Abstract
Objectives
The quality of amoxicillin capsules, ceftriaxone for injection, and ciprofloxacin tablets was evaluated to determine whether there is any difference in quality when comparing the country of origin. This was undertaken because it has been claimed that antibiotics manufactured in Europe are of superior quality to those originating from Africa or Asia.
Methods
Samples of amoxicillin capsules, ceftriaxone for injection, and ciprofloxacin tablets were collected from three randomly selected wholesale pharmacies in each city, namely Arusha, Dar es Salaam and Mwanza, Tanzania. The collected samples of collected brands were subjected to quality control testing as per their respective pharmacopoeial monographs. Amoxil 250 mg capsules (Glaxo Wellcome, Mayenne, France), Rocephin (Roche, Switzerland) and Cipro-Denk 500 (Allphamed Pharbil Arzneimittel GmbH, Gottingen, Germany) were used as reference brands for the other generic brands of amoxicillin, ceftriaxone and ciprofloxacin, respectively.
Results
A total of 31 brands (10 different brands of amoxicillin capsules, 9 of ceftriaxone sodium injections, and 12 of ciprofloxacin tablets) were collected from the targeted regions and subjected to quality control testing. All samples of collected brands complied with the requirements of their respective pharmacopoeial monographs.
Conclusions
There was no significant difference in quality between brands of amoxicillin capsules, ceftriaxone for injection, and ciprofloxacin tablets manufactured in Africa and Asia against those manufactured in Europe in terms of compliance with the respective pharmacopoeial monographs.
Introduction
Antibiotic agents inhibit the growth or kill the bacteria.1 Amoxicillin is a commonly used broad-spectrum antibiotic agent used to treat various bacterial infections, which acts through the inhibition of cell wall biosynthesis, eventually killing the bacteria.2 Ciprofloxacin is a second-generation quinolone, which acts by binding to the bacterial enzymes DNA gyrase and topoisomerase IV, resulting in the formation of a quinolone–enzyme–DNA complex and subsequent cell death.3–5 Ceftriaxone is a third-generation, broad-spectrum cephalosporin and structurally similar to amoxicillin, thus inhibiting bacterial cell wall synthesis by binding to a protein family known as transpeptidases, which catalyse the cross-linking of the peptidoglycan polymers forming the bacterial cell wall.6
Reports indicate that amoxicillin, ceftriaxone and ciprofloxacin (in their different formulations) are the most widely consumed antibacterial agents in Tanzania.7–12 This is supported by the import/export database of the Tanzania Medicines and Medical Devices Authority (TMDA). The irrational use of antimicrobial agents accelerates the development and spread of antimicrobial resistance.12 Poor-quality medicines directly increase mortality and complicate the monitoring and detection of resistance as an epidemiological driver of poor disease outcomes.13–18
Nevertheless, there have been several claims against the quality, safety and efficacy of the registered brands of those products in Tanzania. A significant portion of generic medicines is either manufactured in Tanzania or imported from other African or Asian countries and is repeatedly reported to be substandard or falsified. Furthermore, it is contended that generic medicines from Africa and Asia are not pharmaceutically equivalent to those manufactured in Europe regarding quality and efficacy.19–21 The WHO issued reports supporting these claims and estimates that about 25%–50% of medicines circulating in developing countries are falsified or at least of very poor quality.22,23 Kimaro et al.24 and Malele et al.25 reported a significant correlation between the antibacterial effect and price whereby expensive brands have higher efficacy when compared to generic products. These claims have a serious impact on access to essential antibiotics in low and middle-income countries as the public is forced to opt for the innovator brands, which is difficult for them to afford and government expenditure on medical products is always limited.7,26
Furthermore, Kelesidis et al.27 reported that over 50% of falsified medicines were antimicrobials, and 78% were from developing countries. Similarly, Höllein et al.28 reported several falsifications of antibiotic agents in the Tanzania market. Of note, antibiotics are the most falsified medicines leading to serious health issues in the respective countries.
These reports and the public complaints against the quality of registered medicines warranted the execution of this investigation. The outcome of this study is instrumental in public advocacy and supporting government efforts to improve access to essential medicines. Almost everywhere, using generic medicines cannot be avoided because they are cheaper than innovator brands and available more readily.
