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Pharmaceutical Manufacturing and Packing Sourcer

System Switch

Heat transfer media systems for condensers can offer strong alternative cooling techniques for freeze drying application

The main components of a freeze drying system include the drying chamber, condenser, isolator valve, cooling system and vacuum system, which are all connected together. In the freeze drying process, a liquid pharmaceutical product, such as that found in vials or pre-filled syringes, is placed on shelves in the drying chamber, where it is fully frozen. The solvent (usually water) is then extracted by creating a vacuum and applying heat energy to the product. This technique makes use of sublimation, so that under the right vacuum conditions the solvent vapourises without passing through the liquid phase. The vapour turns to ice on the condenser coils, which can be defrosted at the end of the process. The result of the freeze drying process is a product cake (lyophilisate) which can be rehydrated later on.

To operate a freeze dryer, vacuum pumps and other equipment are needed, but above all a reliable source of cooling is required. Cooling is needed for the condenser and also to lower the temperature of the shelves in the drying chamber. A standard technique is normally used to cool the shelves. Condenser cooling is usually, but not always, based on one particular technique. This article discusses an alternative approach to condenser cooling using heat transfer media systems, and addresses engineering issues, advantages and disadvantages, as well as possible applications.

Cooling Systems – an Alternative Design for Freeze Drying

A cooling system is normally an integral part of stand-alone freeze dryers. In contrast to these distributed cooling systems, a central system can supply cooling to multiple freeze dryers. A heat transfer medium is circulated to the shelves, and cooling takes place via heat exchangers (the same heat transfer media system can also be used to provide heating to the shelves. The heat transfer medium circulates through channels, which loop through the shelves). This design has become the standard.

In most conventional condenser systems, the coils are cooled directly by a vapourising refrigerant, which circulates through the coils. In a variety of applications however, an alternative solution can be the better option. In addition, a heat transfer medium can be used to cool both the ice condenser and the shelves.

Initially, a closer look at heat transfer media systems is needed. These systems provide indirect heating and cooling, and have been used for regulating shelf temperature for many years. This approach ensures that no coolant is present in the area where the pharmaceutical products are placed. Typically, silicon-based oils are used as a heat transfer medium for these applications, although other types of medium might also be used. The following aspects need to be considered during the selection of a heat transfer medium:

  • Thermodynamic properties
  • Price
  • Toxicity
  • Flammability/explosiveness
  • FDA approval

The final selection usually reflects the best possible compromise based on prevailing conditions and the application envisaged.

No matter whether the heat transfer medium is circulated to the shelves or to the condensers, it always remains within a closed loop. The temperature of the heat transfer medium is lowered via heat exchangers as it flows through the chiller. Compressors (normally reciprocating compressors, or in some cases screw compressors), liquid nitrogen (LN2), or a combination of the two provide the cooling. Two-stage compressors are used, and the second stage can function as a second compressor connected in series.

The cooling system can also be configured in stages (cascade). A complete second cooling circuit comprised of the elements listed above is normally installed on the cooling system. The stages operate cumulatively, and once again, energy transfer takes place via heat exchangers. Very low temperatures can be achieved with this type of configuration.

If heat transfer media systems are used in condensers, the heat transfer medium rather than the refrigerant is circulated through the tube coils. Multiple cooling circuits are normally installed inside the condensers on systems that operate by refrigerant evaporation. This is not necessary with heat transfer media systems because redundancy is provided externally in the heat transfer medium circuit (for example in the circulation pumps, the chiller or injection valves depending on the type of cooling or multiple cooling systems) rather than internally.

The heat transfer media systems used for cooling the condensers can be broken down into two categories: distributed and centralised systems. In centralised configurations, one cooling system is connected to multiple freeze dryers, whereas in distributed systems, each freeze dryer has a dedicated cooling system.

