REPUBLIC OF KENYA

MINISTRY OF HEALTH

Pharmacy & Poisons Board and Division of Malaria Control

Antimalarial Medicines in KenyaAvailability, Quality and Registration Status

A Baseline Study Undertaken Prior to Nationwide Distribution of Artemether-Lumefantine (AL) in Kenya

December 2007

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ACKNOWLEDGEMENTS ………………………………………………………….....4

Abbreviations and Acronyms………..……………………………………………………………..…...5.Foreword ………………………………………………………………………………………………..….6

Executive Summary …………………………………………………………………………………..…..7

1 INTRODUCTION AND BACKGROUND……………………………………....10

1.1 Malaria in Kenya…………………………………………………………………………….….10

1.2 Substandard and Counterfeit Medicines …………………………………………………..11

1.3 Drug Regulation in Kenya ……………………………………………………………….…...12

1.4 Study Justification ……………………………………………………………………….……13

1.5 Study Coordination and Technical Support……………………………………………..…14

1.6 Aim………………………………………………………………………………………………..14

1.7 Objectives ………………………………………………………………………………………14

2 METHODOLOGY …………………………………………………………….…15

2.1 Study Scope and Duration …………………………………………………………….……..15

2.2 Sampling ……………………………………………………………………………………......15 2.2.1 Facilities Surveyed ………………………………………………………………………….15 2.2.2 Medicines Surveyed …………………………………………………………………….… .16 2.2.3 Batch Sampling for Laboratory Testing ………………………………………………..…..16

2.3 Data Collection and Processing ……………………………………………………………..17 2.3.1 Data Collectors …………………………………………………………………………….....17 2.3.2 Data Collection ……………………………………………………………………………. …17 2.3.3 Data Verification and Analysis …………………………………………………………..…...17 2.3.4 Laboratory Analysis …………………………………………………………………………..18

3 RESULTS AND DISCUSSION …………………………………………….…...19

3.1 Availability of Antimalarial Medicines ……………………………………………………....19 3.1.1 Overall Range of Medicines …………………………………………………………….…..19 3.1.2 Range of Medicines in Provinces and Sectors ………………………………………….....19 3.1.2.1 Range of Medicines in Each Sector ………………………………………………......19 3.1.2.2 Range of Medicines in Each Province ……………………………………………......20 3.1.3 Range of Products Available ……………………………………………………………......21 3.1.3.1 Brands Available per Product ………………………………………………………....21 3.1.3.2 Products Available in all Sectors in all Provinces …………………………………....21 3.1.4 Origin of the Medicines ……………………………………………………………………...22 3.1.5 Artemisinin Combination- and Mono-therapy Medicines ………………………………...22 3.1.6 Availability of First-Line Treatment ………………………………………………………....23

3.2 Registration Status of Medicines …………………………………………………………....23

3.3 Quality Control ………………………………………………………………………………....24

TABLE OF CONTENTS

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3.3.1 Range of Samples Tested …………………………………………………………........….24 3.3.2 Quality Control Results ……………………………………………………………………..25 3.3.2.1 Results from National Quality Control Laboratory ……………………………….….25 3.3.2.2 Results from CENQAM ……………………………………………………………….26 3.3.2.3 Comparison of Results from NQCL and CENQAM ………………………………....26

3 SUMMARY OF RESULTS …………………………………………………....27

4 CONCLUSIONS ………………………………………………………………28

5 LESSONS LEARNT ………………………………………………………….29

6 RECOMMENDATIONS ………………………………………………………30

GLOSSARY …………………………………………………………………………...32

REFERENCES ………………………………………………………………………..33

ANNEXES ……………………………………………………………………………..35Annex 1: Data Collection Form ………………………………………………………………...35Annex 2: List of Pre-selected Medicines for Laboratory Analysis…………………………....36Annex 3: Drugs Analyzed at the National Quality Control Laboratory ……………………....37Annex 4: Drugs Analyzed at CENQAM ………………………………………………………..38Annex 5: Availability of Medicines in Each Sector …………………………………………....39Annex 6: Availability of Medicines in each Province ………………………………………... .40

ACKNOWLEDGEMENTS

This survey was undertaken through a collaborative project on access to essential medicines of the Ministry of Health, in collaboration with the World Health Organization and Health Action International-Africa, and with additional technical support from Management Sciences for Health (MSH). Financial support came from the UK Department for International Development (DfID) through the WHO Country Office - Kenya, and WHO facilitated the unique collaborative approach and coordinated the necessary technical support for the study. We duly acknowledge and appreciate the DfID funding and the technical support of all the partners; the National Quality Control Laboratory (NQCL) in Kenya and the Center for Quality Assurance of Medicines (CENQAM) in South Africa, where the samples were tested.

Special thanks are due to the following important contributors:

Advisory Group

Dr. Fred Moin Siyoi Chief Pharmacist, Ministry of Health; Registrar, Pharmacy and Poisons Board

Dr. Dorothy Memusi Division of Malaria Control, Ministry of Health

Dr. Steven Kimatu Head of Drug Information, Pharmacy and Poisons Board

Mr. George Muthuri Pharmacy and Poisons Board

Dr Abdinasir Amin Management Sciences for Health - Kenya

Ms Christa Cepuch Collaborations Manager, Health Action International – Africa

Dr. Regina Mbindyo National Professional Officer, Essential Drugs & Medicines Policy, WHO – Kenya

Ms Joanne Greenfield Malaria Advisor, WHO – Kenya

Dr. Augustine Ngindu National Professional Officer, Malaria, WHO – Kenya

Survey ConsultantProf Grace Thoithi Ag Dean, School of Pharmacy, University of Nairobi

Survey CoordinatorsDr. Jayesh Pandit Head of Pharmacovigilance, Pharmacy and Poisons BoardDr. Andrew Nyandingisi Pharmacist, Division of Malaria Control, Ministry of Health

Field Data CollectorsAli S. Kidzuga William Karema Omar Farah IbrahimAbdulahi M. Matan Ibrahim O. Mokaya Wilson Onduso

Peter N. Maina Andrew M. Kairu Grace K. Komen James K. Thuo Rose M. Kiunga Joseph M. Mutungi

Henry O. Lavisa Dr. Hadley Sultani Gideon K. Too Solomon K. Koech

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Abbreviations and Acronyms

ACT Artemisinin Combination TherapyAQ AmodiaquineAL Artemether-LumefantrineAM Antimalarial MedicineARV Anti Retro-Viral medicineASmP Artesunate-Sulphamethoxypyrazine-PyrimethamineB.P. British PharmacopoeiaCENQAM Center for Quality Assurance of MedicinesCQ ChloroquineDC Data CollectorDOMC Division of Malaria ControlHAI Health Action InternationalHPLC High Performance Liquid ChromatographyIM IntramuscularINN International Non-proprietary NameIPT Intermittent Preventive TherapyIV IntravenousKEMSA Kenya Medical Supplies AgencyMEDS Mission for Essential Drugs and SuppliesMOH Ministry of HealthNAT Non-Aqueous TitrationNQCL National Quality Control LaboratoryPh. Int. International PharmacopoeiaPPB Pharmacy and Poisons BoardWHO World Health OrganizationSP Sulphadoxine-PyrimethamineSmP Sulphamethoxypyrazine-PyrimethamineTB TuberculosisU.S.P. United States PharmacopoeiaUV Ultraviolet (spectrophotometry)

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Foreword

Access to quality, effective treatment is the cornerstone of any public health programme,

and it requires an effective regulatory system for medicines. Kenya's National Malaria

Strategy (2001-2010) identifies malaria control as a developmental issue, and highlights

drug regulation as an integral part of effective malaria case-management. The strategy

focuses on implementing interventions that are evidence-based, coordinated and totally

integrated, based on inclusive partnership between the MOH, other stakeholders and

development partners.