Materials and methods
Chemicals and materials
Amoxicillin and ciprofloxacin reference standards were procured from the European Directorate for the Quality of Medicines and HealthCare (EDQM, Strasbourg, France), ceftriaxone and cefadroxil reference standards from the United States Pharmacopoeial Convention (Rockville, USA); methanol (HPLC), orthophosphoric acid and potassium dihydrogen orthophosphate (AnalaR) from Carlo Erba Reagent (Val de Reuil, France), ethyl acetate and sodium hydroxide (AnalaR) and acetonitrile (HPLC) from Fisher Scientific UK (Loughborough, UK), triethylamine and potassium dihydrogen orthophosphate (AnalaR) from Loba Chemie Pvt Ltd (Mumbai, India), disodium hydrogen phosphate, toluene, ammonia and acetone (AnalaR) from BDH Laboratory Supplies (Poole, England), hydrochloric acid and glacial acetic acid (AnalaR) from Carlo Erba Reagents (Viale Luraghi, Italy), tetraheptylammonium bromide (AnalaR) from Acros Organics (New Jersey, USA) and tetradecylammonium bromide (AnalaR) from Sigma–Aldrich (Steinheim, Switzerland).
Purified water for mobile phase and buffer preparation was generated by a ZeroB ECO SMART Reverse Osmosis (Ion Exchange Ltd, India) and further purified by an Ultra clear™ 10 TWF 30 UV UF TM (Evoqua Water Technology, Brunsbuettel, Germany).
Instrumentation
Amoxicillin capsule samples were analysed by using an Agilent HPLC 1260 Infinity II system equipped with an online degasser, a binary pump, an automatic sample injector, a column oven and a photodiode array detection module (Agilent, Santa Clara, USA) employing a ZORBAX SB C-18 column (250 × 4.6 mm, 5 µm particle size) (Agilent Technologies, USA).
Ceftriaxone for injection samples were analysed using a Shimadzu HPLC system (Shimadzu, Tokyo, Japan) equipped with an online degasser, a binary pump, an automatic sample injector, a column oven and a photodiode array detection module (all Shimadzu, Tokyo, Japan), employing a double-bonded and double end-capped ZORBAX XDB C-18 column (250 × 4.6 mm, 5 µm particle size) (Agilent Technologies, USA) for ceftriaxone for injection.
Ciprofloxacin tablets were analysed by the same HPLC system (Shimadzu) using a C-18 column with integrated precolumn (4.6 mm, C18, 5 µm particle size) (Knauer, Berlin, Germany). In addition, the Eurospher 100-5C18 column was used (250 × 4.6 mm, 5 µm particle size, with a polymer-bonded and fully end-capped stationary phase).
Dissolution of ciprofloxacin tablets was performed by using a DT 280 dissolution tester from ERWEKA GmbH (Langen, Germany). Samples and standard solutions were filtered using 0.45 µm syringe filters before quantification by using a Shimadzu UV 3600 UV-Vis-NIR Spectrophotometer (Shimadzu, Tokyo, Japan).
Data acquisition, analysis and reporting for the HPLC and UV-Vis spectrophotometer were performed by LC solution software version 1.25 SP3 (all Shimadzu, Tokyo, Japan) and OpenLab Software version 2.2.0 (Agilent Technologies, USA).
Other instruments included an analytical balance and a pH/conductivity meter (both Mettler Toledo, Greifensee, Switzerland), an FTIR spectrometer from PerkinElmer (Massachusetts, USA), and a Branson 5800 ultrasonicator from Branson Ultrasonics Corporation (Danbury, USA). The details of collected samples for the three products are listed in Table 1.
Table 1.
