The Challenge of Cold Chain Logistics

THE PHARMACEUTICAL cold chain, a temperature controlled system required to preserve and maintain the usability of pharmaceutical products, is a critical part of today’s healthcare supply chain. The cold chain involves constant refrigeration of a product from the time of its production through its transportation, handling, storage and delivery.¹ Responsibility for cold chain logistics originates at the manufacturer of origin and ends at the healthcare facility where the medications are stored until used for patients.

The cold chain was inspired by the World Health Organization (WHO) after it launched a global campaign in 1966 to eradicate smallpox. As part of that campaign, WHO established the Expanded Programme on Immunization (EPI) to assess the feasibility of implementing a single global immunization schedule for six antigens: tuberculosis, polio, diphtheria, pertussis, tetanus and measles. It found, however, that a key challenge of the EPI was the safe delivery of these vaccines, which are temperature sensitive biological products. To meet this challenge, WHO developed the technologies, systems and guidance toward a vaccine cold chain to distribute vaccines.²

Over the past several decades, the need for cold chain activities has substantially increased with the growth of biologics (blood products and vaccines), which require both temperature and time-controlled distribution, as well as other precision medicine breakthroughs such as cellular therapies, biomarker testing and regenerative medicine (stem cells).1 According to Pharmaceutical Commerce’s annual BioPharma Cold Chain Sourcebook, the transport of temperature-sensitive products along a supply chain through thermal and refrigerated packaging methods and the logistical planning to protect the integrity of these shipments is predicted to be a $16.6 billion industry by 2021.³

Who Regulates Cold Chain Logistics?

While there are many parties involved in overseeing cold chain logistics, the main regulatory forces are the U.S. Food and Drug Administration (FDA) and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). FDA co-founded ICH with the European community in 1990 “to decrease unnecessary replication of costly regulatory processes, thereby promoting more efficient manufacturing, processing and distribution methods for regulated products on a global scale.” FDA’s jurisdiction is primarily in the U.S. and Puerto Rico, while ICH’s jurisdiction is over the U.S., Japan and the European Union.⁴

The Complexities of the Cold Chain

Drug safety is heavily reliant on cold chain logistics to manage temperature-sensitive products as they move through the supply chain. Depending on the type of pharmaceutical products, their optimal temperature ranges include between 35 degrees and 46 degrees Fahrenheit (2 degrees and 8 degrees Celsius), sub-zero and cryogenic temperatures, with the majority of drugs requiring refrigeration at between 2 degrees to 8 degrees Celsius. Cryogenic products have their own specifications ranging from –35 degrees to –15 degrees Celsius, –65 degrees Celsius, –120 degrees Celsius and –150 degrees Celsius (see Figure).¹ Exposure to temperatures outside these ranges may result in reduced potency of medicines or the need to discard them, which can result in patients being untreated or, in the case of vaccines, an increased risk of vaccine-preventable diseases.⁵ In fact, too much exposure to heat, cold or light at any step in the cold chain can damage medicines and result in loss of potency. In addition, exposure to freezing temperatures could destroy some medicines.⁶

To ensure medicines are maintained at the proper temperatures, monitoring them through the supply chain process is essential and can be accomplished in several ways. The most basic includes packing discrete devices called temperature data loggers with the shipment that will record a temperature reading of the products that can be manually uploaded into a system. However, more sophisticated data loggers have the ability to measure temperature, shock, humidity, vibration and other attributes. And, some have GPS capability with real-time tracking and reporting. Radio-frequency identification (RFID) technology utilizing electromagnetic fields to automatically identify and track tags attached to packages can be used with software to monitor temperature.¹ Even more advanced and perhaps the newest and most effective monitoring technology is smart refrigeration systems for storage, handling and inventory (see Monitoring the Storage and Handling of Vaccines and Biologics: MinibarRx).

