Assessment of Quality of Anti-Malarial Drugs Used in Private Sectordmc.gov.pk/documents/pdfs/Assessment of Quality of AMDs... · 2018-11-14 · pharmaceutical industries in most developing

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Assessment of Quality of

Anti-Malarial Drugs Used

in Private Sector

2017

DR ZEESHAN HAROON

DR GHULAM MURTAZA

DIRECTORATE OF MALARIA CONTROL

1

CONTENTS

Introduction and Background ................................................................................................................. 2 Methodology: ............................................................................................................................................. 6

Study Design: ...........................................................................................................................................6 Sampling Strategy and Sample Size: .......................................................................................................7 Sample Collection ....................................................................................................................................8

Quality Assessment of AMDs ................................................................................................................. 10

Physical Methods ...................................................................................................................................10 Syrup ................................................................................................................................................. 10 Tablets ............................................................................................................................................... 11

Chemical Testing ...................................................................................................................................12 Tablets ............................................................................................................................................... 12

Syrups and Injectable ........................................................................................................................ 13 Results ...................................................................................................................................................... 14

Current Market Situation .......................................................................................................................14

Survey ....................................................................................................................................................14 Market Trends of Analysis of AMDs: ...................................................................................................16

Quality Assessment of AMDs .............................................................................................................. 17

Quality Control of Injectables ................................................................................................................17 Quality Control Analysis of Syrups .......................................................................................................18

Visual inspection of syrups ............................................................................................................... 18 Syrup volume .................................................................................................................................... 18 Syrup weight ..................................................................................................................................... 18

Syrup pH ........................................................................................................................................... 18 Syrup viscosity and torque ................................................................................................................ 18

Percentage drug release..................................................................................................................... 19 Drug Content:.................................................................................................................................... 19

Quality Control of Tablets .....................................................................................................................21 Diameter and Thickness Variation.................................................................................................... 21 Weight Variation ............................................................................................................................... 21

Hardness testing ................................................................................................................................ 21 Friability testing ................................................................................................................................ 22

Disintegration .................................................................................................................................... 22 Assay of active contents.................................................................................................................... 22 Dissolution ........................................................................................................................................ 23

FATA .....................................................................................................................................................27 Khyber Pakhtunkhwa .............................................................................................................................30

Punjab ....................................................................................................................................................32 Sindh ......................................................................................................................................................34

Balochistan .............................................................................................................................................36 Conclusion ............................................................................................................................................... 39 Recommendations: .................................................................................................................................. 39 Way Forward .......................................................................................................................................... 40 References ................................................................................................................................................ 41

2

List of Abbreviations

AMD Antimalarial Drugs

AL Artemether Lumefantrine

AS+SP Artesunate Sulphadoxine Pyrimethamine

DoMC Directorate of Malaria Control

DG Khan Dera Ghazi Khan

DRAP Drug Regulatory Authority of Pakistan

FATA Federally Administered Tribal Area

GMP Good Manufacturing Practices

KAP Knowledge Attitude Practices

KPK Khyber Pakhtunkhwa

MAT Moving Annual Total

QC Quality Control

USP United States Pharmacopeia

UV Ultra Violet

WHO World Health Organization

3

Introduction and Background There is growing universal concern regarding counterfeit medications. In particular, counterfeit

antimicrobial drugs are a threat to public health with many devastating consequences for patients;

increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating

these patients lose their confidence in the medications used and report high levels of bacterial resistance.

Drug quality is currently receiving renewed international attention.1 Over the past decade, there has been

an increase in public awareness of the existence of counterfeit and substandard drugs,2

which have been

increasingly reported in developing countries where drug regulations are ineffective.3

Although

practically all types of pharmaceutical products have been shown to be involved, the existing data

suggest that anti-infectious agents, particularly antibiotics and antiparasitic agents including

antimalarials, are the most counterfeited products in developing countries.4,5

The quantitative assessment

is a difficult process to carry out. However, to implement effective countermeasures against counterfeit

and substandard drugs, there is a need for research to define the extent of the problem.

The subject of overall drug quality has been addressed in several WHO publications. Substandard drugs

are genuine products that have not passed the quality testing protocols previously set for each

product.7 The testing protocols and specifications are published in official pharmacopoeias such as the

United States Pharmacopoeia (USP), the European Pharmacopoeia and the WHO International

Pharmacopoeia. In addition, many countries have published their own pharmacopoeias. More

specifically, substandard drugs have incorrect quantity of active ingredient, which could be secondary to

excessive decomposition of active ingredient as a result of high temperature and humidity, and poor

quality assurance during the manufacture of pharmaceutical products in less-developed countries.

One special class of substandard drugs is the class of counterfeit drugs. Several countries have their own

definitions as to what constitutes a counterfeit drug and there is no consensus. This poses a problem in

that what may be considered a counterfeit product in one country will not necessarily be so in another

country. The WHO has defined counterfeit drugs as those that are deliberately and fraudulently

mislabeled with respect to identity and/or source.8

Counterfeit products include drugs with the correct

ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredient

or with fake packaging.9 According to a WHO report, analysis of the content of a drug preparation

4

cannot therefore determine whether or not the sample is counterfeit, because the inclusion of

inappropriate quantities of active ingredient during manufacture cannot be identified as deliberate.4

Using the above definitions, the variations in active ingredient and weight above or below the

recognized limits found in different studies in the current report point to problems in good

manufacturing practice, deliberate counterfeiting or poor retail management. Although it is very

important to make a clear distinction between the various terms for poor quality medications such as

‘counterfeit’, ‘fake’ or ‘substandard’, it is difficult to classify whether the substandard drug was

counterfeit or simply the result of a defect in the manufacturing process. 10

Poor quality of drugs is mostly due to lack of good manufacturing practices (GMP) in local

pharmaceutical industries in most developing countries.11

In addition to the existence of substandard

drugs, assurance of the stability of pharmaceuticals marketed in developing countries (most of which

have tropical climates) is a challenging issue as poor storage conditions, high temperature and high

humidity conditions generally enhance chemical degradation and may alter the biopharmaceutical

properties of the drugs,12,

Finally, medicine sellers often exhibit lack of concern about expiration dates

and storage conditions, especially in poor settings and in the absence of national control, and this can

increase the spread of substandard antimicrobials.13,

Manufacture of generic versions of patented drugs

for humanitarian reasons may also be abused in developing countries.14

The magnitude of the drug-counterfeiting problem is considerable and is difficult to gauge as any true

estimate of prevalence is difficult. The WHO estimates that up to 10% of the world's pharmaceutical

trade—25% in developing countries—consists of fakes, 15

whereas up to 25% of all drugs consumed in

poor countries are thought to be counterfeit or substandard, according to the figures from the US Food

and Drug Administration (FDA).16

The quality of antimalarial drugs is especially crucial, given the widespread nature of the disease and its

importance to global public health.17

As more than 40% of the world's population is at risk of malaria,

antimalarial drugs have become a favorite target of counterfeiters. In a WHO survey of seven African

countries, 20% to 90% of antimalarial drugs failed quality testing.18

Many studies have reported that a

considerable proportion of antimalarial drugs obtained from east African countries is of poor

quality19

and that even counterfeits of new antimalarial drugs, such as artesunate and mefloquine, are

5

circulating in southeast Asia.,20

Counterfeit artemisinins are a significant problem in southeast

Asia,21

and are expected to become a serious problem in Africa where artemisinin combination therapy

is being implemented.22

Malaria is considered as a major public health problem in Pakistan with an estimated 1.6 million cases

annually. Pakistan is classified as moderate malaria endemic country with an average API at 1.69. In

Pakistan there is a huge health sector which comprises of both public and private providers. In public

sector the services are available in hospitals and primary health care facilities which mainly include rural

health centers and basic health unit. In case of private sector there is more than one type of provider

which includes general practitioners, private hospitals, homeopathic, traditional healers, etc. In

additional in the private sector there is huge networks of pharmacies which provide all sorts of

medicines mostly without a prescription. There is very little quality check on the type of drugs sold in

these pharmacies.

