Screening Drug Quality Project Report March 2014 - WHO · Screening Drug Quality Project Report ......

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Screening Drug Quality Project Report – March 2014

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Executive Summary

The proliferation of substandard medicines globally has become a public health concern. The scenario is even

worse in sub Saharan African countries which have weak systems of governance and regulation. Despite all

the strategies implemented by the Uganda Ministry of Health, anecdotal evidence shows that counterfeit and

substandard medicines are still prevalent in the Ugandan market. Given the high prevalence of infectious

diseases in the Ugandan population, the dealers in this business target antimicrobial medicines and distribute

them to remote and peripheral areas of the country. Because of the complexity of assuring quality in resource

limited settings, it has been advocated that drug regulatory authority activities are augmented by screening

drug quality programs run in such a manner as to collect accurate information that better represents the quality

of medicines made available to the consumers. Therefore, this drug quality screening project was conducted as

an innovation where the Drug Regulatory Authority cooperates with other stakeholders as an additional

dimension to drug quality assurance in a country such as Uganda with limited capacity.

It was a field based project employing a cross sectional design. Medicine samples of co-trimoxazole 480mg

and 960mg tablets, ciprofloxacin 500mg tablets, amoxicillin 250mg or 500mg capsules and

artemether/lumefantrine 20/120mg tablets were collected from a stratified random sample of drug outlets in

Mbarara, Arua and Iganga/Mayuge districts. The screening of drug quality was conducted in the

Pharmaceutical Chemistry Laboratory at Pharmacy Department in Makerere University using GPHF Minilabs.

Samples for screening drug quality were picked from a total of twenty nine (29) drug outlets from three

regions of Uganda. Each region contributed almost an equal number of outlets to the total sampled units with

the lowest being South West with eight (8) drug outlet and the highest being West Nile with eleven (11) drug

outlets.

All categories of drug outlets including wholesale pharmacies, retail pharmacies, drug shops, clinics, public

health facilities and informal drug outlets were represented in the sampled drug outlets.

Up to 105 drug products of the selected medicines were collected from the sampled drug outlets. These

included 31 samples of Artemether/Lumefantrine 20/120mg tablets, 25 samples of Amoxycillin 250mg or

500mg capsules, 24 samples of ciprofloxacin 500mg tablets and 25 samples of Cotrimoxazole 480mg or

960mg tablets. Consequently, 136 screening tests were conducted on all the samples of medicines.

Of all the sampled products, only Amoxycillin 250mg or 500mg capsules had some failures (5/25 samples) on

the screening tests. These products failed on the identity test as the sample spot intensity was different from

the standard spot intensity. All the other products of Artemether/Lumefantrine 20/120mg tablets,

Ciprofloxacin 500mg tablets and Co-trimoxazole 480mg or 960mg tablets passed the screening tests.

The failed Amoxycillin capsule products were forwarded to NDA Quality Control Laboratory for verification

and confirmatory tests.

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Acknowledgements

The Project implementation team is greatly indebted to the following;

MeTA Council Uganda Chapter for the trust and confidence they showed in assigning this task to the

project team.

MeTA Secretariat for all the effort, time, encouragement and follow up on the project progress and

most importantly for their tireless appraisal of progress and kind reminders.

World Health Organization, Uganda Office and HEPS Uganda for the effort in supervising and

evaluating the project, also providing appropriate administrative structures for conducting the

screening drug quality project.

Representatives from National Drug Authority Headquarters, Quality Control laboratory, Regional

Drug Inspectors, District Drug Inspectors and the people at the drug outlets who interacted with

members of the project implementation for their dedicated commitment, support, advice and

cooperation to ensure that the project succeeded.

And finally, the International MeTA Secretariat and DFID for providing financial support towards

purchase of the GPHF Minilabs and operational costs of implementing the project. This project would

not have been possible without that support.

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Table of contents

Executive Summary ............................................................................................................................................. ii Acknowledgements ............................................................................................................................................. iii Table of contents .................................................................................................................................................. iv 1. Introduction ....................................................................................................................................................... 1 2. Background ....................................................................................................................................................... 1 3. Justification ....................................................................................................................................................... 1 4. Objectives ......................................................................................................................................................... 2

4.1. Specific Objectives .................................................................................................................................... 2 5. Methods and materials ...................................................................................................................................... 2

5.1. Design ........................................................................................................................................................ 2 5.2. Study medicines ......................................................................................................................................... 2 5.3. Sentinel districts/sites................................................................................................................................. 3 5.5. Sampling, sample size and sampling plan ................................................................................................. 4 5.7. Sampling locations ..................................................................................................................................... 5 5.8. Data collection ........................................................................................................................................... 5 5.9 Packaging, labeling, transportation and storage of samples ....................................................................... 6 5.10 Summary of sample handling processes ................................................................................................... 7 5.11 Sample analysis ......................................................................................................................................... 8 5.12 Ethical issues ............................................................................................................................................. 8 5.13 Use of study results ................................................................................................................................... 8