List of different brands of amoxicillin capsule, ceftriaxone for injection and ciprofloxacin tablet
| Amoxicillin capsules | Ceftriaxone for injection (1 g) | Ciprofloxacin tablets (500 mg) | ||||||
|---|---|---|---|---|---|---|---|---|
| Region | Product code (batch numbers) | Country (shelf-life, years) | Region | Product code (batch numbers) | Country (shelf-life, years) | Region | Product code (batch numbers) | Country (shelf-life, years) |
| Africa | A (250 mg); (050040918, 050040918, 050071117) | Tanzania (2) | Africa | A (1806606, 1806606, 1709365A) | Egypt (3) | Africa | A (18005 180001) |
Tanzania (3) |
| Africa | B (250 mg); (71877, 71878, 71879) | Kenya (2) | Asia | B (8007011) | India (2) | Africa | B (1705827) | Egypt (3) |
| Africa | C (250 mg); (8B124, 8C14, 8B125) | Kenya (2) | Asia | C (8007025, 80070332) |
India (2) | Africa | C (170121A) | Egypt (3) |
| Asia | D (250 mg); (1274) | India (3) | Asia | D (V219038) | India (2) | Asia | D (T04787 Dw1386) |
India (4) |
| Asia | E (500 mg); (8B125) | India (2) | Asia | E (1347Z018) | India (2) | Asia | E (472, 476 469) |
India (3) |
| Asia | F (250 mg); (MP18140, MP18140) | India (3) | Asia | F (JNIC18002) | India (2) | Asia | F (CX6081 CX6084) |
India (3) |
| Asia | G (250 mg); (180217, 180217, 171276) | China (3) | Asia | G (B1705044B) | India (2) | Asia | G (CFW5F61) | India (3) |
| Asia | H (250 mg); 1805804) | China (3) | Europe | H (B0400) | Switzerland (2) | Asia | H (17001 17001) |
South Korea (3) |
| Europe | I (250 mg); (MJ2N, 2457) | France (3) | Europe | I (R0012R0027, R0010P0380) | Portugal (2) | Europe | I (21013, 21374 21374) |
Germany (2), (3) |
| Europe | J (250 mg); 6208970409,) | Cyprus (5) | Europe | J (60193 60193) |
Portugal (5) | |||
| Europe | K (0701593 0701594) |
Greece (3) | ||||||
| Europe | L (75847 75845) |
Cyprus (5) | ||||||
Methods
Purposeful sampling was implemented and different brands of amoxicillin capsules, ceftriaxone for injection, and ciprofloxacin tablets were collected from three randomly selected wholesale pharmacies in each city, namely Arusha, Dar es Salaam and Mwanza in Tanzania. The three cities were selected because they have the highest population and consumption levels when compared with other regions.
The sampling plan was designed so that the collected samples of a particular brand for each product were from three geographical locations, namely, Africa, Asia and Europe. The surveyed medicines were selected because they are highly consumed compared with other antimicrobial agents and the Tanzanian National Medicines Regulatory Authority has received several complaints against those products. All collected samples were registered in the laboratory by using the laboratory information management system (LIMS) and stored as per the manufacturer’s prescribed storage condition. The analytical results for each product sample were imported into a validated and access-controlled MS Excel spreadsheet and analysed. The comparisons in terms of the performance of different brands were evaluated by using the F-test and a 95% CI of the mean was determined. The collected samples were analysed at the TMDA Quality Control Laboratory in Dar Es Salaam, a WHO prequalified laboratory.
Analytical methods
Amoxicillin capsules
Amoxicillin capsules were analysed as per the British Pharmacopoeia.29
Preparation of mobile phase for amoxicillin capsules—content determination: The mobile phase was prepared by mixing 80 mL of mobile phase B and 920 mL of mobile phase A, which were prepared as follows: mobile phase A was prepared by independently measuring and mixing 10 mL of acetonitrile, 990 mL of a 25% v/v solution of 0.2 M potassium dihydrogen orthophosphate adjusted to pH 5.0 with 2 M sodium hydroxide. Mobile phase B was prepared by independently measuring and mixing 200 mL of acetonitrile, 800 mL of a 25% v/v solution of 0.2 M potassium dihydrogen orthophosphate previously adjusted to pH 5.0 with 2 M sodium hydroxide. The mobile phase was degassed for 20 min using an ultrasonicator.
Preparation of 0.2 M potassium dihydrogen orthophosphate: The buffer was prepared by dissolving 81.63 g of potassium dihydrogen orthophosphate in a suitable amount of purified water and making the volume up to 3.00 mL using the same solvent; 250 mL of this solution was diluted to 1000 mL, and the pH was adjusted to 5.0 using a 2 M sodium hydroxide solution.
Preparation of standard solution for a system suitability test: 3.0 mg of amoxicillin trihydrate was accurately weighed and dissolved by using approximately 40 mL of mobile phase A. Four milligrams of cefadroxil was accurately weighed, dissolved and diluted to 100.0 mL using mobile phase A; 10 mL of this solution was transferred into another flask and diluted to 100.0 mL using the reference standard solution containing 3.0 mg/mL amoxicillin trihydrate.
