Many regulatory agencies cover the storage standards for blood and blood products, including the Food and Drug Administration (FDA), 21 Code of Federal Regulations (CFR) part 1271, and Good Manufacturing Practices requirements in 21 CFR parts 210 and 211 [1]. The European Union, Canada, and Australia have similar regulations.

To ensure the viability of the blood and blood products, the storage devices are closely monitored. These devices include refrigerators, freezers, incubators, and environmentally controlled rooms.

The maximum allowable storage time for a blood product maintained under controlled temperatures is called its shelf life. During this period, conditions for the storage temperature are maintained such that the effects when are viable when utilized.

The operational requirements for the successful monitoring of blood products include the following:

• Temperature monitoring of the storage unit is maintained 24 × 7
• National Institute of Standards and Technology (NIST) traceable calibration of sensor probes
• A graphical display is available for the end-user to reference to validate compliance
• An alarm/alerting solution is available in the event of an excursion
• Ability to validate the alarm notification process
• Maintain records of the storage unit’s ability to operate within the operational range for ten years
• Recordation of user’s interaction with the system 

• Daily validation of monitor’s performance
• User traceable alert acknowledgment
• Change traceable to the user

Acceptable storage temperature ranges for the use of product storage are [2]:

The devices available for the monitoring and recording of temperature conditions for product storage and transport have evolved. The replacement of the thermometer with a single-use chemical sensor was the first sign of automated monitoring. These devices are single-use, go, no-go indicators that an excursion has occurred. An advancement from these devices is the data logger. The data logger brought to the industry is the continuous recording of the storage unit operation. Unlike the thermometer and single-use instruments, the user must remove the logger and download the recorded data. An added feature with the data logger was the indication [via flashing light-emitting diode (LED)] that a control limit is exceeded. The user would then download the data from the logger, and only then can the extent of the excursion be assessed.

With the advent of wirelessly connected devices, continuous data reporting is now available. These solutions connect to the client WiFi network. In other cases, a private, proprietary system is established for device connectivity. The essential advantage of the continuously reporting solution is that the user(s) are notified promptly in an excursion.

The monitoring of temperature-sensitive goods during transport continues to be accomplished with the data logger, as the wireless network is location-specific. The wireless monitor may be utilized to record the storage conditions during transport; when the wireless network is available, the device can automatically download the data for evaluation, inspection, and automatic alerting.

The requirements for the storage conditions of blood products are described above. These requirements are applicable across the cold chain process. The “cold chain” is illustrated in Figure 1. Despite these requirements, the monitoring methodologies are often not applied at all the process steps. This shortcoming may result from technology being available to everyday practice, i.e., “we've always done it this way.”

Trends in technology

The storage temperature tolerances noted in Table 1 require control of the temperatures within ±2°C. This level of the desired accuracy requires monitoring equipment other than the one-time-use chemical dot. The evolution of sensing technology has experienced significant change with the advent of low-cost integrated electronics. Low-cost microcontrollers with integrated data conversion technology have resulted in the smart sensor becoming increasingly more affordable. These smart devices are available in several communication standards such as WiFi, Bluetooth, ZigBee, and Internet of Things (IoT) (cellular). The cost-effective use of microcontrollers and microprocessors enables the peripherals to support a diverse array of wireless communication standards.

The capability of these devices far exceeds the requirements outlined above. Manual recordation is no longer necessary, as these devices upload data to cloud-based servers¹ where ingestion, storage, and data analysis occur. The presentation of the recorded data and analytics is via a browser application.

Temperature excursions, short or long, cooling or warming, must be represented accurately to understand the stored contents’ effect. Monitoring is usually accomplished through periodic temperature reporting, with the intervals between readings varying from 5 to 30 minutes. While a short time excursion may not be damaging to the stored goods, the cumulative effects of repeated transient events may degrade the contents [3]. This is especially true for refrigerated goods’ freezing, where even a very brief freeze can damage the stored goods. Consequently, it is of utmost importance to accurately represent the contents’ temperature when describing and recording the storage environment.

It is common practice in the cold chain monitoring of pharmaceuticals, vaccines, tissue, and other temperature-sensitive materials to require a temperature buffer consisting of a physical container into which the temperature probe is inserted. When authoring this paper, there is no recommended or standard procedure for selecting this buffer [4]. The physical buffer’s specifics—size, shape, and material—are very rarely chosen consciously but established by default to whatever the company providing the temperature probe uses. A review of these companies’ physical thermal buffers shows little consistency in any of these parameters. Volumes can range from 10 to 300 mL glycol vials and machined and preformed aluminum blocks, plastic, or silicone. The Centers for Disease Control and Prevention recommends a 20 mL Boston Bottle filled with an equal amount of water and glycol. The water/glycol mixture’s purpose is to prevent the buffering solution’s freezing [5]. However, this buffer’s stored goods were observed to include prefilled syringes as small as 0.25 mL to bottles and vials many times that volume.

