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MeTA Uganda

Screening Drug Quality Project

Report by

Freddy Eric Kitutu, MSc.

Pharmacy Department,

Makerere University College of Health Science

Kampala, Uganda

© November 2015

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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 quality of medicine survey with both the field and quality screening components. The field

component included selection of a sample of drug outlets and following the protocol instructions to pick

medicine samples of selected anti-infective and non-anti-infective agents. Quality screening component

included physical and visual inspection and use of GPHF Minilab for semi-quantitative TLC and Color

reactions. The selected medicines for assessment included Ceftriaxone Injection, Cefuroxime tablets and

suspension, Cephixime capsules, tablets and suspension, Cephalexin capsules and suspension, Erythromycin

tablets, suspension and syrup, Furosemide tablets and Injection, Prednisolone tablets. The screening of drug

quality was conducted in the Pharmaceutical Chemistry Laboratory at Pharmacy Department in Makerere

University using GPHF Minilab.

Samples for screening drug quality were picked from three sentinel sites; namely Kawempe division in

Kampala, Mbale and Kasese districts.

Up to 226 drug products of the selected medicines were collected from the sampled drug outlets. These

included 39 Ceftriaxone Injection, 13 Cefuroxime tablets and suspension, 22 Cephixime capsules, tablets and

suspension, 39 Cephalexin capsules and suspension, 55 Erythromycin tablets, suspension and syrup, 25

Furosemide tablets and Injection, and 36 Prednisolone tablets.

Among the selected medicines, ceftriaxone injection, cephalexin suspension and capsules, prednisolone

tablets and furosemide tablets and injection passed the screening tests. The rest of the selected medicines

had suspicious products among them as follows; 12 out of 22 cefixime products were suspicious, 3 out of 13

cefuroxime products were suspicious and 10 out of 40 erythromycin products were suspicious. Further testing

of the failing products is recommended particularly for cefixime, cefuroxime and erythromycin products.

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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.

Medicine sampling and quality analysis teams that diligently worked to ensure that this work is

completed.

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

Acknowledgements................................................................................................................................... 3 1. Introduction .............................................................................................................................................. 5 2. Background ............................................................................................................................................. 5 3. Justification .............................................................................................................................................. 6 4. Objectives ................................................................................................................................................ 7 5. Methods and materials......................................................................................................................... 7

5.1. Design ................................................................................................................................................. 7 5.2. Study medicines .............................................................................................................................. 7 5.3. Sentinel districts/sites ...................................................................................................................... 7 5.4. Personnel and Project Management........................................................................................ 8 5.5. Sampling, sample size and sampling plan .............................................................................. 8 5.7. Sampling locations ......................................................................................................................... 9 5.8. Data collection ................................................................................................................................ 9 5.9 Medicine quality analysis ............................................................................................................. 10 5.10 Example procedures followed ................................................................................................. 10 5.11 Summary of sample handling processes .............................................................................. 14

6. Results of the Analysis .......................................................................................................................... 15 Appendix 0: Photos of samples, reagents and filled forms ........................................................... 22 Annex 1: Testing Methods, Procedures and Testing Data Reporting ........................................... 23 Annex 2 Checklist for Sentinel Site “Drug Testing” Personnel ........................................................ 25 Annex 3: Sentinel Site Drug Sample Collection and Testing Report Form ................................ 26 Annex 4: National Laboratory Testing Report Form ..................................................................... 29 Appendix 1: Test Request Form .............................................................................................................. 32 Appendix 2: General Rules for Interpreting TLC Results .................................................................. 33 Appendix 3 Gantt Chart – Screening Drug Quality Activity ......................................................... 34 8. References ............................................................................................................................................. 35

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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 selected anti-infectives and non-anti-infective

medicines including ceftriaxone, cefixime, cefuroxime, erythromycin, prednisolone and furosemide 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

The imperative to achieving health for all in all health systems is access to quality medicines. Medicines are at

the core of service provision for health systems and for many beneficiaries; consistent availability of quality

medicines is the only manifestation of a properly functioning health system. 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 and a health worker crisis worsened by internal and external brain drain. All

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

pharmaceuticals are accorded to the populace. In the Uganda health structure, the task of ensuring

consistent access to quality medicines is the mandate of Uganda National Drug Authority (NDA). 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. The NDA employs a multi-

faceted approach adapted from best practices recommended by World Health Organization and other

pertinent international organizations. Such interventions include regular current Good Manufacturing

Practice (cGMP) inspection for pharmaceutical manufacturing sites, comprehensive evaluation of product

dossiers prior to granting marketing authorization in Uganda, inspection and analysis of medicine batches at

port of entry and routine post marketing surveillance. Although, there is global consensus on the importance

of post market surveillance, there is evidence to suggest many low and middle income countries do not

have the requisite infrastructure, expertise, processes and systems to mount commensurate post market

surveillance activities to eliminate or drastically reduce prevalence of falsified or substandard medicines in

medicine distribution chains. Additionally, these agencies have inadequate financial resources to undertake

neither field screening nor laboratory testing of medicines and thereby guarantee supply chain systems proof

to penetration of falsified and substandard medicines. Medicine quality assessment on a routine basis

requires well trained personnel, equipment, reference standards and related consumable reagents and

supplies. Field activities and assays are cost intensive and running even full scale post marketing surveillance

activity carries the potential to bankrupt a drug regulatory authority’s annual drug testing budget [7, 9]. Drug

surveillance also requires laboratories for quality testing and NDA has been able to mobilize resources to

establish an up-to-date quality control laboratory. To ensure efficient use of the limited available resources

stakeholders including the drug regulatory agency agree that stronger collaborations with academia and

other actors in the pharmaceutical supply chain should be pursued.

