Quality, availability and storage conditions of oxytocin and misoprostol in Malawi

Abstract

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-and middle-income countries (LMICs). Oxytocin and misoprostol are used for the prevention and treatment of PPH. However, both medicines are chemically unstable and sensitive to environmental conditions. Previous studies reported a high prevalence of substandard oxytocin and misoprostol preparations in LMICs. Methods: In randomly selected health facilities of four districts of Malawi, the availability of oxytocin and misoprostol was determined, and the knowledge of health workers on storage requirements and use of oxytocics was assessed. Temperature loggers were used to record the storage temperature of oxytocics. Samples of oxytocin injections and misoprostol tablets were collected from the health facilities and from wholesalers. Oxytocin samples were analysed for identity, assay (= quantity of oxytocin) and for pH value according to United States Pharmacopeia 40. Misoprostol samples were analysed for identity, assay, dissolution and related substances according to the International Pharmacopeia 2017. Results: All visited hospitals and health centers had oxytocin available. At non-refrigerated storage sites, the recorded mean kinetic temperature exceeded the oxytocic's storage temperature stated on the labels in 42% of the sites. At refrigerated storage sites, the required temperature of 2-8°C was exceeded in 33% of the sites. Out of 65 oxytocin samples, 7 (11%) showed moderate deviations from specification, containing 82.2-86.8% of the declared amount of oxytocin. Out of 30 misoprostol samples, 5 (17%) showed extreme deviations, containing only 12.7-30.2% of the declared amount. The extremely substandard misoprostol was reported to the national authorities and to WHO, leading to an immediate recall of the respective brand in Malawi. The UK-based distributor of this brand closed its business shortly thereafter. Conclusion: Availability of oxytocin was excellent in Malawi, and its quality was better than reported in previous studies in other LMICs. However, storage conditions at the health facilities often did not meet the requirements. Extremely substandard misoprostol tablets were found, representing a serious risk to maternal health. This shows the need for continued efforts for quality assurance in medicine procurement and registration, as well as for postmarketing surveillance.

Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging

“…One brand of misoprostol tablets collected in Rwanda (packaged in double-sided aluminium blisters; manufactured in a country without SRA; not WHO-prequalified) had to be excluded due to extreme deviations from specifications in the assay. Furthermore, Hall [25], Anyakora et al [11] and Hagen et al [12] have reported insufficient misoprostol contents in many misoprostol preparations collected in LMICs. Therefore, quality and/or stability problems are certainly not a rare observation in misoprostol tablets circulating in LMICs.…”

“…In the present study, a decrease of the misoprostol content was observed both at 40˚C and 75% RH and at 25˚C and 60% RH (Fig 2). An investigation of the storage conditions of misoprostol tablets in health facilities in Malawi had shown mean kinetic temperatures at the different storage sites ranging from 21.4˚C to 31.0˚C [12]. In view of these observations, a reduction of the stated shelf-life of the originator brand (Table 1) from three to two years may be advisable, especially for those batches which are exported to countries with hot and humid climates.…”

“…Our group recently investigated the quality of oxytocin and misoprostol samples collected in health facilities and drug outlets in Malawi. Out of the 30 misoprostol samples, five (17%) showed extreme deviations, containing only 12.7-30.2% of the declared content [12]. In the scientific literature, no systematic stability study of finished pharmaceutical products of misoprostol has been published so far.…”

“…If different batches of a certain brand were available, samples from each batch were purchased. In Malawi, certain brands of misoprostol tablets had recently been withdrawn from the market [12], and only one single brand was offered for sale at the time of sample collection, in form of two different batches; both batches were purchased. In Rwanda, three brands were offered at the time of sample collection (only a single batch of each brand), and each brand was purchased.…”

“…It degrades at high temperatures and usually has to be stored at 2-8˚C [3][4][5][6][7]. This storage requirement can be challenging, especially in rural areas of low-and middle-income countries (LMICs) where infrastructure is poor and ambient temperatures are often high [8][9][10][11][12]. Indeed, several previous studies have shown that the quality of oxytocin, especially in LMICs, is often poor [3,[10][11][12][13][14][15][16][17].…”