Cambodian experiences on quality of antimalarial medicines

Dr. Duong Socheat,

National Malaria Centre, Cambodia

Workshop on GMP and Quality Assurance of Antimalarial Medicines for WHO/SEARO and WHO/WPRO regions

18-22 October, Bangkok, Thailand

Location of CambodiaThe Kingdom of Cambodia shares its borders with Thailand and Laos on the north, with Vietnam on the East and South, and with

the Gulf of Siam and Thailand on the South and West.

China

India

Indonesia

Cambodia

N

EW

S

Over viewMalaria situation in CambodiaProblems faced earlier to 1999Policy of prepackaged drugs (2000)Blister packaged Artesunate and Mefloquine (ACT)Experience of blister packaging – GMP concernsChallenges of Quality assuranceCurrent Malaria Treatment PoliciesA Recent Study of Quality of Anti-Malarial DrugsStudy findings of counterfeit antimalaria drugsFuture approaches for good quality antimalaria drugsStrategy of Drug Quality Assurance in Pharmaceutical Development

Malaria Situation in Cambodia

High malaria occurrence among migrants, casual workers during harvest season, forest workers, gem miners, road construction workers, soldiers,and ethnic minoritiesLimited accessibility to public health servicesLack of knowledge about correct treatment among risk groups and private health care providersImprecise diagnosis as poor quality microscopy persists in remote areas even in the public sector because of low salariesImproper, inadequate, expensive and ineffective treatments including counterfeit drugs in the private sector

HISTORICAL PERSPECTIVE

• Malaria, a major scourge in Cambodia for several decades. • Monotherapy mainly followed until 1999 - 1993: Shifted from Chloroquine to Quinine + Tetracycline

- 1994: Changed from Quinine + Tetracycline to Mefloquine• Combination therapy recommended for the first time in

1999 -Artesunate and Mefloquine (without packaging)

• Treatment guidelines revised in 2000 introducing prepackaging of Artesunate and Mefloquine

• Further revisions are due depending on the outcomes of current research underway

Problems accumulated until 1999(which prompted the shift to Combination therapy)

1. Increasing levels of multi drug resistance especially in border areas with Thailand

2. Huge burden of counterfeit or low quality antimalarial drugs in the open market

3. Inappropriate prescription practices in the private sector

4. Inappropriate treatment seeking behavior and drug use

Reasons for pre-packaging by the National Programme

• Necessity to stabilize drug resistance, control counterfeit drugs, and improve drug use of antimalaria drugs for both providers and patients

• Particular response requirements to the malaria burden (ACT)

• Combination treatment of artesunate and mefloquine was not commercially available

• Local pharmaceutical manufacturers were not ready for blister-packaging with GMP standard

• Malaria Program need to provide ACT in blister to assure proper use for both public and private sector

Policy of pre-packaged drugs (2000)

-

• The Sub-Cocom of Ministry of Health declared the country’s malaria treatment policy:• A combination of Mefloquine® + Artesunate® is the

first line treatment for uncomplicated Pf malaria• The regimen have to be pre-packaged in different

age/weight groups

• MOH decided to locate the packaging facility in the compound of Central Medical Store.

Antimalarial combinations currently in useTwo channels of distribution

Public Sector

Private Sector

Routine distribution system (CMS)Routine distribution system (CMS) Public HealthPublic Health ServicesServices

Commercial distributionCommercial distribution

Social marketing schemeSocial marketing schemePrivate Private Drug sellersDrug sellers

Advantage of pre-packaged drugs

• To improve or stabilize resistance levels:– Standardized and effective treatment nationwide– Combination of artesunate and mefloquine

• To improve the patient’s compliance– Short duration of treatment– Pre-packaged treatment

• To improve the patient’s understanding of the treatment administration– User friendly IEC approach (outer box and

instruction notice)

Experiences of production

• Ministry of Health agreement / WHO’s support

• Determine required equipment

• Design moulds for blistering

• Develop packaging unit

• Train workers

• Import raw materials like aluminum foil and PVC as well as drugs

• Maintain program to supply drugs on time

Good Manufacturing Procedures concerns

• Quality assurance issues have been addressed• Cambodia GMP guidelines was published in 2000• Constant monitoring system for GMP / Routine

inspection to manufacturers is under development• Specifications for raw materials must be robust

– Obstacles encountered during procurement process

• Management of the packaging plant must be comprehensive in order to be efficient and effective

• Concerns with the GMP criteria for drugs and other raw materials– No pre-qualified mefloquine is available

Challenges of Quality Assurance of blister packaging A+M

Ports

Central Medical StoreAir conditioning

Storage Storage

National malaria center Air conditioningUnstable power supply

Packaging

Central Medical Store

Transport without air conditioning

Storage

National malaria center

Storage

Central Medical Store

OD pharmacy storeNo air conditioning

StorageHealth CenterNo air conditioning Patients

QC of Law materials

QC of blistersStability test

Results of A+M quality

•Before blister package:

–Mefloquine 250 mg from Denmark : Conform to specification

–Artesunate 50 mg from China : Conform to specification

–Artesunate 50 mg from Vietnam : Problem of Friability

•After blister package:

