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Keywords:

  • anti-TB drugs;
  • drug content;
  • Revised National TB Control Programme

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective

To determine the content of certain antituberculosis (TB) drugs supplied at TB treatment centres of the Revised National TB Control Programme (RNTCP) in the state of Tamil Nadu, India.

Methods

Eight districts across the state were selected, and the following drugs were collected from five settings (District TB centre, TB unit, designated microscopy centres, DOT providers) in each district: rifampicin (150 and 450 mg), isoniazid (300 mg), pyrazinamide (500 and 750 mg), ethambutol (400 and 600 mg), ethionamide (250 mg), levofloxacin (500 mg) and cycloserine (250 mg). A maximum of 10 tablets/capsules were collected from each setting. The drugs were coded prior to analysis. All drugs were assayed by validated spectrophotometric methods. The acceptable limits for drug content were taken as 90–110% of the stated content.

Results

More than 90% of tablets of rifampicin 450 mg, isoniazid 300 mg, pyrazinamide 500 and 750 mg, ethambutol 400 and 600 mg and ethionamide 250 mg were within acceptable limits. Eighty per cent of rifampicin 150 mg, 21% of cycloserine 250 mg and 87% of levofloxacin 500 mg were within acceptable limits. The mean cycloserine content was below the acceptable limit in all districts, the mean drug content being 200 mg (range: 108–245 mg).

Conclusion

This systematic study showed that the stated drug content of cycloserine was not reached in all districts. Deterioration of cycloserine could be minimised by storing the drug in refrigerators. The geographical location of the districts had no influence on the drug content.

Objectif

Déterminer la teneur de certains médicaments antituberculeux fournis dans les centres de traitement de la TB du Programme National Révisé de Lutte Contre la TB (RNTCP) dans l'Etat du Tamil Nadu, en Inde.

Méthodes

Huit districts de l'Etat ont été sélectionnés et les médicaments suivants ont été collectés dans cinq endroits (centre de la TB du district, unité de la TB, centres de microscopie désignés, fournisseurs du DOT) dans chaque district: rifampicine (150 mg et 450 mg), isoniazide (300 mg), pyrazinamide (500 mg et 750 mg), éthambutol (400 mg et 600 mg), éthionamide (250 mg), levofloxacin (500 mg) et cycloserine (250 mg). Un maximum de 10 comprimés/gélules a été collecté dans chaque endroit. Les médicaments ont été codés avant l'analyse. Tous les médicaments ont été analysés par des méthodes de spectrophotométrie validées. Les limites acceptables pour la teneur des médicaments ont été fixées à entre 90% et 110% de la teneur indiquée.

Résultats

Plus de 90% des comprimés de rifampicine 450 mg, d'isoniazide 300 mg, de pyrazinamide 500 mg et 750 mg, éthambutol 400 mg et 600 mg et éthionamide 250 mg étaient dans les limites acceptables. 80% de la rifampicine à 150 mg, 21% de la cycloserine à 250 mg et 87% de la levofloxacin à 500 mg étaient dans des limites acceptables. La teneur moyenne en cycloserine était inférieure à la limite acceptable dans tous les districts, la teneur moyenne du médicament étant de 200 mg (intervalle: 108 à 245 mg).

Conclusion

Cette étude systématique a montré que la teneur en médicament indiqué pour la cycloserine n’était pas atteinte dans tous les districts. La dégradation de la cycloserine pourrait être minimisée en la stockant au réfrigérateur. La localisation géographique des districts n'avait aucune influence sur la teneur des médicaments.

Objetivo

Determinar el contenido de ciertos medicamentos anti-tuberculosis (TB) suministrados por centros para el tratamiento de la TB del Programa Nacional Revisado de Control de la TB en el estado de Tamil Nadu, India.

Métodos

Se seleccionaron ocho distritos a lo largo del estado, y se recolectaron los siguientes medicamentos: rifampicina (150 mg & 450 mg), isoniazida (300 mg), pirazinamida (500 mg & 750 mg), etambutol (400 mg & 600 mg), etionamide (250 mg), levofloxacina (500 mg) y cicloserina (250 mg), de cinco lugares diferentes en cada uno de los distritos (centro distrital de TB, unidad de TB, centros de microscopía, proveedores de DOTS). Se recolectaron un máximo de 10 comprimidos/cápsulas de cada emplazamiento. Los medicamentos se codificaron antes del análisis. Todos los medicamentos fueron evaluados mediante métodos espectrofotométricos validados. Los límites aceptables para el contenido del medicamento se establecieron entre 90–110% del contenido declarado.

