analytical detection of counterfeit dosage...

Chapter 15Analytical Detection of

Counterfeit Dosage Forms

Since pharmaceutical counterfeiting is primarily a form of visual decep-tion, counterfeiters tend to focus most of their energies on replicating thethings that can be easily seen and checked. Therefore, packaging qualityis usually high (and fake packaging is often very hard to distinguish fromthat of the genuine product) but the dosage form itself is often substan-dard. Even if it has some active ingredient, the product is unlikely tohave the same physical or chemical profile as the genuine formulation.One of the most powerful and direct methods to detect counterfeit prod-ucts, therefore, is to analyze the properties of the product itself. This caneither be achieved using laboratory-based testing of purchased or seizedsamples, or can increasingly be done using portable, non-invasive tech-niques. These analytical methods can also be applied to packaging (seefollowing sections), but are especially effective when used to validate theactive ingredients and chemical constitution of the dosage form itself.Because these techniques rely only on physical or chemical properties ofthe product, they are extremely difficult for criminals to circumvent usingcounterfeit materials.

Although this section is about analytical techniques, we should notforget the obvious in pursuit of a technological solution. The simplestnon-destructive method is visual inspection by a well-trained investigator.None of the methods below should substitute for regular communication

Pharmaceutical Anti-Counterfeiting: Combating the Real Danger from Fake Drugs,First Edition. Mark Davison.© 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

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114 ANALYTICAL DETECTION OF COUNTERFEIT DOSAGE FORMS

and liaison by brand owners with customs officials and law enforcement.The value of such a rapport should not be underestimated. If a suspectproduct is identified and the brand owner cannot be present in person,then they may still be able to advise based on visual inspection—mobilephone communications allow pictures of the suspect product to be sentround the world very quickly. A crumbly, gritty, off-color copy can bedifferentiated from the original pill in this way without the need for acorporate investigator to have it in his hand. This allows law enforce-ment to impound the consignment quickly and gives time for the brandowner to react and put the necessary supporting resources in place to helpinvestigate the event.

A wide range of techniques is used in the assessment of pharmaceuti-cal quality during and after manufacture, and I direct the reader to othersources for a fuller discussion of analytical techniques used during produc-tion.1 Although not all of the techniques used in the factory QA processare suited to the routine search for counterfeits, there are many which canbe adapted successfully. The potential methods that are available can bebroken down into a number of categories.

SIMPLE CHEMICAL AND PHYSICAL ANALYSIS METHODS

In a safety-sensitive, highly regulated, and technology-intensive industrylike pharmaceuticals, many of the problems and challenges that we facetend to need complex technical solutions. The attempt to control and erad-icate counterfeits is no exception. However, it is not always possible todeploy these solutions out in the markets where counterfeit drugs are mostcommon. Nor is it possible to send large numbers of seizures or test pur-chases of pharmaceutical products to the brand owner’s laboratory in orderto identify the minority which are counterfeit. In many cases, some formof triage process is appropriate, with simple, portable techniques used ona wide scale and more complex laboratory tools used when suspicions areraised. Therefore, anti-counterfeiting strategies should not overlook someof the more straightforward ways of looking for fake drugs. Some simpletechniques that have been around a long time are still perfectly serviceableas frontline tools. They often have the advantage of being easy to teach,relatively cheap, and applicable to use in developing countries where thecounterfeit problem is most acute. These simple analytical techniques canoften rapidly differentiate between very similar looking products.

Although the techniques below are described individually, in prac-tice they are often used in combination for maximum effectiveness. Forexample, several of these basic tests have been incorporated by the Global

SIMPLE CHEMICAL AND PHYSICAL ANALYSIS METHODS 115

Pharma Health Fund (GPHF) into a field kit2 known as GPHF-Minilab®.This provides a basic drug testing capability that is portable (it packs intotwo suitcases) and provides testing capability for a wide range of activeingredients. The GPHF website3 provides further details of the tests andthe drugs covered. Aimed primarily at developing countries, this initiativeis a good example of pragmatic, low-cost testing that can be undertakenby local staff. Since counterfeits are often rife in remote areas, the porta-bility of the Minilab increases the area that can be analytically surveyedfor fake drugs.

