Risk Management in the Biomaterial Cold Chain

Mitigating risks & ensuring compliance

By Jeff Clark, BioStorage Technologies

The biopharmaceutical cold chain has begun to play an increasingly critical role in pharmaceutical and biotherapeutic development processes. It defines how temperature-sensitive biological assets are packaged, transported and stored throughout the R&D cycle. When building or evaluating their cold chain processes, drug developers must remain aware of one basic, yet often-overlooked principle: the cold chain is the same as any other chain in one key area — it is only as strong as its weakest link.

The Role of the Cold Chain In Biopharma Development

Photo courtesy of BioStorage Technologies, Inc.

Temperature-sensitive biomaterials (clinical trial samples, cell banks, tissue samples, active pharmaceutical ingredients and microbiological and viral samples) play a vital role in bringing new drugs to market. At various phases in development these materials must be transported between collection sites, analytical laboratories and biobanking facilities. During transit and storage they must be managed carefully at all times to maintain their cold or frozen state and meet regulatory guidelines.

Weakness or failure at any point in the chain can compromise product integrity, breach security, delay shipments and ultimately result in financial loss or liability. For example, consider what would happen if clinical trial samples thawed during shipment from collection site to testing lab. If the samples had to be discarded, the sponsor could potentially lose hundreds of thousands of dollars in re-running the trial. Or, if samples didn’t reach their intended destinations on time, testing could be delayed, causing a ripple effect throughout the development schedule.

From a regulatory perspective, lack of compliance can delay biologic shipments at inspection points or subject drug developers to fines ranging from a few hundred to thousands of dollars. Even specific individuals can be fined or, in extreme cases, imprisoned. It is in the best interests of the drug developer to build a reliable, efficient cold chain that protects the company’s biological assets and helps bring products to market faster.

To mitigate both financial and legal risk, biopharmaceutical developers must implement standard operating procedures and comply with complex regulations that don’t necessarily apply to the traditional supply chain. Specific factors that come into play include:

Training & Compliance

The International Air Transport Association (IATA) and the U.S. Department of Transportation (DOT) require organizations and individuals that ship or receive biological materials to be trained properly in handling procedures^1,2. IATA’s annually updated Dangerous Goods Regulations (DGR), which has been incorporated into the DOT’s Code of Federal Regulations (CFR) 49, mandates that personnel involved in preparing, transporting, receiving or otherwise handling dangerous goods must receive training in packaging, labeling, documentation, declaration, hazard assessment and emergency response. They must also receive function-specific safety training and undergo training, testing and certification every one to three years, depending on the company’s mode of shipping transportation.

Since the inception of this regulation, many corporations have established in-house training programs customized to their organization’s specific shipping and receiving needs. Such programs include education on:


Companies that do not have the in-house expertise to develop and administer compliant training programs should consider contracting with external agencies that specialize in dangerous goods training and certification.

Packaging

Proper packaging is essential to maintaining sample integrity throughout the cold chain process. Validated packaging materials and effective packing techniques will protect products during transit and unexpected delays. Because the external environment cannot be controlled during shipping, biopharmaceutical firms maintain the viability of their temperature-sensitive biological materials with specialized packaging. Common issues that can impact biomaterial integrity during transport include prolonged delivery delays caused by transportation glitches, security inspections or customs scrutiny; temperature fluctuations inside shipping vehicles; and seasonal or climate differences between origination site and destination.

To ensure that materials are maintained properly, logistics personnel must be aware of the temperature requirements of the products being transported. They must also understand the unique packaging challenges presented by products with different temperature requirements (that is, controlled ambient, refrigerated or frozen). It is the logistics professional’s responsibility to package the products appropriately, document the specifications for each package and ensure that the shipping company can accommodate and maintain these requirements throughout the entire shipping process, given the temperature hold time of the packaging being used.

Best Practices for Refrigerated Shipments

For biological products that must be maintained at +2 to +8 degrees Celsius, packaging must be properly pre-conditioned prior to shipment to avoid compromising sample integrity. Pre-conditioning helps the packaging maintain its rated temperature for the optimum amount of time. Compliant packaging is irrelevant if it is not properly prepared before its temperature-sensitive contents are inserted.