Global consensus acknowledges the added burden that post market surveillance for quality of medicines

places on drug quality laboratories and recommends that universities and research consortia to play a role

to reduce that pressure while safe guarding public health goals. Academia in resource poor countries can

use the minilab® and hand-held detection technologies to alleviate the added strain surveillance testing will

place on drug quality laboratories and can provide the needed expert workforce dedicated to data

analysis and the prompt dissemination of public alerts when necessary [7].

In line with the above argument and on realization the complexity of assuring quality medicines in resource

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

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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. Pharmaceutical analysis 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 distribution chain. And presence of falsified and substandard medicines in

any pharmaceutical chain has dire short-and long-term consequences for the public health.

Evidence shows that the use of falsified and substandard drugs can have several adverse consequences;

including mass poisoning [1], treatment failure in acute, chronic and infectious diseases [2-5] and

encouraged drug resistance thereby threatening today’s and future populations [6]. Use of falsified and

substandard medicines in unsuspecting health systems presents social and economic consequences such as

wastage of already limited financial resources in terms of raising drug costs to patients and the health

system. Drug resistance also reduces the useful life cycle of a drug and society must bear direct and indirect

costs of new drug development[7, 8]. A compromised drug supply causes stakeholders to lose confidence in

medicine, health care providers and national regulatory agencies[7].

Penetration of falsified and substandard medicines into the legitimate supply chain especially in low and

middle income countries is uniquely important. It has become the focus of public health and policy research

for the following key reasons:

First, incidents of substandard medicines of antibiotic medicines have not been well evaluated in

any systemic manner taking into account the illegal supply chains and unregulated markets.

Second, substandard medicines can penetrate both weak and highly controlled counterfeit

medicines medicine supply chains alike highlighting the need for routine post marketing surveillance to

mitigate determinant vulnerabilities and supply chain complexities.

Finally, this medicine quality assessment supports global and national communities to provide fact-

based recommendations and practices in curtailing antimicrobial resistance and attendant adverse effects

of the use of falsified and substandard medicines. Preserving antimicrobial agents has become imperative

and is significantly dependent on maintaining good quality of drugs as well as promoting rational drug use

[7].

Consequently, evidence of existence of substandard and falsified antimicrobials has mostly been from

incidental findings found in newspaper reports or findings from studies designed to address different

objectives [10-12]. Additional evidence has been adduced from studies that employed convenience

samples and sometimes small numbers of samples hence are non-probabilistic and are not based on valid

sampling frames [11, 12]. Such studies are only good as signaling events of the existent problem, cannot

accurately estimate the population prevalence or incidence of falsified and substandard medicines [7, 13]

and only serve to emphasize the need for more rigorous systematic research [11]. It remains unclear as to

what extent substandard and falsified medicines cause adverse patient outcomes and antimicrobial

resistance.

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.

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4. Objectives

To determine the quality of medicines accessed by the Ugandan population using representative

sampling methods

Specific Objectives

To sample selected medicines from drug outlets in sentinel districts and screen the medicine

products using the GPHF Minilab with the aim of identifying suspicious medicine products.

5. Methods and materials

5.1. Design

It was a field based project employing a cross sectional design. Medicine samples of Ceftriaxone Injection,

Cefuroxime tablets and suspension, Cephixime capsules, tablets and suspension, Cephalexin capsules and

suspension, Erythromycin tablets, suspension and syrup, Furosemide tablets and Injection, Prednisolone

tablets. Samples of these medicines were collected from a stratified random sample of drug outlets in

Kawempe division – Kampala, Kasese and Mbale districts.

5.2. Study medicines

Tracer products of Ceftriaxone Injection, Cefuroxime tablets and suspension, Cephixime capsules, tablets

and suspension, Cephalexin capsules and suspension, Erythromycin tablets, suspension and syrup,

Furosemide tablets and Injection, Prednisolone tablets were selected through an extensive multi-stakeholder

consultative process. There was particular need to determine whether there were poor quality medicines

among the antibacterial medicines given the lack of evidence and the concern of substandard medicines

contributing to antimicrobial resistance.

All the medicine products 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 risk area of distribution of substandard medicines

in the country were prioritized for this phase of the drug quality surveillance project. The sentinel districts

included round of the project were; Kawempe division – Kampala, Kasese and Mbale districts.

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.

Medicines were collected from facilities grouped into public health facilities, private pharmacies, private

drug shops, and clinics.

Once the list of potential sample collection sites was obtained, and it’s big, the study team proceeded to

randomly select which facilities to use as sampling sites.

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5.4. Personnel and Project Management

MeTA Council, Uganda Chapter provides overall responsibility and oversight of the project. This MeTA

Council has multi-stakeholder representation with members from Government institutions and

departments such as Ministry of Health, NMS, NDA PPDA, private pharmaceutical sector and Civil Society

Organizations.

The Project Steering/Technical Team has three representatives from the MeTA Council. The

representatives include WHO representative, CSO, Academia, DRA and the technical consultant team

implementing the project.

The project team refers to the consultants’ team contracted to implement the project.

The District Study team was composed of the DHO or his/her representative, and the research

assistants/mystery buyers. All these members were selected from the district local community to ensure

that the data and medicine samples collected from the field are representative of what the community

access.

5.5. Sampling, sample size and sampling plan

The sampling strategy took into consideration the following; different lots, different locations and all available

sectors.

A sample was 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; ports of

entry, wholesalers or distributors, pharmacies, retail drug outlets, hospitals and clinics, national health

program warehouses, and street vendors.

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

targeted medicines.