Colorimetry

This is a useful and simple field method that involves testing for an activepharmaceutical ingredient (API) using a reagent that reacts with it to causean observable color change. Such reagents are available for a wide vari-ety of common APIs. Absence of the color change, or a weak reaction,is evidence that the test sample may be a counterfeit. The technique isusually only semi-quantitative, and is best used as an initial test to identifycandidates for further testing. However, colorimetry can prove valuableas a triage technique in saving time and resources in the field and help-ing to prioritize samples for further testing.4 For example, the Fast RedTR colorimetric test, used to test for the anti-malarial drug artesunate,has been combined successfully in this way with laboratory analysis byliquid chromatography combined with mass spectroscopy (LC-MS).5 Aswith many colorimetric tests, the Fast Red TR test is quick, simple,and inexpensive but not foolproof. Counterfeiters are starting to circum-vent it by adding small amounts of artesunate to counterfeit anti-malarialdrugs. This makes detection of the fake drugs more difficult, but moreimportantly it could have a devastating effect on public health in malaria-prone areas. The prevalence of sub-therapeutic artesunate could increasethe resistance of malaria parasites to this important drug. The additionof sub-therapeutic quantities of API (or masking agents that mimic theexpected result) to defeat standard tests means that colorimetric testsshould be used with caution, but still have a role to play in the fight againstfake drugs.

Hardness and Dissolution Tests

These tests can be effective, especially against less sophisticated copies,and are also relatively cheap. A very crude measure of hardness can oftenbe gained by hand: poor quality counterfeit tablets are often crumblyor brittle. Most genuine pills cannot easily be crushed to dust between


finger and thumb, so a particularly fragile tablet is often the result of poormanufacturing using a simple, hand-operated tablet press. There are alsoquantitative analytical methods that can be used to test hardness moreaccurately. These measure the compressive strength of the tablet, or theforce (expressed in newtons, N) that it can withstand before failing.

The dissolution profiles of pharmaceuticals have a direct bearing ontheir pharmacokinetics (the action of drugs in the body over time) andtheir efficacy. The dissolution parameters are therefore carefully designed,tightly controlled by the manufacturer, and closely examined by the reg-ulatory authorities. They are highly predictable and reproducible betweenbatches for a genuine product. By dissolving the suspect counterfeit prod-uct in water or a solvent, and comparing the rate of dissolution with thatof a known, genuine reference sample, the analyst can determine anydifferences between the two. The dissolution profiles of two separate for-mulations rarely match by chance and counterfeiters do not usually spendresources matching the characteristics of the real product. Consequently,anomalies in dissolution profile have been a valuable indicator in identi-fying counterfeit and substandard drugs, such as anti-infectives.6 Variousanalytical methods can be used to determine dissolution rates, from visualinspection and the fairly simple tests used in the GPHF-Minilab® to moretechnological approaches.7

Thin Layer Chromatography (TLC)

Thin layer chromatography (TLC) is a simple, low-cost technique thatcan be applied to a wide range of drugs and is suitable for use in mobilelaboratories and in developing countries. It is conceptually similar to theschoolroom experiment of separating the pigments in a spot of black inkusing filter paper dipped in water. Typically, in analytical TLC, the testsample is first dissolved in solvent or a mix of solvents and applied asa small spot or thin horizontal line several centimeters from one end ofa silica-coated glass plate. The plate is then thoroughly dried, as residualsolvent in the plate affects the resolution of the separation. The dried plateis placed in a shallow pool of solvent in a lidded test chamber. The choiceof solvent (known as eluent or the mobile phase) affects the separationcharacteristics and for new analytes may have to be determined by trialand error. The Minilab kit contains detailed pre-determined standard pro-cedures for common pharmaceutical analytes. For optimum resolution, itis important that the test chamber should contain an environment satu-rated with solvent vapor—this is often achieved by dipping filter paperinto the solvent and allowing the wet filter to sit on the inside wall of thedeveloping chamber. It is important that the sample spot remains above

