Mark W. Sawicki

	To keep pace with developments in biology, logistics approaches require reliable and environmentally controlled solutions. This need is now more critical than ever with the advancements in regenerative medicine and advanced therapies.

	Many regenerative medicines in clinical development now are focused on oncology (40%) and cardiovascular disease (10%), followed by the central nervous system and musculoskeletal therapeutic categories. Given the addressable patient population for these therapies, it will take only a few of them to be approved and commercialized to drive an exponential increase in the demand for cryopreserved and other temperature managed cold chain solutions.

	According to a presentation given by Clive Glover, GE Healthcare (May 2015), CAR-T therapy demand is projected to ramp up significantly beginning in late 2017 through 2018. 

	Our clients are supporting these growth projections. Multiple clients are providing demand projections in excess of 100,000 units per year for a single therapy, the first of which is projected to launch in 2017. By 2019, we expect volumes in excess of 1 million units per year.

	Without question, advanced cellular and gene therapies require well-defined cold-chain management solutions that reduce risk and include all elements of packaging, data collection and logistics expertise to ensure high-quality, effective treatments reach the point of care, and ultimately, the patient.

	Cell and gene therapies and certain other biopharmaceuticals are inherently fragile and require exacting control of environmental conditions to maintain efficacy. A temperature excursion can affect the quality and efficacy of the product and/or the data generated for clinical trial evaluation.

	Recently published data is starting to put light onto the risks associated with how critical biologic materials are transported (Kofanova, 2014). The preservation media, shipping temperatures and freeze/thaw methodology can have a profound impact on biologic material viability and functionality potentially leading to data-based bias (Kofanova, 2014; Weinberg, 2010; Olson, 2011). Additionally, primary packaging considerations, if not well vetted, can impact the properties of the materials such as tissues, proteins and cells being stored or transported (Murphy, 2013). Despite this fact, biologic materials for clinical trial testing, as well as active drug substances, are regularly transported using packaging and temperature conditions that are suboptimal, lead to product degradation, or change the characteristics of the material in transit, which can impact the data gathered during a trial or, worse, the efficacy or safety of the drug candidate being administered.

	For many years, dry ice was the standard means to ship “cryogenically” frozen biologic materials. However, for biologic materials related to clinical programs this practice should be critically reviewed. Dry ice can present inherent product quality and logistical risks as well as safety issues compounded by regional restrictions on its use.

	Use of dry ice may negatively impact product quality. Dry ice is known to provide inconsistent temperature profiles and to have material failure rates that can result in cell degradation, shorten product shelf life and alter the pH of certain biologic materials, any of which can affect trials costs and timelines.

	Numerous studies have been done on the impact of temperature excursions on biologic materials. Higher temperatures (above -196â° C), lack of temperature control or temperature cycling have been known to diminish cell growth patterns, negatively impact cell viability, result in protein instability and aggregation, and does not stop the effect of degradative enzymes (Smith, 2007; Murphy, 2013; Hubel, 2011).

	Dry ice is also regulated by the U.S. Department of Transportation and the International Air Transport Association and is classified as a “Dangerous Good.” As a result, airline pilots have the right to restrict quantities and remove freight because of this classification, adding yet another risk to the timely delivery of materials.

	To maintain lower temperatures and longer hold times, many shippers turned to liquid nitrogen. Although it kept samples at -196Â° C, initial packaging was treated as dangerous goods and required specialized handling.

	Advanced phase change packaging technology has resolved the liquid nitrogen handling problem by sequestering the liquid nitrogen in a matrix that holds the liquid nitrogen in suspension. Now, regardless of how the package is situated, the dewars (glass or metal containers that store liquefied gasses) will not leak. Cooling occurs as the liquid nitrogen changes phase into a gas, maintaining a constant -196Â° C, and it also has longer hold times, maintaining temperature for 10 days or more.

	Temperature excursions affect the potency, efficacy and safety of many drugs and can negatively impact the data generated during testing regimens but clinical trial sponsors and investigators can eliminate these by using advanced cryoshipping technology. This technology also makes it easier for clinical trial facilities to organize, manage and gather biologics samples from around the globe for testing and evaluation at a fraction of the cost, time, hassle and risk of dry ice. The technology eliminates the need for HAZMAT documentation, labeling, training or facilities, and the shipments are not restricted by airlines or couriers.

