Cold Chain Integrity for Biologics – Continuous Monitoring and Intelligent Alerting /Decisioning The biopharmaceutical industry has experienced remarkable success and growth in recent years. Innovations and regulatory approvals of RNA technologies such as CAR-T, monoclonal antibody therapies including antibody drug conjugates to fight cancer, the continued growth in the development of biologic therapies to treat autoimmune diseases, as well as the tremendous innovation and speed in the development of RNA based COVID vaccines all have put “biologics” front and center in the fight against disease.
The market for these new therapies is growing rapidly and this growth is outpacing other forms of drugs. Some in the industry predict that biologics may represent about a third of all drugs available to patients in the next few years. Even though these therapies show tremendous promise in terms of patient outcomes they are also creating new challenges for the industry regarding manufacturing, distribution, and storage. Of particular concern is that these drugs can be very expensive and are extremely temperature sensitive.
Biologic therapies require critical temperature and environmental controls and given the complexity of the global supply chain and the many players involved in getting a therapy from point of manufacture to the patient, maintenance of product integrity is a key concern. According to the World Health organization:
“A Cold Chain is a low temperature-controlled supply chain. An unbroken cold chain is an uninterrupted series of refrigerated production, storage and distribution activities, along with associated equipment and logistics, which maintain quality via a desired low-temperature range.”
“The cold chain distribution process is an extension of the good manufacturing practice (GMP) environment that all drugs and biological products are required to follow and are enforced by the various health regulatory bodies. As such, the distribution process must be validated to ensure that there is no negative impact to the safety, efficacy, or quality of the drug substance. The GMP environment requires that all processes that might impact the safety, efficacy or quality of the drug substance must be validated, including storage and distribution of the drug substance.”
As we begin to understand the complex factors that will drive the supply and demand of critical medicinal products, especially vaccines in the light of the current COVID pandemic, we will need to focus on the vaccine supply chain. Specifically, we will need to ensure the integrity and regulatory compliance of the distribution and storage of vaccines under well-defined cold chain protocols.
The US Department of Health and Human Services, Centers for Disease Control and Prevention divide the Cold Chain into 5 distinct yet connected elements. In this document we will focus on section 2, 3 and 4, which addresses distribution, storage, and handling.
- Regulations and best practices assigned to the manufacturer.
- Distribution and the joint responsibility between the manufacturer and distributor.
- Transition between distribution and arrival at the provider
- Storage and handling
- Vaccine distribution
Maintaining the integrity and addressing the efficiency of cold chain management for biologic products and especially vaccines involve three key capabilities. First, the ability to provide continuous and reliablemonitoring of the cold chain across delivery and storage and handling, thus enabling end-to-end transparency for key assets and drive data-enabled action across the supply chain. Second, the ability to track the product of interest from the first step of distribution to its ultimate administration to a patient.
This ensures that guidelines and protocols are followed for distribution / storage while maintaining the integrity of the supply chain for regulatory compliance and patient safety. And finally, building upon the tenants of monitoring and tracking is the ability to optimize across the entire supply chain. By optimizing the cold chain supply system, we allow continuous situational awareness and the ability to maximize efficiency, align supply and demand, and minimize waste, fraud, and spoilage. According to Clint Haynes, a leader in drug supply chain engineering and the Co-Founder / Vice President at Stress Engineering Services:
“Monitoring the integrity of pharmaceutical cold chain is a unique challenge and requires the development of a holistic approach, an ecosystem, that addresses the health of the biologic and forecasts degradation based on the realities of transportation, both inevitable temperature variation, vibration. Fortunately, the technology exists to build such an ecosystem.”
Optimization is defined as “the action of making the best or most effective use of a situation or resource”. Often this is accomplished using historical data, where the results of looking at how a process could be optimized or made more efficient are applied to future events. We believe that the most powerful form of optimization, especially as applied to the cold chain distribution and administration of critical vaccine supplies in a rapidly changing and dynamic supply and demand context , requires continuous monitoring and tracking of vaccines in transit and in storage as well as the application of intelligent and automated alerting and decisioning.
