a suspension, gel or solution, for example.
  • the product may be constructed from the composite substance.
  • the physical structure or composition, chemical structure or composition and/or morphology of the second substance varies over time, or in response to changes in the environmental conditions. It is desirable that these changes occur in a predictable and reproducible fashion and that such changes are reflected in the spectra acquired from the spectroscopic analyses of the second substance.
  • the measurements of the spectrum at various times allow for a measurement of the age of the first substance.
  • the first substance comprises a product which has a finite shelf-life such as a vaccine or perishable food product, for example. It is also of particular utility in detecting repackaged, expired counterfeits which have been reintroduced into the supply chain.
  • the measurements of the spectrum may be used to determine what conditions the first substance has been subjected to. Such embodiments may be desirable where certain environmental conditions are deleterious to the first substance but wherein the damage may not be apparent by only monitoring the first substance.
  • Environmental conditions which may be damaging to the first substance may include extreme temperatures, extreme pressures, fluctuations in temperature and/or pressure, changes in humidity, changes in oxygen or other atmospheric gas levels or exposure to high levels of radiation, for example.
  • step (ii) of the method comprises performing spectroscopic analysis of the second substance at multiple time points to determine one or more environmental conditions to which the second substance has been subjected; and step (iii) comprises evaluating the cumulative environmental conditions data.
  • Environmental conditions include temperature, pressure, humidity and gas exposure.
  • the second substance may comprise one or more compounds selected from the following substances: (i) Raman active compounds including organic derived compounds consisting of at least one carbon atom, or synthesized compounds, compounds containing more than one double bond, compounds consisting of aromatic bonds, compounds consisting of triple bonds.
  • Temperature/ freeze denaturation responsive compounds including organically derived polymers such as proteins, enzymes, peptides, compounds containing peptide bonds, peptide/ protein conjugates with Raman active dyes, protein complexes with metal ions, compounds consisting of peptides with metal ions, proteins consisting of co-factors (e.g. carotenoids or chlorophylls), peptides consisting of the same, glycosylated proteins or peptides; and proteins or peptides consisting of nucleic acids, porphyrins, sugars, carbohydrates, alginate, or alkene groups.
  • organically derived polymers such as proteins, enzymes, peptides, compounds containing peptide bonds, peptide/ protein conjugates with Raman active dyes, protein complexes with metal ions, compounds consisting of peptides with metal ions, proteins consisting of co-factors (e.g. carotenoids or chlorophylls), peptides consisting of the same, glycos
  • Time/ temperature sensitive labels including synthetically derived polymers such as thermosetting plastics, polyvinyl chloride, polycarbonate (PVC), polypropylene (PP), and polyester (PET), polymers containing epoxide groups, polyepoxides.
  • Suitable epoxy resins may be reacted (cross-linked) either with themselves through catalytic homopolymerisation, or with a wide range of co-reactants including polyfunctional amines, acids (and acid anhydrides), phenols, alcohols, and thiols. These co-reactants are often referred to as hardeners or curatives, and the cross-linking reaction is commonly referred to as curing.
  • thermosetting polymer Also useful are the products of the reaction of polyepoxides with themselves or with polyfunctional hardeners to form a thermosetting polymer.
  • Other useful epoxy resins include polyphenols, bisphenols, thiol-containing compounds, epoxy phenol novolacs (EPN) and epoxy cresol novolacs (ECN), glycidyl epoxy resins and cycloaliphatic epoxides, monofunctional (e.g. dodecanol glycidyl ether), difunctional (diglycidyl ester of hexahydrophthalic acid), or higher functionality (e.g.
  • trimethylolpropane triglycidyl ether formulations with anhydride curing agents such as hexahydrophthalic anhydride, cycloaliphatic epoxides containing one or more cycloaliphatic rings in the molecule to which the oxirane ring is fused (e.g. 3,4-epoxycyclohexylmethyl-3,4-epoxycyclohexane carboxylate), triethylenetetramine, polyurethane, acrylics and cyanoacrylates. Particularly useful are diacetylenic monomers (VVM labels) produced by TempTime Corporation.
  • VVM labels diacetylenic monomers
  • diacetlenic monomers comprising at least two conjugated acetylene groups (— C ⁇ C— C ⁇ C— ) and their unique physico-chemical properties, e.g., responsiveness to persistent temperature excursions by transforming into contrastingly colored solid state polymerization reaction products, have been described, for instance, by Patel et al. (U.S. Pat. No. 3,999,946) and by Temptime Corporation (U.S. Pat. No.6924148).