Most of the private sector is Pakistan is unregulated but highly utilized. In certain type of diseases which

mainly include acute illnesses, more than 70% of the people first visit the private health care provider

for treatment.23

In case of malaria, the private sector is considered as a major source of help. The patient

having an acute episode of fever usually prefers to visit a private care provider or a pharmacy store to

get a medicine for quick relief. It has been observed that as a routine practice to treat a case of acute

episode of fever in malarias season, the private providers usually prescribe a combination of medicines

which also often includes an anti-malarial drug.

There is very limited knowledge available which can inform the malaria control program regarding the

quality of anti-malarial drugs being used in the private sector in term of the diagnostic criteria,

preference of anti-malarial drugs both first and second line and follow-up practices. Moreover, as the

private sector is flooded with all sorts of antimalarial so it is difficult to know that to what extent the

prescription of anti-malarials by the private sector is driven by availability of different types of anti-

malarial medicines.

Considering the importance of antimalarial treatment in Pakistan, where malaria is endemic and >95%

of population is at risk of developing malaria, the presence of counterfeit and substandard drugs in the

private sector is a risk to the life of millions of people.

6

Objectives

The objective of this survey was:

To examine the market trend regarding the availability of various type of anti-malarial drugs

being used in the private sector

To evaluate pharmaceutical quality of antimalarial medicines used in the private sector

To provide way forward in choosing the right anti-malarial for malaria control program in

Pakistan

Methodology: Extensive consultations were carried out with experts from DoMC and WHO on survey protocols,

strategies and sampling. Extensive literature review was carried out on the quality of anti-malarials and

its assessment. Survey reports on antimalarials conducted in neighboring countries and other WHO

regions were also consulted.

10 district/region survey teams were identified and were trained on drug collection and market survey. A

central analytic team was also constituted which included experts in pharmaceutics with background in

drugs quality assurance and quality assessment. Market survey questionnaire was pretested before

introduction in the field

Study Design:

This study was as a descriptive cross sectional survey to assess quality of antimalarial drugs and market

trend of antimalarials in the private health sector (pharmacies/medical stores) of the 10 high malaria

burden districts of Pakistan. This study was conducted between May 2017 to December 2017 in these 10

high burden districts. Procurement and team training were undertaken between May and August.

Specimen collection and market survey was conducted during July-August 2017. This being the season

of peak malaria transmission in Pakistan, the availability of AMDs was assumed to be high. The

collected samples were received by the central analytic team and tested between September to December

2017.

7

Sampling Strategy and Sample Size:

For this survey, a sample size was calculated assuming a prevalence of 50% (i.e. assuming 50% of the

AMDs available at pharmacies in the private sector are sub-standard). This choice of estimated

prevalence gave us the largest sample size needed. With absolute precision at 10%, sample size was

estimated to be ~96.

This study was conducted in the five provinces/regions of the country; Baluchistan, Federally

Administered Tribal Areas FATA, Khyber Pakhtunkhwa, Punjab and Sindh. A total of 10 out of 66 high

risk malaria districts targeted by Directorate of Malaria Control, Pakistan DOMC were selected.

Depending upon the province’s share in DOMC target of high burden sharing malaria districts, the 10

districts were divided accordingly. DG Khan, being the only high burden sharing district in the province

was selected from Punjab. From rest of the provinces, 3 districts from Baluchistan and 2 districts/regions

each from Sindh, KPK and FATA were selected randomly.

Below table shows the selected districts from different provinces/regions for this study:

The aim of the survey was not to provide a representative sample of AMDs, but to target the pharmacies

at areas which capture AMDs available in the private sector. With 10 districts selected for survey, the

S# Province / Region District / Agency

1 KPK Lakki Marwat

Charsadda

2 Sindh Mirpur

Thatta

3 Baluchistan

Zhob

Sibi

Noshki

4 FATA

Khyber

Bajaur

5 Punjab DG Khan

8

total target sample size for the study was 100 pharmacies/drug collection points with 10

pharmacies/drug collection points per district/agency. With allocation of 10 pharmacies/ drug collection

points per district/agency, these drug collection points were selected through random walk quota method.

All the AMDs fulfilling inclusion criteria available at the selected pharmacies were collected and sent

for testing. The sampling unit was pharmacies/drug collection point and observation unit was AMDs

Market Trend

For market trend analysis of antimalarials, it was decided to select 1 district/agency fromeach

province/region. Lakki Marwat from KPK, Thatta from Sindh, Noshki from Balochistan and DG Khan

from Punjab were selected randomly from the already selected district and regions mentioned above.

Same pharmacies from urban and rural areas which were selected for antimalarial collection were

surveyed using a pretested questionnaire focusing on the availability of all antimalarials regardless of

them fulfilling inclusion and exclusion criteria

Inclusion Criteria for Quality Assessment 1. Anti-malarials Formulation recommended in National Treatment Guidelines

2. Anti-malarials registered with DRAP

Exclusion Criteria for Quality Assessment 1. Drugs of same brand collected from one pharmacy of a district/ setting available on

another pharmacy within same setting/area will not be tested again

2. Antimalarials which did not have the minimum number of doses required for antimalarial

to be considered as sample

3. Drug of same batch collected from same district/setting will not be tested again

For oral and injectable antimalarials to be considered as an eligible sample, the pharmacies must have 30

tablets, 10 syrup bottles and 12 injections of each available antimalarials at one site

Sample Collection

AMD samples and market trend analysis information were gathered by drug collectors. AMD samples

were purchased from private pharmacies and private clinics. Drugs were purchased by a field worker

who went to the pharmacy as a normal costumer.

AMDs were collected in their packaging, and stored in zip-lock bags marked with the facility code.

After purchase all drug samples were stored in a dark, dry room and at prescribed temperature before

being transported to the lab. One dose was retained as a control.

