Quality of oxytocin and misoprostol in health facilities of Rwanda

Abstract

Sustainable Development Goal 3.1 calls for a reduction of the maternal mortality ratio to less than 70 per 100,000 live births by 2030. The most important cause of maternal mortality is post-partum haemorrhage (PPH). Oxytocin injections and misoprostol tablets are medicines of first choice for the management of PPH in low- and middle-income countries (LMICs). Unfortunately, both substances are chemically unstable, and previous studies have revealed serious quality problems of these medicines in LMICs. The present study is the first report on their quality in Rwanda. From 40 randomly selected health facilities (hospitals, health centers, retail pharmacies and private clinics) in different parts of Rwanda, as well as from six wholesalers and government stores, oxytocin injections and misoprostol tablets were collected. Oxytocin storage temperatures in the health facilities were monitored for six months using temperature data loggers, and found to correctly follow the storage requirements stated by the manufacturers (2-8°C, or room temperature) with few minor deviations. Oxytocin injections (57 samples, representing seven batches of four brands) were tested for their oxytocin content and pH value according to the United States Pharmacopeia. Twenty-four samples from three European manufacturers passed all tests. However, all nine samples of one batch of a Chinese manufacturer showed an excessive content of oxytocin (range 117.2-121.5% of the declared amount). Another batch of the same manufacturer showed extreme variations of the concentration of the preservative benzyl alcohol. Misoprostol tablets (25 samples, representing ten batches of six brands) were tested for content and dissolution according to the International Pharmacopoeia. Fifteen samples passed, but all 10 samples of two brands from India failed with extreme deviations, containing only 42.5-48.7% of the stated amount of misoprostol. In conclusion, oxytocin quality in Rwanda was better than reported from other African countries. However, two extremely substandard brands of misoprostol tablets were found. The Rwandan authorities reacted quickly and efficiently, and recalled these substandard medicines from the market. For oxytocin and misoprostol, with their well-known problems of quality and stability, procurement should possibly be restricted to medicines which are WHO-prequalified or which have been manufactured in countries with stringent regulatory authorities.

Fig 1. Structures of oxytocin (modified from [21]) and misoprostol, and their typical degradation mechanisms.

Commercial misoprostol is a mixture, containing the depicted structure, its epimer at C16, and the enantiomers of both compounds. Likewise, the degradation products of misoprostol contain the corresponding stereoisomers.

Fig 2. Map of the location of the 46 facilities from which oxytocics were collected.

Reprinted (with modifications) from https://d-maps.com/conditions.php?lang=en under a CC BY license, with permission from d-maps.com, original copyright 2007–2020.

Fig 3. Content of oxytocin determined in each of the investigated samples.

The arrow marks a sample with deviating content of the active pharmaceutical ingredient oxytocin and of the preservative benzyl alcohol (see main text and Fig 4).

Fig 4. HPLC detection of the undeclared preservative benzyl alcohol, present in different concentrations in oxytocin samples of the same batch, stated to be manufactured by Jiangxi Xierkangtai Pharmaceuticals Co. Ltd (China).

Fig 5. Content of misoprostol determined in each of the investigated samples.

Fig 6. Dissolution of misoprostol determined in each of the investigated samples.