Expiration analysis of the International Space Station formulary for exploration mission planning

Long-duration space missions pose unique challenges to human health due to the extreme environment and distance from Earth-based medical care. Pharmacological agents are crucial countermeasures. Astronauts on the ISS routinely use medications for various conditions. However, medication expiration, limited resupply, and lack of emergency evacuation present significant operational hurdles for deep-space missions, such as a Mars expedition. Ensuring a safe and effective onboard pharmacy, capable of Earth-Independent Medical Operations (EIMO), is therefore paramount. Drug stability, guided by ICH and FDA guidelines, is essential, as instability can alter drug properties and potentially harm patients. Manufacturers conduct stability testing to establish shelf-life, which is the minimum time a drug remains stable under recommended conditions. However, US law doesn't require expiration dates on labels, creating a knowledge gap that jeopardizes the success of long-duration missions. This study aims to evaluate the terrestrial shelf-lives of medications in the ISS formulary using publicly available data from international registries.

Previous studies have examined medication use on the ISS, revealing common conditions treated and the average medication doses administered per week. The lack of resupply and risk of expired medications during long missions, such as a Mars mission, have been acknowledged. The International Conference on Harmonisation (ICH) provides guidance on drug stability evaluation, including the acceptable range of potency (95-105%). Stability studies guide the estimated shelf-life, with manufacturers extrapolating data to determine supported and maximum shelf-lives. The labeled shelf-life, shorter of the two, is printed on the label and used to calculate the expiration date, but it's a minimum estimate and not reflective of the true shelf-life, which may be significantly longer. Existing studies highlight the challenges of supplying a space-based pharmacy and the degradation of medications in space, but these often do not include a complete formulary and shelf-life data. One study compared the stability of medications after 880 days on the ISS to a control group on Earth, revealing degradation in a substantial proportion of medications.

The researchers obtained the ISS formulary (a list of medications and medical equipment) through a Freedom of Information Act (FOIA) request. The formulary, received August 2, 2023, details drug products, strength/volume, route of administration, quantity, side effects, comments, and location but lacks expiration data. The study analyzed 106 unique drug products (two diluents and three duplicates were excluded). US shelf-life data was sought from NDAs, monographs, and the 2023 AHFS Drug Information Compendium. International data (UK/EU, NZ, AU) were obtained from emc, Medthority, MedSafe, and ARTG, respectively. Data were descriptively analyzed in Microsoft Excel. Both minimum and maximum labeled shelf-lives were used for analysis. Kaplan-Meier survival curves were manually created using a Microsoft Excel add-in. Inclusion criteria included OTC and prescription products, brand and generic products, and products with similar dosage forms, APIs, routes of administration, and strengths to those in the ISS formulary. Exclusions were made for products with differing routes of administration, combination products with different APIs, and products no longer available for marketing or distribution in the US. Additionally, case-by-case exclusions were made depending on indication, formulation, or purpose compared to the ISS formulary.

The 2023 ISS formulary contains 106 unique drug products. Shelf-life data was unavailable for 15 (14%). For the remaining 91 medications, 54 (59.3%) had a maximum labeled terrestrial shelf-life ≤36 months, and 89 (97.8%) had a minimum labeled terrestrial shelf-life ≤36 months. Fourteen medications will expire within 24 months, including an ophthalmic lubricant, an advanced life support medication, an anaphylaxis treatment, a benzodiazepine, an antianginal, two corticosteroids, a local anesthetic, a topical urinary jelly, two antibiotics, an antipsychotic, an inhaler, and an ear wax removal medication. A Kaplan-Meier survival curve visually represents the cumulative number of medications expiring over five years. The range of shelf-lives varied among manufacturers and sources, often due to differences in drug product, formulation, and packaging. Significant variations were observed among the various databases across the various countries (e.g. Promethazine tablets have a shelf-life of up to 60 months from NZ and AU manufacturers, but a shelf-life of 36 months in the UK/EU). The study also considered the implications of pharmaceutical supply chains, noting that delays could reduce the functional shelf-life of medications by the time they reach the ISS.

The lack of expiration data for 14% of the ISS formulary presents a risk of therapeutic failure during extended space missions. A crewed Mars mission (approximately 24-36 months) would be significantly impacted by the expiration of many medications. The difficulties in obtaining US expiration data due to proprietary concerns necessitated the use of international sources, which may have variations in shelf-lives due to differences in excipients, packaging, and standards. Repackaging of medications on the ISS could further shorten shelf-lives. The findings align with previous research but are more comprehensive, including medications not previously considered. This study highlights the need for collaboration between pharmaceutical suppliers and spaceflight operators, as well as research into extending medication shelf-lives or finding alternative solutions for EIMO.

This study provides valuable data on the terrestrial shelf-lives of medications currently in the ISS formulary. The significant proportion of medications expiring within 36 months presents a serious challenge for long-duration space missions. Future research should focus on extending medication shelf-lives, alternative supply methods, including on-demand manufacturing or 3-D printing, and pharmacokinetic/pharmacodynamic studies in microgravity to inform appropriate dosing regimens. Improved medication tracking applications are also needed to optimize formulary selection and pharmacovigilance. The study emphasizes the need for collaboration and transparency to address the challenges of supplying a safe and effective pharmacy for deep-space exploration.

The study focused solely on terrestrial shelf-lives and didn't account for potential accelerated degradation in space due to factors like radiation. The analysis is based on publicly available data up to August 2023 and may not represent the current formulary or future changes in stability studies. Variations in dosage forms, containers, and packaging between the ISS formulary and the data sources could affect the accuracy of the shelf-life estimates. The study doesn't include medications that may be used for commercial astronauts and space tourists.