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Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2): 242-249 Scholarlink Research Institute Journals, 2013 (ISSN: 2141-7016) Jjo g Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) Quality Control of Drugs: A Case of Erythromycin Tablets in
Chemist Shops of Meru Town. Kenya
1Dr. Kei Robert M. and 2Dr. Mutuma Kenneth
1School of Public Health , Moi University. Kenya. Corresponding Author: Kei Robert M.
__________________________________________________________________________________________
Abstract
Erythromycin stearate has been used for long in treatment of infections caused by susceptible strains of the
designated organisms in many diseases. Because of this widespread use of the drug, there is an equally increased
demand for cheaper generic erythromycin stearate tablets, of which their potency remains uncertain and hence
compromise health. Therefore, there is need to determine quality of drugs sold to the public. Chemist shops
selling human medicine in Meru Town. Fifty (50) chemist shops selling human medicine in Meru Town. The
objective is to analyze erythromycin tablets for their quality performance by determining their potency through
microbiological assay, disintegration time test and friability test. This was analytical study design. The samples
of erythromycin tablets from selected manufacturers were bought from sampled chemists in Meru Town and
analysed in the laboratory in order to determine their quality. All the samples examined passed the disintegration
time test; friability test except microbiological assay. Perhaps, this may be due to faulty quality assurance and
control during the process of manufacture and storage. There is need for sustained market surveillance of
erythromycin tablets to ensure quality standards are maintained. Also further research should be done in order
to establish the quality of other drugs in the market.
__________________________________________________________________________________________
Keywords: quality control; microbiological assay: disintegration time test; friability test.
INTRODUCTION
market is efficacious, safe and of good quality. The supply of good quality essential drugs was (Editorial Afr J pharm2003). Thus most countries recommended in the Alma-Ata declaration of 1978 as require that drugs must be evaluated and registered one of the prerequisites for the delivery of health before they are allowed to be freely sold within their care. When the concept of Essential Drugs List jurisdiction.(Thoithi 2003). In some countries drug (EDL) was introduced by World Health Organization registration exercises are complemented by a Drug (WHO) some governments embraced it, Kenya Quality Control Laboratory which monitors quality of included. They developed EDLs on which they based products on the market. In some cases the laboratory their procurements in terms of maximum quantity at carries out an analysis in order to finalize an minimum cost. The drugs procured from both local and international suppliers are assumed to be of good quality. This however, seems to have resulted in A new product so termed “the innovator brand” sets “cheap” drugs which in some occasions are of the bench mark on quality of the drug molecule. The pharmaceutical development of a dosage form and use of the same in clinical trials will establish quality The WHO Certification Scheme on the quality of parameters such as, quantity of active ingredient, pharmaceutical products moving in international allowable levels of degradation products and related commerce has not achieved the desired results. The substances and dissolution disintegration tests reasons for this are many and varied. They amongst others. Other quality indicating parameters nevertheless revolve around the tenets of WHO must conform to compendia requirements for the type procurements which usually assume that an adopting of dosage form.(Renington 1990). Any generic or implementing country has the will and formulations that may be developed later on must of implementing mechanisms to achieve the objectives. necessity be equivalent to the innovator product in Nevertheless, a quality drug is the most critical terms of quality. The quality of generics is an area armamentarium in the treatment or management of that requires critical scrutiny during the vetting of some disease states. Drug registration constitutes the documents. While the drug molecule is well known first line activity in ensuring that a product on the in terms of safety and efficacy, pharmaceutical Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) formulations cannot be the same. In Kenya, samples The data generated by previous researchers goes to of products are sent to the National Quality Control emphasize that there are both good quality and poor Laboratory (NQCL) for evaluation of quality before quality products in Kenya (Chitneni et.al 2004). The magnitude of poor quality products remains to be determined. This would require well thought out Quality Assurance (QA) in the pharmacy context market surveillance programmes by NQCL, Drug refers to the total sum of all those processes that are Analysis and Research Unit (DARU) and any other necessary to ensure the drug product is of good similar laboratories. Such programmes should be quality, effective and safe up to the point it is funded by the Pharmacy and Poisons Board as one of administered to the patient within its stated shelf life. their objectives in ensuring quality drugs in the It involves several aspects which broadly fall into four categories. The first aspect of QA involves registration of the drug product prior to marketing in Situation in Kenya