6.0 Results of the Screening Tests ........................................................................................................................ 9 7.0 Conclusion .................................................................................................................................................... 15 Annex 1: Testing Methods, Procedures and Testing Data Reporting ................................................................... 16 Annex 2 Checklist for Sentinel Site “Drug Testing” Personnel .......................................................................... 18 Annex 3: Sentinel Site Drug Sample Collection and Testing Report Form........................................................ 19 Appendix 2: General Rules for Interpreting TLC Results ................................................................................... 22 8. References ....................................................................................................................................................... 23

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1. Introduction

The Medicines Transparency Alliance (MeTA) is a DFID initiative that brings together public, private and

civil society stakeholders with an interest in the outcomes of the medicines market. MeTA aims to increase

transparency in the medicines market specifically in low- and middle-income countries, thereby strengthening

healthcare governance and encouraging responsible business practice.

MeTA Uganda conducted a quality assessment project on four selected medicines including Co-trimoxazole,

Amoxycillin, Ciprofloxacin and Artemether/Lumefantrine tablets to augment efforts of the National Drug

Authority in curtailing sale of poor quality medicines to the population. The project was implemented by

Makerere University Department of Pharmacy in collaboration with the National Drug Authority.

2. Background

Health care professionals and patients assume that the medicines they use are of good quality, but recent

reports indicate that substandard and counterfeit medicines are widely available, especially in countries with

resource constraints, inadequate regulations and shortage of human resources for health. The Uganda Health

system like other developing countries is over-stretched with over-whelming disease burden and limited

resources to fund ever increasing drug needs. The health worker crisis has been worsened by brain. All these

factors affect the impact of efforts implemented to ensure safe, quality and efficacious pharmaceuticals are

accorded to the populace.

The task of ensuring quality medicines in Uganda is the mandate of Uganda National Drug Authority. It is

directed by law, to ensure the quality, safety, and efficacy of all pharmaceutical products marketed in Uganda

in addition to cosmetics, chemical devices and household chemicals. Once a product has been granted

marketing authorization by the NDA Board, the quality of consequent batches of the product either locally

manufactured or imported is to be assessed regularly. Currently, the National Drug Authority conducts for-

cause testing of all anti-retroviral drugs, anti-malarial drugs, anti-tuberculosis drugs and condoms. Other

pharmaceutical products are analyzed on a needs basis.

Despite all the strategies implemented by the Uganda Ministry of Health, anecdotal evidence shows that

counterfeit and substandard medicines are still prevalent in the Ugandan market. Given the high prevalence of

infectious diseases in the Ugandan population, the dealers in this business target antimicrobial medicines and

distribute them to remote and peripheral areas of the country. Because of the complexity of assuring quality in

resource limited settings, it has been advocated that drug regulatory authority activities are augmented by

screening drug quality programs run in such a manner as to collect accurate information that better represents

the quality of medicines made available to the consumers. Such interventions should be adapted to the reality

in the field of each sentinel site, taking into consideration the availability of human and financial resources, all

the logistics required for sampling and testing drugs, and most importantly the close collaboration between

the critical stakeholders in the ensuring a healthy population. Therefore, the drug quality screening project was

conducted with this view mind so as to add another dimension to drug quality assurance in a country such as

Uganda with limited capacity.

3. Justification

The quality of medicines is a topic of global concern. Hence, monitoring the quality of all essential medicines,

once they are on the market is a high priority for the Ministry of Health. Testing is the only way to check

quality of marketed medicines. Ministry of Health and National Drug Authority has made tremendous advance

in improving the quality of medicines available to the Ugandan population. However, there is incongruence

between human and financial resources available to them versus the scale of geographical area and medicine

quality control activities to cover that some substandard and counterfeit pharmaceuticals end up in the

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distribution chain. As a result, the screening drug quality project was proposed by MeTA Uganda as a

pragmatic strategy to augment existing regulatory and oversight infrastructure of the Uganda Ministry of

Health and National Drug Authority.

Furthermore, it was prioritized in this project that some pharmaceutical distributors in Uganda are supported to

establish or strengthen drug quality assessment and monitoring systems in their practice. The strength of such

an arrangement lay in the fact that it permits an independent and neutral external quality assurance mechanism

while building capacity of drug quality assurance in the private sector pharmaceutical distributors.

4. Objectives

To improve the quality of medicines accessed by populations in the rural areas of Uganda by

employing innovative drug quality surveillance process.

4.1. Specific Objectives

To determine the proportion of the sample medicines that has not been granted marketing

authorization by the National Drug Authority.

To screen selected drug products using the Minilabs so as to identify suspicious medicine products

To establish a mechanism of sharing information about quality of medicines between reputable

pharmaceutical distributors and the Drug Regulatory Authority.

5. Methods and materials

5.1. Design

It was a field based project employing a cross sectional design. Medicine samples of co-trimoxazole 480mg

and 960mg tablets, ciprofloxacin 500mg tablets, amoxicillin 250mg or 500mg capsules and

artemether/lumefantrine 20/120mg tablets were collected from a stratified random sample of drug outlets in

Mbarara, Arua and Iganga/Mayuge districts.

