Alternative refrigerants

Future-proof refrigeration systems in freeze drying

Alternative coolants and correct cooling technology are booming because synthetic coolants are gradually disappearing from the European market and other regions of the world due to legal regulations. This raises the question, which alternatives are suitable for what application? The article also features a unique testing option at Optima.

The “new” coolants are proven in terms of their functionality; however, to date this has mostly occurred outside of pharmaceutical lyophilization. The properties of the synthetic coolants matched the specific requirements of pharmaceutical freeze-drying processes too well, so that the alternatives met with little approval. Now that climate protection has become increasingly important, the situation is changing with choices like the synthetic coolant R404A with a global warming potential of 3922 (expressed in the GWP value, see box on next page) and an alternative, natural coolant, such as R170 (ethane) that has a GWP value of just six.

Not only EU legislation is gradually restricting the sale of synthetic coolants with the F-Gas Regulation (fluorinated greenhouse gases). Similar regulations exist in places like Switzerland or the state of California in the United States. Industry experts are convinced that as availability decreases, the prices for these and the less harmful coolant blends such as R452A will continue to rise sharply. Anyone planning new freeze-drying systems today will therefore, rely on alternatives in cooling technology.

Important for you
  • The EU's F-Gas Regulation, other international regulations and climate protection in general require future-proof refrigeration technology.
  • A wide variety of refrigeration technology solutions meet the most diverse requirements of pharmaceutical freeze drying.
  • Future-proof solutions are: climate-neutral refrigerants in cascade systems, liquid nitrogen (LN2) directly or via heat exchangers, air refrigeration systems, as well as combinations of the systems mentioned.
  • Synthetic cooling agents (R452A and R410A) are increasingly limited in the EU and are considered as a transitional solution to a limited extent.
  • Tests with a Mirai air Cooling systems at a GT production plant (15 m²): Coming soon at Optima Pharma!
Rendering freeze drying
Liquid nitrogen cooling system during assembly. Liquid nitrogen itself is a climate friendly and a proven medium for freeze drying processes. Liquid nitrogen will be produced with different methods – energy-intensive, as a side product from other processes or using regenerative energy.
Different cooling objectives within the system

The freeze-drying process requires low temperatures in the freeze-drying chambers for its shelves and the ice condensers. Nevertheless, the requirements of the two components differ significantly in terms of cooling technology.

On the chamber side containing the shelves, the cooling technology meets several tons of stainless steel. As part of the batch preparation, the internal surfaces are cleaned and then steam sterilized at more than 120 °C. After external re-refrigerating and the loading process, temperatures as low as -65 °C are required on the shelves in order to freeze the pharmaceutical liquids.

This means the absolute temperature target is not extremely low. The temperature difference, the large mass to be cooled, and the time factor are the main challenges that cooling technology has to meet vigorously. Since the quality of a lyophilizate is particularly influenced by the freezing phase of the drug, the controllability of the cooling capacity is also important. A temperature curve should ideally be linear and not show any upward or downward deflections over time.

On the other hand, there is sufficient time to control the temperature of the ice condenser’s cooling coils. The cooling target can reach as low as -80 °C. In contrast, a linear progression is not an essential requirement in this process.

In classic freeze-drying systems with synthetic coolants, a common cold source is sufficient to achieve these different cooling objectives. When using alternative coolants instead of a second cooling source, a second cooling system may be used to meet the cooling targets in each case.

In general, further aspects must be taken into account in the system’s design for a suitable “overall package”. These are usually the specific requirements of the pharmaceuticals to be freeze-dried, the spatial requirements at the installation site, the existing technical infrastructure, and the importance placed on environmental protection.

Transitional period or uncompromising?

GWP values down to zero can now be achieved in cooling technology and are practical in pharmaceutical freeze-drying. 

An overview of the currently leading, future-proof technical solutions:

1. Carbon-neutral coolants in the cascade system (flammable)

2. Liquid nitrogen (LN2) for direct cooling or for cooling via heat exchangers

Pioneering, but not yet established on an industrial scale in the pharmaceutical freeze-drying industry:

3. Air cooling systems (some with booster system)

4. The means and technologies mentioned above are combined in an overall system that implements the different cooling targets of the ice condenser and freeze-drying chamber, as well as customer-specific aspects.

