In this article, we shall take a look at cryogenics as a whole and expound on what it all means. We’ll explore the different cryogenic applications out there while identifying some of the products shipped or stored in cryogenic containers. By the end, you should also have some insight on what you need to consider when choosing a cryogenic container and how to use it correctly.
If you’ve worked in the medicine, chemistry, biology, or cold electronics arena before, you’ve likely dealt with cryogenics at one point or another. Its applications extend to a host of sectors, including biological science, electronics, supply engineering, and space science, facilitating everything from lower temperature packaging and storage to shipment of samples.
Cryogenic containers are rapidly gaining popularity as the more efficient way of shipping cell and gene therapies, cord blood, as well as patient and biological samples. Through cryopreservation, living tissues and cells can be indefinitely preserved at extremely low temperatures.
But that’s just the tip of the iceberg. Let’s delve a bit more into cryogenic applications in the pharmaceutical industry.
What is Cryogenics?
Cryogenics can best be understood as a science dealing with the production, use, and effect of materials at very low temperatures. To put it into perspective, water usually becomes ice at about 32°C. Cryogenic temperatures, on the other hand, are much lower, ranging from about -150°C to -273°C. At such temperatures, gases like oxygen, hydrogen, nitrogen, and helium transition to liquid. And in this state, they can be used to freeze other materials.
As technology advances, cryogenic processes are becoming more and more popular, with new applications popping up every day. Currently, cryogenics is applied in three major ways. They include:
Research and Development
Research and Development
Research and development (R&D) generally refers to the process of formulating a new product and taking it to market. And now in the midst of the COVID-19 pandemic, among other seasonal ailments like the flu, there’s a pressing need for newer, more effective vaccines and medication.
Cold chain providers are at the forefront of providing support for the thousands of clinical trials taking place. Using cryogenic containers and other cryogenic equipment, they are able to better facilitate the transport of temperature-sensitive samples and drugs to laboratories and study sites worldwide.
In this context, cryogenics is used in two main ways:
Store and Transport Human Biological Samples (HBS) During R&D
Human biological samples, like tissues, cells, blood, organs, and subcellular materials like DNA, have long been an invaluable asset when conducting clinical research. They are what help doctors determine how well internal organs like the liver, thyroid, kidneys, and heart respond to the experimental treatments. With HBS, researchers get to evaluate if the new treatment is toxic to human cells before development.
To guarantee viable results, human biological samples need to be safely extracted and protected from any contaminants or adverse temperature changes throughout the journey.
For this, cryogenic equipment has proven to be most effective in preventing any temperature excursions. This can be either during research or as they are transported to and from the lab. Usually, they are used hand in hand with advanced monitoring systems, telemetry, and data-driven modelling equipment.
Store and Transport Small Active Ingredients During R&D
Active pharmaceutical ingredients (API) are the active ingredients contained in medicines and vaccines. The general rule is that APIs should be manufactured and maintained at deep frozen temperatures (about -40°C to -80°C) or cryogenic temperatures (ranging from -160°C to -180°C). These temperatures should be maintained while storing and transporting these ingredients.
As research initiatives in the pharmaceutical industry continue to advance, APIs continue to become more complex. In fact, at the moment, low-temperature cryogenic chemistry has become almost imperative to facilitate extremely temperature-sensitive transformations. For instance, the transformation of highly reactive compounds like organolithium reagents cannot be achieved at higher temperatures.
Through the cold chain and the aid of cryogenic processes, researchers are more able to maintain the integrity of the APIs and obtain the required selectivity.
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When the term cryogenics is used, it generally involves temperatures that are lower than about -150°C. But in traditional API manufacturing, temperatures of about -80°C were deemed cold enough to satisfy a lot of the current good manufacturing practice (cGMP) manufacturing requirements. So, why the need for cryogenic equipment, you ask?
For starters, there are now several emerging molecular transformations requiring super cold conditions (sometimes, even lower than the standard freezing temperatures). A cryogenic environment is perfect for facilitating such transformations. Also, you’ll find that the newer, more efficient routes to manufacturing already existing products are starting to rely on cryogenic processes.
In manufacturing, cryogenic temperatures can help:
- Reduce impurities
- In processing really reactive compounds like organolithium agent
- Reduce any undesired side reactions
- Aid in reaction selectivity
- Prevent the formation of ice crystals
- Reduce compound volatility as the conversion takes place to increase safety
Investigational medicinal products (IMP) can include any product being tested in a clinical trial or used to reference the trial. It can be a newly developed drug. It can also be an already licensed drug that’s being tried on a new condition or in a different packaging or formulation.
Regulatory authorities have certain procedures set for the development and handling of IMPs to maintain their safety and quality. Among them is that each facility has an area set aside for this purpose per certain storage conditions.
