Regenerative Medicine Advanced Therapy (RMAT) is a major opportunity, and one that promises to revolutionize treatment for diseases from hemophilia to cancer. The regenerative medicines market generated $17.03 billion in revenue in 2016 and is expected to reach $50.55 billion by 2025.¹

There is a great deal at stake for the companies that are racing to develop these revolutionary therapies. Challenges range from integrating new manufacturing techniques, answering bioethics questions, to ensuring product safety, product efficacy, and more. Every stakeholder in the evolving regenerative therapy ecosystem—biopharmaceutical companies, healthcare providers and payers, patients, and government—is discovering that new possibilities require a new approach.

However, as you’d expect from a new and evolving class of pharmaceuticals, there are a multitude of new approaches but comparatively limited standardization. With so many companies doing so much pioneering work in a fast-paced market, there is significant work ahead to establish uniform standards for collection, manufacturing, and distribution.
Precision medicine requires end-to-end precision traceability: everything from Chain of Custody, to Chain of Condition, to Chain of Identity. But the fragility of RMAT products—and the urgent need for standardization—means that a fourth chain is now required: the Chain of Compliance.

This can be defined as the complete traceability of the equipment, processes, and logistics handling used in managing the environmental control of the therapy while it is in transit. Today this is a smart practice and not yet the law. But make no mistake: regulations are catching up.

The 21st Century Cures Act accelerates the pace of change
In December 2016, Congress passed The 21st Century Cures Act to speed approval of important new treatments. Now that new therapies have been approved, the supply chain of patient- and donor-derived regenerative medicine products will fall under increasing pressure for standardization and increased regulatory requirements. So far, the regulatory framework established by the FDA on November 16, 2017 has focused on recovery, isolation and delivery.

However, it’s not hard to predict that regulatory focus will soon expand to include the supply chain. Today’s supply chain was not built for tomorrow’s treatments, and there are new risks that even experienced logistics executives may not be fully aware of.

The new drug products are significantly more fragile and valuable than tablets or pills, and if they are damaged in shipment, it’s not obvious. They don’t change in smell, or color. The only way to be certain if the therapy is viable is through a constant flow of data. Even a slight temperature deviation will render the product unusable. Data can be seriously compromised. Clinical trial outcomes become uncertain or compromised. A single treatment worth $475,000 could be destroyed.

Yet even those outcomes are not the worst imaginable. The products involved are often patient-specific and entirely irreplaceable, and the patient needs are critical. Small mistakes can literally become a matter of life or death.

This means that to succeed in the RMAT market, companies will need to strike the right balance. Race to market too cautiously, and you risk missing first-mover advantage; race too quickly, and problems in the supply chain can ramp up your costs, shrink your odds of success, and threaten patient safety.

For biopharmaceutical companies, a great deal of investment rides on their ability to deliver sensitive biologic materials, such as regenerative medicine, including immunotherapies, stem cells and CAR-T cells—which require far more careful handling than vials or pills—to market intact.

What types of risks must be considered?
There are many factors, which vary by packaging type and handling realities. As just one example, when evaluating logistics for CAR-T therapies, there are four key factors to consider.

1. Packaging. What is the LN2 charging/conditioning process? Can your packaging stay within the required 2-8°C temperature range in a truck trapped in bumper-to-bumper traffic on a blazing hot 107° F Texas summer day? What is the capacity, the nitrogen evaporation rate (NER), and how long may the package be held? Can you be certain of package integrity, and that the temperature remained stable throughout? Remember that elements such as the liquid nitrogen (LN2) capacity, nitrogen evaporation rate and orientation of the dewar being shipped vary with each shipment, and can change materially from one use to the next.

2. Logistics. How certain are you of your carrier’s handling and performance? Weather, customs and security will impact the time in transit. How much visibility will you have into that, and how well will you be able to mitigate against failure? Remember that if equipment performance is “inspected in” at the end of the transit cycle, it will be too late to take corrective action.

3. Informatics. How accurate is your data, and how has its integrity been ensured? How is that data transmitted? Remember that your informatics must have the ability to correlate third party effects including shock, temperature excursion, dewar orientation, and more. An improperly stacked or tipped dewar can impact its hold time by as much as 50%.

Package handlers are only human: not a day goes by where some package isn’t dropped and compromised. A small drop can adversely impact the integrity and temperature holding time of any package, whether it’s 2-8°C package or a cryogenic shipper. A bigger drop, for example one in which the cryogenic shipper’s neck cracks will unseal the vacuum, gives the transportation provider just hours to secure the commodity before it is rendered useless.