SIMPLE CHEMICAL AND PHYSICAL ANALYSIS METHODS 117

the initial level of the solvent. The solvent diffuses upward through thesilica plate (known as the stationary phase) and when it reaches the sam-ple application area, it causes the components of the dissolved sampleto migrate upward through the rest of the silica matrix at different rates.Before the upward-migrating solvent front (i.e., the edge of the “wet” areaof the plate) reaches the top of the plate, the plate is removed from thechamber and is then dried. Since many analytes are colorless, the plateusually then needs to be developed with a suitable chemical to reveal thepattern of spots—potassium permanganate or iodine are often used. Thedeveloped plate can be visualized under visible or UV light (depending onthe plate chemistry and developer used). Comparison of suspected coun-terfeits with reference samples on the same plate provides a relativelyquick, but not foolproof, field test of authenticity. The separation of prod-ucts can be converted into a semi-quantitative number called the retentionfactor (Rf), which is the ratio of the distance moved by the analyte to thedistance moved by the solvent front. This is prone to variation dependingon the exact physical conditions of the experiment, therefore is not fullycomparable between experiments. It is always preferable to use referencestandards on the same plate to provide a direct comparison. The Minilabprovides materials and full methods for the TLC analysis of a number ofdifferent drugs.

Ultraviolet and Visible Spectroscopy

Spectroscopy is the study of the light emitted or absorbed by a sample asan incident light beam passes through it. The simplest and oldest techniqueis visible spectroscopy, which derives from studies of the effects of prismson a light beam. Modern instruments typically measure in both ultravioletand visible areas of the spectrum, hence the technique is often knownas UV/visible spectroscopy. Many APIs and excipients have characteris-tic absorption spectra when examined under ultraviolet or visible light,so this technique provides a useful, simple, and quantitative approach todetermining the presence and concentration of the key constituents of apharmaceutical preparation. The absorbance of a solution is directly pro-portional to the concentration of the absorbing compound(s) in it and to thedistance the light travels through the sample (the path length), a relation-ship known as the Beer–Lambert law.1 Thus, if a fixed path length is used(typically, a 1-cm cuvette), this relationship can be used to determine theconcentration of compounds in a test solution by reference to a calibrationcurve. In order to maximize the visibility of the signal from the analyteand to prevent background interference, the absorption of UV/visible lightby the solvent itself needs to be minimized: ethanol and water are usually


the solvents of choice since they do not absorb strongly in this regionof the electromagnetic spectrum. The spectrophotometer corrects for theabsorption of the solvent by subtracting a reference spectrum (obtainedusing a separate cuvette containing only solvent). This allows measure-ment of only the residual light due to the absorption of the dissolvedmolecules, which is usually plotted as a graph of light intensity versuswavelength.

UV/visible spectrophotometers are relatively inexpensive and portablepieces of equipment and with simple calibration can be very accurate andquantitative. They can be used on a standalone basis with manual fillingof glass or silica cuvettes. Care should be taken in sample preparation toensure that the test material is dissolved and during removal to ensure thatthe cuvettes are thoroughly cleaned between samples to prevent contam-ination and erroneous results. Automated UV/visible spectrophotometers,with continuous flow cells rather than manual cuvettes, are also usefulas downstream detectors after separation of sample constituents by liquidchromatography (LC).

LABORATORY-BASED METHODS

The methods described above are all quite portable and lend themselvesto field-based testing. However, not all samples are suitable for these tech-niques and there are often challenges in sample preparation and analysis.This, coupled with the need for greater analytical resolution in differ-entiating more sophisticated counterfeit products, means that laboratorymethods are often needed. The techniques described below represent across section of the methods used, but this is not an exhaustive list. Someof them are also available as portable instruments. Note that many brandowners do not disclose their analytical methods, for obvious securityreasons.