Preparation of mobile phase for amoxicillin capsules—related substances testing: mobile phase A was prepared by independently measuring and mixing 10 mL of acetonitrile and 990 mL of pH 5.0 buffer solution. Mobile phase B was prepared by independently measuring and mixing 200 mL of acetonitrile and 800 mL of pH 5.0 buffer solution. The mobile phase was degassed for 20 min by using an ultrasonicator.
Preparation of standard solution for content determination: 14.20 mg of amoxicillin trihydrate was accurately weighed two individual times and dissolved by using mobile phase A to 20 mL and filtered; 50 µL of each solution was injected into the HPLC system.
Preparation of standard solution for related substance determination: 10.0 mg of cefadroxil reference standard was accurately weighed, dissolved and diluted to 50 mL by using mobile phase A, and 6.0 mg of amoxicillin trihydrate reference standard was accurately weighed and dissolved by using approximately 50 mL of mobile phase A. Forty millilitres of cefadroxil and 50 mL of amoxicillin reference standard solution were transferred, and diluted to 200 mL by using the same solvent.
Preparation of sample solutions for content determination: To a quantity of mixed contents of 20 capsules containing the equivalent of 60 mg of amoxicillin, 80 mL of mobile phase A was added, shaken for 15 min, sonicated for 1 min, and diluted to 100 mL by mobile phase A. The resulting solution was filtered using a 0.45 µm filter.
Preparation of sample solution for related substance determination: Solution 1: to a quantity of mixed contents of 20 capsules containing the equivalent of 150 mg of amoxicillin, 80 mL of mobile phase A was added, shaken for 15 min, sonicated for 1 min, and diluted to 100 mL by mobile phase A. The resulting solution was filtered using a 0.45 µm filter. Solution 2: 1 mL of test solution 1 was diluted to 100 mL with the mobile phase. Solution 3: standard solution was prepared as described above.
Ceftriaxone for injection
Ceftriaxone for injection was analysed as per the United States Pharmacopoeia 41 NF 36 requirements.30
Preparation of standard solution for a system suitability test: For ceftriaxone sodium and USP ceftriaxone E—isomer reference standard, 5.3 mg was accurately weighed, dissolved and diluted to 100 mL with mobile phase to make a final concentration of 53 µg/mL for each. The resulting solution was filtered by using a 0.45 µm filter.
Preparation of standard solution for content determination: For ceftriaxone sodium USP reference standard, 7.0 mg was accurately weighed, dissolved and diluted to 20 mL with mobile phase. The resulting solution was filtered using a 0.45 µm filter.
Preparation of mobile phase for ceftriaxone injection content determination: The mobile phase was prepared by weighing approximately 5 g of tetradecylammonium bromide and tetraheptylammonium bromide in a mixture of 1100 mL of water, 137.5 mL of solution (1), 12.5 mL of solution (2) and 1250 mL of acetonitrile. Solution (1) was prepared by mixing 152.8 mL of a solution containing 24 g/L dibasic sodium phosphate dodecahydrate in water and 97.3 mL of a solution containing 9 g/L monobasic potassium phosphate in water, adjusting to pH 7.0 with dilute orthophosphoric acid. Solution (2) contained 20 g/L citric acid in water, adjusting to pH 5.0 with 10 N aqueous sodium hydroxide.
Preparation of sample solution: The content of 10 vials of ceftriaxone for injection was mixed. A quantity of powder equivalent to 15 mg of ceftriaxone was accurately weighed, dissolved and diluted to 50 mL with mobile phase to make a final concentration of 0.3 mg/mL. All solutions were filtered using a 0.45 µm filter.
Ciprofloxacin tablets
The samples of collected brands of ciprofloxacin tablets were analysed as per the British Pharmacopoeia (2018).31
Preparation of mobile phase for ciprofloxacin tablets content determination: The mobile phase was prepared by first preparing 0.245% w/v orthophosphoric acid and then adjusted to pH 3.0 with triethylamine, and 870 mL of prepared solution was then mixed with 130 mL of acetonitrile.
Preparation of standard solution for the content determination: For the ciprofloxacin reference standard, 11.60 mg was accurately weighed, dissolved, and diluted to 20 mL with the mobile phase.
Preparation of sample solution for content determination: Twenty tablets were weighed and ground to obtain a fine powder, and then the amount of powder equivalent to 200 mg of ciprofloxacin was accurately weighed, added to 10 mL of the mobile phase, sonicated for 10 min, and diluted to 100 mL by using the same solvent. Five millilitres of the resulting solution was transferred into 20 mL and diluted to volume with the mobile phase. All solutions were filtered using a 0.45 µm filter.
