Many over-the-counter and prescription drugs can be stored under normal, ambient conditions. As long as the temperature is reasonably controlled, humidity is low, and they’re kept out of direct sunlight, they have a long shelf life.
However, an increasing number of pharmaceuticals must be stored within specific temperature ranges. These usually contain large molecules, complex mixtures, or biologically-derived materials that are chemically fragile. Exposing them to temperatures outside of their recommended ranges can result in accelerated degradation or even complete deactivation.
Maintaining precise, consistent temperature control in the refrigerators and freezers where these products are stored has become a critical role for pharmacies. The primary motivation for maintaining temperature control is to protect patient health and safety. Furthermore, some of the most temperature-sensitive materials handled at pharmacies are also the most expensive and scarce, so there is also a financial motivation to maintain robust temperature control and monitoring equipment. For this reason, cold storage for pharmaceuticals has become an area of focus for pharmacies.
The US Pharmacopeia defines a few general categories of cold storage temperatures:
- “Refrigerated” is the most common category and refers to materials that must be stored between 2 and 8 °C (36 and 46 °F)
- “Frozen” pharmaceuticals are stored below -15 or -20 °C, to as low as -50 °C (-58 to 5 °F)
- In some special cases, like for recently developed COVID-19 vaccines, recommended storage temperatures include “ultra-cold” conditions (< -50 °C, < 58 °F). We’ll discuss COVID-19 vaccine storage in more detail later in this article.
- Some other terms for drug storage include “cool” (8-15 °C, or 46-59 °F) and “controlled room temperature” (20-25 °C, or 68-77 °F).
The World Health Organization, European Pharmacopoeia, and Japanese Pharmacopoeia provide analogous ranges for common terms used outside the US.
To maintain specified temperatures, most pharmacies use specialized refrigeration equipment, like medical-grade refrigerators or ultra-cold freezers. A critical part of any temperature control hardware is the system used for temperature monitoring. These systems range from manual, stand-alone sensor units for single refrigerators to large networks of wireless data loggers that continuously upload temperature data to cloud-based storage. They’re sometimes called environmental monitoring systems since they can also measure humidity and other environmental conditions.
The right environmental or temperature monitoring system can maximize the efficiency and reliability of your temperature control equipment. It can also grow and adapt as your needs change as the requirements around cold storage for pharmaceuticals become more complex.
In this article, we’re going to talk in more detail about why certain drugs are sensitive to elevated temperature, the equipment that’s used for cold storage in pharmacies, and where pharmacies fit into the refrigerated supply chain or “cold chain”. As we discuss those topics, we’ll keep a particular focus on the role of temperature monitoring.
What Can Be Stored in Cold Storage?
The equipment used for pharmaceutical cold storage covers a wide range of sizes. Larger facilities, like distribution hubs, large pharmacies, or hospitals, may have walk-in cold rooms that can store large volumes of materials. At the most extreme scale, entire temperature-controlled warehouses can temporarily store materials in transit.
The investment into large-scale refrigeration equipment is growing, in part due to the deployment of COVID-19 vaccines with stringent temperature control requirements. A larger driver, however, is the ongoing development and approval of biologic pharmaceuticals that are also highly sensitive to temperature. We’ll talk more about these materials in the next section.
Smaller operations, like retail pharmacies, may use medical-grade reach-in refrigeration units that are also specially designed for use with pharmaceuticals.
Regardless of size, temperature range, or application, the temperature monitoring component of refrigeration equipment is always a critical element of cold storage for pharmaceuticals. At their most basic level, the monitoring hardware measures and records temperature at predefined intervals and alerts staff if the temperature goes outside of a specified range (this is known as a “temperature excursion”).
If conditions are normal, the monitoring system provides a complete record proving that any sensitive materials were kept within a safe range. The temperature record is also important if an excursion takes place since it contains information about the amount of time the temperature was out of range, and how far out of range it was. This information can be extremely helpful when formulating a plan to respond to the excursion.
What are Cold Chain Drugs?
The products we discuss in this article must be kept within their safe temperature window from the point of manufacture until they’re administered or handed off to the patent. This is achieved using a temperature-controlled supply chain, also known as a “cold chain”.
An unbroken process of temperature control is maintained along the cold chain using a variety of logistical elements, including refrigerated warehouses, shipping containers, and specially designed insulated packaging materials. The responsibility of maintaining the cold chain begins with the manufacturer, then transfers to the companies involved in transport and distribution, then to the pharmacy once the material is delivered.
