In biopharmaceutical development, ancillary business operations such as logistics and supply chain management are frequently perceived as secondary objectives to the ultimate goal of discovering treatments and cures for devastating diseases. However, in the hypercompetitive world of drug development, forward-thinking companies have found that optimizing their clinical-trial supply chain can provide a strategic advantage to accelerating drug development.

The globalization of clinical research has made the safe, punctual, and compliant transport of study drugs and other temperature-sensitive materials increasingly complex. Two other trends are also increasing the demand for transporting sensitive materials: Biotech companies are creating more large-molecule drugs, which are much less stable than most small-molecule drugs. Furthermore, although blood, urine, and microbiological and viral sampling has always been common, increasing numbers of tissue samples are being collected to support biomarker research.

Cold-chain management defines how temperature-sensitive materials are packaged, transported, and stored throughout a clinical research process. Any weak link in the chain can compromise drug or sample integrity, breach security, delay shipments, and ultimately lead to financial loss or liability. Moreover, consider the repercussions of a clinical-trial sample being lost in transit or rendered useless because of temperature excursion during transport. That could have a trickle down effect that may delay studies, thereby increasing the time to drug approval and reducing the potential time a drug is on the market. A delay to market could cost a sponsor millions of dollars in potential sales. So it is vital for clinical-trial materials to be packaged and shipped in compliance with industry and government standards and to be closely monitored by properly trained individuals.

To ensure compliance and diminish both financial and legal risk, study sponsors should take a holistic approach to cold-chain management.

Factors to consider include:

• regulations and customs agencies

• training and compliance

• packaging and shipping controlled-temperature materials

• labels and documentation

• temperature monitoring

• international transportation.

Regulations

Global agencies have been steadily developing regulations regarding temperature-controlled transportation; however, those rules vary significantly from county to country and region to region. In addition to the regulatory bodies — e.g., the World Health Organization (WHO) and International Air Transport Association (IATA) — independent organizations such as the Parenteral infectious substances must include an itemized list of contents enclosed between the secondary and outer packaging. A completed Dangerous Goods Declaration form must also be attached to Category A infectious substance (e.g., Bacillus anthracis and Hepatitis B cultures) shipments to prevent shipping delays and corresponding risks to product integrity. Dry ice, for example, is classified by DOT and IATA as a miscellaneous hazard, class 9 material. So specific procedures must be followed when packaging and shipping materials with dry ice.

The DOT’s HMR specify requirements for the safe transportation of hazardous materials by rail car, aircraft, shipping vessel, and motor vehicle. 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 noncompliance and lack of awareness of HMR requirements.

Temperature Monitoring

Some materials may require temperature monitoring during shipment. Temperature indicators typically consist of chemically treated pieces of paper that indicate the minimum and maximum temperature experienced by a payload. When stringent and detailed tracking is required, reusable data loggers can be placed inside the packaging to monitor temperature and time continuously. Those data can be downloaded for graphing, reporting, and inclusion in audit trails.

If a temperature excursion outside a required range occurs, it must be evaluated and documented. All corrective actions should be promptly implemented and documented. Clear directions should be provided to the recipient for evaluation or disposition of indicators and package contents, depending on material sensitivity or requirements to prove material stability during transport. In some cases, a material may still be viable. And in others, it must be destroyed. In others, laboratory analysis is required to determine disposition.

International Transportation

Shipping across international borders presents more complexities than those related to domestic transport. Each country has its own regulations, codes, policies, procedures, and customs that affect international shipments.

Customs personnel and other agencies protect their countries’ population from hazards such as infectious materials. They also enforce laws that govern import and export tariffs, quotas, and other economic policies to generate revenue and protect local industry.

To protect sample integrity, regardless of temperature requirements, study sponsors must ensure that transportation companies can maintain required temperatures while shipments pass through customs and other government formalities.

Such requirements change from country to country and can be quite intricate. China, for example, requires companies to make entry arrangements with a Chinese corporation that has a relationship with the Chinese government. Otherwise, the supply may be delayed or the company may need to use a freight forwarder with a Class A license. In India, commercial invoices are stamped and become import permits. In Europe, shipments can be made to one EU country and can then be freely circulated within the European Union, subject to some minor exceptions (1).

To help ensure that customs and government formalities are expedited, it is advisable to send copies of all required documentation to the consignee (recipient) before shipment for verification and approval. Prior approval of required documentation can help prevent long delays and even possible confiscation.

Shipping within the United States has its own complications. In 2007, Congress mandated that all cargo transported on passenger aircraft be 100% screened for explosives (2). That does not apply to shipments on cargo aircraft, but it could in the future. However, organizations that have a designated Certified Cargo Screening Facility as approved by the US Transportation Security Administration (TSA) have the ability to prescreen shipments — onsite at their location — before shipping to an airport. This can significantly reduce delays at airport inspection terminals and diminish the risk of damage to shipped materials, because it requires less handling.

Some regulations must be followed to ensure that temperature-sensitive biological shipments are not delayed at customs (therefore risking product integrity and de
laying development schedules). Below are examples of such regulations.

Harmonized Tariff Schedule: All goods that enter the United States are categorized according to the Harmonized Tariff Schedule (HTS) issued by the US International Trade Commission, which prescribes the classification of merchandise by product type and determines how much duty will be collected. Importers are responsible for properly classifying merchandise before it enters the United States and ensuring that the HTS number is accurately noted on import documents.

