Click for next page ( 256


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 255
6 Detection Technology This chapter provides an overview of the technologies commonly used to detect substandard and falsified drugs, ranging from inexpensive field as- says to highly sophisticated laboratory methods. It does not describe every technique used or the pharmaceutical application of each technology, but rather explains how technology can be used to identify illegitimate drugs. Modern science has opened up immensely powerful and expensive fo- rensic chemistry techniques that can give investigators information on the unique fingerprints manufacturers leave on their products. Such an analysis can give prosecutors the evidence necessary to tie falsified drugs to particu- lar sources, but such sensitivity comes at a cost. Forensic chemistry assays cost $5,000 to $15,000 per test on average (personal communication, Ben Paulson, Chemir, January 25, 2013). They are not practical for routine product quality market surveillance in any country and may be out of reach entirely in many of the low- and middle-income countries most affected by the problem (Fernandez et al., 2008; Power, 2008). Keeping in mind the high costs of these laboratory analyses, this chapter discusses inexpensive and sustainable detection technologies that can be used for routine product quality assessments in all markets. QUALITATIVE AND QUANTITATIVE METHODS Detection technologies provide varying degrees of qualitative and quan- titative data about medicines. Qualitative techniques provide information about a drug’s identity, such as its active ingredient, color, or labeling. Quantitative techniques provide information about a drug’s content and 255

OCR for page 255
256 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Key Findings and Conclusions •  criminals become more sophisticated, there will be an increased As need for expensive technologies to detect falsified medicines. •  There are several categories of techniques to analyze pharmaceuti- cals. They include visual inspection of product and packaging; tests for physical properties such as disintegration, reflectance spectros- copy, and refractive index; chemical tests including colorimetry and dissolution; chromatography; spectroscopic techniques; and mass spectrometry. •  Novel technologies are constantly being developed to detect falsified and substandard medicines. how that content will be absorbed in the body. Qualitative assays may be used to quickly detect the least sophisticated falsified drugs, such as those with the wrong or no active ingredient. Quantitative deficiencies, such as an unacceptably high level of impurities or an unacceptably low or high dosage of active ingredient, are more common among substandard drugs. Tests for drug quality use both qualitative data (e.g., the identity of ingredi- ents, the presence and nature of any packaging and inserts, the presence or absence of impurities, and any data referring to the drug’s appearance) and quantitative data (e.g., the amount of an ingredient present, tablet hardness, the rate and extent of disintegration and dissolution, and measured levels of impurities). A full evaluation of drug quality requires a range of qualitative and quantitative testing to verify the identities and amounts of active ingredi- ents, check for impurities, and ensure acceptable disintegration, dissolu- tion, stability over time, and sterility (USP, 2007). Identifying falsified and substandard drugs does not always follow the same process as a rigorous quality evaluation. A few simple tests can identify a product with no active ingredient or one made under gross manufacturing negligence. More so- phisticated fakes resist easy detection. Appearance, content, and therapeutic effect can all be considered in classifying falsified drugs. Box 6-1 outlines one method for making categories. Criminals in the business of making falsified drugs can buy crude active ingredients, chemicals that have not undergone the appropriate purification steps required to meet pharmacopeial standards or manufacturer’s dossier requirements, for example. The drugs made from such chemicals would pass most tests. Only highly sophisticated and expensive assays could de-

OCR for page 255
DETECTION TECHNOLOGY 257 BOX 6-1 Classifying Falsified Medicines One way to classify falsified medicines is to assign categories based on the sophistication of the fake. This is an example of such categorization. • Category 1: Completely fraudulent products with unknown con- tents and therapeutic effects significantly different from the gen- uine drug. • Category 2: Look somewhat similar to the drug being imitated, but the drug composition is not known. • Category 3: Look very similar or identical to the genuine product but contain an entirely different drug, if any. • Category 4: Look very similar or identical to the actual product but contain an alternative drug or synthetic analogue provid- ing similar therapeutic value to that of the authentic product; intended to create repeat business. • Category 5: Visually identical, highly sophisticated copies or syn- thetic analogues with some therapeutic value that cannot be detected using most field and laboratory methods. tect trace contaminates. Figure 6-1 gives an overview of the different levels of technology needed to catch progressively more complex falsified drugs. Overview of Detection, Screening, and Analytical Techniques The main categories of techniques for pharmaceutical analysis can be broken down as follows: visual inspection of product and packaging; tests for physical properties such as disintegration, reflectance spectroscopy, and refractive index; chemical tests including colorimetry and dissolution; chro- matography; spectroscopic techniques; and mass spectrometry. Within each of these categories, some technologies are appropriate for use in the field with minimal training, while others require sophisticated lab equipment and a high level of technical expertise. Visual Inspection and Package Technologies An expert can identify some drug quality problems by sight. Therefore, visual inspection of a product and its packaging by someone who knows the properties of the authentic drug or is able to compare the sample to

OCR for page 255
SOPHISTICATION OF TECHNIQUES 258 Someone with little to TLC and colorimetry can no training can detect detect falsified products falsified drugs with that look genuine but con- obvious physical differ- tain no active ingredient or ences including color, an incorrect active ingredi- weight, and size (Box 6–1, ent. Physical differences categories 1–2). including color, weight, and size may also be useful (Box 6-1, category 3). TLC and colorimetry can Some falsified drugs HPLC can detect falsified SOPHISTICATION OF DRUGS sometimes detect falsified lacking active ingredients drugs containing an alter- drugs containing an or containing the wrong nate drug therapy (Box alternate drug therapy active ingredients are 6–1, category 4) and drugs (Box 6–1, category 4) detectable with near- with the wrong amount of and drugs with the infrared, Raman, or UV- active ingredient. wrong amount of active visible spectroscopy Dissolution tests can ingredient. (Box 6–1, category 4). detect substandard and Physical tests such as falsified drugs with poor disintegration and weight dissolution. may detect fakes that Gas chromatography appear identical to the and HPLC can detect authentic product. impurities. The most sophisticated falsified drugs, such as those containing analogues of active ingredients, may require nuclear magnetic resonance spectroscopy or mass spectrometry to detect minute structural differences (Box 6–1, category 5). FIGURE 6–1 More sophisticated fakes require more sophisticated technologies to detect them. NOTE: HPLC = high-performance liquid chromatography; TLC = thin layer chromatography; UV = ultraviolet.