  • diacetylenes include 2,4-hexadiyn-l,6-bis(alkylurea), wherein the monomer component is selected from the group consisting of ethyl-, propyl-, and octyl- substituted 2,4-hexadiyn-l,6-bis(alkylurea);
  • Temperature/ UV labels (Reference Yoon et al, An inkjet-printable microemulsion system for colorimetric polydiacetylene supramolecules on paper substrates, J. Mater. Chem., 2012, 22, 8680-8686) including dual temperature and UV active material such as compounds which form polydiacetylene molecules.
  • pH labels such as natural and synthetic dyes including Congo Red, Methyl Orange, Methyl Red, Chlorophenol Red, (e) Bromocresol Purple, Alizarin, Nitrazine Yellow, Bromothymol Blue, Brilliant Yellow, and PhenolRed.
  • the second substance may comprise a compound of biological origin such as a protein for example, which in some embodiments undergoes structural changes such as denaturation or aggregation in response to temperature, time, pressure, oxygen levels, radiation or agitation and the like.
  • the structural changes to the second substance may provide predictable changes in the obtained spectra such that the environmental conditions to which the first substance has been subjected to can be inferred.
  • One particular protein which may be used is the fluorescent protein DSRed which becomes denatured at +77°C and can also be used as an ice-crystal or glass transition (Tg) biosensor at low temperatures.
  • Tg glass transition
  • the second substance may comprise a visual indicator.
  • visual indictors include those which change colour and/or colour density over time or upon exposure to various environmental conditions.
  • the second substance may comprise the commercially available Vaccine Vial Monitor (VVM30), manufactured by TempTime Corporation, New Jersey, USA.
  • VVM30 employs active substituted diacetylenic monomers to effect a visible change in colour density over time through the mechanism of solid state polymerisation.
  • the visible spectra of the visual indicator as well as the non-visible spectra may also be analysed according to the method of the invention in order to more accurately determine the exact passage of time, which cannot be confirmed from a purely visible inspection of the indicator using the naked eye.
  • each second substance may be monitored such that, for example, increases or decreases in temperature and/or pressure, fluctuations in temperature and/or pressure, changes in humidity, changes in oxygen or other atmospheric gas levels and/or levels of radiation exposure can be analysed simultaneously.
  • each second substance is monitored to analyse a single factor affecting the first substance.
  • the second substance may have a complex or unique spectroscopic signature such as that of an unnatural protein containing elements that are not normally found in nature (e.g. fluorine, bromine).
  • the signatures of unnatural proteins may comprise thousands of points of reference and are therefore almost impossible to duplicate by other means (e.g. with combinations of conventional dyes and inks) or to reverse-engineer on the basis of their spectra or chemical composition. These points of reference may also be used as product identifiers and/or to encrypt data such as factory and batch codes or date of manufacture.
  • the packaging or label substrate may comprise paper, cardboard, glass, plastics, wood, metal (including alloy), rubber, leather, fibre-glass or any combination of two or more of the aforesaid substrates.
  • the first substance may comprise one or more of a pharmaceutical, protein, food product, luxury or consumer good, or high value industrial product and material.
  • pharmaceuticals and proteins include human or animal pharmaceutical solid dose tablets, biopharmaceuticals, regenerative medicines (e.g. stem cells), tissues, organs, and reproductive cells (sperm and ova).
  • food and drink products include champagne, wine, caviar, truffles, and the like.
  • luxury goods include precious metals, gems, artwork contemporary and antique goods (paintings, sculptures etc).
  • consumer goods include electronic goods, such as computers, tablet computers and mobile phones; and high value products and materials e.g. Swiss watches, critical components parts for transport (e.g. aviation parts).
  • the spectroscopic analysis of each substance may be performed by means of absorbance spectroscopy, fluorescence spectroscopy, infra-red spectroscopy, or thermal spectroscopy, for example.
  • data may be acquired using Raman spectroscopy. Any suitable form of spectroscopy may be employed and the choice of method will be dependent on the substance to be analysed and/or the physical and/or chemical state to be analysed. In some embodiments a plurality of spectroscopic methods are employed to analyse the or each substance.
