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European Biopharmaceutical Review

The Physics of Failure

A clinical trial of a cell-based therapy can fail for any number of reasons, including distribution and handling – although this issue should not have to be an investigator’s primary concern. There are numerous explanations as to why cold chain and other elements of handling can fail, but many of them can be easily avoided. The most preventable causes of such failure are governed by the basic principles of physics – thermodynamics, gravity and entropy – which are often either ignored or assumed to be of little consequence.

Thermodynamics

By definition, thermodynamics is “the measurable physical quantity of heat energy required to change the temperature of an object or body by a given amount”. Based on our familiarity with liquid nitrogen storage tanks and dry shippers, we tend to downplay the difficulty of maintaining massive differences in temperature on two sides of a container wall. But consider that it requires managing a temperature differential equivalent to cooling your summer home on the planet Mercury.

This may seem like an absurd analogy, but the average temperature on Mercury is 167°C. The average home is maintained at 22°C, a delta of 145°C, while the average cell therapy drug is stored at -130°C or colder. The average ambient temperature on earth is 15°C – also a delta of 145°C.

The thermodynamic challenge exists in both the storage and transport of material, but is most acute when material is in transit – in a dry shipper. If clearly understood and tested, dry shippers can do an excellent job of protecting cellular material while en route. However, there are two prevalent misconceptions that can lead to serious problems. The first is that they are all the same – a fact which could not be further from the truth. Each shipper is designed to handle a specific amount of material and to maintain the temperature of that material for a specific period of time; they are not interchangeable. The second misconception is that every new dry shipper meets the manufacturer's specifications. This is also not true.

However, in addition to deviations that occur outside of the box, every new variable adds to further departure from the original dry shipper specifications. For instance, adding a data logger introduces a heat wick via the probe, which reduces static hold to some degree – but this reduction is not uniform across shippers. Furthermore, the effect of adding the racking system and the payload can also have a dramatic effect, and the rack in particular can make a significant difference. This is magnified if you are using a custom rack that has not been tested for its thermodynamic properties, or if its heat transfer is not clearly understood.

Shipping and Storage Tests

The following are tips for minimising the effects of thermodynamics on dry shippers:
  • Carefully select a dry shipper that possesses the qualities needed to meet the requirements and specification of your study
  • Test each dry shipper to establish a baseline for each unit, and reject any unit that does not reasonably meet the manufacturer’s specification
  • Test each dry shipper with all components in place 
While shipping cellular material poses the greatest challenge to maintaining appropriate temperature, the effects of thermodynamics as they relate to the storage of the material cannot be ignored. Like dry shippers, each vapour phase storage tank needs to be individually tested to determine not only that it is capable of maintaining temperature, but mapped to determine the actual temperature gradient that exists between the bottom and the top of the tank.

This is because each vapour phase storage tank possesses a temperature gradient when holding material in a static state. The gradient varies from model to model and, to a lesser degree, among units of the same model. Therefore, it is necessary to temperature-map each unit when acquired, and again after every three to five years of use. This will establish the upper most usable area of the dewar, based on the upper temperature limit of the material to be stored.

Force of Gravity

The forces of nature that influence the proper functioning of a dry shipper are not limited to thermodynamics – gravity plays a major role as well. As Sir Isaac Newton instructed, gravity is “the force that attracts a body toward the centre of the Earth or any other physical body having mass”. It is also a force that has an effect on a dry shipper when the unit is not in an upright position; a dry shipper on its side can lose 40-70% of its hold time in only eight hours, while one that is completely inverted can lose as much as 90% in the same timeframe.

Therefore, the question is not whether orientation matters, but rather what can be done about it. In the short run, the best advice is to procure dry shippers with sufficient hold times to compensate as much as possible for gravitational effects. The next phase is monitoring the orientation during shipment to determine a reasonable assessment of the actual expected hold time. This technology exists and is being implemented in a number of applications.

However, although orientation can be monitored, there is presently no carrier capable (or willing) to intervene and correct a situation en route. Current carrier/courier systems have been designed for speed and volume, not for custom transit.

There are no real solutions to this problem, but there are some rules of thumb that can help:
  •  Use dry shippers with extended hold times
  • Use the smallest neck diameter possible (the larger the diameter, the bigger the problem)
  • Avoid times when shipping volumes are unusually high; about half of our orientation issues occur between Thanksgiving and Christmas
In the long run, the solution is reengineering and innovation. There are a number of manufacturers working on ways to improve hold times, manage size, reduce weight, and integrate telemetry into their designs. This will lead to improvements that will minimise the orientation challenge in the not too distant future.

Managing Entropy

Entropy is defined as “lack of order or predictability; gradual decline into disorder”. The gradual decline of dry shippers occurs in both the hydrophobic material which holds the liquid nitrogen, and the vacuum that exists between the inner and outer dewars. Both are critical components that directly affect the ability of the dry shipper to hold temperature for prolonged periods of time. They will deteriorate naturally, but the deterioration of both can be accelerated by mishandling.

Although entropy cannot be stopped, it can be managed in such a way that it does not jeopardise the material being shipped. This can be achieved by measuring the deterioration of the shipper over time, so that a company knows when to retire a unit and minimise risk. By starting with a new, qualified shipper, it can be charged according to protocol and weighed immediately before adding the payload – this becomes the baseline weight. The process can be repeated on a regular basis (each shipment, once a month or once a quarter). By tracking the weight data, the deterioration curve can be defined and the point of requalification of equipment can be established.

This process helps to track gradual deterioration. However, the equipment must be checked any time for damage to the dewar or to the interior components, including lids, data loggers, vacuum ports and connectors.

Tips on extending the life of the unit include:
  • Keeping the unit charged at all times, if possible. Allowing the dry shipper to warm to ambient conditions hastens the deterioration of the hydrophobic material
  • Not using any form of chemical decontamination on the inside of the shipper
  • Ensuring the outer container was manufactured specifically for the model you are using
  • Ensuring you check the outer container for damage before adding the shipper
  • Adding ties or tamperproof seals to the locking device on the dry shipper’s outer container
Precise Planning

Delivering cell-based drug products from manufacturer to patient involves overcoming some fundamental laws of physics. However, there are ways of managing them, which mainly call for precise planning, meticulous preparation and flawless execution. By paying appropriate attention to the physics of failure, the focus can stay on the patients and the clinical trial, and not on distribution and delivery.

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Dan O’Donnell is the Director of Cell Therapy Logistics at Fisher BioServices, where he has worked extensively in the development and deployment of logistical
strategies for both international and domestic Phase 2 and Phase 3 clinical trials. He is a specialist in cryogenic and ultra-low temperature product management
and distribution, with an emphasis on the creation of a project specific 21 CFR Part 11 compliant chain of custody. Previously, Dan served as a Vice President for Disease Management programmes with both Baxter Healthcare and United Healthcare.


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