How regulators and stability science decide whether heat-stressed medicines are safe to use

When a shipment of vaccines, injectable medicines, or other temperature-sensitive therapies slips outside its labeled storage range, manufacturers and healthcare organizations face a decision that can directly affect patient safety, treatment efficacy, and institutional liability: is the product still suitable for use, or must it be discarded? A new review published in AAPS Open on 5 October 2026 examines how that decision should be made, drawing together regulatory expectations from ICH, USP, CDC, EMA, and Health Canada and the stability science tools used to support them. The authors, led by Christopher Latoz with Kim Huynh-Ba, Lori McCaig, and Yan Wu, argue that disposition decisions should rest on scientific justification and quality risk management rather than the default rejection of affected product.

The stakes are considerable. The review notes that disposing of a temperature-compromised drug that may still be completely safe and efficacious is not only wasteful but may also be detrimental to a patient’s health if they cannot receive a medicine critical for treating a severe disease or condition. At the same time, administering a product whose potency has been lost can result in treatment failure or subtherapeutic dosing. Loss of potency remains the primary clinical concern following an excursion, but temperature stress can also accelerate impurity formation, including potentially toxic degradation products. For biologics and protein-based therapies, thermal exposure may lead to irreversible denaturation or aggregation, rendering the product ineffective.

Impurity risks extend beyond simple degradation. The review cites concerns that impurities increasing in temperature-compromised drugs can result in adverse reactions in a patient, including immunogenicity, infection, genotoxicity, and carcinogenicity. Of particular concern in recent years are nitrosamine impurities, which pose a risk due to their mutagenic properties and can arise from product degradation among other sources; the USP published General Chapter <1469>, Nitrosamine Impurities, in 2021 to identify sources and associated risks, and control strategies such as redesigning synthetic routes or adding antioxidants can reduce nitrosamine formation. Physical and chemical attributes such as pH, solubility, viscosity, appearance, and dissolution may also be affected by an excursion, and although the product may still retain its potency, changes in these attributes may make it less desirable to the end user.

Recent recalls illustrate how these risks play out in practice. In 2021, Sandoz Inc. recalled one lot of Enoxaparin Sodium Injection due to a temperature excursion during shipment that could potentially impact its effectiveness. In 2023, BioFire recalled BCID2 Panels because of temperature excursions caused by shipping delays that could potentially impact the panels’ performance. In 2025, Cardinal Health Inc. recalled ONE TOUCH ULTRA 100 test strips after temperature excursions during shipping delays that could lead to inaccurate results. The decision to recall products that have undergone a shipping temperature excursion is usually made as a last resort, and implementation can be challenging because it is difficult to ensure that the amount initially distributed is returned.

The risks are viewed differently by different stakeholders, and the review categorizes them into three dimensions: clinical, regulatory and legal, and business and reputational. Regulatory agencies expect manufacturers and distributors to ensure product quality throughout the supply chain, and temperature excursions must be documented, investigated, and justified using stability data and quality risk management principles. Failure to implement appropriate controls or to make appropriate disposition decisions may result in recalls, enforcement actions, or legal liability, particularly if it can be proven that the company knew or should have known the drug was temperature-compromised. The review points to legal action against Family Dollar for storing products at unsafe temperatures, which resulted in a $41.7 million class-action settlement after unsafe products were sold across many U.S. states.

Reputational and business consequences can extend well beyond the immediate costs of investigation, product replacement, or recall. An excursion event may weaken confidence among patients, healthcare providers, regulators, healthcare institutions, distributors, and commercial stakeholders, and public recalls, regulatory communications, media coverage, litigation, or repeated distribution failures can amplify this effect, particularly when supporting stability data are incomplete or insufficient to justify disposition decisions. Loss of stakeholder confidence can affect customer retention, tender opportunities, clinical trial enrollment, future product launches, product acceptance, and market access. High levels of product waste associated with inadequate temperature control may also reinforce external perceptions that the supply chain is unreliable; some estimates suggest that a substantial proportion of vaccine waste is associated with inadequate temperature control and logistics. Certain authorities, including the TGA and ANVISA, may require region-specific stability data or excursion studies to support product distribution, and failure to generate adequate supporting data can limit market access or delay product launches.

Although no single global standard governs cold chain management, the review finds that regulatory expectations are consistent across the major guidance documents it samples, which include the CDC Guidelines for Maintaining and Managing the Vaccine Cold Chain, the EMA Guidelines on Good Distribution Practice of Medicinal Products for Human Use, USP <1079> on Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products, and Health Canada’s GUI-00069 Guidelines for Environmental Control of Drugs During Storage and Transportation. Across these sources, temperature excursions must be documented and investigated, disposition decisions require scientific and technical justification, stability data should support acceptable excursion limits, and quality risk management principles should be applied. Notably, the ICH Q1 draft revision dated 11 April 2025 explicitly acknowledges that transient excursions outside labeled storage conditions may be acceptable when supported by stability data or modeling, and USP <1079> similarly allows brief excursions when product quality, safety, and efficacy are not adversely affected.

