The quality of veterinary medicines and their implications for One Health

Abstract

ObjectiveSubstandard and falsified (SF) veterinary medicines affect animal health, agricultural production and food security and will influence antimicrobial resistance (AMR) in both animals and humans. Yet, our understanding of their extent and impact is poor. We assess the available public domain evidence on the epidemiology of SF veterinary medicines, to better understand their prevalence and distribution and their public health impact on animals and humans.MethodsSearches were conducted in Embase, PubMed, MEDLINE, Global Health, Web of Science, CAB Abstracts, Scopus, Google Scholar, Google and websites with interest in veterinary medicines quality up to 28 February 2021. Identified articles in English and French were screened for eligibility. The Medicine Quality Assessment Reporting Guidelines were used to assess the quality of prevalence surveys.ResultsThree hundred and fourteen publications were included with a failure frequency (the percentage of samples that failed at least one quality test) of 6.5% (2335/35 733). The majority of samples were from post-marketing surveillance by medicines regulatory authorities of the Republic of Korea and China. A small proportion (3.5%) of samples, all anti-infectives, were from 20 prevalence surveys, with more than half (53.1%, 662/1246) collected in low-income and lower middle-income countries in Africa and Asia. The prevalence survey sample size ranged from 4 to 310 samples (median (Q1–Q3): 50 (27–80)); 55.0% of surveys used convenience outlet sampling methods. In 20 prevalence surveys more than half of the samples (52.0%, 648/1246) failed at least one quality test. The most common defects reported were out-of-specification active pharmaceutical ingredient(s) (API) content, failure of uniformity of units and disintegration tests. Almost half of samples (49.7%, 239/481) that failed API content tests contained at least one of the stated APIs below pharmacopoeial limits. Fifty-two samples (4.2% of all samples) contained one or more incorrect API. One hundred and twenty-three publications described incidents (recalls/seizures/case reports) of SF veterinary medicines in 29 countries.ConclusionThe data suggest that SF veterinary products are likely to be a serious animal and public health problem that has received limited attention. However, few studies of SF veterinary medicines are available and are geographically restricted. Lower API content and disintegration/dissolution than recommended by pharmacopoeial standards risks treatment failure, animal suffering and contribute to AMR. Our findings highlight the need of more research, with robust methodology, to better inform policy and implement measures to assure the quality of veterinary medicines within supply chains. The mechanism and impact of SF veterinary products on animal and human health, agricultural production, their economy and AMR need more transdisciplinary research.

Quality of amoxicillin/clavulanic acid oral formulations for intended veterinary use in the UK, Malaysia, Serbia and Thailand

“…Global prevalence rate of failure from at least one of the active was 20.8%, but due to the small sample size, the CI of this proportion is wide [binomial proportion 95% CI: (7.1% to 42.2%), Clopper-Pearson exact method]. However, it was not possible to distinguish between substandard quality as a result of (1) non-compliance with good manufacturing practice versus (2) post-production degradation due to inappropriate storage (Vidhamaly et al 2022). It is possible that some of the formulations that included degraded products left the factory as formulations of good quality.…”

“…Selection of antimicrobial resistance (AMR) by bacterial strains can occur due to low bioavailability of amoxicillin or insufficient protection against beta-lactamases with low availability of clavulanic acid. AMR selection, in turn, poses risks to both animal and public health due to the close link between owners and their pets (Vidhamaly et al 2022, Zabala et al 2022. Subtherapeutic exposure due to substandard formulations can contribute to the selection of extended-spectrum beta-lactamase (ESBL) producing bacteria, which increase mortality and cost of care globally due to limited therapeutic options.…”

“…When focussing on antibiotics only, the percentage of observed failure rate was 7.2% (95% CI 6.8 to 7.7). The prevalence studies for SF veterinary antibiotic medicines are rare (13 studies in the last 20 years) (Vidhamaly et al 2022). These studies mainly focus on production animal formulations in Asia and Africa; they report failure rates between 11% and 93%, depending on the study design (Pellicaan et al 1996, Gberindyer et al 2019.…”

“…2019, Vidhamaly et al . 2022). In Europe, a small amount of the production is monitored by the manufacturer and by the official medicines control laboratories (Official Medicines Control Laboratories 2022), under the direction of the European Directorate for the Quality of Medicines, but SF formulations may still be encountered.…”

The quality of antiretroviral medicines: an uncertain problem

“…As in previous systematic reviews by our group,13 15 26 we define ‘failure frequency’ (FF) as the proportion of samples included in a prevalence survey that failed at least one quality test described in the report. We define a ‘data point’ as a specific location where medicines were collected for quality analysis, at a given time and for a given study.…”