Along the cold chain, temperature monitoring equipment maintains a record of temperature during transit and alerts the responsible party if a problem arises. The monitoring system usually includes a combination of different types of equipment, like stationary data loggers that monitor temperature-controlled storage rooms, and sensors that are embedded at a package level. Embedded sensors can ride along with the shipment end-to-end, by using compact BlueTooth monitors or individual vaccine vial monitors.
The appropriate temperature range for a given product, along with the shelf life when kept within this range, and the response protocol for temperature excursions, are all determined during the pre-approval drug development stages. Biologics, which are drugs derived from biological sources, are one class of materials that commonly require a cold chain. In addition, large molecules that are liable to breakdown, and chemical mixtures that chemically react with one another at elevated temperature also use cold chains.
Some common examples include:
- Vaccines, a common temperature-sensitive class of pharmaceuticals, are usually stored in a refrigerated or frozen state. Some are delivered in two parts, an active material, and a diluent, which have different storage requirements.
- Insulin, although it can also be stored for limited periods at room temperature by patients before injection.
- Monoclonal antibodies.
- Some types of asthma inhalers, oncology medicines, and interferons.
- Certain test supplies and kits (such as those used for HIV testing).
In general, temperature control is needed because chemical reactions, which are the root cause of degradation, take place much faster at elevated temperatures. Therefore, the effect of an excursion on a temperature-sensitive material is a function of both how much the temperature exceeded recommended range, and for how long.
A convenient way to summarize the combined effect of the temperature and duration of an excursion is to calculate a mean kinetic temperature (MKT). This calculation determines a representative temperature that is weighted by the chemical kinetics of degradation. Knowing the MKT, which can be calculated accurately using a detailed record of temperature over time, is critical when making a plan for the disposition of an affected batch of pharmaceuticals.
It’s also important to note that colder is not always better. Some complex drugs, like ones that are delivered as emulsions or contain other physically fragile structures, can be irreversibly damaged by freezing, or by multiple freeze-thaw cycles.
Like many aspects of vaccine development, mRNA-based COVID-19 vaccines have introduced new approaches to the way vaccines are distributed and stored. The Pfizer-BioNTech vaccine, in particular, is shipped at -90 to -60 °C, using specially developed containers and temperature monitors. In their updated vaccine storage and handling toolkit, the CDC provides detailed instructions on how to check, unpack, and store COVID-19 vaccines after arrival at the pharmacy. Similar information has been published for the Moderna vaccine.
Looking at COVID-19 storage specifications illustrates another point about cold storage of pharmaceuticals, which is that specific guidelines can change over time as more data is collected. In a December 2020 blog post, we discussed the very stringent temperature requirements for mRNA COVID-19 vaccines as they were known at that time. Since then, the guidance has changed. For one, the FDA has issued updated information indicating that the Pfizer vaccine can be stored in a refrigerated state (2 to 8 °C) for up to 1 month, whereas the original guidance gave only 5 days of refrigerated storage. These changes allow greater use of the existing cold chain, among other advantages.
Note that pharmaceuticals aren’t the only materials distributed by cold chain. Food products, specialty chemicals, human blood products, and tissue samples are also stored and distributed by cold chain.
The Attributes of Cold Storage for Pharmaceuticals
In view of the categories of cold storage for pharmaceuticals, it makes sense that there are different types of cold chains. These include:
- Refrigerated cold chains (2-8 °C), used for flu vaccine, insulin, and many other medicines
- Frozen cold chains, maintained at roughly -20 °C, used for example for varicella-containing vaccines
- Special ultra-cold supply chains, used for some of the COVID-19 vaccines we’ve discussed, and for the Ebola vaccine
Some materials can be stored either frozen or refrigerated. This is a complex topic area, and for specific product information, the manufacturer’s package inserts and labels are a good source of information. The FDA maintains a searchable database of these.
As we mentioned above, cold chains are maintained by a wide variety of logistical components, including refrigerated warehouses and shipping containers, as well as packagings like gel packs, dry ice, liquid nitrogen, or advanced solutions like eutectic plates and other phase change materials. These logistics are needed for maintaining refrigeration over long distances, including land, sea, and air transport, and are selected based on a balance of cost and product requirements.