Resultados

Más del 90% de los comprimidos de rifampicina 450 mg, isoniazida 300 mg, pirazinamida 500 mg & 750 mg, etambutol 400 mg & 600 mg y etionamida 250 mg estaban dentro de los límites aceptables. Un 80% de la rifampicina de 150 mg, 21% de la cicloserina de 250 mg y 87% de la levofloxacina de 500 mg estaban dentro de los límites aceptables. El contenido medio de la cicloserina estaba por debajo del límite aceptable en todos los distritos, siendo el contenido medio de medicamento de 200 mg (rango: 108–245 mg).

Conclusión

Este estudio sistemático muestra que el contenido declarado de ingrediente activo para la cicloserian no se alcanzaba en todos los distritos. El deterioro de la cicloserina podría minimizarse guardando la medicación en neveras. La localización geográfica de los distritos no tenía influencia alguna sobre el contenido del medicamento.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Tuberculosis (TB) can be effectively treated using standard short-course chemotherapy containing isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) and ethambutol (EMB) for drug-susceptible strains of TB Mitchison 1993. The Revised National TB Control Programme (RNTCP) in India provides quality-assured anti-TB drugs through personalised boxes. A substantial number of RMP and INH medications from several countries, especially fixed-dose combinations, were substandard Laserson et al. 2001; Kelesidis et al. 2007; : about 12% of RMP and 9% of INH collected from the private sector in two Indian cities proved substandard Bate et al. 2009. Bate and others assessed the quality of RMP and INH procured from private sector pharmacies in 19 cities in Africa and Asia and found that 16.6% in Africa, 10.1% in India and 3.9% in other middle-income countries were substandard and falsified drugs Bate et al. 2013. A few studies have also shown good quality of anti-TB medicines Ellard 1999; Ashokraj et al. 2004.

The RNTCP has a drug quality assurance system in place, in which samples of anti-TB drugs are tested. Drugs are mostly collected from District TB centres (DTC). The aim of this study was to determine the content of certain anti-TB drugs supplied at different TB treatment centres of the RNTCP, such as TB units (TU), designated microscopy centres (DMC) and DOT providers in the state of Tamil Nadu, India.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Eight districts spread across Tamil Nadu with varying geographical terrain, accessibility and availability of DOTS plus drugs were selected. In each district, drugs were collected from DTC, TU, two DMCs and DOT providers. Within each selected district, the TU that was geographically closest to the DTC was selected. Within the selected TU, two DMCs, one each with highest and lowest case loads, were selected. DOT providers were selected by convenience sampling. A maximum of 10 each of the following drugs was collected from each setting:

  • rifampicin (RMP) (150 and 450 mg)
  • isoniazid (INH) (300 mg)
  • pyrazinamide (PZA) (500 and 750 mg)
  • ethambutol (EMB) (400 and 600 mg)
  • ethionamide (Eth) (250 mg)
  • levofloxacin (LFX) (500 mg)
  • cycloserine (Cs) (250 mg)

The drugs were taken from personalised patient boxes that were in current use. Boxes belonging to patients on category I/II/IV treatment during the intensive phase were selected. Collected drugs were replaced with drugs from the State Drug Stores (SDS), Chennai. For analysis, drugs stored in the SDS, and drugs purchased and used for clinical trial patients in our Institute were also included. Drugs were stored at room temperature in all the districts and in air-conditioned rooms in the SDS. All drugs were coded and sent to the laboratory for analysis; the laboratory staff was blinded regarding the source of the drugs.

Drug analysis

Drugs were assessed for their active ingredient according to validated spectrophotometric methods Rao et al. 1971; Jones 1956; Gurumurthy et al. 1984. Pure drug powder was used to prepare calibration standards of known concentrations and processed alongside the tablet/capsules. The acceptable limits for content of the active ingredient applied to the individual drugs were taken as 90–110% World Health Organisation report 2011.

Sample size calculation and statistical evaluation

It was assumed that 95% of drugs included in this study would be within the acceptable range. Considering type I error to be 5%, relative precision to be 20% with a design effect of 2, the required sample size was 10 tablets from each setting.

Statistical analysis was performed using SPSS (version 14.0). Multiple linear regression analysis was performed to determine which of the factors influenced drug content.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Table 1 summarises the content of all the drugs along with outliers in all the districts. RMP 450 mg content was below the acceptable limits in one district (76%). RMP 150 mg content was below the acceptable limits in five districts. EMB 400 mg content was below acceptable limits in one district (80%). PZA 750 mg content was below acceptable limits in two districts (70% and 82%). Of the 10 tablets analysed in one TU, the mean drug content was 226.6 mg (range: 137.4–634.7 mg); nine tablets had a mean drug content of 181.3 mg (range: 137.4–235.4 mg). The content of Cs 250 mg was below acceptable limits in all the districts; 23% of tablets from the districts were within acceptable limits. The percentage of tablets falling within the acceptable limits ranged from 0 to 40%. LFX 500 mg content was below acceptable limits in three districts.