Kenya's malaria control efforts have recently begun to demonstrate positive results in

reducing morbidity and mortality. The use of effective drugs for malaria treatment, available

free of charge from public and mission health facilities, has contributed to this positive

result. This trend needs to be further supported by ensuring that only recommended

treatments for malaria are available and in use in Kenya, in line with global and national

treatment guidelines. The continued use of ineffective medicines undermines disease

control efforts, jeopardizes patients' health and wastes valuable resources. The medicines

regulatory authority plays a vital role of ensuring the quality, safety and efficacy of all

medicines in the market.

This anti-malarial survey, undertaken jointly by the Pharmacy & Poisons Board and the

Division of Malaria Control, is a bold step to create more direct linkages between medicines

regulation and treatment guidelines implementation. The findings should guide the PPB to

root out substandard anti-malarial medicines, and those that do not conform to regulatory

and treatment policy requirements. Further, the lessons learnt should guide an integrated

approach that addresses the wide range of pharmaceutical issues in disease control

interventions, including establishing regular medicines quality surveillance.

The multi-stakeholder approach of the study has drawn on technical expertise and

resources from government and partners, in line with the National Health Sector Strategic

Plan II and the sector-wide approach. Strategic areas for investment and support by

government and health sector partners are identified. It is anticipated that the collaborative

approach will continue in tackling the recommendations and the broader issues that the

study highlights.

Dr Fred Siyoi Dr Willis AkhwaleRegistrar, Pharmacy & Poisons Board Head, Division of Malaria Control

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Executive Summary

Background: To provide regulatory support to the malaria treatment policy in Kenya, a

baseline study of antimalarial medicines was undertaken in May 2006, immediately

following introduction of the new malaria treatment guidelines, and prior to nationwide

distribution and deployment of artemisinin combination therapies in the country. The

survey aimed to provide baseline information to guide implementation of the MOH malaria

treatment policy and to identify strategic issues for strengthening the national medicines

regulatory system. The results and recommendations would guide the MOH, health sector

development and implementing partners in making appropriate inputs and policy

interventions to ensure availability of safe, efficacious and quality medicines in the country.

Method: Data on availability of antimalarial medicines was collected from 200 facilities

nationwide, covering public, mission, private and general retail (informal) outlets, using a

survey methodology adapted from WHO and HAI. Registration status of the medicines

was verified by the Pharmacy and Poisons Board (PPB). Selected medicines were

sampled and their quality tested at the National Quality Control Laboratory (NQCL) and

some at the Center for Quality Assurance of Medicines (CENQAM), a WHO pre-qualified

laboratory.

Results

Availability: Forty unique formulations of antimalarial medicines were found in the market,

and of these, only 11 formulations (27.5%) are in the revised national malaria treatment

guidelines. A total of 187 antimalarial products were found, comprising innovator brands,

branded and non-branded generics. Sulphadoxine-pyrimethamine (SP) tablets had the

highest number of products (31); other commonly available medicines were amodiaquine,

artemether, artesunate, dihydroartemisinin and quinine. Artemether-lumefantrine (AL),

the first-line treatment for uncomplicated malaria and quinine, first-line treatment for

severe malaria were available in all the formal sectors in all provinces. Six oral artemisinin

mono-therapy formulations were found. The antimalarial medicines found in the country

were manufactured in 20 different countries by 113 manufacturers. Fourteen of these

manufacturers were from Kenya, and they accounted for 48.3% of the samples

encountered in the market.

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Registration Status: Of the products found in the market, 42.6% of them were registered

by the Pharmacy and Poisons Board, 42.2% were not registered and the registration status

of 15.2 % of the products could not be established. Of the unregistered products found in

the market, the majority were from Kenya and India.

Quality Control: Overall, 7 of the 43 batches tested at either of the two laboratories failed

analysis, a failure rate of 16%. The drugs that failed were amodiaquine tablets, quinine

mixture and tablets, artemether injection and sulphadoxine-pyrimethamine (SP) tablets.

Conclusions

1. A wide range of antimalarial medicines are available in the market, and the majority of

them are not in current national malaria treatment guidelines.

2. A high proportion of the antimalarial medicines were un-registered, with the majority of

un-registered products originating from Kenya and India.

3. Some medicines found in the market did not meet quality standards. Of particular

concern in relation to the guidelines, are SP, artemether injection and quinine tablets.

Key Lessons Learnt

1. Government leadership is crucial to systematically address medicines quality and

safety.

2. There are gaps and challenges in enforcing medicines regulation in Kenya. Capacity

building in this area is an ongoing process that requires coordinated partner support

3. Medicines regulation and disease control strategies are interdependent and require

a systematic and collaborative approach. Disease control programmes and the PPB

can work together, to positively influence and mutually support public health.

4. There is a lack of strategic engagement on medicines regulation at the wider health

sector level, and a lack of awareness of the role and work of the medicines regulator

(PPB).

5. The capacity of the WHO pre-qualified laboratory in South Africa is overstretched, and

there is need to enhance national capacity for medicines quality control.

6. Access to prompt and effective treatment is a pillar of the National Malaria Strategy, and

this cannot happen without an effective medicines regulatory authority. This applies to

all key public health programmes.

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Key Recommendations

1. PPB should enforce the withdrawal from the market of all non-recommended and

sub-standard malaria medicines, and enforce compliance with set pharmaceutical

regulations.

2. Computerize fully data management for medicines registration; information on

registration status of products should be readily accessible to the public.

3. Establish a post-market surveillance system to curb sub-standard and unregistered

products in the market.

4. Local QC laboratory capacity should be enhanced, including all necessary support

towards WHO pre-qualification.

5. Medicines regulation should link to the broader health sector planning and M&E, to

guide coordinated support to this important health sector function.

6. Consumers should participate actively in medicines regulatory issues, including

reporting of suspected sub-standard or counterfeit medicines to the PPB.

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1 INTRODUCTION AND BACKGROUND

1.1 Malaria in Kenya

Malaria is a leading cause of morbidity and mortality in Kenya, mostly affecting the rural

poor, especially young children and pregnant women. It accounts for 30% of outpatient

attendance and 19% of admissions to health facilities. Malaria is the most important cause

of death in children under 5 years of age and is estimated to cause 20% of all deaths in this

age group. In spite of this situation, malaria is a preventable and curable disease.

Evidence shows that malaria can almost always be successfully managed with positive

outcomes when safe and effective medicines are readily accessible to, and used rationally

by the population. Ensuring all of this is challenging, especially in countries experiencing

the trend of increasing resistance to many traditional first-line therapies. Kenya is no

exception, a country where resistance to chloroquine (CQ) is above 60%, to sulfadoxine-

pyrimethamine (SP) around 23% and to amodiaquine almost 8%.

The Ministry of Health (MOH) has prioritized malaria as one of the diseases for control and

has developed the National Malaria Strategy (2001-2010) and the National Health Sector

Strategic Plan II (2005-2010). The Strategy outlines interventions aimed at reducing the

morbidity and mortality associated with malaria. A key component is a change in the malaria

treatment guidelines, adopting Artemisin-based combination therapies (ACTs) as first-line

treatment for uncomplicated malaria. Artemether-lumefantrine (AL) is the ACT selected for

public procurement and distribution to government and mission facilities. To facilitate

implementation of the Strategy, the Division of Malaria Control (DOMC) developed detailed 1guidelines for malaria case management. These guidelines are summarized in Table 1.

Prior to these guidelines, artemether-lumefantrine (AL) had only been used in Kenya to a

small extent in the private and mission sectors, as it had not yet been made widely available

in the public and mission sectors, where the majority of Kenyans access treatment for

malaria. The MOH has only recently introduced this new medicine into the public and

mission sectors through financing from the Global Fund. The product is being procured

through a special arrangement between the manufacturer (Novartis), and World Health

Organization (WHO), providing it at cost to countries that have adopted AL as first-line

treatment for malaria. The product being procured for Kenya is pre-qualified by the WHO,

and is therefore expected to meet the minimum national standards of quality and efficacy.

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Introduction of this new treatment entails a fundamental change in the management of

malaria, and is expected to result in significant reduction in malaria morbidity and mortality

for all age groups, and particularly for children less than 5 years, the age group most

affected by malaria in Kenya.

