Pharmaceutical Forensics

Hand in hand with our efforts in the field of ambient MS and DTIMS, we became heavily involved in investigating the problem of the increased prevalence of falsified drugs in developing countries of SE Asia, Africa, and a few Latin-American countries, in particular antimalarials. We cannot think of a better example of a problem with the highest societal impact that also requires expertise in detection science and technology. Because we believe that scientists should give back to society, we have made this project a focal point of our work at Georgia Tech [1-17]. Existing methods commonly used for counterfeit drug detection are far from satisfactory [18], and direct analysis by DESI and DART is very well suited to the high-throughput needs of these studies.

Although it is known that falsified (counterfeit, fake) drugs are more common in developing countries, little quantitative information is available on their prevalence. As part of the Bill and Melinda Gates-funded Artemisinin Combination Therapy Consortium (ACTc), our group has been involved in several countrywide antimalarial drug quality surveys in countries such as the Lao PDR [13], Rwanda, Tanzania, and Nigeria involving thousands of samples.  In addition, we regularly receive suspicious samples collected in developing countries by non-governmental organizations (NGOs) and medicine regulatory authorities (MRAs). To channel these informal interactions, we have set up a network of collaborators named the “Counterfeit Drug Forensic Investigation Network” (CODFIN) [19]. We also maintain a Microsoft Sharepoint repository with information regarding fake drugs obtained in the last 9 years. The information in this repository is now being mapped by the Antimalarial Quality Surveyor, a visualization tool developed by the WorldWide Antimalarial Resistance Network (wWARN) [20].

More than 90% of the counterfeit drugs investigated by our group contain “wrong” active ingredients [1, 4, 10, 12, 13, 16, 18, 21]; having found counterfeit artesunate antimalarials containing artemisinin, chloramphenicol, erythromycin, paracetamol, metronidazole, and metamizole [1, 2, 9], for example. Using DART and DESI MS information on “wrong” active ingredient identity, we contributed in 2008 to the closure of a very active drug counterfeiting ring in China [9]. Fake ACTs from Africa have been recently studied by our group, and some found to contain sildenafil, the active ingredient in Viagra® [16]. In a recent unpublished case study, we examined counterfeit emergency contraceptives. DART MS and MS2 showed that these fakes did not contain the expected active, levonogestrel, but the cheaper sulfa drug, sulphamethoxazole.
 