5.2. Study medicines

Tracer products of co-trimoxazole 480mg tablets, ciprofloxacin 500mg tablets, amoxicillin 250mg or 500mg

capsules and artemether/lumefantrine tablets were selected through an extensive multi-stakeholder

consultative process involving MeTA Council and the Drug Regulatory Authority. Further explanation about

the choice of medicines is provided below;

1. Antimalarial medicine; Artemether/Lumefantrine is recommended as the first line medicine for treatment

of uncomplicated malaria in the National Malaria Treatment Policy. Malaria causes significant

proportion of disease burden in Uganda and hence the antimalarials market was considered by the project

team as a good target for unscrupulous suppliers of poor quality medicines.

2. Antibacterial agents including Amoxicillin capsules, Co-trimoxazole tablets and Ciprofloxacin tablets.

Amoxicillin is widely used for conditions that have a high prevalence in Uganda such as pneumonia in

children and other bacterial respiratory infections. Co-trimoxazole is also used for bacterial respiratory

infections, enteric infection and primary prophylaxis in HIV/AIDS victims. Ciprofloxacin is used to treat

the deadly Salmonella typhi infection and urinary system infections. Because of the high prevalence of

conditions in which these medicines are used, there is high affinity for supplying poor quality medicines

and the potential negative impact of distributing sub-standard products is significant.

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All the brands of the study medicine/formulation available at the sampled drug outlets in the sentinel

districts during the study period were collected and assessed.

5.3. Sentinel districts/sites

Sentinel districts were selected basing on information about high risk areas for poor quality medicines. In

consultation with NDA, districts that were considered major beneficiaries of unregulated ports of entry of

medicines into the country were prioritized for the first phase of this drug quality surveillance project. The

sentinel districts included in this phase/ sampling round of the project were;

Arua which is located in West Nile at a corner border point among Uganda, Southern Uganda and

Democratic Republic of Congo.

Iganga/Mayuge district which are major destinations and market for medicines that are smuggled across

lake Victoria from Kenya and Tanzania

Mbarara district which is located in the South West of Uganda. It serves as a gate way to the South West

and parts of the Western Uganda.

Within each sentinel district, the District Health office (DHO) was the point of entry and planning for

collection of data and samples in that district. Once the DHO had been briefed on the nature and approach of

the project, he delegated the District Drug Inspector to work with the consultant in planning the sampling of

drug outlets and eventual collection of medicine samples. All this was done with the knowledge of the

Regional NDA Inspector who had been contacted earlier.

The study team assumed that the District Drug Inspector was a person who was knowledgeable about the

various drug outlets that acted as sources of medicines for the population.

The study team designed this component/aspect of data collection so that the community of drug outlets did

not link the data collectors to the National Drug Authority. Any association of the data collectors and study

team with the National Drug Authority would render it difficult to collect samples of study medicines from

informal drug outlets.

The starting point for sampling was the following; for Mbarara, Iganga and Arua, the main or biggest public

hospital in the area, i.e. Mbarara Regional referral hospital, Iganga hospital and Arua hospital respectively.

Within the sentinel districts, drug outlets were categorized into formal and informal facilities.

The formal facilities were further be grouped into public health facilities, private pharmacies, private drug

shops, and clinics. Once the list of potential sample collection sites was obtained, the study team proceeded to

randomly select which facilities to use as sampling sites; two facilities of each category.

Table 1. Sampling frame for each category of facilities in Iganga/Mayuge and Arua districts

S.No Drug Outlet Total Number of Facilities

Iganga/Mayuge District

1 Public Health Facilities (Hospitals & HC IV) 2

2 Pharmacies 12

3 Drug shops 145

4 Clinics 25

5 Informal outlets (estimate) 30

Arua

1 Public Health Facilities (Hospitals & HC IV) 1

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2 Pharmacies 7

3 Drug shops 45

4 Clinics 33

5 Informal outlets (estimate) 30

5.5. Sampling, sample size and sampling plan

5.5.1 Sampling and selection of drug outlets per category in the districts

Iganga / Mayuge

Two public health facilities were studied; Mayuge HC III and the Iganga Hospital. This was to represent the

urban and rural health facilities. The available trace drugs were collected from the centres. Mayuge district had

only one wholesale pharmacy, which was conveniently included in the sample. Other pharmacy outlets were

randomly sampled using labelled papers put in a polythene bag. Three were selected to represent wholesale

and retail outlets.

The drug shops were selected from both districts. Random sampling was done to identify each with one from

each district. Only one clinic had the tracer medicines needed in their original packs. Most did not either have

the medicines or the quantities needed were not enough in their original pack. The informal outlets did not

have the required medicines and therefore could not avail any samples for our study.

Arua

There is only one public health facility (Arua Regional Referral Hospital) situated in Arua town along the busy

Arua Main avenue. This facility was chosen to represent the public sector.