Table 1: Treatment guidelines for malaria in Kenya (Summary)

IM: Intramuscular. IV: Intravenous.

1.2 Substandard and Counterfeit Medicines

According to the WHO definition the term 'substandard' is used to describe the quality

status of genuine drugs produced by legitimate manufacturers. A drug is considered

substandard, if, upon laboratory testing in accordance with the specifications it claims

to comply, it with fails to meet the specifications. A counterfeit medicine is defined by

WHO as “a medicine which is deliberately and fraudulently mislabeled with respect to

identity and/or source. Counterfeiting can apply to both branded and generic products

and counterfeit products may include products with the correct ingredients or with the

wrong ingredients, without active ingredients, with insufficient active ingredients or with 2fake packaging.”

Condition Medicine Strength FormulationUncomplicated malaria Artemether-Lumefantrine 20 mg/120 mg Tablets (Co-formulated, individual dose packs for specific weight categories)

Severe malaria Quinine dihydrochloride 600 mg/2ml Injection(IM/IV phase)

Severe malaria Quinine sulphate 200 mg or 300 mg Tablets(Continuation phase) or Quinine dihydrochloride 300 mgAll trimesters pregnancy or Quinine bisulphate 300 mgChildren below 5Kg or Quinine hydrochloride 300 mgIntermittent Preventive

Prophylaxis non-immune Mefloquine hydrochloride 250 mg Tabletsvisitors Atovaquone-Proguanil 250 mg/100 mg Tablets for adults

Atovaquone-Proguanil 62.5 mg/25 mg Tablets for children

Sulphadoxine- 500 mg/25 mg Tablets Therapy Pyrimethamine

Various studies and reports have been published on the quality and registration status

of medicines circulating in various world markets and the need to strengthen national

medicines regulatory systems, including post-market surveillance of quality and 3-9safety. In Kenya, quality studies done over the last three decades indicate failure

10-15rates vary with the type of medicine, the manufacturer and the country of origin. In

these studies, which involved analysis of hundreds of drugs over a period of years,

drug categories of greatest concern included antimalarials, antibiotics and anti-TB

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drugs, which consistently had failure rates of up to 30%. Electrolytes, skin preparations and vitamins/minerals all showed greater than 30% failure. Some individual drugs showed even higher failure than the category average. Amodiaquine and sulphadoxine-

16-18pyrimethamine (SP) have shown failure of up to 45% and 30%, respectively.

In Kenya, counterfeit drugs have been encountered in the market and some have been

detected during laboratory testing. These included antimalarials, antibiotics, antiretrovirals

and corticosteroid skin creams. The PPB has proceeded to take various measures,

including public alerts through media outlets, impounding the medicines and arresting the

perpetrators. Besides the studies on drug quality, there are other recent studies conducted 19-22in Kenya, to assess availability, cost and registration status of medicines. Findings have

indicated limited availability in some sectors, unregistered products in the market and

prices that are not affordable to the majority of the Kenyan population.

The majority of studies on quality of AMs in Kenya were undertaken by academia, and

focused mainly on the private sector and on a limited range of products. The studies

provided useful insights and made relevant recommendations on quality of products in the

market, but lacked linkages to regulatory follow-up and action on the findings. This is the

first study undertaken with the full participation of the regulator and MOH implementing

department, and covering the full range of products relevant to malaria control.

1.3 Drug Regulation in Kenya

The Pharmacy and Poisons Board is the drug regulatory authority of the Ministry of Health

Kenya, established in 1957 under the Pharmacy and Poisons Act, Chapter 244 of the laws

of Kenya. PPB has the mandate to regulate pharmaceutical services, ensure the quality,

safety and efficacy of human and veterinary medicines and medical devices, and advise

the Minister of Health on all aspects of medicines regulation, in order to safeguard the

health of Kenyans.

Within the PPB, the Department of Pharmacovigilance, set up in late 2004 is responsible for developing appropriate systems for detecting, reporting and monitoring adverse drug reactions within Kenya, as well as to develop and implement relevant tools and systems for post-market surveillance, to ensure that the quality and safety of medicines in Kenya meet the required standards. The scope of work for this department also encompasses other relevant issues such as medication errors, efficacy reporting, the use of medicines for indications that are not approved and for which there is inadequate scientific basis, case

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reports of acute and chronic poisoning, assessment of drug-related mortality, abuse and misuse of medicines, as well as adverse interactions of medicines with chemicals, other medicines and food. To achieve its objectives, the department links closely with the departments of medicines registration, pharmaceutical inspection, drug information and the National Quality Control Laboratory.

The National Quality Control Laboratory (NQCL) is the technical arm of the PPB

responsible for evaluating the quality of medicines and selected medical devices. The

NQCL carries out examination and testing of drugs and medical devices by use of

chemical, physical, pharmacological and other pharmaceutical evaluation. At the request

of the Board and on behalf of the Government, it tests locally manufactured and imported

drugs or medicinal substances with a view to determining whether such drugs or medicinal

substances comply with set standards. Whenever necessary, PPB utilizes the services of

a WHO-prequalified laboratory for analysis.

The NQCL is in the process of pursuing WHO pre-qualification, to enhance its capacity to

serve national and regional needs for medicines quality control.

1.4 Study Justification

Currently, therapeutic alternatives to artemisinin combination therapy (ACT) are limited

and thus it is crucial to safeguard the effectiveness of these medicines as much as

possible, through evaluating their safety and quality and ensuring their appropriate use.

To contribute to the overall evaluation and impact assessment of the new malaria

treatment guidelines, there was need to establish baseline information on the availability,

registration status and quality of the full range of antimalarial medicines (AMs) currently

being used in Kenya. This was a comprehensive baseline survey that covered all the major

health sectors and all geographical regions, rather than previous studies that covered

mostly the private retail sector and only selected districts or provinces.

The study was designed to provide a strategic linkage between national malaria control

and medicines regulation, and the findings will inform policy interventions to ensure that

the right AMs are in use in Kenya, and that they meet prescribed standards of quality and

safety. The lessons learnt will also strengthen the national medicines regulatory authority,

and ensure better alignment and responsiveness to disease control strategies.

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1.5 Study Coordination and Technical Support

The PPB undertook the survey, in collaboration with the Ministry of Health DOMC.

Technical support was provided by WHO and Health Action International (HAI)-Africa, in athe context of a global WHO/HAI joint collaborative project on access to medicines.

Funding for the study came from DFID (UK) through the WHO Country Office, and

additional technical support came from Management Sciences for Health (MSH). The PPB

established a 'Survey Advisory Group' comprising technical staff from the collaborating

departments and partners. This multi-stakeholder approach aimed to elucidate lessons for

the PPB in establishing comprehensive systems for the surveillance of medicines quality

and safety; and for DOMC towards better regulation of antimalarial medicines for the

success of the malaria control strategy. The survey also serves as a platform for the

engagement of other stakeholders interested in strengthening medicines regulation to

support disease control.

1.6 Aim

The aim of this survey was to establish baseline data on the current availability, registration

status and quality of antimalarial medicines in the public, mission and private health

sectors, as well as in the informal (general retail) sector in Kenya, prior to the introduction of

the new malaria treatment guidelines.

1.7 Objectives

The specific objectives of the survey were to:

1. Assess the range and availability of products for the treatment of malaria in the

three formal health sectors in Kenya (public, private and mission) as well as in the

general retail (informal) sector.

2. Determine the registration status in Kenya of each available antimalarial product.

3. Assess the quality of the available products through laboratory testing of a

representative sample.

4. Make appropriate recommendations, based on the findings, for improving

availability, quality and use of antimalarial medicines in Kenya.

a The goal of the WHO/HAI Collaborative Project is improved policies and practices to increase access to essential medicines

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2 METHODOLOGY

2.1 Study Scope and Duration

The study covered all antimalarial medicines in the market in all eight provinces in Kenya,

and data was collected from four defined sector outlets, namely public, mission, private

and general retail (informal) outlets. Public facilities were pharmacies in MOH provincial,

district or sub-district hospitals. Mission sector outlets were pharmacies in mission

hospitals and medicine outlets that are run by faith-based organizations. Private facilities

were privately-owned pharmaceutical retail outlets (chemists), while the general retail

facilities (informal sector) were supermarkets and small shops ('kiosks'). The field survey

was conducted in May 2006, and laboratory testing took place between December 2006

and September 2007.

