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Quality of procured medicines

What may go wrong Jitka Sabartova, Deus Mubangizi

WHO Prequalification of Medicines Programme

Copenhagen, Denmark, 23-25 September 2013

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PQP monitors medicines after prequalification

• Variations to the dossier of prequalified product • Re-inspections (risk based planning, approx. 2 years) • Re-qualification (5 years) • Management of complaints • Sampling and testing projects • De-listing or suspension (if and when appropriate)

Copenhagen, Denmark, 23-25.9.2013

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Independent quality control by procurers (1)

• Guarantee that the procured product – Complies with specifications approved during prequalification – Has been manufactured in the approved site

• Considerations on necessity/frequency of testing – Based on defined QA policy and risk assessment

• Selection of a reliable laboratory – WHO-prequalified – ISO 17025 accredited

• Not always guarantees appropriate testing of medicines, e.g. investigation of out-of-specification result, appropriate qualification of equipment

Copenhagen, Denmark, 23-25.9.2013

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Prequalified/interested QCLs (September 2013) Prequalified QCLs:

• South Africa, RIIP+CENQAM (2005) • Algeria, LNCPP (2005) • South Africa, Adcock Ingram (2007) • Morocco, LNCM (2008) • Kenya, NQCL (2008) • India, Vimta Labs (2008) • France, CHMP (2008) • Vietnam, NIDQC (2008) • Kenya, MEDS (2009) • Singapore, TÜV (2009) • Canada, K.A.B.S. Laboratories (2010) • Ukraine, CLQCM (2010) • Ukraine, LPA (2010) • Peru, CNCC (2010) • Uruguay, CCCM (2010) • Bolivia CONCAMYT (2010) • Tanzania, TFDA (2011) • India, SGS (2011) • Belgium, SGS (2011) • Netherlands, Proxy (2011) • Portugal, INFARMED (2011) • Brazil, FUNED (2011) • Russia, FSBI-SCEEMP (2012) • Belarus, RCAL (2012) • Thailand, BDN (2012) • NIFDC, China (2012) • Laboratorios Basi, Portugal (2013)

Copenhagen, Denmark, 23-25.9.2013

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QCLs in the procedure (September 2013)

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Inspections / Pre-audits performed within QCL prequalification procedure

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Independent quality control by procurers (2)

• Selection of specifications and methods to be used for testing – Manufacturer's specifications and methods

• Procurer should ensure the availability • Laboratory should perform method transfer • Shelf-life specifications to be used

– Pharmacopoeia monograph • Laboratory should perform appropriate verification

• Specifications and methods should be agreed with the supplier in advance – Will avoid problems when non-compliant results are found

Copenhagen, Denmark, 23-25.9.2013

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Independent quality control by procurers (3)

• When a non-compliant result is found – Laboratory should investigate and exclude any error

– Manufacturer should be contacted

– WHO PQP should be informed

• Email: prequalinspection@who.int • Complaint procedure is initiated by inspectors • Possible inspection and/or testing in an independent

laboratory

Copenhagen, Denmark, 23-25.9.2013

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Procurers may endanger quality

• Pushing price too low – Quality has its price

• Number of rush orders results in – Smaller batches, poor production planning, higher cost

of materials (especially APIs), and increased cost of shipping (air freight instead of sea freight)

• Changing requirements – E.g. labelling

Copenhagen, Denmark, 23-25.9.2013

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WHO-Prequalification Programme Quality Monitoring Projects

• Objectives – Monitor quality of medicines procured by UN agencies/

prequalified products – Contribute to quality control of medicines – Contribute to capacity building by cooperation with MRAs

(strengthening of health systems)

• Sampling and testing projects – a tool • Importance of reliability of quality control laboratories

used – Prequalified laboratories, if available – If not, laboratories for which the evidence of reliability is

available

Copenhagen, Denmark, 23-25.9.2013

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Principles • Focus on HIV/AIDS, malaria, TB medicines • Pre-established protocol with defined study objectives • Selection of medicines and sampling sites based on risk

analysis • Cooperation with NMRAs in countries

– Discussion of protocol, preparation of national sampling plans, collection of samples

• Specifications and methods from major pharmacopoeias (Ph.Int., USP, BP)

• In case of non-compliant results, the respective NMRAs and manufacturers informed without delay

• Results discussed with MRAs before publication • Publication of detailed report

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Copenhagen, Denmark, 23-25.9.2013

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Quality survey of antiretrovirals in Africa (2007)

• Cooperation with NDRAs in Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia

• Monocomponent products (didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine), FDCs (lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine)

• 394 samples collected in official procurement and treatment centres, both private and public and tested according Ph.Int., USP, IP and in-house laboratory methods

• 7 samples of 394 failed • No critical deficiencies • 53% PQed products • 3 of 7 failing were PQed products 98.2%

1.8% Total failure = 1.8%

Compliant

Non-compliant

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Quality survey of antimalarials in Africa (2011) • Cooperation with NDRAs in Cameroon, Ethiopia, Ghana,

Kenya, Nigeria, Tanzania • ACTs and sulfadoxine-pyrimethamine • 935 samples collected at all distribution levels including

informal market and screened by Minilab • 306 tested in laboratory according to Ph.Int., USP or laboratory method

• Failure for PQed products 4% • Failure for non PQed products 40%

Total failure = 28.5%

71.5%

16.9%

11.6% Compliant

Non-extremedeviationsExtremedeviations

32

44

0 0

27

56

8

0

63 67

0

17

0

10

20

30

40

50

60

70

Failu

re ra

te (%

)

