Thermolabile drugs represent a substantial portion of the pharmaceutical inventory in hospitals. These medications require storage within the cold chain, a series of logistical protocols designed to ensure that they are maintained at temperatures between 2 and 8 °C throughout storage, handling, transportation, and distribution.1

In clinical practice, unforeseen circumstances (e.g., power outages, cold-storage malfunctions, inadequate transportation, etc.) may disrupt the cold chain.2 The storage conditions specified by the manufacturer and outlined in the summary of product characteristics (SmPC) ensure the stability, efficacy, and safety of the product until its expiration date. Disruptions in the cold chain can compromise the drug's properties to varying degrees, depending on the temperature reached and the duration of exposure. Additionally, such incidents may have significant economic repercussions for the healthcare system due to the high cost of many thermolabile drugs.1,3

According to Spanish legislation, Hospital Pharmacy departments are responsible for the custody and proper storage of drugs purchased by the facility.4 Furthermore, a substantial proportion of medications dispensed to ambulatory patients by hospital pharmacies are thermolabile, and some studies suggest that these drugs frequently experience cold chain breaches post-dispensing.5,6 Consequently, hospital pharmacies are often contacted by patients seeking information on the stability of these drugs following such incidents. For this reason, as well as the aforementioned factors, numerous publications have addressed this issue over the years.7–10

In recent decades, the development of new drugs—many of which are thermolabile—has increased exponentially. In many cases, data on the room temperature stability of drugs labeled for refrigeration is not available in the SmPC, necessitating a more in-depth search for information. The aim of this study was to provide updated information in an accessible format regarding the maximum stability of thermolabile drugs at room temperature, based on data from SmPCs, published literature, and information provided by pharmaceutical manufacturers.

We selected all thermolabile drugs (requiring storage between 2 and 8 °C) stored at our hospital. Experimental drugs, frozen drugs, and compounded pharmaceutical formulations were excluded.

The primary source of stability data was the SmPC. If information regarding room temperature stability was not available in the SmPC, we consulted published literature from a preliminary exploratory search, described below. In cases where no data could be obtained through these sources, we contacted the manufacturer via telephone or email. We inquired about the maximum duration for which the drug could remain stable at room temperature or, alternatively, whether it could remain stable for at least 24 h under these conditions.

In several instances, the information provided referred to specific cases of storage errors that had occurred within our department prior to this study. In these situations, we requested details on the specific conditions of the storage error (e.g., storage of a medication at temperatures above 8 °C for 18 h, reaching a maximum of 17 °C). These particular cases may not be entirely generalizable to other situations.

The literature search mentioned above was an exploratory search conducted in the MEDLINE database using the terms “Freezing,” “Stability,” “Thermolabile drugs,” and “Cold chain,” without restrictions on publication years. Given that information on this topic is often found in gray literature (hospital guidelines, documents from professional societies, conference abstracts, online repositories, etc.), we also conducted searches using the same terms in Google and Google Scholar databases.

We collected the following data: drug product, trade name, manufacturer, acceptable duration of storage at room temperature, and source of information. To improve usability, we compiled a table summarizing the stability data (Table 1. Acceptable duration of room-temperature storage for medications labeled for refrigeration). This table includes stability information from the SmPC and, when available, data from other sources.

We selected 203 thermolabile drugs which are showed in Table 1.

Among these drugs, 37 (18.2%) exhibited stability for 24 h at room temperature, 36 (17.7%) showed stability for 48 h to 1 week, 63 (31%) had stability between 1 week and 1 month, and 52 (25.6%) maintained stability for 1 month or more. Conversely, 12 drugs (5.9%) demonstrated stability of less than 24 h. Finally, 3 drugs (1.4%) had other stability data at room temperature.

Information for 95 of the 203 thermolabile drugs (46.7%) was obtained from the SmPC. The stability data for 56 (27.5%) drugs were sourced from published articles and gray literature: 36 (17.7%) from Mateo et al.,11 8 (3.9%) from Ricote-Lobera et al.,12 1 (0.49%), from Ardanaz et al.,13 1 (0.49%) from Bovaira et al.,14 and 1 (0.49%) from Periáñez et al., (2011)2 and 9 (4.4%) from various references.

Finally, a total of 27 manufacturers were contacted to provide relevant information for the remaining 52 (25.6%) drugs. In 21 instances, the stability information was applicable only to specific cases of storage errors, characterized by distinct storage conditions and pertaining to specific batches of the product (these drugs are indicated in bold type in the table).

Our study demonstrates that the vast majority of drugs requiring refrigeration maintain adequate stability at room temperature for at least 24 h. In practice, most temperature excursions in hospital refrigeration systems (including pharmacy services and other clinical units or outpatient clinics) are identified before reaching 24 h. Therefore, our findings indicate that, in most cases, it is unnecessary to discard medications due to these excursions. Furthermore, a significant proportion of outpatient medications dispensed by hospital pharmacy services exhibit excellent stability at room temperature over extended periods. This is particularly relevant given that some studies reveal that less than 10% of patients manage to keep their thermolabile medications within the recommended temperature range of 2–8 °C throughout the entire duration of home storage,6,15,16 while the medications included in our study account for one-third of the total. Additionally, temperature excursions for outpatient medications are typically detected less rapidly than in the hospital environment due to a lack of temperature control, monitoring systems, and alarms.