OCR for page 255
DETECTION TECHNOLOGY 259 the authentic product is the standard first step in any drug quality analysis (Martino et al., 2010). These visual inspections provide qualitative data about drugs’ identities. Differences from the authentic materials in color, size, shape, tablet quality, and packaging indicate a possible falsified or substandard drug. These differences range from subtle to obvious. An educated consumer could probably identify a very-poor-quality fake, such as a pill of entirely the wrong color or shape, if they knew some proper- ties of the authentic product, but even experts struggle to recognize more subtle inconsistencies. The Global Pharma Health Fund’s Minilab toolkit promotes visual inspection as the first step to identifying falsified and sub- standard drugs but admits that this is challenging even for experts (Jähnke et al., 2008; Sherma, 2007). In recent years, criminals have produced very accurate reproductions of legitimate packaging. And, as Chapter 4 men- tions, poor-quality drugs can sometimes be hidden in legitimate packaging (Sherma, 2007). Visual inspection of a product can yield useful information, however. Some substandard drugs are of visibly low quality. Tablets that are cracked or falling apart are products of poor manufacturing practices (Kaur et al., 2010). Falsified drugs’ packaging may have missing or misplaced expiry dates, lack instructions or manufacturing information, not have a batch number, or differ from the genuine packaging in many other ways. Some- times poorly written instructions and spelling errors expose fake medicines; poor-quality inks may dissolve in water (Kaur et al., 2010). Similarly, the drugs may be the wrong color, size, or shape, have the wrong markings on them, have a different coating or texture, or be otherwise different from what is expected (Kaur et al., 2010). Sometimes the differences are obvi- ous: fake Viagra seized in Hungary was pink instead of the well-known blue color of the genuine product. Further analysis revealed that the tablets contained 15 milligrams of amphetamine instead of the correct active ingre- dient (U.S. Drug Enforcement Administration Office of Forensic Sciences, 2004). Visual inspections are often unreliable because substandard and falsi- fied drugs and their packaging often appear identical or very similar to the genuine products. Criminals have copied holograms, barcodes, packaging styles, and tablet colors and markings with astonishing accuracy (Lim, 2012). Microscopic packaging analysis can identify some of these very care- ful copies. Under magnification, fine differences in printing, imprints, and alignment become clear. Figure 6-2 shows a high-magnification comparison of the lettering on a legitimate and fake blister pack. As this illustration sug- gests, visual inspection alone is not adequate to test for drug quality (Lim, 2012; Martino et al., 2010). Though a trained inspector can draw conclu- sions about drug quality by visual inspection, physical analysis is generally a more reliable way to identify fakes.

OCR for page 255
260 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS FIGURE 6-2 The printing on a fake Cialis blister pack is less crisp at 32× magnification. SOURCE: Lim, 2012. Physical and Bulk Property Testing As Chapter 4 explains, active ingredients are the most expensive com- ponent of drugs; dilute or impure active ingredients can translate into vastly increased profits for an unscrupulous manufacturer. Some tests that rely on pH and other bulk properties can help identify active ingredients. Bulk properties, also called intensive properties, are properties that do not depend on the amount of the chemical sampled. Density, solubility, reflec- tance spectra, refractive indices, and optical rotation are examples of bulk properties (Brown et al., 2011). The malaria drug artesunate, for example, has some distinctive physical properties: It yields characteristic crystals when precipitated from water, and its extract acidifies water (Deisingh, 2005; Newton et al., 2006). These properties can be used to distinguish some authentic and fake antimalarials. The refractive index, the measure of how light passes through a sub- stance relative to the speed at which light passes through a vacuum, is a similarly useful bulk property. The refractive index can be used to measure the purity of pure liquids and can detect materials separated by liquid chro- matography. Field inspectors can use handheld refractometers to measure the refractive index and use it as a quantitative test for some active ingre- dients (Kaur et al., 2010). Green and colleagues explored the practical use of refractive index to measure the amount of active ingredients selectively dissolved in certain solvents (Green et al., 2007). They found that while the refractive index can measure the amount of an unknown active ingredient, colorimetry can be used to help confirm its presence (Green et al., 2007).

OCR for page 255
DETECTION TECHNOLOGY 261 Colorimetry and Other Chemical Testing A variety of simple chemical reactions can test for the presence of active ingredients. Colorimetry is one such technique. It relies on chemicals that undergo color changes when reacted with certain compounds to provide qualitative data about a drug’s identity. Colorimetry protocols exist for the active ingredients in many essential drugs. Fast Red TR dye tests for the active ingredient in some antimalarials by turning yellow in the presence of artesunate (Green et al., 2001). In addition to verifying the presence of an active ingredient, colorimetry can serve as a semi-quantitative technique to provide information about tablet potency; a more drastic color change or deeper color generally indicates a larger amount of ingredient. More precise colorimetric testing is possible with a handheld photometer, a spectroscopic device that measures absorbance of light through a substance (Newton et al., 2006). Colorimetry gives limited information and destroys the sample under investigation, but it is invaluable to field inspectors because it is an inexpensive technique that requires very little training. Disintegration and dissolution testing may identify common formula- tion problems. Disintegration tests measure how rapidly solid dosage forms disintegrate in a solution; dissolution tests analyze the rates at which drugs dissolve (USP, 2007). Dissolution tests require more training than colorim- etry and disintegration testing but may help predict the bioavailability of drugs, an important aspect of their efficacy. If a drug has poor dissolution, then the target dose of active ingredient may not be available to the patient. Incorrect excipient formulation, poor-quality manufacturing, and improper storage conditions can all lead to poor dissolution (Kaur et al., 2010). Even if the drug contains the correct dose of active ingredient, disintegration and dissolution tests may be able to identify an illegitimate drug (Deisingh, 2005). Disintegration tests are fairly simple and can be done in the field, but dissolution tests require sophisticated equipment (Kaur et al., 2010). Chromatography Chromatography separates mixtures into their constituent parts based on a variety of chemical and physical properties. It can be used to separate drug ingredients for further testing and, when used with appropriate detec- tors, provides both qualitative and quantitative information about active ingredients and impurities (Kaale et al., 2011). Chromatography is there- fore the most common analytical method used in drug evaluations (Martino et al., 2010). Chromatographic techniques range from basic techniques, such as thin layer chromatography (TLC) with visual inspection, to more specialized laboratory methods, such as high-performance liquid chroma-