9

At each site, 30 tablets, 10 syrup bottles and 12 injections of each available antimalarial drug fulfilling

inclusion criteria were purchased and sent for testing

Following groups’ antimalarial formulations will be collected based on the national guideline:

1. Tab Artesunate + Sulphadoxine/Pyrimethamine

2. Tab Artemether + Lumifentrine (20/120mg, 40/240mg, 80/480mg)

3. Tab Chloroquine

4. Syrup Chloroquine

4. Inj. Artesunate

The selection of these formulations was based on the fact that national malaria treatment guidelines

recommend only these formulations for effective malaria treatment. No manufacturer in Pakistan is

currently producing quinine and primaquine Hence, excluded from the survey.

10

Quality Assessment of AMDs Quality assessment of AMDs was conducted at COMSAT labs. Samples were divided into batches by

type of drug and collection site. The sample of AMDs were tested using both physical and chemical

methods.

Physical Methods

1. Syrup

Visual Inspection: Visual inspection of syrups included discoloration or cloudiness of solutions,

flocculants or sediments in the solution.

Syrup volume/Uniformity of volume: For this test, 10 filled containers of each sample were selected

and the weight of the contents of each container was determined. Weight per ml was determined and the

net volume of the contents of each container was calculated.

Consistent with compendia, the average net volume of the contents of the 10 containers should not be

less than the labeled amount, and the net volume of the contents of any single containers should not be

less than the percentage deviation as shown in the below table

Syrup weight/Uniformity of weight: For this test 10 filled containers of each sample were selected and

labeling were removed that might alter in weight. The contents of the containers were removed. The

outer surfaces of the containers were cleaned and dried and each container was weighed. The contents

from each container were removed quantitatively. Each empty container was dried and weighed again.

The difference between the two weights is the net weight of the contents of the container.

As per compendia, the average net weight of the contents of the 10 containers should not be less than the

labeled amount and the net weight of the contents of any single containers must not be less than the

percentage deviation as shown in in below table

11

Syrup pH: The pH value of a solution was determined potentiometrically by means of a glass electrode,

a reference electrode and a digital pH meter.

Syrup viscosity and torque: This test was carried out using the Brookfield viscometer mounted on a

Helipath stand. The T-bar spindle was made to descend slowly into the suspension, and the dial reading

on the viscometer was noted.

2.Tablets

Tablet diameter: The diameter of individual tablets was measured with a digital Vernier caliper.

Diameter should be controlled within ± 5% variation of a standard value.

Tablet thickness: The thickness of individual tablets was measured with a digital Vernier caliper.

Thickness should be controlled within ± 5% variation of a standard value.

Weight variation test: The USP weight variation test was run by weighing 20 tablets individually,

calculating the average weight, and comparing the individual tablet weights to the average. The tablets

meet the USP test if not more than 2 tablets are outside the % limit and if no tablet differs by more than

double that percentage limit. The weight variation tolerances for uncoated tablets differ depending on

average tablet weight

Average weight of tablets (mg) Maximum percentage difference allowed

130 or less ± 10

130 – 324 ± 7.5

More than 324 ± 5

Hardness (Crushing strength): To perform this test, a tablet was placed between two anvils of

mechanical hardness tester and the crushing strength that just causes the tablet to break was recorded.

The mean crushing strength of 10 randomly selected tablets was calculated and recorded. Crushing

strength of 4-8 Kg for uncoated tablets was considered as acceptable

12

Friability test: The measurement of friability was made by Roche friabilator. A number of tablets were

weighed and placed in the tumbling apparatus where they were exposed to rolling and operated shocks

resulting from the free falls within the apparatus. After a given number of rotations, the tablets were

weighed again and the loss in weight indicated the ability of the tablets to withstand this type of wear. If

the value of friability (% loss) is less than or equal to 1%, the sample results was accepted.

Disintegration test: Disintegration is the time it takes a tablet to disintegrate and is measured by

disintegration apparatus. The disintegration apparatus consists of a basket rack containing 6-open-ended

glass tubes held in a vertical position. A number 10-mesh stainless steel wire screen is attached to the

bottom. To test for disintegration time, one tablet is placed in each tube and the basket rack is positioned

in a 1-L beaker of water, simulated gastric fluid (pH 1.2), or simulated intestinal fluid (pH 7.4), at 37 oC.

A standard motor driven device is used to move the basket assembly containing the tablets up and down

through a distance of 5 to 6 cm at a frequency of 23 to 32 cycles per minute. The time of each tablet to

disintegrate through the 10-mesh screen was noted

To be in compliance with the BP standards, the tablets must disintegrate, and all of the particles must

pass through the 10-mesh screen in the time specified. The tablets should disintegrate within 15 minutes

(uncoated tablets). If one tablet fails to disintegrate within 15 minutes, the disintegration test is repeated

on 12 additional tablets. Not less than 16 out of the total 18 tablets tested must disintegrate completely

within 30 minutes.

Chemical Testing

1.Tablets

Dissolution test

In the pharmaceutical industry, drug dissolution testing is routinely used to provide critical in vitro drug

release information for both quality control purposes, i.e., to assess batch-to-batch consistency of solid

oral dosage forms such as tablets, and drug development, i.e., to predict in vivo drug release profiles.

Dissolution test is close proximate to the bioavailability this is the reason it is required to perform to

confirm drug release pattern of the dosage form as well as efficacy of dosage form.

The dissolution test was performed by using Dissolution Tester-USP type 2. To determine drug release,

900 ml of phosphate buffer was used as dissolution medium. The 5, 10, 15, 30, 45, and 60 minutes were

set as a sampling time. The dissolution medium was heated up to 37±0.5°C by an auto-heater. One tablet

was put into all six baskets and stirred immediately at 50 revolutions per minute (rpm). After specified

https://en.wikipedia.org/wiki/In_vitro

https://en.wikipedia.org/wiki/Quality_control

https://en.wikipedia.org/wiki/In_vivo

13

time intervals the 5-ml solution was withdrawn and the amount of dissolved drug was determined by

using UV-Visible spectrophotometer (Shimadzu, Japan) by taking absorbance at the wavelength of

maximum absorbance at the relevant lemda max in comparison with a standard drug solution in the

same medium. By measuring the absorbance, the percentage (%) of drug release was calculated.

Drug Content

The potency (drug content) of tablet is expressed in terms of gm, mg, or mcg (for some potent drugs) of

drug per tablet and is given as the label strength of the product. Official compendia or other standards

provide an acceptable potency range around the label potency.

For highly potent, low-dose drugs, this range is usually not less than 90% and not more than 110% of

the labeled amount. In general, official potency analytical methods require that a composite sample of

tablets be taken, ground up, mixed, and analyzed to produce an average potency value.

20 tablets per sample were taken, grounded and weighed and then weight equivalent to standard was

taken and diluted in same media as standard. The absorbance of sample was measured by UV-Visible

spectrophotometer (Shimadzu, Japan) and compared with the standard curve of the pure/standard drug.

From absorbance, drug content was calculated using standard equation.

2. Syrups and Injectable

For syrups and injectable, drug content analysis was the only chemical test performed. For syrups, the

sample syrup was diluted in the same solvent as of the standard drug for standard curve and absorbance

was measured by UV-Visible spectrophotometer and compared to standard cure.