2.2 Sampling

There were 3 aspects of sampling for this study, namely sampling of facilities and

medicines to be surveyed, and sampling of medicine products and specific batches for

laboratory testing.

2.2.1 Facilities Surveyed

The survey adopted a methodology developed by WHO and HAI, for measuring medicines 21availability and prices . A total of 192 facilities were sampled nationally, comprising six

facilities per sector in each of the eight provinces, thus totaling 48 facilities per sector or 24

facilities per province. For each province, the public provincial hospital was selected, as

well as five public district or sub-district hospitals. For each of these six public health

facilities, and within a 5-kilometer radius of the facility, one mission health facility, one

private health facility and one general store were selected. However, the actual number of

facilities visited was 200, due to situations encountered in the field, which led to fewer

facilities surveyed in three provinces; and more than 24 facilities visited in four provinces.

Table 2 gives the number of facilities visited for each sector in each province.

Table 2: Number of facilities surveyed in per sector per province

Province General Mission Private Public TotalCentral 6 7 8 7 28Coast 6 3 4 5 18Eastern 7 7 12 6 32Nairobi 7 7 7 7 28North Eastern 6 5 6 6 23Nyanza 4 4 6 6 20Rift Valley 6 6 7 8 27Western 6 6 6 6 24Total 48 45 56 51 200

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2.2.2 Medicines Surveyed

All antimalarial medicines found in the selected facilities on the day of data collection were

surveyed. Data was collected at each health facility using a standardized data collection

tool (Annex 1). The tool contained listed AMs presumed to be in the market (32

formulations), and allowed for any additional products to be included. A total of 40 unique

formulations were found in the market, and these were all included in the survey. Physical

samples were only obtained for a pre-selected list of eight (8) medicine formulations to be

subjected to laboratory analysis (see section 2.2.3).

2.2.3 Medicines for Laboratory Analysis

Whereas the data collection form captured relevant details for all antimalarial medicines

found in the facility, physical samples were not required for each medicine. Physical

samples for laboratory analysis were only obtained for eight (8) medicines (Annex 2), pre-

selected by the Survey Advisory Group on the basis of their relevance to the country's

previous and new malaria treatment policy. For the eight medicines, samples were

obtained for all batches of each product found in the facilities, and the samples collected

were sent to PPB, to be processed centrally for laboratory testing.

2.2.4 Batch Sampling for Laboratory Testing

Sampling of batches for quality control testing was done centrally at the PPB after all the

samples were received from the field, appropriately recorded and coded. This centralized

sampling was intended to minimize bias by blinding the data collectors as to which

products and batches would be sent to the laboratory for testing. Where similar batches

were collected from two or more facilities, the quantities were combined into one sample for

purposes of batch sampling. For each of the 8 medicine formulations collected from the

field, a representative number of batches for quality control testing were sampled as

follows:

Testing at NQCL: For each type of product, all batches collected were listed. Where more

than 3 batches had been collected, a random sample of N+1 batches was selected.

Where less than 3 batches of a product had been collected, all the batches were included

on the NQCL List. Batches that did not have sufficient quantities for testing were excluded

from the list. A total of 41 batches were thus sampled for testing at NQCL.

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Testing at CENQAM: The batch numbers randomly selected for analysis at the NQCL were

listed. From this list, a random sample of 14 (about 30%) of these batches was selected for

confirmatory testing at Center for Quality Assurance of Medicines (CENQAM), a WHO pre-

qualified laboratory in South Africa.

2.3 Data Collection and Processing

2.3.1 Data Collectors

There were sixteen (16) data collectors for the survey, comprising pharmaceutical personnel

from the public sector, drawn from health facilities located in or around the study areas. A

survey manager was engaged to coordinate the survey, assisted by two survey coordinators

from the PPB and the DOMC respectively. Most of the data collectors were experienced in

data collection on pharmaceutical products, and were already participating in an ongoing

MOH monitoring of medicines availability and prices. A two-day pre-survey training was

carried out in Nairobi to orientate the DCs on the rationale and methodology of the survey

and to pre-test and adapt the data collection tools. The Chief Pharmacist MOH issued each

data collector with a letter of introduction to facilitate the collection of data from facilities.

2.3.2 Data Collection

At each facility and for each anti-malarial product found in that facility, the following details

were recorded on the data collection form: name of facility and contact details; international

non-proprietary name (INN) and brand name of product, formulation, strength, pack size,

batch number, name of manufacturer, and country of origin.

Where a physical sample was required, this was obtained either free of charge or purchased

from the facility. Samples collected each day were coded and labeled appropriately by the

data collectors (DCs), and sent to the Pharmacy and Poisons Board by overnight courier.

Every attempt was made to ensure that the samples were appropriately handled during

collection, storage and transportation.

2.3.3 Data Verification and Analysis

The data collection forms and medicine samples were received at the PPB, verified for

completeness and accuracy and appropriately coded. Doubtful entries on the forms were

validated by contacting the data collector, the health facility or both. For the remaining data

collection tools, random verifications on the information collected were done by phone. The

medicine samples were sorted according to presentation and batch number, recorded and

kept in a secure store within the PPB premises.

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® ®Data from the tools was analyzed using Microsoft Access and Microsoft Excel . All data

entries were counterchecked against the tools and samples. The PPB Medicines

Registration Department verified registration status of the complete list of products found in

the facilities surveyed, using computerized drug registration records and in some cases,

manual checking of actual registration dossiers. Registration data was analyzed using an ® 21Excel workbook adapted from the WHO/HAI price survey manual.

2.3.4 Laboratory Analysis

All tablets were subjected to the tests of uniformity of weight, dissolution and assay. Oral

drops and mixtures were tested for microbial load and content of active pharmaceutical

ingredient (assay), while parenteral injections were tested for sterility and content.

Wherever possible, methods from official compendia, British Pharmacopoeia (B.P.),

International Pharmacopoeia (Ph. Int.) and United States Pharmacopoeia (U.S.P.) were

used. In cases where no compendia methods were available, the manufacturer's in-house

method was used as is or after adaptation. Annexes 3 and 4 give summaries of the tests,

methods and the compendia used for the drugs that were analyzed at the NQCL and

CENQAM, respectively. Each laboratory issued a certificate of analysis for the samples

tested, and NQCL prepared a separate detailed report of the actual method used to test

each sample and the result obtained.

19

3 RESULTS AND DISCUSSION

3.1 Availability of Antimalarial Medicines

3.1.1 Overall Range of Medicines

Thirty two formulations were presumed to be in the market (Annex 1), but a total of 40

different types of AM formulations were found (Annexes 5 and 6). Only 11 of the

formulations are in accordance with the revised national malaria treatment guidelines. The

40 formulations comprised 31 oral preparations (12 paediatric and 19 adult), 6 injectable

preparations and 3 suppositories.

All the medicines recommended in the treatment guidelines were encountered, except

atovaquone-proguanil, which was not found in any of the facilities. Of the medicines found,

amodiaquine, artemether, artesunate, chlorproguanil-dapsone, chloroquine,

dihydroartemisinin, dihydroartemisinin-piperaquine, halofantrine, primaquine and

proguanil are not recommended in the treatment guidelines. The most commonly available

medicines were sulphadoxine-pyrimethamine (suspension and tablets), amodiaquine

(suspension and tablets), artemether (tablets and injection), artesunate tablets,

dihydroartemisinin tablets and quinine (all dosage forms).

In each of the facilities, every antimalarial formulation that was found on the day of the

survey was given a sample number. Thus, there were 2535 samples found in the 200

facilities.