  • An important use of the method of the invention is the predictability and therefore the accuracy of the tracking of time using the polymerization of monomer diacetylenes using the Arrhenius' equation.
  • This algorithm allows the accurate prediction of Raman spectra for the temperature dependence of polymerisation rates of diaceylenes.
  • embodiments using proteins allow the predictability by means of enzymes turnover of substrates which is dictated by known enzyme kinetic equations (i.e. a change in the Raman activities of substrates or products).
  • the spectroscopic analysis or method comprises monitoring a product
  • the method may be repeated at various time intervals corresponding to different points along a product supply chain. For example, it may be desirable to analyse the product upon manufacture, and upon receipt and delivery of the product to various supply chain partners, such as a warehouse, retail establishment or vehicle.
  • the method may further comprise cross referencing or storing the acquired spectroscopic data with a product identifier such as a unique barcode, for example, such that information on the manufacture of the product and the events and conditions subsequent to its manufacture is compiled for each product.
  • a product identifier such as a unique barcode, for example, such that information on the manufacture of the product and the events and conditions subsequent to its manufacture is compiled for each product.
  • the product identifier may be provided prior to manufacture of the product such that information regarding the manufacture may be cross-referenced or stored with the product identifier.
  • the product identifier is prepared after the manufacture of the product such that it comprises information regarding the manufacture. If the product is analysed at each stage of the process, and the results of such analyses are cross referenced or stored with the product identifier, it makes it increasingly difficult for a potential counterfeit product to be introduced into the supply chain as such a counterfeit product will not possess any information on its manufacturing process and its subsequent movements.
  • the method comprises coupling the data acquired to information regarding the location of the substance/product at the time of analysis.
  • the movement of the substance/product can also be monitored.
  • the method may further comprise uploading the data acquired from the spectroscopic analyses onto at least one server or database such that it can be accessed at a later point in time.
  • the or each server may comprise a remote server such that the spectroscopic analysis data may be uploaded to, and subsequently accessed, remotely.
  • the data may be stored on at least one cloud based server.
  • the expected values of the spectroscopic analyses may be stored on the or each server such that upon upload of the acquired data, the data can be compared instantaneously with the expected values and to the previously acquired data for the corresponding product.
  • the method may further comprise encrypting the acquired data.
  • the encryption may take place before the data is uploaded on the server or database.
  • the encryption will make it increasingly difficult for a would-be counterfeiter to duplicate the data in order to introduce counterfeit products with the duplicated data into the supply chain.
  • the spectroscopic analysis may be performed using a handheld device.
  • the handheld device may be operable to perform a number of different types of spectroscopy depending on the nature of the substance/s to be tested.
  • the method may comprise uploading the data acquired by the handheld device onto a server or database directly.
  • the data may be uploaded onto the server or database over the internet.
  • a handheld device for monitoring a first substance using the method according to the first aspect of the present invention comprising a spectrometer and a means to analyse cumulative spectroscopic data acquired using the spectrometer and compare the acquired data to known values.
  • the handheld device comprises a means to obtain spectroscopic data from the first and/or second substance.
  • the handheld device may comprise a Raman spectrometer, a fluorimeter, a spectrophotometer, or an infra-red spectrometer, for example.
  • the handheld device comprises a plurality of spectrometers such that various methods of spectroscopy may be performed using the single device.
  • the handheld device may comprise a sample chamber.
  • the sample chamber may be operable to receive a sample of the first and/or second substance.
  • the spectroscopic analysis of the first and/or second substance may be performed whilst the first and/or second substance is within the sample chamber.
  • the handheld device may comprise a means to identify the product through verification of a product identifier.
  • the handheld device may comprise a means to connect the device to a product in order to identify the product.
  • the handheld device may be operable to scan a unique barcode located on the product, or on the packaging within which, or on which the product is located.
  • the handheld device may comprise an internal storage in which the expected values for the acquired data are stored.
  • the handheld device may comprise a means to connect to each server. In such embodiments the handheld device comprises a wired internet connection means, a wireless internet connection means, or both.
  • the wireless connection means may comprise a Wi-Fi transmitter operable to communicate over a local area network (LAN) comprising a wireless access point such as a router, or through Bluetooth, for example.
  • LAN local area network
  • the handheld device may connect to the or each server by accessing the internet over a cellular network.