Dissolution
Dissolution medium: Approximately 900 mL of purified water, at a temperature of 37°C, was used as the medium.
Preparation of standard solution for dissolution testing: For the ciprofloxacin reference standard, 5.2 mg was accurately weighed, dissolved in purified water, and diluted to 100 mL with the same solvent; 5 mL of the resulting solution was transferred into 50 mL, and diluted to volume with the same solvent.
Dissolution test: For the dissolution medium, 900 mL was accurately measured and placed in the dissolution vessels. Six tablets from each batch were weighed individually. Tablets were placed in the dissolution tester, which was run at 37°C and 50 rpm for 30 min. After the dissolution run, a portion of the resulting solution from dissolution vessels was passed through a 0.45 µm filter into sample vials and then 1 mL was transferred, diluted to 100 mL with the same solvent, and an absorbance reading taken using the UV/Vis spectrophotometer.
Results
Sampling
A total of 31 samples were collected including 9 different brands of ceftriaxone for injection, 12 of ciprofloxacin tablets, and 10 of amoxicillin capsules. More than one batch was collected for some brands, or the same batch was collected from different pharmacies or cities. The collection of more than one batch for some brands allowed for the comparison of the quality of a particular batch of the product collected from different sampling areas and provided feedback on the quality of storage facilities of the sampled pharmacies, as well as providing room for the evaluation of the consistency of the manufacturing process from one batch to another.
Three out of the 10 brands of amoxicillin capsules were sourced from the African region, 5 from Asia, and 2 from Europe, as highlighted in Table 1. These brands were manufactured in 2018, except for those from Europe (2014, 2016 and 2017, respectively). Their shelf-life ranged from 24 to 60 months, and all were within their shelf-life at the time of collection and analysis.
Two different batches were collected for the reference amoxicillin capsule product, i.e. Amoxil 250 mg capsule (Brand I, Glaxo Wellcome, Mayenne, France). One of the batches was collected from both Mwanza and Dar es Salaam. However, the two batches were of different numbering formats, which may be associated with falsification even though the product complied with the investigated quality parameters.
One out of nine ceftriaxone for injection brands was imported from an African country, six from Asia, and two from Europe, as shown in Table 1. Their shelf-life was 24 months for the Asia brands and 36 months for those from Africa and Europe. Rocephin (Brand H, Roche, Switzerland) was selected as a reference brand.
Three out of 12 ciprofloxacin tablet brands were manufactured within African countries, 5 in Asia, and 4 in Europe, as summarized in Table 1. One out of the three brands from the African countries were manufactured in Tanzania (Brand A). The shelf-life was 36 months for those from Africa, 36–48 months for those from Asia, and 24–60 months for the European brands. Cipro-Denk 500 (Brand I, Allphamed Pharbil Arzneimittel GmbH, Gottingen, Germany) was chosen to be the reference brand.
Quality control test results
All brands of the amoxicillin capsules complied with the British Pharmacopoeia amoxicillin capsules monograph requirements on identification and related substances (Table 2), and assay test (Figure 1). The average assay value was 98.2%, 97.2% and 97.8% for the Africa, Asia and Europe regions, respectively, which was within the acceptable limits of 92.5%–110.0% or 231.25—275 mg per capsule.
Table 2.
Identification test, pH, bacterial endotoxin and related substance test for collected samples
| Amoxicillin capsules | Ciprofloxacin tablets | Ceftriaxone for injection | ||||||
|---|---|---|---|---|---|---|---|---|
| Product code | ID test | Related substance | Product code | ID test | Product code | ID test | pH | BE |
| A | Complies | Complies | A | Complies | A | Complies | 6.89 | Complies |
| B | Complies | Complies | B | Complies | B | Complies | 6.79 | Complies |
| C | Complies | Complies | C | Complies | C | Complies | 7.07 | Complies |
| D | Complies | Complies | D | Complies | D | Complies | 6.88 | Complies |
| E | Complies | Complies | E | Complies | E | Complies | 6.71 | Complies |
| F | Complies | Complies | F | Complies | F | Complies | 6.73 | Complies |
| G | Complies | Complies | G | Complies | G | Complies | 6.76 | Complies |
| H | Complies | Complies | H | Complies | H | Complies | 7.08 | Complies |
| I | Complies | Complies | I | Complies | I | Complies | 7.08 | Complies |
| J | Complies | Complies | J | Complies | ||||
| K | Complies | |||||||
| L | Complies | |||||||
Figure 1.