3.1.2 Range of Medicines in Provinces and Sectors

3.1.2.1 Range of Medicines in Each Sector

The private sector had the highest range of medicines and only primaquine tablets and

artemether suppositories were not found in this sector (Annex 5 and Table 3). Mission

hospitals had 30 (75%), while public hospitals had 27 (67.5%) of the full range of medicine

formulations. The general (informal) sector had 5 (12.5%) of the formulations, namely

amodiaquine (suspension and tablets), SP (suspension and tablets) and

sulphamethoxypyrazine-pyrimethamine tablets. The recommended first-line medicines,

i.e. AL tablets and quinine (tablets and injection) were found in all the formal sectors

(mission, private and public). AL suspension (not in the guidelines) was only found in the

private sector, and in only two facilities in (Annex 5).

20

In relation to the total number of samples encountered, the private sector had more than

half of the samples (59.2%), while the general (informal) sector accounted for 4.4% of the

samples. The number of samples from the mission and public sector are almost the same,

i.e. 20% and 16.4% respectively (Table 3).

3.1.2.2 Range of Medicines in Each Province

The number of medicines available in the provinces ranged from 24 for Coast to 34 for

Central province (Annex 6, Table 4). The number of facilities sampled in Coast, North

Eastern and Western provinces were relatively few (Table 2) and this is reflected in the

percentage of samples from these provinces. Although only 20 facilities were visited in

Nyanza, the results show that the province had a wide range of medicines and samples.

The wide range of medicines, most of which are not in the guidelines, may be an indication

of widespread lack of adherence to national treatment guidelines. For example,

chloroquine, to which there is a high resistance rate, was found in all provinces except

Coast province. On the other hand, the recommended artemether-lumefantrine tablets

and quinine (tablets and injection) were found in all the provinces.

Table 3: Proportion of medicines encountered in each sector

General Mission Private PublicNumber and % of medicine formulations(out of 40) Number and % of 112 (4.4%) 507 (20%) 1501 (59.2%) 416 (16.4%)samples encountered (out of 2535)

5 (12.5%) 30 (75%) 38 (95%) 27 (67.5%)

* Percentages do not add up to 100 since similar medicines were encountered in the different sectors

Central Coast Eastern Nairobi North Nyanza Rift Western Eastern Valley No and % of Medicine (85%) (60%) (82.5%) (82.5%) (70%) (72.5%) (72.5%) (67.5%)formulations(out of 40)No. and % of 15.9 7.5 18.6 11.9 6.9 11.4 18.2 9.6samples encountered(out of 2535)

34 24 33 33 28 29 29 27

Table 4: Proportion of medicines available in each province

21

3.1.3 Range of Products Available

3.1.3.1 Brands Available per Product

A total of 187 antimalarial products were found, with the number of pharmaceutical

products per medicine formulation ranging from 1 to 31. The products found comprised

innovator brands, branded generics (the majority) and unbranded generics. Table 5 shows

that SP tablets had the greatest number of products and were also the most widely

encountered (13.4% samples). Amodiaquine (tablets and suspension), artemether

injection, doxycyline and sulphadoxine-pyrimethamine suspension had many products

and were widely distributed. Artesunate and artemether tablets had few samples

encountered, but many products.

3.1.3.2 Products Available in all Sectors in all Provinces

The private sector had the highest number of products, followed by the mission and public

sectors. The general sector had the smallest number of products, and this is expected

since the range of medicines accessed through this sector are few. In this sector, high

numbers of brands were encountered in Nyanza and Eastern provinces. None of the

general facilities surveyed in the North Eastern province had any antimalarial medicines.

Generally, many products were encountered in the Rift Valley, Eastern and Central

provinces (Table 6).

Table 5: The most commonly encountered medicines

Medicine No. and % of products (N=187) (N=2535)Sulphadoxine-pyrimethamine tablets 31 (16.6%) 341 (13.4%)Amodiaquine tablets 18 (9.6%) 300 (11.8%)Amodiaquine suspension 16 (8.6%) 241 (9.5%)Artemether injection 16 (8.6%) 147 (5.8%)Doxycycline tablets/capsules 20 (10.7%) 142 (5.6%)Sulphadoxine-pyrimethamine suspension 18 (9.6%) 137 (5.4%)Artesunate tablets/capsules 23 (12.3%) 84 (3.3%)Artemether tablets 16 (8.6%) 79 (3.1%)

No. and % of samples

Table 6: Number of products found in each sector in each province

General Mission Private PublicCentral 6 46 110 31Coast 3 25 49 28Eastern 17 45 119 20Nairobi 3 53 67 34North Eastern - 23 59 16Nyanza 26 35 86 31Rift Valley 8 35 132 50Western 5 33 74 20

22

3.1.4 Origin of the Medicines

The products found in the market came from 113 different manufacturers in 20 countries of

Africa, Asia, Europe and North America (Table 7). Kenya, India and China were the most

significant countries in terms of origin of products found. Locally manufactured AMs were

the most frequently encountered (48.3% of samples), although they accounted for only 16

(14.2%) of the manufacturers. AMs from India accounted for the highest number of

manufacturers (33.6%), but only 16.5% of the samples encountered. AMs from China

accounted for the same number of manufacturers as Kenya (16), but only 9.1% of the

samples encountered. Countries in Europe accounted for few manufacturers each, but in

total, Europe accounted for 28.3% of the manufacturers and 19.7% of the samples. The

only medicines from the U.S.A. were two brands of doxycycline found in two mission

hospitals. These drugs were not registered and they may have entered the market as

donations. Three products from China and one each from Morocco, Senegal and South

Africa were manufactured for multinational companies based in Europe.

Table 7: Number of countries and manufacturers of medicines

Continent Country Manufacturers Percentage of SamplesAsia China 16 9.1

Hong Kong 2 aIndia 38 16.4Pakistan 2 2.0

Africa Kenya 16 48.3Morocco 2 aSenegal 1 3.3South Africa 1 aTanzania 1 a

Europe Austria 2 1.5Belgium 3 5.4France 6 2.9Germany 6 1.5Greece 1 aItaly 1 1.1Netherlands 4 aNorway 1 aSwitzerland 3 5.6UK 5 1.2

America USA 2 aa: Samples less than 1%

3.1.5 Artemisinin Combination- and Mono-therapy Medicines

Of the 12 artemisinin based oral medicines, six were combinations, namely AL (tablets

and suspension), artesunate-amodiaquine, artesunate-sulphamethoxypyrazine-

pyrimethamine, artesunate-mefloquine and dihydroartemisinin-piperaquine tablets

(Annexes 5 and 6). Although oral artemisinin based medicines should be used in

23

3.1.6 Availability of First-line Treatment

The recommended first line treatment for uncomplicated malaria, AL (tablets) was found in

all sectors and in all provinces (Annexes 5 and 6), but in only 33% of the facilities. (At the sttime of this survey, the deployment of AL as 1 line treatment was just starting, without a full

country-wide scale-up. (After the study, and following countrywide distribution of AL

through public and mission sector free of charge, availability of AL in these sectors has risen 6to over 90% and 80% respectively ). All formulations of quinine, the first-line treatment for

severe malaria, were widely available in all formal sectors and provinces.

3.2 Registration Status of Medicines

Out of all the products found in the market, 42.6% were registered by the PPB, 42.2%

were not registered and the registration status of 15.2% of the products could not be

established at the time of the survey. Medicines which had all their products registered

were AL tablets (5 products), artesunate-sulphamethoxypyrazine-pyrimethamine (1),

chlorproguanil-dapsone (1), dihydroartemisinin tablets (6) and halofantrine suspension

and tablets (2 each). Medicines which had many products in the market also had a high

proportion of the same not registered (Table 8) Of major concern are amodiaquin tablets

and suspension, artemether tablets and injection, artesunate tablets and capsules and

SP tablets and suspension, all of which were widely available (Table 8) in most sectors

and provinces (Annex 5 and 6).

.

b The availability and prices of selected medicines is monitored quarterly by MOH Division of Pharmacy, with technical support from WHO and HAI-Africa. Figures quoted are for the monitoring report of October 2007, which can be viewed at www.health.go.ke.