To summarise, the following characteristics differentiate (at this point) heat transfer media systems which provide an alternative approach to condenser cooling:

  • Centralised systems
  • Distributed systems
  • The type of cooling system, including two-stage compressors; one-stage compressors, in series; cascade and LN2 coolant
  • The type of cooling used, including flammable/potentially explosive but eco-friendly coolants, and safety coolants

Applications – Typical Scenarios

What reasons could arise in practical terms for deviating from the standard technique mentioned at the beginning of this article, and using a heat transfer medium for cooling the condenser instead? A number of scenarios can occur which typically result in a logical choice between heat transfer media.

Operation of Multiple Freeze Dryers

A central cooling system is a viable option for pharmaceutical companies that operate more than one freeze dryer. The use of compressors for cooling has operational cost advantages, but maintenance is more expensive and time consuming. In contrast, LN2 has the advantage of shorter maintenance times, but consumption of LN2 coolant drives up operating costs. If more than one freeze dryer is in operation, another possibility would be to connect the two systems so that maintenance can be performed ‘on the fly’: a central system offers a combination of compressors with refrigerant and LN2 to handle peak loads or allow maintenance while the freeze dryers continue to operate.

Some pharmaceutical companies already have a supply of chilled heat transfer medium which can be used for freeze drying. When that is the case, there is no need for a (distributed) cooling system. Less space is needed in the equipment rooms, and the freeze dryer can be more compact, making efficient use of available space in the sterile room.

Sometimes, multiple freeze dryers run with a scheduled time offset. In other words, they are not all used to freeze pharmaceutical products at the same time. Cooling demand varies considerably over the course of the freeze drying process, and the time offset means that peak loads do not occur at the same time, resulting in a more efficient use of resources. Compressors, which would otherwise be needed to meet peak demand, can be shut off.

This approach also avoids another undesirable secondary effect. Cooling demand is highest during the freezing cycle, and during the secondary drying cycle, cooling is only needed to keep the ice cold, which compensates for the externally induced rise in temperature. Due to system design, the compressors also have a minimum operating time, which usually means that they continue to run after the end of the cycle. During that time, they consume energy for no benefit. If however one system supplies cooling to several freeze dryers which operate with a time offset, cooling output is balanced in the central cooling system, and unnecessary peaks in energy consumption can be avoided.

When cooling is supplied from a central system, it can be beneficial to include LN2 cooling as well. If that is the case, LN2 can cover peak demand, and the compressors can be designed to handle the baseline load. Since the investment costs for an LN2 heat exchanger are lower in relation to the increase in performance, LN2 is a good choice for backup systems. Depending on tank volume, the backup system can even bridge the gap when the compressors are down due to maintenance, faults or problems with the cooling water. LN2 capacity can be sufficient to cover both the baseline load and demand peaks.

An LN2 backup system is relatively easy to install, as no other internal equipment is needed in the containers. When the cooling system is replaced or the user migrates to a different type of cooling, no change is made to the freeze dryer, eliminating the need for complete product validation.

Overcoming Physical Separation

Depending on the plant layout, the freeze drying chamber may not be located in the same place as the cooling system. The distance between the two can be quite considerable, particularly when central cooling systems are involved. With conventional designs, the following situation would occur. The refrigerant has to be circulated to and through the compressor and then back again. The compressors are oil lubricated, and some of the oil is released into the refrigerant. There is a risk of oil deposits forming in the condenser coils, degrading cooling performance over time. The gas flow has to be maintained at a minimum however, achieving this in long connecting pipes causes additional difficulties. At high flow rates, pressure losses increase because the pipes are relatively large. As a result, the end temperatures cannot reach the required levels; consequently, conventional condenser designs reach their limits when long distances are involved.

