Ultra-Low Freezing Explained

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<p class="blog-h2">Summary</p>

In this article, we answer the question “What is ultra-low temperature freezing?” and explain how it works. We also answer other questions, such as “What types of ultra-low temperature freezers are available?” and enumerate their pros and cons. We will also clarify misconceptions about ultra-low freezing and identify best practices for long-term, ultra-low temperature storage.

<h1 class="blog-h1">What is Ultra-Low Temperature Freezing?</h1>

Ultra-low freezing (ULT) technology is often required as part of a process used to preserve biological materials such as cells, tissues, organs, and pharmaceuticals or biopharmaceuticals at extremely low temperatures. The technology is becoming increasingly important as researchers and manufacturers seek ways to store and transport these materials for use in manufacturing, research, and life sciences applications. ULT freezers are commonly utilized by organizations dealing with temperature-sensitive specimens, therapies, or mRNA vaccines. These cold storage devices preserve the cold chain for industries such as pharmaceuticals, biotech, life sciences, and healthcare. With the recent ultracold temperature requirements of mRNA-based COVID-19 vaccines, ultra-low cold storage is a key focus for bulk vaccine storage and commercial distribution.

Ultra-low temp cold storage typically refers to storage at or below -20°C to -80°C. Ultra-low freezers, which are commonly used in life science applications, can struggle to maintain these temperatures, and preserve valuable biological samples for long periods. Traditional ULT freezers can have temperature ranges from -40°C to -86°C (-40°F to -122.8°F), with some suppliers reaching up to -80°C over days or weeks. Some models offer an 'upright temperature range' based on the configuration. These ultracold temperatures protect biological materials- such as cells and tissues, and biomolecules like proteins, oligonucleotides, and mRNA from heat damage and denaturation. ULT freezers come in upright, chest, under-counter/benchtop, portable, and configurable models.

<h2 class="blog-h2">Advantages of Ultra-Low Temp Freezers</h2>

One of the main advantages of ultra-low freezing technology is its ability to enable the preservation of biological materials for long periods of time. Traditional methods of preservation, such as refrigeration or freezing at higher temperatures, do not sufficiently slow or stop biologic activity, leading to damage or spoiling. Ultra-low freezing, on the other hand, can slow down cellular metabolism which can enable biological materials to be stored for extended periods without significant deterioration.

Another key benefit of ultra-low freezing technology is its ability to enable the transportation of biological materials over long distances. Traditional methods of preservation are often inadequate for this purpose, as due to the inability maintain precision temperatures. Fluctuation in temperatures in can cause damage to the materials during transport. With ultra-low freezing, biological materials can be transported over long distances, making it possible to share resources and collaborate on research projects across the globe. Compared to alternatives like dry ice or liquid nitrogen, ultra-low temperature freezers often include precise and reliable temperature control, easy access to samples, optimized storage, and temperature uniformity for stored specimens. Ultra-low freezers are the optimal way to preserve the cold chain integrity and are much easier to maintain than liquid nitrogen which evaporates and is expensive to store.

Convection-based cooling is an advanced ultra-low temperature freezing technology that has improved temperature uniformity, reliability, and temperature recovery. Older ultra-low freezers (ULT), also known as ‘cold wall’ freezers, lack the built-in redundancy and uniformity of the newer convection-based models. Convection technology forces air, tempered to the target temperature, through a chamber. This technology aims to force sufficient air volume through the chamber at uniformity to ensure consistent and repeatable cooling throughout the chamber enclosure. This technology is especially relevant for bulk loading in commercial drug manufacturing as the more uniform freeze profiling reduces compressor stress and extends asset lifecycle.

<h2 class="blog-h2">Important Considerations for Ultra-Low Freezing Equipment Selection</h2>

When purchasing a new ultra-low-temperature freezer, it is important to understand the technology to ensure optimal performance. Additional factors to consider include temperature setpoint range, energy efficiency, maximum storage capacity, portability, integrated temperature monitoring, backup systems, open-door recovery, and freezing uniformity. Furthermore, workflow and process matter. it’s best to know if the storage system accepts all container types or if it is limited to a certain type of storage system.