A total of seven (7) pharmacy outlets are in the district town centre, 2 are exclusively wholesalers and the

others (5) conduct both wholesale and retail business activities. The two wholesalers were conveniently

included in the sample, whereas two others were randomly sampled to represent the retailers. The names of

five pharmacy outlets were written on small pieces of paper folded and put in a polythene bag and mixed. Two

papers were randomly picked for the study.

Drug shops are spread across the district with most being in shopping centres and towns. Most are under

stocked and could not provide the required drug samples needed for this study. One registered drug shop was

identified and provided the drug samples. Similarly two clinics were sampled from the registered total, and we

took samples from one of them.

The informal outlets number was an estimate, since all are not know by the authorities. We did not have a

sampling frame for them. They were identified randomly during the movement to other drug outlets. One drug

shop and two clinics were able to avail the trace drugs we were interested in.

5.5.2 Sample size and sampling plan

The sampling strategy took into consideration the following; different lots, different regions, different

categories of drug outlets and all available sectors.

A sample consisted of a number of tablets/capsules of the same manufacturing batch collected at the same

collection site.

A sample was made of: a) three sets of at least 60 tablets (or capsules) each or b) the number of sealed

packages that is necessary to make three sets of at least 60 tablets or capsules each.

Hence, sample size was three sets of at least 60 units from the same lot number, same location/outlet; except if

fewer units are found.

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A sample of all branded and/or generic presentations (i.e. same product name, same manufacturer, same

dosage form, same package size, same packaging material and same strength) of the selected medicines

available at each sampling site was collected. All administration units (e.g. tablet, capsule) of one sample were

of the same batch or the same dispensing container in the case of loose items.

5.7. Sampling locations

Convenience sampling was used based on following principles;

Sectoral coverage – public and private, formal and informal; give priority to following order;

wholesalers or distributors, pharmacies, retail drug outlets, hospitals and clinics.

Geographical coverage – urban, suburban and rural areas within the sentinel site areas

Main route/ flow of drug supply or distribution or circulation route of medicines and how it affects

physical access.

Common drugs and preparations from different brands, sources of manufacture, lots/batches of

artemether/lumefantrine 20/120mg, ciprofloxacin 500mg, amoxicillin 250mg and 500mg and co-

trimoxazole 480mg and 960mg.

5.8. Data collection

All samples were collected between August 29th and November 10

th 2013 from the sentinel district agreed

upon by the Study Steering Committee. Samples were sent to the testing site (Makerere University Pharmacy

Department, Pharmaceutical Chemistry laboratory) as soon as possible.

Sample collection

The study team collected up to 3 samples (cumulative) of each of the tracer medicine products; ensuring, as far

as possible, that a) all surveyed medicines and b) all circulating batches were represented while ensuring that

all units of one sample were of the same batch. If this was not possible, then less than 3 samples were sent for

testing.

The data collectors filled out the following form;

Sentinel site drug sample collection and testing report form

Additional precautions for sample collection

Sampling form was properly filled out and safely attached to sample container

The medicine samples were kept/stored according to manufacturer’s recommended storage conditions

The samples were managed in such as a manner as to allow traceability of the sample source; where

possible samples were left in their original container or package with drug label.

Arrangements were made to ensure replacement or purchase of samples collected at sampling sites,

when necessary.

Sample coding and labelling

In order to avoid confusion each sample was assigned a unique code number for identification and traceability.

This code included the sentinel district name, type of facility/drug outlet, generic name, sampling date and a

sequential number of the sample, as follows;

District name: AR for Arua, IG for Iganga, MB for Mbarara,

Type of drug outlet: Formal, F; Public Health facility: PHF

Informal I; Pharmacy, PHA

Drug shop, DS

Clinic, CL

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Generic name of medicine (INN): AL, AM, CI, CO

Sampling date: DD-MM-YY

Sample sequential number: from 01 to 99.

E.g. for the first sample of Artemether/Lumefantrine collected in Arua on 10 August 2013, from public health

facility, the code would be: AR-PHF-AL-100813-01

Whenever it was necessary to collect more than one original package in order to obtain the required number of

units, all original packages were marked with the appropriate sample code.

Sample envelopes were labelled mentioning the sample code number as well as the generic and trade

name of each product.

Information collected

The product details were indicated for each sample collected in the Sample Collection Form, see Annex

3.

At the end of sampling the technical consultant informed the study team to organize the validation of

sampling, i.e. the verification of the samples collected (quantity, appropriateness, and suitability for

sending to testing facility) and completeness and accuracy of documentation that accompanies samples.

5.9 Packaging, labeling, transportation and storage of samples

Whenever possible such as blister pack preparations, the samples were picked in their original packaging and

labeling. The sampling form was filled out and attached to drug sample. The container or plastic bag used was

sealed, tamperproof/tamper-evident and appropriately labeled. Precaution was taken to prevent contamination,

adulteration and deterioration due to light, air and moisture. The drug samples were kept at the manufacturer’s

recommended storage conditions found on the label. Protection during transportation was done by filling the

container with cotton batting or other suitable material. Once a sample container was opened by the analyst,

the individual responsible would initial and date it.

