Lean, mean cold-chain machine

The challenges associated with cold chain are well established. If a company is looking to transport temperature-sensitive products, then it’s going to have to ensure they stay in perfect condition throughout. This means controlling the temperature within a narrow range and ensuring the products are not damaged or spoiled at its changeover points.

A less discussed, but fast emerging, topic is cryogenic distribution networks – for example, what happens when a regular cold chain isn’t cold enough. For certain advanced therapy medical products (ATMPs), including cell therapies, it’s important to maintain shipping temperatures well below the 2–8°C that is typical for cold chains.

This comes about because living cells will rapidly lose their viability when stored in ambient conditions. Generally speaking, the lower the temperature the longer the shelf life.

Sometimes, dry ice shippers will suffice. Dry ice is the solid form of carbon dioxide, which sublimates (becomes gas) at -78.5°C. In other cases, the product needs to be stored in deep-freeze conditions, -150°C or lower. Through using liquid nitrogen-based shippers or other deep-freeze technologies, logistic providers need to maintain this temperature all the way from manufacturer to patient.

Pluristem Therapeutics, the Israeli biotherapy company, is well versed in these issues. The company currently has two products in phase-III clinical studies, for indications with unmet medical needs.

New developments

“Pluristem is developing novel biological products from the human placenta,” says Omri Machnay, the company’s supply chain director. “PLacenta eXtracted cell therapy products are off-the-shelf, requiring no tissue matching prior to administration. The cells are grown using the company’s proprietary 3D expansion technology. After a simple administration, the cells release a range of therapeutic proteins in response to signals from the patient’s body, in cases such as inflammation, ischemia, muscle trauma, haematological disorders and radiation damages.”

Its’ two late-stage clinical programmes, for critical limb ischemia and muscle regeneration following hip surgery, are ongoing at the time of writing. In both cases, the studies have received funding from the EU’s Horizon 2020 programme and involve well over 200 patients. Because of the global nature of these trials – they are taking place across the US, Europe and Israel – transport and distribution are critical topics.

One of the most challenging considerations here is the fact that the products need to be delivered quickly – often within a matter of hours. In the muscle regeneration study, for instance, patients receive the cell product during the surgery itself, via injections in the operated leg.

“The products’ shelf life is long and under CryoStorage temperature, they are very stable,” says Machnay. “The limited time aspect is only relevant due to the immediate need for the products, such as in one of our ongoing clinical studies, which requires emergency operations and therefore availability of our cell therapy at the hospital.” At a recent conference, Machnay discussed how Pluristem had dramatically cut down its delivery times. As he explains, this is something the company is very proud of. “Pluristem’s ability to deliver products globally within only a few hours is one of our biggest achievements,” he says. “We had to go to the bottom of our supply chain steps, dive into the basic elements of our processes and actually reinvent our supply chain from zero.”

The secret lies with understanding the biggest gaps in the supply chain, innovating with equipment, involving the company’s engineering teams and expanding its logistics footprint in different territories.

“A tailor-made solution was the key. However, the principles and the concepts had to stay as clear and simple as possible, with full control over every step of the supply chain,” says Machnay.

Keep it cold

The main requirement, when dealing with Pluristem’s placenta-based cell therapies, is to keep the temperature extremely low. During transportation, the temperature is controlled and measured via a data logger specifically tailored to measure -196°C. (At this temperature, all cellular activity essentially ceases.)

The company also monitors the products via GPS tracking. This enables them to track the location remotely and proactively interfere when needed, reducing the risk of temperature excursions.

“The products need to be stored with liquid nitrogen temperature on a vapour phase from the moment they have been produced until the moment they will be thawed for treatment at the hospital or the clinical site,” says Machnay. “Dealing with liquid nitrogen (LN2) and cryogenic temperature through all the supply chain carries a few elements that are not common with conventional medicines, and must be well understood and addressed.”