OCR for page 255
262 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS tography (HPLC) coupled with mass spectrometry. Like colorimetric tests, chromatographic analysis destroys the drug sample. TLC is a planar chromatographic technique that is ideal for field drug testing (Martino et al., 2010). In TLC comparisons, authentic samples travel the same distance on a TLC plate and yield main spots of highly similar shapes, colors, intensities, and sizes as reference standards. TLC is a qualitative and, when used with visual detection, semi-quantitative tech- nique. The distance the sample travels is associated with its identity; the intensity of the spot correlates with the amount of the drug present. High concentrations of impurities may be visible on a TLC plate as well (Kaur et al., 2010). In a convenience sample of tuberculosis drugs in Botswana, TLC indicated 31 percent of the samples tested were substandard (Kenyon et al., 1999). In China, researchers used TLC to distinguish between authentic and falsified versions of several antibiotics (Hu et al., 2005). TLC is an uncomplicated assay useful in developing countries because it yields “versatile and robust” results at a low cost (Kaale et al., 2011). Each TLC plate costs about $2, and most solvents used in TLC are common and inexpensive. The plates are only used once, preventing contamination and limiting maintenance requirements (Kaale et al., 2011). Compared to other chromatographic techniques such as HPLC, TLC requires significantly less equipment and expertise. Modern instrumental TLC applications give quantitative assessments similar to those obtained with other instrumental chromatography procedures. High-performance TLC is a more effective and efficient version of TLC. Disposable HPLC plates cost about $15 each but can run 18-36 samples at the same time (Kaale et al., 2011). The main drawbacks to TLC are its limited semi-quantitative data (when used with visual detection) and the need for accurate technique (Kaale et al., 2011). TLC solvents are often toxic or flammable, so these chemicals may be difficult to transport for field use. Furthermore, TLC pro- vides limited information about a drug’s identity; two samples that travel different distances are definitely not the same substance, but two different substances could appear identical using any chromatography technique if they are chemically similar enough. The inspector running the TLC assay must spot the plate correctly with the sample, which requires some training, and then compare the results to those obtained with reference standards. Accurately estimating the amount of drug on a TLC plate can be difficult without experience (Kaale et al., 2011). Despite its limitations, a trained operator can glean significant information from a TLC experiment with visual detection (Jähnke et al., 2001; Kaale et al., 2011). Advanced chromatography techniques  HPLC is a more selective tech- nique and, when coupled with sensitive detectors, is generally regarded as the definitive technique for drug content analysis (Martino et al., 2010).

OCR for page 255
DETECTION TECHNOLOGY 263 Depending on the associated detection technology, it can be expensive and require skilled operators and expensive, often scarce, solvents. The systems also require reliable electrical power, which can be an obstacle in develop- ing countries. Figure 6-3a shows an HPLC chromatogram that clearly distinguishes between the antimalarials chloroquine, mefloquine, and quinine. Although the drugs are chemically similar (see Figure 6-3b), mefloquine is signifi- cantly more expensive, and the cheaper drugs are sometimes sold labeled as mefloquine (Gaudiano et al., 2006). HPLC can identify and measure active ingredients and many impurities, but may not detect excipients that are not soluble in the mobile phase. It can be used with an array of detec- tion technologies such as mass spectrometry and UV-visible spectroscopy (Martino et al., 2010). Diode array detection is now standard with many HPLC assays and can be used to confirm the presence of active ingredients. It is a type of UV spec- troscopy that is particularly useful because it can operate at varying wave- lengths, allowing it to be fine-tuned for analyses, and can help detect the presence of several components hidden in a single HPLC peak (Kazakevich and McNair, 1996). Titier and colleagues developed an HPLC with diode array detection method to detect and quantify eight antidepressants for use in cases of suspected poisonings (Titier et al., 2003). The main advantages of the method were its speed, ease of use, and accuracy. Gas chromatography, the most powerful chromatographic technol- ogy, provides similar information as the other chromatography systems. However, it may only be used for separation of volatile materials, such as residual solvents, undeclared ingredients, and any volatile impurities. This technique can only be used when the compounds of interest are gaseous in the analytical temperature range and do not degrade at or before the assay’s minimum temperature. For example, artemisinin derivatives for treating malaria are too unstable for gas chromatography (Martino et al., 2010). Investigators can use gas chromatography to develop profiles of drugs’ volatile impurities and use those profiles to link batches of drugs from the same source. The great deal of natural variation in impurities allows this; even batches of genuine product from different sources are distinguishable, and the same is true among different falsified and substandard versions. In a review of the forensic applications of impurity profiles, Mulligan and colleagues concluded that drugs with very similar impurity profiles may be from the same place. Statistical analysis of impurity data can determine the probability that different samples have a common source (Mulligan et al., 1996). Unlike TLC, advanced chromatography techniques require consider- able investment; the equipment needed is expensive to buy and maintain (Kaale et al., 2011). These tests can only be done in central laboratories,

OCR for page 255
264 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS 1,000 800 Mefloquine Absorbance (mAU) 600 Chloroquine Quinine 400 200 0 1 2 3 4 5 6 7 8 9 10 Time (minutes) FIGURE 6–3a An HPLC chromatogram with distinct peaks for chloroquine, quinine, and mefloquine can be used to identify cheap chloroquine and quinine treatments labeled as the more expensive mefloquine. NOTE: HPLC = high-performance liquid chromatography; mAU = milli absorbance unit. SOURCE: Adapted from Gaudiano et al., 2006. Reprinted with permission from Elsevier. CF3 N N CF3 HN HO N O H H Cl N N N HO Chloroquine molecule Quinine molecule Mefloquine molecule FIGURE 6–3b The similar chemical structures of chloroquine, quinine, and mefloquine. .

