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Longer packouts are becoming the rule, as logistics service providers and sponsors gain experience planning logistics for clinical trials involving novel therapies.
As manufacturers move into new markets and launch new clinical research programs, including work in the development of cell, gene, and tissue therapies, ensuring the integrity of the cold chain has become more important, and more challenging, than ever.
Success involves careful partner selection and logistics planning, as well as proactive communication with shippers, freight forwarders, and logistics specialists. It also depends on new temperature-control technologies, a number of which have recently been commercialized (see Sidebar).
In 2016, UPS bought Marken Technologies, which specializes in clinical trial shipments, to strengthen its capabilities in this area. In this article, Dan Bell, vice-president of quality, compliance and technical affairs at Marken, discusses overall trends, along with Ron Swistock, director of global healthcare strategy at UPS, as well as Mike Sweeney, senior director of global service development, and James Klingelhoefer, regional sales director, both with World Courier, who share insights into some of the challenges posed by cell and gene therapies.
PharmTech: What recent advances have been made in packaging equipment?
Bell (Marken): A few advances we are seeing in packaging equipment include more efficient insulation using nano-technology to improve the thermal resistance, or ‘R’ factors of vacuum-insulated panels, which allow for greater payloads and longer validation times without compromising weight.
Also, a greater focus is being placed on pallet sized and unit load device (ULD) solutions utilizing passive technology. We’re seeing a push toward lower temperatures as alternatives to dry ice, and competitively priced solutions for controlled room temperature (CRT) (15 °C to 25 °C). Another advancement is integration of technology, especially global positioning system (GPS) tracking and remote reporting from environmental sensors.
PharmTech: How are the industry’s packaging needs changing?
Swistock (UPS): Pharmaceutical companies are under increased pressure to understand carrier ambient environments in order to develop or justify their transportation methods and risk mitigation plans.
You’ll see more efforts placed on sustainable materials, and demand will grow for carriers to offer more temperature controls within their networks to minimize packout complexities, costs, and requirements. An increased number of pharmaceutical companies are also innovating and collaborating with reputable third-party logistics companies to create better efficiencies for shipping biopharmaceuticals and clinical trial specimens.
PharmTech: What specific changes are you seeing?
Swistock (UPS): Reuseable shippers are getting more interest. These may be more expensive up front but they enable a ‘just-in-time’ business model. For the receiving lab, this approach not only offers environmental disposal advantages, but saves floor space because they no longer have to store used shippers.
PharmTech: What improvements are you seeing in pack-outs?
Bell (Marken): We are seeing a shift to universal packout configurations that remove the need for phase change materials at different temperatures and reduce the risk of user error during conditioning and assembly. Another example of packout improvements is the addition of chemical indicators to phase change plates to ensure correct conditioning prior to assembly and deployment.
Swistock (UPS): Temperature-control technology is improving, and packouts can be much longer than they were in the past. Traditionally, the packout standard has been 24 hours up to 48 hours, but now we are working to bring that up to 96 hours. If shippers can provide this level of protection for a two-day trip, it will ensure safety in case of transportation and weather delays.
Important capabilities include replenishment of dry ice and ensuring the integrity of shipment. UPS works closely with its business partner, Cryoport, and uses Cryoport’s dewars, and shipments can be initiated from either Cryoport’s or UPS’ websites.
PharmTech: How is serialization affecting packaging equipment design and features?
Bell (Marken): In packaging, we are seeing a greater focus on security around seals and tamper-evident closures along with greater use of GPS tracking and geo-fencing to address Drug Supply Chain Security Act (DSCSA) concerns for drugs in transit. From a technology standpoint, chain of identity solutions--based on the integration of GPS, radiofrequency identification (RFID), and Bluetooth technologies--are being built into packaging and linked to cloud-based tracking software. This becomes especially critical for cell, gene, and immunotherapy products that are patient-specific or derived from patient initially.
PharmTech: What role are new biological treatments (e.g., cell and gene therapies) playing in the clinical trial logistics business today, and how does planning for trials with these products differ from planning for traditional clinical trial logistics?
Swistock (UPS): These treatments are still a small part of the clinical trials business, but they require a disproportionate amount of front-end planning. Over the past few years, we’ve seen that sponsors really want to know how integration can play a greater role. These studies require cryogenic shipping, so the question is how many more dewars can be accommodated in our network. This work is also highly specialized. For example, we need to perform special studies for autologous compounds, which require cryogenic shipment on two legs of the journey. In general, these projects require a very complex and integrated network.
Sweeney (World Courier): Cell and gene-therapy products require extensive logistical planning. In the case of autologous cell therapies, the patient’s cells are the active pharmaceutical ingredient used in the manufacturing of the end therapy. Therefore, the patient becomes a part of the supply chain, and he or she can be directly impacted by delays or problems during the logistics process. Additionally, particularly with consideration to the severity of the patient’s illness, the logistics timelines are always extremely tight and any deviation can have a far reaching impact on the clinical team, end-therapy manufacturer, and patient.
