Clinical Updates in Reproductive Health

Misoprostol product quality

Last reviewed: January 22, 2021

Recommendation:

  • Providers should track medical abortion success rates to ensure they are using an effective misoprostol product.
  • Purchase misoprostol in double-aluminum blister packs, and keep the misoprostol in its original packaging; check the integrity of packaging before use. Avoid purchasing polyvinyl chloride (PVC) or polyvinylidene chloride (PVDC)/aluminum blister packs.
  • Store misoprostol in a cool, dry place.

Strength of recommendation: Strong

Quality of evidence: Low

Manufacture and quality of misoprostol

Good Manufacturing Practice is a system for ensuring medications are consistently produced according to quality standards (World Health Organization [WHO], 2014). There are at least 30-40 manufacturers of misoprostol worldwide, and some manufacturers subcontract production of the drug, which makes the enforcement of Good Manufacturing Practice and the assurance of quality across all brands difficult (Hall & Tagontong, 2016). Misoprostol brands approved by stringent regulatory agencies (such as the European Medicines Agency or the United States Food and Drug Administration) or prequalified by the WHO (WHO-PQ) conform to Good Manufacturing Practice and are of high quality (Hagen, Bizimana, Kayumba, Khyluza, &Heide, 2020a).

Exposure to heat and humidity during manufacturing, packaging, shipping or storage may compromise the stability and quality of misoprostol (Cayman Chemical, 2012; Hagen et al., 2020a). Degradation decreases the effectiveness of misoprostol, leading to decreased success rates of medical abortion and unsuccessful treatment of incomplete abortion and postpartum hemorrhage.

Three studies have examined the quality of misoprostol products obtained from low- and middle-income countries. A 2016 study analyzed 215 misoprostol samples from countries all over the world (Hall & Tagontong, 2016). When samples were tested for content and purity, 5% contained more misoprostol than expected (110-121% of labeled content, to allow for degradation), 55% were within specification per the International Pharmcopeia, meaning they contained between 90-100% of labeled content, and 40% were below specification, containing less than 90% of labeled content. Of the 85 samples that were below specification, 14 contained no misoprostol at all. A 2018 study tested the quality of 166 misoprostol samples obtained from a variety of health care providers across Nigeria, ranging from federal medical centers and state hospitals to patent and proprietary medicine vendors (Anyakora et al., 2018). Although all samples passed a visual inspection, 34% did not meet specification as defined above. A similar study in Malawi found 23 of 30 samples from health centers and pharmacies around the country met specification for misoprostol; all samples meeting specification were packaged in aluminum-aluminum blister packs (Hagen, Khuluza & Heide, 2020b). A systematic review and meta-analysis of the quality of medicines, including oxytocics, in low- and middle-income countries included these three studies and found that 39% of all misoprostol samples failed to meet specification (Torloni, Bonet, Betran, Ribeiro-do-Valle, & Widmer, 2020).

Three factors influence misoprostol integrity:

  • impact of moisture at all stages from production to patient
  • manufacture and quality of the active pharmaceutical ingredient
  • packaging

Clinic use and storage

Even misoprostol manufactured in high-quality conditions and packaged well can degrade if it is shipped or stored in conditions that expose it to heat or humidity for prolonged periods of time. Quality misoprostol is stable when stored properly in room temperature conditions (25°C and 60% humidity). There have not been large field studies on the stability of misoprostol when stored in tropical climates, but laboratory studies have shown that misoprostol is less stable when exposed to moisture or heat (Chu, Wang, Pang, & Rogers, 2007; WHO, 2009).

Misoprostol packaged in double-aluminum blister packs (aluminum on top and bottom) retains the most active ingredient; after one year, 100% of pills packaged in plastic and single-aluminum blister packs will degrade, compared to 28% of misoprostol packaged in double-aluminum blister packs (Hall & Tagontong, 2016). The integrity of the double-aluminum blister packs must be preserved to maintain drug potency (Hagen et al., 2020a). If the packaging is inadvertently opened or perforated, even in normal room-temperature conditions, the tablets’ potency degrades within 48 hours and continues to degrade over time (Berard et al., 2014; Hagen et al., 2020a).

Quality assurance

If providers notice a decrease in medical abortion success rates from expected baseline, they should stop using the current lot of misoprostol and start a new lot. Providers should contact the pill vendor or manufacturer to ensure that there are no recalls of the affected lot. Providers should consult the Medical Abortion Commodities Database (www.medab.org) to assess the quality of products available in their setting (Hagen et al., 2020b). In some cases, providers may need to consult with one another to determine which local misoprostol brands are most effective. Store misoprostol in dry conditions at temperatures at or below 25°C (77°F) (Pfizer, 2016).

References

Anyakora, C., Oni, Y., Ezedinachi, U., Adekoya, A., Ali, I., Nwachukwu, C., … Nwokike, J. (2018). Quality medicines in maternal health: Results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits. BMC Pregnancy and Childbirth, 18, 44.

Berard, V., Fiala, C., Cameron, S., Bombas, T., Parachini, M., & Gemzell-Danielsson, K. (2014). Instability of misoprostol tablets stored outside the blister: A potential serious concern for clinical outcome in medical abortion. PLoS ONE, 9(12), e112401.

Cayman Chemical. (2012). Product Information: Misoprostol. Retrieved November 14, 2012, from https://www.caymanchem.com/pdfs/13820.pdf

Chu, K. O., Wang, C. C., Pang, C. P., & Rogers, M. S. (2007). Method to determine stability and recovery of carboprost and misoprostol in infusion preparations. Journal of Chromatography B857(1), 83-91.

Hall, P. E., & Tagontong, N. (2016). Quality of misoprostol products. WHO Drug Information, 30(1), 35-39.

Hagen, N., Bizimana, T., Kayumba, P.C., Khuluza, F., & Heide, L. (2020a). Stability of misoprostol tablets collected in Malawi and Rwanda: Importance of intact primary packaging. PLoSONE 15(9), e0238628.

Hagen, N., Khuluza, F., & Heide, L. (2020b). Quality, availability and storage conditions of oxytocin and misoprostol in Malawi. BMC Pregnancy and Childbirth, 20, 184.

Pfizer. (2016). Cytotec product label. Retrieved January 26, 2018, from http://labeling.pfizer.com/showlabeling.aspx?id=559

Torloni, M.R., Bonet, M., Betra ́n, A.P., Ribeiro-do-Valle, C.C., & Widmer, M. (2020). Quality of medicines for life-threatening pregnancy complications in low- and middle-income countries: A systematic review. PLoSONE 15(7), e0236060.

World Health Organization. (2009). Application to include Misoprostol for prevention of postpartum hemorrhage in WHO Model List of Essential Medicines: comments from Departments of Making Pregnancy Safer & Reproductive Health and Research. Retrieved from http://www.who.int/selection_medicines/committees/expert/17/application/WHO_Misoprostol.pdf  

World Health Organization. (2014). WHO good manufacturing practices for pharmaceutical products: Main principles (Annex 2, WHO Technical Report Series 986). Geneva, Switzerland: WHO Press.