If the systems are separated using heat exchangers and heat transfer media (alternate design), the problems can be resolved. The compressor lubricating oil only moves within a small ‘zone’ inside the cooling circuit. The heat transfer medium is pumped through the connecting pipes and the condenser coils. Heat transfer media systems can bridge larger distances, and all of the crucial parameters for the freeze drying process can be kept under control. Once again, there is a beneficial side effect. Compared to direct evaporation, less coolant is needed because the amount of pipe that requires a ‘supply’ of coolant is lower.

Environmental Protection

Refrigerants are available in many variations with very different properties. Besides specific process-relevant characteristics such as condensation and boiling point, environmental protection is becoming an increasingly important consideration. It is generally understood that ‘natural’ coolants such as ethane/ propene have a significantly better global warming potential (GWP) value than ‘conventional’ coolants such as R404A and R23, and so they are regarded as eco-friendly. Natural coolants have the disadvantage that they are highly flammable and pose an explosion risk. To manage these hazards, increased effort and expense are required to provide monitoring systems and explosion protection. The coolants and monitoring systems can be installed in boxes which are not in the rooms and buildings where the freeze dryers are located. Due to the distances which are normally involved, heat transfer media systems are a logical choice. The basic design of these systems is comparable to that of a cascade cooling system.

Other Basic Advantages and Disadvantages of Heat Transfer Media Systems

One potential advantage of heat transfer media systems, which benefits the machinery manufacturer as well as the customer, is the opportunity to standardise the freeze dryers. Despite the fact that freeze dryers are special machines tailored to customer needs, the possibility nevertheless exists to develop machines which have an identical basic design. On systems with heat transfer media, the behaviour of the freeze dryers is identical regardless of the cooling source. Any major changes would be limited to the heat exchangers and the cooling systems which are connected to them. Up to this point, control of all subsystems such as the heater has been performed by the freeze dryer. On heat transfer media systems, control could be moved to the central cooling system. In that case, the freeze dryer would simply request a specific temperature from the cooling system. Any essential differences would affect the cooling system only. In particular, this would significantly reduce validation effort for the freeze dryer.

Because the systems which provide the source of cooling have their own controllers, less programming effort is needed for the separate freeze dryers. Changes to programmes in the freeze dryers have no effect on the central cooling system. This architecture also has advantages when changes are made to the cooling system. As long as the selected temperature and required differential pressure are maintained in the freeze dryers, the changes do not affect the freeze dryers.

It is also important to keep in mind the arguments against heat transfer media systems. The pumps which are needed to circulate the heat transfer medium always release heat to the circuit, which is a disadvantage of this constellation. The output of the cooling system has to increase in order to compensate for the rise in temperature. To maintain a constant temperature in the condenser, the temperature at the heat exchanger has to be reduced by an additional 5-10K. The conventional direct expansion method is better from the energy standpoint.

As a general rule, conventional systems have a less complex design compared to heat transfer media systems. A lower component count translates to lower up-front investment costs (which can however be offset by operating multiple freeze dryers from a central heat transfer media system). Theoretically at least, there are fewer potential sources of faults. In this context (system reliability), there is also a risk on central systems that a fault in a non-redundant component, for example pipework, can affect the entire system.

Conclusion

There are obvious reasons why conventional designs are normally used for condensers. Design simplicity and higher efficiency are good arguments in favour of these systems. However, these advantages can be offset by central systems which supply cooling to multiple freeze drying chambers. Heat transfer media systems in a range of variations can offer substantial advantages compared to conventional condenser cooling. Heat transfer media systems are an important portfolio enhancement which enable machine suppliers to deliver the best possible solutions to meet the customer’s requirements.


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Carsten Dettmann started his career as an apprentice technician for cooling devices. He went on to study Energy and Heat Engineering, before gaining a University of Applied Sciences degree. His working career proper began with a refrigeration and air conditioning company, where he planned complex systems for customers. Four years ago, he joined Optima Group Pharma GmbH (Gladenbach facility, Germany) where he is responsible for cooling technologies within the department of process engineering for freeze dryers. Email: carsten-roland.dettmann@optima-pharma.com
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