  • the handheld device may comprise a display. The results of the spectroscopic analysis may be displayed on the display.
  • the display may also be operable to display to a user information regarding the operational status of the device.
  • the handheld device may further comprise a GPS transceiver such that the location of the device is known.
  • the information on the location of the device may be coupled with the data acquired by the device such that the location of the first substance at a given time is known.
  • the method comprises monitoring a product, as the movement of the product can be mapped to further limit the possibility of the entry of counterfeit products into the supply chain.
  • the device may comprise modified versions of the NANORAM (RTM) device manufactured by BW Tek, Inc. Newark, Delaware, USA or the TRUSCAN (RTM) device or the ND3300 fluorimeter manufactured by ThermoScientific, Waltham, Massachusetts, USA, which have been modified to enable storage and analysis of multiple readings over different time points.
  • the handheld device may comprise a cell or mobile phone (such as a "smart" phone), tablet computer or laptop computer.
  • a product comprising a first substance; and a second substance; wherein the non-visible spectra of the second substance is variable with time and/or in response to changes in environmental conditions.
  • the second substance may comprise a label or marker connected to or mixed with the first substance.
  • the second substance may be directly connected to the first substance, or is intimately mixed with the first substance, such as a homogeneous mix, suspension or solution for example, and the product may comprise a composite substance.
  • the second substance may be indirectly connected to the first substance, such as by way of an intermediate barrier substance or where the first substance is coated.
  • the second substance may comprise a label or marker applied to packaging in which or on which the product is located.
  • the second substance may be located on the outside of the packaging, may form part of the packaging or may be located within the packaging. There may be provided more than one second substance.
  • each second substance may be directly connected to the first substance, indirectly connected to the first substance, comprise a label/marker applied to packaging in which, or on which, the product is located, or any combination thereof.
  • the non-visible spectra of the second substance may change in response to increased or reduced temperature and/or pressure, fluctuations in temperature and/or pressure, changes in humidity, changes in oxygen or other atmospheric gas levels and/or levels of radiation exposure, for example.
  • the second substance may comprise a compound of biological origin such as a protein, for example, which in some embodiments undergoes structural changes such as denaturation or aggregation in response to temperature, time, pressure, oxygen levels, radiation or agitation.
  • the non-visible spectra of the second substance may vary in response to environmental conditions which affect the physical and/or chemical state of the first substance. In some embodiments the non-visible spectra of the second substance may vary in response to environmental conditions which are deleterious to the first substance.
  • Figure 1 is a schematic diagram illustrating the method and apparatus of an embodiment of the present invention.
  • Figure 2 is a graphical representation of data showing the change in Raman spectra over time of the commercially available TempTime VVM30 (time and temperature sensitive labels) stored at 60°C over 120 hours focussed on the 1440-1510 cm "1 wavenumber range, as used in an embodiment of the method of the invention.
  • Figure 3 illustrates the changes in the colour and fluorescence of DSRed at different temperatures, as used in an embodiment of the method of the invention.
  • Figure 4 is a graphical representation of the Raman spectrum of DSRed before and after denaturation by heating at 100°C for 30s, as used in an embodiment of the method of the invention.
  • Figure 5 is a graphical representation of the Raman spectra of an ice crystal or Tg biosensor illustrating the changes to the spectrum at varying temperatures, as used in an embodiment of the method of the invention.
  • Figure 6 illustrates the loss of colour of DSRed on the formation of large ice crystals and their corresponding fluorescence spectra, as used in an embodiment of the method of the invention.
  • Figure 7 is a graphical representation of the Raman spectra of a formulated bioink illustrating the changes to the spectrum at varying temperatures (heat and freeze), as used in an embodiment of the method of the invention.
  • Figure 8 is a graphical representation of data showing the change in fluorescence spectra over time of a formulated bionik; a fusion GFP protein incubated with a tobacco etch virus (TEV) protease over time shows an increase in fluorescence as used in an embodiment of the method of the invention.
  • TSV tobacco etch virus
  • Figure 9A illustrates the changes in the colour after UV exposure of a formulated GFP bioink, as used in an embodiment of the method of the invention.
  • Figures 9B to 9E are graphical representations of the cumulative Raman spectra of the formulated GFP bioink illustrated in figure 9A before and after UV exposure, as used in an embodiment of the method of the invention.
