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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)
Copenhagen, Denmark, 23-25.9.2013
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Inspections / Pre-audits performed within QCL prequalification procedure
Copenhagen, Denmark, 23-25.9.2013
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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: [email protected] • 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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
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
Copenhagen, Denmark, 23-25.9.2013
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1. METHODOLOGY - RAPID ALERT FORM
Copenhagen, Denmark, 23-25.9.2013
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2. METHODOLOGY - DATABASE
Incident
Classification
Health Analysis and Impact
Dissemination and exchange
Risk Assessment
Suspect Product
Copenhagen, Denmark, 23-25.9.2013
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Cambodia Croatia Georgia Indonesia Kyrgyzstan
Malaysia Philippines Russia Ukraine Vietnam
3. METHODOLOGY - PILOT STUDY
Copenhagen, Denmark, 23-25.9.2013
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4. METHODOLOGY - PROGRAM DEPLOYMENT
Planned Workshops 2013
Current Participants
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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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
Copenhagen, Denmark, 23-25.9.2013
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Thanks for your attention
[email protected] [email protected] www.who.int/prequal
Copenhagen, Denmark, 23-25.9.2013