5.8. Data collection

Proposed survey dates

All samples were collected between July 1st 2015 and September 30th 2015 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) for solid dosage forms and 1 to 5 samples for

suspensions and injection dosage forms 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 forms;

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: KS for Kasese, KM for Kampala, MB for Mbale,

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

Informal I; Pharmacy, PHA

Drug shop, DS

Clinic, CL

Generic name of medicine (INN): TRI (ceftriaxone), IXI (cefixime), ALE (cefalexin), URO (cefuroxime), PRE

(prednisolone), FUR (furosemide), ERY (erythromycin)

Sampling date: DD-MM-YY

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Sample sequential number from 01...

E.g. for the first sample of Ceftriaxone collected in Kasese on 7th July 2015, from public health facility, the

code would be: KS-PHF-TRI-070715-01

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.

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.

5.9 Medicine quality analysis

The medicine quality screening followed the following phases of assessment;

Visual and physical inspection using an adapted checklist

TLC for identity and semi-quantification

Color reaction tests for identity if available

Disintegration test for solid dosage forms

5.10 Example procedures followed

Visual inspection

Visual inspection of the sampled products was done to identify deficiencies in labeling, packaging and

dosage forms using an adapted checklist/reporting form (see Appendix). All the product particulars were

documented using the reporting form as a guide.

Disintegration test

All quick release tablets and capsules should pass the disintegration test. They should disintegrate in water at

37°C in less than 30 minutes.

Specific drug screening for Cefixime – Semi quantitative TLC

Cefixime was extracted from tablets and capsules with methanol and determined by TLC with reference to

an authentic secondary standard.

Preparation of a stock standard solution

A reference tablet was wrapped into aluminium foil and crushed to fine powder using a pestle. The powder

was emptied into a 40-ml glass bottle and residual solids were washed down with 25ml of methanol using a

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straight pipette. The bottle was shaken for about three minutes until most of the solids were dissolved. The

solution was left to sit for at least five minutes to allow undissolved residues to settle below the supernatant

liquid.

To prepare the 100% working standard solution, 1 ml of stock standard solution was pipetted into a 10-ml vial

and 7ml of methanol was added. The vial was shaken. This solution has concentration of 1mg of drug per ml

and was labeled Cefixime Working Standard Solution 100%.


and 9ml of methanol was added. The vial was shaken. This solution has concentration of 0.8mg of drug per

ml and was labeled Cefixime Working Standard Solution 80%. This is the lower acceptable limit for good

quality.

Preparation of stock sample solution from a product claiming to contain:

1. 200mg of Cefixime – Sample tablet was crushed in aluminium foil into fine powder. The powder was

transferred to 40ml glass bottle. For capsules, even the cap and body shell were transferred. To extract,

25mls of methanol were added using a straight pipette, the bottle was closed and shaken for three

minutes until most of the solids were dissolved. The solution was left to sit for at least 5 minutes for

undissolved residues to settle below the supernatant.

2. 400mg of Cefixime per unit. – Sample tablet was crushed in aluminium foil into fine powder. The powder

was transferred to 100ml glass bottle. For capsules, even the cap and body shell were transferred. To

extract, 50mls of methanol were added using a straight pipette, the bottle was closed and shaken for

three minutes until most of the solids were dissolved. The solution was left to sit for at least 5 minutes for

undissolved residues to settle below the supernatant.

N.B: All stock sample solutions produced finally contained 8mg of total drug per ml and were labeled as

Cefixime Stock Sample Solution.

Caution: For each test, these solutions were freshly prepared. The lab technicians ensured we work with clear

or hazy supernatant liquids.

To prepare working sample solution for each sampled product, 1ml was pipetted from the stock sample

solutions (above) into 10ml and 7mls of methanol were added. The preparation was shaken and labeled as

Cefixime Working Sample Solution.

It was ensured that the concentration of Cefixime in the working sample solution is 1mg per ml, to match the

concentration of Cefixime of the higher working standard solution produced above.

Spotting:

An origin line parallel to and about 1.5cm from the bottom edge of the chromatoplate is marked. 2

microlitres of each test and standard solution are applied on the line using microcapillary pipettes. Four spots

were placed on each TLC plate; 100% working standard solution, 80% working standard solution and two

spots of the working sample solution.

Uniformity of all spots was checked using UV light of 254nm. Effort was taken to ensure spots are circular in

shape and equally spaced across the origin line. The spotting step was repeated whenever homogeneous

spotting was not achieved first time.

Caution: Although their intensities might differ, their diameters never should. Residual intensities are due to

residual amounts of tablet and capsule excipients or different drug concentrations in the sample solutions. A

difference in spot size, however, relates to poor spotting.

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Development:

12.5ml of ethyl acetate, 5ml of acetone, 5ml of glacial acetic acid and 2.5ml of water were pipetted into the

jar, (TLC developing chamber). After closing the chamber, the solution was mixed thoroughly. Filter paper

was lined along the chamber’s wall for about 15 minutes to ensure saturation of the chamber with solvent

vapour. TLC plates were carefully loaded into the jar. The jar was the closed and chromatoplate developed

until the solvent was at 8cm from the line of spotting, developing time being about 25 minutes. The plates

were removed from the chamber, and laid on tissue to allow any excess solvent to evaporate, using a hot

plate if necessary.

Detection: Once the chromatoplates were dry, they were observed under UV light of 254nm using the

battery-driven lamp. Semi-quantification was done at this point. Whenever needed, the plates were stained

in iodine chambers and observed in daylight.

What should be observed at UV 254nm - A grayish-violet spot at a travel distance of about 0.22 indicates the

presence of Cefixime in the test solution.