  • Figure 1 illustrates an embodiment of the method of the invention of monitoring a first substance in the form of a product 2.
  • Product 2 is monitored through spectroscopic analysis of a second substance in the form of bioink label 4.
  • Bioink label 4 is located on a surface of a container 6 housing the product 2.
  • the spectroscopic analysis of bioink label 4 is performed using handheld device 8 which is an embodiment of the apparatus of the invention.
  • the handheld device 8 comprises a means to obtain spectroscopic data in the form of Raman spectrometer 10 and a display in the form of LCD screen 12.
  • handheld device 8 is operable to connect with a server 14 through wireless connection 12.
  • Handheld device 8 scans bioink label 4 and compiles a set of data based on the results acquired from the Raman spectrometer 10. The results are subsequently displayed on LCD screen 12 for viewing by a user. In addition, handheld device 8 uploads the results to server 14 over wireless connection 12. The results are then processed by server 12 by comparing the set of data to expected values and updating the profile of product 2. The profile comprises information on the manufacture and subsequent movement of the product from previous scans using the same method. The server 14 is further operable to connect with handheld device 8 informing the user of the results of the comparison. The results are displayed on LCD screen 12.
  • the method as illustrated in Figure 1 may be repeated at various stages along a product supply chain. It is not necessary for the analysis to be undertaken by the same handheld device 8. In fact, the analysis may be undertaken by a plurality of handheld devices at various points along the supply chain, each handheld device uploading the results to the same server 14.
  • Figure 2 is a graphical representation of data showing the change in the Raman spectrum over time of the commercially available Temp Time VVM30 (time and temperature sensitive labels) stored at 60°C over 120 hours focussed on the 1440-1510 cm "1 wavenumber range.
  • Figure 3 illustrates the changes in the colour and fluorescence of the fluorescent protein DSRed at different temperatures.
  • an embodiment of the handheld device 8 includes a fluorimeter, and the spectroscopic analysis comprises fluorescence spectroscopy.
  • the images illustrate that DSRed is fluorescent at 25°C, but when heated, in this case to 77°C, DSRed loses its fluorescence. This is due to the protein becoming denatured at high temperatures.
  • Figure 4 provides a graphical representation of the Raman spectrum of DSRed before and after denaturation by heating at 100°C for 30s.
  • the Raman spectrum of DSRed before heating shows a number of peaks in the intensity at varying wavenumbers, and after denaturation the number of peaks dramatically reduces.
  • DSRed as a label will therefore provide an indication of whether or not the first substance/product has been exposed to increased temperatures. Such temperatures may be deleterious to the product so it may be desirable to obtain this information.
  • Figure 5 is a graphical representation of the Raman spectra of an ice crystal or Tg biosensor illustrating the changes to the spectrum at varying temperatures. Ice crystal and Tg biosensors are particularly useful as they can distinguish between a fast freezing event and a slow freezing event due to the nature of the ice crystals formed in such events and/or the concentration of solutes into an unfrozen fraction.
  • Using an ice crystal or Tg biosensor will therefore provide an indication of whether the first substance/product has been exposed to a slow freezing event which may be damaging to the substance/product.
  • Figure 6 illustrates the loss of colour of DSRed on the formation of large ice crystals and/or a concentration of solutes in the unfrozen liquid fraction.
  • Figure 6 illustrates the corresponding fluorescence spectra at these temperatures. It is apparent from these spectra that fluorescence spectroscopy may also be used to determine prior conditions to which the first substance/product has been exposed to.
  • Figures 7, 8 and 9B to 9E show the results of further embodiments of the use of the methods of the invention to measure cumulative changes to a substance.
  • Figure 7 shows the results of Raman determination of cumulative changes to a bioink subjected to fluctuating temperatures.
  • Mutant DsRed protein was used to develop a dual functional biosensor capable of detecting both heat and freeze events and therefore cumulative changes over time.
  • the mutant DsRed was incuabted with an ice nucleating agent and subjected to freeze and heat (>55°C) denaturation (as described in WO2013153392).
  • Figure 8 shows the results of florescence spectroscopy determination of the cumulative age of a bioink formulation comprising a fusion of GFP protein and tobacco etch virus protease, as determined using the method of the invention, described for Figure 1.
  • a quenched EGFP and a tobacco etch virus (TEV) protease one can demonstrate the production of a fluorescent protein formulation that reports on time by means of fluoremetery and/or Raman spectrometer.