(1)        F. M. Fernandez, R. B. Cody, M. Green, C. Y. Hampton, R. McGready, S. Sengaloundeth, N. J. White, P. N. Newton; "Characterization of solid counterfeit drug samples by desorption electrospray ionization and direct-analysis-in-real-time coupled to time-of-flight mass spectrometry". ChemMedChem 1, 702-705 (2006).doi: 10.1002/cmdc.200600041
(2)        K. A. Hall, P. N. Newton, M. D. Green, M. De Veij, P. Vandenabeele, D. Pizzanelli, M. Mayxay, A. Dondorp, N. J. White, F. M. Fernandez; "Characterization of counterfeit artesunate antimalarial tablets from SE Asia". Am. J. Trop. Med. Hyg. 75, 804-811 (2006).
(3)        P. N. Newton, M. D. Green, F. M. Fernandez, N. P. Day, N. J. White; "Counterfeit anti-infective drugs". Lancet Infect Dis 6, 602-613 (2006).doi: 10.1016/S1473-3099(06)70581-3
(4)        P. N. Newton, R. McGready, F. Fernandez, M. D. Green, M. Sunjio, C. Bruneton, S. Phanouvong, P. Millet, C. J. Whitty, A. O. Talisuna, S. Proux, E. M. Christophel, G. Malenga, P. Singhasivanon, K. Bojang, H. Kaur, K. Palmer, N. P. Day, B. M. Greenwood, F. Nosten, N. J. White; "Manslaughter by fake artesunate in Asia--will Africa be next?". PLoS Med 3, e197 (2006).doi: 10.1371/journal.pmed.0030197
(5)        M. D. Green, H. Nettey, O. Villalba-Rojas, C. Pamanivong, L. Khounsaknalath, M. Grande Ortiz, P. N. Newton, F. M. Fernandez, L. Vongsack, O. Manolin; "Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality". J. Pharm. Biomed. Anal. 43, 105-110 (2007).doi: 10.1016/j.jpba.2006.06.047
(6)        F. E. Dowell, E. B. Maghirang, F. M. Fernandez, P. N. Newton, M. D. Green; "Detecting counterfeit antimalarial tablets by near-infrared spectroscopy". J. Pharm. Biomed. Anal. 48, 1011-1014 (2008).doi: 10.1016/j.jpba.2008.06.024
(7)        F. M. Fernandez, M. D. Green, P. N. Newton; "Prevalence and detection of counterfeit pharmaceuticals: A mini review". Ind. Eng. Chem. Res. 47, 585-590 (2008).doi: Doi 10.1021/Ie0703787
(8)        V. Keoluangkhot, M. Green, L. Nyadong, F. M. Fernandez, M. Mayxay, P. N. Newton; "Impaired clinical response in a patient with uncomplicated falciparum malaria who received poor quality and underdosed intramuscular artemether". Am. J. Trop. Med. Hyg. 78, 552-555 (2008).
(9)        P. N. Newton, F. M. Fernandez, A. Plancon, 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. Soong, B. Santoso, W. Zhiguang, J. Newton, K. Palmer; "A collaborative epidemiological investigation into the criminal fake artesunate trade in south east Asia". PLoS medicine 5, e32 (2008).doi: 10.1371/journal.pmed.0050032
(10)      P. N. Newton, C. Y. Hampton, K. Alter-Hall, T. Teerwarakulpana, S. Prakongpan, R. Ruangveerayuth, N. J. White, N. P. Day, M. B. Tudino, N. Mancuso, F. M. Fernandez; "Characterization of "Yaa Chud" medicine on the Thailand-Myanmar border: Selecting for drug-resistant malaria and threatening public health". Am. J. Trop. Med. Hyg. 79, 662-669 (2008).
(11)      C. Ricci, L. Nyadong, F. Yang, F. M. Fernandez, C. D. Brown, P. N. Newton, S. G. Kazarian; "Assessment of hand-held raman instrumentation for in situ screening for potentially counterfeit artesunate antimalarial tablets by ft-raman spectroscopy and direct ionization mass spectrometry". Anal. Chim. Acta 623, 178-186 (2008).doi: 10.1016/j.aca.2008.06.007
(12)      L. Nyadong, G. A. Harris, S. Balayssac, A. S. Galhena, M. Malet-Martino, R. Martino, R. M. Parry, M. D. M. Wang, F. M. Fernandez, V. Gilard; "Combining two-dimensional diffusion-ordered nuclear magnetic resonance spectroscopy, imaging desorption electrospray ionization mass spectrometry, and direct analysis in real-time mass spectrometry for the integral investigation of counterfeit pharmaceuticals". Anal. Chem. 81, 4803-4812 (2009).doi: 10.1021/Ac900384j
(13)      S. Sengaloundeth, M. D. Green, F. M. Fernandez, O. Manolin, K. Phommavong, V. Insixiengmay, C. Y. Hampton, L. Nyadong, D. C. Mildenhall, D. Hostetler, L. Khounsaknalath, L. Vongsack, S. Phompida, V. Vanisaveth, L. Syhakhang, P. N. Newton; "A stratified random survey of the proportion of poor quality oral artesunate sold at medicine outlets in the Lao PDR - implications for therapeutic failure and drug resistance". Malaria J. 8, 252-257 (2009).doi: 10.1186/1475-2875-8-172
(14)      H. Kaur, D. Hostetler, F. M. Fernandez, M. D. Green, P. N. Newton; "Antimalarial drug quality-methods to detect suspect drugs". Therapy 7, 49-57 (2010).
(15)      P. N. Newton, M. D. Green, F. M. Fernandez; "Impact of poor-quality medicines in the 'developing' world". Trends Pharmacol. Sci. 31, 99-101 (2010).doi: DOI 10.1016/j.tips.2009.11.005
(16)      P. N. Newton, M. D. Green, D. C. Mildenhall, A. Plancon, H. Nettey, L. Nyadong, D. M. Hostetler, I. Swamidoss, G. A. Harris, K. Powell, A. E. Timmermans, A. A. Amin, S. K. Opuni, S. Barbereau, C. Faurant, R. C. Soong, K. Faure, J. Thevanayagam, P. Fernandes, H. Kaur, B. Angus, K. Stepniewska, P. J. Guerin, F. M. Fernandez; "Poor quality vital anti-malarials in Africa - an urgent neglected public health priority". Malaria J. 10, 352 (2011).doi: 10.1186/1475-2875-10-352
(17)      S. D. Rhodes, F. M. Fernandez, J. S. Leichliter, A. T. Vissman, S. Duck, M. C. O'Brien, C. Miller, A. M. Wilkin, G. A. Harris, D. M. Hostetler, F. R. Bloom; "Medications for sexual health available from non-medical sources: A need for increased access to healthcare and education among immigrant latinos in the rural southeastern USA". Journal of immigrant and minority health / Center for Minority Public Health 13, 1183-1186 (2011).doi: 10.1007/s10903-010-9396-7
(18)      F. M. Fernandez, D. Hostetler, K. Powell, H. Kaur, M. D. Green, D. C. Mildenhall, P. N. Newton; "Poor quality drugs: Grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries". Analyst 136, 3073-3082 (2011).doi: 10.1039/C0an00627k
(19)      "Codfin", www.codfin.org, (2012).
(20)      P. Tabernero, P. N. Newton; "The wwarn antimalarial quality surveyor". Pathog. Glob. Health 106, 77-78 (2012).doi: 10.1179/204777312X13419245939520
(21)      L. Nyadong, M. D. Green, V. R. De Jesus, P. N. Newton, F. M. Fernandez; "Reactive desorption electrospray ionization linear ion trap mass spectrometry of latest-generation counterfeit antimalarials via noncovalent complex formation". Anal. Chem. 79, 2150-2157 (2007).doi: 10.1021/ac062205h