What you observe in daylight after iodine staining: All Cefixime spots observed at 254nm turn yellowish brown.

When you observe the plate when iodine evaporates, spots reflecting poor quality products disappear first

gradually followed by the reference spots representing a drug content of 80 and 100 percent, respectively.

The chromatogram was observed for similarity in travel distance, and intensity. Also size and shape were

considered.

Specific drug screening for Cephalexin – Semi quantitative TLC

Cephalexin is extracted from tablets and capsules with methanol and determined by TLC with reference to

an authentic secondary standard.

Preparation of a stock standard solution

A reference tablet was wrapped into aluminium foil and crushed to fine powder using a pestle. The powder

was emptied into a 40-ml glass bottle and residual solids were washed down with 25ml of methanol using a

straight pipette. The bottle was shaken for about three minutes until most of the solids were dissolved. The

solution was left to sit for at least five minutes to allow undissolved residues to settle below the supernatant

liquid.

The solution obtained should contain 10mg of total drug per ml and be labelled as “Cephalexin Stock

Standard Solution”. For each test, we freshly prepared this solution. We avoided working with clear or hazy

supernatant liquid.


and 7ml of methanol was added. The vial was shaken. This solution has concentration of 1.25mg of drug per

ml and was labeled Cefixime Working Standard Solution 100%.


and 9ml of methanol was added. The vial was shaken. This solution has concentration of 1mg of drug per ml

and was labeled Cefixime Working Standard Solution 80%. This is the lower acceptable limit for good quality.

Preparation of stock sample solution from a product claiming to contain:

1. 250mg of Cephalexin – The powder from the capsules was transferred to 40ml glass bottle. For capsules,

even the cap and body shell were transferred. To extract, 25mls of methanol were added using a

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straight pipette, the bottle was closed and shaken for three minutes until most of the solids were

dissolved. The solution was left to sit for at least 5 minutes for undissolved residues to settle below the

supernatant.

2. Cephalexin 125mg/5ml suspension– The powder for suspension was reconstituted as per manufacturer’s

instructions. 10mls of the suspensions was measured off a well shaken suspension and transferred to 40ml

glass bottle. The measuring can was also transferred. To extract, 25mls of methanol were added using a

straight pipette, the bottle was closed and shaken for three minutes until most of the solids were

dissolved. The solution was left to sit for at least 5 minutes for undissolved residues to settle below the

supernatant.

N.B: All stock sample solutions produced finally contained 10mg of total drug per ml and were labeled as

Cephalexin Stock Sample Solution.

To prepare working sample solution for each sampled product, 1ml was pipetted from the stock sample

solutions (above) into 10ml and 7mls of methanol were added. The preparation was shaken and labeled as

Cephalexin Working Sample Solution.

It was ensured that the concentration of Cephalexin in the working sample solution is 1.25mg per ml, to

match the concentration of Cephalexin of the higher working standard solution produced above.

Spotting:

An origin line parallel to and about 1.5cm from the bottom edge of the chromatoplate is marked. 2

microlitres of each test and standard solution are applied on the line using microcapillary pipettes. Four spots

were placed on each TLC plate; 100% working standard solution, 80% working standard solution and two

spots of the working sample solution.

Uniformity of all spots was checked using UV light of 254nm. Effort was taken to ensure spots are circular in

shape and equally spaced across the origin line. The spotting step was repeated whenever homogeneous

spotting was not achieved first time.

Caution: Although their intensities might differ, their diameters never should. Residual intensities are due to

residual amounts of tablet and capsule excipients or different drug concentrations in the sample solutions. A

difference in spot size, however, relates to poor spotting.

Development:

12.5ml of ethyl acetate, 5ml of acetone, 5ml of glacial acetic acid and 2.5ml of water were pipetted into the

jar, (TLC developing chamber). After closing the chamber, the solution was mixed thoroughly. Filter paper

was lined along the chamber’s wall for about 15 minutes to ensure saturation of the chamber with solvent

vapour. TLC plates were carefully loaded into the jar. The jar was the closed and chromatoplate developed

until the solvent was at 8cm from the line of spotting, developing time being about 25 minutes. The plates

were removed from the chamber, and laid on tissue to allow any excess solvent to evaporate, using a hot

plate if necessary.

Detection: Once the chromatoplates were dry, they were observed under UV light of 254nm using the

battery-driven lamp. Semi-quantification was done at this point. Whenever needed, the plates were stained

in iodine chambers and observed in daylight.

What should be observed at UV 254nm - A strong blue spot at a travel distance of about 0.36 indicates the

presence of Cephalexin in the test solution.

What you observe in daylight after iodine staining: All Cephalexin spots observed at 254nm turn yellowish

brown.

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When you observe the plate when iodine evaporates, spots reflecting poor quality products disappear first

gradually followed by the reference spots representing a drug content of 80 and 100 percent, respectively.

The chromatogram was observed for similarity in travel distance, and intensity. Also size and shape were

considered.

5.11 Summary of sample handling processes

Ethical issues

Ethical issues did not arise: quantities sampled were either purchased from the private outlets and if from

public health facilities were too small to affect availability of needed medicines or viability of businesses

where sampling had taken place.