–A+M4: Conform to specification

•Quality after 3 month in the field

– A+M4: Conform to specification

•Stability tests for A+M and Malarine was conducted and passed

Current Malaria Treatment PoliciesPublic Sector Treatment guidelines for 3 Day combination therapy using

mefloquine and artesunate after obligatory use of rapid diagnosis test or microscopy

Pre-packaging and distribution of dipsticks and anti-malarial combination treatment for hospitals & health centers free of charge

Private Sector Social Marketing of Rapid Diagnostic Test & a brand-named pre-

packaged combination therapy Health Education through advertisement of the product on Mass

Media Village Malaria Workers I male and I female villagers are trained for RDT and ACT 300 villages will be covered under GF round 2

Handing over of Blister packaging of A+M to

pharmaceutical manufacturer

•Cambodia Pharmaceutical Enterprise (CPE) has been established since 1999•MOU between the National Malaria Centre and the Cambodia Pharmaceutical Enterprise (CPE) in May 2004•Renovation of Blister Packaging Room•Australia Business Volunteers for GMP Jan, 2005(Training manager of GMP and Quality Assurance, Abbott Australia)

•CPE will start blister-packaging for A+M early 2005

1. To obtain and document evidence-based data from the field on the quality of selected antimalarial drugs in Cambodia

To quantify fake antimalarials using MiniLab technology along Thai border areas

To assess the prevalence of drug shops where fake anti-malaria drugs are soldTo increase skills of provincial health staff in research methodology including sample collection, analysis using MiniLab, and reporting

2. To present suggestions to policy-marker on developing and implementing appropriate strategies to address the drug quality problems

Counterfeit Antimalaria DrugsPreliminary Investigation of Quality

There are 3 kinds of legal drug shops in the country

Pharmacy= responsible by Pharmacist, 393

Depot A= responsible by assistant Pharmacist, 175

Depot B = responsible by retired midwives or nurses, 446

Illegal drug outlets in Cambodia, 2461

(Department of Drug and Food, 2002)

Drug sellers in Cambodia

Sites for preliminary study 10 Operational Districts in 4 provinces

No. of outlets

in the 4 provinces

–23 Pharmacies

–12 Depot A

–72 Depot B

–391 illegal drug outlets

171/ 498 (~34%) drug outlets visited for collection 240 samples in 4 provinces Samples claimed to be

Results

Chinese products, 23%

Unkown origin, 15%

Cambodian products, 3.80%

Other countries , 14%

Thai products , 44%

Overall results from 3 rounds in10 districts in 4 provinces

Quinine Mefloquine Chloroquine Artesunate

Sample size

N

CFN (%)

Sample size

N

CFN (%)

Sample size

N

CFN (%)

Sample size

N

CFN (%)

85 61*

72%

46 3

6.5%

93 7

0.1%

92 18**

20%

CF: Counterfeit drugs* Brainy: unidentified manufacturer**Sophisticated counterfeit of Guilin artesunate blister

Summary of the study findings

The burden of fake antimalarials is significant Impossible to determine the source of the counterfeit drugs Difficult to identify counterfeit drugs by visual meansCounterfeit drugs were found both in legal and illegal shopsNo counterfeit drugs were found in registered drugs sampled Drug registration appears important to reduce problems

Anecdotal evidence Community awareness campaigns appeared to have some beneficial outcomes – TV campaign for “Brainy drugs”Drug sellers buy drugs without knowing the quality

Main causes of the problem of counterfeit drugs in Cambodia

• Effort has developed pharmaceutical law and regulations, but are still weak

• The weak law enforcement• The weak education campaign • The poverty of Cambodian population• The insufficient number of drugs inspectors • The unsuccessful intervention of the MoH in

previous years due to the limited collaboration and cooperation among concerned regulatory agencies

Future approaches for good quality antimalaria drugs

• Continued monitoring of drug resistance to guide the revision of national drug policy

• Continued monitoring of anti-malarial drug usage

• Implementation of regular quality control of anti-malaria drugs in the private as well as public sector (including storage conditions)

• Ensuring the adequate supplies of combination drugs in the public and private sectors

• Strengthen procurement capacity

• Enacting legislation prohibiting the selling of non-recommended regimens

• Building up all possible partnership networks for improving implementation of national treatment guidelines.

• Conduct sustained community awareness campaigns

Strategy of Drug Quality Assurance in Pharmaceutical Development

• Strengthen management of pharmaceuticals and other medical supplies by introducing GMP, GPP, GLP, GSP and appropriate inventory system

• Improve access of consumers to appropriate good quality pharmaceuticals in the public and private sector

• Promote the quality of prescription and dispensing and appropriate use of drugs

• Improve attitudes of pharmaceutical service providers towards consumers for improving communication

• Strengthen the implementation of drug policies, laws and regulations for public safety

• Reduce potential for harm to people’s health from counterfeit, sub-standard, poor quality and other dangerous drugs

• Strengthen Drug Quality Control • Increase the skill of pharmaceutical workers in the private and public sector to

follow national policy and procedures and achieve desired quality of work • Strengthen procurement and distribution of essential medical supplies

country-wide (3 years rolling plan of Department of Drug and Food)

Partners

• National Center for Parasitology Entomology Malaria Control program

• Provincial Health Departments• National Laboratory for Drug Quality Control• Department of Drugs and Food• Cambodia Pharmaceutical Enterprise• US Pharmacopoeia / Drug Quality Information• USAID/AusAID/World Health Organization

Thank you !