Transportation Guidelines

Even though the cold chain is regulated, there isn’t “a single standard, guidance, regulator, document or arbiter with the final say on a compliant cold chain for a given region.” Therefore, distributors must rely on only basic requirements for pharmaceutical distribution, as well as other sources such as conferences, technical reports and recommendations from companies that specialize in cold chain logistics.⁴

That being said, one set of rules is becoming the “de-facto standard around the world” and has resulted in stepped-up regulation of cold chain logistics. This is the “European Commission Guidelines on Good Distribution Practices of Medicinal Products for Human Use,” which was revised in 2013 and established good distribution practices (GDP) requirements for pharmaceutical products.⁷

Items outlined in the GDP are quality management; personnel; premises and equipment; documentation; operations; complaints, returns, suspected falsified medicinal products and medicinal product recalls; outsourced activities; self-inspections; transportation; specific provisions for brokers; and final provisions. The guidelines can be found at ec.europa.eu/health/sites/health/files/files/eudralex/vol1/2013_c343_01/2013_c343_01_en.pdf.⁸

The European Commission transportation guidelines specifically state it is the “responsibility of the supplying wholesale distributor to protect medicinal products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport.” This includes ensuring vehicles and equipment used to distribute, store or handle products are suitable for their use and appropriately equipped to prevent exposure to conditions that could affect their quality and packaging integrity; written procedures are in place for the operation and maintenance of all vehicles and equipment; and risk assessment is conducted of delivery routes.⁸

Yet, these and other guidelines, as mentioned previously, are merely basic requirements; they don’t dictate specifically how these guidelines should be accomplished to comply with cold chain logistics. So, one supply chain consultant suggests distributors, logistic providers and carriers coordinate actions to address the ongoing challenges of cold chain logistics. And, distributors should be able to answer some key questions that should ensure they are in compliance:³

• What is the strategy for ensuring end-to-end cold chain visibility?
• How is temperature monitored through the delivery cycle?
• Are logistics providers prequalified for cold chain?
• What processes are in place to assure proper handling and storage once product leaves the facility?
• How is compliance measured?

CDC Storage and Inventory Guidelines

While the handling of vaccines and other medicines begins with the manufacturer, once they arrive at the facility, healthcare providers are responsible for storage, handling and administration. Following is a brief breakdown of the Centers for Disease Control and Prevention (CDC) guidelines for storing vaccines, which can be applied to other medicines requiring refrigeration:⁵

1) Medicine packages should be opened immediately to assess for damage and temperature. Damaged or incorrect temperature drugs should be segregated in a separate location, and the supplier should be contacted for advice on how to proceed.

2) Medicines should immediately be stored at the recommended storage temperature. To assist with this, it is recommended a sign be placed on the refrigerator that lists the appropriate storage temperatures.

3) Medicines should be stored in the middle of refrigerators, never in doors, and in their original packaging inside designated storage trays positioned 2 inches to 3 inches from refrigerator walls. When new product arrives, the stock should be rotated by placing newer medicines behind older ones.

4) Temperature inside refrigerators should be monitored and recorded at least twice a day to ensure they are within the proper range.

5) It is recommended to place temperature log sheets on refrigerators and document the twice-daily checks.

6) If it is suspected medicines have been exposed to out-of-range temperatures or have been left out of refrigerators, they should be marked with “Do Not Use” and transferred to a functional refrigerator at the proper storage temperature while determining whether the medicine is still viable.

CDC also has step-by-step guidelines for inventorying medicines. Briefly described, these include:⁶

1) A stock record should be used to keep track of inventory. The record can be in paper or electronic form, or it can be part of an information system with the capacity to manage drug inventory. The stock record should be updated weekly, and it should account for and document every dose of the medicine, including:

• Date of delivery (and initials of the person who unpacked the delivery)
• Medication and diluent name and manufacturer
• Number and expiration date for each lot (including expiration dates based on beyond-use-date guidance in the product information)
• Number of doses received
• Condition of each medication and diluent upon arrival
• Center for Comparative Medicine reading if included in the shipping container (and actions taken if the monitor was triggered, signaling a possible temperature excursion)
• Number of doses used (i.e., administered, wasted, compromised, expired or transferred [and destination])
• Balance of remaining doses after subtracting the amount used

2) At least once a month and before placing any order, all medications and diluent doses should be counted to ensure the number of doses in the storage unit matches the number of doses documented in the stock record. At the end of each month, the total number of medications and diluent doses used during the month and the amount of stock still available should be determined. And, at the end of the year, the stock record should be used to determine the number of doses received and used during the year to help minimize future waste.