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 was shared with or was disclosed to third

parties until it had been verified and discussed among the relevant authorities or agencies concerned (NDA,

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

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

15

6. Results of the Analysis

Table 1. Number of samples collected, then analyzed and medicine samples that failed the screening test

per product

Ceftriaxone Cefixime Cefuroxime Cefalexin Erythromycin Prednisolone Furosemide

Samples collected: 39 22 13 39 55 36 25

Visual and physical

inspection:

39 22 13 39 55 36 25

Tablets 7 10 20 36 14

Oral Suspension 10 3 22 35

Capsules 5 17

Injection 39 11

Analysed: 36 22 13 34 40 17 17

Failed/Suspicious: 0 12 3 0 10 0 0

Cefuroxime had the fewest medicine samples of 10 while Erythromycin had the most samples of 55. The rest

were as follows; Cefixime 22, Furosemide 25, Prednisolone 36, Cefalexin 39, Ceftriaxone 39. The screening

tests for each selected medicine was per batch and hence the number of samples that were analysed was

lower the total number of collected samples for all the study medicines. No suspicious products were

observed from among Ceftriaxone, Cefalexin, Prednisolone and Furosemide. Twelve samples of Cefixime

were suspicious, three from Cefuroxime products and ten from Erythromycin products.

Table 2. Results of the Screening tests per sampled furosemide product

Code Dosage

form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample

Spot Intensity

Basic Test

Overall

Conclusion

MB/FUR/430 Injection Pass 2.50 Pass BTN 80&100 Pass

MB/FUR/467 Injection Pass 1.88 Pass BTN 80&100 Pass

MB/FUR/427 Tablets Pass 0.00 Pass BTN 80&100 Pass

MB/FUR/487 Tablets Pass 0.00 Pass BTN 80&100 Pass

KS/FUR/85 Tablets Pass 0.00 Pass BTN 80&100 Pass

KS/FUR/07 Tablets Pass -0.63 Pass BTN 80&100 Pass



KS/FUR/39 Injection Pass 1.25 Pass BTN 80&100 Pass



KM/FUR/176 Tablets Pass 1.25 Pass BTN 80&100 Pass






All the furosemide products passed the visual and physical inspection, TLC refractive index and TLC sample

spot intensity. The conclusion therefore was that the furosemide products contained the correct active

ingredient and in similar concentration as the reference tablet.

16

Table 3. Results of the Screening tests per sampled prednisolone product

Code Dosage

form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample Spot

Intensity

Basic Test Overall

Conclusion

MB/PRE/434 Tablets Pass 1.25 Pass BTN 80&100 Pass

KS/PPRE/84 Tablets Pass 0.63 Pass BTN 80&100 Pass

KS/PRE/33 Tablets Pass 0.63 Pass BTN 80&100 Pass



KM/PRE/121 Tablets Pass -0.62 Pass BTN 80&100 Pass



KM/PRE/169 Tablets Pass -1.25 Pass BTN 80&100 Pass


KS/PRE/43 Tablets Pass -0.63 Pass BTN 80&100 Pass


KM/PRE/114 Tablets Pass 2.50 Pass BTN 80&100 Pass



KM/PRE/165 Tablets Pass 0.62 Pass BTN 80&100 Pass


All the prednisolone products passed the visual and physical inspection, TLC Rf and TLC sample spot intensity.

The conclusion therefore was that the prednisolone products contained the correct active ingredient, in

similar concentration as the reference tablet.

17

Table 4. Results of the Screening tests per sampled Cefuroxime product

Code Dosage form

Visual

and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample

Spot Intensity

Basic Test

Overall

Conclusion

KS/URO/76 Suspension Pass 0.63 Pass BTN 80&100 Pass



MB/URO/466 Tablets Pass 0.00 Pass BTN 80&100 Pass

KS/URO/64 Tablets Pass 0.00 Pass BTN 80&100 Pass






MB/URO/66 Suspension Pass 1.25 Pass Less than 80 Fail

MB/URO/85 Suspension Pass 0.00 Pass Less than 80 Fail

MBURO/603 Tablets Pass 0.63 Pass Less than 80 Fail

Ten of the cefuroxime products passed the visual and physical inspection, TLC Rf indicator and TLC sample

spot intensity. However, three sampled products did not pass the TLC sample spot intensity. The conclusion

therefore was that the three out of thirteen cefuroxime products did not contain the correct active

ingredient in similar concentration as the reference tablet.

18

Table 5. Results of the Screening tests per sampled Ceftriaxone product – Ceftriaxone

Code Dosage

form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample Spot

Intensity

Basic Test

Overall

Conclusion

KS/TRI/93 Injection Pass 0.00 Pass BTN 80&100 Pass




MB/TRI/463 Injection Pass 0.00 Pass BTN 80&100 Pass





KS/TRI/59 Injection Pass -0.63 Pass BTN 80&100 Pass














KM/TRI/135 Injection Pass 0.00 Pass BTN 80&100 Pass







MB/TRI/450 Injection Pass -0.63 Pass BTN 80&100 Pass





All the ceftriaxone products passed the visual and physical inspection, TLC Rf and TLC sample spot intensity.

The conclusion therefore was that the ceftriaxone products contained the correct active ingredient, in similar

concentration as the reference tablet.

Table 6. Results of the Screening tests per sampled Erythromycin product

19

Code Dosage

form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample

Spot Intensity

Basic Test

Overall

Conclusion

KS/ERY/32 Suspension Pass 1.25 Pass Less than 80 Fail

KM/ERY/143 Tablets Pass 1.25 Pass BTN 80&100 Fail

KM/ERY/170 Tablets Pass 1.25 Pass BTN 80&100 Fail

KS/ERY/22 Tablets Pass 1.25 Pass BTN 80&100 Pass

KS/ERY/80 Suspension Pass 0.00 Pass BTN 80&100 Pass




KM/ERY/153 Suspension Pass 0.00 Pass BTN 80&100 Pass

KS/ERY/52 Suspension Pass 15.00 Fail Less than 80 Fail





MB/ERY/483 Suspension Pass 71.25 Fail Less than 80 Fail



MB/ERY/422 Suspension Pass 1.87 Pass BTN 80&100 Pass



MB/ERY/503 Tablets Pass 2.50 Pass BTN 80&100 Pass



KS/ERY/05 Suspension Pass -1.88 Pass BTN 80&100 Pass

KS/ERY/11 Suspension Pass No spot Fail No spot Fail


KM/ERY/118 Tablets Pass 7.50 Pass BTN 80&100 Pass




MB/ERY/469 Suspension Pass 5.00 Fail BTN 80&100 Fail

MB/ERY/490 Suspension Pass 1.25 Pass Less than 80 Fail

KS/ERY/48 Suspension Pass -1.88 Pass BTN 80&100 Pass







KS/ERY/23 Tablets Pass -0.63 Pass BTN 80&100 Pass

Out of 40 sample products of Erythromycin products (tablets and suspensions), 10 sample products failed the