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5.10 Summary of sample handling processes

Sample collected

Assign unique code

Finalize sample forms

and make copy

Verify that samples and

documentation are in

order

Properly pack samples and

all documentation and

dispatch by air courier to

testing laboratory

Validation

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5.11 Sample analysis

After validation, samples were sent (see sample transportation below) to the Pharmaceutical Chemistry

Laboratory at Pharmacy Department, Makerere University.

Testing was done as explicated in Annex 1.

5.12 Ethical issues

No ethical issues should arise: quantities sampled were too small to affect availability of needed medicines or

viability of businesses where sampling takes place.

5.13 Use of study results

Due to the sensitive nature of drug quality monitoring and possible conflicts of interest, NO DATA or

RESULT of any preliminary or initial test data obtained at the sentinel sites will be shared with or disclosed to

third parties until it has been verified and discussed among the relevant authorities or agencies concerned

(NDA, MoH, respective distributor), and if applicable with WHO.

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6.0 Results of the Screening Tests

Samples for screening drug quality were picked from a total of twenty nine (29) drug outlets in the three

sentinel districts selected for the screening project.

Figure 1. Distribution of drug outlets by Sentinel Region

Each region contributed almost an equal number of outlets to the total sampled units with the lowest being

South West with eight (8) drug outlet and the highest being West Nile with eleven (11) drug outlets.

Figure 2. Number of drug outlets per category in the total sampled units

The majority of the sampled drug outlets were wholesale pharmacies followed by drug shops/clinics. The

fewest drug outlets were public health facilities.

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Table 2. Number of drug outlets by category in each sentinel region

Category of drug outlet No. of Outlets per Sentinel Region Total

West Nile South West East Central

Wholesale Pharmacy 2 3 3 8

Retail Pharmacy 2 1 2 5

Drug shop & Clinics 2 2 3 7

Informal Outlets 4 2 0 6

Public Health Facilities 1 0 2 3

Total 11 8 10 29

All categories of drug outlets were represented in the sampled drug outlets.

Table 3. Number of each drug product by category of drug outlet in each sentinel region

Drug outlet Artemether/Lumefa

ntrine 120/20mg

Amoxycillin 250mg

or 500mg

Ciprofloxacin

500mg

Co-trimoxazole

480mg or 960mg

WN SW EC WN SW EC WN SW EC WN SW EC

Wholesale Pharmacy 1 7 3 2 3 3 1 3 3 2 4 3

Retail Pharmacy 2 2 2 2 2 3 2 2 2 2 2 1

Drug Shops & Clinics 2 2 3 1 1 3 0 3 3 2 2 3

Informal Outlets 1 3 0 2 0 0 3 0 0 0 1 0

Public Health Facilities 1 - 2 1 - 2 0 - 2 1 - 2

Total 7 14 10 8 6 11 6 8 10 7 9 9

Key; WN – West Nile, SW – South West, EC – East Central

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Table 4. Results of the Screening tests per sampled Amoxycillin 250mg and 500mg tablet product

Code Brand

Code

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample Spot

Intensity

Basic Test

Overall

Conclusion

MB-AM-02 I Pass 2.22% Pass BTN 80&100 Pass

MB-AM-13 I Pass 0.00% Pass BTN 80&100 Pass

AR-AM-10 I Pass 0.00% Pass BTN 80&100 Pass

AR-AM-23 I Pass 0.00% Pass BTN 80&100 Pass

IG-AM-19 II Pass 2.27% Pass LESS THAN 80 Fail

AR-AM-09 II Pass 0.00% Pass LESS THAN 80 Fail

IG-AM-21 III Pass 0.00% Pass BTN 80&100 Pass

MB-AM-20 IV Pass 0.00% Pass LESS THAN 80 Fail

IG-AM-03 IV Pass 0.00% Pass BTN 80&100 Pass

MAY-AM-12 IV Pass 0.00% Pass BTN 80&100 Pass

MB-AM-14 V Pass 0.00% Pass BTN 80&100 Pass

AR-AM-19 V Pass 0.00% Pass BTN 80&100 Pass

AR-AM-27 V Pass 2.50% Pass BTN 80&100 Pass



MAY-AM-07 VI Pass 0.00% Pass BTN 80&100 Pass

IG-AM-20 VII Pass 0.00% Pass LESS THAN 80 Fail

MAY-AM-04 VII Pass 0.00% Pass BTN 80&100 Pass

IG-AM-15 VII Pass 0.00% Pass LESS THAN 80 Fail

AR-AM-14 VII Pass 0.00% Pass BTN 80&100 Pass

IG-AM-27 VIII Pass 0.00% Pass BTN 80&100 Pass


AR-AM-04 VIII Pass 0.00% Pass BTN 80&100 Pass


AR-AM-20 VIII Pass 1.96% Pass BTN 80&100 Pass

Out of 25 sample products of Amoxycillin capsules (250mg or 500mg), 5 sample products failed the basic

screening test. The reason for all the failures was that the sample spot intensity was different from that of the

standard spot.