FDA Product Code: Certain shipments also require an FDA product code on import documents. This represents industry, class, subclass, product, and other important details. The Office of Regulatory Affairs offers an online tool for building valid FDA product codes (www.accessdata.fda.gov/scripts/ora/pcb/pcb.htm).

Participation in the Customs-Trade Partnership Against Terrorism (C-TPAT) offers an additional means to expedite imported cargo shipments. Participating businesses ensure the integrity of their security practices and verify the security guidelines of their supply chain partners. In exchange, they receive reduced inspections and priority processing for CBP inspections and are assigned a specialist who will validate and enhance security throughout the company’s international supply chain.

Drug Association (PDA) and the United States Pharmacopeia (USP) are developing standards (e.g., PDA Technical Report 39 and USP <1079>). Canada’s regulatory agencies also released guidelines for shipping cold-chain products, GUI-0069. Other regulations are evolving, and new guidelines are being released.

The US Department of Transportation’s (DOT) Hazardous Materials Regulations (HMR) and IATA’s Dangerous Goods Regulations (DGR) specify requirements for the safe transportation of hazardous materials by rail car, aircraft, shipping vessel, and motor vehicles. Those 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 lack of compliance with transportation regulations (see box).

Personnel should know about import/export regulations that may impede the transportation of biological materials. To prepare for possible delays in completing import/export requirements, temperature-sensitive material may be consigned with a courier capable of replenishing refrigerant in the event of a delay. As much as three additional days’ worth of refrigerant may be recommended with shipments for cases in which customs clearance may be difficult.

Training and Compliance

IATA and the DOT require organizations and individuals that ship or receive biological materials to be trained properly in handling procedures. 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 a company’s mode of shipping transportation. Training typically includes education on

• assessment of temperature ranges for biological materials

• validated packaging options for temperature-sensitive biological materials

• methodologies for preconditioning packaging (for 2–8 °C shipments)

• documentation and audit trails

• supplier qualification for in-bound shipments

• regulations and industry guidelines.

Improper packaging and handling are common causes of temperature deviations in clinical-trial shipments. Proper training and qualification of all cold-chain partners minimizes such problems.

US Hazardous Materials Violation Penalties

Civil penalty for a knowing violation: $250–50,000

Criminal penalty for a knowing violation: five years of imprisonment and $250,000 fine for individuals, $500,000 for corporations (maximum)

Civil penalty for training-related violation: $450 (minimum)

Failure to provide initial/recurrent hazmat training: $450 (minimum)

Failure to create/maintain training records: $500 (minimum)

Failure to provide security training (security plan in place): $2,500

Failure to develop a security plan: $3,000 (minimum)

Civil penalty for violation resulting in death, serious illness, or injury or substantial property destruction: $100,000 (maximum)

Criminal penalty for hazardous material release resulting in death/bodily injury: 10 years of imprisonment (maximum)

References

1 Hazardous Materials Program Procedures. US Code of Federal Regulations, Title 49 Part 107.

2 General Information, Regulations, and Definitions. US Code of Federal Regulations, Title 49 Part 171.

Packaging, Shipping Controlled-Temperature Materials

Sensitive materials are transported in one of three states — frozen, refrigerated, or controlled-ambient — through an unpredictable environment of hot and cold temperatures and shipping delays. Structural integrity, insulation, and refrigerant (typically dry ice) are obvious elements of suitable packaging, but even the package itself and placement of contents are important. If a package is too large, excess air will enter and cause dry ice to dissipate too quickly. Validated packaging solutions, along with IATA- and DOT-approved packing techniques, exist to help safeguard materials in transit.

For dry-ice shipments, use a qualified shipping carton that meets your requirements of duration and temperature and follow the manufacturer’s directions for packing. For liquid-nitrogen shipments, a shipper must use properly validated dry canisters. Before samples are packaged into dry shippers, the containers must first be properly charged in accordance with manufacturer instructions.

To prevent compromising the sample integrity of refrigerated biological materials that must be maintained at 2–8 °C, packaging must be properly preconditioned before shipping. The temperature-control refrigerants inside a shipping carton need to be brought to the specified temperature ~24–48 hours before packing, depending strictly on manufacturer guidelines. Once refrigerants are preconditioned and placed inside a shipping carton, the carton should rest for one to two hours to ensure that the payload compartment reaches the desired shipping temperature. The payload compartment can then be filled.

Labels and Documentation

Pharmaceutical and biotechnology companies that ship biological or hazardous materials must follow strict standards for labeling and documentation.

DOT and IATA standards for labels and documentation vary by hazard class. Shipments classified as

Meeting Cold-Chain Challenges

Maintaining the cold chain from clinical site to final destination is vital, and often extremely complex. A global clinical trial in 10 countries needs to manage at least 10 cold chains and probably many more if there are outbound and inbound shipments through multiple border crossings and transshipment points. Packaging, labels, documentation, and temperature monitoring vary for different materials, destinations, and routes.

Fortunately, developing countries are improving their infrastructures and becoming more familiar with the needs of temperature-sensitive materials. For instance, companies across the globe are finding that the ability to re-ice and/or maintain refrigerated temperatures is becoming easier
. By partnering with the logistics industry, life sciences companies today are more knowledgeable about transportation regulations and cold-chain best practices.

Once an afterthought, logistics now plays a critical role in the clinical research process. It requires not only a profound understanding of shipping and warehousing, but demands adherence to compliant processes and constant awareness of changing regulatory guidelines.

Author Details
Russ Hager is senior director of global biorepository operations at BioStorage Technologies; Russ.Hager@biostorage.com.

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