Similarly, the results of our study show that many storage errors reported by patients for various reasons (e.g., forgetfulness, malfunctioning refrigeration systems) do not necessarily require the affected medications to be discarded. The exponential increase in drug costs makes it increasingly important to optimize storage practices to mitigate costs associated with storage errors. In the case of thermolabile drugs, the financial implications of a storage error are generally greater than in other cases, as many of the higher-cost drug categories require refrigeration (e.g., monoclonal antibodies, biological drugs).

Notably, in 40.3% of the inquiries made, manufacturers indicated that the stability information provided was applicable only to specific cases of storage errors, which were characterized by unique storage conditions and specific batches of the product. In such instances, manufacturers recommended contacting them if any irregularities were detected in the maintenance of the cold chain. This percentage aligns with findings from other studies.12

Several studies have been published on this topic,3,7–13 generally employing methodologies similar to ours. Most of these studies include information about thermolabile drugs listed in the hospital's pharmacotherapeutic guide. To obtain this information, non-systematic reviews were conducted, utilizing similar sources. The results were also presented in a comparable format. Thus, the primary contribution of our study lies in its compilation and update of all existing information on this subject, providing data for a greater number of medications than previous works.

Considering these factors, our study can serve as a valuable resource for healthcare professionals responsible for medication storage at the hospital level, enabling quick consultation regarding the maximum stability of the majority of drugs currently used in the hospital environment and/or dispensed by hospital pharmacy units. This information, which is often difficult to locate, represents the most up-to-date and comprehensive study of its kind published to date. Without exposing patients to any risk, our results table can help prevent unnecessary drug loss and minimize time wasted due to inappropriate storage temperatures.

One limitation of our study is that we did not conduct a systematic review of the literature, which may have resulted in the omission of some stability data. However, the published literature on this issue is limited, and the information available constitutes only a portion of our study. Furthermore, this type of information is often found in gray literature, which is more challenging to access compared to that published in scientific journals. We also did not perform a systematic search for this type of literature, so information contained in those sources may have been overlooked. Additionally, our study did not present information in languages other than English or Spanish. Another limitation is that we only collected data from the pharmacotherapeutic guide of our hospital.

It is also important to emphasize that in some cases, the information provided by manufacturers was applicable only to specific instances of temperature excursions involving particular batches of the drug. Consequently, this information may not be fully extrapolated to other cases of temperature excursions. Therefore, we recommend consulting the manufacturer regarding the viability of affected batches.

As noted by other authors, it is necessary for pharmaceutical manufacturers to publish the results of stability studies conducted outside the recommended storage conditions specified in the SmPC to facilitate access to this critical information, even if accompanied by a disclaimer indicating that the data should be considered indicative only.

The number and cost of thermolabile drugs have increased exponentially in recent years. The majority of these drugs maintain adequate stability at room temperature for limited periods, with some exhibiting stability for longer durations. To date, our study presents stability data for the largest number of drugs. Therefore, the results of our study constitute a highly valuable and updated tool for saving time and resources in hospital pharmacy units. It is essential for pharmaceutical manufacturers to publish the results of stability studies conducted outside the recommended storage conditions in the SmPC.

In our study, we summarize the existing evidence published to date regarding the storage of thermolabile drugs. Additionally, we update this information and augment it with new stability data for various medications. To our knowledge, this is the largest published work on this issue worldwide and represents a modest yet valuable contribution to the clinical practice of hospital pharmacists.

The results of our study are presented in a tabular format, serving as a highly useful and up-to-date resource for saving time and reducing costs in hospital pharmacy units.

This work has not received funding.

To Laura Campano Pérez, for her contribution to the field work.

The authors declare that they have no conflicts of interest.

Not applicable to the present work.

Conception and design of this work: Hector Acosta García, Paloma Suarez Casillas and Santiago José Lora Escobar.

Data collection: Tao Li, Paloma Suarez Casillas and Santiago José Lora Escobar.

Article writing and critical review with important intellectual contributions: Paloma Suarez Casillas, Santiago José Lora Escobar and Hector Acosta García.

Approval of the final version for publication: Paloma Suarez Casillas, Santiago José Lora Escobar, Hector Acosta García, Tao Li and Elena Montecatine Alonso.

Paloma Suárez-Casillas: Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization. Santiago José Lora-Escobar: Writing – original draft, Formal analysis, Data curation. Elena Montecatine-Alonso: Writing – review & editing, Conceptualization. Tao Li: Formal analysis, Data curation. Hector Acosta-García: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Conceptualization.