Dr Harparkash Kaur presents at the European Congress on Tropical Medicine and International Health in Basel, Switzerland on 9 September 2015.

1. Systematic Sampling Approach Reveals Fewer Falsified
First Line Antimalarials than Previously Reported
Harparkash Kaur
Answering key questions on malaria drug delivery 1
London School of Hygiene & Tropical Medicine

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Falsified Antimalarials Abound
Health professionals and patients assume that the medicines that
they are prescribing/prescribed are of good quality.

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• Use 2 stage testing (MiniLab® and QC Lab) DO NOT differentiate drugs in terms of
counterfeit, substandard or degraded
• WHO report of 6 countries in Africa highlights that 1/3 samples (ACTs and SP) are
substandard possibly counterfeit. It also said that the MiniLab® underestimates the
negative results by x3.
• Sampling method seems to be convenience, NOT random
ACTc DQ-project set out to determine the quality of drugs following representative
sampling in various geographical regions.
REPORTS
WHO January 2011

4. 4
Goal of the ACT Consortium
To develop and evaluate mechanisms to improve ACT delivery
25 projects in 10 countries, working on:
ACCESS
TARGETING
SAFETY
QUALITY
Answering key questions on malaria drug delivery

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Utility and relevance
• How useful are the findings likely to be to policy makers and other stakeholders
both within and outside the country?
• Is there an important initiative in the country that may impact on drug quality, i.e.
Affordable Medicines Forum for malaria (AMFm……….. )?
• Absence of other ongoing DQ surveillance and does the availability capacity
lack sophisticated equipment.
Feasibility
• Is there an existing ACTc project in that country?
• Is there potential for piggy backing on to ongoing surveys?
• Local co-operation – willing, capable and resources available.
• Conducive political and regulatory environment.
Criteria for Site Selection
Answering key questions on malaria drug delivery

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Countries where samples collected
RWANDA (2008)
TANZANIA (2010 & 2011)*
CAMBODIA (2010)*
KINTAMPO, GHANA (2011)*
ENUGU, NIGERIA (2013)
EQUATORIAL GUINEA, BIOKO ISLAND (2014)
ILORIN , NIGERIA (2013) Ϯ
THAILAND (2014)Ϯ
BURMA (2014)Ϯ
ACTC COUNTRY
NON-ACTC COUNTRY
*AFFORDABLE MEDICINES FACILITY FOR
MALARIA (AMFM )
Ϯ TRACKING RESISTANCE TO ARTEMISININ
COLLABORATION (TRAC)

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Agreement Signed with
MOH in a Country & LSHTM

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Local clearance and permission to sample
LSHTM ethics clearance
Ethics clearance LSHTM & Local plus Permission

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Sample Collection

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Packaged Carefully Before Shipping to LSHTM

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Processing
Logging onto Epi info

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Drug Samples
LSHTM (UK)
Harparkash Kaur
• All samples logged
• Scanned & tablet dimensions noted
• HPLC analysis for % API content
• Results compiled into a report
CDC (Atlanta)
Mike Green
• ~10 %of samples tested to confirm
HPLC analysis from partner (LSHTM)
GT (Atlanta)
Facundo Fernandez
• Mass spec analysis
INFORMATION ON QUALITY OF DRUGS
DISSEMINATED TO MOH
All collected samples
Samples sent for
mass analysis
Report complied and sent
Flow of Sample & Corroborative Analyses
All information is logged on to a
database
Manuscripts

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% Active ingredients
HPLC
Forced ageing at 60˚C
0 - 21 days
Degradation studies
LC/MS
0.00 1.00 2.00 3.00 4.00 5.00 6.00
-
20
25
50
75
120
mAU
min
Artemether – 3.8
Lumefantrine – 4.6
Chemical Content Analysis of ACTs at LSHTM

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Classification of ACTS
Drug quality % Stated API detected Method used
Acceptable quality 85-115 HPLC & MS & LC/MS
Falsified 0 HPLC & MS & LC/MS
Substandard < 85 - > 115 HPLC & MS & LC/MS
Degraded < 85 plus products of degraded APIs MS & LC/MS

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Drug quality survey in Enugu Metropolis, Nigeria
Malaria Burden – Highest in SS Africa; 48 Million clinical episodes; 180,000 deaths per year
ACTs adopted in 2005
Types of providers – pharmacy, patent medicine vendors and public health facilities
Sampling methods – convenience, mystery client and overt sampling approaches
Total no of samples analysed – 3024 artemisinin containing antimalarials