Atomic Absorption Spectrophotometry (AAS)

This method requires the sample to be atomized (usually with a flame)and illuminated by a light beam. The light is then analyzed after pass-ing through the sample to give a quantitative breakdown of the elementalcomposition of the sample. Modern instruments allow the direct analy-sis of solids without the lengthy sample preparation required previously.Typically used to detect metals, this technique is not normally used in thefirst-line testing of suspected counterfeits but may provide useful confir-matory information.

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X-ray Techniques

In contrast to atomic absorption spectroscopy (AAS), X-ray fluorescencespectroscopy8 is a non-destructive technique but one which also probesthe atomic structure of a sample. Energy dispersive X-ray spectroscopy(EDX or EDS) is one of the commonly used variants, and uses a beam ofeither charged particles or X-rays to eject electrons from the inner orbitalshells of the constituent atoms of the sample. The return of the atomsto the stable ground state, as the empty inner orbitals are refilled withelectrons from the outer shells, is accompanied by the emission of X-rays.The energy of the emitted X-rays is related to the difference in energybetween these two electron shells, which is distinctive and predictable fordifferent transitions in different atoms. A plot of the number and energyof the X-rays emitted therefore gives the elemental composition of thesample, which can be compared with known reference standards. In thelaboratory, the technique is frequently coupled with scanning electronmicroscopy (SEM).

Nuclear Magnetic Resonance (NMR) Spectroscopy

Nuclear magnetic resonance (NMR) techniques can also be a very use-ful, often non-destructive analytical technique. The concept relies on theinteraction of a specific class of atomic nuclei with an applied magneticfield. Atomic nuclei that have an odd number of protons and neutrons,such as 1H and 13C, have non-zero spin values and therefore interactwith magnetic fields, whereas nuclei with an even number of both pro-tons and neutrons (including those of atoms common in pharmaceuticalchemistry such as 12C and 16O) have zero spin values and do not inter-act. Importantly, the magnetic interaction of a 1H or 13C nucleus withthe applied field depends on the electron environment around the nucleus,which in turn depends on the adjacent chemical bonds to other atoms.Each bond gives a characteristic signal, or chemical shift, expressed inparts per million or ppm. NMR spectra therefore give useful informationon the composition and structure of complex molecules. The ubiquity of1H in organic molecules means that quantitative nuclear magnetic reso-nance spectroscopy (qNMR) is a highly versatile and important techniquewith many applications in pharmaceutical science. Although 1H NMR isby far the most common technique, 13C is also widely used and given asufficiently powerful magnetic field, it is possible to use other, rarer nucleiwith non-zero spin values. Traditionally used to study compounds in solu-tion, NMR detection can be coupled with many of the sample separationtechniques described in this section. Solid phase NMR spectroscopy is


also an excellent tool for the characterization of the water content, poly-morphism, and formulation of solid dosage forms such as tablets andpowders. The ability of NMR to differentiate between biochemically andstructurally very similar chemicals is an important tool. After the heparincontamination incident of 2008, an NMR method was developed by FDAand Baxter scientists to analyze crude heparin and to identify the closelyrelated adulterant, over-sulphated chondroitin.9 For a fuller description ofNMR techniques in pharmaceutical analysis, see elsewhere.10,11

Mass Spectrometry (MS)

Mass spectroscopy (MS) measures the mass-to-charge ratio of moleculesand molecular fragments. The sample is vaporized and then ionized andfinally its constituents are separated by an electromagnetic field beforereaching a detector. This quantitative technique allows the mass of indi-vidual molecules or fragments to be determined quickly and accurately andis also useful for isotope ratio analysis of suspect packaging.12 Coupledwith various front-end sample preparation techniques, MS can provide anunequivocal fingerprint of a complex pharmaceutical sample or its pack-aging and enables counterfeits to be readily identified. Especially usefulin this regard are techniques such as DART (direct analysis in real time),which allow much easier MS analysis without extensive sample prepa-ration.13 Mass spectrometry can be used as a standalone technique orcan be coupled with a preceding sample separation stage such as gaschromatography (GC), LC, or capillary electrophoresis (CE).