As a transitional solution:

5. The synthetic coolant mixtures R452A and R410A in the classic design of freeze-drying systems are less future-proof (their availability is already limited due to legal requirements in the EU and will gradually be further restricted).

During a transition phase, synthetic coolant mixtures can be considered as an alternative with significant restrictions. Compared to conventional synthetic coolants, these mixtures are less harmful, but still unsafe for the environment. R452A and R410A have a GWP of 2140 and 2088 respectively. Although these coolants are available within the EU, the quantities are limited and they are gradually being phased out. Since the typical life cycle of freeze-drying systems is approximately 30 years, this alternative will only make sense for new systems in exceptional cases.

GWP values and current EU regulations

The higher the GWP value, the more harmful the substance to the climate. A concrete example: The CO₂ equivalent of the organic coolant mixture R410a is 2,140 – always considered over a period of 100 years. This means that within the first 100 years after release, one kilogram of R410a contributes 2,140 times more to the greenhouse effect than one kilogram of CO₂. The release of 1 kg of R410a corresponds to the release of 2,140 kg of CO₂.

The European Parliament is now discussing additional F-Gas Regulation (EU) No. 517/2014. A reduction in emissions of 80-95% by 2050 is under discussion.

(Regulation (EU) No. 517/2014 of the European Parliament and Council dated April 16, 2014)

Better, sustainable

In order to create a sustainable freeze-drying system on the ice condenser side, a system with a separate cooling circuit often proves very practical. This means the ice condenser coils can be supplied with a heat transfer medium, regardless of the actual cold source. The system therefore, consists of cooling technology, a heat exchanger and a separate cooling cycle. This is in contrast to the direct evaporation of synthetic coolants, for example, which evaporate immediately in the ice condenser coils.

A fluid circulates in the separate cooling circuit as a heat transfer medium, at temperatures of as low as -80 °Celsius. The ice condenser coils and the cooling technology are connected via the heat exchanger. The type of cooling technology used remains variable. (The fluid on the side of the freeze-drying chamber has always circulated in the shelves according to the same principle.)

A second climate-friendly variant of ice condenser cooling is the evaporation of liquid nitrogen. Liquid nitrogen can escape into the atmosphere as a harmless gas. This solution has proven itself many times in the pharmaceutical freeze-drying industry. (The overall environmental balance of using liquid nitrogen in turn depends heavily on its production process.)

The individual variants of the environmentally friendly cooling systems and their possible uses will be examined more closely. The specific requirements for the chamber and of the ice condenser must be taken into consideration.

Lyophilization machine
Coolants, harmful to the environment, are replaced by alternative solutions. Cascade system (cooling with liquid nitrogen), air refrigeration technologies and combinations of both are considered sustainable.
Process freeze drying
Schematic of a system with liquid nitrogen. The set of shelves is evenly cooled with heat exchangers. Direct evaporation of the liquid nitrogen takes place in the ice condenser.
Natural, climate-neutral coolants in the cascade system

The gases R1270 (propene, GWP 3) and R170 (ethane, GWP 6) are usually used as coolants. These gases are in the cooling circuits and are not “consumables” - or operating materials. If these escape into the atmosphere, they are practically harmless to the environment.

For the required cooling capacity, natural coolants are pressurized in cooling circuits with compressors and released again. The resulting change in the aggregate states (gaseous and liquid) uses the cooling capacity (enthalpy) generated during evaporation. In the cascade system, this cooling capacity is “handed over” to a second circuit via a heat exchanger. This cycle works on the same principle and reaches an even lower temperature level. Depending on the size of the cooling system and the required redundancies, several cascades, each with two compressors, are used. With this cooling capacity, the adjustable shelves and/or the ice condenser coils are finally cooled with heat exchangers and circulating fluid.

Leaking natural coolants form a potentially explosive mixture in combination with air in closed rooms. Therefore, natural coolants should only circulate in an enclosed, controlled area – not beyond, neither through the shelves nor through the ice condenser coils. Still, in the enclosed area, heat exchangers transfer the coolants to the fluids. While gas detectors monitor the enclosed area, a slight vacuum is created through suction and evacuation. Optima Pharma has developed a particularly safe concept that detects potentially dangerous air/gas concentrations. If, for example, the explosion-proof fan should fail, in the event of a leak, there would be more time to react.

