Quality assessment of oxytocin injection and misoprostol tablets in Côte d'Ivoire and Senegal

1 Introduction#

Postpartum haemorrhage (PPH) is defined as blood loss of at least 500 ml within 24 hours after birth and it affects about 5% of all women giving birth around the world.^{[1, 2]} PPH is the leading cause of maternal mortality worldwide, being responsible for nearly a quarter of all maternal deaths.^[3] However, the majority of these deaths could be avoided through timely and appropriate administration of prophylactic uterotonics during labour and delivery.^[4] Improving care of women during childbirth to prevent PPH is a necessary step toward the achievement of the Sustainable Development Goals by 2030^[5].

WHO recommends the use of oxytocin injection as an effective uterotonic for the prevention of PPH during the third stage of labour for all births.^[4] Importantly, oxytocin is included in the WHO Essential Medicines List and in the UN Commission on Life-Saving Commodities (UNCoLSC).^[6] Proper storage conditions for oxytocin are crucial as it is temperature sensitive and should be stored between 2-8°C to maintain its effectiveness.^[7-9] In many low- and middle-income country (LMIC) settings, maintaining the required storage conditions for medicines, including oxytocin, can be a challenge. Deviations from the recommended storage temperature can impact the stability of oxytocin, leading to degradation and potentially compromising its efficacy.^[10]

Misoprostol is an affordable generic medicine, suggested as an alternative to oxytocin and listed in the WHO Essential Medicines List.^[11] However, it’s essential to note that misoprostol is sensitive to humidity and can degrade rapidly if not stored properly.^[12]

Ensuring that essential medicines like oxytocin and misoprostol are stored correctly in health facilities is crucial to maintain their effectiveness. The presence of substandard oxytocin and misoprostol in LMICs poses a significant challenge to maternal healthcare. While studies have highlighted this problem in Anglophone countries, there is a lack of data from Francophone African countries.^[13] Addressing the quality and availability of these essential medicines is crucial for improving maternal health outcomes.

In 2019, West African Economic and Monetary Union countries (WAEMU) took steps to enhance the quality of oxytocin by convening to address this issue in the region. The group formulated and ratified the “Dakar Roadmap,” which outlined essential activities to be executed at the national level to enhance the availability of high-quality oxytocin. This collaborative effort aligned with the guidelines established by WHO, UNICEF, and UNFPA on the proper management of oxytocin within the cold chain.^[7] This regional initiative meant a significant stride towards ensuring the accessibility and reliability of oxytocin in the region.

Given the crucial role that assured quality and affordable uterotonics play in addressing maternal health disparities worldwide, and in response to the concerns raised by certain West African countries, WHO in collaboration with the National Medicines Regulatory Authorities from Côte d’Ivoire and Senegal conducted a post-marketing surveillance study. This study aimed to evaluate the quality of oxytocin and misoprostol products within these markets, underscoring the commitment to ensuring safe and reliable maternal healthcare interventions in the region.

2 Methods#

2.1 Sampling framework#

The post-marketing surveillance (PMS) survey, was coordinated by WHO in partnership with the national regulatory authorities and quality control laboratories of Senegal and Côte d’Ivoire. Both countries, are among the world’s 49 poorest countries as identified by the “Every Woman Every Child (EWEC)” movement.^[14]

The study protocol, developed by WHO and approved by the National Medicines Regulatory Authorities (NMRAs) in the participating countries, involved a sampling plan based on the Medicines Risk Assessment tool (MedRS) from the United States Pharmacopoeia (USP). The sampling strategy targeted facilities at three levels of the supply chain: level-1 (points of entry to the market, warehouses of importers, central medical stores); level-2 (wholesalers and/or distributors); and level-3 (authorized dispensers such as pharmacies, hospitals, health center depots, health posts, district hospitals, clinics, maternity and treatment center); and followed a 20%:20%:60% ratio (level-1:level-2:level-3) in both public and private health sectors.^{[15, 16]} The highest risk was assigned at the levels where medicines were dispensed directly to the patients with limited or poor management oversight. All regions were targeted considering similarity of conditions throughout the country. In Côte d’Ivoire, 13 out of 31 regions and in Senegal 7 out of 14 regions were selected for sampling the medicines.

Ethical approval for the survey was obtained from the relevant committees and Ministries of Health in Côte d’Ivoire and Senegal. Informed consent was not required as the study solely focused on sample collection and storage information.

2.2 Sample collection#

For this study, a sample was defined as an item collected from each medicine’s form, including details such as the name, dosage of active pharmaceutical ingredient (API), dosage form, strength, batch/lot number, and manufacturer, all from the same collection site. For oxytocin, each sample comprised 10 units from the same manufacturer and batch, while for misoprostol, a minimum of 60 tablets from the same manufacturer and batch constituted a sample.

Sample collectors were equipped with logistical support and ensured temperature-controlled storage during sample handling and transportation. They were also responsible for assessing and reporting on the storage conditions of the samples at the health facilities during collection.

