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This article reviews the global implications associated with the use of counterfeit drugs in developing and developed countries. It emphasizes on the recent technologies used for the control and detection of the counterfeiting drugs. These recent techniques include Raman spectroscopy, X-Ray Powder Diffraction [XRPD]. These methods are non-invasive detection of counterfeit drugs through blister packs and opaque plastic bottles and the rapid quantitative analysis of bulk content of tablets and capsules without sub-sampling.
Keywords: Counterfeit, Substandard drugs, Problems encountered due to counterfeit drugs, XRD, Raman spectroscopy.
Most widely used definition was proposed by World Health Organization (WHO), which states: "A counterfeit drug (CD) is one which is deliberately and fraudulently mislabeled with respect to identifier and/or source. Counterfeiting can apply to both branded as well as generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredient, with insufficient active ingredient or with fake packaging". Counterfeiting of pharmaceutical drugs poses a significant and fast growing threat to human health and public safety. It also causes an economic problem for genuine drug manufacturers, decreasing their revenue and reputation. Moreover, it decreases the confidence of their medicines in public as well as in international market.
KEY FACTS OF COUNTERFEIT DRUGS: 
Counterfeit drugs are those which are deliberately and/or fraudulently mislabeled. 
These counterfeits thus cause treatment failure or even death.
Public confidence on the health-care and treating system are eroded on detection of these counterfeits.
Branded products as well as generics are counterfeited.
These counterfeit medicines vary from drugs against life threatening to simple day to day used medicines like anti-histamines to analgesics. (Table 1).
Counterfeit medicines may be those with little active ingredient, no active ingredient, with spurious active ingredient etc.,
Table 1: Examples of counterfeit medicines 
Country and year
Anti diabetic traditional medicine
Contained six times the normal dose of Glibenclamide (2 people died,9 people hospitalized)
Metakelfin (Anti malarial)
United Republic of Tanzania, 2009
Discovered in 40 pharmacies; lacked sufficient active ingredient
Viagra and cialis (for erectile dysfunction)
Smuggled into Thailand from an unknown source in an unknown country
Xenical (for fighting obesity)
United states of America, 2007
Contained no active ingredient and sold via Internet sites operated outside USA
Zyprexa (for treating bipolar disorder and schizophrenia)
United kingdom, 2007
Detected in the legal supply chain: lacked sufficient active ingredient
Lipitor (for lowering cholesterol)
United kingdom, 2006
Detected in the legal supply chain: lacked sufficient active ingredient
Even though precise data on counterfeit drugs are impossible to obtain, it is widely believed that 10% of drugs worldwide are likely to be counterfeited. This single broad ratio is not suitable to describe the situation, as the amount of counterfeit drugs represents close to 1% of the market value in developed countries, whereas more than 50% of medicines purchased over the internet are fake as well as between 30 to 60% of those sold in various areas of many countries in Latin America, southeast Asia, and sub-Saharan Africa.
The global trade in counterfeit medicines is growing as it is a enormously profitable business due to the continued high demand for cheap medicines and low production costs. Indeed, it is calculated that counterfeit drugs sales will reach US $75 billion in 2010. (Table -2; Figure - 1)
Table - 2: Global Pharmaceutical Commerce Estimates 
Percent of total
Total International Drug Commerce
Figure 1: Global Pharmaceutical Commerce Estimates
Any kind of product can be counterfeited and it has already been counterfeited till date. For instance, luxurious lifestyle drugs such as those for treating erectile dysfunction, fat reduction or sleeping remedies, antibiotics, anticancer drugs, medicine for lowering hypertension or cholesterol and cheap versions of simple painkillers or histamines (Figure - 2). In developing countries, the most worrying issues are the easy availability of counterfeited medicines for the management of life threatening diseases such as Malaria, Tuberculosis, and AIDS. 