The stability science toolkit described in the review is broad. Stress studies assess the effect of conditions more severe than accelerated conditions, while forced degradation studies deliberately degrade a sample under conditions more severe than accelerated conditions, investigating potential degradation pathways, gaining product knowledge, understanding intrinsic stability, and confirming the stability-indicating nature of the analytical procedure; thermal degradation experiments are commonly run at elevated temperatures for one to five days. In-use stability testing addresses conditions after a primary container is first opened, answering questions such as how long a refrigerated insulin pen can remain at room temperature before the insulin becomes ineffective. Bulk stability work covers intermediate and bulk products stored before packaging, and photostability testing evaluates whether light exposure during shipping or administration results in unacceptable change. Thermal cycling studies repeatedly cycle a product between high and low temperatures and measure critical quality attributes including assay, impurities, and potency; one recommended method for a product labeled for refrigerated storage at 2 to 8 degrees Celsius involves a cycle of minus 20 degrees Celsius for 48 hours followed by 25 degrees Celsius and 60 percent relative humidity for 48 hours, usually repeated three times. The review stresses that completing a thermal cycling study does not by itself require placing the cycled material on a full long-term stability program through the labeled shelf life; the need for subsequent monitoring should be determined using a science- and risk-based approach that considers product knowledge, prior stability data, the magnitude and duration of exposure, the critical quality attributes evaluated, and the intended use of the study. Transportation and distribution simulation testing, meanwhile, uses laboratory testing such as impact, compression, environmental conditions, and altitude to simulate the stresses a packaging system may experience during real-world transport by rail, air, or freight carriers, ensuring that the packaging adequately protects the product and that it maintains safety and efficacy after distribution.

To translate these data into decisions, the review describes structured assessment tools that should complement, rather than replace, product-specific stability knowledge and scientific judgment. Quality risk management tools aligned with ICH Q9 and referenced in ICH Q12 are effective for identifying critical failure modes in temperature-sensitive supply chains, and Failure Mode and Effects Analysis allows organizations to prioritize risks based on severity, likelihood, and detectability and to implement targeted control strategies. Mean Kinetic Temperature, as defined in USP <1079.2>, is the single calculated temperature at which the total degradation over a given period equals the sum of the individual degradations that would occur at various temperatures; it converts a variable temperature to an equivalent steady-state temperature used to assess the effect of an excursion on product quality, and is considered acceptable practice for storage and can be considered for excursions during transit. In practice, electronic devices such as temperature data loggers that record temperatures at frequent intervals are included in product shipping containers, and USP <1079.2> provides guidance on maximum excursion temperature, MKT limits, and calculation periods for refrigerated and controlled room-temperature storage.

A further concept is the stability budget, a quantitative risk-management concept describing the allowable cumulative degradation a drug product can experience over its intended shelf life while remaining within approved specifications. In practical terms, it represents the remaining quality margin between the product’s current condition and the specification limits established during development and lifecycle management, and temperature excursions consume a portion of this budget at rates depending on both the magnitude and duration of exposure. Translating excursion conditions into an equivalent degradation impact allows manufacturers to determine whether sufficient stability margin remains to justify product release, and stability budget consumption can also be incorporated into FMEA scoring by refining severity assessment. Together, these approaches would avoid both unjustified release and unnecessary rejection of temperature-compromised product, with application proportionate to the nature of the product, the excursion, the available stability evidence, and the uncertainty of the assessment. The review concludes that clear standard operating procedures addressing quarantine, investigation, patient risk assessment, documentation, regulatory reporting, and corrective and preventive actions are essential for consistent handling of excursions post-distribution, and that a robust pharmaceutical quality system incorporating proactive stability planning, excursion preparedness, and clearly defined procedures strengthens regulatory compliance, reduces unnecessary product loss, and maintains confidence in the pharmaceutical cold chain.

Subject of Research: A regulatory and stability science review of how temperature-excursed drug products are assessed and dispositioned

Article Title: Systematic approaches to determining the disposition of temperature-compromised drug products: a regulatory and stability science–based review

Article References: Latoz, C., Huynh-Ba, K., McCaig, L., & Wu, Y. (2026). Systematic approaches to determining the disposition of temperature-compromised drug products: a regulatory and stability science–based review. AAPS Open, 12(1), Article 65. https://doi.org/10.1186/s41120-026-00202-1

Image Credits: AI Generated

DOI: 10.1186/s41120-026-00202-1

Keywords: temperature excursions, cold chain, drug stability, ICH Q1, USP, Mean Kinetic Temperature, thermal cycling, stability budget, quality risk management, FMEA, vaccine waste, pharmaceutical supply chain