Table 8: Number of products registered for some of the most available drugs

Medicine Registered Not registered Not established TotalAmodiaquine 50 ml/5ml 7 9 0 16Amodiaquine tablet 200 mg 9 9 0 18Artemether tablets 9 5 2 16Artemether injection 5 7 4 16Artesunate tablets/capsules 10 11 2 23Doxycycline tablets/capsules 4 7 9 20Sulphadoxine/Pyrimethamine susp 7 11 0 18Sulphadoxine/Pyrimethamine tablets 15 13 3 31

combination with other antimalarial medicines, six mono-therapy formulations were found and these were artemether, artesunate and dihydroartemisinin suspensions and tablets. It is noteworthy that the PPB has since discontinued registration of AM mono-therapies, and has given notice to manufacturers and importers to stop producing or importing these monotherapies, and to re-register their AM products in accordance with national malaria treatment guidelines.

24

c All CENQAM samples had the same batch numbers as NQCL samples, except for two of the four SP samples, which were from the same manufacturer, but of different batch numbers.

Table 9: Products Analyzed in Quality Control Laboratories

Medicine NQCL CENQAMAmodiaquine hydrochloride 50 mg/5ml suspension 3 -Amodiaquine hydrochloride 200 mg tablet 9 -Artemether 80 mg/ml injection 2 -Artemether 100mg/ml injection 1 -Artemether 20 mg/Lumefantrine 120 mg tablets 1 1Artemether 180 mg/Lumefantrine 1080 mg/60 ml suspension 1 1Artesunate 50 mg tablets 3 -Dihydroartemisin 60 mg tablets 3 3Halofantrine 250 mg tablets 1 -Quinine dihydrochloride 200 mg/ml drops 2 1Quinine dihydrochloride 50 mg/ml mixture 2 1Quinine dihydrochloride 600 mg/2 ml injection 2 1Quinine bisulphate 50 mg/5 ml suspension - 1Quinine sulphate 200 mg tablets 1 -Quinine sulphate 300 mg tablets 2 -Sulphadoxine 500 mg/Pyrimethamine 25 mg tablets 6 4Sulphamethoxypyrazine 500mg/Pyrimethamine 25mg tablets 2 1Total 41 14

Table 10: Countries of origin for batches analyzed

Continent Country NQCL Samples CENQAM Samples

Africa Kenya 23 9Senegal 1 0South Africa 1 0

Asia China 3 2

India 7 0Pakistan 1 1

Europe Austria 1 0Belgium 2 0France 1 0

Greece 1 0Netherlands 0 1Switzerland 0 1

Total 41 14

3.3 Quality Control

3.3.1 Range of Samples Tested

Forty one samples were tested at the NQCL, and 14 samples at CENQAM, as

summarized in Table 9. A total of 43 unique batches were tested. This is because all

except 2 samples tested at CENQAM were the same batch as the samples tested at

NQCL. The 43 batches originated from 33 manufacturers based in 12 countries in

Africa, Europe and Asia (Table 10). Local manufacturers accounted for 23 (53%) of

the batches tested.

25

3.3.2 Quality Control Results

3.3.2.1 Results from National Quality Control Laboratory

The range of laboratory tests performed included weight uniformity, dissolution and assay

for tablets; microbial load and assay for oral liquids; and sterility and assay for injections

(Annexes 3 and 4). Of the 41 samples tested at NQCL, 36 samples (87.8%) passed and 5

samples (12.2%) failed to comply with quality specifications. The results of laboratory

testing at NQCL are summarized in Table 11 below.

Of the five samples that failed testing at NQCL, 3 failed on content of active ingredient and 2

failed the dissolution test. Four of the failed products were locally manufactured, while one

(artemether injection) was from India. Two of them (quinine mixture and SP tablets) were

from the same manufacturer. Out of the five samples that failed analysis, one was

registered, two were not and the registration status of two could not be established.

Two out of the nine samples of quinine analyzed (tablets and syrup) failed on the content of

active ingredient. This is of great concern because quinine is the first-line treatment for

severe malaria and could easily lead to treatment failure and resistance.

Table 11: Quality control results from NQCL

Medicine Samples tested failed failed (for failed

batches) Amodiaquine hydrochloride 50mg/5ml suspension 3 - -Amodiaquine hydrochloride 200mg tablet 9 1 Dissolution Not registeredArtemether 80mg/ml injection 2 1 Content Registered -Artemether 100mg/ml injection 1 - -Artemether 20 mg/Lumefantrine 120 mg tablets 1 - -Artemether 180mg/Lumefantrine 1080mg/60ml suspension 1 - -Artesunate 50mg tablets 3 - -Dihydroartemisin 60mg tablets 3 - -Halofantrine 250mg tablets 1 - -Quinine dihydrochloride 200mg/ml drops 2 - -Quinine dihydrochloride 50mg/5ml mixture 1 - -Quinine dihydrochloride 600mg/2ml injection 2 - -Quinine bisulphate 50mg/5ml mixture 1 1 Content Not establishedQuinine sulphate 200 mg tablets 1 1 Content Not establishedQuinine sulphate 300 mg tablets 2 - -Sulphadoxine 500 mg/Pyrimethamine 25 mg tablets 6 1 Dissolution Not registeredSulphamethoxypyrazine 500mg/Pyrimethamine25mg tablets 2 - -Total 41 5

Samples Test Registration

26

3.3.2.2 Results from CENQAM

Five (35.7%) of the 14 samples tested at CENQAM, failed analysis. All the four SP samples

analyzed failed the dissolution test of pyrimethamine, although two of them were

registered. One sample (quinine dihydrochloride mixture) which was not registered, failed

to meet specified standards as it contained active ingredient below the required amounts

(Table 12).

3.3.2.3 Comparison of Results from NQCL and CENQAM

Only about a quarter of samples that were analyzed at NQCL were also analyzed at

CENQAM. The five samples that failed analysis at NQCL were not part of the samples sent

and analyzed at CENQAM.

Although 5 samples failed analysis in each laboratory, the majority were similar batches.

Of the 43 unique batches tested in either laboratory, the overall number of failures was

16% (7 batches). Out of the fourteen samples analyzed at CENQAM, 12 were of the same

batches as those analyzed at NQCL and two (sulphadoxine-pyrimethamine tablets) were

from the same manufacturer, but of different batches. Of the 12 same-batch samples, 8

passed all tests performed at both NQCL and CENQAM (Annexes 3 and 4). One quinine

dihydrochloride injection failed on the content of active ingredient and two SP batches

failed on dissolution of pyrimethamine at CENQAM, but passed at NQCL. One batch of

quinine bisulphate mixture failed on content at NQCL, but passed at CENQAM. At both

laboratories, SP tablets from the same company but of different batches failed the

dissolution test of pyrimethamine.

Table 12: Quality control results from CENQAM

Medicine Samples Samples Tested Failed (for failed batches)Artemether-lumefantrine 20/120mg tablets 1 - -Artemether 180 mg/Lumefantrine 1080 mg/60 ml suspension 1 - -Dihydroartemisin 60mg tablets 3 - -Quinine dihydrochloride 200mg/ml drops 1 - -Quinine dihydrochloride 600mg/2ml injection 1 - -Quinine bisulphate 50mg/5ml mixture 1 - -Quinine dihydrochloride 50mg/5ml mixture 1 1 Content Not RegisteredSulphadoxine 500 mg/Pyrimethamine 4 4 Dissolution 2 Registered25 mg tablets 2 Not RegisteredSulphamethoxypyrazine 500mg/Pyrimethamine 25mg tablets 1 -Total 14 5 -

Test Failed Registration

27

4 SUMMARY OF RESULTS

1. A wide range of antimalarial medicines are available in the Kenyan market. Only 27.5%

of these formulations are recommended in current national treatment guidelines.

2. The private sector has the widest range of antimalarial medicines (95%), with the

mission and public sectors also distributing a wide range of antimalarials (75% and

67.5% respectively).

3. The widespread distribution of non-recommended medicines occurs in all provinces.

Central, Eastern and Nairobi provinces have the widest medicines range (over 80%

each).

