The National Aeronautics and Space Administration (NASA) is planning exploration space missions to Mars, which will require plans for a wide array of medical contingencies, most of which require treatment with medications. A major challenge is that medications cannot be resupplied beyond Earth orbit, and many medications will exceed their labeled expiration date over the duration of an exploration-class mission. Furthermore, the spaceflight environment may alter the rate or pathways involved in the degradation of active pharmaceutical ingredients (APIs). However, the stability of only a handful of drugs have ever been tested after prolonged exposure to spaceflight. Existing ground-based drug stability studies do not include key factors associated with spaceflight, such as levels of carbon dioxide (CO₂) and ionizing radiation that are significantly higher than on Earth. Therefore, there is a risk that some expired or degraded medications will accumulate hazardous impurities, that, at sufficiently high doses, could cause acute or long-term health effects in astronauts. To address this risk, an assessment framework is proposed based on the accepted principles of chemical risk assessment. This communication describes the five steps of the proposed risk assessment framework, which are: (1) defining the use scenario of the drug, (2) identifying the API degradants, (3) assessing hazards and dose-response of the degradation products, (4) assessing the dose of degradant products, and (5) characterizing the risk for adverse health effects. To predict and identify drug degradants, this framework leverages known chemical reaction pathways and API chemistry (i.e. susceptible moieties) and data from stability studies. The framework focuses on health effects of greatest concern: high acute toxicity, sensitization, and mutagenicity and carcinogenesis. Hazard analysis uses chemical hazard databases, in silico prediction tools, and available terrestrial and spaceflight drug degradation studies. Risk is characterized relative to established health-based exposure limits (HBELs) or threshold of toxicological concern values (TTCs). A companion article describes case studies that apply this framework to four different classes of APIs under consideration for use during exploration spaceflight: azithromycin, diclofenac, gabapentin, and oral contraceptive (combination of ethinyl estradiol and norethindrone