Figure 3. Number of Amoxycillin 250mg or 500mg capsule products that passed or failed the screening

tests

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Table 5. Results of screening tests for Artemether/Lumefantrine 20/120mg tablet products

Sample Code

No.

Brand

Code Basic Test

Overall Conclusion

Visual & Physical

Inspection

Conclusion

Disintegration (time)

Disintegration Conclusion

TLC: Principal Spot

Rf % Sample

Difference

TLC: Principal Spot

Conclusion

TLC: Sample Spot Intensity


Conclusion

TLC: Presence of

Impurity

Spots

TLC: Impurities

Conclusion

1 MB-AL-26 I Pass 2MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS



4 IG-AL-12 I Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS



7 MAY-AL-02 I Pass 5MINUTES PASS 2.27% PASS BTN 80&100 PASS N/Ap PASS PASS


9 AR-AL-16 II Pass 6MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

10 IG-AL-01 II Pass 7MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

11 MB-AL-35 II Pass 7MINUTES PASS 1.12% PASS BTN 80&100 PASS N/Ap PASS PASS

12 IG- AL- 06 III Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

13 MB-AL-18 III Pass 4 MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

14 MB-AL-05 III Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

15 AR-AL-01 III Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

16 MB-AL-36 IV Pass 2MINUTES PASS 2.27% PASS BTN 80&100 PASS N/Ap PASS PASS

17 IG-AL-16 IV Pass 2MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

18 IG-AL-05 IV Pass 2MINUTES PASS 2.27% PASS BTN 80&100 PASS N/Ap PASS PASS

19 AR-AL-11 IV Pass 2MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

20 IG-AL-14 V Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

21 IG-AL-02 V Pass 6MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

22 MB-AL-29 V Pass 3MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

23 AR-AL-06 V Pass 6 MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

24 AR-AL-18 V Pass 5MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS

25 MAY-AL-06 V Pass 2MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS




29 MAY-AL-01 V Pass 4MINUTES PASS 0.00% PASS BTN 80&100 PASS N/Ap PASS PASS



All the Artemether/Lumefantrine 20/120mg tablet products passed the screening tests.

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Table 6. Results of screening tests for sampled Co-trimoxazole 480mg and 960mg tablet products

Sample Code No.

Brand Code

Basic Test Overall

Conclusion

Visual &

Physical

Inspection Conclusion

Disintegration

(time)

Disintegration

Conclusion

TLC: Principal Spot

Rf % Sample

Difference

TLC:

Principal Spot

Conclusion

TLC: Sample

Spot Intensity

TLC: Sample

Spot Intensity

Conclusion

TLC: Presence

of Impurity

Spots

TLC:

Impurities

Conclusion

1 IG-CO-07 I Pass 2minutes Pass 0.00% pass 100 Pass N/Ap Pass Pass

2 MB-CO-03 I Pass 1minute Pass 0.00% Pass 100 Pass N/Ap Pass Pass

3 AR-CO-28 II Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

4 AR-CO-02 III Pass 1 minute Pass 0.00% Pass 100 Pass N/Ap Pass Pass

5 MAY-CO-10 III Pass 1minute Pass 1.06% Pass 100 Pass N/Ap Pass Pass

6 MB-CO-07 III Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass



9 MAY-CO-03 III Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

10 AR-CO-15 IV Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

11 AR-CO-25 IV Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

12 MB-CO-33 V Pass 2minutes Pass 0.93% Pass 100 Pass N/Ap Pass Pass

13 MB-CO-21 V Pass 4minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

14 IG-CO-09 V Pass 1minute Pass 0.00% Pass 100 Pass N/Ap Pass Pass

15 IG-CO-25 V Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

16 MB-CO-17 V Pass 1minute Pass 0.00% Pass 100 Pass N/Ap Pass Pass

17 AR-CO-22 VI Pass 2 minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

18 AR-CO-17 VI Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

19 MB-CO-12 VI Pass 1minute Pass 1.77% Pass 100 Pass N/Ap Pass Pass

20 IG-CO-10 VI Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

21 AR-CO-05 VII Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

22 MAY-CO-08 VII Pass 2minutes Pass 1.22% Pass 100 Pass N/Ap Pass Pass

23 IG-CO-17 VII Pass 3minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

24 IG-CO-26 VII Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

25 MB-CO-11 VII Pass 2minutes Pass 0.00% Pass 100 Pass N/Ap Pass Pass

All the co-trimoxazole 480mg or 960mg tablet products passed the screening tests.