the recipient country. A dossier containing all In Kenya, the National Quality Control Laboratory relevant information on the product is submitted and (NQCL) is the quality control arm of the Pharmacy evaluated by a committee of experts representing and Poisons Board established under the Pharmacy different specialties. Information sought includes and Poisons Act, Cap 244. The objective of the evidence of quality, safety and efficacy. QA measures NQCL is to ensure that the quality of drugs available must meet internationally accepted standards as on the Kenyan market are safe, efficacious and of high quality. This is achieved by appropriate testing Pharmacopoeia, British Pharmacopoeia, and US of drugs before the Pharmacy and Poisons Board recommended shelf life must be submitted. Other information includes evidence of registration in Over the past years, Kenya has been treated to press country of origin and other countries where quality reports about poor quality pharmaceuticals in the market and problems with the same in public institutions (Leal 2001). This therefore, raises The second aspect of QA is evidence of Good concern about the quality of generic drugs in the Manufacturing Practice (GMP), which must focus on market. Defects in the regulatory procedures have the standard of raw material, the manufacturing made it attractive for some traders to introduce facility, the in-house production and control substandard generic medicines in the market. The measures, packaging, storage, quality control of Generic drugs are as safe as their branded finished product, qualifications and competence of counterparts only if the later have passed the quality personnel. In earlier years emphasis had been on control and safety tests. However, there still remains analysis of finished product, but later in the 1970’s a question on the quality of these drugs. During manufacture of antibiotics, the drug content The third aspect of QA is the control of the finished and physical characteristics are closely monitored to product. Although the manufacturer of a drug product avoid incidences of producing substandard products. is expected to carry out analysis of the product as part of GMP, it is necessary for such results to be validated by an independent and reputable laboratory. This is done through in-process quality control and Tests include confirmation of label specifications, quality control of finished products. However, dissolution rates, and limit tests for contaminants and incidences of antibiotics having less drug content degradation products. For a generic product, the than the claimed content are common. The products innovator product serves as point of reference. For especially tablets may also have poor disintegration antibiotics, chemical assay serves a limited purpose and the antimicrobial assay is preferable. For generic Previous work shows that there are both good quality and poor quality products in Kenya. The magnitude of poor quality products remains to be determined. The fourth aspect of QA is pharmacosurveillance This would require well thought out market (post marketing surveillance) of drug products. surveillance programmes by NQCL, DARU and any Despite all the precautionally measures taken to ensure safe and effective product, there are some Previous market surveillance studies have been done on many products on the Kenyan market. A previous negatively as the product moves along the supply line study on quality of amoxycillin preparations on the from the manufacturer, wholesaler, retailer/hospital, Kenyan market indicates that following the and eventually the patient (Editorial Afr J.pharm evaluation of the content of some 33 amoxycillin capsule formulations, all the failed products were Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) manufactured locally. (Kamau et.al 2003). In the the Kenyan market and that erythromycin is also same study, the evaluation of the amoxicillin content listed in the Essential Drug List, so far there is no in oral suspensions indicates that the content of study on erythromycin as to matters of quality. amoxicillin in all the products changed within the Therefore, this study is directed at ascertaining the seven days under the storage conditions. Study done quality of some of the erythromycin products on the on quality control of antiretroviral drugs analyzed in the Drug Analysis and Reasearch Unit during 2000- 2003, indicates that a total of 33 drugs samples were Erythromycin
