1. USP Drug Quality and Information Antimalarial Drug Quality Monitoring in the Mekong Sub-region Workshop on GMP and QA of Antimalarial Medicines with Emphasis on Pre-qualification of ACTs 18-22 October, 2004 Bangkok, Thailand S. Phanouvong, Pharm.D., Ph.D. United States Pharmacopeia Drug Quality and Information Program

2. USP Drug Quality and Information Presentation outline 1.Key points to alert us about poor quality medicines 2.Antimalarial drug quality monitoring in Mekong Sub-Region  Brief overview of the project  Progress to date  Preliminary results 3.Observation, action taken and closing remarks

3. USP Drug Quality and Information Drug Quality  Definition The suitability of a drug product for its intended use is defined by WHO:  Its efficacy weighed against safety (health risks) according to a label claim or as promoted or publicized; and  Its conformity to specifications regarding identity, strength, purity, and other characteristics. Quality assessment ─ compliance with established pharmacopeial specifications and regulatory requirements.

4. USP Drug Quality and Information Poor quality medicines (contd) Substandard  A genuine product that does not conform to its set pharmacopeial standards  WHO definition “product with genuine packaging with incorrect quantity of ingredient (not deliberate).”

5. USP Drug Quality and Information Poor quality medicines (contd) Counterfeit  Definition varies  U.S. Federal FDA Act definition “a drug which, or the container or labeling of which, without authorization, bears the trademark, trade name, or other identifying mark, imprint, or device, or any likeness thereof, of a drug manufacturer, processor, packer, or distributor other than the person or persons who in fact manufactured, processed, packed, or distributed such drug and which thereby falsely purports or is represented to be the product of, or to have been packed or distributed by, such other drug manufacturer, processor, packer, or distributor.”

6. USP Drug Quality and Information Poor quality medicines (contd) Counterfeit drug (continued)  WHO definition “a product that is deliberately and fraudulently mislabeled with respect to identity and/or source; may include products with correct ingredients, wrong ingredients, without active ingredients, with incorrect quantity of active ingredient or with fake packaging.”

7. USP Drug Quality and Information Poor quality medicines – technical factors 1. Poor manufacturing practices 2. Counterfeiting 3. Inappropriate procurement practices 4. Inadequate storage, distribution, dispensing and handling practices.

8. USP Drug Quality and Information Poor quality medicines – other factors 1.Lack of adequate legislation and/or its enforcement with weak penal sanctions 2.Absent or weak drug regulatory authority 3.Corruption and conflicts of interest 4.Trade involving many intermediaries 5.Demand exceeding supply and high prices 6.Inadequate regulation in exporting countries and within free trade zones 7.Inefficient cooperation between stakeholders

9. USP Drug Quality and Information Availability of poor quality medicines They are widely available and are: A constant threat to global health Most affecting people living in countries with limited regulatory capacity and resources FDA estimated that up to 10% of drugs worldwide are counterfeit, and in some countries more than 50% of the drug supply is made up of counterfeit drugs Costing about 22 billion USD per year, representing about 7% of world-wide pharmaceutical sales

10. USP Drug Quality and Information Availability of poor quality medicines Source: Carpenter J P, 2003. Drug quality report matrix of USAID-assisted countries by the USP DQI Program Countries: Cambodia, Ghana, Laos, Myanmar, Nigeria, Senegal, Thailand, Tanzania, Vietnam

11. USP Drug Quality and Information Consequences of using poor quality medicines 1.Trust into national programs credibility is fading away 2.Waste of limited financial resources 3.Health is at risk, prolonged illness, treatment failure, and some cases lead to drug resistance 4.Death

12. USP Drug Quality and Information Presentation outline 1.Key points to alert us about poor quality medicines 2.Antimalarial drug quality monitoring in Mekong Sub-Region  Brief overview of the project  Progress to date  Preliminary results 3.Observation, action taken and closing remarks

13. USP Drug Quality and Information Aim and objectives of project AIM: To strengthen country capability in drug QA/QC systems at national and program levels Objectives: 1.To obtain and document field evidence-based data on quality of selected antimalarial drugs in Mekong Sub-Region countries 2.To make suggestions to policy-makers/drug regulators for developing and implementing appropriate strategies to address the problems

14. USP Drug Quality and Information

15. Methodological framework for monitoring Review of malaria and QA/QC situation Selection of sentinel sites Training in GLP, basic testing, sampling, data management Field operation: sample collection, testing and reporting Data analysis and documentation Suggestions/ Recommendations for policy development and implementation by country governments