CameroonEthiopia

GhanaKenya

Nigeria

Tanzania

ACTs SPs

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Quality survey of anti-TB medicines in NIS (2011)

• Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan

• Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin • 291 samples collected at hospitals, dispensaries, pharmacies and

tested according to Ph.Int. or USP

None of 38 samples of WHO-prequalified products failed

Total failure = 11.3%

88.7%

10.3%

1.0%Compliant

Non-extremedeviationsExtremedeviations

10 107

23

4

13

0

5

10

15

20

25

Failure rate (%)

Armenia

Azerbai

jan

Belarus

Kazakhs

tan

Ukraine

Uzbekis

tan

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Survey of the quality of antimalarials supplied within AMFm project

• Affordable Medicines Facility – malaria – Innovative financing mechanism to expand access to ACTs managed

by GFATM (www.theglobalfund.org/en/activities/amfm)

• In 2012 two articles questioned quality of PQed products supplied within AMFm – Artemisinin component allegedly below 75%

• Complaint procedures initiated by PQP inspectors with manufacturers – No non-compliance found

• 3 out of 12 suspect batches independently sampled and tested before shipment within GFATM QA policy and found compliant

Copenhagen, Denmark, 23-25.9.2013

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Survey of the quality of antimalarials supplied within AMFm (2)

• To verify quality of AMFm medicines sampling & testing project organized – Sampling

• In Ghana, Nigeria, Uganda, in cooperation with NMRAs • At points where delivered by manufacturers and at pharmacies

– Testing • According to manufacturers' methods and specifications approved in

prequalification, Ph.Int. monograph for artemether/lumefantrine tablets • 54 samples produced by 6 manufacturers collected in countries

– 4 samples with the content of artemisinin component below 90% (the lowest 86.4%) – Investigation with manufacturers on-going

• 4 samples obtained from R.Bate (2 remaining tablets per sample) – 87.4 – 95.3% of artesunate, tested 3-4 months after expiry

• 1 retention sample of an allegedly substandard batch collected at a manufacturer – 97.4% of artesunate, tested 3 months after expiry

Copenhagen, Denmark, 23-25.9.2013

SUBSTANDARD, SPURIOUS, FALSELY LABELLED, FALSIFIED AND COUNTERFEIT

(SSFFC) MEDICAL PRODUCTS

Global Surveillance and Monitoring Project

Michael Deats, SFFC Project Manager

deatsm@who.int

Copenhagen, Denmark, 23-25.9.2013

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PROJECT OBJECTIVES

Scale • Quantity • Value

Scope • Medicines • Vaccines • Diagnostics

Extent • Geographic

coverage

Harm • Public

Health

Improve the quantity and quality of data concerning SSFFC medical products

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1. METHODOLOGY - RAPID ALERT FORM

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2. METHODOLOGY - DATABASE

Incident

Classification

Health Analysis and Impact

Dissemination and exchange

Risk Assessment

Suspect Product

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Cambodia Croatia Georgia Indonesia Kyrgyzstan

Malaysia Philippines Russia Ukraine Vietnam

3. METHODOLOGY - PILOT STUDY

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4. METHODOLOGY - PROGRAM DEPLOYMENT

Planned Workshops 2013

Current Participants

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Outcomes Significantly improve our knowledge • Which medical products, therapeutic categories and dosage forms • Which Regions / Sub regions / Freight routes • Scientifically tested methods to identify harm caused

Enable evidence based policy making • Incentivise reporting • Build capacity for Countries and sub regions most negatively

affected • Establish the root causes and shape policy to prevent SSFFC

Protect Public Health • Increase vigilance in countries and global 'pinch points' • Focused market surveillance • Increased and improved screening and laboratory analysis • Timely and wide publication of International Drug Alerts

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High Level Statistics

• 76 Incidents

• 143 Different Batches of medical products

• 98 Different Medical Products

• 65 Active Pharmaceutical Ingredients

• Reported from 27 Member States

• 11 Incidents involved serious adverse reactions

• 7 Cases involved fatalities

• 4 WHO Drug Alerts

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Published information - Drug Alerts www.who.int/medicines/publications/drugalerts

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Copenhagen, Denmark, 23-25.9.2013

Falsified batches of Postinor 2 in African countries

• No active ingredient

• 150 000 doses discovered by NAFDAC at Lagos airport

• Cooperation with the manufacturer

• Falsified batches found also in 2011/12 in Ghana, Kenya, Angola

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Copenhagen, Denmark, 23-25.9.2013

Falsified batches of Coartem in Western and Central Africa

• No active ingredient

• Discovered by a pharmacist in Cameroon

• Cooperation with the manufacturer and NMRAs

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Contaminated Dextromethorphan API

• Dextromethorphan cough syrup killing 60 people in Pakistan

• All death cases seemed to be linked to drug addiction

• Medicine contained also high percentage of levomethorphan (potent opiate)

• API manufacturing quality failure

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Contaminated Isotab

• More than 107 deaths and 450 severe ADRs with isosorbide mononitrate manufactured in Pakistan

• Clinically resembled Dengue fever

• Passed quality control testing

• Forensic investigation revealed pyrimethamine in toxic quantities

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Thanks for your attention

sabartovaj@who.int mubangizid@who.int www.who.int/prequal

Copenhagen, Denmark, 23-25.9.2013