analyzed of which 31 (93.9%) were generic products Erythromycin, produced by Saccharopolyspora and only 2 were innovator products (Obuga et.al 2003). This reflects the current government policy to erythraeus) is a complex macrolide antibiotic encourage marketing of generic ARVs, which are far consisting of erythromycin A, a 14 membered lactone much affordable than the brands. The analysis results ring with a 9-keto group, carrying a neutral and obtained showed that 30 of the samples complied amino sugar (Labenda 1987). It has two glycosidic with the USP specifications while 3 generic products bonds and a basic dimethylamino group on desosamine. The biosynthesis of erythromycin can be divided into two phases. In the first phase the Surveys have also been done on quality of polyketide synthase (PKS) catalyzes sequential sulphadoxine/pyrimethamine tablet products on the condensation of one unit of propionyl CoA and six Kenyan market (Kibwage et.al 2000). This involved the evaluation of parameters of the tablets that are likely to affect their bioavailability, that is, the content of active ingredients (APIs) and dissolution. deoxyerythronolide B is elaborated by a series of In the study 26 batches were analyzed of which the "tailoring" enzymes which include regiospecific content of APIs for all the examined batches were hydroxylases, glycosyl transferases, and methyl within the USP limits of the label amount except for transferases. From the biosynthetic point of view one batch which was below the limits. On the most interest is focused on the operations of the PKS dissolution test only 30% of the analyzed samples in phase 1, but the late steps are essential to produce passed the test. A study done on the quality of active antibiotics. Semi-synthetic derivatives of ampicillin preparations on the Kenyan market Erythromycin have been directed at producing indicate that upon evaluation of the chemical content compounds with increased potency and increased of 20 ampicillin capsules and 2 tablet products, four stability in acidic and basic environments. These capsule products failed to comply with the include roxithromycin, azithromycin, flurithromycin pharmacopoeal label claim (Kamau et.al 2001). In the same evaluation the content of ampicillin in oral suspensions for five products failed the test. Analysis Erythromycin Indications
of co-trimoxazole products on the Kenyan market has Erythromycin stearate has been used for long in also been done whereby in the study there were a treatment of infections caused by susceptible strains total of 9 samples from 7 local products of which 2 of the designated organisms in many diseases which failed the content. Of the 9 imported products, 13 includes respiratory tract infections especially upper samples were analyzed and 4 failed the content respiratory tract infections of mild to moderate specifications. Six samples failed the specifications pyogenes,
for content of active ingredients.(Kibwage et.al Streptococcus pneumoniae, or Haemophilus and
1998). An observation on drug quality control in lower-respiratory tract infections of mild to moderate
Kenya by the Drug analysis and Research Unit severity caused by Streptococcus pneumoniae or
indicates that the failure rate of drugs analyzed in Streptococcus pyogenes. It is also used in respiratory
DARU over the period 1996-2000 is higher (23.6%) tract infections due to Mycoplasma pneumoniae and
compared to those analyzed in the same laboratory in skin and skin structure infections of mild to moderate
the period 1991-1995 (17.5%) (Thoithi 2002). There severity caused by Streptococcus pyogenes or is therefore need for manufacturers to pay attention to such batch to batch variations that may arise and identify causes of them. The use of poor quality In addition, it is indicated in pertussis (whooping products especially antibiotics can have serious cough) caused by Bordetella pertussis. Erythromycin consequences including development of drug is effective in eliminating the organism from the resistance and therapeutic failure. The results of these nasopharynx of infected individuals rendering them studies support the continuing need for quality noninfectious. In infections due to Corynebacterium certification before and market surveillance after diphtheriae, it is used as an adjunct to antitoxin to products are released into the market by reputable prevent establishment of carriers and to eradicate the laboratories as more products enter the Kenyan organism in carriers. Erythromycin is also used in market. Despite the many studies on drug products on intestinal amebiasis caused by Entamoeba histolytica, Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) acute pelvic inflammatory disease caused by variation of responses, replication of treatment is Neisseria gonorrhoeae and treatment of infections necessary (William et.al; 2001). Microbiological assay has an advantage over physical and chemical tetracyclines are contraindicated or not tolerated, methods of assay in that it directly detect biological erythromycin is indicated for the treatment of activity and measure potencies of antibiotics hence nongonococcal urethritis caused by Ureaplasma are preferred in the analyses of antibiotics. In case of urealyticum. Moreover, it is indicated in primary related substances which show activity, this method cannot be used. It is time consuming and labor Erythromycin (oral forms only) is an alternative choice of treatment for primary syphilis in patients allergic to the penicillins. It is also used in Disintegration Time Test
Disintegration is defined as that state in which no pneumophila and prophylaxis in prevention of initial residue of the tablets and capsules, except fragments of undissolved coating, remains in the test solution. Erythromycin has been used for treatment of several The method provides a rough estimate of the time infection diseases and in patients allergic to the limit (30 minutes) required for all uncoated tablets effervescent, and film-coated tablets, that is, all quick Microbiological Assay