For injectables, the powder for injection was dissolved in the provided solvent. The standard curve was

also measured using the same provided solvent. The absorbance was calculated using UV-Visible

spectrophotometer. From absorbance, drug content was calculated using standard equation.

14

Results

Current Market Situation

Currently according to Moving Annual Total (MAT), 173 companies are registered with Drug

Regulatory Authority of Pakistan (DRAP) which have continuous quarterly sales of antimalarials. In

first quarter of 2016, 13 million units of Anti malarials were sold across Pakistan in private sector. Out

of 173 registered companies, following is the breakdown of manufacturing and unit sale

Ingredient Number Unit Sale

1. Artemether (Single Ingredient) 38 1.38 million

2. Artemether + Lumifentrine 110 8.33 million

3. Artesunate (Single Ingredient) 2 0.91 million

4. Artesunate + Sulphadoxine/Pyrimethamine (co) 8 0.07 million

5. Chloroquine Phosphate 15 2.43 million

11 out of 38 companies manufacturing Artemether (Single Ingredient) are selling >20,000 units per

quarter. In Artemether + Lumifentrine group, 31 companies are dispensing >40,000 units/quarter. Only

2 companies have a significant market share in Artesunate + Sulphadoxine/Pyrimethamine (co) with sale

of 66000 and 4001 units/ quarter respectively. 8 companies in Chloroquine phosphate group have

quarterly sale of more than 8000 units.

Survey

During survey total of 289 AMDs were collected from 100 pharmacies. Out of the total samples

collected, 261 AMD samples fulfilled the inclusion criteria. These included 173 samples of tablet

Artemether+Lumefantrine, 33 samples of tablet Chloroquine Phosphate, 3 samples of tablet

Artesunate+Sulphadoxine+Pyrimethamine, 18 samples of Syrup Chloroquine and 34 samples of

injectable Artesunate

15

AL constituted the highest proportion 66.2% of the collected AMDs. Sample collection captured all the

three strengths 20/120mg (48.55%), 40/240mg (28.90%) and 80/480 (22.55) of AL. The 173 collected

samples of AL captured 34 brands of AL out of 110 registered brands in Pakistan. AL was available in

all the 10 districts with highest number of AL (27) collected from Khyber Agency.

Inj Artesunate formed 13% of the collected sample. Inj Artesunate was collected from all the districts

except Noshki due to non-availability in the surveyed pharmacies. Chloroquine tablets and syrup were

estimated to be 12.64% 6.89% respectively of the collected AMDs. During survey in Thatta, both tablet

and syrup Chloroquine were not found in any of the surveyed pharmacies. Whereas, tablet Chloroquine

and syrup Chloroquine were not available in any of the drug collection points in district Sibi and Noshki

respectively.

AS+SP was found in only 3 pharmacies across 10 selected districts in two agencies namely Khyber and

Bajaur agencies AS+SP samples comprised 6.89% of all the collected AMDs.

District /

Agency

Tab Chloroquine

Samples Brands

Syp Chloroquine

Samples Brands

AS+SP

Samples Brands

A+L

Samples Brands

Inj Artesunate

Samples Brands

Lakki

Marwat

3 1 2 2 0 0 21 13

3 1

Charsadda 6 3 2 1 0 0 16 9

1 1

Mirpur 5 1 1 1 0 0 10 3 5 1

Thatta 0 0 0 0 0 0 20 12 8 1

Zhob 2 2 1 1 0 0 25 15 4 2

Sibi 0 0 5 1 0 0 13 9 0 0

Noshki 1 1 0 0 0 0 10 5 3 1

Khyber 5 2 4 3 1 1 27 14 5 1

Bajaur 7 2 2 1 2 1 14 9 1 1

DG Khan 4 2 1 1 0 0 17 12 4 2

Total 33 3 18 5 3 1 173 34 34 2

16

Market Trends of Analysis of AMDs:

Lakki

Marwat3 2 0 16 2

4 0 0 2 0 3 0 1

Thatta 1 2 0 14 1 3 0 1 2 1 1 0 0

Noshki 1 1 0 9 1 4 0 0 1 0 0 0 0

Khyber 2 3 1 17 2 3 0 0 1 0 4 0 0

DG Khan 2 2 0 19 25 0 0 3 0 2 0 1

Total 3 3 1 42 2 5 0 0 3 1 4 0 1

Inj

ArtemetherSyp SP

Tab

Quinine

Brands

Tab SP

BrandsSyp A+L

Inj

Quinine

Brands

Inj

Chloroquine

Brand

Tab

Chloroquine

Brands

Syp

Chloroquine

Brands

Tab

AS+SP

Brands

Tab A+L

Brands

Inj

Artesunate

Brands

Tab

Primaquine

Bands

District /

Agency

Market trend analysis of AMDs revealed that most commonly found AMD is Artemether +

Lumefantrine. On average 4 brands of AL were available per drug collection point. This average

changed slightly in urban and rural setting. On average 6 brands were available in urban pharmacies

whereas, 3 brands of AL were available in rural pharmacies. Most common brands available were Gen-

M, Arcevea and Artem Plus in 38%, 21% and 16% of drug collection point respectively

At least one brand of tablet Chloroquine was available in the surveyed pharmacies. Syrup chloroquine

was available in 70% of the pharmacies. In injectable AMDs, on average 1 out of 2 registered brands in

Pakistan of Artesunate was available in the surveyed pharmacies. Whereas on average 3 brand of Inj

Artemether per drug collection point were found during the market analysis.

Despite the ban on Inj Chloroquine, 2 sample from single manufacturer were found in 2 pharmacies

during the survey. Despite Monotherapy not being recommended for treatment of malaria, S+P

monotherapy was widely available in the surveyed pharmacies. At least 1 brand of S+P monotherapy

was available in 92% of the pharmacies.

Another interesting finding was availability of Syp S+P and Syp A+L. Single sample of Syp SP was

found form Thatta, while availability of 4 different brands of A+L was identified in the surveyed

districts. 68% of pharmacies had the availability of Syp A+L during survey.

During pregnancy, national treatment guidelines recommend tab Quinine for uncomplicated falciparum

malaria and, Inj Quinine for complicated malaria. Both of these antimalarials were not found in private

sector pharmacies.

17

Tab AS + SP and tab Primaquine despite being part of national treatment guideline as first line treatment of falciparum malaria and

radical cure of vivax malaria respectively were also not available in private sector. Absence of these drugs from private sector

undermines the efforts for effective treatment and malaria transmission prevention.