The two purposes of the buffered temperature probe are somewhat in opposition to each other. A larger volume buffer will prevent “false” alerting from transient changes caused by regular use; however, that same buffer may fail to respond quickly enough to freezing or warming events in time to prevent spoilage of the storage unit’s contents. Both objectives can only be achieved when the buffer is thermally matched to the stored goods [6].

Consequence of improper storage

The “blood cold chain” is an established system for processing, storing, and transporting blood and blood products within the prescribed temperature range and conditions, from the point of collection processing and storage to the time of transfusion to the patient [7].

Deviations from specified temperature ranges and conditions during storage and transportation of blood and blood products can seriously affect the blood’s viability, leading to reduced clinical benefits. It can also increase the risk of bacterial proliferation in blood components during storage and potentially cause life-threatening transfusion reactions. A break in the “blood cold chain” may lead to wastage and discard of blood units.

Modern innovation

There are specific tools available to ensure that the “blood cold chain” is maintained. These begin with temperature monitoring and processing equipment. The evolution of sensing technology has experienced significant change with the advent of low-cost integrated electronics. Cheap microcontrollers with integrated data conversion technology have resulted in the smart sensor becoming increasingly more affordable. These smart devices are available in several communication standards, such as WiFi, Bluetooth, and ZigBee. The cost-effective use of microcontrollers and microprocessors enables the peripherals to support a diverse array of wireless communication standards.

A new and emerging technology standard is the IoT. Internet of Things technology, coupled with the Internet’s pervasiveness, a new era of sensing technology is ushered into use. When selecting a monitoring solution, one must consider many options and wade through a preponderance of information to determine the best application for their needs.

Continuous monitoring is commonly achieved utilizing WiFi technology. The monitor device communicates via the client WiFi to a data collection server, either locally or cloud-based. This communication method works well for fixed-based storage units as the WiFi signal is present and locally maintained. For obvious reasons, this is not applicable for off-site storage or transportation. Cellular-based IoT monitoring devices serve both applications, fixed locations, and transport [8]. These devices require no interaction with the client Information Technology Department (IT) and are suitable for continuous monitoring during transport or off-premises use.

Data analytics

With the implementation of the technology associated with IoT devices and cloud computing, data analytics becomes an even more powerful tool. Discussed earlier is the need for temperature buffering. Typically, this is accomplished using a physical buffer; the air temperature data is modified, resulting in a significant loss of “information” that may be processed further [9]. Using a mathematical model, an algorithm can precisely demonstrate the impact of a temperature excursion on the stored good. Each container—size, contents, and geometry—may be modeled and data displayed. This solution is referred to as Virtual Temperature Buffering (VTB) [10],[11].

Notification in the event of an out-of-bounds condition is critical in the assurance of product quality. Predictive analytics may be employed utilizing the air temperature data providing early warning of a failure condition. Alerting is not limited to temperature excursions alone. Power failure, device monitor battery state, and monitoring probe condition are device health alerts that are available.

Platelet agitators are monitored using an accelerometer; cessation of motion triggers an alert condition. Devices such as the BacT blood culture system offer an audible alarm in a fault condition. The audible alarm provides no value if no one is present to hear the alarm. A solution that can detect the alert state and provides an alert notification is beneficial. Alerting is accomplished via email, text, and voice messaging.

User training

The system user becomes an essential part of the “blood cold chain.” Through inadequate training, it is the user that becomes a contributor to breaking the cold chain. A data analytics tool called Compliance Quotient (CQ) provides a report card that can be utilized to determine the need for additional training [12]. This same report provides a score on the storage equipment performance and the effect of the external environment on the equipment.

¹Cloud server is just a computer, what makes it a “Cloud” server is that you get access to it through some form of cloud service—public, private, etc. What that means is that you don't actually deal with the hardware (virtual or physical) that you will be using.

The cold chain process associated with collecting, transport, processing, and storing blood and blood products must be carefully assessed. So often, the standards providing the guidance do not reflect the most current technology. The successful monitoring of these materials assures the products’ quality while minimizing waste due to missteps in the cold chain process. Through continuous monitoring, sampling at five-minute intervals, and automatic recording of data in the cold chain, accurate temperature records are assured. Advances in technology have enabled low-cost monitoring solutions. Cloud computing and the power of data analytics further enhance the solution. Devices such as cellular IoT-enabled monitors and virtual temperature buffering compiled with extensive data analytics provide a cost-effective solution that assures the “blood cold chain.”