3) Expiration dates on medications and diluents should be checked at least once a week. And, expired medications should be immediately removed to avoid inadvertently administering them. Expired medications should be documented on the stock record.

It should be noted that many of these processes can now be automated with more sophisticated storage and inventorying technologies.

The Future of the Cold Chain

As the pharmaceutical industry becomes more regulated to ensure compliance with cold chain logistics, the need grows for more sophisticated methods of ensuring drug safety as medicines are transported from manufacture to dispensing. Innovation has inspired great strides over the past several decades, but it stands to make even greater improvements with advancing technologies. This is especially true now with advanced therapies such as regenerative medicine and cellular therapies.

Today, next-generation technology, artificial intelligence (AI) and intelligent packaging and software solutions are paving the way for improvements in cold chain logistics. Next-generation shippers and data management devices can report on chain of custody and condition, as well as interact with a user and be reprogrammed instantly to update documentation and airway bills or provide real-time visibility of environmental conditions. Enhanced tracking technology is made possible with augmented GPS (Bluetooth, WiFi, IoT), next-generation data loggers and enhanced software management capabilities. RFID technology and 5G-enabled sensors are next-generation technologies that are improving the safety of cold chain medicines. AI-enabled robotics can analyze and track data, as well as generate predictions to improve the supply chain. And, intelligent packaging solutions can be integrated into driver management or freight management platforms to integrate and optimize supply chain performance.⁹

To meet the rising demand for biopharmaceuticals, reliance on cold chain logistics is expected to increase substantially. In light of many recent technological breakthroughs, as well as increased regulatory oversight, the safety of cold chain medicines as they travel from manufacturer to site of administration is projected to vastly improve aided by the implementation of smart technology.Chance H. Cold Chain Logistics in Pharma. HCL Technologies, June 28, 2018. Accessed at www.hcltech.com/blogs/cold-chain-logistics-pharma. 2. Lloyd J and Cheyne J. The Origins of the Vaccine Cold Chain and a Glimpse of the Future. Vaccine, 35 (2017); 2115-2120. Accessed at www.sciencedirect.com/science/article/pii/S0264410X17300476. 3. Sedlak PS. Cold Chain Challenges in the Pharmaceutical Industry. Sedlak Supply Chain Consultants, Jan. 12, 2018. Accessed at www.jasedlak.com/blog/view/cold-chain-challenges-in-the-pharmaceutical-industry. 4. Vaisala. FDA & ICH: Regulations and Standards for Temperature-Controlled Supply Chains. Accessed at www.vaisala.com/sites/default/files/documents/Cold_Chain_FDA_ICH-Application-Note.pdf. 5. Tennermann J. Cold Chain for Beginners. Pharmaceutical Processing, June 20, 2012. Accessed at www.pharmpro.com/article/2012/06/cold-chain-beginners. 6. Centers for Disease Control and Prevention. Vaccine Storage & Handling Toolkit 2018. Accessed at www.cdc.gov/hcp/admin/storage/toolkit/storage-handling-toolkit.pdf. 7. A New Rx for Pharmaceutical Cold Chain Products. Inbound Logistics, January 2016. Accessed at www.wdsrx.com/new-rx-pharmaceutical-cold-chain-logistics. 8. Information from European Union Institutes, Bodies, Offices and Agencies. European Commission Guidelines of 5 November 2013 on Good Distribution Practice of Medicine Products for Human Use. Accessed at ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/2013_c343_01/2013_c343_01_en.pdf. 9. Sawicki MW. The Future of Cold Chain Logistics. Pharm Manufacturing, Dec. 3, 2019. Accessed at www.pharmamanufacturing.com/articles/2019/the-future-of-cold-chain-logistics.