1. Abdelkrim Smine, Ph.D. Global Assistance Initiatives Drug Quality and Information Program 12601 Twinbrook Parkway Rockville, MD 20852. www.USPDQI.org Antimalarial drug quality in Mekong countries Supported by USAIDICIUM 2004

2. Antimalarial drug quality in Mekong countries - USP DQI Program - Antimalarial drugs quality in Mekong countries - Drug quality surveillance at WHO sentinel sites - Data for Cambodia study - Future activities of the program

3. u Cooperative agreement between USP and USAID u Objectives :  To improve availability and appropriate use of good quality pharmaceutical products  To increase availability and use of health information u USP DQI is working on drug quality issues in many countries in SE Asia, Africa and Latin America u USP DQI is partially funded by USAID United States Pharmacopeia Drug Quality and Information

4. Drug quality assurance APIs and dosage forms Supply management Use Producer (s) Manufacturer (s) Importer, wholesaler, exporters, retailer, procurement agents patients Drug regulatory authority - GMPs and GLPs - license authorization - specifications, norms - inspection for GMPs - documentation - registration / licensing - storage / distribution - basic tests, lab tests - information - monitoring - information - surveillance - monitoring - rational use

5. AIM: To strengthen the drug quality control and drug quality assurance systems. Objectives: 1.To obtain and document field evidence-based data on antimalarial drugs quality in Mekong countries 2.To make suggestions to policy-makers/drug regulators for developing and implementing appropriate strategies to address the problems Antimalarial drug quality in Mekong countries

6. Methodological framework for monitoring 1.Assessment of drug quality control systems 2.Identify and select sites 3.Training course on drug sampling, basic tests and drug quality data reporting 4.Field operations (sampling, testing and data reporting) 5.Data collection and analysis based on selected indicators 6.Address drug quality problems

7. Myanmar Thailand Laos Vietnam Cambodia China Mekong Sub-Region: Sentinel sites 17 sites were selected for USP DQI drug quality monitoring project

8. Antimalarial drug quality in Mekong countries -USP DQI in collaboration with WHO has conducted an assessment of drug quality control capabilities in Cambodia, Laos, Thailand, Vietnam, and Yunnan Province in China (2002) Found that trade in counterfeit antimalarial drugs is widespread Inadequate or non existence of drug quality control programs Non compliance of local manufacturers to GMP

9. Antimalarial drug quality in Mekong countries - USP DQI conducted training workshops for Malaria health workers from selected sentinel sites in five Mekong countries. -The training covered: - Sampling procedures - Good Laboratory practices - Basic tests : Visual/physical inspection, Disintegration, and Thin Layer Chromatography (TLC) using GPHF mini-lab - Data management and reporting - USP DQI provided GPHF mini-labs to all selected provinces

10. Testing for quality Activity and requirements Level of testingQuantity/number of samples Sample collection Basic testing Sentinel site Test: 100% of samples collected. Send: - all doubtful samples to NDQC Lab for verification - 5-10% of failed samples - 5-10% of passed samples Verification Basic test and/or Pharmacopeial specifications NDQC or designated Lab Test all samples received From sentinel sites for verification. Confirmation Pharmacopeial specification Reference Lab Test: all samples received from NDQC Lab/designated Lab

11. Antimalarial drug quality in Cambodia Objective: Monitor the quality of anti malarial drugs in 4 sentinel sites (SS) Selection of SS: Battambang, Pailin, Pursat and Preah Vihar, all border provinces with high Malaria cases and abundance of poor quality drugs. Antimalarial drugs: All antimalarial drugs used in the public and private sectors and from legal and illegal drug outlets. Study design: Collect solid dosage forms only from different lot numbers. Collect all the information about the samples. Perform visual/physical inspection, simple disintegration and TLC. Fill out data reports and send samples for confirmation. Confirmation tests: Selected samples are tested in National Lab. Of Cambodia using TLC. Full laboratory testing on selected samples is also conducted in Thailand and USP DQI labs.