basic screening tests of TLC and colour reactions. The reason for the failures was either that the sample spot

intensity was different from that of the standard spot, or had different travel distance or did not perform as

expected on the colour reaction test.

Table 7. Results of the Screening tests per sampled Cephalexin product

20

Code Dosage

form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample

Spot Intensity

Basic Test

Overall

Conclusion

KM/ALE/149 Capsules Pass -1.25 Pass BTN 80&100 Pass

KS/ALE/60 Capsules Pass 0.00 Pass BTN 80&100 Pass






KM/ALE/157 Capsules Pass 1.25 Pass BTN 80&100 Pass


MB/ALE/457 Capsules Pass -0.62 Pass BTN 80&100 Pass

MB/ALE/457 Capsules Pass 0.00 Pass BTN 80&100 Pass

KS/ALE/10 Capsules Pass -1.25 Pass BTN 80&100 Pass



KM/ALE/124 Capsules Pass 0.00 Pass BTN 80&100 Pass

MB/ALE/401 Suspension Pass 0.63 Pass BTN 80&100 Pass

KS/ALE/78 Suspension Pass -0.63 Pass BTN 80&100 Pass

KM/PHA/160 Suspension Pass -0.63 Pass BTN 80&100 Pass

KM/PHA/134 Suspension Pass 1.25 Pass BTN 80&100 Pass

MB/ALE/454 Suspension Pass -0.63 Pass BTN 80&100 Pass


KS/ALE/53 Suspension Pass 0.63 Pass BTN 80&100 Pass



KS/ALE/68 Suspension Pass -0.63 Pass BTN 80&100 Pass



KM/ALE/132 Suspension Pass 1.25 Pass BTN 80&100 Pass





KM/ALE/120 Suspension Pass -1.25 Pass BTN 80&100 Pass

KM/ALE/127 Suspension Pass 0.00 Pass BTN 80&100 Pass

All the cefalexin products passed the visual and physical inspection, TLC Rf and TLC sample spot intensity. The

conclusion therefore was that the cefalexin products contained the correct active ingredient, in similar

concentration as the reference tablet.

21

Table 8. Results of the Screening tests per sampled Cephixime product

Code Dosage form

Visual and

Physical

Inspection

TLC; Rf %

difference

TLC:

Conclusion

TLC: Sample

Spot Intensity

Basic Test Overall

Conclusion

MB/XI/441 Suspension Pass 0.00 Pass BTN 80&100 Pass

KS/IXI/92 Suspension Pass 1.25 Pass BTN 80&100 Pass

MB/IXI/409 Suspension Pass 0.00 Pass BTN 80&100 Pass

MB/IXI/465 Capsule Pass 0.00 Pass BTN 80&100 Pass

KS/IXI/67 Tablets Pass 0.63 Pass BTN 80&100 Pass

MB/IXI/407 Tablets Pass 0.63 Pass BTN 80&100 Pass

MB/IXI/428 Capsule Pass -1.25 Pass BTN 80&100 Pass


KS/IXI/58 Capsule Pass -0.63 Pass BTN 80&100 Pass


MB/IXI/406 Capsule Pass 0.00 Pass BTN 80&100 Pass


KS/IXI/66 Capsule Pass 1.25 Pass BTN 80&100 Pass










Out of 22 sample products of Cefixime products (tablets, capsules and suspension), 12 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. However, the analysis team recommend running additional screening tests

before they can conclude on these 12 cefixime samples.

22

Appendix 0: Photos of samples, reagents and

filled forms

23

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 described in the GPHF-Minilab Manual

and the reference substances/product provided by GPHF-Minilab kits should be 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)

• Verification and confirmation tests: These tests will be conducted at the NDA or other NDA designated

labs for the following objectives;

Identity – verifies identity of active principle ingredient

Assay – determines API content

Disintegration – determines that the solid dosage form will disintegrate

Dissolution – demonstrates that medicine will dissolve in the body

Testing procedures and assay methods will be carried out according to the current official

monographs in established pharmacopeias, including International Pharmacopoeia (IP),

USP/NF, or if available national pharmacopeias.

24

2. Testing levels

Tests will be performed at two levels and third level will be considered if applicable; sentinel/study team sites

& NDA lab. The third level if done is the reference lab.

Activity and requirements

Level of testing

Quantity/number of samples

Sample collection

Basic testing:

visual, disintegration and TLC

Sentinel site/study team

Test: 100% of samples collected.

Send:

ƒ 100% doubtful samples to

NDA or designated Lab for

verification

ƒ 100% of failed samples

ƒ 5-10% of passed samples

Verification: Validated

methods or Pharmacopeial

specifications

Confirmation:

Pharmacopeial specifications

NDA or designated Lab

Reference Lab

Test: 100% samples received from

sentinel sites.