Quality Assessment of AMDs

Quality Control of Injectables

Only 2 artesunate-containing antimalarial injectable products are manufactured and marketed in Pakistan and both products were

included in the tested samples. All the collected injectable artesunate were tested. For QC analysis of these products, visual inspection

and drug assay were conducted. All the injectable products were visually clear, without having any particulate entities or other

undesired features. Drug contents in all injectables were in the allowed limits, i.e. 90 – 110%, except five products. These injectable

formulations contained drug contents lesser than the 90% of documented concentration. Three substandard products were collected

from Baluchistan. 2 from district Noshki and 1 from district Zhob and two substandard products were collected from Khyber agency

FATA

Table 1. QC analysis of Inj Artesunate products (injections n = 34)

Products Properties Compendial limits

Number of products

Above compendial limits Within compendial limits Below compendial limits

Punja

b

KP

K Sindh

Baluch

istan

FAT

A

Punjab KP

K Sindh

Baluch

istan

FAT

A

Punjab KP

K Sindh

Baluch

istan

FAT

A

Injectable

s

Drug contents 90 – 110% - - - -

4 4 13 4 4 - - - 3 2

18

Quality Control Analysis of Syrups

All the 18 collected Syrup Chloroquine were tested. These samples comprised of 5 registered brands.

For QC analysis of these syrup products, various tests including visual inspection, volume, weight, pH,

viscosity, torque, and percentage drug release of syrups were conducted. The findings of these testes are

briefly described below.

Visual inspection of syrups

All syrups were visually clear, without having any particulate entities or other undesired features.

Syrup volume

All syrup containers had a volume of 60 ml, except one syrup product (collected from KPK) that

contained slightly larger volume of liquid than that of claimed on the monogram.

Syrup weight

In all products/batches, the weight of syrup contents (excluding the weight of containers) ranged

between 54.08 - 74.36 g (68.04 g ± 6.95 g).

Syrup pH

Except seven products collected from district DG Khan Punjab, district Charsadda, KPK, district Mirpur

Khas Sindh, and district Zhob, Baluchistan, the pH of all other syrup formulations ranged between 4.99

and 5.09 that was in the recommended limit. The samples that gave degranged pH values were mostly

from one brand. Syrup medicines showing pH below the critical value (5.5) can increase their cariogenic

and erosive potentials.

Syrup viscosity and torque

The viscosity and torque of all syrup products was variable ranging between 11.2 – 169.8 and 0.06 -

0.712, respectively. One syrup products collected from district Lakki Marwat, KPK and Khyber agency

in FATA exhibited more than 5% variation in viscosity and torque. The allowed limit of variability in

syrup viscosity and torque is < 5%.

19

Percentage drug release

The percentage drug release from all syrup formulation was more than 96% in first 15 min.

Drug Content:

Drug contents in all the syrups were in the allowed limits, i.e. between 90 – 110%

Table 2. QC analysis of chloroquine syrup products (n = 18)

Properties Compendial limits

Number of products (%)


Punjab KPK Sindh Baluc

histan

FATA Punjab KPK Sindh Baluc

histan

FATA Punjab KPK Sindh Baluch

istan

FATA

Volume Claimed, i.e. 60 ml - - - - 1 1 4 1 6 5 - - - -

Weight < 5% variation - - - - 1 4 1 6 6 - - - -

pH 5.5 – 8.5 - - - - - 2 - 4 5 1 2 1 2 1

Viscosity and torque < 5% variation 1 - - 1 - 3 1 6 5 - 1 - -

Percentage drug release in initial 15

min

> 85% - - - - 1 4 1 6 6 - - - -

Drug Content 90%-110% - - - - - 1 4 1 6 6

In addition to the syrup chloroquine 8 samples of AL collected from district Lakki Marwat KPK (2) and district Thatta, Sindh (6) were

also tested for both physical and chemical properties. All the samples were found to be satisfactory and within the prescribed limits

20

Table 3. QC analysis of artemether - lumifantarine suspension products (15 + 90 mg/5 ml) (n = 8)


Number of products


Punjab KP

K Sindh

Baluch

istan

FAT

A Punjab KPK Sindh Baluchistan

FAT

A Punjab KPK Sindh

Baluch

istan

FAT

A

Drug contents 90 – 110%

- - -

2 6 - - -

- - - -

21

Quality Control of Tablets

29 (88%) out of 33 samples of Chloroquine and 149 (86%) samples of AL out of 173 collected samples were tested for quality assessment.

AMDs with same batch from same district in same settings of urban and rural area were omitted from testing.

All tablet samples taken for the evaluation were within their shelf life at the time of investigation. The visual organoleptic properties testing

found that all brands were in good condition where each individual tablet was free from cracks, depression and pinholes. In addition, the

tablets color, surface roughness and polish were uniform on whole surface for the sample batch tested.

Diameter and Thickness Variation

All tablet products exhibited diameter and thickness variation within allowed limits (< 5% variation).

Weight Variation

All tablet products exhibited weight variation within allowed limits (< 5% variation) except 8 products. These substandard products included

2 artemether - lumefantrine products (80/480) (collected from district Charsadda KPK and Bajaur agency FATA), 4 artemether -

lumefantrine products (40/240) (collected from district Lakki, KPK, Bajaur agency, FATA, district Thatta Sindh, and DG Khan, Punjab),

and 2 artemether - lumefantrine products (20/120) (both collected from Khyber agency, FATA).

Hardness testing

Two third of the total tablet products had hardness within allowed limits (4 – 10 kg), while the rest of the tablet products (1/3 of total) had

hardness more than 10 kg. The substandard products included 6 chloroquine products (collected from district DG Khan Punjab, district

Lakki, KPK, Khyber agency FATA and district Zhob Baluchistan), 10 artemether - lumefantrine products (80/480) (collected from Punjab,

KPK, and Baluchistan), 15 artemether - lumefantrine products (40/240) (collected from district DG Khan, Punjab, Lakki, KPK, both districts

22

from Sindh, and district Noshki and Zhob from Baluchistan), and 5 artemether - lumefantrine products (20/120) (collected from district DG

Khan Punjab, Bajaur agency FATA and district Thatta from Sindh,).

Friability testing

Friability of thirty-four tablet products was more than 1%, while the remaining number of tablet products showed acceptable friability.

However, two products, i.e. (tab Arther, 20/120 mg from district CHarsadda) and 2 (Artedoxin, artesunate 100 mg from Bajaur agency)

exhibited profoundly high friability, revealing extremely friable nature of these tablet products. Product and province-wise data revealed that

3 artemether - lumefantrine products (80/480) (collected from DG Khan, Punjab, district Charsadda KPK, and district Zhob from

Baluchistan), 6 artemether - lumefantrine products (40/240) (collected from district Lakki and Charsadda, KPK, Khyber agency from FATA,

and district Sibbi and Zhob from Baluchistan), and 10 artemether - lumefantrine products (20/120) (collected from DG Khan, Punjab, district

Charsadda KPK, both agencies from FATA and district Zhob and Sibbi from Baluchistan) did not meet compendial standards. Two tablet

products containing pyrimethamine – sulphadoxine were also out of allowed limits.

Disintegration

Eight tablet products containing chloroquine (belonging to district Lakki KPK, Mirpur Khas, Sindh, and Khyber and Bajaur agencies from

FATA) and 3 artemether - lumefantrine products (80/480) (collected from district Zhob and Sibi from Baluchistan) showed higher

disintegration time (more than 40 min), while rest of the products fulfilled BP criteria for disintegration test, i.e. 15 min.