OCR for page 255
DETECTION TECHNOLOGY 265 and countries most affected by falsified and substandard drugs have lim- ited access to such facilities (IOM, 2012). HPLC and gas chromatography are time-consuming, especially considering the time spent preparing the samples for analysis. The return on the time investment is mixed, as chro- matography separates a minimum number of components present in a sample. A peak assumed to represent one compound may be hiding several other compounds. Spectroscopy Spectroscopy is a class of analytical techniques that measures the in- teraction of matter and radiation, thereby giving insight into chemical structure and contents. These techniques all provide qualitative data, and some provide significant quantitative data as well. Often referred to as the chemical fingerprints of drugs, the various spectra produced using these techniques elucidate different aspects of drug composition; characteristic absorption or emission peaks correspond to aspects of chemical composi- tion and molecular structure. A chemist can extract detailed chemical and structural information from a spectrum, and an inspector with minimal training can also identify falsified and substandard medicines by comparing the drug spectra to reference materials in drug spectra databases (Kaur et al., 2010). The WHO maintains a digital version of the International Phar- macopoeia with drug quality determination protocols for many common medicines (WHO, 2011). This guide includes a reference infrared spectrum for each drug. Molecular vibration and rotation energies occur in the infrared regions of the electromagnetic spectrum, and these movements may be observed with infrared, near-infrared, or Raman spectrometers. These techniques are relatively straightforward to use and moderately expensive, and routine comparative applications do not require extensive training. Chemists ana- lyze the absorption peaks in these spectra primarily to identify molecular functional groups; most active pharmaceutical ingredients and some or- ganic excipients and impurities have characteristic spectral peaks or spectral fingerprints that can be used to help identify them. Infrared spectroscopy  The infrared range of the electromagnetic spectrum can be divided into three subregions: the near-infrared, mid-infrared, and far-infrared. The mid-infrared range is the more discerning and commonly used region (Deisingh, 2005). Figure 6-4 shows the different infrared spec- tra of the antimalarial artemisinin and its derivative, artemether. This comparison can identify the common substitution of artemisinin for more effective and expensive antimalarials (Kaur et al., 2010). There are several ways to collect infrared spectra, each having ad-

OCR for page 255
284 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS FIGURE 6-10 Genuine (left) and falsified (right) holograms on artesunate blister packs found in Southeast Asia. SOURCE: Newton et al., 2008. standard drugs. Technologies can protect consumers and also help generate accurate estimates of the magnitude of the problem. An understanding of the technological landscape, the range and gaps in available technologies, and the likely improvements in the near future is necessary for using tech- nologies in developing countries. The Technological Landscape Technology is a constantly evolving field. New techniques developed specifically for detection and analysis are always emerging. As some of the standard assessment techniques become smaller, lighter, cheaper, and more durable, the boundary between field and laboratory testing is blurring. Navigating the technological landscape is a formidable challenge, espe- cially in low- and middle-income countries. The committee believes that interdisciplinary collaboration yields the best and most efficient advances in detection technologies, especially technologies that can be useful in de- veloping countries. Regulators in these countries have relatively infrequent opportunities to interact with academic and industry experts (IOM, 2012). Working in rela- tive isolation translates into few opportunities to advocate for research on their behalf. This chapter gives some overview of the detection technologies that exist now, but a different expert working group could better articulate what technologies will be useful in the future. It is also unclear under what conditions the cost-to-benefit analysis favors the use of different detection technologies.

OCR for page 255
DETECTION TECHNOLOGY 285 Recommendation 6-1: The National Institute of Standards and Tech- nology should fund the development of a central repository for existing and newly innovative detection, sampling, and analytical technologies, ranging from field and rapid screening technology to sophisticated laboratory-based assessments, to identify substandard and falsified medicines. The cost of development is the main barrier to having robust, sustain- able, easy-to-use, and inexpensive detection technologies available in the field. The committee believes that public funding for development would direct academic interest and attention to this important problem. The National Institute of Standards and Technology (NIST), a division of the Department of Commerce, has the depth in physical and materials science necessary for developing and adapting drug testing technologies (NIST, 2008). The institute is committed to innovative interdisciplinary research for bioscience and health (NIST, 2010). Drug quality analysis draws from At a Minilab training session in Angola, field inspectors learn how to test drug quality. SOURCE: Minilab Saves Lives, 2012.

OCR for page 255
286 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS material, basic, and computer science, and a range of engineering disci- plines. The FDA and the pharmaceutical industry also have technical depth in these areas, and they should work with NIST on a technical working group about drug detection technologies. The NIST has worked closely with the FDA before, such as in their work on the measurement of drug delivery systems with secondary ion mass spectrometry (NIST, 2009a). Every year, the institute’s Small Business Innovation Research (SBIR) program awards contracts to small businesses for science and engineering research (NIST, 2009b). Proposals need to respond to the specific terms set out in the SBIR annual solicitation (NIST, 2009b). Although an em- phasis on field technologies that are useful in developing countries would be a departure from the Department of Commerce’s charge of promoting American industry, there is enough of a shared stake in drug safety that they might consider a SIBR solicitation for innovative technologies to detect poor-quality drugs. There is considerable scope for innovative research in drug detection TABLE 6–1 Techniques for Detecting Poor-Quality Drugs Technique Good for Cost Visual inspection Detecting unsophisticated falsified drugs: Inexpensive wrong color, size, shape, packaging, etc. Packaging technologies: Detecting fake packaging Inexpensive holograms, barcodes, pedigrees Physical and bulk property Varies, but usually identifying the active Varies testing (e.g., density, ingredient solubility, refractive index) Colorimetry Identifying functional groups in ingredients, Inexpensive relative amount of active ingredients Disintegration tests Determining whether product will Inexpensive disintegrate correctly Dissolution tests Determining whether product will dissolve Expensive correctly, a measure of bioavailability Thin layer chromatography Identifying active ingredients, determining Inexpensive (TLC) amount of active ingredients

