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 AboundHealth 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

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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 sampleLSHTM 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 validation

Samples sent for mass analysis

Results sent

Results sent

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˚C0 - 21 days

Degradation studies

LC/MS

0.00 1.00 2.00 3.00 4.00 5.00 6.00-20

25

50

75

120mAU

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 yearACTs 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 AcceptableQuality 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 brownSoft 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 LimitedIndia AM/LUM 43 97.7 % 0 2.3 %

Amatem Tab® 20/120

Micro Labs LimitedIndia AM/LUM 31 71.0 % 12.9 % 16.1 %

Arcofan 20/120

Naxpar Lab Pvt LtdIndia AM/LUM 15 0 0 100.0 %

Artemetrin® 80/480

A.C. Drugs LtdNigeria AM/LUM 5 20.0 % 0 80.0 %

Artrin® Medreich LimitedIndia AM/LUM 15 73.3 % 0 26.7 %

Ogamal QSVapi Care Pharma Pvt

LtdIndia

AM/LUM 35 91.4 % 2.9 % 5.7 %

MaltarkaVapi Care Pharma Pvt

LtdIndia

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 - 5.2Artemisinin - 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

120mAU

min

Artemether – 3.8

Lumefantrine – 4.6

Detection of APIs - Content analysisHPLC 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

2.05x10

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

5x10Intens.

175 200 225 250 275 300 325 350 375 m/z

DART-MS/MSFragmentation 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

2.55x10

Intens.

175 200 225 250 275 300 325 350 375 m/z

[Ciprofloxacin + H]+ instead of artemetherDART-MS

Nigeria Falsified samples; DART-MS at GT

Ciprofloxacin NIST MS/MS

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Stated brand Stated country of manufacture

Stated manufacturer

StatedAPI 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 NigeriaDHA/PIP formulation locally manufactured

AM/LUM formulations

No S-APIs detected

Yes S-APIs detected

No S-APIs detected

Yes S-APIs detected

Pkt has 1 extra marking

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ACTc DQ: Sampling methods used

COUNTRYMethod of sampling

OUTLETSMethod 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 FoundGhana - 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 FoundNigeria - Enugu Metropolis (2013) 3024 131 92.2% 6.6% 1.2% FoundBioko 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 countryOf 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 testsAS 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 informationProject summary, publications, video & evidence brief in English, Portuguese and French:

www.actconsortium.org/drugquality