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      Quality of oxytocin ampoules available in health care facilities in the Democratic Republic of Congo: an exploratory study in five provinces

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          Abstract

          Background

          Oxytocin injection is the first line therapy for the prevention and treatment of postpartum haemorrhage (PPH), the leading cause of maternal mortality. Currently access to high quality oxytocin in low and middle-income countries (LMICs) is compromised by variable manufacturing quality and the requirement for cold chain supply and storage to prevent product deterioration. Previous studies of oxytocin ampoules sampled from Africa, the region with highest maternal mortality rates, indicate that over half do not contain the specified amount of oxytocin. International efforts continue to further understand the issues relating to oxytocin quality in LMICs and this study is the first to assess oxytocin quality in the Democratic Republic of Congo (DRC), a country that bears one of the highest global rates of maternal mortality (693 maternal deaths per 100 000 live births). Importantly, the study methodology includes the use of investigative analytical techniques to understand the cause of quality deficiencies and inform remedial measures.

          Methods

          The study involved sampling of oxytocin injection ampoules from public and private health care facilities (n = 15) in urban and rural areas within five provinces of the DRC. Where available, each sample comprised 20 ampoules of oxytocin injection (10 IU/mL) with smaller numbers collected where supplies were limited. Sample collection used overt sampling and mystery shopper approaches, as appropriate. Analysis of ampoules for oxytocin content and known degradation products utilised validated HPLC and LCMS methods, respectively. Sterility testing was conducted in accordance with the United States Pharmacopeia monograph.

          Results

          Eighty percent of ampoules collected contained less than 90% of the specified content. Known degradation products of oxytocin were identified, indicating likely exposure to elevated temperatures post-manufacture. All samples contained an unknown impurity at a level of approximately 12.3% (8.0-20.5%) of the oxytocin main band peak. No samples failed sterility testing.

          Conclusions

          There is evidence of a high prevalence of poor quality oxytocin ampoules in health facilities in the DRC likely resulting from both manufacturing quality issues and uncontrolled storage. A more comprehensive post-marketing surveillance study of oxytocin quality is warranted.

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          Most cited references 5

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          Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature.

          Oxytocin is the drug of choice for preventing and treating postpartum haemorrhage, an important cause of maternal death. Oxytocin is widely available in low and middle-income countries (LMIC) but there are concerns about its quality.
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            Towards Heat-stable Oxytocin Formulations: Analysis of Degradation Kinetics and Identification of Degradation Products

            Purpose To investigate degradation kinetics of oxytocin as a function of temperature and pH, and identify the degradation products. Materials and Methods Accelerated degradation of oxytocin formulated at pH 2.0, 4.5, 7.0 and 9.0 was performed at 40, 55, 70 and 80°C. Degradation rate constants were determined from RP-HPLC data. Formulations were characterized by HP-SEC, UV absorption and fluorescence spectroscopy. Degradation products were identified by ESI-MS/MS. Results The loss of intact oxytocin in RP-HPLC was pH- and temperature-dependent and followed (pseudo) first order kinetics. Degradation was fastest at pH 9.0, followed by pH 7.0, pH 2.0 and pH 4.5. The Arrhenius equation proved suitable to describe the kinetics, with the highest activation energy (116.3 kJ/mol) being found for pH 4.5 formulations. At pH 2.0 deamidation of Gln4, Asn5, and Gly9-NH2, as well as combinations thereof were found. At pH 4.5, 7.0 and 9.0, the formation of tri- and tetrasulfide-containing oxytocin as well as different types of disulfide and dityrosine-linked dimers were found to occur. Beta-elimination and larger aggregates were also observed. At pH 9.0, mono-deamidation of Gln4, Asn5, and Gly9-NH2 additionally occurred. Conclusions Multiple degradation products of oxytocin have been identified unequivocally, including various deamidated species, intramolecular oligosulfides and covalent aggregates. The strongly pH dependent degradation can be described by the Arrhenius equation.
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              Stability of essential drugs during shipment to the tropics.

              To determine whether present methods of international transport of essential drugs by sea adversely affect their quality. Controlled longitudinal study of drug shipments sent by sea from Unicef in Copenhagen to Lagos; to Mombasa and by land to Kampala; and to Bangkok. 11 essential drugs were stored in four locations on board the ships. Main shipping routes from Unicef, Copenhagen, to tropical countries. Temperature and relative humidity in the test packs during the journey. Amount of active ingredient in the drugs before and after shipment. Temperatures recorded within the test packs range from -3.5 degrees C to 42.4 degrees C and were 3-12 degrees C higher than the ambient temperature. Relative humidity within the packs ranged from 20% to 88%. Differences between the locations on board were negligible. Ergometrine injection, methylergometrine injection, and retinol capsules lost 1.5-5.8% of their activity. Ampoules of ergometrine showed a large variation in the amount of active ingredient after shipment, with three of 80 samples having concentrations 60% below those stated. Ampicillin, benzylpenicillin, phenoxymethylpenicillin, and tetracycline were not affected by transport. Drugs were exposed to a much higher temperature and humidity than is recommended by the manufacturer, especially in tropical harbours and during inland transport. Except for ergometrine and methylergometrine the transport would not affect clinical effectiveness.
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                Author and article information

                Journal
                J Glob Health
                J Glob Health
                JGH
                Journal of Global Health
                Edinburgh University Global Health Society
                2047-2978
                2047-2986
                December 2018
                06 September 2018
                : 8
                : 2
                Affiliations
                [1 ]Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
                [2 ]Mission in Health Care and Development, Luvungi MHCD Hospital, Uvira, Democratic Republic of Congo
                Author notes
                Correspondence to:
Michelle P. McIntosh
Drug Delivery, Disposition and Dynamics
Monash Institute of Pharmaceutical Sciences
Monash University
Parkville
Victoria 3052
Australia
 michelle.mcintosh@ 123456monash.edu
                Article
                jogh-08-020415
                10.7189/jogh.08.020415
                6126516
                Copyright © 2018 by the Journal of Global Health. All rights reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 13, Pages: 6
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                Public health

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