Survey of the quality of anti-tuberculosis medicines circulating in selected newly independent states of the former Soviet Union

EXECUTIVE SUMMARY:

The aim of this survey was to explore the quality of anti-tuberculosis medicines in use in selected newly independent states of the former Soviet Union (NIS), as one of the potential factors contributing to the high burden of multidrug-resistant tuberculosis (MDR-TB) observed in all of these countries. Samples of selected first and second-line anti-TB medicines were collected from public and private sector procurement and treatment centres in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, and Uzbekistan. A total of 291 samples of medicines containing rifampicin, isoniazid, kanamycin or ofloxacin produced by 33 manufacturers were collected from 84 collection sites. Samples were tested by preselected reliable laboratories for appearance, identity, assay (content of active ingredient), related substances, dissolution and uniformity of mass. Injections, solutions, and powders for injection were also tested for pH value, sterility, and bacterial endotoxins. No sample was suspected to be of a spurious, falsely-labelled, falsified or counterfeit product. There were no quality problems identified with samples of kanamycin powder for solution for injection, isoniazid solution for injections or ofloxacin solution for infusion. Isoniazid/rifampicin FDC was the only medicine of which WHO-prequalified samples were collected in this survey. Of 42 isoniazid/rifampicin FDC samples collected, 38 were of prequalified products and none of those failed to comply with pre-set specifications. Neither did any of the 42 samples supplied through the Global Drug Facility (GDF), 25 of which were of WHO-prequalified products. Overall 33 samples (11.3%) failed to meet the specifications set for the survey. The highest failure rate was found for mono-component products containing rifampicin - more than a quarter of rifampicin samples (28.3%) failed to meet the specifications, and the predominant reason for this was that the content of active ingredient was below the acceptable limit. For the purpose of differentiating between deviations which are likely to impact the health of patients and those which are not, the category of extreme deviations was arbitrarily defined as the content of API deviating by more than 20% from the declared content and/or average dissolution value of tested units below pharmacopoeia Q value minus 25%.Focusing only on extreme deviations from specifications, the total failure rate reached 1.0%. This seems to reflect relatively good overall compliance with quality standards, and the zero failure rate among WHO-prequalified samples and those supplied through GDF indicates that these mechanisms are effective in assuring the quality of anti-TB medicines. On the other hand, low content of rifampicin, substantial inconsistencies in ofloxacin dissolution, as well as batch-to-batch and intra-batch inconsistencies are of concern and need to be addressed. These findings may be caused by a combination of inconsistent application of Good Manufacturing Practices (GMP) and insufficient regulatory supervision. An impact of inappropriate distribution and storage conditions could not be excluded, but there was not enough information to relate the quality problems identified to specific distribution or storage problems. The results of the survey cannot be generalized to the overall anti-TB medicines market in the surveyed countries because of limitations in the sampling, and - although they are encouraging - they indicate that further efforts are required to facilitate access to medicines that meet international quality standards in order to ensure the provision of quality anti-TB medicines to patients in the region. The results of the survey were analysed with representatives of participating countries, and agreed recommendations on further steps to improve the situation are listed in Box 1. (PDF)