OCR for page 255
DETECTION TECHNOLOGY 287 and analysis. All of the methods described in this chapter, for example, are relevant to small molecules, but hormones, oral contraceptives, low-dose vaccines, and biologics are also vulnerable to quality failures, failures that are much harder to detect. Even the existing technologies to detect falsi- fied and substandard small molecules could be improved. For example, the Minilab, a useful and elegant kit, can test only 63 drugs (GPHF, 2012b). The Global Pharma Health Fund should expand this inventory; the WHO should help identify which products are the first priority for inclusion. Similarly, expansion of the Raman active ingredient database would make handheld Raman spectrometers more useful in detecting falsified drugs. All drug detection technologies would be more powerful if there were a full authentication database with information about drug color, shape, size, weight, Raman and near-infrared reflectance, and a TLC proce- dure for assay. Drug companies may balk at releasing this information, but the committee believes that stringent regulatory agencies should require it. Sharing all drug authentication information in a drug quality library would vastly improve the power of existing drug detection technologies. Level of Used in Training Speed Field? Example Low Fast Yes A sample of falsified Viagra in Hungary was pink instead of the correct blue color. Further analysis revealed that the tablets contained 15 mg amphetamine instead of the correct active ingredient (U.S. Drug Enforcement Administration Office of Forensic Sciences, 2004). Low Fast Yes mPedigree developed scratch-off codes for prescription boxes. Consumers text the code to a phone number and receive a confirmation—or not—that their product is genuine (Sharma, 2011). Low-high Varies Varies An artesunate extraction should significantly lower the pH of water, and some falsified versions do not do this (Newton et al., 2006). Low Fast Yes Fast Red TR dye turns yellow in the presence of artesunate (Green et al., 2001). Low Fast Yes Close to 12% of drugs sampled from Delhi in a study of drug quality in India failed disintegration testing (Bate et al., 2009b). High Slow No In one study, 14% of drugs that initially passed dissolution testing subsequently failed, rendering them substandard, after 6 months of storage in tropical conditions (Kayumba et al., 2004). Low- Fast Yes Detected substandard tuberculosis drugs with the moderate wrong amount of active ingredient in Botswana (Kenyon et al., 1999). continued

OCR for page 255
288 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 6–1 Continued Technique Good for Cost Gas chromatography (GC) Identifying and quantifying volatile active Expensive with appropriate detection ingredients, residual solvents, volatile technology contaminants, undeclared ingredients High-performance liquid Identifying and quantifying active Moderate chromatography (HPLC) ingredients, impurities and various with appropriate detection nonvolatile components technology Mid-infrared (IR) Identifying active ingredients and excipients; Moderate-expensive spectroscopy some techniques can analyze packaging and tablet coatings Near-infrared spectroscopy Identifying and quantifying active Moderate-expensive ingredients, excipients Nuclear magnetic resonance Identifying and quantifying active ingredients Expensive (NMR) spectroscopy and excipients; provides detailed structural information Raman spectroscopy Identifying active ingredients and excipients, Moderate-expensive (conventional) relative concentration of ingredients; identifying tablet coating composition Raman spectroscopy Same as conventional Raman spectroscopy, Moderate (portable) but can be less reliable Mass spectrometry (MS) Identifying active ingredients, excipients, Expensive undeclared ingredients, impurities Direct mass spectrometry Identifying active ingredients, excipients, Expensive (DART-MS, DESI-MS) undeclared ingredients, detecting analogues Gas chromatography-mass Volatile active ingredients, residual solvents, Expensive spectrometry (GC-MS) volatile contaminants, undeclared ingredients High-performance liquid Identifying and quantifying active Expensive chromatography-mass ingredients, excipients, undeclared spectrometry (HPLC-MS) ingredients, impurities

OCR for page 255
DETECTION TECHNOLOGY 289 Level of Used in Training Speed Field? Example High Slow No Organic volatile impurities detected by GC can help link different batches of falsified drugs back to common manufacturers (Mulligan et al., 1996). Moderate-high Slow No Common antimalarials chloroquine, quinine, and mefloquine produce different peaks in an HPLC chromatogram (Gaudiano et al., 2006). Moderate Fast No Artemisinin and artemether produce different IR spectra. Artemisinin is sometimes substituted for its derivatives, such as artemether, in falsified products (Kaur et al., 2010). Moderate Fast Yes Was able to distinguish real from falsified artesunate tablets with 100% accuracy in an analysis of samples from Southeast Asia (Dowell et al., 2008). High Slow No Diffusion-ordered proton NMR spectroscopy identified incorrect active ingredients in a study of falsified artesunate samples and was able to detect excipient ingredients that two mass spectrometric techniques could not (Nyadong et al., 2009). Moderate Fast No Close examination of Raman spectra comparing a suspected falsified drug to a real sample revealed a slight discrepancy due to differences in tablet coating (Witkowski, 2005). Low Fast Yes Falsified artesunate samples did not produce the strong fluorescence characteristic of artesunate when scanned with a portable device (Ricci et al., 2008). High Slow No Falsified halofantrine containing a sulphonamide antibiotic detected with MS (Wolff et al., 2003). Moderate Fast No Detected falsified artesunate that contained paracetamol (Martino et al., 2010). High Slow No Detected falsified Captagon tablets containing alternative stimulants (Alabdalla, 2005). High Slow No Distinguished between falsified and genuine samples of Nigerian dihydroartemisinin (Kaur et al., 2010).