Gas Chromatography (GC)

GC is a useful, versatile, and widely used technique for pharmaceuticalanalysis.14 Molecules in the sample are separated on the basis of theirmigration rate through a thin column containing a stationary phase—a thinlayer of liquid on a fixed solid matrix —and a mobile phase comprisinga pressurized inert or unreactive gas such as helium or nitrogen. Theinteraction of the test sample constituents with the two phases determinestheir rate of progress. The time taken to traverse the column and reachthe detector at the other end (the retention time) is distinctive for a givenmolecule in the same analytical system. The series of peaks in the detectorreadout therefore corresponds to different molecules exiting or elutingfrom the column and the presence of the expected constituents of a testsample can be verified by comparison with known reference peaks. Sincethe mobile phase is gaseous, the test sample must be vaporized beforeseparation. This can be problematic if one or more critical analytes are

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prone to decomposition. GC is often used with a thermal conductivitydetector or can be coupled to a mass spectrometer (GC-MS), NMR, orother detection system.

Liquid Chromatography (LC)

LC uses a solid supporting matrix, usually in the form of a column, anda liquid mobile phase, which is usually pumped through the matrix underpressure. The test sample is introduced in a small volume at one endof the column and its constituent molecules then migrate through thematrix at different rates according to their molecular size, weight, andcharge. As for GC above, the retention time is reproducible for a givenmolecule in the same system. The technique can be used as a relativelylow-technology method, using hand-filled columns, but the more usualform is high-performance liquid chromatography (HPLC) in which thesolvent is pumped through a tightly packed stationary phase in a steel-encased column at high pressure. This technique allows smaller samplevolumes, quicker and more quantitative analysis, and greater sensitivity.The output from the HPLC column is coupled to a detector, which maybe a UV/visible spectrophotometer, mass spectrometer, or other detectionmethod (see above). HPLC is an excellent method for the identificationof impurity profiles and adulterants in complex mixtures as well as forconfirming the presence and concentration of active ingredients.

Capillary Electrophoresis (CE)

This technique allows the separation of a mixture of charged moleculeson the basis of their size and charge. The sample components move atdifferent rates, under an electric field, along a small capillary filled withan electrolyte. As they elute at the other end, they are detected, usuallyeither by a UV/visible spectrophotometer or a mass spectrometer. Thetechnique only requires a small sample size and can be very sensitive butdoes not work effectively for many neutral molecules. Samples must bedissolved as the technique cannot be used for solid state analysis.

Forensic Palynology

The analysis of naturally occurring and harmless contaminants in pharma-ceutical preparations can be a useful adjunct to the measurement of APIsand excipients. Palynology is the study of tiny organic particles such asplant pollen and fungal spores. Originally used to analyze fossil micropar-ticles in rocks to gain evidence of earlier climatic conditions, the same


techniques can now be used for forensic analysis of suspected counterfeitdrugs. Tiny amounts of plant pollen are found naturally everywhere, evenin clean manufacturing environments, and become incorporated into bothreal and counterfeit tablets and capsules. Although pollen can be widelydispersed by the atmosphere, the pollen found in a pharmaceutical sam-ple comes predominantly from the plant species that are common in thenearby region. Under an electron microscope, pollen grains from differentplants have distinctive shapes and surface features (Figure 15.1). By ref-erence to known samples, a pollen grain can often be identified down tothe species level. Careful analysis of the number and relative abundanceof pollen types present in suspected counterfeits can therefore reveal theflora of the area in which the pills were produced. This can help to iden-tify the likely geographic origin of the fake drugs, often pinpointing thelikely location within a relatively small geographic region15.

By narrowing the search area, palynology can therefore enable lawenforcement activities to be better targeted, and it raises the chancesof discovering and closing down criminal production facilities. In mostcases, counterfeit drugs are made in a different geographical area to the

PILL

10

Figure 15.1. Forensic Palynology. Specific types and mixtures of plant pollen are identifiedusing an electron microscope and compared with the known distribution of plant species.