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Sampling approach No of outlets Total no of ACAs
Acceptable
Quality
Substandard Degraded Falsified
Convenience 23 200
(49 bands)
84.5% 10.5% 2.0 % 3.0 %
Mystery clients 279 1919
(102 brands)
91.1% 5.8% 1.3% 1.2%
Overt 119 905
(79 brands)
91.5% 6.9% 1.0% 0.6%
Quality of ACAs purchased in Enugu, Nigeria; n = 3024
Outlets included Pharmacies; Patent medicine vendors; Public health facilities

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Residue
ResidueMottled brown
Soft and sticky
Blister torn
& buckled
Degraded samples – Appearances are deceiving
NO degraded products detected
Degraded products detected

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Brand Stated manufacturer
Stated
API
Total no
samples
Acceptable
Quality
Substandard Degraded
Amatem Forte®
Micro Labs Limited
India
AM/LUM 43 97.7 % 0 2.3 %
Amatem Tab®
20/120
Micro Labs Limited
India
AM/LUM 31 71.0 % 12.9 % 16.1 %
Arcofan
20/120
Naxpar Lab Pvt Ltd
India
AM/LUM 15 0 0 100.0 %
Artemetrin®
80/480
A.C. Drugs Ltd
Nigeria
AM/LUM 5 20.0 % 0 80.0 %
Artrin®
Medreich Limited
India
AM/LUM 15 73.3 % 0 26.7 %
Ogamal QS
Vapi Care Pharma Pvt
Ltd
India
AM/LUM 35 91.4 % 2.9 % 5.7 %
Maltarka
Vapi Care Pharma Pvt
Ltd
India
AS/S/P* 5 0 33.3 % 66.7 %
Brand specific degraded of ACTs from Enugu, Nigeria

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0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.50
mAU
min
Impurity DHA - 4.3
Artesunate - 4.8
Dihydroartemisinin - 5.2
Artemisinin - 5.5
Artemether - 8.1
0.0
5.0
10.0
20.0
15.0
25.0
0.00 1.00 2.00 3.00 4.00 5.00 6.00
-20
25
50
75
120
mAU
min
Artemether – 3.8
Lumefantrine – 4.6
Detection of APIs - Content analysis
HPLC separation
145.1035
163.1158
221.1599
249.1543
267.1652
284.1895
316.2168
406.1738
528.1798
+MS, 4.6-5.5min #(276-328), Background Subtracted
0.0
0.5
1.0
1.5
2.0
5x10
Intens.
150 200 250 300 350 400 450 500 550 m/z
[Lumefantrine + H]+
[Artemether + NH4]+
DART-MS

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205.0784 231.0933
245.1113
268.1451
288.1540
332.1418
+MS2(332.1400), 4.4-4.6min #(262-272), Background Subtracted
0
1
2
3
5x10
Intens.
175 200 225 250 275 300 325 350 375 m/z
DART-MS/MS
Fragmentation pattern indicates
ciprofloxacin
241.1821 259.1923
332.1464
371.3172
+MS, 3.7-4.9min #(219-291), Background Subtracted
0.0
0.5
1.0
1.5
2.0
2.5
5x10
Intens.
175 200 225 250 275 300 325 350 375 m/z
[Ciprofloxacin + H]+ instead of artemether
DART-MS
Nigeria Falsified samples; DART-MS at GT
Ciprofloxacin
NIST MS/MS

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Stated brand
Stated country of
manufacture
Stated
manufacturer
Stated
API
Compound found
Artesunat® Vietnam Mekophar AS† DEHA or DOA
Artesunat® Vietnam Mekophar AS† DEHA or DOA
Artesunat® Vietnam Mekophar AS† Acetaminophen
Artesmequine® China Greenfield AS-MEF Unidentified
Coartem® (USA) USA Novartis AM-LUM
Chlorzoxazone
(Muscle relaxant)
Coartem® (USA) USA Novartis AM-LUM Chlorzoxazone
Coartem® (USA) USA Novartis AM-LUM Chlorzoxazone
Lonart-DS® India Bliss GVS AM-LUM
Ciprofloxacin
(antibiotic)
Lonart-DS® India Bliss GVS AM-LUM Ciprofloxacin
Duo-Cotecxin® China Zheijang Holley DHA-PIP DEHA or DOA
Waipa Act Nigeria Kunimed DHA-PIP Acetaminophen
Note: † = mono therapy;
DEHA or DOA = petroleum products [Bis(2-ethylhexyl) adipate or Dioctyl adipate]
Falsified samples from Nigeria – Details