12. Provinces Result QuinineArtesunateMefloquineChloroquineTetracyclineDHA Atemethe r Sa mp les Failed (%) Sa mp les Failed (%) Sa m pl es Failed (%) Sa m pl es Failed (%) Sa mp les Failed (%) Sa mp les Faile d (%) Sa mp les Fail ed (%) BTB 9 8 (89%) 11 3 (27.2) 708080NF Preah Vihear 9 5 (56%) 10 2 (20%) 805 1 (20%) 5 1 (20%) 20NF Pailin 10 9 (90%) 904 1 (25.5) 9012 3 (25%) 20NF Pursat 11 8 (73%) 11 2 (18%) 6 1 (17%) 9 3 (33%) 14 4 (29%) 2020 Total 3930 (77%) 417 (17%) 252 (8%) 31 4 (13%) 398 (21%) 6020 NF = Not found in the market DHA = Dihydroartemisinin Antimalarial drug quality in Cambodia

13.  Fake drugs available –~22% in registered shop –~30% in unregistered shop QuinineArtesunateMefloquineChloroquine Tetracycline Fake / Samples (%) Fake / Samples (%) Fake / Samples (%) Fake / Samples (%) Fake / Samples (%) 30 / 39 (76.9) 7 /41 (17.1) 2 / 25 (8.0) 4 / 31 (12.9) 8 / 39 (20.5)  Prevalence of fake drugs Antimalarial drug quality in Cambodia

14. Antimalarial drug quality in Cambodia Sample IDAverage weigh per tablet (mg) ID test HPLCContent of quinine (90- 110 %) Dissolution: Not less than 80 % 006/03 BTB618.43WAINA 007/03 BTB373.73authentic94.7 % - conform106 % - conform 015/03 BTB622.78WAINA 024/03 BTB457.61authentic92.1 % - conform108 % - conform 016/03 PL618.74WAINA 021/03 PL684.71WAI- 029/03 PL602.96WAI- 008/03 PS632.96WAI- 031/03 PS752.04WAI- 054/03 PS698.85WAI- 003/03 PVH769.96WAI- 012/03 PVH648.17WAI-

15. Training - Completed in all countries Sample collection and quality testing at sentinel sites Cambodia - 1 st, 2 nd and 3 rd rounds - completed Laos - 1 st round completed, 2 nd ongoing Thailand - 1st round completed Vietnam - 1st round completed Yunnan China - 1st round completed Verification/confirmatory testing - underway for all countries The program covers 17 sentinel sites in five countries, it will be expanded to 13 more sites by 2005 Progress to date

16. Antimalarial drugs quality Conclusion: The quality control program of antimalarial drugs in sentinel sites has proven to be an excellent way to survey the quality of drugs. Basic tests, such as visual inspection, disintegration and TLC are excellent tools to screen the quality of pharmaceuticals at a non laboratory setting and with a low cost. Counterfeit drugs are still widespread. In this survey most of the failed samples were deliberately fraudulent. 77 % of quinine sulfate tablets were counterfeit, this is alarming because quinine sulfate is given to severe malaria cases. Illegal pharmacies and unregistered drugs seem to contribute to the abundance and the free trade in counterfeit drugs.

17. Future activities - Strengthening National Labs for drug quality control - Strengthening Drug registration procedures - Work with local manufacturers on GMP - Strengthen collaboration with different players in the field - Strengthen regional collaboration on drug quality issues - Expand activities to other disease control programs (TB, HIV/AIDS )

18. Acknowledgments USAID: A. Clements, D. Caroll, A. Boni & M. Summer and country mission staff. WHO: K. Thimasarn, E. Christopher, A. Schapira, R. Tsuyoka NMC Cambodia and all malaria staff in Cambodia, Thailand Laos, Yunnan – China and Vietnam BDN Thailand, NLDQC CAmbodia and NIDQC Vietnam JICA, MSH, CDC USP