OCR for page 255
290 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS REFERENCES Alabdalla, M. A. 2005. Chemical characterization of counterfeit Captagon tablets seized in Jordan. Forensic Science International 152:185-188. Barlow, R. 2012. A new counterfeit problem: Anti-malarial drugs. BU Today, July 26. Barras, J., K. Althoefer, M. D. Rowe, I. J. Poplett, and J. A. S. Smith. 2012. The emerging field of medicines authentication by nuclear quadrupole resonance spectroscopy. Applied Magnetic Resonance 43(4):511-529. Bate, R., and A. Mathur. 2011. Working paper: The impact of improved detection technology on drug quality: A case study of Lagos, Nigeria. Washington, DC: American Enterprise Institute. Bate, R., R. Tren, K. Hess, L. Mooney, and K. Porter. 2009a. Pilot study comparing technolo- gies to test for substandard drugs in field settings. African Journal of Pharmacy and Pharmacology 3(4):165-170. Bate, R., R. Tren, L. Mooney, K. Hess, B. Mitra, B. Debroy, and A. Attaran. 2009b. Pilot study of essential drug quality in two major cities in India. PLoS ONE 4(6):e6003. Brown, T., H. E. LeMay, B. Bursten, C. Murphy, and P. Woodward. 2011. Chemistry: The central science. 12th ed. Boston, MA: Prentice Hall. Deisingh, A. K. 2005. Pharmaceutical counterfeiting. Analyst 130(3):271-279. Dowell, F. E., E. B. Maghirang, F. M. Fernandez, P. N. Newton, and M. D. Green. 2008. Detecting counterfeit antimalarial tablets by near-infrared spectroscopy. Journal of Phar- maceutical and Biomedical Analysis 48:1011-1014. EurekAlert. 2012. New technology represents next-generation tool for detecting substan- dard and counterfeit medicines. http://www.eurekalert.org/pub_releases/2012-07/up- ntr072612.php (accessed January 31, 2013). Fernandez, F. M., M. D. Green, and P. N. Newton. 2008. Prevalence and detection of coun- terfeit pharmaceuticals: A mini review. Industrial and Engineering Chemistry Research 47:585-590. Fernandez, F. M., D. Hostetler, K. Powell, H. Kaur, M. D. Green, D. C. Mildenhall, and P. N. Newton. 2011. Poor quality drugs: Grand challenges in high throughput detection, coun- trywide sampling, and forensics in developing countries. Analyst 136(15):3073-3082. Filho, A. F. M., P. Blanco, and L. E. Ferreira. 2010. Pharmaceutical products traceability sys- tem pilot project in Brazil. 2010/2011 GS1 Healthcare Reference Book. http://www.gs1. org/docs/healthcare/case_studies/Case_study_Brazil_pharma_traceability.pdf (accessed March 7, 2013). Gaffney, A. 2012. New portable anti-counterfeiting technology promises “paradigm shift.” http://www.raps.org/focus-online/news/news-article-view/article/2020/new-portable-anti- counterfeiting-technology-promises-paradigm-shift.aspx (accessed March 7, 2013). Gamble, B. M., S. R. Gratz, J. J. Litzau, K. J. Mulligan, and R. A. Flurer. 2008. FDA forensic investigations using mass spectrometry. Paper presented at Conference on Small Molecule Science, San Jose, CA. Gaudiano, M. C., E. Antoniella, P. Bertocchi, and L. Valvo. 2006. Development and valida- tion of a reversed-phase lc method for analysing potentially counterfeit antimalarial medicines. Journal of Pharmaceutical and Biomedical Analysis 42:132-135. Gottlieb, H. E., V. Kotlyar, and A. Nudelman. 1997. NMR chemical shifts of common labora- tory solvents as trace impurities. Journal of Organic Chemistry 62:7512-7515. GPHF (Global Pharma Health Fund). 2012a. GPHF-Minilab®—fact sheet. http://www.gphf. org/web/en/minilab/factsheet.htm (accessed July 30, 2012). ———. 2012b. The GPHF-Minilab®—focusing on prevalent medicines against infectious dis- eases. http://www.gphf.org/web/en/minilab/wirkstoffe.htm (accessed November 5, 2012).