To pre-condition packaging, gel packs that will be used to maintain temperature inside the shipping carton must be brought to the specified temperature for 24 to 48 hours before packing. Once the gel packs are preconditioned and placed inside, the carton should rest for one to two hours to ensure that the internal compartment reaches the desired shipping temperature. (Cartons that have been stored in extremely hot locations should be brought to room temperature before the gel packs are placed inside.) Only then should the samples be placed into the carton. Additionally, it is important that specific instructions provided by the packaging manufacturer be followed.

Strategic packing technique brings an added measure of temperature control to the shipment. One method is to double-layer the package with a combination of refrigerated gel packs directly around the biological product and frozen gel packs outside the refrigerated packs to prevent temperature fluctuations during transportation. 

Best Practices for Frozen Shipments

Dry ice and liquid nitrogen are commonly used to ship biological materials that must be maintained in a frozen state. Often, logistics personnel are unfamiliar with best practices that should be followed when using these sub-zero substances to maintain the integrity of perishable biological materials.

Season & Climate Considerations

Seasonal temperature fluctuations and geographical climate conditions are critical factors when developing a logistics strategy for temperature-sensitive biological materials — especially specimens traveling across significantly different climate zones. External temperatures can have a profound impact on packages (and their bio-contents) during transit.

For instance, consider the fluctuating internal temperature of trucks and airplane cargo holds during the height of summer or the freeze of winter. And consider the possibility that packages might be stored temporarily on outside loading docks — exposing them to extreme outside temperatures — before they are loaded into shipping vehicles or when they are being transferred from one vehicle to another (for example, when being carried from a truck to an airplane cargo hold). Both of these situations can compromise the biomaterials.

Manufacturers of temperature-controlled packaging typically validate their cartons in a controlled environment; however, the cartons are not validated with specific products inside. Therefore, pharmaceutical and life science logistics personnel should always test packing supplies in conditions that approximate the hottest and coldest temperature conditions in which the biological materials might be stored during shipment. This ensures that the packaging performs as advertised, avoiding potentially disastrous product losses. Personnel who don’t have access to external validation services can devise their own tests to gauge the performance of packaging products and cartons in extreme temperature conditions.

Temperature Monitoring Devices

Beyond selecting the proper packaging and using it correctly, there are additional methods that logistics personnel can utilize to confirm that the packaging did indeed maintain the contents at the desired temperature throughout shipment. These include the use of:


A variety of factors — including FDA regulations and internal corporate guidelines — must be considered when determining which situations require the use of temperature monitoring devices.

Labeling & Documentation

Pharmaceutical and biotechnology companies that ship biological or hazardous materials must follow strict standards for labeling and documentation. The DOT’s Hazardous Materials Regulations (HMR) specify requirements for the safe transportation of hazardous materials by rail car, aircraft, shipping vessel and motor vehicle¹. These regulations dictate specifications for classification, packaging, hazard communication, shipping papers, incident reporting, handling, loading, unloading, segregation and movement of hazardous materials. Fines and shipping delays often result from non-compliance and lack of awareness of HMR requirements.

Pharmaceutical logistics personnel must understand their products’ hazardous characteristics and applicable regulations to avoid delivery delays, liability and financial penalties. They must determine the appropriate hazard class and shipment description to establish the required packaging, markings, labels and documentation.

Infectious Substances

Shipments classified as infectious substances (that is, any viable microorganism that causes or may be reasonably expected to cause disease in humans or animals) must include an itemized list of contents enclosed between the secondary and outer packaging³. These shipments should also bear an Infectious Substances label on the outer package as well as a clear display of the common or technical name of the contents enclosed. A completed Dangerous Goods Declaration Form must also be attached to all infectious substance shipments to help avoid shipping delays and the corresponding risks to product integrity.

Hazmat Violation Penalties Civil penalty for a knowing violation: $250 to $50,000 Criminal penalty for a knowing violation: 5 years’ imprisonment and $250,000 fine for individuals, $500,000 for corporations (max.) Civil penalty for training-related violation: $450 (min.) Failure to provide initial/recurrent hazmat training: $450 (min.) Failure to create/maintain training records: $500 (min.) Failure to provide security training (security plan in place): $2,500 Failure to develop a security plan: $3,000 (min.) Civil penalty for violation resulting in death, serious illness or injury or substantial property destruction: $100,000 (max.) Criminal penalty for the above: 10 years’ imprisonment (max.) Criminal penalty for hazardous material release resulting in death/bodily injury: 10 years’ imprisonment (max.) Source: Department of Transportation, Pipeline and Hazardous Materials Safety Administration, 49 CFR Parts 107 and 171, Hazardous Materials: Revisions to Civil and Criminal Penalties; Penalty Guidelines, February 2006.