Table 1. Drug content (Median & IQR) and the percentage adherence to stated content in eight districts
DrugNo. of tabletsMedian (mg) (IQR)No. (%) of tablets below, within & above the acceptable range
Below (<90%)Within (90–110%)Above (>110%)
Rifampicin 450 mg398448.6 (433.2–461.3)26 (7)366 (92)6 (2)
Rifampicin 150 mg80151.7 (144.3–157.4)5 (6)64 (80)11 (14)
Isoniazid 300 mg406295.2 (288.3–303.2)16 (4)389 (96)1 (0)
Ethambutol 600 mg346600.0 (584.5–614.2)2 (1)335 (97)9 (3)
Ethambutol 400 mg94402.5 (392.0–415.0)1 (1)91 (97)2 (2)
Pyrazinamide 750 mg406732.2 (719.5–747.7)22 (5)382 (94)4 (1)
Pyrazinamide 500 mg17501.0 (494.5–506.0)0 (0)17 (100)0 (0)
Cycloserine 250 mg70212.0 (185.8–224.0)54 (77)16 (23)0 (0)
Ethionamide 250 mg64242.0 (239.0–244.0)0 (0)64 (100)0 (0)
Levofloxacin 500 mg67480.0 (470.0–492.0)9 (13)58 (87)0 (0)

Multiple linear regression analysis was carried out to determine which of the factors (district, company and healthcare facility level) influenced drug content. Except for Cs, drugs did not have good fit as indicated by poor R2 value. The manufacturing source was a statistically significant variable for Cs. Compared with source A, which supplied the maximum number of Cs tablets, source B had significantly lower drug levels; drug content from both sources was below the acceptable range.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The circulation of substandard and spurious, falsely labelled, falsified or counterfeit medicines has been acknowledged to be a serious clinical and public health problem, with sales ranging from 1% in developed countries to more than 10–30% in developing countries Caudron et al. 2008; Newton et al. 2006; International Medical Products Anti-Counterfeiting Taskforce Brochure 2008. The existence of substandard anti-TB medicines has been documented in surveys from a number of countries World Health Organisation report 2011. The majority of quality problems for anti-TB medicines were due to inadequate content of the active ingredient. It is a customary in our institute to assay the content of anti-TB and antiretroviral drugs in tablets/capsules. During this process, drugs with suboptimal content are occasionally encountered, more frequently with Cs.

In this study, we determined the content of anti-TB drugs available at the RNTCP centres in Tamil Nadu. The percentage adherence to the stated content of the drugs was calculated based on that used by WHO in its survey of the quality of anti-TB drugs in the Soviet Union World Health Organisation report 2011. We observed that percentage adherence of the mean drug content to the stated content for most drugs was within acceptable limits. However, drugs not falling within acceptable limits in certain districts were occasionally observed. Batch-to-batch variations in drug content are expected to occur occasionally, but the drop in PZA content to the extent we saw in a TU in a particular district is a matter of concern. On close scrutiny, this batch of PZA tablets was not present in any other treatment centre. Hence, this could be an isolated problem restricted to this particular batch, probably due to a manufacturing deficit.

The percentage adherence of Cs to the stated content was not satisfactory in all districts; one district had content ranging from 108 to 148 mg. This district had Cs supplied by manufacturing source B, which turned out to be a significant factor influencing Cs content in multiple linear regression analysis. Cs is a second-line anti-TB drug and an important component of the DOTS plus regimen used to treat MDR TB patients. Gross deterioration of Cs during transit and storage in the tropics has been previously reported, and this was attributed to high humidity, rather than high temperature Rao et al. 1968. Deterioration of Cs could be minimised by storage in tightly closed containers in air-conditioned rooms (18 °C). The Cs tablets analysed in this study were directly collected from the DOT providers’ home who could afford to store the drug only at room temperature; most of them lived in thatched huts. India being a tropical country has high levels of humidity and temperature for most part of the year. This problem can be solved to some extent by storing Cs in refrigerators in the DTCs and giving no more than a week's supply to the DOT provider at a time. In fact, the label suggests storing the drug in a cool place. Supply of Cs tablets with low content to patients could have serious effects, as the deteriorated product is inactive, and the margin between adequate and inadequate dosage of Cs is small Canetti 2007. Substandard manufacturing conditions coupled with adverse storage conditions could lower Cs content drastically.