	This technology also expands the potential pool of physicians and locations able to participate in clinical trials. Because dewars can be used as temporary freezers, physicians can collect patient samples throughout the week, store them in the dewar and ship them together in one or two weekly shipments. For patients, this enhances their ability to access cutting-edge therapies and provides the assurance that samples - sometimes taken painfully - arrive at the lab in viable condition. 

	The ability of cryogenic packaging to maintain -196Â° C temperatures for 10 or more days also enables clinical trials to occur throughout the world, expanding access to treatment naÃ¯ve populations and emerging markets. By applying advanced liquid nitrogen dry vapor technology, life science organizations can engage clinics and patients in clinical studies that were previously beyond their reach.

	Temperature data monitors are used to record temperatures of products in transit. However, temperature-based data loggers also alert shippers to potential tampering. Because the temperature probe is inside the specimen chamber, a temperature spike is recorded whenever that chamber is opened. Then, when that data is compared with carriers’ transportation records, shippers know when and where the breach occurred.

	Advanced software solutions should also enable shippers to track shipments and download temperature and condition information to their desktops, allowing condition confirmation before shipments are accepted and verification of multiple touchpoints during the shipment. Such chain of condition documentation is a valuable adjunct to chain of custody validation, supporting claims that a specimen, sample or therapeutic was maintained at cryogenic temperatures throughout shipment.  

	Increasing costs to develop advanced therapies are driving companies to look at logistics optimization as a means to manage costs. We have seen companies reduce their logistics expense by up to 50 percent using dry vapor shippers by saving on capital investments, dry ice purchases, labor, overnight shipping, hazardous goods shipping charges and, most importantly, product loss. This value doesn’t even contemplate the potential benefits to data integrity and clinical trial outcomes, which could be incalculable.

	Companies frequently ship materials overnight to avoid temperature excursions. Switching to an advanced cryoshipping solution that can maintain its temperature longer allows researchers to choose more cost-effective shipping options. Dry vapor shippers offer the possibility of shipping via ground transport, while still delivering materials in a deep frozen condition.   

	Clinical sites that use advanced cryoshippers also have a time and flexibility advantage by being able to prepare one or two shipments per week, rather than daily, and can schedule patients accordingly. Since a dry vapor shipper maintains a steady temperature for a longer period of time, companies can optimize shipping frequency and resources that ultimately yield cost savings.

	Governments throughout the world recognize the challenges of global clinical trials and are responding with new distribution guidelines that incorporate temperature monitoring and data logging, often along with track and trace or serialization guidelines. 

	Against that background, regulatory bodies and industry organizations are framing new guidelines governing the distribution of temperature-sensitive pharmaceuticals and clinical trial materials. Guidelines relating specifically to the cold chain are in place in Argentina, Australia, Bahrain, Brazil, Canada, China, Egypt, the European Union, India, Jordan, Mexico, Singapore, Saudi Arabia, South Africa, South Korea, the United Arab Emirates, the United States, Syria and Venezuela. The Food & Drug Administration, the Parental Drug Association, the U.S. Pharmacopeia, the International Air Transportation Association and other organizations also have established guidelines for the transportation of temperature-sensitive life sciences products. Despite slight differences in the guidelines, they all typically call for data logging, temperature monitoring and, sometimes, humidity monitoring.  

	As the industry expands into emerging markets, shipping infrastructure challenges become increasingly significant. Whether airports have cold storage facilities and personnel trained to actually transport temperature-sensitive shipments to the proper temperature-controlled holding areas can make the difference between success and failure for dry ice shipments.  

	Many developing markets generally have inadequate transportation infrastructures, security issues and bureaucracies with sometimes unique interpretations of regulations. Although the infrastructure in and around the major cities may be substantial, it generally does not extend throughout the country, logistics experts say. Shippers should select a partner with deep experience in global shipping and navigating local customs.

	As regenerative medicine research increases, so too will the need to safely transport these materials. Because logistics problems can compromise critical materials and data, it is essential to examine the entire cold chain. Companies that rely on dry ice, the standard for years, would do well to fully consider the risks this choice poses and explore the advantages offered by liquid nitrogen dry vapor shippers to ensure the integrity of their materials.  

	Mark W. Sawicki, PhD, is Chief Commercial Officer at Cryoport.

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Articles

Without question, advanced cellular and gene therapies require well-defined cold-chain management solutions that reduce risk and include all elements of packaging, data collection and logistics expertise to ensure high-quality, effective treatments reach the point of care, and ultimately, the patient.

Mark W. Sawicki

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How Cold Chain Logistics Work in Clinical Trials