Prior to sampling, each country team was required to identify all registered oxytocin and misoprostol brands approved by their national regulatory authorities. The goal was for each country to collect a total of 100 samples (50 oxytocin and 50 misoprostol), all obtained in their original packaging.

2.3 Laboratory analysis#

The oxytocin samples were tested by the Monash Institute of Pharmaceutical Sciences (MIPS) laboratory in Australia, while the samples of misoprostol were tested by the National Laboratory of the Ugandan National Drug Authority (NDA), from both countries. Testing was conducted according to the guidelines specified in the International Pharmacopoeia (Ph. Int) 10th Edition (2020).^[17]

The Ph. Int monograph for oxytocin injection specifies requirements for description, labeling, packaging, identification, assay, pH, particulate matter, and related substances. The Ph. Int monograph for misoprostol tablets outlines specifications for various parameters including description, labeling, packaging, storage, identification, assay, uniformity of content, and dissolution.

Any test result that fell outside the acceptance criteria set by the Ph. Int monographs was considered a failed test, leading to the classification of the sample as substandard. In cases where tests for dissolution and uniformity of content failed at level-1, they were deemed inconclusive if there were insufficient sample units available to carry out the subsequent testing levels as outlined in the Ph. Int monograph for misoprostol tablets.

3 Results#

Between August and December 2021, a total of 196 samples of oxytocin injection and misoprostol tablets were collected from 130 health facilities across Côte d’Ivoire and Senegal. Côte d’Ivoire collected 100 samples (52 oxytocin and 48 misoprostol) from 62 facilities, while Senegal collected 96 samples (62 oxytocin and 34 misoprostol) from 68 facilities. Detailed information about the samples of oxytocin and misoprostol collected in both countries can be found in Tables S1 and S2 and in Figures S1 and S2 respectively. Tables 1 and 2 present the products sampled in Côte d’Ivoire and Senegal based on the source of manufacture. Figures 1 and 2 display the distribution of oxytocin and misoprostol samples according to the level of supply in both the public and private sectors in Côte d’Ivoire and Senegal. Notably, the majority of samples (71%) were collected from Level-3 facilities in both countries. Although oxytocin ampules in both countries were stored in refrigerators at all facilities, the sampling teams reported inadequate temperature monitoring equipment and absence of alert systems linked to the refrigerators at the time of sampling. The sampling teams were instructed to verify the registration status of all collected samples with the NMRAs. Table 3 provides information on the registration status at national level and WHO prequalification status of all samples included in this survey.

3.1 Results of oxytocin and misoprostol products sampled in Côte d’Ivoire#

The quality control results revealed that all 52 oxytocin samples met the monograph specifications for description, identity, pH, and particulate matter. However, 9.6% of the samples tested failed the assay test, and 48% failed the related substances test. This amounts to a 54% failure rate (Table 4). Notably, 92% of the oxytocin samples that failed were not registered with the local NMRA.

The National Laboratory (Laboratoire National de Santé Publique, LNSP) in Côte d’Ivoire conducted identity, pH, and assay tests on the same oxytocin samples tested by MIPS. Their findings indicated that all samples met the requirements for identity and pH tests. However, 33% of the samples failed the assay test according to the Ph. Int monograph. The assay test failure rate reported by LNSP was higher than the MIPS results (Table 5). LNSP did not conduct any out-of-specification investigations for the assay tests on the oxytocin samples, and related substances tests were not performed by LNSP.

The quality control of 47 tested misoprostol samples met the Ph. Int monograph specifications for description, packaging, labeling, identification, and assay tests. One sample was excluded from the analysis due to its expiration. While 95.8% of the samples passed the tests, 2 samples (4.2%) yielded inconclusive results. One sample failed the level-1 uniformity of content test, and the other failed the stage-1 dissolution test. However, due to insufficient units for further testing, both results were deemed inconclusive as per Ph. Int guidelines (Table 6). Substandard oxytocin and misoprostol samples were identified at both level-2 and level-3 of the supply chain in Côte d’Ivoire, mainly within public health facilities (Table 7).

3.2 Results of oxytocin and misoprostol products sampled in Senegal#

The quality control results revealed that 62 samples of oxytocin met the Ph. Int specifications for description, particulate matter, identity, pH, and related substances tests. However, 5% of the samples failed the assay test (Table 8). Among the three non-compliant samples, two were from public level-3 and one from private level-1 facilities.

The quality control of 33 misoprostol samples met the specifications outlined in the Ph. Int monograph for description, storage, identification, and assay. One sample was excluded from the analysis due to its expiration. Only one sample failed the uniformity of content test. However, due to insufficient tablets to complete the subsequent test stage, the results were reported as inconclusive. Additionally, 41.4% samples failed at the first dissolution stage, but the lack of sufficient units prevented continuation to stage 2, resulting in inconclusive results (Table 9). A significant proportion, 83%, of the failed samples were from the same manufacturer. Overall, the majority of failed misoprostol samples were found in the public sector. Although substandard products were present at all levels of the public sector supply chain, it was predominantly level-3 in the private sector where these were found (Table 9).