release formulations of a drug dosage form to This is a technique whereby the potency or the disintegrate in water at 37± 2°C. If a drug product concentration of a chemical substance may be does not pass this test, there is a major defect in its determined by its effect on the growth of a quality because it will not dissolve, absorb and microorganism either by promoting the growth or by become bioavailable. The product can be rejected at inhibiting the growth. The potency of a sample of an this stage with no further investigation (Renington antibiotic is determined by comparing the dose that inhibits the growth of a suitable susceptible microorganism with the dose of the standard Friability Test
preparation of that antibiotic that produces similar This is one of the criteria for testing mechanical inhibition. Biological methods directly detect strength of tablets. During the process of coating and biological activity and measure potencies of transportation, the tablet will lose some weight. To antibiotics hence are preferred in the analyses of measure the weight loss the samples are counted and antibiotics. The procedures employed in microbial weighed. Thereafter, the friability test is performed assay of antibiotics may be broadly divided into two. following the individual monographs of the relevant The first is the turbidimetric method where the extent pharmacopoeia. When finished, the samples have to of growth of an organism in a liquid nutrient medium be de-dusted and weighed again. The difference is dependent on the quantity of the active substance between the weight before and after the test is added to and mixed uniformly with the liquid determined as friability, which should not usually medium. Growth of the microorganism is measured LIMITATIONS OF THE STUDY
The second is the cylinder plate method in which an Tablet Hardness Test was not done because there aqueous solution is placed in contact with a solid agar were no B.P. Specifications for film coated gel on a plate. The solute diffuses from the solution erythromycin tablets. Again, due to financial into the gel until equilibrium is set. The agar contains constraints the study could not cover other drugs in nutrients to support the growth of the microorganism and is inoculated with a suspension of the test organism. The organism grows and multiplies until it MATERIALS AND METHODS
is inhibited by the antibiotic, yielding a clear zone of The study was carried out in Meru Town of Meru inhibition. The zone is as a result of the outward County, Kenya. This was to determine the quality of diffusion of the antibiotic from a reservoir into a generic erythromycin tablets sold in the chemist layer of the inoculated medium to yield a circular shops selling human medicine. The study was guided zone of inhibition. The critical concentration of the by analytical study design, through, performing antibiotic, the period of growth of the organism and microbiological assay, disintegration test and the population of the microorganisms affects the zone After listing the chemists (50), erythromycin tablets The test solutions are made as dilutions in a series of (20) were purchased from randomly sampled two ore more concentrations prepared from reference chemists (20) and taken to the laboratory for analysis, standard and the unknown samples for application on the test system. To minimize the effect of random Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) To ascertain the quality of generic Erythromycin Namur, Belgium) used for ensuring complete tablets collected, the following tests were carried dissolution of solutes. MEMMERT incubator Range out:- disintegration time test, friability test and BE (analis, Namur, Belgium) used for incubating the microorganism cultures. AC600 Series vertical laminar flow workstation (Vermeulen I.j, Germany) used for carrying out the microbiological procedures. Brand name
Manufacturer
Supplier
Mettler Toledo PB3002 Data Range weighing balance (Switzerland) used for weighing reagents and media. Dixons ST19 Aluminium portable autoclave (UK) used for sterilizing the media. MEMMERT Universal Oven and Sterilizer Model U (Analis sa, Belgium) used for drying and sterilizing glassware. LMS Laboratory refrigerator used for storing culture plates and microorganisms. An electronic digital caliper used for measuring the zone of inhibition. Disintegration Time Test
One tablet or capsule was placed into a 100-150 mL wide neck bottle containing 100 mL water at close to 37± 2°C. The liquid was then stirred by swirling the bottle periodically. The time (in minutes) when EQUIPMENT AND APPARATUS
disintegration is complete was read and recorded. The Sartorius CP225D Balance (Elisters 2000 Ltd., test was repeated on five additional tablets. Namur, Belgium) used for weighing accurately the samples. Friabilator model PTF1 (Pharmatest GmbH, The batch passes disintegration time test if all six Germany) used for carrying out the friability test. tablets disintegrate within 30 minutes. Should one Disintegration tester PTZ1 (Pharmatest GmbH, tablet fail to disintegrate, the entire test cycle was to Hainburg, Germany) used for carrying out the be repeated. The batch fails disintegration test if one disintegration time test. Schleuniger-2E, tablet of the additional tablets fail again in the second run. hardness tester used for carrying out the tablet hardness test. BRANSON 2200 stirrer (analis,

Table 11: Disintegration Time Test
Time in Minutes
Erocos 250
