A post-marketing assessment of critical quality and short-term stability attributes of heat-stable carbetocin injection products marketed in India

Intramuscular carbetocin injection has comparable efficacy to the first-line therapy, oxytocin injection, when used for prevention of postpartum haemorrhage, the leading cause of global maternal mortality. A novel heat-stable injectable formulation of carbetocin, first marketed in 2020, overcomes the requirement for refrigerated storage and aims to increase access to quality-assured uterotonic products in resource-limited settings where cold chain infrastructure is lacking or unreliable. Generic heat-stable carbetocin products have now emerged in India. In the context of widespread evidence that generic oxytocin injection products claiming stability outside of the cold chain do not meet stability requirements for non-refrigerated storage in hot and humid climates, this study is the first to assess the quality and stability of these carbetocin products. Two heat-stable generic carbetocin products were assessed in comparison to the innovator product for key quality attributes (assay, impurities and pH) and stability during a six-month program at temperatures ranging from 2 to 8 °C to 60 °C. All heat-stable products assessed met recognised quality standards for drug content (108.93% − 109.90%) and total impurities (0.57% − 0.85%). The generic products showed robust stability in terms of drug content, with no significant differences in degradation rates to the innovator product at all temperatures over the period tested. However, the rate of total impurity formation was higher than the innovator product at temperatures exceeding 30 °C, largely driven by hydrolytic degradation (e.g. total impurities after six months storage at 40 °C – generic 3.4–3.6%, innovator 1.8%). Impurity formation may be associated with the lower pH of these formulations (generic pH 4.7 vs. innovator pH 5.5) catalysing this degradation process. While long-term testing of multiple batches would be required for definitive conclusions, this study provides no indications of quality issues associated with the generic heat-stable carbetocin products based on the attributes tested. Furthermore, these products demonstrate similar stability to the innovator during short-term stability testing at their registered storage conditions (i.e. up to 30 °C).