Send:

ƒ 100% doubtful samples to

reference lab for confirmation

ƒ 100% of failed samples,

where possible

ƒ 5-10% of passed samples

Test: all samples received from

NDA Lab/designated Lab

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) and a copy of the National

Laboratory Testing Report Form (Annex 4). All results (passed and failed) should be sent simultaneously

to DRA and malaria program.

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.

25

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.

26

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

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

SAMPLE INFORMATION

Sample Serial Number: / (Province name)

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

, and 10 for injectables)

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)

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

27

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)

DISINTEGRATION TEST

Time of complete Time of complete Did the drug pass

disintegration expected Disintegration observed disintegration test? (30 minutes for

uncoated tablet)

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

RESULT OF TLC TEST (see Appendix 2 for TLC result interpretation)

Rf Standard: --------

Rf Sample:- --------

Did the drug and the standard

Spots have the same intensity?

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

Was there any contaminant spot on TLC?

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

Did The sample pass quality by using the

TLC Test?

Yes No

FINAL COMMENTS

The sample passes basic testing

The sample failed basic quality testing (Reason:……………………………………………..………………………….) The sample is doubtful for its

basic quality testing (Reason:……………………………….……..……………….……)

REPORT PREPARED BY:

Date: …………………………………....

Name:……………………………………. Signature:

………………………………

REPORT REVIEWED BY:

Date : …………………………………. Name:

…………………………………… Signature

:…………..……………………

ACTION TO BE TAKEN BY THE PROVINCIAL SENTINEL SITE3

Report the result to malaria program

Date of report …………………………..

Signature…………….……………….

Send the remaining sample units together with this Form to

malaria program or to the National Lab for further testing

Date……………Signature………………………….

Reasons given for the chosen action:

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

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

28

Sample Collection Form

District: Code assigned to the sample: ……………………………

Sampling site: Facility name, address, contact person Commercial/

Public/NGO

Brand name of product:

INN of active ingredient(s):

Dosage form: Strength (e.g. mg/tablet):

Primary container (e.g. strips, PVC bottle):

in original sealed package in original package but not sealed loose units

Quantity collected (specify pack size):

Batch number: Manufacturing date: Expiry date:

Name, address and contact details of manufacturer:

Marketing authorization holder and number:

Any other comment (e.g. mention if storage conditions are not appropriate):

Date of sample collection, name(s) and signature(s) of the person(s) who collected the sample and of the

Focal Person for Sampling (if different)

Name, designation and signature of the responsible person at the sampling site present at the time of

sampling

Note: Samples collected must be in their original containers, intact and unopened. Package leaflet must be

included.

29

Annex 4: National Laboratory Testing Report Form

Report no. /[name of the lab]

SAMPLE INFORMATION (This section should be filled out when receiving the incoming sample or if the repot is attached to the Sentinel Site Sample Collection and Testing Report Form, only discrepancies should be marked) Sample Serial Number or Code (use the same number as the Sentinel Site Sample Collection and Testing Report Form

Drug Name (trade or brand name) Generic or INN4 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

Name and address (with telephone and fax number, if applicable)of location/place where sample was collected

Date when the Lab receives sample Name of test requester or sender of the sample/date/sign

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)

Manufacturing date Expiry date Storage conditions Expiry date or manufacturing date Storage conditions

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)

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

30

DISINTEGRATION TEST (IF TESTED)

Time of complete Time of complete Did the drug pass Disintegration expected Disintegration observed Disintegration test?

30 min ------------- -------------

RESULT OF TLC TEST (IF TESTED) (see Appendix 2 for TLC result interpretation)

Rf Standard: ------

Rf Sample: --------

Did the drug and

the standard Spots have the same intensity?

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

--------------- Was

there any

contaminant spot

on TLC plate?

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

-

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

Did The sample pass quality by

using the TLC Test?

Yes No

DISSOLUTION TEST (IF TESTED, SPECIFY METHOD OR PROCEDURE AND ACCPETANCE CRITERIA…………………………………………………………………………………………………)

Result: -------------------------------------------------------------------- Passed Failed

OTHER TEST USED FOR VERIFICATION OF IDENTIFICATION AND CONTENT OF ACTIVE INGREDIENT (API)

Specify the test method(s) and reference to a pharmacopeial monograph e.g. IP 3rd ed., USP26 ……………………………………………………………………………………………………… Identification Name of API(s) Results

1. Present

Not present 2. Present

Not present Assay for content Name of API(s) Acceptance

criteria Results

1.

2.

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 : Date: ………………………………....

Name………………………….

Signature:

………………………………

REPORT REVIEWED : Date: ……………………………….

Name: ………………………………

Signature

:…………..……………………

31

Content of analytical test report

Sample and report registration numbers :

Any other codes written on sample containers :

Name and address of testing laboratory :

Name and address of entity requesting analysis :

Sample information

Name of product (INN, brand name(s), etc.):

Dosage form: Strength:

Marketing authorization number (if applicable):

Description (appearance of container and contents):

Batch number(s): Required storage conditions:

Date received:

Date of manufacture: Expiry date:

Name and address of original manufacturer:

Telephone: Fax: email:

Name and address of re-packer/trader (if applicable):


Test procedure (reference) Result (numerical, if applicable) Acceptance criteria (limits)

Conclusions:

Compliance with acceptance criteria: YES NO

Date test performed/finalized:

Name and address of head of laboratory/authorized person:


Date &Signature:

32

Appendix 1: Test Request Form

Request submitter: ………………….......................................... For National Lab Use Only

Contact details: Telephone: ……………………………………………………...

Fax: …………………………………………………………..

Email: …………………………………………………………..

Street address: ………………………………………………….