  • the quenched GFP with an engineered TEV protease cleavage site allows the release, over time, of increased fluorescence.
  • Figure 8 demonstrates the situation, where over time the incubation of TEV protease with the quenched EGFP shows an increase in fluorescence intensity of EGFP as measured cumulatively by a fluoremeter.
  • Figures 9A to 9E show the cumulative results of UV exposure of a GFP bioink, both in terms of colour change (Fig 9A) and Raman spectra changes (Fig 9B to 9E), as determined using the method of the invention described for Figure 1.
  • the microemulsion and liposome preperations consisted of a thermochromic component, one which requires initial activation through a UV source (and further colour/flourescence changes upon heat activation).
  • Incorporating GFP into the formulation allows for a method to detect UV changes by a clear visual /fluorescence change (Figure 9A) overtime and by Raman methods ( Figures 9B to 9E).
  • the method may further comprise performing spectroscopic analysis of the product 2. Such analysis is performed using handheld device 8 and uploaded to server 14 in the same way as the results of the spectroscopic analysis of bioink label 4. The analysis of product 2 may be undertaken in order to confirm the authenticity of product 2.
  • bioink labels 4 each indicating via spectroscopic analysis different conditions to which the product 2 has been subjected to, for example temperature, time and/or radiation exposure.
  • the second substance may not be provided on a surface of a container housing the first substance.
  • the second substance may be incorporated into the first substance, mixed with the first substance, or applied onto the surface of the first substance such that they form a composite substance.
  • Figure 1 illustrates the first substance as a liquid medicinal product however, this method is not limited to such products. In fact, the method may be used to monitor any substance, solid or fluid, which may or may not be a pharmaceutical product.
  • the spectroscopic analysis of the or each substance may be performed by a plurality of spectroscopic methods which may or may not include Raman spectroscopy, such as absorbance spectrophotometry, fluorescence spectroscopy, infra-red spectroscopy, or thermal spectroscopy, for example.
  • the handheld device may comprise a fluorimeter, an infra-red spectrometer and/or a thermal spectrometer in addition to, or a replacement for the Raman spectrometer 10.
  • the handheld device 8 may comprise a sample chamber and the spectroscopic analysis of the first and/or second substance may be performed whilst the first and/or second substance is within the sample chamber.
  • the handheld device 8 may comprise a means to identify the product through verification of a product identifier or comprise means to connect the device to the product 2 in order to identify the product 2.
  • Handheld device 8 may be connected to each server.

Landscapes

  • Physics & Mathematics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

La présente invention concerne des procédés et des dispositifs pour surveiller une première substance, en particulier des produits et matériaux tels que des produits pharmaceutiques en utilisant une analyse spectroscopique d'indicateurs d'une seconde substance fixée à une telle première substance de manière à authentifier, suivre et surveiller des événements après la fabrication de telles substances, de tels produits et de tels matériaux à divers moments et en divers emplacements à mesure qu'ils passent par la chaîne d'alimentation. La réponse spectrale de la seconde substance qui fait office d'indicateur change en fonction du temps, par ex. également en fonction de la température, et peut par conséquent être utilisée pour suivre l'historique (cumulé) de la première substance depuis sa fabrication en supposant que la seconde substance est placée à proximité de la première substance immédiatement après une telle fabrication. Les conditions qui peuvent être surveillées par l'intermédiaire de la réponse de la première substance sont par exemple le temps, la température, la pression, l'humidité et des changements des gaz atmosphériques ou de l'exposition au rayonnement.
PCT/GB2015/050536 2014-02-26 2015-02-25 Procédé et dispositif de surveillance de substances WO2015128635A1 (fr)

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GB1614493.3A GB2537787A (en) 2014-02-26 2015-02-25 A method and device for monitoring substances

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GB201403391A GB201403391D0 (en) 2014-02-26 2014-02-26 A method and device for monitoring substances

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EP3908814A4 (fr) * 2019-01-08 2022-10-12 ChemImage Corporation Systèmes et procédés d'identification secrète

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CN110618116B (zh) * 2019-08-28 2022-01-11 江苏大学 一种可视化检测肉类新鲜度智能指示标签的制备方法及应用

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GB201614493D0 (en) 2016-10-12
GB2537787A (en) 2016-10-26

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