The renewed focus, and breakneck development pace, on novel therapies such as regenerative therapies and other personalized medicines are creating new and constantly evolving challenges. Critical elements which are rapidly manifesting themselves as a significant stumbling block in the clinical trial execution and commercialization of regenerative therapies are the very complex packaging and associated logistics expertise needed to support such programs. This is too often considered late in trial or commercial launch planning with these new paradigm therapies. Movement of sensitive biomarkers, patient samples and the therapies themselves, all require exact, time-limited logistics support. Packaging and logistics need to be equally considered as they tend to be co-dependent. It is not atypical to see three to four different temperature requirements for a single supply chain for a regenerative therapy. This further complicates the logistics by creating the need for multiple packaging modalities within the same trial or treatment regimen. Coordinating these new and complex supply chain issues requires both forethought and dynamic flexibility.
Some regenerative therapy transportation requirements must be met within hours, not days or weeks. Additionally, the samples being transported are often patient-specific which require distinct, independent, ID codes specific to the patient, while also being in compliance with HIPAA and other global regulatory standards. The ability of logistics service providers to deliver integrated solutions with clinics, manufacturing sites and logistics carriers is key to a successful, well-coordinated trial and commercial distribution strategy. With many regenerative therapies currently being developed, aphaeresis, cell manufacturing, patient pretreatment protocols and logistics for each step must be timed and executed impeccably, or there is a risk not only of treatment failure, but the potential loss of the patient as well.
The success of these clinical trials and ultimately commercialization, critically depends on achieving and maintaining optimal performance conditions for these temperature-sensitive biomarkers, patient samples, and therapies throughout the trial. Careful planning of all packaging, transport, storage, and handling steps, as well as strict adherence to planned processes, is needed to ensure that delays and/or temperature excursions do not jeopardize the quality of any of the materials transported in support of the program and, thus, the results of the clinical trial. Manufacturers work very hard to produce high-quality products which meet exacting standards applied to every stage of the production process and these exacting standards should extend beyond the manufacturing site to the packaging, shipping logistics and even storage of these valuable lifesaving products.
Taking into consideration the aforementioned challenges, outlined here are the primary issues to consider when seeking a cold chain logistics partner. The primary points to review and evaluate, early in product development and in depth are the following:
- Initial validation process and the requalification process after every use of the shippers.
- The ability, via sophisticated data capture equipment and IT solutions, to monitor chain of custody and chain of condition of the shipper and product payload.
- Detailed and long term monitoring of integrator and specialty carrier performance to optimize product delivery and associated costs.
- Overall logistics expertise and ability to coordinate with multiple types of shipping partners.
- Coordination and IT integration ability from patient identification to manufacturing to delivery of the therapy to patients.
- The ability to bring “science to logistics.”
- Return logistics for high value of capital asset shippers and other key equipment to help contain costs and maintain efficient product delivery.
Initial Validation of Shippers and Requalification Every Use of the Shippers
Cryogenic shippers, commonly known as dewars, are themselves commodities. Anyone can purchase and use them. No special expertise or skills are required to handle them. However, transportation of high-value temperature-controlled products such as regenerative or other personalized therapies requires more than just purchasing the dewar and sending it with traditional carriers. While the dewar manufacturers do validate basic performance characteristic of their vessels, they do not perform full validation to IATA and other international shipping standards. This should be done by the service provider chosen for logistics support by the pharmaceutical client. This validation should be done to all applicable logistics quality standards as well as the new Good Distribution Practices (GDP).
Another consideration in choosing a partner for cryogenic shipments is to determine how they test and verify that the dewar will perform for each individual shipment. To ensure performance, a cryogenic shipper should be requalified after each use. Most users only re-test performance of dewars quarterly, semi-annually or only when originally put into service. In these cases, there is no ability to predict, let alone ensure, that the valuable payload is safe and maintained at the required -150⁰C or below temperatures. To ensure this level of performance, a dewar fleet should be serialized for individual use tracking. This allows each shipper to be tested and individual performance tracked over time. This serialization and subsequent performance tracking allows shippers with declining or failing hold times to be repaired or retired if needed to best protect those shipments where the payload can easily reach tens of thousands of dollars in catalog value. In the case of personalized regenerative cell based therapies, the cost is a patient’s life or chance at life. No price can be put on this and every possible care must be taken.
The Need for Sophisticated Data Capture Equipment and Associated IT Solutions, to Monitor Chain of Custody and Chain of Condition of the Shipper and Product Payload
Traditional integrators (FedEx, UPS, DHL, etc.) and specialty couriers offering “white glove” transport services generally provide web-based tracking of point to point shipments. This is certainly key in monitoring shipment location, but does not tell the much more critical story of the condition of the shipper and high value biological payload. Therapeutic developers would be wise to choose a logistics partner who has strong IT and data logging solutions. This includes an integration with courier software to pull all relevant data into one dashboard for the supplier to view and monitor the complete chain of condition and custody of the treatment. This requires a total IT and data logging solution that tracks position, internal and external temperature, dewar orientation (critical to maintaining hold times), shock events and one that does so in real-time with the ability to view all relevant data in real-time. This is critical as it allows for the software solution to not only track these parameters, but to send alarms and notifications to the logistics provider and others when any of these data points move beyond acceptable ranges. With this data, intervention can be attempted before the shipper warms and the product is lost. Without it, if an adverse shipping event occurs in regards to payload integrity, it will only be known after the fact and treatment is lost. As was discussed earlier, the real cost of a lost payload goes well beyond the sticker price of the product. Lifesaving and preserving therapies are being transported, upon which no price can be placed.