OCR for page 255
DETECTION TECHNOLOGY 291 ———. 2012c. The GPHF-Minilab®—protection against counterfeit medicines. http://www. gphf.org/web/en/minilab/index.htm (accessed July 30, 2012). ———. 2012d. The Global Pharma Health Fund (GPHF). http://www.gphf.org/web/en/start/ index.htm (accessed October 24, 2012). ———. 2012e. Tanzanian food and drugs authority receives four unique mobile compact laboratories. http://www.gphf.org/web/en/news/pressemitteilungen.htm?showid=164 (ac- cessed October 24, 2012). Green, M. D., D. L. Mount, and R. A. Wirtz. 2001. Short communication: Authentication of artemether, artesunate and dihydroartemisinin antimalarial tablets using a simple colori- metric method. Tropical Medicine & International Health 6(12):980-982. Green, M. D., H. Nettey, O. V. Rojas, C. Pamanivong, L. Khounsaknalath, M. G. Ortiz, P. N. Newton, F. M. Fernández, L. Vongsack, and O. Manolin. 2007. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality. Journal of Pharmaceutical and Biomedical Analysis 43(1):105-110. Hsu, C.-P. S. 1997. Infrared spectroscopy. In Handbook of instrumental techniques for ana- lytical chemistry, edited by F. Settle. Arlington, VA: National Science Foundation. Pp. 247-283. Hu, C.-Q., W.-B. Zou, W.-S. Hu, K.-K. Ma, M.-Z. Yang, S.-L. Zhou, J.-F. Sheng, Y. Li, S.-H. Cheng, and J. Xue. 2005. Establishment of a fast chemical identification system for screen of counterfeit drugs of macrolide antibiotics. Journal of Pharmaceutical and Biomedical Analysis 40:68-74. IOM (Institute of Medicine). 2012. Ensuring safe foods and medical products through stronger regulatory systems abroad. Washington, DC: The National Academies Press. Iqbal, M., S. T. Hakim, A. Hussain, Z. Mirza, F. Qureshi, and E. M. Abdulla. 2004. Ofloxa- cin: Laboratory evaluation of the antibacterial activity of 34 brands representing 31 manufacturers available in Pakistan. Pakistani Journal of Medical Science 20(4):349-356. Jähnke, R. W. O., H. J. Kallmayer, C. Breyer, M. D. Green, V. Rubeau, and A. Paulke. 2008. A concise quality control guide on essential drugs and other medicines: Colour reaction tests. Germany: Global Pharma Health Fund. Jähnke, R. W. O., G. Küsters, and K. Fleischer. 2001. Low-cost quality assurance of medicines using the GPHF-Minilab®. Drug Information Journal 35:941-945. Jin, S. 2007. Mobile labs developed in China for detection of counterfeit drugs. Paper read at 3rd Global Forum on Pharmaceutical Anticounterfeiting, Prague, Czech Republic. Kaale, E., P. Risha, and T. Layloff. 2011. TLC for pharmaceutical analysis in resource limited countries. Journal of Chromatography A 1218(19):2732-2736. Kaur, H., M. D. Green, D. M. Hostetler, F. M. Fernández, and P. N. Newton. 2010. Antima- larial drug quality: Methods to detect suspect drugs. Therapy 7(1):49-57. Kayumba, P. C., P. G. Risha, D. Shewiyo, A. Msami, G. Masuki, D. Ameye, G. Vergote, J. D. Ntawukuliryayo, J. P. Remon, and C. Vervae. 2004. The quality of essential antimicrobial and antimalarial drugs marketed in Rwanda and Tanzania: Influence of tropical stor- age conditions on in vitro dissolution. Journal of Clinical Pharmacy and Therapeutics 29:331-338. Kazakevich, Y., and H. McNair. 1996. Diode-array detectors. In Basic liquid chromatography: Text book on high performance liquid chromatography (HPLC). http://hplc.chem.shu. edu/HPLC/index.html (accessed March 7, 2013). Kenyon, T. A., A. S. Kenyon, B. V. Kgarebe, D. Mothibedi, N. J. Binkin, and T. P. Layloff. 1999. Detection of substandard fixed-dose combination tuberculosis drugs using thin-layer chromatography. International Journal of Tuberculosis and Lung Disease 3(11):5347-5350. Koehler, F., E. Lee, L. Kidder, and E. N. Lewis. 2002. Near infrared spectroscopy: The practical chemical imaging solution. Spectroscopy Europe 14(3):12-19.

OCR for page 255
292 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Lim, C. C. 2012. Detection of counterfeit drugs—Singapore’s approach. Presentation at Understanding the Global Public Health Implications of Counterfeit, Falsified, and Sub- standard Drugs: Meeting One, Washington, DC, March 12-13. Marini, R. D., E. Rozet, M. L. A. Montes, C. Rohrbasser, S. Roht, D.Rhème, P. Bonnabry, J. Schappler, J.-L. Veuthey, P. Hubert, and S. Rudaz. 2010. Reliable low-cost capillary elec- trophoresis for drug quality control and counterfeit medicines. Journal of Pharmaceutical and Biomedical Analysis 53(5):1278-1287. Martino, R., M. Malet-Martino, V. Gilard, and S. Balayssac. 2010. Counterfeit drugs: Ana- lytical techniques for their identification. Analytical and Bioanalytical Chemistry 398(1): 77-92. Minilab Saves Lives. 2012. Caught in the act, first by customs, then by minilabs. https:// www.facebook.com/media/set/?set=a.10151243315994666.481256.182507359665& type=1 (accessed November 14, 2012. Mulligan, K. J., T. W. Bruggemeyer, D. F. Crockett, and J. B. Schepman. 1996. Analysis of organic volatile impurities as a forensic tool for the examination of bulk pharmaceuticals. Journal of Chromatography B 686:85-95. Newton, P. N., F. M. Fernández, A. Plançon, D. C. Mildenhall, M. D. Green, L. Ziyong, E. M. Christophel, S. Phanouvong, S. Howells, E. McIntosh, P. Laurin, N. Blum, C. Y. Hampton, K. Faure, L. Nyadong, C. W. R. Soong, B. Santoso, W. Zhiguang, J. Newton, and K. Palmer. 2008. A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Medicine 5(2):e32. Newton, P. N., M. D. Green, F. M. Fernández, N. P. J. Day, and N. J. White. 2006. Counterfeit anti-infective drugs. Lancet Infectious Diseases 6(9):602-613. NICPBP (National Institute for the Control of Pharmaceutical and Biological Products). 2012. Introduction to mobile labs. http://www.nicpbp.org.cn/en/CL0324 (accessed November 5, 2012). NIST (National Institute of Standards and Technology). 2008. NIST general information. http:// www.nist.gov/public_affairs/general_information.cfm (accessed November 5, 2012). ———. 2009a. Next generation metrology for drug delivery systems. http://www.nist.gov/ mml/mmsd/83705-next-generation-metrology-for-drug-delivery-systems.cfm (accessed November 26, 2012). ———. 2009b. Small business innovation research program. http://www.nist.gov/tpo/sbir/ index.cfm (accessed November 5, 2012). ———. 2010. Bioscience & health portal—overview. http://www.nist.gov/bioscience-and- health-portal.cfm (accessed November 26, 2012). Nyadong, L., G. A. Harris, S. Balayssac, A. S. Galhena, M. Malet-Martino, R. Martino, R. M. Parry, M. D. Wang, F. M. Fernández, and V. Gilard. 2009. Combining two-dimensional diffusion-ordered nuclear magnetic resonance spectroscopy, imaging desorption elec- trospray ionization mass spectrometry, and direct analysis in real-time mass spectrom- etry for the integral investigation of counterfeit pharmaceuticals. Analytical Chemistry 81(12):4803-4812. Power, G. 2008. Anti-counterfeit technologies for the protection of medicines. Geneva: IMPACT and WHO. Putze, E., E. Conway, M. Reilly, and O. Madrid. 2012. The deadly world of fake drugs. Washington, DC: American Enterprise Institute. Ricci, C., L. Nyadong, F. Yang, F. M. Fernandez, C. D. Brown, P. N. Newton, and S. G. Kazarian. 2008. Assessment of hand-held Raman instrumentation for in situ screening for potentially counterfeit artesunate antimalarial tablets by ft-Raman spectroscopy and direct ionizatoin mass spectrometry. Analytica Chimica Acta 623:178-186.