Figure 2: Therapeutic categories counterfeit incidents (based on 2009 data)
What makes a counterfeit drug varies from country to country depending on the regulator and the situation. The challenge for public health safety is to detect and dispose of the poor-quality medicines available in the market. This includes counterfeit drugs that have an under or over concentration of active ingredient, and/or are contaminated or degraded. However, it is unclear whether a poor-quality drug is a result of deliberate counterfeiting or substandard production, transport and storage conditions. , 
Figure 3 Incidents-Regions of the world Pharmaceutical Security Institute
COUNTERFEITING DRUGS IN INDIA
India: Capital of Counterfeit Drugs
According to WHO data, India produces 35% of the counterfeit products, Nigeria accounts for 23% and Pakistan accounts for 15%. The effect of counterfeit is particularly worst in Asia. India is becoming capital of counterfeit drugs, producing around one-third of the fake drugs worldwide.
The pharmaceutical industry, including those manufacturing spurious drugs, is growing at the rate of 20% yearly, which means that every year the chances of buying a medicine that can do more damage than good is also rising proportionately. Despite the use of hologram by many pharmaceutical companies to protect their products, spurious drugs business continues to increase in Punjab, Haryana, Himachal Pradesh, Delhi, Utter Pradesh, Gujarat, Maharashtra and Karnataka.
Figure 4: Big pharmaceutical companies facing the problem of counterfeiting 
Several pharmaceutical industries are using highly pressurized marketing practices like unrecorded discounts, dumping goods, and rising fake invoices in the name of hospitals. These drugs never reach the hospitals and are sold in the open market without proper bills. Manufacturers of spurious drugs are taking advantage of these circumstances and selling their spurious drugs in major drug markets like Patna, Agra, Kanpur, Satna, Coimbatore, Bangalore, Mumbai, Kolkata and Delhi. Nearly 60% of the total fake drugs and black marketing in the country are sold under the very middle of the central government at Bhagirath place in Delhi. This threat is resulting in thousands of sales promotion employees losing their jobs. "Everyone knows where counterfeit drugs are sold in Delhi" says a scientist from the Delhi science forum, a non government organization (NGO). "Anyone can go to Bhagirath place and buy any medicine one wants including empty capsules at a fraction of their actual price and no action has ever been taken," he points out "the authorities just don't want to address problem. The reason is widespread corruption in the drugs control system in the country".
Sources also add that counterfeit medicines worth lakhs of rupees are bought and sold openly in Ludhiana and Jalandhar in Punjab by the drugs mafia after every two to three days as the cities are considered to be the biggest market of spurious medicines in that part of the region. These drugs are brought to the city through the borders of Delhi, Haryana and Ghaziabad.  
Table 3: Samples tested by government labs during the period of 1995-2003 
Not of standard quality
Not of standard quality %
World Health Organization (WHO) has created International Medical Products Anti-Counterfeiting Taskforce (IMPACT) in 2006 to develop control measures for counterfeit drugs. Different methods have been proposed to control CD. Nowadays, the first step in identifying CD is to compare the physical appearance (organoleptic characters) and text on packets, leaflet inserts, and blister packs of alleged samples with those of known genuine products. However, with increased counterfeiter sophistication, this visual inspection is not efficient to distinguish between fake and authentic drugs. It must therefore be followed chemical analysis, most often using high performance liquid chromatography (HPLC), considered as the standard analytical tool in drug analysis, but also with simple in field detection methods [e.g., colorimetric test and thin-layer chromatography (TLC)] or more sophisticated laboratory techniques [e.g., mass spectrometry (MS), vibrational spectroscopy (Raman or IR), and nuclear magnetic resonance (NMR) spectroscopy]. These analytical techniques allow one to quantitatively determining the chemical composition of the drug [active pharmaceutical ingredients (APIs) as well as impurities and excipients] and hence to identify low quality medicines, which include not only CD's but also substandard drugs.  But problem with the above detection methods is, all are invasive and hence the blister packs in which the drugs are packed has to be opened in order to perform the test. But nowadays there is development of new techniques which are noninvasive and hence destruction of blister packs for testing is avoided. This article mainly focuses on those techniques developed recently, which are noninvasive in nature except physical-chemical identifiers (PCID's). 