Assay of active contents

The active drug contents in all tablet products were within compendial range (90- 110 %), except three products containing Artemeteher

Lumefantrine. 2 products with strength of 20/120 mg and 1 product of with 40/240 mg of AL, MosQinet from district Lakki Marwat KPK,

Mether Plus from Khyber agency and Xomal Plus from Khyber Agency FATA, had drug content <90% of standard values.

23

Dissolution

From all tablet products except two, percentage drug release in initial 15 min was more than 85% as per compendial requirement. Only one

tablet product containing artemether - lumefantrine products (40/240) (collected from Khyber Agency, FATA) and one tablet product

containing artemether - lumefantrine products (20/120) (collected from district Lakki, KPK) fell out of the standard criteria. Both the

products MosQinet and Mether Plus also exhibited substandard drug content concentrations

Table 4. QC analysis of chloroquine tablet products (n = 29)


Number of products


Punjab KPK Sindh Baluch

istan

FAT

A

Punjab KPK Sindh Balo-

chistan

FAT

A


chistan

FAT

A

Diameter and Thickness Variation < 5% variation - - - - 4 8 4 3 10 - - - -

Weight Variation < 5% variation - - - - 4 8 4 3 10 - - - -

Hardness testing 4 – 10 kg 1 2 - 1 2 3 6 4 2 8 - - - -

Friability testing < 1% - - - - 4 8 4 3 10 - - - -

Disintegration time 15 min - - 4 1 3 4 8 - 2 7 - - - -

Drug contents 90 – 110% - - - - 4 8 4 3 10 - - - -

Percentage drug release in initial 15 min > 85% - - - - 4 8 4 3 10 - - - -

Table 5. QC analysis of artemether – lumifantarine tablet products (80/480) (n = 30)


Number of products



chistan

FAT

A


chistan

FAT

A


chistan

FAT

A


Weight Variation < 5% variation - 1 - - 1 2 7 1 14 4 - - - -

Hardness testing 4 – 10 kg 2 1 - 4 3 - 7 1 10 2 - - - -

Friability testing < 1% 1 1 - 1 1 7 1 13 5 - - - -

Disintegration time 15 min - - - 3 2 8 1 11 5 - - - -

Drug contents 90 – 110% - - - - 2 8 1 14 5 - - - -

Percentage drug release in initial 15 min > 85% - - - - 2 8 1 14 5 - - - -

24

Note: No. of products collected from Punjab = 02, KPK = 08, Sindh = 01, Balochistan = 14 and FATA = 05.

Table 6. QC analysis of artemether - lumifantarine tablet products (40/240) (n = 42)


Number of products



chistan

FAT

A


chistan

FAT

A


chistan

FAT

A


Weight Variation < 5% variation - 1 1 1 1 2 7 8 17 5 - - - -

Hardness testing 4 – 10 kg 1 2 6 6 - - 6 3 11 6 - - - -

Friability testing < 1% - 3 - 2 1 1 5 9 15 5 - - - -

Disintegration time 15 min - - - - - 2 8 9 17 6 - - - -

Drug contents 90 – 110% - - - - - 2 8 9 17 5 - - - - 1

Percentage drug release in initial 15 min > 85% - - - - - 2 8 9 17 5 - - - - 1

Note: No. of products collected from Punjab = 02, KPK = 08, Sindh = 09, and Balochistan = 17 and FATA = 06.

Table 7 QC analysis of artemether - lumifantarine tablet products (20/120) (n = 77)


Number of products



chistan

FAT

A Punjab KPK Sindh Balo-chistan FAT

A Punjab KPK Sindh Balo-

chistan

FAT

A


Weight Variation < 5% variation - 2 - - 2 14 11 17 16 17 - - - -

Hardness testing 4 – 10 kg 2 - 1 - 1 12 11 16 16 18 - - - -

Friability testing < 1% 1 1 - 4 5 13 10 17 12 14 - - - -

Disintegration time 15 min - - - - 14 11 17 16 19 - - - -

Drug contents 90 – 110% - - - - 14 10 17 16 19 - 1 - -

Percentage drug release in initial 15 min > 85% 1 - - - 14 10 17 16 19 - 1 - -

Note: No. of products collected from Punjab = 14, KPK = 11, Sindh = 17, and Balochistan = 16 and FATA = 19.

25

Table 8. QC analysis of Tab Artesunate products (tablets = 2)

Products Properties Compendial limits

Number of products


Punjab KPK Sindh Baluch

istan

FAT

A Punjab KPK Sindh Baluch

istan

FAT

A Punjab KPK Sindh Baluch

istan

FAT

A

Tablets

Diameter and Thickness Variation < 5% variation - - - - - - - - 2 - - - - - Weight Variation < 5% variation - - - - - - - - 2 - - - - -

Hardness testing 4 – 10 kg - - - - - - - - 2 - - - - - Friability testing < 1% - - - - - - - - 2 - - - - -

Disintegration time 15 min - - - - - - - - 2 - - - - - Drug contents 90 – 110% - - - - - - - - 2 - - - - - Percentage drug release in initial 15 min > 85% - - - - - - - - 2 - - - - -

Note: No. of products collected from Punjab = 00, KPK = 0, Sindh = 0, and Balochistan = 0, and FATA = 02.

Table 9. QC analysis of pyrimethamine – sulphadoxide tablet products (n = 2)


Number of products



chistan

FAT

A


chistan

FAT

A


chistan

FAT

A

Diameter and Thickness Variation < 5% variation - - - - - - - - - 2 - - - -

Weight Variation < 5% variation - - - - - - - - - 2 - - - -

Hardness testing 4 – 10 kg - - - - - - - - - 2 - - - -

Friability testing < 1% - - - - 2 - - - - - - - - -

Disintegration time 15 min - - - - - - - - 2 - - - -

Drug contents 90 – 110% - - - - - - - - 2 - - - -

Percentage drug release in initial 15 minutes > 85% - - - - - - - - 2 - - - -

26

In addition to the AMDs collected from private sector, AMDs supplied by DoMC to the public sector health facilities were also tested for

reference. All the different classes of AMDs provided by DoMC showed consistent results within the recommended limits.

