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Quality Problems with Antimalarials
Dr Mary R. CouperQuality Assurance and Safety: Medicines
World Health Organization
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Quality of Medicines
Good quality medicines are essential to promote public health - in some African countries 30-50% of samples tested are of poor quality 429 samples from Cameroon, Madagascar, Chad
tested - 18% failed, 16 were counterfeit 175 samples from Tanzania tested - 17% failed 581 samples from Nigeria tested - 48% failed 788 samples tested in Zimbabwe - 17% failed
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Seven-country study: antimalarial quality differs among countries - content and dissolution problems
020406080
100
Chloroquine tablets- % failure*
Content DissolutionSamples were judged to have “failed” if content was <93% or >107%, and dissolution <80% in 45 minutes.
020406080
100
Sulfadoxine/pyrimethamine - % failure*
Content DissolutionSamples were judged to have “failed” if content was <90% or >110%, and dissolution <65% in 30 minutes.
Identifying quality problem
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Quality problems Many African countries medicines are sold in
open market places and by street vendorsMany medicines are smuggled or imported
illegallyMost domestic manufacturers do not meet
Good Manufacturing PracticesStorage and distribution conditions are
inappropriateCorruption is a serious problem
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About 50% of the countries in sub-Saharan Africa have very limited/no capacity to control the market-where regulatory authorities exist enforcement is weak
48.0% 42.0%
10%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
V. limited capacity Basic capacity Moderate capacity
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Antimalarial Drugs on WHO’s Essential Drug List
artemether + lumefantrine (core)chloroquine (core)primaquine (core)quinine (core) doxycycline (comp.)sulfamethoxazole+pyrimethamine (comp.)artemether (restrict)artesunate (restrict)
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Artemisinin derivatives availableartesunate (oral)arteminol (dihydroartemisinin) (oral and rectal)artemether (oral and i.m.)artemether+lumefantrine (oral)artesunate (i.v. and i.m.)artemotil (i.v and i.m.)artesunate + mefloquine (oral)artesunate + amodiaquine (oral) artesunate + sulfadoxine/pyrimethamine (oral)
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Quality concerns
Partners in Roll Back Malaria, such as WHO, UNICEF, and UNDP, and many other UN organizations are involved in the procurement of antimalarial drugs.
The supply of antimalarial products that are effective and of acceptable quality has become a major concern at both international and country level.
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Prequalification scheme
Why was the launch considered? Countries and other interested parties asking
WHO to initiate pre-qualification of essential drugs referring to positive experience of vaccines pre-qualification
Increasing pressures to increase access to artemisinin derivatives owing to resistance
… but artemisinin combinations are not typical “generic” drugs
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Not Typical “generic” drugsUsually generic drugs “well established” …
Artemisinin combinations are relatively new, or very new drugs
Limited information available in public domainFor most artemisinin products reference standards not
readily available and for combinations no “originator” product exists
Difficulties of proving “interchangeability”Regulators have limited experience with this group of
drugs ...
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Activities of Prequalification Scheme
Assessment of dossiers: teams of professionals from national drug regulatory authorities:: Including Canada, Denmark, Estonia, Finland, France, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden and Zimbabwe
Manufacturing site inspections: teamwork of inspectors: WHO representative (qualified GMP inspector), inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries) and inspector(s) from national drug Regulatory authorities
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Current Status20 Product dossiers assessed2 Manufacturers have been inspectedNo dossier meets WHO standards yet
Incomplete data include lack of safety and efficacy data, lack of specifications for starting materials, information on method of manufacture of the product, lack of process validation, incomplete stability data.
Assessment is ongoing
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How WHO can helpIssue guidelines and informationProvide training seminars - 3 planned for
2003New monographs for all artemisinin based
products recently published in International Pharmacopoeia
http://www.who.int/medicines/library/pharmacopoeia/pharmacop-content.shtml
Provide Basic Tests for confirmation of identity of active ingredient
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Counterfeit
40% of artemisinin-based antimalarials on the market are counterfeit Nigeria reported 50% of the medicines on
the market are counterfeit Some other African countries show that
about 19% of products are counterfeit
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Counterfeit database 2002
Reports from 46 countries of which 3 are African countries: Zambia - chloroquine phosphate Gabon - chloroquine and quinine Tanzania - quinine
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Examples of Counterfeit
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Challenge
Quality of products can only be achieved by building reliable and effective national regulatory authority