METHODS FOR THE DETECTION OF COUNTERFEIT DRUGS:
There are several techniques used for the detection of counterfeit drugs. These techniques ranges from simple thin layer chromatography (TLC) to more complex methods like near-infrared spectroscopy(NIR), Liquid chromatography-mass spectroscopy (LC-MS) etc.,
Simple chemical approaches
Bulk property testing
Method recommended by The German Pharma Health Fund Mini-Lab (GPHF)
Chromatography and Mass spectroscopic techniques
Physical-chemical identifiers (Newer technology)
X-ray powder diffraction
Near infrared spectroscopy
In this technique, the drugs which are packed in blister packs or opaque plastic bottles are to be tampered before assay procedure. So once the pack is tampered off, the whole blister pack or bottle is of no use or not to be sold. Hence this tampering off is considered one of the biggest problem in case of these non invasive techniques.
This technique overcomes the problems which are posed in invasive techniques. Hence the use of these non invasive techniques for the detection of counterfeit drugs is carried out nowadays.
The near-IR region of the electromagnetic spectrum includes the wavelength range of about 800-2500 nm. Molecular overtone and combination vibrations form the source for this analytical method. The molar absorptivity in the near-IR region is very little as these transitions are forbidden. But the near-IR has a superior penetration power than mid-infrared radiation. Although it is not a sensitive technique, it can be used for the evaluation of bulk materials. Another advantage is that this technique requires no sample preparation in many cases. The extensive nature of the molecular overtone and combination bands in the near-IR consequences in complex spectra. This makes it difficult to assign precise features to specific chemical components. Principal component analysis or partial least squares are mainly used as a multiple wavelength calibration technique. This helps in understanding the chemical nature. The application of near-IR analytical method mainly dependents upon two key factors - the calibration samples and calibration techniques. 
The instrumentation consists of a source, a detector, and a dispersive element. Quartz halogen light bulbs, light-emitting diodes, etc. are also used as a source of near-IR radiation. Silicon-based charge-coupled devices, indium gallium arsenide devices, and lead sulfide devices are vastly used as detectors. A 2D array detector with an acousto-optic tunable filter is used for chemical imaging. Diffracting gratings are majorly used for the purpose of dispersion of the radiation though prism.
Measurement and data analysis:
Transmittance mode and reflectance mode measurements are possible with NIR spectroscopy depending upon the position of the sample and the detector. The ratio of the intensity of radiation that passes through the sample to the intensity of radiation falling on it is called as transmittance whereas the ratio of the intensity of radiation reflected by the sample to the intensity of radiation falling on it is called as reflectance. The process of diffuse reflectance involves the re-emergence radiation after penetration into the bulk of the analyte and undergoing multiple reflections within the sample substance. For the evaluation of solid analyte like tablets, mainly reflectance spectroscopy is used. NIR spectra are complex with several broad overlapping peaks. This necessitated the use of chemometric data processing to collect sample properties from spectral information. Iyer et al. have carried out comparative studies of the reflectance and transmittance methodologies for the evaluation of tablets. The results showed that both methods might be sensitive to sample in homogeneity and those transmittance measurements are sensitive to path length changes. Typically to correct co linearity and the typically poor selectivity of NIR spectra, multivariate models are used though some researchers were able to develop a univariate calibration technique for pharmaceutical analysis based on NIR spectra. 
Applications in identification of counterfeit drugs:
The noninvasive evaluation of tablets using the NIR technique has been studied in detail as an alternative for the current destructive methods of evaluation. The increasing in hardness of tablets was found to cause increased absorbance of NIR radiation. Dissolution and disintegration time were also found to be quantitatively associated to the absorbance of NIR radiation as these factors are caused by a direct effect of tablet hardness. The detection and quantification of drugs and excipients were also found to be possible from the previously reported research works. Tablet coating processes were also found to be easily monitored with this technique. Several other statistical techniques and software are reported to be useful for carrying out this technique. NIR spectroscopy is considered to be of high significance in terms of process analytical technology and is gaining wide acceptance as a rapid and simple real time in-process testing. The appropriateness of this technique even after packaging renders it highest suitability for pharmaceutical evaluation. It is also suitable for day to day quality control of tablets. 
