Using cryogenic solutions in the biopharmaceutical cold chain

A primary characteristic of biologics such as vaccines is their sensitivity to temperature and other external stressors. Many are inherently unstable, especially at room temperature, and require cold chain protection from manufacture to dose delivery to ensure safety and efficacy.

This blog by Air Products discusses how established cryogenic solutions for storage and distribution answer directly to the requirements of vaccine manufacturers, enabling the safe delivery of these critical products.

Freezing, distribution and storage solutions for vaccine delivery

Storage requirements for pharmaceuticals (notably temperature) differ from product to product, but are especially demanding for biologics. The increasing use of cell and gene-based therapeutics, blood-based products and vaccines brings growing challenges for safe and efficient handling.

Focusing on vaccines, those that use a viral vector (adenovirus), as exemplified by seasonal flu vaccines, are typically stored and shipped at 2°C - 8°C (35.6°F - 46.4°F). Messenger RNA (mRNA) vaccines, which as recent events have shown hold much promise for the future, are far more challenging needing sub-zero storage and shipping, potentially down to -80°C ( -112°F) or even lower. For some biologics temperatures as low as -180°C (-292°F) are needed.

The pharmaceutical industry has successfully overcome the challenges of manufacturing and scaling up these life-saving products, though there is always scope for further optimization. Secure cold chain solutions are also in place, but here there also remains room for improvement. More compact, easier to use equipment and lower energy comsumption are important goals.

Methods proven over decades for the storage of blood, animal breeding samples and other cell-based products are potentially transferable to meet this goal. Cryogenic solutions and equipment have already been developed and proven to tackle each temperature-related challenge that biopharmaceutical manufacturers face, and they can be helpful to establish each link of the cold chain from manufacturing, storage, and distribution up to the point of use.

Controlled freezing and compact solutions

A reduction in product temperature in the latter stages of manufacture marks the beginning of the biologics cold chain. Using liquid nitrogen in place of mechanical refrigeration means equipment is compact, and it can help reduce overall cooling and freezing time, potentially shortening batch cycle times.

Cryogenic batch and ultra-low temperature (ULT) freezers, powered by cryogenic fluids such as liquid nitrogen, are well-proven for:

• Product freezing. Preserving live materials with liquid nitrogen enables precise process control down to a very low temperature. Benefits of liquid nitrogen for this application include an extremely low boiling temperature and high refrigeration capacity.
• Lyophilization (freeze drying). This two-step process involves removing water to increase product viability and yield. First the product is frozen with liquid nitrogen and nitrogen vapor at ULT, then dehydrated in a vacuum. This produces a highly stable product with an extended shelf-life that is easily reconstituted at the point of administration.

Reliable, low-energy storage solutions

Traditional ULT freezers are an effective choice for storing materials at temperatures as low as -150°C (-238°F). However, these widely used work-horse units are typically cooled by electrically powered compressors and can consume significant amounts of energy. This can be particularly problematic when large storage volumes are required at a single location.

In addition, mechanical freezers are vulnerable to mechanical failure and emit large amounts of heat, necessitating the use of ventilation and air conditioning (HVAC) which further increases energy consumption.

Cryogenic freezers are a readily available alternative that avoid many of these issues. For example, variable temperature or nitrogen vapor ULT freezers are powered by a regular flow of ultra-cold liquid nitrogen making them an energy efficient choice for storing products at temperatures between -20°C (-4°F) and -190°C (-310°F). These units are particularly useful for prolonged, centralized storage at manufacturing sites and at the point of distribution.

Having liquid nitrogen storage on site provides a steady, reliable means of maintaining stable temperatures, even in the absence of mains power, reducing the risk of losing the freezer's contents in the event of a power outage.

Efficient shipping solutions

There are multiple cryogenic options for shipping and storing sensitive materials from point-to-point while maintaining temperature stability. The most convenient is to pack in dry ice (solid carbon dioxide [CO₂]), a refrigerant widely used to transport food and medical samples in a frozen state.

Dry ice is a simple, easy-to-use and reliable alternative to mechanical methods and other refrigeration systems, particularly suitable for transport over ‘the last mile’, to the point of use.

At locations with specialized equipment it can be made on demand to exact shapes and amounts, as needed to deliver a specified storage time for a given package size. This approach helps to ensure an effective, economic shipment.

Alternatively dry ice can be purchased as required from suppliers. An important additional benefit of dry ice is that it creates a bacteriostatic environment, providing further protection for the product and adding to its appeal for biopharmaceutical product shipping.

Liquid nitrogen and nitrogen gas can also be an effective option for shipping temperature-sensitive products. Liquid nitrogen is often used in special dry shippers that operate at very low temperatures to keep cryogenically preserved materials intact for extended periods. These dry or cryo-shippers have no free-flowing liquid as they contain a hydrophobic compound which absorbs the liquid nitrogen, creating a dry, spill-free packaging solution.

Cryogenic and industrial gas safety

Cryogenic gases are safe, effective, and easy to use, but need to be handled correctly. Cryogenic liquids are liquefied gases with a normal boiling point below -90°C (-130°F) and here too users should follow appropriate safety measures.

Special protective equipment and caution is advised when handling and it is essential to strictly adhere to safety guidance from the manufacturer. The temperature difference between a cryogenically stored product and the surrounding environment is usually substantial, even in winter, so protection/insulation from the surrounding ‘heat’ is vital.

Dry ice is simple and easy to use, although the correct precautions must always be followed to safely deal with its extremely cold temperature and to ensure safe gas vapor venting during product use.

Each biopharmaceutical manufacturing process, storage, or distribution requirement may be unique, but the benefits of cryogenic industrial gases are universally relevant. The reliability, consistency, and availability of liquid nitrogen and carbon dioxide are well-established making these materials worthy of consideration for each step of the vaccine cold chain.

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