Part of the problem is that, since this is a relatively new therapeutic field, logistics expertise isn’t all that common. Liquid nitrogen can also be hard to source in certain places.

“The supply chain networks are limited – equipment, suppliers, employees, third-party logistics, hospitals, couriers,” says Machnay. “When looking at the supply chain from A to Z as I see it today, a few challenges and bottlenecks in some places still need to be resolved and developed to support more flexibility and more volumes, which we will see in the near future.”

Beyond that, any company dealing with these products will need to familiarise themselves with a lot of complex regulation. Since these are novel therapies, there can be issues surrounding their classification – what is the product defined as and what regulatory requirements apply? The regulations around liquid nitrogen will also need to be checked, which can vary from location to location.

“Storage of our product under LN2 in different locations involves quality, regulatory and safety aspects, which requires preparation and approval by several entities,” says Machnay. “We must assure the use of facilities that are capable to handle cryopreserved material, which are not yet common in many places.”

More broadly, if ATMP therapy is going to be rolled out globally, it’s important to consider local laws and import requirements at the earliest stages of development. As Machnay explains, this could become even more complicated as it is moved out of the clinical development phase and towards market authorisation.

“As not all authorities and countries are familiar with cell therapies, we at Pluristem have to create new definitions and develop the correct terminology with the customs,” he explains. “These aspects need to be part of the industry focus as we move towards the commercial phase, and the volumes and values involved are increased. Today we serve clinical trials with no real commercial value, but as we prepare for our next phase as a commercialised company, we are aware that we will be facing this issue soon.”

Licensed pioneers

To date, there is only a limited number of ATMPs licensed for use on patients, which means companies like Pluristem are genuine pioneers in the field. That’s a challenge, but it’s also a big opportunity – the early movers can determine what the supply chain should look like and pave the way for the companies that will follow in its footsteps.

On top of that, as the industry evolves, some of the present teething problems will naturally be resolved. The necessary infrastructure will be developed, the supply chain gaps will be filled and companies like Pluristem will be much better placed to sell their products around the world.

“The volumes and the market needs will become more and more demanding,” says Machnay. “The evolution of the complete supply chain will create more dedicated suppliers, and more infrastructure and equipment, which will support the increased quantity on a global level.”

He adds that GPS location monitoring will be essential for success, while logistics providers will have to get better at handling liquid nitrogen. These days, they’re rarely called upon to transport massive quantities of LN2 from the manufacturing sites to the main depots. But it’ll become far more common in future and will necessitate changes from an equipment point of view. Finally, Machnay thinks the ‘last mile’ of the supply chain is something that’s due for an overhaul.

“The last mile will become, in my opinion, one of the major aspects where the supply for the industry will have to improve and develop new methods,” he says. “The quantities of shippers for the clinical sites will create bottlenecks at the depots, the necessary dry shippers’ fleet and data loggers will have to be dealt with, as well as the possible challenge facing the clinical staff that deal with the cell therapy products on a daily basis.”

All in all, though, it’s an exciting time to be involved in the cryogenic supply chain, “I truly believe that the concept we are now creating, the infrastructure and approach we have developed during recent years, will be the base for future supply chain for Pluristem and for other similar companies,” says Machnay.

The demand for cell therapies

With the rising demand for cell therapies, the following growth opportunities have multiplied:

• Wide-ranging therapeutic focuses across both oncology and non-oncology conditions. With more than 959 ongoing regenerative medicine clinical trials, the market finds opportunity across both stem cell and non-stem cell based therapies.
• Curative combination therapies, which helps to improve response rates among patients while reducing the duration of response. These therapies also find application in identifying the right patient as well as predicting the immune response in cancer patients.
• Manufacturing automation by means of implementation of IT solutions and single-use manufacturing techniques for optimising small-volume, high-value manufacturing of novel cell therapies, thereby reducing the time to market drastically.
• Emerging business models, which help market players focus on academic and research collaborations alongside industry collaborations to support therapeutic and technological innovations.

Source: Frost and Sullivan

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