Assay results of different brands of amoxicillin capsules collected per region. UL, upper limit; LL, lower limit. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Samples of all collected brands of the ceftriaxone for injection complied with the USP 41 NF 36 ceftriaxone monograph requirements on all investigated parameters (Figure 2). The average assay value for all brands ranged from 98.4% to 114.0%, within the acceptable limit of 90.0%–115% (0.90–1.15 g/vial).
Figure 2.
Assay results of different brands of ceftriaxone for injection 1 g samples collected. UL, upper limit; LL, lower limit. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Ciprofloxacin tablets were analysed as per the British Pharmacopoeia (2018), in which the appearance, identification, assay and dissolution test parameters were investigated. All samples complied with the requirements of ciprofloxacin tablets monographs, as summarized in Figures 3 and 4 and Table 2. The average assay value ranged from 98.0% to 105.0%, which is within the acceptable limit of the British Pharmacopoeia (2018) of 95.0%–105.0% or 475.0—525.0 mg/tablet.
Figure 3.
Assay results of different brands of ciprofloxacin 500 mg tablets collected. UL, upper limit; LL, lower limit. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Figure 4.
Dissolution test results of different brands of ciprofloxacin 500 mg tablets collected. IVM, in vitro medicines release (corresponding to % ciprofloxacin released per label claim); NLT, not less than. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.
Two batches were collected for the reference brand from two different outlets. The average assay results were 102.9% (514.5 mg/tablet), 103.8% (519.0 mg/tablet) and 103.6% (518.0 mg/tablet), respectively. There was no significant difference in average assay results for the three samples even though the former was expiring earlier than the latter batch (December 2020 against March 2021).
Discussion
There was no significant difference between Amoxil 250 mg capsules and other brands on all investigated parameters except on average assay results when compared statistically by ANOVA—single-factor [α = 0.05, Fcalc < Fcrit (7.709)]; only three brands, namely A, D and E, matched the reference brand, which was collected in Mwanza. The remaining brands had amounts of active pharmaceutical ingredient that were significantly less than the reference brand even though they were still within the acceptable limits.
Significantly different assay results were observed for the two samples (two different batches) of brand I (reference brand) in which one was collected from Mwanza and the other from Dar es Salaam. A higher assay result was observed for the former (101.1% ± 0.2%) against 96.7% ± 0.2% for the latter. Furthermore, the assay results for the batch collected in Mwanza, (expiring in March 2020) were 101.1% ± 0.2% compared with 94.8% ± 0.1% for the batch collected in Arusha, which was expiring later, in July 2020.
Similar observations were made for brand J for the batch that was expiring in October 2019, in which the assay results were higher (100.0% ± 0.1%) than the batch that was expiring later in November 2021 (96.2% ± 0.1%). These atypical results could be attributed to the variability and efficiency of storage facilities provided in the respective pharmacies.32
In the case of ceftriaxone, there was no significant difference between the reference brand (H), and other brands in terms of all investigated parameters, except on average assay results when compared statistically by ANOVA—single-factor [α = 0.05, Fcalc < Fcrit (18.513)]; only four out of nine brands, namely D, E, G and I, matched with the reference brand (H). The other brands had amounts of active pharmaceutical ingredient that were significantly lower than the reference brand even though they were all within the acceptable limits.
It is also important to note that there was no significant difference between the assay results of the two batches of brand A, which was collected from two different outlets (106.6% ± 0.1% and 105.6% ± 1.5%), which suggests consistency in the amount of active pharmaceutical ingredient in different vials of the same batch and that the product was appropriately stored as per the manufacturer’s prescribed conditions.
For ciprofloxacin tablets, similarly, there was no significant difference between the reference brand and other brands on all parameters except on average assay results and dissolution when compared statistically by ANOVA—single-factor [α = 0.05, Fcalc < Fcrit (7.710) and α = 0.05, Fcalc < Fcrit (4.965)], for the averaged assay and dissolution test results, respectively.
In the assay result, at least one batch of each brand except for brand G matched the reference brand. There were slightly different assay results for the two samples of brand K (104.9% ± 0.6% and 100.9% ± 1.0%, respectively).