Raman spectroscopy holds particular assure in this area due to its inherent high chemical specificity (higher than that of NIR), the ability to investigate sample in the presence of water and its potential for high penetration depth into non absorbing samples such as pharmaceutical powder(similar to that of NIR absorption spectroscopy). The higher chemical specificity of Raman spectroscopy relating to NIR absorption raises from the fact that NIR spectrum consists of overlapping overtone and combination bands of fundamental vibration modes. In contrast, Raman spectra exhibit much sharper bands equivalent to fundamental vibration modes
The Raman Effect is the inelastic scattering of photons from molecules through interaction with the vibrational modes within a molecule. In this process, the photon energy and consequently the photon wavelength are altered giving spectra unique to each chemical species undergoing scattering. Most commonly the photon looses energy and its wavelength is shifted usually by several hundreds to thousands of wave numbers away from the laser wavelength, towards longer wavelength. The Raman shift, or energy loss, is in direct relationship with the frequencies of vibrational motion activated within the molecule which dependents on chemical constitution; thus the identity and structure of the molecule can be deduced. 
Methods for deep Raman spectroscopy of turbid media:
A major obstacle in preventing conventional Raman spectroscopy from gaining signals from deep areas of turbid samples is the presence of intense Raman signals coming from the surface layers of the probed samples which masks the weaker subsurface signals. The Raman signals from deeper zones are substantially diluted due to the wide diffusion of laser and Raman photons away from the vicinity of the deposition area due to the long pathways necessary to sample to target layer. 
Spatially offset Raman spectroscopy (SORS):
The SORS concept is simple Raman signal is collected from areas that are spatially offset (by a distance Î”s). The key point is the spectra obtained at a single spatial offset contain different relative contributions from sample layers located at different depths due to wider spread of photons originating from deeper layers on the sample surface. The lateral offset also effectively differentiates against photons propagating side-ways within the surface layers as they shows a higher loss at the air to sample interface than photons propagating through deeper layers. Consequently the SORS technique effectively decreases the interfering Raman and fluorescence signals originating from the surface layers. 
In this technique, the laser beam impacts on one side of the sample and the Raman signal is obtained from the other side. Although the transmission Raman spectroscopy was established in very early days of Raman spectroscopy, its use for the non-invasive probing of the bulk content of pharmaceutical products have not been recognized. In this technique, there is elimination of sub-sampling problem (the ability to probe deeper layers of turbid samples) and the effective decrease of fluorescence and Raman signals originating from surface layers. This concept can be considered to be a special case of SORS with the illumination and collection of signals to the maximum extent.  
XRD SCREENING OF BLISTER-PACKAGED TABLETS
XRPD enables the effective, rapid and reliable screening of pharmaceutical solid dosage forms like tablets without the need of removing them from the original blister packaging even with opaque blister pack. The method's unique fingerprinting mechanism allows differentiation between counterfeit and authentic drugs. Furthermore, XRPD allows the detection of structural changes that can occur during production, packing or storage. In both cases, the ability to assay tablets without removing them from their packaging is a major benefit. Â Â
A crystal lattice is arranged to form a series of parallel planes differentiated from each other by a distance (d), which varies based on the nature of the material. For any crystal, planes occur in a number of different orientations each with its own specific d-spacing. The phenomenon of x-ray diffraction by crystals results from a method, in which X-rays are scattered by the electrons of the atoms in the material. When a monochromatic X-ray beam with wavelength lambda is projected onto a crystalline material, diffraction occurs only for those angles theta where the conditions of the so called Bragg's law are satisfied. The intensities of the diffraction maxima are related to the strength of those diffractions in the sample; they depend on the nature as well as quantity of the material. Plotting the angular positions and intensities of the resultant diffracted peaks of radiation gives a pattern, which is characteristic of the analyte like a finger print.