Detailed and Long Term Monitoring of Integrator and Specialty Carrier Performance to Optimize Product Delivery and Associated Costs
In choosing a logistics provider, an important factor is to find someone who is carrier agnostic. What does that mean? The solution provider is able to track, and use the performance of, each carrier to their client’s and ultimately the patient’s benefit. No one carrier performs at peak levels in all shipping lanes. An IT solution that tracks, by shipping lane, the cost, on-time performance and more should be made available. A therapeutic manufacturer needs to be able to pick the optimal carrier for each leg of shipment to ensure the best delivery performance to the treatment/clinical trial location. This carrier performance data collection is a key part of the IT solution the logistics solution provider offers to the supplier/manufacturer for consideration in carrier choice. The ability to make shipping decisions in this manner allows for best practices in delivery to patients and containing costs, not only in initial decision making, but on an ongoing basis. This constant ability to refine logistics lends the best value to all involved.
Coordination and IT Integration Ability from Patient Identification to Manufacturing to Delivery of the Therapy to Patients
A new added complexity for cold chain logistics with cell-based therapies is patient tracking from initial cell harvesting (aphaeresis) to the manufacturing site and back to the patient. This introduces not only patient identification challenges, but also may introduce other cold chain temperature band issues. In particular, many manufacturers transport the initial aphaeresis cell harvest at refrigerated (2-8⁰C) versus cryogenic temperatures (-150⁰C). This creates the need for additional transport packaging considerations that require the same ability to track chain of custody and condition as cryogenic transport. While this is a different temperature band, it remains just as critical to maintain that temperature throughout the transport cycle in order to ensure the cells can be manufactured to meet the patient’s treatment needs.
Another point to consider here is the ability to integrate IT solutions for initial patient cell harvest, logistics, manufacturing scheduling and return shipment. While not critical to patient treatment and packaging strictly, it would simplify an otherwise very complex chain of events (See Figure 1 below). There are strong patient treatment and clean room manufacturing scheduling programs such as TrackCell™ and iCAN™ which could be fully integrated into a strong logistics partner’s IT chain of condition and chain of custody solution. This would allow a full one stop view of primary patient aphaeresis, manufacturing clean room scheduling, ordering of appropriate shipper(s), scheduling of carriers for transport of all legs to and from manufacturer and back to the patient. In the past, this has all been done in silos. The opportunity is now available to combine all these processes by choosing the right logistics solution provider.
Figure 1.Combine Science and Logistics
Another challenge all too often not adequately considered in therapeutic cold chain logistics is the science behind the therapy. When choosing solution providers for cold chain management, most look only at the transportation logistics involved. Frequently the knowledge base of the provider in regards to the therapeutic area are not brought into question. In order for a cold chain logistics provider to provide a truly comprehensive, innovative and powerful solution, they must understand the therapy, the patient and how logistics and packaging choices intertwine. This means any solutions chosen should combine the best of all areas of expertise. Ultimately the melding of knowledge from computer science, medical science and drug development expertise with logistics is key to creating the best possible cold chain logistics solutions for the manufacturer and the patient both during clinical development and commercialization of the therapy.
Return Logistics for High Value of Capital Asset Shippers
Historically, manufacturers of cell based products have purchased and maintained their own fleet of cryogenic shippers. These fleets come with high capital costs as dewars can cost up to $5000 USD each. For large scale manufacturers, the needed fleet size to distribute their products worldwide can number in the thousands of units resulting in tens of millions of dollars in upfront capital expenditures. If the return logistics of these costly shippers is not managed well, larger fleets are needed due to low return rates; and without proper logistics management, the shippers may not be available for future shipments. Also, manufacturers typically have poor internal resources and IT systems to manage return logistics which generally results in higher lost dewar rates and the need for replacement of dewars on an ongoing basis which can easily add millions of additional dollars in capital expenditures every year. Even worse, without predictable return of shippers for re-use, there is no ability to reliably budget for this additional capital cost.
In partnering with an experienced cryogenic logistics solutions provider, with a robust IT tracking system, these costs can be managed efficiently and minimized. This also results in the need for smaller fleets and lower upfront capital expenditures. The improved return logistics solution will then result in lower annual capital fleet replacement costs as well. As mentioned earlier, a logistics provider with a strong ability to serialize, assess dewars and requalify after each use, repair or replace shippers as needed and be tracked via their IT platform, allows these capital costs to be constantly evaluated for opportunities for reduction and managed most effectively. An optimal logistics solution partner can also use their IT platform which tracks carrier performance and cost to choose the most efficient and cost effective carrier for the return shipping segments to aid in more effectively managing those variable expenses.
In summary, there are several key factors to consider when choosing a logistics provider of cryogenic shipping services for biological products. One should look for a partner with the strongest possible integrated solutions to accomplish and track the following:
- The most stringent shipper fleet validation and requalifying processes.
- Sophisticated data capture equipment and associated IT solutions, to monitor chain of custody and chain of condition of the shipper and product payload.
- The ability to precisely track the chain of condition and chain of custody of their valuable temperature controlled therapies.
- A carrier agnostic approach and the database to track individual carrier performance on any shipping lane globally.
- The expertise to combine science and logistics in providing solutions.
- Strong ability to manage return logistics of high cost capital dewar assets.
Cryogenic and other temperature critical distribution and shipping of cell based products comes with many challenges and issues not faced by traditional pharmaceutical products. The needed solutions regarding the associated logistics are somewhat rare skill sets, but they do exist. These priceless innovative treatments require innovative comprehensive cold chain solutions. Critical examination of potential partners will provide a vast improvement in capital cost management, care provider satisfaction and therapeutic adoption and patient treatment.
Kirk Randall, Sales Director, Cryoport, www.cryoport.com