16. USP Drug Quality and Information Performing TLC test

17. USP Drug Quality and Information Yunnan Province of PR of China LaosVietnam Mang LaSayaburiLai Chau Rui LiSavannakethQuang Tri ChampasakDaklak Binh Phuoc CambodiaThailand PursatMae Hong Son PailinKanchanaburi BattambangChanthaburi/Trat Preah VihearRanong 17 sites participating Mekong Sub-Region: Sentinel sites

18. USP Drug Quality and Information Testing – levels of current practice Activity and requirementsLevel of testingQuantity/number of samples Sample collection Basic testing (physical/visual inspection, simplified disintegration, TLC) Sentinel site Test: 100% of samples collected. Send: 1. 100% doubtful samples to NDQC or designated Lab for verification 2. 100% of failed samples 3. 5-10% of passed samples Verification Basic test and/or Pharmacopeial specifications NDQC or designated Labs Test: 100% samples received from sentinel sites. Send: 1. 100% doubtful samples to reference lab for confirmation 2. 100% of failed samples, where possible 3. 5-10% of passed samples Confirmation Pharmacopeial specification Reference Labs Test: all samples received from NDQC Lab/designated Lab

19. USP Drug Quality and Information General Rules for Interpreting TLC Results This simple guideline uses the percent Rf error, defined below, to determine the fate of a sample based on simple TLC. Rf Sample Error = {|Rf (standard) – Rf (sample)| / Rf (standard)} x 100% Example From multiple TLC experiments, the following Rf values were obtained: Rf (standard) = 0.55 Rf (sample) = 0.53 Then, Rf Sample Error = {(0.55 – 0.53)/0.55} x 100% = 3.6 % Interpretation of TLC Results Based on the typical Rf values, broadness of TLC spots and simple error analysis[1], some broad rules can be applied to interpret TLC results. It is important to note that these rules should only be considered semi-quantitative and not absolute.[1] When Rf Sample Error is 5% or less, the sample can be considered “Pass” When Rf Sample Error is 10% or more, the sample can be considered “Fail” When Rf Sample Error is between 5% and 10%, the sample can be considered “Doubtful” Note: If the TLC chamber and plates were not well saturated, or if the saturation has been disturbed the spots may not be horizontal and this could give high Rf sample error. Always make TLC in duplicate and compare the Rf of both runs. When Rf sample error is more than 5%, always make another duplicate run under optimal conditions to double check the doubt. [1][1] Quantitative Chemical Analysis, 6th Edition. Daniel C. Harris, W. H. Freeman, New York, 2003.

20. USP Drug Quality and Information Indicators used for monitoring Background Indicators Process Indicators Outcome Indicators Impact Indicators

21. USP Drug Quality and Information Indicators used – core OC 1: Number of batches or lots failing quality tests that are removed from the National Malaria Program or from the market. OC 2: Administrative or regulatory actions taken against providers or manufacturers that sell poor quality antimalarial drugs

22. USP Drug Quality and Information Progress to date TrainingRound 1 Round 2 Round 3 Remark Cambodia  Laos  Thailand  To expand to +5 sites Viet Nam  To expand to +2 sites Yunnan of China  Activity Country Verification/confirmatory testing – on going

23. USP Drug Quality and Information Sentinel sites by country and No. of samples CountrySentinel sitesR1 Sample/ Lot R2 Sample/ Lot R3 Sample/ Lot CambodiaBattambang; Pursat, Paillin; Preah Vihar 179/85175/82123/75 LaosChampasack; Savannakhet; Sayaboury 108/95 -- ThailandChantaburi; Kanchaburi; Mae Hong Son; Ranong 104/88122/97143/102 VietnamBinh Phuoc; Daklak; Lai Chau; Quang Tri 75/4760/38 - YunnanMengla; Ruili39/3678/64 - Total505/351 --

24. USP Drug Quality and Information Preliminary data from countries Lot/Batch failure percentage – Round 1 data (no. failed/total) ARTDIHCHQMEFQUIS/PTET Cambodia23 (4/17) 0 (0/4) 4.5 (1/22) 0 (0/13) 43 (3/7)NA 3.8 (1/26) Laos67 (2/3)NA 0 (13/26) 0 (0/3) 14 (3/22) 0 (0/10) 13 (4/31) Thailand0 (0/9)NA 0 (0/23) 0 (0/6) 3.8 (1/26) 0 (0/2) 3.8 (1/26) Vietnam0 (0/16)NA 27 (3/11) 0 (0/1) 0 (0/9) 0 (0/10)NA Yunnan25 (2/8)NA 0 (0/14)NA 0 (0/7) 0 (0/7)NA