Imagine the following scenario where we are optimizing the cold chain within the specified regulatory and environmental constrains. We have three objective functions or goals by which we will dynamically optimize the cold chain distribution, storage, and handling system for critical vaccines. Those goals are to maximize availability of the vaccine to where it is needed most, maintain vaccine viability, and to
minimize waste and spoilage. Waste and spoilage may include potentially criminal activity such as product diversion or the introduction of counterfeit product into the supply chain.
What will enable this approach will be the application of real time or streaming analytics and specifically, the application of machine learning (ML)and artificial intelligence (AI) models based on continuous telemetry from environmental sensors measuring, temperature, humidity, vibration and light exposure and location information as well as a subset of other data. Such data, collected in real time, will make possible a high level of “algorithmic automation and intelligence with regard to alerting and responding to alerts. The diagram below shows how a decisioning workflow can be built to incorporate data from the alerting system and how to develop both “automated” intelligent decisioning and as well as human “Decision Support”:
- Check if the temperature threshold is reached by comparing the current temperature with previous temperature at appropriate time points.
- If temperature threshold was reached check if there was an alert sent already for the trailer id.
- If new alert, then get shipment information for the trailer.
- According to the current truck position get the closest centers within a certain distance. Get the distance to each center. Identify the 4 closest distance wise.
- Get the time it takes to the original target destination. If the time no more than 30 minutes the truck can go straight there.
- If it takes more than 30 minutes to go to the original target destination, we calculate the time to deliver the product when delivered for each alternative center.
- Optimization is invoked with all necessary data to calculate alternative strategies.
- A marker is set for the trailer id that an alert was sent, so we don’t send it again.
The scenario above demonstrates how it would be possible to enable rapid and informed decisionmaking through real time analysis of sensor telemetry used in monitoring equipment reliability and the supporting infrastructure critical to the distribution and storage of vaccines. The goals are to reduce human cognitive and physical workloads through digitization and automation of associated workflows while maintaining real-time situational awareness of vaccine integrity and availability through intelligent alerting and decisioning technologies.
The first step in moving to a more automated and intelligent cold chain storage and handling system is the recapitulation of the very manual and often paper based status quo to a more digital and connected system of devices, sensors, and workflow automation. This transition creates the basis upon which higher levels of intelligence in alerting and decisioning can be applied. This higher level of automation, with regard to alerting and decisioning, reduces human workload, decreases false positives and false negative alerts, automates continuous record keeping, alert and response logging and provides a level of transparency and accountability to maintain the highest level in the integrity of the vaccine cold chain in storage and handling and facilitates predictive and prescriptive actions to maintain that integrity with appropriately triaged alerting to potential events that may cause out of range temperature alerts.
Building upon the integrated, digitalized, and automated capabilities of an intelligent cold chain storage and handling system we now have the means by which we can integrate inventory management. Intelligent inventory management is a critical component of a connected and intelligent cold chain vaccine storage and handling system. This is where we extend automation, optimization, predictive and prescriptive insight across the supply and across multiple facilities.
As the number of therapies requiring cold chain keeps increasing and as their value and the scale of the logistics challenges also increases, for example the global distribution of billions of doses of vaccines, maintaining product quality and integrity at all points of transfer and exchange, from point of manufacture to shipping, distribution and storage will real time situational awareness and the introduction of intelligence and automated monitoring and alerting will be critical. Perhaps the most important element of a scalable, modern, connected and intelligent cold chain supply and logistics solution will the application of advanced and streaming analytic capabilities which will provide a new degree of situational awareness that will secure the integrity of the lifesaving products making their way across the globe to patients.
View this SAS Global Forum 2021 video to see an in-depth presentation of this topic.
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Chief Health Analytics Strategist, IoT
Principal – Global IoT Commercialization