Table 10. QC analysis of DoMC provided AMDS

D=diameter,T=thickness,W=weight variation,H=hardness,F=friability,DC=drug content, DD=dissolution,DT=disintegration time

Chloroquine Phosphate (Tablets) Satndard Drug Name Strength D T W H F DC DD DT

Chloroquine phosphate 250mg

Artesunate (Tablets) Satndard Drug Name Strength D T W H F DC DD DT

Artedoxin 100mg x x

Artemether/Lumifantrine (Tablets) (20/120 mg)

Satndard Drug Name Strength D T W H F DC DD DT

Combiart 20/120

Pyrimethamine/Sulfadoxine (Tablets) Satndard Drug Name Strength D T W H F DC DD DT

Artedoxin 25/500 mg x x

Artesunate (Injections) Satndard Drug Name Strength

DC

Artesun 60mg

27

Below are the detailed results of quality assessment of AMDs both physical and chemical for 5 provinces/region

FATA

Chloroquine Phosphate (Tablets)

District Brand Name Strength D T W H F DC DD DT

Khyber Resochin 250mg ×

Khyber Nivaquine P 250mg ×

Khyber Resochin 250mg ×

Bajaur Nivaquine P 250mg ×

Bajaur Resochin 250mg

Bajaur Nivaquine P 250mg ×




Bajaur Nivaquine P 250mg

Chloroquine Phosphate (syrups)

District Brand Name Strength Volume (60 ml) weight pH Viscosity/torque DC

Khyber CHLOROQUINE 50mg/5ml X x

Khyber CHLOROQUINE 50mg/5ml x

Khyber CHLOROQUINE 50mg/5ml

Khyber OROQUINE 50mg/5ml

Bajaur NIVAQUINE P (81mg+50mg)5ml

Bajaur NIVAQUINE P (81mg+50mg)5ml



Khyber Alurine 20/120mg x

Khyber Herme 20/120mg

Khyber Qmetem 20/120mg

28

Khyber ARTECXIN 20/120mg x

Khyber Xomal Plus 20/120mg

Khyber Artecxin 20/120mg x

Khyber Arceva 20/120mg x

Khyber Artem Plus 20/120mg

Khyber Hi-servin 20/120mg x

Khyber Mether Plus 20/120mg x

Khyber Gen-M 20/120mg

Bajaur Artecxin 20/120mg x

Bajaur Xomal 20/120mg

Bajaur Neo-Cotecxin 20/120mg x

Bajaur Ufan-ft 20/120mg

Bajaur Artham 20/120mg x

Bajaur Gen-M 20/120mg

Bajaur Xomal Plus 20/120mg

Bajaur Arceva 20/120mg



Khyber Xomal plus Ds 40/240mg x x x

Khyber Safart 40/240mg

Khyber Malavel 40/240mg

Khyber Gen-M 40/240mg

Bajaur Artecxin Forte 40/240mg x

Bajaur Lumiter 40/240mg



Khyber mosqinet 80/480mg x

Khyber Arceva 80/480mg

Khyber Gen-M 80/480mg x

Bajaur Neo-Cotecxin DS 80/480MG x

29

Bajaur Qmetem DS 80/480mg x

Artesunate (Injections) District Brand Name Strength

DC

Khyber Gen-m 60mg

x Khyber Gen-m 60mg

Khyber Gen-m 60mg

Khyber Gen-m 60mg

Khyber Gen-m 60mg

x Bajaur Gen-m 60mg

Artesunate (Tablets) District Brand Name Strength D T W H F DC DD DT

Bajaur Artesul (S35-A16) 100 mg

Bajaur Artesul (S38-A26) 100 mg

Pyrimethamine/Sulfadoxine (Tablets) District Brand Name Strength D T W H F DC DD DT

Bajaur Artesul (S35-A16) 25/500 mg x

Bajaur Artesul (S38-A26) 25/500 mg x

30

Khyber Pakhtunkhwa

Chloroquine Phosphate (Tablets) District Brand Name Strength D T W H F DC DD DT

Lakki Resochin 250mg ×

Lakki Resochin 250mg ×

Charsadda Nivaquine P 250mg

Charsadda Resochin 250mg


Charsadda Chloroquine P 250mg

Charsadda Nivaquine P 250mg




Lakki OROQUINE 50mg/5ml

Lakki CHLOROQUINE 50mg/5ml ×

Charsadda CHLOROQUINE PHOSPHATE (81mg+50mg)/5ml ×

Charsadda CHLOROQUINE PHOSPHATE (81mg+50mg)/5ml ×

Artemether/Lumifantrine (Tablets) (20/120 mg) District Brand Name Strength D T W H F DC DD DT

Lakki Artem Plus 20/120 mg

Lakki Gen-M 20/120 mg

Lakki MosQinet 20/120 mg × ×

Lakki Artecxin 20/120 mg

Lakki Hi-servin 20/120 mg

Charsadda Artecxin 20/120 mg ×

Charsadda Gen-M 20/120 mg

Charsadda Hi-servin 20/120 mg

Charsadda Arther 20/120 mg

31




Lakki Artem Ds Plus 40/240mg

Lakki Neo-Cotecxin Forte 40/240mg ×

Lakki Biofantrine 40/240mg

Lakki Artine 40/240mg × ×

Lakki Qmetem DS 40/240mg × ×

Lakki Artecxin Forte 40/240mg

Charsadda A-fantrine DS 40/240mg ×

Charsadda Artem DS plus 40/240mg


Lakki Malgo 80/480mg

Lakki Co-Misomal QS 80/480mg

Lakki Neo-Cotecxin DS 80/480mg

Lakki Arceva 80/480mg

Lakki Hi-servin BD 80/480mg

Charsadda A-fantrine BD 80/480mg ×

Charsadda Arceva 80/480mg

Charsadda Simetrine 80/480mg × ×

Artesunate (Injections) District Brand Name Strength DC

Charsadda Misonate 60 mg

Lakki Gen-M 60 mg

Lakki Gen-M 60 mg

Lakki Gen-M 60 mg

Artemether/ Lumefantarine (Suspension)

32

District Brand Name Strength DC Lakki Malamether 15mg+90mg/5ml

Lakki Malamether 15mg+90mg/5ml

Punjab


Dera Ghazi Khan Chloroquine P 250mg

Dera Ghazi Khan Resochin 250mg ×





Dera Ghazi Khan Chloroquine Phosphate (81mg+50mg)/5ml × ×


Dera Ghazi Khan Artem Plus 20/120 mg

Dera Ghazi Khan Artine 20/120 mg

Dera Ghazi Khan Malgo 20/120 mg

Dera Ghazi Khan Arceva 20/120 mg

Dera Ghazi Khan Artine 20/120 mg

Dera Ghazi Khan Neo-Cotecxin 20/120 mg ×

Dera Ghazi Khan Artham 20/120 mg

Dera Ghazi Khan Gen-M 20/120 mg

Dera Ghazi Khan Neo-Cotecxin 20/120 mg ×

Dera Ghazi Khan Artham 20/120 mg ×

Dera Ghazi Khan Artem Plus 20/120 mg

33

Dera Ghazi Khan AluMax 20/120 mg




Dera Ghazi Khan Indomal DS 40/240 mg

Dera Ghazi Khan Ufan-TF 40/240 mg × ×


Dera Ghazi Khan Temprin Plus 80/480 mg × ×

Dera Ghazi Khan Alumax Forte 80/480 mg ×


Dera Ghazi Khan Gen-M 60mg

Dera Ghazi Khan Misonate 60mg

Dera Ghazi Khan Misonate 60mg

Dera Ghazi Khan Gen-M 60mg

34

Sindh


Mirpur Khas Nivaquine P 250mg x






Mirpur Khas Nivaquine P (81mg+50mg)5ml x


Thatta Mether Plus 20/120mg

Thatta Gen-M 20/120mg


Thatta Artelum 20/120mg

Thatta Hi-servin 20/120mg

Thatta Artem Plus 20/120mg

Thatta Qmetem 20/120mg



Thatta Hi-servin 20/120mg ×

Thatta Qmetem 20/120mg



Mirpur Khas Gen-M 20/120mg





35


Thatta Salvaj-DS 40/240 mg

Thatta Arthem DS plus 40/240 mg

Thatta Malther DS 40/240 mg

Thatta Gen-M 40/240 mg ×

Thatta Arceva 40/240 mg ×

Thatta Qmetem DS 40/240 mg × ×

Mirpur Khas Gen-M 40/240 mg ×




Thatta Arti Forte 80/480 mg


Mirpur Khas Gen-m 60 mg





Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Thatta Gen-m 60 mg

Artemether/ Lumefantarine (Suspension)