But if there is no notification that any of these problems have occurred, there’s nothing you can do to intervene. Trusting third party bolt on systems with non-indexed data streams to packaging and logistics can be a costly mistake.

4. Return logistics. It’s also important to consider time in transit on the return, as well as how all items will be cleaned and requalified.

The rising importance of the Chain of Compliance
The Chain of Compliance is the complete traceability of the equipment, processes, and logistics handling used in managing the environmental control of the therapy while it is in transit. This requires a robust informatics platform in place to scientifically monitor and evaluate the individual impacts of packaging, temperature, and time. Without constant monitoring, there will always be uncertainty of the efficacy or activity of the therapy upon delivery.

The Chain of Compliance requires a complete historical archive of the use of the equipment at the unit level, inclusive of the following elements:

• Serialization of the shipper and any components or accessories;
• (Re)Qualification data for the shipper after every transportation cycle of the equipment;
• Performance history of the shipper/courier including any handling issues, etc.;
• Commodity history of the shipper contents;
• Deviation history of the shipper/courier;
• Transportation history of the shipper/courier, routes, sites, etc.;
• Maintenance/refurbishment history of the shipper; and
• Calibration data and history of the data logger.

The ability to collect, interpret, and leverage all of this data enables a significantly more intelligent supply chain. Rather than reactively trying to determine what has gone wrong after multiple failures, it becomes possible to take a proactive approach.

With a complete picture of every element and a data-rich understanding of how those work in the real world, you can apply Quality by Design (QbD) risk management processes to your supply chain strategy. QbD is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound sciences and quality risk management. Put simply, Quality by Design yields better results than “Quality by Hindsight”.

What’s more, having complete data gives you the ability to learn and improve over time to significantly reduce the risk of product failure. Robust data reveals patterns that you can leverage to shrink risk, year after year.

Perhaps most important, robust real-time data can alert you to problems before they become costly failures. Having the ability to assess risk and intervene when unexpected problems arise in transit has the power to save time, money, and even lives.

The work of RMAT logistics must include the work to shrink risk and improve results as an integral part of the process.

As the great management thinker Peter Drucker memorably put it, “Work implies not only that somebody is supposed to do the job, but also accountability, a deadline and, finally, the measurement of results—that is, feedback from results on the work and on the planning process itself.”

Five imperatives for everyone involved in RMAT supply chain logistics

1. If you haven’t already done so, consider conducting a comprehensive scientific study to determine the individual impacts of packaging, transportation and temperature ranges on the viability of the products you must deliver. Or, research vendors who have already done this work and have a significant track record in RMAT.
2. Plan quality into the process. A Quality by Design (QbD) end-to-end approach will help you define the right Critical Quality Attributes (CQA) and the right Critical Process Parameters (CPP) to avoid problems you might otherwise encounter. For example, in RMAT your CQA might be temperature, pH, and viability and your CPP might be hold time, time in transit, orientation, handling, and shock.
3. Add a robust Chain of Compliance to your standard cold chain logistics practice. This should include tracking and understanding courier performance, equipment validation, requalification, performance, sterility controls and cleaning processes. It should also include the ability to manage the packaging being shipped as carefully as the equipment used to create the therapy in manufacturing. Ensure you have real-time integrity measures, and a way to manage problems that will inevitably arise.
4. Integrate all four chains—Chain of Custody, Chain of Condition, Chain of Identity, and Chain of Compliance—into a single data stream for cross-referencing and accountability. When evaluating potential partners, look carefully at their fleet performance, and track record in RMAT.
5. Insist on world-class Informatics, and real-time integrity measurements. Without the right data, you’re blind. With the right data, you can fix issues before things go irretrievably wrong.

Regenerative Medicine Advanced Therapy (RMAT) promises to revolutionize the treatment of diseases. Reconsidering or completely re-engineering your cold supply chain is entirely necessary—and entirely worth the effort. 

References

1. https://www.businesswire.com/news/home/20180125005536/en/Global-Regenerative-Medicines-Market-2017-2025—Focus

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Mark W. Sawicki, PhD, is chief commercial officer at Cryoport. With more than 15 years of business development and sales management experience in senior leadership roles, he has a proven record of consistently delivering on corporate revenue and market share goals in the pharmaceutical and biotechnology industries. msawicki@cryoport.com