NON-DESTRUCTIVE METHODS 123

genuine product. Therefore, forensic palynology is a potentially power-ful technique as it is almost impossible to manipulate the pollen contentof the fake product without infeasibly heavy investment in clean roomtechnology.

NON-DESTRUCTIVE METHODS

Many of the methods described above require varying degrees of irre-versible sample preparation (removal from sealed container or blister pack,crushing into powder, dissolution with solvent, etc.) and therefore cannotbe used in non-destructive mode. This can be a drawback for a number ofreasons: there may not be the time or facilities during a field investigationto undertake complex sample preparation; the owner of the consignmentto be checked may reasonably object to having their consignment openedso that a sample can be removed for analysis; if the product is packed andsealed in bulk, then opening it for examination could render it unsellableand represents a significant and unnecessary financial loss to the ownerif the batch is subsequently confirmed as genuine. For these reasons, andoften because of the cost and bulk of the instruments used, most of theabove techniques are used for secondary analysis of suspected counter-feits that have been identified in the field by other, usually non-destructive,methods such as those described below.

X-ray Diffraction

Portable X-ray diffraction (XRD) instruments are now becoming avail-able, often adapted from instruments used in the analysis of minerals inmining operations.16 These instruments operate under the same techni-cal principles as laboratory diffractometers, but using a small, portableX-ray source. By comparing the observed diffraction spectrum from thetest sample with known spectra in a database, the machine can identifythe presence or absence of key ingredients or contaminants. The portableXRD machines are not as cheap as the portable infrared machines dis-cussed below, but the technique is versatile and offers complementarycapabilities to the infrared techniques.

Infrared Spectroscopy

The most common non-destructive approach used to check pharma-ceuticals in situ, while still in their packaging, is currently infraredspectroscopy. This technology has several different variations, each with


their own strengths and weaknesses, which are discussed below. Infraredmachines can be very portable and, while also not cheap, are nowavailable at a price that is affordable for regulatory bodies in developingcountries.

The infrared portion of the spectrum is commonly divided into threesub-regions, termed near, mid, and far based on their proximity to thevisible spectrum. Each region of the spectrum can provide different infor-mation on the molecular structure of the sample. Infrared analyzers typ-ically consist of an infrared laser and a detection system. Light fromthe laser interacts with the sample depending on the molecular propertiesof the various substances within it and is absorbed at specific resonantfrequencies corresponding to the energies of molecular vibrations in thesample. These interactions result in a spectrum of transmitted light, whichis analyzed to form a spectral “fingerprint” of the sample. Measurementstaken in a production facility or in the field, using portable or handhelddevices, can be cross referenced to a database of known reference scansto identify the constituents of the sample. Often it is possible to differ-entiate not only between different products but also between differentbatches of the same product. This can be particularly useful when inves-tigating cases where batch numbers or expiry dates appear to have beenchanged. Additionally, the ability of the technique to discriminate betweenbatches of product from the same manufacturer makes it possible to iden-tify when the product manufactured for one destination (e.g., a donationto a developing country) has been diverted and illegally resold in anothermarket.

Fourier transform infrared (FTIR) spectroscopy, near-infrared (NIR)spectroscopy, and Raman spectroscopy are related but distinct infraredtechniques and all three are commonly used in pharmaceutical applica-tions. Infrared spectroscopy can be highly selective and is well-suited forboth raw material validation during manufacture and product identificationand verification in the field.

Fourier Transform Infrared (FTIR) Spectroscopy

FTIR, or mid-infrared spectroscopy, was the first vibrational spectroscopytechnique to be widely used for material identification. It measures lightabsorption by the sample across a range of wavelengths simultaneously,using the Fourier transform data processing technique to produce a spec-trum corresponding to fundamental molecular vibrations within the samplemolecules. FTIR has excellent selectivity, but sample presentation can bequite demanding. The sample must usually be in direct contact with theinstrument and only the surface of the material can be analyzed.