Diagnostic Specimens

While products such as diagnostic specimens are not considered hazardous under DOT regulations, their temperature-sensitive nature dictates that proper packaging and labeling be a priority for laboratories, hospitals, biological storage facilities and biopharmaceutical developers that are shipping or receiving these materials.

Several simple steps that will maintain DOT compliance and improve the likelihood of a timely delivery include the addition of the following identifying information with every package:

Air Transportation

Since the 9/11 terror attacks, global air cargo security regulations and precautions have been tightened significantly⁴. And, due to the heightened fear of bioterrorism and the fact that it can be extremely difficult to positively identify the contents of biological shipments, there are more rigorous controls and restrictions placed on biologic shipments than ever before. These new fears and stricter controls have had a critical impact on cold chain processes for pharmaceutical and biotechnology companies. Biopharmaceutical firms must thoroughly understand and follow all of the regulations associated with biological shipments — a single error or omission in documentation, packaging or labeling could delay delivery, potentially interrupting clinical trials and stalling the development process.

Pharmaceutical and biotechnology logistics personnel must factor new rules and regulations into their cold chain logistics process to ensure uninterrupted shipment:

International Shipping

For pharmaceutical and biotechnology firms that receive temperature-sensitive biological materials such as clinical trial samples from outside the U.S., cold chain logistics staff must be aware of regulations that, if not followed properly, can delay the delivery of time- and temperature-sensitive materials and result in costly fines. These regulations place the onus for compliance on the company that is receiving the biological materials. The U.S. Customs Service has dictated that it is the responsibility of the importing company to ensure that inbound materials meet admissibility requirements and that proper permits are obtained in advance of the goods’ arrival in the U.S.⁶

Regulations that must be followed to ensure that temperature-sensitive biological shipments are not delayed at customs, therefore risking product integrity and delaying development schedules, include:

Biomaterial Integrity Is In Your Hands

Global economics, heightened security threats and strict regulatory conditions have placed new burdens on the biopharma cold chain and the logistics personnel responsible for it. Add to these factors the perishable nature of temperature-sensitive biological shipments and the competitive market forces of the biotechnology and pharmaceutical industries, and it becomes apparent there is no room for error in the complex logistics cycle.

While logistics may have once been a back-office function, it has now come to the forefront of the life science sector. It requires deep understanding not only of shipping, handling and warehousing, but also demands extensive training in temperature-control, strict adherence to compliant processes and constant vigilance of changing regulatory mandates. Failure to reinforce all of the links in the cold chain can have serious ramifications for the biotech and pharma firms competing for market share—as well as the logistics professionals responsible for moving biomaterials from point A to point B.

The complexity and demands of today’s biological cold chain have produced a new culture of corporate and personal accountability. No longer is the integrity of biomaterials the only issue at stake; now it is also a matter of reputation, liability and safety.

Jeff Clark is the Executive Director of Operations for BioStorage Technologies, Inc., a dedicated biorepository service provider that stores, ships and manages temperature-sensitive biomaterials for pharmaceutical and biotechnology firms worldwide. He can be reached at jeff.clark@biostoragetech.com.

---

Footnotes

1    Department of Transportation, Research and Special Programs Administration, 49 CFR Chapter I. Hazardous Materials;  Advisory Guidance on Packaging and Shipper Responsibilities, May 6, 2002.

2      International Air Transport Association, Dangerous Goods Regulations, 47th Edition, 2006.

3      Office of Environmental Health & Safety, Shipping Dangerous Goods: University Guidelines, February 3, 2004.

4      “TSA Issues New Regulations to Substantially Strengthen Air Cargo Security,” U.S. Department of Homeland Security, Transportation Security Administration Press Office, May 17, 2006.

5      “Non-Compliance with TSA Regulations May Slow Air Freight,” Calderwood, James A., Logistics Today, August 2006.

6      U.S. Customs and Border Protection, U.S. Import Requirements, http://www.cbp.gov.

7  U.S. Customs and Border Protection, Duty Rates/HTS, http://www.cbp.gov.

8  Office of Regulatory Affairs, Product Code Builder, http://www.accessdata.fda.gov/scripts/ora/pcb/pcb.htm.

9  U.S. Customs and Border Protection, Customs-Trade Partnership Against Terrorism (C-TPAT): Partnership to Secure the Supply Chain, http://www.cbp.gov.