Countering the Problem of Falsified and Substandard Drugs (2013) / Chapter Skim
Currently Skimming:
6 Detection Technology
6 Detection Technology
Pages 255-294
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 255... ...
QUALITATIVE AND QUANTITATIVE METHODS Detection technologies provide varying degrees of qualitative and quantitative data about medicines. Qualitative techniques provide information about a drug's identity, such as its active ingredient, color, or labeling.
|
From page 256... ...
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.
|
From page 257... ...
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; chromatography; spectroscopic techniques; and mass spectrometry.
|
From page 258... ...
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)
|
From page 259... ...
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 properties 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 substandard drugs but admits that this is challenging even for experts (Jähnke et al., 2008; Sherma, 2007)
|
From page 260... ...
Field inspectors can use handheld refractometers to measure the refractive index and use it as a quantitative test for some active ingredients (Kaur et al., 2010)
|
From page 261... ...
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.
|
From page 262... ...
. The main drawbacks to TLC are its limited semi-quantitative data (when used with visual detection)
|
From page 263... ...
. Diode array detection is now standard with many HPLC assays and can be used to confirm the presence of active ingredients.
|
From page 264... ...
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.
|
From page 265... ...
Spectroscopy Spectroscopy is a class of analytical techniques that measures the interaction 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.
|
From page 266... ...
100 266 80 CH3 60 O O H O %T H3 C O 40 H O H CH3 20 0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400 cm-1 100 80 CH3 H O 60 H3 C O O %T H H 40 O CH3 O 20 H3C 0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400 cm-1 FIGURE 6–4 Infrared Spectra for artemisinin (top) and artemether, an artemisinin derivative (bottom)
|
From page 267... ...
. Near-infrared can identify active ingredients and is particularly useful for detecting incorrect concentrations of excipients, a common inconsistency in falsified and substandard drugs (Deisingh, 2005)
|
From page 268... ...
. Raman spectroscopy can readily identify many active ingredients and give further information about excipients, as well as the relative concentration of active ingredients to excipients (Deisingh, 2005)
|
From page 269... ...
. But some investigators maintain that the fluorescence of genuine artesunate can serve as a tool to distinguish between good- and poor-quality samples, as those without sufficient active ingredient will not produce as much fluorescence (Ricci et al., 2008)
|
From page 270... ...
. In NMR analysis, all of the compounds in the mixture (including active ingredients, excipients, and impurities)
|
From page 271... ...
X-ray diffraction can be used to analyze active ingredients and excipients, while X-ray fluorescence is used for elemental analyses that can often distinguish real from falsified drugs (Kaur et al., 2010; Martino et al., 2010)
|
From page 272... ...
Among these are very close analogues of genuine active ingredients. These analogues can be so chemically and structurally similar that they behave the same under nearly any analysis.
|
From page 273... ...
. PharmaCheck uses microfluidics, the control of fluids at a sub-millimeter scale, for rapid field drug testing (EurekAlert, 2012)
|
From page 274... ...
The information a technique provides, as well as its reliability, cost, required expertise, speed, and portability make it more or less appropriate in any given situation. In order to conclude that a drug is of good quality, an inspector must test a sample for all of the main deficiencies of substandard and falsified drugs: fake packaging, incorrect color, shape, or markings, absent or incorrect active ingredients, incorrect quantities of ingredients, impurities, and reduced dissolution or disintegration.
|
From page 275... ...
TABLE 6–2 Product Quality Attributes and Assessments Detection Techniques Chemical or Spectroscopy Physical Visual Package Microbiological and Mass Measurements Problems Inspection Technologies Tests Spectrometry or Examination Chromatography Reflectance Absent or incorrect active ingredient Wrong color Wrong shape or markings Fake packaging Incorrect quantities of ingredients Impurities Dissolution Disintegration Uniformity of dosage units Microbial contamination 275
|
From page 276... ...
testing NOTE: AI = active ingredient; CODFIN = Counterfeit Drug Forensic Investigation Network; DOSY NMR = diffu sion ordered spectroscopy nuclear magnetic resonance; HPLC = high-performance liquid chromatography; IRMS = isotope-ratio mass spectrometry; MS = mass spectrometry; Y Pass N NIR = near infrared; XRD = x-ray diffraction; XRF = x-ray Genuine Substandard dissolution? fluorescence.
|
From page 277... ...
Similarly, while colorimetry and TLC are field techniques for testing for the presence of a particular ingredient, knowing a sample's full content requires more testing. Spectroscopic techniques are useful for identifying active ingredients but cannot rule out the presence of countless possible impurities.
|
From page 278... ...
These hyphenated techniques have broad capabilities. For example, liquid chromatography-mass spectrometry is a highly reliable separation technique, but does not directly provide quantitative data about the amount of active ingredient present; analysts must compare results to standards to determine content (Kaur et al., 2010)
|
From page 279... ...
can detect many falsified and substandard drugs. As the previous section explains, these techniques are durable, fast, relatively inexpensive, and fairly easy to use, making them attractive to regulators interested in monitoring drug quality.
|
From page 280... ...
. Members of the Thai FDA, for example, visited Chinese mobile labs in 2006 (Jin, 2007)
|
From page 281... ...
Informed patients can assist in identifying falsified and substandard drugs. Visual inspection of drug packages and color can identify gross differences between authentic and fake medicines.
|
From page 282... ...
. The Minilab relies on a combination of accessible techniques for simple, fast, and reliable detection of falsified and substandard drugs.
|
From page 283... ...
. By using colorimetry, which tests for the identity of active ingredients, and TLC, which provides information about potency, the kit is capable of testing for the top three kinds of substan dard and falsified drugs: those that contain no active ingredient, those that contain too little active ingredient, and those that contain the wrong active ingredient (GPHF, 2012c; Jähnke et al., 2001)
|
From page 284... ...
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.
|
From page 285... ...
. Drug quality analysis draws from At a Minilab training session in Angola, field inspectors learn how to test drug quality.
|
From page 286... ...
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
|
From page 287... ...
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 procedure for assay.
|
From page 288... ...
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)
|
From page 289... ...
. 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)
|
From page 290... ...
2008. FDA forensic investigations using mass spectrometry.
|
From page 291... ...
Germany: Global Pharma Health Fund. Jähnke, R
|
From page 292... ...
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.
|
From page 293... ...
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.
|
From page 294... ...
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.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.