In this case, IMPs needing room temperatures (15°C to 25°C) can be stored in the dispensary, and anything needing refrigerated storage (2°C to 8°C) would be stored in refrigerators within the dispensary. On the extreme end, IMPs that require ultra-low temperatures (-80°C and below) or cryogenic temperatures (-150°C to -273°C) should be kept in a very low-temperature freezer or cryogenic facility.
On the same note, if it is a completely new IMP with no stability budget, the safest option would be storing and transporting it in a cryogenic facility such as cryogenic containers or cryotubes and vials (if they are in small quantities).
One of the main concerns in the supply chain of pharmaceutical products is how to protect the product from spoiling or damage during transit. High-value biologics like stem cell treatments are usually shipped at about -150°C to halt cellular activity and maintain cell integrity.
Using liquid nitrogen, cryogenic containers can keep the product frozen at temperatures as low as -150°C during transit and storage. This is far more efficient than the traditional dry ice, whose lowest temperature is -78°C. And this is not really suitable for cell preparation.
On top of that, cryogenic containers are intuitively designed to keep the products stable even with all the movement. Good practice is to supplement them with monitoring and proactive intervention technologies that continuously keep track of the state of the product. This way, they can single out any shipments that are likely to experience delays and intervene accordingly at any stage of the journey.
QUOTE: Monitoring technologies also help manage any processes, including logistics and shipment tracking and documentation.
As a distributor, it is your duty to ensure that documentation covers the entire scope of your activities. It should be written in a clear, concise, and error-free language. Also, every employee involved should have access to the documentation for a smooth, error-free task execution.
Here are a few examples of how cryogenics are used in the transport process:
Collecting Human Biological Samples During a Clinical Trial
As we saw earlier, HBS need to be consistently kept at low temperatures from the moment they leave the human body. As it stands, the most commonly used medium for temperature management is dry ice (solidified carbon dioxide). But while dry ice has been effective in maintaining the cold environment needed for transporting biological materials, it is not recommended for the transport of cryogenic samples.
For instance, in a case where encapsulated liver cell steroids were kept at -80°C for a month, it resulted in a greater decrease in cell function and viable cell numbers than when the same cells were stored at -170°C. In this case, the liquid nitrogen cryogenic environment was better able to keep the samples safe.
Transporting and Storing Retention Samples in Bio Banks
Biobanking generally involves collecting and systematically organizing human biological samples for long or short-term research. Since below-freezing temperatures are best at maintaining the stability and functionality of the biological samples, a cryogenic environment is recommended when transporting or storing retention samples.
Usually, they would be transported and stored in different types of cryogenic equipment, such as freezers, liquid nitrogen tanks, cryogenic boxes, and cryogenic vials.
As scientific research processes like cell-based therapy and cord blood banking continue to advance, you can expect to see a drastic increase in cryogenic biobanking facilities in the near future.
Transportation of API From Manufacturing to Filing Sites
More and more of today’s complex APIs are starting to need cryogenic temperatures in manufacturing. This mainly applies to reactions having unstable intermediates like organometallic reagents, which can’t be done at near room temperature. Processes that involve gaseous reagents are also generally better achieved at low temperatures.
After the manufacturing process, such APIs also need to be transported to filling sites in cryogenic temperatures to prevent any unwanted side reactions in the process or volatility of the compounds.
Since most filling sites require that the APIs maintain precise volumes and sterility, using cryogenic technology will help prevent corruption or contamination of the APIs during transit.
Transporting and Storing Finished Products (especially where there is no stability budget)
Other than APIs and HBS, cryogenic equipment is also being used to transport and store finished products. This applies more so in situations where there is no stability budget or a confirmed period the product can survive outside the recommended storage temperatures.
In the absence of more reliable facilities, the cryogenic vessel will keep the product preserved at extremely low temperatures, limiting any potential loss due to damage.
Biologics and IVF
Currently, a majority of biological products are preserved under the “refrigerated category,” which ranges from 2°C to 8°C. But as we saw, more and more of today’s biologic therapies, including COVID-19 vaccine clinical trials and the latest CGT, are starting to require deep frozen temperatures (-40°C to -80°C), as well as cryogenic temperatures, which use liquid nitrogen and range from -160°C to -180°C.
Other than that, cryogenics is also becoming the preferred method of preserving biological material, including human tissue, blood samples, and semen. As CGTs continue to grow in the supply chain, you can expect an increase in the demand for cryogenic storage systems and dry shippers that can sustain an internal temperature of between -150°C and -180°C for extensive periods.
In summary, cryogenics is generally applied in situations that demand extremely low temperatures (ideally -160°C to -180°C). As APIs today continue to become more complex, they need such temperatures to facilitate molecular transformation.
To maintain the integrity of specimens and samples, it is crucial that you sustain the cryogenic environment from the manufacturing stage to transport and storage. For even better results, you are advised to use monitoring solutions like ELPRO to help keep track of your product as it moves through the supply chain.