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Near-Infrared (NIR)

The bands observed in NIR, which as the name suggests uses higherenergy, shorter wavelength light than mid-infrared FTIR, predominantlyarise from stretching of O–H, C–H, and N–H bonds. The bands are gen-erally much broader than those seen in FTIR. Owing to band broadeningand the ubiquity of these molecular bonds in organic molecules, the differ-ences between NIR spectra of different compounds are often very subtleand require greater processing. Thus NIR often gives a lower molecularselectivity than FTIR. However, NIR offers much more convenient samplepreparation than FTIR.

Raman Spectroscopy

When light is scattered by interaction with matter, most of the light retainsthe same frequency. However, around one in a million of the scatteredphotons changes frequency (the Raman effect). This effect, despite its lowincidence, can be readily measured and is highly sensitive to molecularstructure. Raman spectroscopy can analyze substances through glass andplastic, allowing pills to be analyzed while still in blister packs or bulk APIto be analyzed while double-bagged in drums. Since water gives a veryweak Raman signal, the technique can also be used to analyze materialsin aqueous solutions. An advantage, particularly for portable devices, isthat little or no sample preparation is needed before performing a Ramananalysis.

Scanners are now more portable and easier to use, making infraredtechniques ideal for field use by regulatory agencies, customs officials,police forces, etc. Although not cheap (scanners typically cost from20,000 to 50,000 US dollars), the technology is now also within theprice range of developing countries—often, the most severely affectedby counterfeit drugs. The Nigerian regulator, National Agency forFood and Drug Administration and Control (NAFDAC), has investedin this technology to combat the high level of fake drugs entering thecountry.17

Several of the major drug companies have also implemented portableRaman devices (Personal communication 23 September 2010). These areused by company investigators to authenticate their products in the field.The companies concerned have undertaken in-depth development andsystems integration, in partnership with instrument vendors, to ensurethat causes of variability are eliminated. False positives or negativescan be caused by defects in instrument calibration or inadequate usertraining. Instrument-to-instrument variability must also be eliminated asfar as possible.


Terahertz Imaging

The region of the electromagnetic spectrum between infrared andmicrowaves, at frequencies around 1 Terahertz, has recently beenexploited for non-destructive (although not yet fully portable) test-ing devices, which allow imaging of solid dosage forms in threedimensions.18 This allows comparison of coatings and layers in theformulations under examination. This could prove valuable in examiningsuspected counterfeits that appear to have the correct dosage of API, butwhich may have different (and potentially) dangerous pharmacokineticproperties because of variations in their structural and release properties.

CONCLUSIONS ON THE ANALYSIS OF DOSAGE FORMS

The prevention of counterfeiting is largely based on deterrence, and ahigh likelihood of detection increases the risks for the criminals whoare producing fake drugs. Although the identification of suspect, fake,or altered packaging is often a useful proxy (and often the only feasibleoption) when looking for counterfeit medicines themselves, the rapid, non-destructive, and unequivocal detection of the counterfeit dosage formsdirectly is a much more robust method when available.

For law enforcement officials, especially in developing countries, theadvantages of portable, non-destructive technologies such as infrared spec-troscopy are several:

• Spot checks can be made quickly and without warning.• Evidence is provided almost immediately, allowing rapid seizure of

suspect items without recourse to brand owner verification.• It is not necessary to equip every customs post or train every officer.• Expensive equipment can be controlled and monitored securely.• Opportunities for corruption can be minimized.

The encouragement by the US FDA of physical–chemical identifiers inpharmaceutical products will encourage the development of more sophisti-cated ways to use markers, perhaps tuned to specific detection techniques.By its very nature, though, the physico-chemical analysis of drugs can onlyever be a spot-check mechanism, used on a tiny subset of the medicinesin circulation. In order to reach a higher proportion of medicines and con-sumers, we need to look at other methods of applying security. The nextsection looks at how secure packaging can help to differentiate genuinefrom counterfeit products.

analytical detection of counterfeit dosage...

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