The same is true for on-site cold storage for pharmaceuticals. Pharmacies can select different sizes of storage units, specific types of temperature control, and monitoring hardware, based on their product mix. A retail pharmacy has different needs than a hospital, or clinic pharmacy, which might stock more specialized or sensitive drugs.
Smaller operations may use medical-grade “reach-in” refrigerators or freezers, which are specifically designed for pharmaceutical storage, with features like:
- Glass doors, so that the contents can be seen without opening the door. Door openings are a primary cause of temperature variation.
- Audible alarms to alert onsite staff when doors are inadvertently left open.
- Design elements like wire shelves and strategically placed vents to promote airflow.
- Soft door seals to prevent air leaks.
- On-board backup power to maintain a temperature in the event of a power outage.
These storage units can also protect against other environmental factors that can be harmful to pharmaceuticals, notably humidity, light, and oxygen. Humidity can be an issue for the breakdown of pharmaceutical packaging, as well as pharmaceuticals themselves, which is why some products come with instructions to store them in a dry place. (“Dry” refers to < 40% relative humidity at 20 °C, as defined by the US Pharmacopeia.)
Like any chemically sensitive material, all pharmaceuticals should be kept out of direct sunlight. However, additional caution should be taken with especially light-sensitive materials like the Bacille Calmette-Guerin (tuberculosis), measles-mumps-rubella, and some flu vaccines. Oxygen in air can also lead to accelerated degradation, another reason the refrigerators used for cold storage for pharmaceuticals to seal completely.
Even when they’re stored in proper conditions, pharmaceuticals can deteriorate slowly over time, losing effectiveness as they do. This is why pharmaceuticals have finite shelf lives and expiration dates. Certain drugs can experience rapid degradation even faster, or even become more toxic over time. For this reason, pharmacies also use systematic stock rotation and inventory check procedures to prevent deteriorated or expired products from reaching consumers.
Monitoring Cold Storage After Installation
For vaccines, the CDC recommends a few minimum characteristics for temperature monitoring systems, which are useful guidelines for any type of cold storage for pharmaceuticals. These include having alarms for out-of-range temperature and low battery, current/low/high-temperature readings which can be reset by the user, and a detachable, buffered temperature probe. In this context, “buffered” means that the temperature probe is submerged in a material like glycol, glass beads, or Teflon, which more accurately represents the temperature of the stored material compared to a bare probe in air.
The next level of automation are digital data loggers or DDLs which record temperature (or temperature and humidity) at preset intervals, commonly every 30 minutes. This is a required feature for monitoring equipment used in the Vaccines for Children program. Monitoring data can be downloaded from a DDL using a USB port or through wireless or hard-wired connections.
However, modern environmental monitoring systems such as those offered by Dickson incorporate a number of additional features and improvements that can be very powerful for pharmacy temperature monitoring. These include:
- Continuous uploading to cloud-based data storage, wirelessly or by wired ethernet connection, so that data can be accessed in real-time from anywhere
- Integration with web-based software tools that can quickly process and organize incoming data, and identify problems across all monitored sensors
- Customizable alarms that can be sent to specific individuals or groups by SMS text, email, or phone call, when user-defined limits are reached
These features can improve the reliability of small operations, and are also highly scalable to large pharmacies, networks, or chains with temperature-controlled storage units distributed across many physical locations.
For example, a network of temperature sensors can be connected via the cloud-based DicksonOne system to a central hub, where temperature issues and trends can be continuously monitored. This also alleviates the burden of temperature monitoring and recording from onsite staff, so they can focus on more critical tasks while reducing or eliminating the potential for human error.
Pharmacies represent the last step in the cold chain that is used to deliver temperature-sensitive pharmaceuticals to consumers. Robust, reliable temperature control equipment such as refrigerators and freezers are needed to make sure that these products maintain their full efficacy until they’re administered.
An important part of any controlled-temperature storage system is having the capability to continuously measure temperature, humidity, and other important environmental conditions. Modern environmental monitoring equipment and software can greatly improve the reliability and efficiency of a pharmacy operation, reducing the risk to patients and helping to safeguard valuable pharmaceuticals.
As more complex pharmaceuticals are developed, we should expect cold storage requirements at the pharmacy level to become more numerous and complex. Questions about the pharmaceutical cold chain, or how your pharmacy can implement a modern environmental or temperature monitoring system? Contact the experts at Dickson.