36

District Brand Name Strength DC Thatta Malera 15+90 mg/ 5ml

Thatta Artelum 15+90 mg/ 5ml

Thatta Arteget 15+90 mg/ 5ml

Thatta Artem Plus 15+90 mg/ 5ml

Thatta Gen-M BS 15+90 mg/ 5ml

Thatta Qmetem Plus 15+90 mg/ 5ml

Balochistan


Zhob Resochin 250mg x

Zhob Chloroquine Phosphate 250mg

Noshki Nivaquine P 250mg x



Zhob Chloroquine Phosphate (81mg+50mg)5ml x

Sibbi Nivaquine P (81mg+50mg)5ml




Sibbi Nivaquine P (81mg+50mg)5ml x



Zhob Artelum 20/120mg

Zhob Xomal Plus 20/120mg

37

Zhob A-Mal 20/120mg

Zhob Artem Plus 20/120mg

Zhob Artecxin 20/120mg x

Zhob Artine 20/120mg x

Sibbi Artine 20/120mg x

Noshki Artecxin 20/120mg x

Sibbi Gen-M 20/120mg

Sibbi Arceva 20/120mg

Noshki Gen-M 20/120mg

Sibbi Arti 20/120mg

Sibbi neo-cotecxin 20/120mg

Sibbi Gen-M 20/120mg

Sibbi Artecxin 20/120mg

Zhob Xomal Plus 20/120mg



Sibbi Artecxine Forte 40/240mg

Noshki Artem DS plus 40/240mg

Noshki Gen-M 40/240mg x

Sibbi A-fantrine DS 40/240mg x

Zhob Qmetem DS 40/240mg x

Zhob Co-Misomal Ds 40/240mg

Zhob Gen-M 40/240mg x

Zhob Arceva 40/240mg x

Zhob Artem Ds 40/240mg

Zhob Neo-Cotecxin Forte 40/240mg

Zhob A-Fantrine Ds 40/240mg x

Zhob A-Mal 40/240mg

Zhob ArteMax Ds 40/240mg

Zhob MalEra Ds 40/240mg


38

Sibbi Artecxin Forte 40/240mg




Sibbi Artine DS 80/480mg x

Sibbi Gen-M 80/480mg x

Sibbi Hi-servin BD 80/480mg

Zhob MalEra max 80/480mg x x

Zhob Artine DS 80/480mg x

Zhob Gen-M 80/480mg x

Zhob Artem Ds Plus 80/480mg

Zhob Artine DS 80/480mg x

Zhob Arceva 80/480mg

Zhob Co-Misomal Qs 80/480mg

Zhob A-Fantrine BD 80/480mg x

Noshki Gen-M 80/480mg

Noshki Artem DS Plus 80/480mg

Noshki Hi-servin bd 80/480mg


Noshki Gen-m 60mg x Noshki Gen-m 60mg

Noshki Gen-m 60mg X

Zhob Gen-m 60mg

Zhob Gen-m 60mg

Zhob Gen- 60mg

Zhob Misonate 60mg X

Zhob Misonate 60m

D=diameter,T=thickness,W=weight variation,H=hardness,F=friability,DC=drug content, DD=dissolution,DT=disintegration time

39

Provincial/Agency quality assessment analysis of AMDs suggests that 6 brands of A+L namely Gen-M, Artem Plus, Artexcin, Hi-servin and

Arceva consistently showed results comparable to the standard ranges. These results were consistent between batches and within batch,

within district and between districts of one province and across provinces of Pakistan. Similar results were observed for AS+SP where both

the tested samples showed acceptable quality assessment results. Tablet and Syrup Chloroquine showed mixed results. Results of physical

properties of some brands were not compendial to the standards. However, the drug content was within the standard 90-100% of the standard.

Unlike other AMDs, quality assessment results of injectable artesunate revealed that both the brands in their collected samples had

substandard drugs in term of drug content

Conclusion A wide range of antimalarial drugs are available in the market. Artemether+Lumefantrine are by far the most commonly available oral AMD

whereas injectable Artemether is widely available parenteral AMD. AS+SP which is first line antimalarial for falciparum malaria is not

easily available and was only found in FATA. Tab Quinine, injectable quinine and tablet primaquine which are recommended by national

treatment guidelines and essential for effective treatment are unavailable in private sector. This indicates that strict compliance with national

treatment protocols is neither practiced nor possible in private sector which caters most of the patients. Around 97% of the tested AMDs had

satisfactory quality in terms of drug content.

The presence of injectable Chloroquine in the market is a cause for concern – this drug is associated with (potentially fatal) cardiotoxicity

and should be removed from the private market. It has no advantages over the currently available drugs in the National Treatment

Guidelines, and has been banned by DRAP

Recommendations: Based on the findings of this study, the following recommendations are made:

1) DoMC may expand efforts to engage the private sector in appropriate use of antimalarial drugs and in employing the national treatment

guidelines for appropriate and effective treatment of malaria cases

2) Establishment of effective coordination channels with DRAP and engaging DRAP to

40

1. Maintain vigilance by monitoring of anti malarial drug quality of local manufacturers through routine surveillance

2. Banning of mono therapies

3. Prevent over the counter sale of mono therapies

3) Engaging DRAP on the pre-qualification of local AMD manufacturers

4) Engage DRAP in encouraging local manufacturers to manufacture AMDs currently being imported e.g Primaquine, Quinine etc

5) Engage DRAP in registration of Primaquine, Quinine from the local manufacturers

6) KAP surveys and prescription practices survey to identify issues with effective malaria case management

7) Quality assessment of antimalarials in public sector

Way Forward DoMC is currently procuring AMDs from international sources. The above given in vitro results suggest that the quality of AMDs

manufactured in Pakistan comply with official pharmaceutical standards. It provides opportunity to DoMC to consider national procurement

of AMDs. This will not only reduce the cost in terms of unit price but will also significantly reduce the logistics requirement and purchase

order lead time. However before considering local procurement, further in vivo investigation of AMD brands meeting the standard criteria is

mandated.

DoMC can take on board reputed manufacturers with international accreditation and encourage them to manufacture quality assured AMDS

such as primaquine and Quinine and ensure facilitation in registration of these AMD through DRAP. In addition to the local manufacturers,

DoMC must identify regional manufacturers of Primaquine and Quinine so that the continuous supply of these AMDs can be assured.

Different surveys both in public and private sector regarding prescription practices and treatment practices will give necessary information to

make informed decision in Malaria control and elimination policy making.

41

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