Quality Problems with Antimalarials Dr Mary R. Couper Quality Assurance and Safety: Medicines World Health Organization

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

Identifying quality problem Seven-country study: antimalarial quality differs among countries - content and dissolution problems Samples were judged to have “failed” if content was <93% or >107%, and dissolution <80% in 45 minutes. Samples were judged to have “failed” if content was <90% or >110%, and dissolution <65% in 30 minutes.

Quality problems Many African countries medicines are sold in open market places and by street vendors Many medicines are smuggled or imported illegally Most domestic manufacturers do not meet Good Manufacturing Practices Storage and distribution conditions are inappropriate Corruption is a serious problem

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

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)

Artemisinin derivatives available artesunate (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)

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.

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

Not Typical “generic” drugs Usually generic drugs “well established” … Artemisinin combinations are relatively new, or very new drugs Limited information available in public domain For 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 ...

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

Current Status 20 Product dossiers assessed 2 Manufacturers have been inspected No 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

How WHO can help Issue guidelines and information Provide training seminars - 3 planned for 2003 New 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

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

Counterfeit database 2002 Reports from 46 countries of which 3 are African countries: Zambia - chloroquine phosphate Gabon - chloroquine and quinine Tanzania - quinine

Examples of Counterfeit

Challenge Quality of products can only be achieved by building reliable and effective national regulatory authority