Deliverables
A chromatographic method based on liquid chromatography to obtain trace impurity profiles has been developed.
The method is based on either a LC-LC-MS or LC-LC-UV system: it consists in injecting a highly concentrated solution on a short column called preconcentration column, in order to eliminate the main product. Impurities in the solution containing the sample are then eluted from this short column towards an analytical column where chromatographic separation occurs. Two types of detectors are connected to the outlet of the analytical column:
UV-Vis and mass spectrometers. This enables peaks to be recognised by both retention time and molecular mass.
Anti-counterfeiting methodology using a combination of stable isotope analyses, chromatographic impurity data and chemometric classification techniques. This is designed to protect pharmaceutical patents for European firms by confirming the authenticity of the starting materials and the method of production of pharmaceutical products.
A complete strategy modelled and tested on phenolic derivatives but that is applicable to a large number of series of analogous compounds. The work carried out in this project will provide the basic framework for setting up similar product/process data bases for an entire range of compounds.
Current status: a decision tree summarising the chosen methods/approaches in function of the type of counterfeiting problem encountered is available (project final report).
Stable isotopes are (non-radioactive) naturally-occurring chemical tracers (13C, 2H, 15N) of synthetic or biosynthetic pathways. Measured at natural abundance level, this isotopic information provides a unique fingerprint of the active compound or of selected synthons that can be used to authenticate the synthetic process. These isotopic techniques are applied on a routine basis to the authentication of food products, for example to detect addition of sugar in fruit juice, to determine the natural status of an aroma molecule. The key innovative feature proposed here is the use of these techniques to trace the synthetic pathway that a molecule of pharmaceutical importance has undergone during its elaboration. This provides a means of proving that a product has or has not followed a patented process.
The techniques have been tested on generic molecules that are widely available throughout the world (aspirin, ibuprofen, paracetamol) demonstrating the potential of these methods for providing market intelligence. A number of other pharmaceutical compounds of interest have been included as test cases.
The expected benefits are to the pharmaceutical companies or to the European enforcement authorities in their attempt to clamp down on counterfeit medicines in Europe.
As reported under result 17887, isotopic techniques can be used to prove whether or not a given molecule of pharmaceutical importance has been produced by a specified patented process. They can be applied in conjunction with impurity profiling by chromatographic methodologies (results 17888 and 17889) to provide a combined patent-infringement and anti-counterfeiting detection strategy. However, particular challenges may arise in the case of biotechnological products and processes, where synthetic routes may be isotopically indistinguishable if the producing organisms share the same or closely similar biosynthetic pathways, and where impurity profiles reflect the origins both of the feedstock(s) and of other components of the culture media, as well as the characteristics of the producing organisms themselves, leading to unpredictable variability in overall impurity profiles. Using vanillin as a model compound, we have developed a solution to this problem that makes use of naturally occurring, metabolisable analogues of the feedstock for vanillin production (ferulic acid) that can be introduced into the feedstock in defined, small quantities. These metabolisable analogues are then converted during the biotechnological process to analogues of vanillin that are detectable in the final product. Thus a process can be individually and specifically "tagged" with metabolisable analogues that may be incorporated at predetermined levels (and which may be varied at will), leading to an unequivocal identification of the products of a specific process.
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