4. The first-line treatment for uncomplicated malaria, AL (tablets) was found in all the

sectors and provinces, but in only 33% of all the facilities surveyed.

5. Besides AL tablets, there are 5 other ACTs in the Kenyan market, namely: AL

suspension, Artesunate-Sulphamethoxypyrazine-Pyrimethamine, artesunate-

amodiaquine, artesunate-mefloquine and dihydroartemisinin-piperaquine (all tablets).

These ACTs are largely distributed through the private sector, but some are found to a

small extent in the mission and public sectors.

6. For the same medicine formulation, a wide range of products from different

manufacturers are found in the market.

7. Kenya, India and China are the most significant sources of origin for antimalarial

medicines in the country.

8. Of the antimalarial products found in the market, almost half (42.2%) were un-

registered.

9. The majority of unregistered antimalarials are either manufactured in Kenya or India.

10. The majority of unregistered antimalarial products found in the market, are not

recommended in the national malaria treatment guidelines.

11. The registration status of 15.2% of the antimalarial products found in the market could

not be established at the time of the study.

12. Overall, 84% of the antimalarial medicines tested passed quality control tests, with a

failure rate of about 16%.

13. Of the drugs that failed quality tests, SP tablets, artemether injection, amodiaquine and

quinine tablets are of particular concern from a malaria control perspective.

28

5 CONCLUSIONS

The widespread availability of non-standard therapies, even in the formal public sector

undermines the national malaria treatment policy. The limited availability of AL, the first-

line treatment for malaria is consistent with the timing of the current survey which was

conducted during the initial roll-out of the new policy, and prior to the nationwide

distribution and deployment of this product in the public and mission sectors; subsequent

surveys and ongoing monitoring by the MOH have shown that AL is available in over 90%

of public sector facilities. The widespread availability of quinine (the first-line treatment for

severe malaria) in the formal sector and in all provinces augurs well for malaria treatment

and is an indicator of successful distribution by MEDS and KEMSA.

This survey highlights a number of regulatory challenges given 1) the high number of

products for any given medicine, especially the more established ones such as SP and

amodiaquine, 2) the presence of unregistered products in the market 3) the presence in

the market of non-recommended malaria medicines, such as amodiaquine, pointing to a

policy-drug registration and distribution disconnect and the 4) poor quality of SP (for

intermittent presumptive treatment), quinine and artemether injection. There is a need for

a concerted effort by the PPB, MOH and stakeholders in pharmaceutical sub-sector to

strengthen post-market surveillance to protect the market and patients from the dangers

posed by medicines whose safety, quality and efficacy cannot be guaranteed.

29

6 LESSONS LEARNT

1. There have been many studies on medicines quality in Kenya, but these have not

necessarily influenced policy. Leadership of the national regulator (PPB) was crucial in

this study, and it enabled faster action on the findings. For example, PPB noted the high

proportion in the market of AMs that are not recommended in treatment guidelines, and

initiated remedial measures including:-

Discontinued registration of new oral artemisinin mono-therapies

Gave notice to manufacturers to discontinue production, distribution or sale of

products that do not conform to malaria treatment guidelines (by March 31 2008)

Set up a task force to spearhead establishment of a post-market surveillance

system for medicines quality in the country.

2. There are gaps and challenges in enforcing medicines regulation in Kenya. Capacity

building in this area is an ongoing process that requires coordinated partner support

3. There are opportunities for disease control programmes and the medicines regulator to

work together, to positively influence and mutually support public health.

4. The capacity of the WHO pre-qualified laboratory in South Africa is overstretched, and

there is need to enhance national capacity for medicines quality control.

5. There is a lack of strategic engagement on medicines regulation at the wider health

sector level, and a lack of awareness of the role and work of the medicines regulator

(PPB).

6. Access to prompt and effective treatment is a pillar of the National Malaria Strategy.

This cannot happen without an effective medicines regulatory authority. This applies to

all key public health programmes.

30

7 RECOMMENDATIONS

A) Pharmacy & Poisons Board (PPB)

1. Enforce the withdrawal of oral artemisinin monotherapies, un-registered and sub-

standard products from the Kenyan market.

2. Use the survey data to inform drug registration and pharmaceutical inspection.

3. Establish a post-market surveillance system, to curb substandard and un-

registered drugs in the market. Develop an appropriate strategy, guidelines and

implementation framework with clearly defined mandates, roles and

responsibilities.

4. Involve relevant MOH departments and implementing partners from all sectors, in

developing the post-market surveillance and other regulatory systems

5. Computerize fully data management systems for medicines registration and make

accessible information to the public to ensure that registration status of products dcan be verified at all times .

6. Enforce compliance by all stakeholders with set pharmaceutical regulations.

7. Link implementation of medicines regulation to the health sector planning and M&E

systems (NHSSP II and AOPs), to guide support by MOH and development

partners. Develop an appropriate communication strategy to raise stakeholder

awareness on the role and work of PPB.

B) Division of Malaria Control (DOMC)

1. Spearhead countrywide dissemination, promotion and enforcement of malaria

treatment guidelines and involve all partners in the health sector. Engage more fully

with the private sector to facilitate greater compliance with the guidelines.

C) Ministry of Health (MOH)

1. Advocate for and increase financial support to strengthen key pillars of medicines

regulation, in line with the health sector support framework.

2. Support strengthening of local capacity for QC testing, to avoid delays when

samples are sent outside the country. In this regard, the NQCL and other

laboratories should receive all necessary support towards attaining WHO pre-

qualification.

d The suitability of systems like SIAMED and other relevant software should be fully explored, with the necessary adaptation or development of a customized system. In this regard, MOH, WHO and other development partners should provide the necessary support.

31

D) Development Partners

1. Support the strengthening of key pillars of medicines regulation, within the

health sector support framework. Such support should encompass human

resource capacity (numbers and skills enhancement) and strengthening of

logistical infrastructure for: market surveillance, data management, QC testing

and pharmaceutical inspections.

E) MOH Disease Control Programmes (HIV, TB, Malaria, etc)

1. Establish linkages with the PPB, to address regulatory and other

pharmaceutical issues in an integrated manner. This should include:-

collaboratively developing a national post-market surveillance strategy and

system

harmonized resource mobilization for relevant medicines regulatory

functions

jointly undertaking similar surveys to guide regulatory policy for other

classes of drugs (e.g. ARVs, medicines for TB, reproductive health, non-

communicable diseases, etc)

F) Pharmaceutical Producers, Importers and Distributors

1. Withdraw all non-recommended and sub-standard antimalarial products from

the market, through reverse-logistics in the various public, mission and private

sector distribution channels.

2. Comply with PPB regulations by ensuring that:-

only recommended antimalarial products are produced and distributed in

Kenya

all medicines are duly registered and meet specified standards of quality

G) Consumers & Consumer Groups

1. Participate actively in medicines quality and regulatory issues. This includes

reporting of suspected substandard or counterfeit products to the PPB.

32

Glossary

Active pharmaceutical ingredient: The chemical substance responsible for a product's pharmacological effect.

Brand name: Name given to a pharmaceutical product by the manufacturer e.g. Camoquin is the innovator brand (trade) name for amodiaquin. Brand names may also be used for generic products (branded generics).

Dosage form: The form in which a completed pharmaceutical product is administered e.g. tablet, capsule, injection.

Drug: See Medicine

Generic medicine: A pharmaceutical product that is manufactured without a licence from the innovator manufacturer and marketed after the expiry of patent or other exclusive rights. A generic medicine may be marketed under a non-proprietary name (such as amodiaquin) or under a branded name (such as Amochin, a branded generic amodiaquin from Kenya).

Formulation: The administration form of a completed pharmaceutical product, inclusive of the strength of the active pharmaceutical ingredient per unit dose e.g. amodiaquine 200 mg tablet, sulphadoxine 250mg-pyrimethamine12.5 mg/5ml.

Innovator brand: The product that was first authorized world wide for marketing on the basis of documentation of its efficacy, safety and quality e.g. Camoquin .