………………………………………………………………….. …………………………………………………………………..

…………………………………………………………………..

Project or Receipt Number:

……………………………….

Receiving Officer: ……………………………….

Date:……………………………….

Date of request:…………………………………………………

Type of request: (check where applied)

Verification testing

Confirmation testing

Others (specify)……………………………………………………………………….

Tests request for: (check where applied)

Identification of active ingredient(s) (API)(s)

Dissolution

Assay for content of active ingredient(s) (API)(s)

Others (specify)………………………………………………………………………

Suggested Method to be used (check where applied)

International Pharmacopeoia (specify Edition number or Year)

U.S. Pharmacopeia (specify Edition number or Year)

Other (specify)………………………………………

Desired Completion Date:……………………………….. Provide reasons for the date:……………………………………………………………………….

Attachments and/or materials provided with this Request Form:

Samples (if more than one sample, attach a separate list of the samples with names and

other details e.g. sample code)

Sentinel Site Drug Sample Collection and Testing Report Form

Others (specify)……………………………………………………………………….

Please send invoice/bill of testing charge to:……………………………………………………… Telephone: ………………………… …………………….Fax: ………………………………….

Email: ……………………………………………………

Street address: ……………………………………………………………………………………..

……………………………………………………………………………………………………... ……………………………………………………………………………………………………...

33

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.

34

Appendix 3 Gantt Chart – Screening Drug Quality Activity

Activity description Responsible June 2015 July 2015 Aug to Oct

2015

1 2 3 4 1 2 3 4 1 2 3 4

Meeting to review selected medicines for this phase of

screening using the Minilabs

MeTA secretariat, MeTA Quality of Medicines

taskforce, NDA, MakCHS

Finalize and place order for reagents, chemicals and

reference standards to supplier of GPHF Minilabs

Department of Pharmacy, MakCHS

Signing of the contract to conduct activity between World

Health Organization, Country office and Makerere University

College of Health Science (MakCHS)

World Health Organization, Country office,

MakCHS

Transfer (remit) of funds from to Makerere University College

of Health Sciences (MakCHS)

World Health Organization, Country office

Delivery of reagents, chemicals and reference standards

from supplier of GPHF Minilabs, (importation) to MakCHS

Local supplier, German Pharmaceutical

Health Fund (GPHF) (Manufacturer)

Meeting to review the locations where sampling should

occur and the sampling strategy



Training data collectors on field procedures on how to

sample and obtain medicine samples

MakCHS, MeTA Quality of Medicines

taskforce

Fieldwork to obtain medicine samples MakCHS

Analysis of medicine samples using the GPHF Minilabs and

procedures at pharmaceutical chemistry laboratory

MakCHS

Meeting to review and discuss the results from the drug

quality assessment exercise



Report writing and related literature review MakCHS

MakCHS – Makerere University College of Health Sciences, MeTA – Medicines Transparency Alliance, NDA – National Drug Authority, WHO – World

Health Organization.

35

8. References

1. Akuse, R.M., et al., Diagnosing renal failure due to diethylene glycol in children in a resource-

constrained setting. Pediatr Nephrol, 2012. 27(6): p. 1021-8.

2. Asamoah, B.O., et al., Distribution of causes of maternal mortality among different socio-

demographic groups in Ghana; a descriptive study. BMC Public Health, 2011. 11: p. 159.

3. Stanton, C., et al., Uterotonic drug quality: an assessment of the potency of injectable uterotonic

drugs purchased by simulated clients in three districts in Ghana. BMJ Open, 2012. 2(3).

4. Xiang, Z., Deadly counterfeit diabetes drugs found outside China’s Xinjiang. , in China View, 2009.

5. Cheng, M.M., Is the drugstore safe? Counterfeit diabetes products on the shelves. J Diabetes Sci

Technol, 2009. 3(6): p. 1516-20.

6. Leslie, T., et al., Epidemic of Plasmodium falciparum malaria involving substandard antimalarial

drugs, Pakistan, 2003. Emerg Infect Dis, 2009. 15(11): p. 1753-9.

7. IOM (Institute of Medicine), Countering the problem of falsified and substandard drugs., 2013, The

National Academies Press.: Washington, DC.

8. Kaitin, K.I., The Landscape for Pharmaceutical Innovation: Drivers of Cost-Effective Clinical

Research. Pharm Outsourcing, 2010. 2010.

9. Medicine), I.I.o., Ensuring safe foods and medical products through stronger regulatory systems

abroad., 2012, The National Academies Press.: Washington, DC.

10. PQM (Promoting the Quality of Medicines in Developing Countries), Media reports on medicine

quality: Focusing on USAID-assisted countries., 2012, United States Pharmacopeia,: Rockville, MD:.

11. Kelesidis, T., et al., Counterfeit or substandard antimicrobial drugs: a review of the scientific

evidence. J Antimicrob Chemother, 2007. 60(2): p. 214-36.

12. Kyriacos, S., et al., Quality of amoxicillin formulations in some Arab countries. J Clin Pharm Ther,

2008. 33(4): p. 375-9.

13. Newton, P.N., et al., Guidelines for field surveys of the quality of medicines: a proposal. PLoS Med,

2009. 6(3): p. e52.

14. Annual Health Sector Performance Report, 2006/07, 2007.08

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

16. MeTA Country Work Plan Guidelines VS.6 January, 2009

17. MeTA Phase II Proposal, 2012

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

Kampala: Ministry of Health.MoH.

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

20. Private Sector Mapping Uganda Mission report, December 2008.

21. Uganda MeTA Scoping mission report, April 2008

22. World health Organization Medicines Strategy 2004-2007

23. 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

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

25. 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

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