Quality Problems with Antimalarials

Dr Mary R. CouperQuality 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

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

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

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

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 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)

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” 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 ...

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 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

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

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