International non-proprietary name (INN): A common generic name selected by designated experts , using procedures and guiding principles adopted by the World Health Assembly, for the unambiguous identification of a new pharmaceutical substance. This name is often identical to the generic name e.g. amodiaquin

Medicine: Any dosage form containing a substance approved for the prevention and treatment of a disease.

Pharmaceutical product: Any medicine intended for human use, presented in its finished dosage form, that is subject to control by pharmaceutical legislation (registered). A product may be sold under a brand name or under a generic name.

Sample: For the purposes of this study, each of the medicines found in each facility on the day of the survey was given a sample number e.g. in one facility there may have been six samples: Camoquin suspension, Camoquin tablets, Amochin tablets, unbranded amodiaquin, chloroquin injection, chloroquin tablets. Numbering of similar or different medicines from other facilities continued sequentially giving a total of 2535 samples in the 200 facilities.

33

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15. G. N. Thoithi, K. O. Abuga, J. M. Nguyo, G. Mukindia, O. King'ondu, J. K. Ngugi and I. O. Kibwage. Drug quality control in Kenya: Observations in Drug Analysis Research Unit during the period 1996-2000. East Cent. Afr. J. Pharm. Sci. 5(2002)28-32.

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18. A. A. Amin, D. A. Hughes, V. Marsh, T. O. Abuya, G. O. Kokwaro, P. A. Winstanley, S. A. Ochola and R. W. Snow. The difference between effectiveness and efficacy of antimalarial drugs in Kenya. Tropical Medicine and International Health. 9(2004)967-974.

19. A. A. Amin and R. W. Snow. Brands, costs and registration status of antimalarial drugs in the Kenyan retail sector. Malaria Journal. 4(2005)36.

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22. Survey of the quality of antiretroviral medicines circulating in selecting in selected African countries.WHO/PSM/QSM/2007.9. Geneva Switzerland. World Health Organisation. 2007.

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Annexes

Annex 1: Data Collection Form

ANTIMALARIAL MEDICINE DATA COLLECTION FORM

Use one form for each health facility and medicine outlet

Date: Area number:

Name of town/Village/District:

Name of Health facility/Pharmacy (Optional):

Health facility/Pharmacy ID (mandatory):

Distance in km from nearest town (Population>50,000):

Type of facility:

Public

Private retail pharmacy

Mission

Other (please specify)

Name of manager of the facility:

Name of person(s) who provided the information on medicines (if different)

Data collectors:

Verification:

To be completed by the area supervisor at the end of the day.

Signed:

Date:

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Annex 1. Data collection form ……………………………………………Continued

ANTIMALARIAL DATA COLLECTION FORM

A B C D E F G H Available Tick for Name facturer Of size number Yes Origin foundAmodiaquine suspension 50 ml/5mlAmodiaquine tablet 200 mgArtemether injectionArtemether tabletsArtemether/Lumefantrine tabletsArtesunate injectionArtesunate suppositoriesArtesunate tablets/capsulesArtesunate/AmodiaquineArtesunate /MefloquineAtovaquone-Proguanil tablets (Adult)Atovaquone-Proguanil tablets (Paediatric)Chloroquine syrupChloroquine injectionChloroquine tabletsDihydroartemisinin satchetDihydroartemisin tabletsDihydroartemisinin-Piperaquine tabletsDoxycycline tablets/capsulesHalofantrine suspensionHalofantrine tabletsMefloquine tabletsProguanil tablets 100 mgQuinine dropsQuinine injectionQuinine suspensionQuinine tabletsSulphadoxine/Pyrimethamine dropsSulphadoxine/Pyrimethamine injectionSulphadoxine/Pyrimethamine suspensionSulphadoxine/Pyrimethamine tabletsSulphamethoxypyrazine/Pyrimethamine suspensionSulphamethoxypyrazine/Pyrimethamine tablets

Brand Manu- Country Pack Batch Comments

sS

Annex 2: List of Pre-selected Medicines for Laboratory Analysis

1. Amodiaquin

2. Artemether

3. Artesunate

4. Artemether/Lumefantrine

5. Dihydroartemisinin

6. Halofantrine

7. Sulphadoxine/pyrimethamine

8. Quinine

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Annex 3: Drugs Analyzed at the National Quality Control LaboratoryMedicine Samples Test Method CompendiaAmodiaquine hydrochloride 50 mg/5ml suspension 3 Microbial load Plate count BP 2002 II

Assay UV USP29NF24-AAmodiaquine hydrochloride 200 mg tablet 9 Weight uniformity Weight BP 2002 II

Dissolution UV USP29NF24Assay UV USP29NF24

Artemether 80 mg/ml injection 2 Sterility Filtration* BP2002 IIAssay HPLC IP Vol.5

-Artemether 100g/ml injection 1 Sterility Filtration* BP2002 IIAssay HPLC IP Vol.5

Artemether 20 mg/Lumefantrine 120 mg tablets 1 Weight uniformity Weight BP2002 IIDissolution HPLC , UV IHAssay HPLC IH

Artemether 180 mg/Lumefantrine 1080 mg/60 ml Susp 1 Microbial load Plate count BP2002 IIAssay HPLC IH

Artesunate 50 mg tablets 3 Weight uniformity Weight BP2002 IIDissolution HPLC IHAssay HPLC IP Vol. 5

Dihydroartemisin 60 mg tablets 3 Weight uniformity Weight BP2002 IIDissolution UV IHAssay UV IH

Halofantrine 250 mg tablets 1 Weight uniformity Weight BP2002 IIDissolution LC IHAssay LC IH

Quinine dihydrochloride 200 mg/ml drops 1 Microbial load Plate count BP2002 IIAssay NAT BP1980 II A

Quinine dihydrochloride 50 mg/ml mixture 1 Microbial load Plate count BP2002 IIAssay NAT BP1980 II A

Quinine dihydrochloride 600 mg/2 ml injection 2 Sterility Filtration* BP2002 IIAssay NAT BP1980 II A

Quinine bisulphate 50 mg/ml mixture 2 Microbial load Plate count BP2002 IIAssay NAT BP1980 II A

Quinine sulphate 200 mg tablets 1 Weight uniformity Weight BP2002 IIDissolution UV BP2002 IIAssay NAT BP2002 II

Quinine sulphate 300 mg tablets 2 Weight uniformity Weight BP2002 IIDissolution UV BP2002 IIAssay NAT BP2002 II

Sulphadoxine 500 mg/Pyrimethamine 25 mg tablets 6 Weight uniformity Weight USP29NF24Dissolution HPLC USP29NF24Assay HPLC USP29NF24

Sulphamethoxypyrazine 500mg/Pyrimethamine 25mg tablets 2 Weight uniformity Weight USP29NF24

Dissolution HPLC USP29NF24Assay HPLC USP29NF24

Total 41

BP1980 II A : Method adopted from BP 1980 II. USP29NF24-A: Method adopted from USP29NF24-A. * Membrane filtration

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Annex 4: Drugs Analyzed at CENQAM

Medicine Samples Test Method CompendiaArtemether 20 mg/Lumefantrine 120 mg tablets 1 Assay, Dissolution HPLC , UV IHArtemether 180 mg/Lumefantrine 1080 mg/60 ml suspension 1 Assay HPLC IH

thDihydroartemisin 60 mg tablets 3 Assay HPLC IP 4 EdQuinine dihydrochloride 200 mg/ml drops 1 Assay NAT BP 2007Quinine dihydrochloride 600 mg/2 ml injection 1 Assay NAT BP 2007Quinine dihydrochloride 50 mg/5ml mixture 1 Assay NAT BP 2007Quinine bisulphate 50 mg/5ml mixture 1 Assay HPLC BP 2008Sulphadoxine 500 mg/Pyrimethamine 25 mg tablets 4 Assay, Dissolution HPLC USP2007Sulphamethoxypyrazine 500mg/Pyrimethamine 25mg tablets 1 Assay, Dissolution HPLC USP2007Total 14

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Annex 5: Availability of Medicines in Each Sector

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