When contrasted with small-molecule or biologics products, we find that there is much less margin for error with the logistics of cell and gene-therapy products. Scoping suitable time, critical routings, and educating airlines on the special nature of these products are all parts of the process.
PharmTech: How should sponsors and contract partners approach collaboration for these projects? What questions are critical to ask logistics and shipping specialists, and what specific functions should each partner assume?
Swistock (UPS): Important questions should revolve around service partners’ experience and safety record with dewars, as well as packouts and how long the shipments will remain viable without taking additional steps.
Klingelhoefer (World Courier): Sponsors and contract partners should collaborate in early planning stages for both early clinical and commercial development. Although early clinical-stage development requires careful planning, when the scale is increased to commercial application, it is absolutely imperative that sophisticated scheduling and tracking is put into place.
It is extremely beneficial for logistical plans for both early clinical-stage development and commercial development to be discussed during the planning phases. Questions can range widely and should include the following, all of which must be addressed at the onset of planning:
PharmTech: What issues must be taken into account, and how do they affect the choice of temperature-control and other technology, and overall planning?
Klingelhoefer (World Courier): Generally, it will help sponsors to have a basic understanding of the shipping lanes, transit time requirements, and temperature-control parameters to be able to anticipate potential issues and allow solutions to be pre-emptively created. For example, if the end therapy is going to be transported in a liquid nitrogen dry shipper, then who is going to provide the liquid nitrogen shipper? And, who is going to ensure that the dry shipper unit is properly charged with liquid nitrogen? The answers to these questions will help determine responsibilities, a plan of action, and timeframes.
PharmTech: What are the unique challenges of moving autologous, as compared with non-autologous cell and gene therapies, and other personalized medicines?
Swistock (UPS): With autologous therapies, the biggest complexity is that, not one, but two really high-performance shipments are involved. There can be challenges, for instance, when the patient visits a facility where blood is collected. Often these trials are run in dispersed locations. In some cases, there will be fewer labs available to send the blood. In general, with autologous treatments, special planning is particularly important for the journey’s second leg.
Sweeney (World Courier): The obvious main difference is that an autologous cell-therapy scenario involves a circular supply chain, where the allogeneic model is more of a straight line between two points. With the circular supply chain, there is generally more of a need for careful coordination between apheresis and manufacturing slots. With allogeneic, there is likely more room for maneuvering because it relates to the time between when the therapy is manufactured and the time it is needed for infusion into a patient. The more complex circular supply chain for autologous requires precision planning with no room for error or delays. The straight line supply chain for allogeneic relies on experienced specialists.
PharmTech: What special temperature-control technologies, storage, and transportation options are required for these advanced therapies?
Klingelhoefer (World Courier): This will vary on the product and pharmaceutical sponsor requirements. Sponsors often require temperature-controlled packaging for apheresis samples (typically 2 °C-8 C packaging) and packaging for end-therapy product (typically liquid nitrogen dry shippers). In some cases, customers will ask for GPS tracking devices to help enhance visibility of their shipments.
PharmTech: Some clinical-trial materials are now delivered direct to patients’ (DTP) homes. Do you see that approach being used in the future for these types of materials, and how would that complicate the overall process?
Bell (Marken): Absolutely. The key with DTP in clinical trials is maintaining thermal integrity over the last mile. This is a critical link in the clinical supply chain and essential to the success of a clinical trial. Regulators are looking now at how to include and enforce standards around the last mile through good distribution practices (GDPs).
Further, with more pharma companies including both direct-to and direct-from patient homes as options in more of their protocols, we expect to continue to see increased demand. Finding packaging solutions that work well for delivery or collection from a patient at home, along with coordinating this service with in-home nursing care can be very challenging.
Swistock (UPS): We are seeing a relatively small amount of activity in DTP, but great interest. DTP exists for rare diseases, but the logistics for clinical trials, involving ambient temperatures, are easier. We’ve had success with these studies. Investigational medicinal products must be delivered on a regular basis, typically in one or two doses. In a clinical setting, they may be delivered less frequently. But if people have mobility problems, DTP studies open up potential business.
So far, there have only been a few DTP studies involving cell and gene therapies, and they have required a lot of upfront work. In one case, the client had little compound available before each shipment, but doses had to be shipped 365 days a year. This required working with special operating places for Sundays and holidays, or when the patient was not home.Not every tudy is a good candidate for this type of approach, but we do expect DTP to become more important in the future.
Sweeney (World Courier): At the moment, the majority of shipments would be beyond the scope of home coordination. For many situations, the end-therapy product must be sent at frozen temperatures, including some cryogenically frozen material, which then requires a sophisticated thawing process before infusion. Currently, it is unrealistic to expect a DTP scenario for most cell and gene-therapy products.
Vol. 41, No. 2
When referring to this article, please cite it as A. Shanley, "Cold Chain: Zeroing In on the Last Mile," Pharmaceutical Technology 41 (2) 2017.