In the case of dissolution tests, all batches of the six brands, namely B, D, I, K, L and M, matched with the reference brand. Similar results were obtained by Desta H et.al.3 in Ethiopia, in which the collected brands of ciprofloxacin complied with all investigated parameters.
Nevertheless, the amount of active pharmaceutical ingredient released for brands D, G and one batch of reference brands J, K, L and M were significantly higher than those observed under the assay test. This suggests that the formulations were more soluble in the dissolution medium than in the diluent used for the assay test.
The observed difference in assay value for the same batch collected at different sites could be attributed to poor storage conditions in the respective pharmacies where the products were collected. High temperature and humidity adversely affect drug formulation during transport, distribution and storage, to a varying degree however, depending on the nature of the drug and formulation type.22,33,34 Kaale et al.35 reported similar outcomes during the survey of selected essential medicines (which included amoxicillin capsules) sold in accredited dispensing outlets in Tanzania. Similarly, Kimaro et al.24 reported that all four samples of amoxicillin/clavulanic acid (500 mg of amoxicillin and 125 mg of clavulanic acid) complied with the specifications according to the British Pharmacopoeia.
Furthermore, despite the significant differences in terms of the content of active pharmaceutical ingredients observed for ceftriaxone for injection, the brands can still provide therapeutic equivalents to that of the innovator brand because their content was within acceptable limits and the product is delivered directly into the systemic circulation, unlike the oral formulation that needs to be metabolized before being absorbed.17Similarly for amoxicillin capsules and ciprofloxacin tablets, even though some brands were significantly different from the reference brand on the amount of active pharmaceutical ingredients, due to the fact that all were within acceptable limits of the British Pharmacopoeia, therapeutic results may be guaranteed.3,4,36
In conclusion, the outcome of the investigated parameters revealed that all targeted products complied with their respective compendial monograph specifications. This shred of evidence suggests that the registered medicines of surveyed products circulating in the Tanzania market are of the required quality with regard to the amount of active ingredient and dissolution where applicable. Furthermore, these results demonstrated that there is no significant difference in terms of quality as to whether the product is domestically manufactured or imported. It also shows that products that are domestically manufactured or imported from either other African or Asian countries offer similar quality and efficacy as those from Europe.
Acknowledgements
We wish to thank the management of the Tanzania Medicines and Medical Devices Authority (TMDA) for funding this study. We also thank Abdalla Juma, Halima Sembe, Mariamu Mbelwa and Gerald Ng’ombo for performing some of the analytical testing and Angelo Maarifa for participating in the sample collection.
Contributor Information
Yonah Hebron Mwalwisi, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Adam Mitangu Fimbo, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Ludwig Hoellein, Pharmaceutical and Medicinal Chemistry, Institute for Pharmacy and Food Chemistry, Universität Würzburg, 97074 Würzburg, Germany.
Moses Nandonde, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Gerald Sambu, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Babuali Ahmed, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Abdalla Juma, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Siya Augustine, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Danstan Hipolite Shewiyo, Human and Veterinary Medicines, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania; Laboratory Services, Tanzania Medicines and Medical Devices Authority (TMDA), Dar es Salaam, Tanzania.
Eliangiringa Amos Kaale, Pharm R&D Lab, School of Pharmacy, Muhimbili University of Health and Allied Sciences, P.O. Box 65545, 11103, Upanga West, Dar es Salaam, Tanzania.
Ulrike Holzgrabe, Pharmaceutical and Medicinal Chemistry, Institute for Pharmacy and Food Chemistry, Universität Würzburg, 97074 Würzburg, Germany.
Funding
This work was funded by the Tanzania Medicines and Medical Devices Authority (TMDA), Dodoma, Tanzania. The data collected during this study were part of the routine work of TMDA.
Transparency declarations
The authors have none to declare. All authors are employees of the Tanzania Medicines and Medical Devices Authority. A.M.F. is a researcher and expert in medicines regulation and pharmacovigilance; Y.H.M. and D.H.S. are also researchers who specialized in pharmaceutical analysis. S.A., G.S., B.A., A.J. and M.N. are analysts in medicines quality control.
U.H. and L.H. are employees of the University of Wuerzburg.
Author contributions
Y.H.M., A.M.F. and D.H.S. designed the study. Y.H.M. drafted the manuscript. All analysts performed the quality control testing of medicines. L.H., E.A.K. and U.H. reviewed the manuscript critically for intellectual content and finalized the submission.
References
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