In transmission X-ray diffraction experiments, the incident x-ray beam is not reflected by the sample, but instead travels through the analyte, where the diffraction occurs. Materials consisting of light atoms such as organic compounds like drugs are relatively 'transparent' for X-rays. In the transmission geometry the X-ray beam, coming off from the X-ray tube, is typically focused on the detector by an incident beam conditioner-an X-ray mirror, for instance. 
PHYSICAL-CHEMICAL IDENTIFIERS (PCID'S)
The Physical-Chemical Identifiers (PCID's) is a substance or combination of substances having a unique physical or chemical property that clearly assays and authenticates a drug product or dosage form. A unique physical-chemical characteristic of that ingredient makes it possible to detect and authenticate genuine dosage forms and identify counterfeits.
Examples of those that may be incorporated into Solid Oral Dosage Forms (SODF) as PCIDs include inks, pigments, flavors, and molecular taggants. Such PCIDs may allow product authentication by their presence alone or may be helpful to code the product identity into the SODF. There are various available means for detection of PCIDs (e.g., photolithography, holography, laser scanning devices, and excitation/fluorescence detection). Many identifying characteristics, such as pigments or flavors, could be easily observed by patients, physicians, medical practitioners, and pharmacies. Some could require the use of instrumental detection (e.g., a scanner device or photometric detector). 
Factors to be considered for designing a Solid Oral Dosage Form (SODF) along with PCID:
A substance employed as a PCID should not adversely affect the identity, strength, quality, purity, potency, or bioavailability of the SODF. To minimize the risk of adverse effects, FDA recommends that drug manufacturers add a PCID to an SODF at the minimum level that ensures identification of the dosage unit.
Manufacturers should judge the location of the PCID within the drug product. When considering where to place a PCID, the manufacturer may find it useful to conceptually subdivide an SODF into sections that differ in composition that may or may not contain active ingredient. For example, a core section in an SODF is likely to contain one or more active ingredient, while the external sections of the SODF may not have. If any manufacturer places a PCID inside a core section of the SODF, that placement may increase the chances of interactions due to incompatibility with the drug substance that may result in degradation. If the manufacturer is concerned the PCID will interact with core components, incorporating the PCID into an external section of the SODF (e.g., in a coating or an ink-imprinted logo) may reduce the decrease of such interaction.
The manufacturer should also consider whether the presence of the PCID might interfere with control of the drug release pattern of a modified-release SODF (SODF-MR), which includes extended-release and delayed-release dosage formulations.
Several aspects of pharmaceutical counterfeiting like examples, the adverse effects, data regarding the distribution as well as the number of cases in different countries, methods of detection and the anti counterfeiting measures have been discussed in this review. However, none of these would be useful without idea to combat the rise in the number of cases of fake and/or substandard products on the market.
In Europe and Asia, the international chamber of commerce's (ICC) commercial crime services unit has also developed initiatives to fight the rise against counterfeit drugs cases. The counterfeit pharmaceuticals initiative (CPI) was launched by the ICC at the beginning of 2003 and its action is to collect and publish information of both confidentially and publicly. The objectives of CPI are:
The design of a counterfeit pharmaceuticals database with online search facility
Creation of a dedicated CPI website
Compilation of a list of international contact in government, law enforcement and customs.
Communicate with regulators
Providing aid to members by investigation
Special projects and surveys majorly on internet pharmacies
Implementation of anti-counterfeiting technologies
There is no simple remedy that can be applied to get rid of counterfeit medicines nor can the problem be solved by an individual company or government. The problem has reaches global level and needs a global approach. Development of a system which helps in reporting counterfeit drugs, implementation of anti counterfeiting technologies, enforcement of stringent, proven anti counterfeiting laws and regulations, and severe punishments as well as penalties on convicted offenders will help combating counterfeit drugs. However, developing technologies like NIR, XRPD, PCID, Raman spectroscopy can prove useful in providing rapid detection method.