Erocos 500
Rythro 500
BN: 062202
BN: 062117
BN: 6F250
BN: RE6001
Friability test
friabilator. The results obtained are shown in table The test was carried out as per the B.P 2007 VOLUME 1V APPENDIX XVII G method using a
Table 111: Friability Test
Parameter /tablet
Erocos 250
Erocos 500
Rythro 500
BN: 062202
BN: 062117
BN: 6F250
BN: RE6001
Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) Microbiological assay
hours. The diameters of the zones of inhibition Diffusion Assay Method A BP (2005)
produced by various concentrations of the Standard Tryptone Soya Agar (4.0g) was suspended in 100.0 Preparation and the substance being examined were mL of distilled water and brought to boiling to then measured using the zone reader (British pharm dissolve completely. This was then sterilized by 2005). The potency was then calculated according to autoclave at 121˚C for 15 minutes. A solution of phosphate buffer of pH 8.0 was prepared by mixing Formula 1:
orthophosphate with 46.80 ml of 0.2M NaOH VS and diluted to 200.0 mL with water. A concentration of 30 mg/50 mL of the standard in distilled methanol was prepared by weighing 31.05 mg of erythromycin A base 96.6% and dissolving in methanol in a 50.0 % LC = Weight of Standard x Antilog m x Purity x 100 The test sample was prepared by weighing and powdering 20 tablets. A quantity of the powder corresponding to the most concentrated to the least containing the equivalent of 30 mg of Erythromycin concentrated of the standard samples respectively and was dissolved as completely as possible in sufficient T3, T2 and T1 are zone diameters corresponding to methanol to produce 50.0 mL and the biological the most concentrated to the least concentrated of the assay of antibiotics for erythromycin carried out. Dilution of the sample and standard solutions was carried out as follows. From the original solution, 5.0 Table 1V: Potency of the products analyzed mL of the solution was transferred to a 25.0 mL volumetric flask and made up to the mark with the % label claim
phosphate buffer. 10.0 mL was further diluted to 25.0 mL with the phosphate buffer. Finally, 10.0 mL of this solution was transferred to a third 25.0 mL volumetric flask and made up to the mark with the phosphate buffer. The volumetric flasks were labeled DISCUSSION
Petri dishes were filled to a depth of 3 to 4 mm with a According to the B.P. (2005) specifications for tryptone soy agar medium that has previously been uncoated tablets the tablets disintegrate within 15 inoculated with 1% w/v of a suitable inoculum of minutes unless otherwise justified and authorized. If Bacillus pumilis. When the inoculum consisted of a the preparation fails to comply because of adherence suspension of vegetative organisms, the temperature of the tabs to the discs, a repeat of the test on a of the molten agar medium was not exceed 48˚C to further 6 tablets omitting the disc is required. The 50˚C when it was inoculated was kept at a preparation being examined complies with the test if temperature of 37˚C. The dishes were specially all 6 tablets have disintegrated. Rythro 500 (BN selected with flat bottoms and placed on a level RE6001) is an uncoated erythromycin tablets. The surface so as to ensure the layer of the medium will disintegration time test for the six tablets was about be of a uniform thickness. The inoculated plates were one minute. All the tablets disintegrated within this allowed to dry for 30 minutes at room temperature time. The tablets therefore, comply with the B.P disintegration test for tablets and capsules. In case of coated tablets, unless otherwise justified and Wells 5 to 8 mm in diameter were bored in the authorized, film coated tablets disintegrate within 30 medium with a sterile borer. Solutions of the standard minutes and other coated tablets disintegrate within preparation of known concentration and solutions of 60 minutes. The preparation being examined the substance being examined were prepared in a complies with the test if all 6 tablets have sterile phosphate buffer of a suitable pH value. The disintegrated in the medium. Erocos 250 (BN solutions were then introduced to the wells by means 062202), Erocos 500 (BN 062117), Elocin (BN of a pipette. Three different doses of the standard 6F250) and Elocin (BN 7C55) were film coated preparation and of the sample being examined having erythromycin tablets. The four batches comply with the same presumed activity as the solutions of the the B.P. disintegration test for tablets and capsules. standard were used in order to be able to assess the validity of the assay. The plates were maintained at In reference to the B.P. (2007) specifications, room temperature for 2 hours, during which time generally the friability test is run once. If obviously diffusion of the antibiotic into the medium occurs cracked, cleaved or broken tablets are present in the then incubated at suitable 37˚C for approximately 18 tablet sample after tumbling, the sample fails the test. Journal of Emerging Trends in Engineering and Applied Sciences (JETEAS) 4(2):242-249 (ISSN: 2141-7016) A maximum loss of mass (obtained from a single test 2. That further research should be done in or from the mean of 3 tests) not greater than 1% is order to establish the quality of other drugs considered acceptable for most products. All the samples passed the friability test as per the B.P. REFERENCES
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