Our observation of 80% of RMP 150-mg capsules falling within the acceptable range was probably due to the narrow acceptable range (135–165 mg). Further, we observed 94% of RMP 450 mg, INH, PZA 750 mg and EMB 600 mg to be within acceptable limits; the corresponding values for Cs, Eth and LFX were 23%, 100% and 87%. Our findings are strengthened by the fact that the entire analysis was undertaken in a blinded manner; drugs from SDS and those used at our institute were randomly included. Our Institute follows a stringent procedure in the purchase of drugs, and necessary precautions are taken to purchase good-quality drugs. This is especially important in viewing Cs values, as drugs with good content were also analysed alongside the RNTCP tablets. The geographical location of the districts (coastal/hilly/inland) did not influence drug content.

In summary, this study showed that the content of most anti-TB drugs adhered to stated content in Tamil Nadu, which is quite encouraging. Low content of Cs observed in all the districts is a matter of concern. It is advised to store Cs in refrigerators in the DTCs.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors thank the Central TB Division for permitting to collect drugs from the various RNTCP treatment centres, State TB officer, Tamil Nadu, District TB officers and their staff for their kind cooperation during drug collection. The technical assistance rendered by Mr. M. Subramani and Mr. B. Anand Kumar in drug analysis, and Ms. Basilea Watson and Mr. B. Senthil Kumar in coding and randomising drugs is gratefully acknowledged. This study was funded by the MDP through the USAID.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • Ashokraj Y, Agrawal S, Varma MVS et al. (2004) Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study. The International Journal of Tuberculosis and Lung Disease 8, 10811088.
  • Bate R, Tren R, Mooney L et al. (2009) Pilot study of essential drug quality in two major cities in India. PLoS ONE 4, e6003.
  • Bate R, Jensen P, Hess K, Mooney L & Milligan J (2013) Substandard and falsified anti-tuberculosis drugs: a preliminary field analysis. The International Journal of Tuberculosis and Lung Disease 17, 308311.
  • Canetti G (2007) Host factors and chemotherapy of tuberculosis. In: Barry VC ed. Chemotherapy of tuberculosis, London, Butterworths, p 175. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. Journal of Antimicrobial Chemotherapy 60, 214236.
  • Caudron JM, Ford N, Henkens M, Mace C, Kiddle-Monroe R & Pinel J (2008) Substandard medicines in resource-poor settings: a problem that can no longer be ignored. Tropical Medicine & International Health 13, 10621072.
  • Ellard GA (1999) The colorimetric analysis of anti-tuberculosis fixed dose combination tablets and capsules. The International Journal of Tuberculosis and Lung Disease 3(Suppl 3), S343S346.
  • Gurumurthy P, Narayana ASL, Raghupati Sarma G & Somasundaram PR (1984) Assay of ethambutol in pharmaceutical preparations. Lung India 2, 143145.
  • International Medical Products Anti-Counterfeiting Taskforce Brochure (2008). Available at: www.who.int/impact/FinalBrochureWHA2008a.pdf, accessed on 14 Feb, 2013.
  • Jones LR (1956) Colorimetric determination of cycloserine: a new antibiotic. Analytical Chemistry 28, 39.
  • Kelesidis T, Kelesidis I, Refailidis PI & Falagas ME (2007) Counterfeit or substandard antimicrobial drugs: a review of scientific evidence. Journal of Antimicrobial Chemotherapy 60, 214236.
  • Laserson KF, Kenyon AS, Kenyon TA, Layloff T & Binkin NJ (2001) Substandard tuberculosis drugs on the global market and their simple detection. The International Journal of Tuberculosis and Lung Disease 5, 448454.
  • Mitchison DA (1993) Assessment of new sterilising drugs for treating pulmonary tuberculosis by culture at 2 months. The American Review of Respiratory Disease 147, 10621063.
  • Newton PN, Green MD, Fernandez FM, Day NP & White NJ (2006) Counterfeit anti-infective drugs. The Lancet Infectious Diseases 6, 602613.
  • Rao KVN, Eidus L, Evans C et al. (1968) Deterioration of Cycloserine in the tropics. Bulletin of the World Health Organization 39, 781789.
  • Rao KVN, Kailasam S, Menon NK & Radhakrishna S (1971) Inactivation of isoniazid in a syrup preparation. Bulletin of the World Health Organization 45, 625632.
  • World Health Organisation report. Survey of the quality of anti-TB medicines circulating in the newly independent states of the former Soviet Union. 2011.