Overall, substandard oxytocin and misoprostol samples were identified at level-1 and level-2, and at levels 1-3 respectively (Table 10). In Senegal, the oxytocin and misoprostol samples collected were not tested by the local national laboratory.

4 Discussion#

This post-marketing surveillance study revealed that 30% of oxytocin samples (54% in Côte d’Ivoire; 5% in Senegal) and 23% of misoprostol samples (4.2% in Côte d’Ivoire; 41.4% in Senegal) were deemed substandard across all levels of the supply chain in both public and private sectors.

Of significant concern are the findings on substandard oxytocin samples passing the assay test but failing the related substances test as it suggests that impurities in the finished product formulations might be responsible for the non-compliance, rather than degradation of the active pharmaceutical ingredient. This indicates that storage conditions alone might not be the sole cause for the substandard quality of these products. Notably, 44% of the identified substandard oxytocin in Côte d’Ivoire originated from a single manufacturer.

In Côte d’Ivoire, only 4.2% of misoprostol samples were substandard, while in Senegal, 41.4% of misoprostol samples were found to be substandard at the first dissolution test. Given that the majority of these substandard samples from Senegal originated from the same manufacturer and batch, and were collected from various levels of the supply chain with dissolution values below 85%, it is reasonable to deduce that samples from this batch are likely to fail further stages of the dissolution test.

This study represents the first assessment of oxytocin and misoprostol quality in West Africa, showing results consistent with similar surveys conducted in Anglophone African countries^{[13, 18-22]}.

The study’s limitations included difficulties in obtaining sufficient units per sample, compounded by the packaging of two misoprostol tablets per pack, which impeded the collection of adequate number of units from the same batch. Determining the optimal number of units for testing remains a challenge necessitating a balance between cost considerations, the risk of potential medicine shortages, and technical demands of testing requirements.

It is to be noted that the substandard batches of both misoprostol and oxytocin were withdrawn from the market following investigations by national agencies post-analysis.

The study also evaluated the registration status of the collected products. In Senegal, all the sampled brands were registered by the NMRA; however, in Côte d’Ivoire, only 4 out of the 13 identified brands were registered by the NMRA. This implies a potential prevalence of substandard products in the market, posing a considerable risk to the community. These findings align with other studies conducted LMICs assessing the quality of oxytocin and misoprostol, revealing instances of unregistered or unlicensed medicines.^{[13, 18-20, 23]} Typically, unregistered medicines are commonly discovered in private and informal sectors during such surveys. However, this study identified unregistered medicines in level-2 and level-3 of public health facilities in all regions evaluated, except in Abidjan in Côte d’Ivoire. Furthermore, while most misoprostol products were sourced from WHO prequalified manufacturers, none of the oxytocin samples were sourced from WHO prequalified manufacturers.^[24]

This study aimed to enhance the capabilities of the national laboratories in both countries. The LNSP in Côte d’Ivoire conducted all the tests except for related substances due to capacity constraints. Interestingly, all the samples that failed the testing at the MIPS laboratory also failed at the LNSP laboratory. However, the LNSP identified more failed samples compared to the MIPS lab. This variance in results between the MIPS and LNSP laboratories could be attributed to factors such as varying levels of experience in testing these specific medicines, differences in the quality management systems, and the qualifications of personnel, among other reasons.

Lastly, the discovery of similar brands of oxytocin and misoprostol in both Côte d’Ivoire and Senegal underscores the necessity for West African countries to conduct cross-border surveys on the quality of essential medicines. Moreover, some of the oxytocin and misoprostol brands examined in this study were also identified in Rwanda, the Democratic Republic of Congo (DRC), Ghana, and Malawi.^{[18, 20-22]} Sharing information on substandard and falsified medicines among NMRAs, particularly through the WHO Global Surveillance and Monitoring System (GSMS), can significantly aid in identifying reliable suppliers of uterotonic drugs. The study results were shared with the authorities in Côte d’Ivoire and Senegal. Subsequently, the NMRAs swiftly initiated investigations to identify the underlying causes of substandard products’ presence in the market and recalled the substandard product batches from circulation. This underscores the effectiveness and significance of PMS surveys in strengthening health systems. By compiling data based on evidence and conducting comprehensive analyses, informed decisions were taken to protect public health.

To combat the proliferation of falsified and substandard uterotonic medicines, strengthening regulatory systems within these countries is essential. Moreover, it is recommended that a comprehensive and risk-based post-marketing surveillance of oxytocin and misoprostol in the market should be regularly conducted as part of the overall management of these medications and as a mechanism to bolster the national supply chain.

5 Conclusion#

A substantial proportion of oxytocin and misoprostol products available in Côte d’Ivoire and Senegal were found to be substandard. Investing in quality-assured medicines is crucial for delivering safe and effective healthcare, reducing overall healthcare costs, and securing the long-term success of universal health coverage in low-income countries.