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Examples of Falsified Samples from Enugu
DHA/PIP formulation locally manufactured
AM/LUM
AS monotherapy
AS/MF

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Visual inspection of Falsified samples from Nigeria
DHA/PIP formulation locally manufactured
AM/LUM formulations

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ACTc DQ: Sampling methods used
COUNTRY
Method of sampling
OUTLETS
Method of sampling
DRUGS
Bioko Island,
Equatorial Guinea
Random / National survey
• Mystery client
• Overt
Cambodia Random / National survey*
• Mystery client
• Overt
Ghana Random / 1 locality • Mystery client
Nigeria Random / 1 region
• Mystery client
• Overt
Rwanda Random / National survey • Mystery client
Tanzania Random / National survey • Overt
* from malaria endemic areas only

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Country
(date of collection)
Samples Brands
Acceptable
Quality
Substandard Falsified
Artemisinin
Monotherapy
Tablets
Rwanda (2008) 97 1 93.8% 6.2% 0 found Not Found
Cambodia (2010) 291 21 68.7% 31.3% 0 found Found
Ghana - Kintampo (2011) 257 31 63.0% 37.0% 0 found Not Found
Tanzania (2010) 1737 37 88.0% 12.0% 0 found Found
Tanzania (2011) 2546 46 97.8% 2.2% 0 found Found
Nigeria - Enugu Metropolis
(2013)
3024 131 92.2% 6.6% 1.2% Found
Bioko Island- Equatorial
Guinea (2014)
677 142 91.0% 1.6% 7.4% Found
Nigeria - Ilorin city (2013) 1450 77 91.5% 7.7% 0.8% Found
Quality of ACTs found per country
Of all 10,079 samples analysed we found:

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No falsified, but concerns about substandard medicines
Tanzania
Am J Trop Med Hyg. 2015 Jun;92(6 Suppl):75-86

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No falsified, but concerns about substandard medicines
Cambodia
Am J Trop Med Hyg. 2015 Jun;92(6 Suppl):39-50

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Falsified medicines found, but focus stil on substandards
Nigeria
PLoS One. 2015 May 27;10(5):e0125577

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Confirmed concerns about substandard medicines
Nigeria

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Large sample sizes in a wide range of geographic settings
- Between 3 laboratory findings and 2 different detection methods.
- Results inform understanding of the reliability of stated APIs,
unexpected (toxic) compounds and risk factors
Overall reassuring results, but “no room for complacency”
- Results from Nigeria and Bioko Island show falsified
- Substandard drugs are prevalent in all countries (up to 1 in 3 samples)
- Monotherapy tablets still available
Data highlights the need for continuous drug quality monitoring by NRAs
- ACTcDQ provides insights into the performance of different sampling
approaches and sample analysis methods.
Summary of Findings

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- HPLC - Dissolution Testing - LCMS
Laboratory Techniques available at LSHTM
Field Colorimetric Screening Tests
Testing the net
Test 1 Test 2
ACA tests
AS AQ/ASBL AQ
DNP
FBS

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Share our experience and methods
Collaborate with national authorities
Ensure better monitoring
Need to analyse samples from more countries!
Next steps?

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ACKNOWLEDGEMENTS
• Enugu State Ministry of Health, Nigeria
• Ifakara Health Institute, Dar es Salaam, Tanzania
• Cambodia National Malaria Centre, Cambodia
• Ministry of Health and Social Welfare Malabo, Equatorial Guinea (through
Medical Care Development International Bioko Island Malaria Control Project)
• Rwanda Ministry of Health Malaria Unit, Rwanda
• Kintampo Health Research Centre, Ghana
Teams on the ground purchasing and transporting the samples to LSHTM
Work presented has been supported by the Gates Malaria Partnership and ACT
Consortium, who received funding through grants from the Bill and Melinda Gates
Foundation to the London School of Hygiene and Tropical Medicine
Answering key questions on malaria drug delivery

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More information
Project summary, publications, video & evidence brief in English, Portuguese and French:
www.actconsortium.org/drugquality