25. USP Drug Quality and Information Preliminary data from countries Lot/Batch failure rate percentage – Round 2 data (no. failed/total) Sites in ARTDIHCHQMEFPRIQUIPYRS/PTET Cambodia 27 (4/15) 0 (0/8) 0 (0/32) 12 (1/8) NA 50 (9/18) NA 5.9 (2/34) Thailand 14.3* (1/7) NA 17.6 (3/17) 0 (0/9)NA 0 (0/14)NA 0 (0/3) 0 (0/23) Vietnam 25 (1/4) NA 0 (0/15)NA 0 (0/1) 0 (0/10)NA 0 (0/7)NA Yunnan 10 (1/10) NA ? (!1/27)NA 0 (0/16) 0 (0/7) 0 (0/4) NA * Substandard (low API content

26. USP Drug Quality and Information Name of sites No. of samples collected No. of samples tested that failed basic tests at sentinel sites Lai Chau210 (0%) Quang Tri152 (13.3%) Dak Lak251 (4%) Binh Phuoc 140 (0%) Total753 (4%) Summary of test results in rounds 1 & 2 – Viet Nam Name of sites No. of samples collected No. of samples tested that failed basic tests at sentinel sites Lai Chau190 (0%) Quang Tri91 (11.1%) Dak Lak190 (0%) Binh Phuoc 130 (0%) Total601(1.7%) Round 1 Round 2

27. USP Drug Quality and Information Name of drug samplesNo. of samples collected/L ot No. of Lots tested and failed using basic tests at sentinel sites or failed at NIDQC No. of samples collected/L ot No. of samples tested and failed using basic tests at sentinel sites [verification test results not yet available] Chloroquine phosphate tablet 250mg 14/113 (27%) 2 in Quang Tri 1 in Dak Lak 15/90 Quinine sulfate 250mg12/82 (25%)10/60 Quinine Dihydrochloride 500mg 1/1000 Artesunate 50mg27/16021/161 (6.3%) (1 out of 4 Lot failed = 25% in Quang Tri Mefloquine 250mg5/1000 Fansidar tablet (Sulf 500mg+Pri 25mg) 16/10013/70 Primaquine001/1- Total75/475 (10.6%)60/391 (2.6%) Failure rates by drug in rounds 1 & 2 – Viet Nam Round 1 Round 2

28. USP Drug Quality and Information Test results summary in Cambodia

29. USP Drug Quality and Information Test results summary in Cambodia (contd)

30. USP Drug Quality and Information Test results summary in Cambodia (contd) –Round 1 by drug

31. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmaceutical Co. Artesunate 50 mg 002-03 PVH lot 000902 of labeled as “Guilin Pharmaceutical Co.”

32. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmaceutical Co. Artesunate 50 mg 002-03 PVH lot 000902 of labeled as “Guilin Pharmaceutical Co.”

33. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmaceutical Co. Artesunate 50 mg 002-03 PVH lot 000902 of labeled as “Guilin Pharmaceutical Co.”

34. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmaceutical Co. Artesunate 50 mg 071-03 PS lot 010401ot of labeled as “Guilin Pharmaceutical Co.”

35. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmaceutical Co. Found after 1998 in Vietnam and Cambodia

36. USP Drug Quality and Information Genuine artesunate hologram of Guilin Pharmace utical Co. Fake found in 2002/03 in Laos and Cambodia

37. USP Drug Quality and Information Presentation outline 1.Key points to alert us about poor quality medicines 2.Antimalarial drug quality monitoring in Mekong Sub-Region  Brief overview of the project  Progress to date  Preliminary results 3.Observation, action taken and closing remarks

38. USP Drug Quality and Information Observations 1. It is clear that poor quality antimalarial medicines are widely available and used in all countries – much to be done 2. Continuing support and commitments of Governments and donors at all levels are needed  Financially – for project sustainability  Integrate into GFATM activities?  Law and regulations enforcement

39. USP Drug Quality and Information Action taken by different parties USP DQI 1. Contacted Yunnan of China (YIPD) and WPRO on 2 lot-artesunates 2. Contacted Viet Nam NIMPE, NIDQC and DAV 3. In process of contacting CMPE, FDD and FDQCC of Laos 4. In process of contacting CNM, FDD and NLDQC of Cambodia

40. USP Drug Quality and Information Even if these principles are followed 1. Qualified / trained health care provider consulted 2. Proper diagnosis made 3. STGs followed i.e.“correct” drug prescribed in right dose and right route of administration 4. Objective information obtained 5. Treatment regimen complied Closing thoughts there will be no cure if the quality of medicines used is poor Collaborative and persistent actions are required from the responsible authorities at local, national and regional levels