Depending on the installation location, an exhaust air ventilation should be installed from the enclosed area to the outside of the building when installing a freeze-drying system with a cascade cooling system. Since people work near the equipment, these rooms must be classified accordingly. Country-specific regulations may need to be observed.

Liquid nitrogen as an alternative

Liquid nitrogen is often used for indirect cooling with heat exchangers, since it is largely climate-neutral. In this case, the production process determines environmental compatibility. In particular, when liquid nitrogen is obtained from regenerative energies, it offers the ideal con­ditions for use in cooling technology. The idea of sustainability can be extended even further if the evaporated liquid nitrogen is absorbed and accessible as purified nitrogen for use in other processes.

Liquid nitrogen is very suitable for cooling the shelves and, as shown, is used for cooling of the ice condenser. It requires a storage tank in the infrastructure, which many pharmaceutical companies already have on site. The technical implementation of the freeze-drying systems involves comparatively little effort. Liquid nitrogen greatly reduces the use of electricity and cooling water in the systems.

Air as a coolant

The principle of air-cooling is not new either, but was only available for mass production in recent years by the Mirai Company. The investment is currently higher than for other cooling systems, but the system works solely with air as a coolant and is particularly environmentally friendly.

Air cooling systems have one special characteristic: they are an extremely efficient way to achieve very low temperatures with consistent performance. Therefore, their use in freeze-drying is preferred for cooling the ice condenser. The dynamics are less favorable when components need to be cooled as quickly as possible, as is the case with the shelves. This is still possible, though, by setting up an additional oil storage tank as a “booster”. This tank can be cooled to -80 °Celsius over an extensive time period. If the shelves are then to be cooled in the freeze-drying process, the desired cooling capacity is available. In this setup, an air cooling system serves an entire freeze-drying system. In larger freeze dryers, two or three air cooling systems are required.

System mix with a second cold source

With the combination of different cooling systems, their respective strengths can be combined for optimal results. This requires a certain investment or the integration of existing infrastructure into the new freeze-drying project.

Very few pharmaceutical companies have had the chance to gain experience with air cooling technology or cascade cooling systems. Optima Pharma has invested in an air cooling system from Mirai to give interested parties and ur customers the opportunity to choose a different system. This system is combined with a production freeze-dryer with a footprint of 15m² and will be available for tests at the beginning of 2023.

Freeze drying graphic
Schematic of a freeze-drying system with an explosion-proof cold cascade system. Both components – freeze-drying chamber with shelves and ice condenser – receive cold air from a central cooling system via heat exchangers and fluids in their own circuits.
Test Air-Refrigeration Technology!

Optima Pharma has also carried out extensive test series at its in-house production test facility with a cascade cooling system and alternative coolants. It was available for several weeks exclusively for this purpose. Optima Pharma shared the latest findings with customers and interested parties. These findings are currently being incorporated into a major project at a Swiss location, where four large freeze-drying systems are being cooled using cascade cooling technology and natural coolants. This project is nearing completion. Jörg Rosenbaum is happy to talk more with you about cascade cooling technology – please reach out today!

Pharmaceutical companies will be able to make sustainable and safe decisions with expert advice from Optima.

Classic coolants and retrofit: Two FAQs

The question often arises as to why the use of climate-damaging gases have been and continues to be the norm, although there have been other options for a long time? The main reason is the specific coefficient of performance of a coolant. The performance of the synthetic, environmentally harmful coolants ideally correspond to the technical requirements of freeze drying systems. Climate-neutral coolants, on the other hand, are flammable, they have a narrower range of applications, and they require higher compression performance (i.e. a different compressor design). This is also an indication of why the subsequent change to another coolant only rarely makes economic sense.

A second frequently asked question revolves around the ice condenser coils: could a subsequent “system change” work? Until now, ice condenser coils have mostly been designed for the physical effect of the synthetic coolants that evaporate and then liquefie again in the circuit. This requires an exactly coordinated geometry of the ice condenser coils in interaction with the compressor performance. In new, environmentally friendly systems, fluid is now mostly used in the cooling coils of the ice condenser in a cooling cycle (without evaporation). In most cases, specific designs of the ice condenser coils prevent an economical retrofit. Subsequent conversion to the direct evaporation of liquid nitrogen in the ice condenser coils is only cost-effective in rare cases. The coolant (performance coefficiency), the geometry of the ice condenser coils and the performance of the compressors always form a coordinated overall system.

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