14

Table 7. Results of screening tests for Ciprofloxacin 500mg tablet products

Sample Code No. Brand

Code Basic Test

Overall Conclusion

Visual & Physical Inspection

Conclusion

Disintegration (time)

Disintegration Conclusion

TLC: Principal Spot Rf % Sample

Difference

TLC: Principal Spot

Conclusion



Conclusion

TLC: Presence of Impurity

Spots

TLC: Impurities

Conclusion

1 AR-CI-26 I Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

2 IG-CI-22 II Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

3 IG-CI-13 III Pass 4minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

4 MB-CI-32 III Pass 7minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass




8 MAY-CI-09 III Pass 4minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

9 AR-CI-21 IV Pass 2minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

10 AR-CI-12 IV Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

11 IG-CI-24 V Pass 2minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

12 IG-CI-18 V Pass 3minutes Pass 2.38% Pass BTN 80&100 Pass N/Ap Pass Pass

13 MB-CI-09 V Pass 4minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

14 MB-CI-15 V Pass 6minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

15 MAY-CI-11 VI Pass 3minutes Pass 0.56% Pass BTN 80&100 Pass N/Ap Pass Pass

16 AR-CI-08 VII Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

17 MAY-CI-05 VII Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

18 IG-CL-08 VII Pass 4minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

19 IG-CI-23 VII Pass 5minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

20 IG-CI-11 VII Pass 2minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

21 AR-CI-03 VIII Pass 3minutes Pass 1.19% Pass BTN 80&100 Pass N/Ap Pass Pass

22 AR-CI-24 IX Pass 3minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

23 MB-CI-23 IX Pass 3minutes Pass 2.27% Pass BTN 80&100 Pass N/Ap Pass Pass

24 MB-CI-01 IX Pass 2minutes Pass 0.00% Pass BTN 80&100 Pass N/Ap Pass Pass

All the ciprofloxacin 500mg tablet products passed the screening tests.

15

7.0 Conclusion

Of all the sampled products, only Amoxycillin 250mg or 500mg capsules had some failures (5/25

samples) on the screening tests. These products failed on the identity test as the sample spot intensity was

different from the standard spot intensity. All the other products of Artemether/Lumefantrine 20/120mg

tablets, Ciprofloxacin 500mg tablets and Co-trimoxazole 480mg or 960mg tablets passed the screening

tests. The failed Amoxycillin capsule products were forwarded to NDA Quality Control Laboratory for

verification and confirmatory tests.

16

Annex 1: Testing Methods, Procedures and Testing Data Reporting

1. Testing methods and reference materials, substances and/or standards

• Basic testing/screening level: Testing methods and procedures are described in the GPHF-Minilab

Manual and the reference substances/product provided by GPHF-Minilab kits were used. These

tests are in conformance with USP DQI. The tests cover:

Physical/visual inspection/examination (manufacturing source, counterfeit or suspicious

drugs)

Simple disintegration for solid dosage forms

TLC (identity of active ingredient, content/concentration, impurities versus authentic

reference standards) (see Appendix 2 for General rules TLC result interpretation)

17

3. Testing data reporting

The Report from the Study team to DRA and key stakeholders should include a copy of the

completed Sentinel Site Drug Sample Collection and Testing Report Form (Annex 3). All results

(passed and failed) should be sent simultaneously to DRA.

For-cause or emergency reporting (as necessary) – The site must report any “for cause” incidents

to the NDA Lab, which will verify the testing results and will take any necessary action.

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Annex 2 Checklist for Sentinel Site “Drug Testing” Personnel

Before going out for sampling, the sampling team must check that all the following has been complied

with:

- Training of the sampling team

- Developed written itinerary to travel efficiently and reach the maximum number of sampling sites

in shortest time and most economical way

- Checked availability of all items related to sampling and brought checklist along

- Enough Sampling Forms

One form is to be filled out for each sample - consider extra forms in case of mistakes

- Sampling Plan

The sampling team must prepare a sampling plan in accordance with the study protocol and plan

ahead of time for each day of sampling

- Enough Sampling Containers

Obtain new plastic (zipper bags are ideal), opaque, clean containers to store and transport samples.

Each sample requires a container, a label (with name of collector, name of drug, sampling site, date

of collection), and containers must be tightly closed.

Sampling forms should go into plastic bags (double check that the sampling form contains all

required information before inserting it).

Samples collected from the same site need to be placed in one labelled box.

- Indelible markers, pens and pencil

Use indelible markers to label the sampling containers

- Dedicated book to keep all notes on survey

Please use a separate book dedicated only to the study and record complete and accurate information

about samples right when they are collected.

- Sampling tools

Scissors, Gloves, Tape, Watch, Labels

- Logistics

Transportation, money (or other appropriate means) for purchasing samples, cardboard boxes to

store the samples collected.

- Optional items

If your office already has a digital camera used in pharmaceutical inspections, please use it to

take pictures of sample sites and samples.

19

Annex 3: Sentinel Site Drug Sample Collection and Testing Report Form

Report No. -------------/-----------------------------(district name)

SAMPLE INFORMATION

Sample CODE/Serial Number: )

Name of location/place where sample was taken

Street address (with telephone and fax number, if

applicable)

Date of sampling

Drug Name (trade or brand name)

Generic or INN1 name

Dosage form and strength

Manufacturer’s Batch or Lot Number

Manufacturing date

Expiry date

Registration or licensed number (if applicable)

Manufacturer name and address

Number of sample units taken (minimum 30

tablets or capsules; 50 for FDCs2)

taken in original package taken from bulk container

Brief physical/visual description of sample

Name of collector(s)/date/sign

Name of seller or representative identified of

establishment where sample was taken

PHYSICAL/VISUAL INSPECTION TEST

Labeling (requirements)

Brand Name of the drug sample (if applicable)

Generic or INN name of active ingredient(s)

Dosage form and strength

Name of reference standard used (as claimed on label

e.g.