OCR for page 255
DETECTION TECHNOLOGY 293 Rivier, L. 2003. Criteria for the identification of compounds by liquid chromatography-mass spectrometry and liquid chromatography-multiple mass spectrometry in forensic toxicol- ogy and doping analysis. Analytica Chimica Acta 492:69-82. Saving Lives at Birth. 2012a. The challenge. http://savinglivesatbirth.net/challenge (accessed March 7, 2013). ———. 2012b. Partners. http://savinglivesatbirth.net/partners (accessed March 7, 2013). ———. 2012c. Round 2 innovators. http://savinglivesatbirth.net/innovation/2012/innovators (accessed November 14, 2012). Seiffert, D. 2012. BU professor gets grant for counterfeit drug detector. Mass High Tech, August 1. Sharma, Y. 2011. Fighting fake drugs with high-tech solutions. http://www.scidev.net/en/health/ detecting-counterfeit-drugs/features/fighting-fake-drugs-with-high-tech-solutions-1.html (accessed March 7, 2013). Sherma, J. 2007. Analysis of counterfeit drugs by thin layer chromatography. Acta Chromato- graphica 19:5-20. Singh, S., B. Prasad, A. A. Savaliya, and R. P. Shah. 2009. Strategies for characterizing silde- nafil, vardenafil, tadalafil, and their analogues in herbal dietary supplements, and detect- ing counterfeit products containing these drugs. TRAC 28(1):13-28. Smine, A., and M. Hajjou. 2009. USP DQI workshop on basic tests of antimalarials using Minilabs®: Establishing drug quality monitoring in five sentinel sites in Ghana. Rockville, MD: U.S. Pharmacopeia Drug Quality and Information Program. Sprey, K. 2010. Using radio waves to identify counterfeit drugs. http://www.gizmag.com/using- radio-waves-to-identify-counterfeit-drugs/16233 (accessed March 7, 2013). Staub, A., S. Rudaz, J.-L. Veuthey, and J. Schappler. 2010. Multiple injection technique for the determination and quantitation of insulin formulations by capillary electrophoresis and time-of-flight mass spectrometry. Journal of Chromatography A 1217(51):8041-8047. Stroh, M. 2007. Nose for trouble: A portable germ scanner exposes tainted food. Popular Science, September. Titier, K., N. Castaing, E. Scotto-Gomez, F. Pehourchq, N. Moore, and M. Molimard. 2003. High-performance liquid chromatographic method with diode array detection for iden- tification and quantification of the eight new antidepressants and five of their active metabolites in plasma after overdose. Therapeutic Drug Monitor 25(5):581-587. Trefi, S., C. Routaboul, S. Hamieh, V. Gillard, M. Malet-Martino, and R. Martino. 2008. Analysis of illegally manufactured formulations of tadalafil (Cialis®) by 1h NMR, 2D DOSY 1h NMR and Raman spectroscopy. Journal of Pharmaceutical and Biomedical Analysis 47(1):103-113. U.S. Drug Enforcement Administration Office of Forensic Sciences. 2004. Intelligence alert: Viagra® mimic tablet containing amphetamine in Fejer County, Hungary. Microgram Bulletin 37(6):106-107. USP (U.S. Pharmacopeia). 2007. Ensuring the quality of medicines in resource-limited coun- tries: An operational guide. Rockville, MD: U.S. Pharmacopeia Drug Quality and Infor- mation Program. Venhuis, B. J., and D. d. Kaste. 2012. Towards a decade of detecting new analogues of silde- nafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks. Journal of Pharmaceutical and Biomedical Analysis 69:196-208. Wellcome Trust. 2012. Enabling technlogy. http://www.wellcome.ac.uk/Funding/Technology- transfer/Funded-projects/Enabling-technology/index.htm (accessed March 7, 2013). WHO (World Health Organization). 2008. The international pharmacopoeia. Second Supple- ment, Fourth Ed. Geneva: WHO. ———. 2011. The international pharmacopoeia: Fourth edition 2011 (incl. first and second supplements). http://apps.who.int/phint/en/p/about (accessed March 7, 2013).

OCR for page 255
294 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Wilkinson, N. 2012. Briefcase encounter: An invention to detect fake drugs. Wellcome Trust. http://wellcometrust.wordpress.com/2012/11/12/briefcase-encounter-an-invention-to- detect-fake-drugs (accessed March 7, 2013). Witkowski, M. R. 2005. The use of Raman spectroscopy in the detection of counterfeit and adulterated pharmaceutical products. American Pharmaceutical Review 8:56-62. Wolff, J.-C., L. A. Thomson, and C. Eckers. 2003. Identification of the “wrong” active pharmaceutical ingredient in a counterfeit Halfan™ drug product using accurate mass electrospray ionisation mass spectrometry, accurate mass tandem mass spectrometry and liquid chromatography/mass spectrometry. Rapid Communications in Mass Spectrometry 17:215-221. World Customs Organization. 2012. High-impact customs operation tackles illicit medi- cines in Africa. http://www.wcoomd.org/en/media/newsroom/2012/october/high-impact- customs-operation-tackles-illicit-medicines-in-africa.aspx (accessed November 14, 2012). Yang, M., T.-Y. Kim, H.-C. Hwang, S.-K. Yi, and D.-H. Kim. 2008. Development of a palm portable mass spectrometer. Journal of the American Society for Mass Spectrometry 19:1442-1448. Zook, A. 2012. Detection of counterfeit pharmaceuticals: Merck case study. Presentation at Committee on Understanding the Global Public Health Implications of Substandard, Falsified, and Counterfeit Medical Products: Meeting One, Institute of Medicine, Wash- ington, DC.