When evaluating cold needs for an upcoming project or installation or development of the User Requirements Specification, consider deploying forced-air convection cooling if the following considerations apply:

  • Larger loads
  • Wide range of potential load scenarios
  • Tight temperature uniformity within the chamber
  • High-value materials
  • Frequent door openings
  • Unique material handling solutions including full-batch transfer carts

For freezing materials, some manufacturers have created ultra-low freezers that work through plate freezing. Just as you would expect, this freezing process utilizes two very cold plates and freezes a specimen between them. While this process is better than liquid nitrogen or dry ice, it limits the storage possibilities to bags only. Comparatively, cold-wall freezers and convection-based cooling chambers allow modularity and customization by the end user.

The commercialization of cold storage required biologics and their bulk drug substances have placed substantial stress on ULT cold-wall technologies to perform in applications for which they were not designed or intended. The industry increasingly views the conventional ultra-low temperature (ULT) cold wall as a ‘consumable’ despite the sustainability and operational issues caused by asset failures ahead of their anticipated life.

Put simply, conventional cold-wall technology, as deployed in all ULT freezers, is designed to promote cooling via expansion of a refrigerant through a series of chamber wall capillaries. This technology focuses on making the ULT shell as cold as possible, given that the ULT’s center would eventually reach the target temperature with minimal door openings and warm loads.

<h2 class="blog-h2">Use Cases for Ultra-Low Temperature Freezers</h2>

Ultra-low freezers are often used during the research and manufacturing of pharmaceuticals. Pharmaceutical manufacturers, including contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs), use ultra-low freezers to store temperature-sensitive products such as vaccines, biopharmaceuticals, and other medical products that need to be stored at extremely low temperatures to preserve their potency and effectiveness. These ultra-low freezers are often required to reach temperatures as low as -80°C, which is crucial for maintaining the stability of the stored products over time and helping to prevent degradation. Additionally, ultra-low freezers are equipped with advanced features such as alarms, temperature monitoring systems, and backup power supplies, all aimed to support the preservation of the stored products in the event of power outages, natural disasters, or other unexpected events.


<h2 class="blog-h2">Different Types of Ultra-Low Temperature Freezers</h2>

ULT freezers are used in the pharmaceutical and biomedical industry to store precision temperature-sensitive materials such as vaccines, blood products, cell lines, and tissue samples at ultra-low temperatures (-20 to -80°C). Types of ultra-low freezers include:

  • Chest ultra-low freezers (chest freezers) - typically not used in manufacturing facilities; more often used in laboratories.
  • Portable ultra-low freezers - usually used for transporting biospecimens.
  • Cold wall storage (upright ULT freezer) - traditional freezing technology; slower recovery times and cooling cycle.
  • Convection-based models - the most efficient and uniform ultra-low temperature long-term storage option.

<h2 class="blog-h2">Ultra-Low Temperature Freezers and COVID-19</h2>

At FARRAR, we are often asked which ultra-low freezing considerations are specific for COVID-19 vaccinations, and which best practices should be implemented for storing these pharmaceuticals. Here are our recommendations for storing mRNA vaccines:

  1. Choose an ultra-low freezer with the widest temperature setpoint range to optimize ultracold storage for all mRNA vaccine candidates and their bulk drug substances or Active Pharmaceutical Ingredients (AIPs).  
  2. Opt for freezers with the smallest freezer footprint, maximum storage capacity, and best portability for optimum flexibility within the application setting.
  3. Select ULT models with integrated or cloud-based temperature monitoring services and analytics to detect and help prevent issues before they lead to a temperature excursion.  
  4. Ensure you have a modular interior, offering virtually limitless storage configurations.
  5. Redundancy is key. The best ULT systems should offer built-in backup cooling and control systems.
  6. Check the temperature range. Does the model support storage at -80°C?
  7. Is the ULT freezer built for long-term storage?
  8. Cool down period from ambient temperature to -80°C often gives an indication of the freezer’s cooling capacity and ability to recover from a door opening.  

<h2 class="blog-h2">Final Thoughts</h2>

Ultra-low temperature freezing is a crucial technology to support the preservation of biological materials - such as cells, tissues, organs, and pharmaceuticals. It offers advantages over traditional methods, such as preserving the integrity of biological materials for longer periods of time, enabling the safe transportation of materials over long distances, and providing precise temperature control, temperature uniformity, and maximized storage space. It is important to recognize that today’s biologic drug development and manufacturing processes demand performance not available from several types of freezers.  Consider how the freezer will be utilized, from door opening frequency to freezing materials to the size of the sample,  when selecting the best model for the your process.

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