USP, BP, IP, EP)

Manufacturer’s Batch or Lot Number

Name of manufacturer and address (with telephone and

fax number if applicable)

20

Manufacturing date

Expiry date

Storage conditions

1 INN is the International Non-proprietary name of a drug product

2 FDCs stand for fixed-dose combination preparations

Packaging

Material (blister pack/card, bottle, others specify)

Unit dose per blister card or container stated

Any print on the backing foil (if packed in blister pack

or

card)

Description of dosage form

Shape (circular, oval, flat sides, other)

Uniformity of shape

Uniformity of color

No physical damage (cracks, breaks, erosion, abrasion,

sticky)

Other observations (no foreign contaminant, dirty marks,

proper seal - for capsule)

Sample serial Number/Code

Specify the test method (s) and reference to a pharmacopeial monograph e.g. USP26, BP e.t.c

DISINTEGRATION TEST

Time of complete

Disintegration expected

30 minutes

Time of complete Disintegration

observed

---------------

Did the drug pass Disintegration

test?

Yes

No

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RESULT OF TLC TEST

Distance moved by

Solvent front:

------------ mm

Did the drug and the standard Spots

have the same intensity?

Yes

No

Did the sample pass quality by

using the TLC test?

Yes

No

Distance moved by the

Standard spot:

------------- mm

Distance moved by the

Sample spot:

------------ mm

Rf(Sample error)

Was there any contaminant spot

on the TLC plate?

Yes

No

Rf (Standard)

Rf (Sample)

Name of API COLOUR REACTION Did sample pass colour reaction

test?

Yes No

Name of API

Yes No

FINAL COMMENTS

The sample meets standards

The sample does not meet standards. Reason:____________________________________

The sample is doubtful for its quality testing. Reason:______________________________

And further testing is needed at a reference lab

Report prepared by:

Date:

Name:

Signature:

Report reviewed by:

Date:

Name:

Signature:

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Appendix 2: General Rules for Interpreting TLC Results

This simple guideline uses the percent Rf error, defined below, to determine the fate of a sample

based on simple TLC.

Rf Sample Error = {|Rf (standard) – Rf (sample)| / Rf (standard)} x 100%

Example

From multiple TLC experiments, the following Rf values were obtained: Rf

(standard) = 0.55

Rf (sample) = 0.53

Then, Rf Sample Error = {(0.55 – 0.53)/0.55} x 100% = 3.6 %

Interpretation of TLC Results

Based on the typical Rf values, broadness of TLC spots and simple error analysis1, some broad rules

can be applied to interpret TLC results. It is important to note that these rules should only be

considered semi-quantitative and not absolute.

1. When Rf Sample Error is 5% or less, the sample can be considered “Pass”

2. When Rf Sample Error is 10% or more, the sample can be considered “Fail”

3. When Rf Sample Error is between 5% and 10%, the sample can be considered

“Doubtful”

Note:

1. If the TLC chamber and plates were not well saturated, or if the saturation has been disturbed the spots may not be horizontal and this could give high Rf sample error.

2. Always make TLC in duplicate and compare the Rf of both runs.

3. When Rf sample error is more than 5%, always make another duplicate run under optimal

conditions to double check the doubt.

1 Quantitative Chemical Analysis, 6th Edition. Daniel C. Harris, W. H. Freeman, New York, 2003.

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8. References

Annual Health Sector Performance Report, 2006/07, 2007.08

Health Sector Strategic Investment Plan III 2010/11-2014/15

MeTA Country Work Plan Guidelines VS.6 January, 2009

MeTA Phase II Proposal, 2012

Ministry of Health.MoH. (2008). Access to and use of medicines by households in Uganda. Kampala:

Ministry of Health.MoH.

Ouagadougou Declaration on primary health Care and Health Systems in Africa 2008

Private Sector Mapping Uganda Mission report, December 2008.

Uganda MeTA Scoping mission report, April 2008

World health Organization Medicines Strategy 2004-2007

The United States Pharmacopeial Convention, Inc 2003 Guidelines for Sampling of Antimalarial Drug

Samples in the USP DQI Antimalarial Drug Quality Monitoring Project in Mekong Sub-region Countries

Newton PN, Lee SJ, Goodman C, Fernández FM, Yeung S, et al. (2009) Guidelines for field surveys of the

quality of medicines: A proposal. PLoS Med 6(3): e1000052. doi:10.1371/journal.pmed.1000052

Quantitative Chemical Analysis, 6th Edition. Daniel C. Harris, W. H. Freeman, New York, 2003

World Health Organization. WHO Technical Report Series (TRS), No. 902 (2002). Annex 3: Good practices for

national pharmaceutical control laboratories. http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37

http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37

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