1. Introduction

Many biological processes require low temperature. Normally, the process will take place in a closed environment where the system controls these low temperatures. Nevertheless, if it is a critical open process and a low temperature is required for the product stability, we will require a low temperature cleanroom. The use of traditional industrial refrigeration systems, like evaporators inside the room, is not recommendable from a GMP point of view.

One example of these processes is the precipitation of human plasma proteins by centrifugation or filtration, usually under grade C. This process is well described here: Modern Plasma Fractionation.

Let’s see in this post which are the key points to consider for low temperature cleanroom design.

Traditional cold room not suitable for GMP classified environment applications

2. Air Changes

In low temperature cleanrooms, let’s say design temperature of 5 ± 3°C as an example, we will require a lower supply temperature to remove the generated heat in the room. Note that this supply temperature should be above 0°C to avoid freezing of the moisture contained in the air stream.

In our past post explaining the number of air changes normally used for Pharmaceutical HVAC design, we were discussing the importance of the heat gains. We should consider carefully this aspect because the difference between room temperature and supply temperature will be very close. If we design the room at 5°C, that means the maximum supply temperature should be 1°C. With a ΔT of only 4°C, it is likely probable that the air changes per hour required, exceeds the minimum number of air changes for room classification.

Following the same example, imagine we are designing a room with 25 Air Changes or a minimum air supply temperature of 1°C. The total room sensible heat (including people, lighting, equipment, transmission) of 4,500 W.

We obtain the following results:

By using the formulas described in the mentioned post About Air Changes the required airflow for compensating heat gains for a temperature difference of 4ºC is greater than the calculated for 25 Air Changes. So finally we have to design the system with almost 30 ACH.

Note that if there is present in the room high heat generation equipment, like centrifuges, the air changes could reach up to 60.

3. The Air Handling Unit

The specifications of the air handling units are crucial to a successful low temperature cleanroom design. We have two main risks that we need to solve by design:

• Condensation
• Freezing

Then, we should include the following in the specifications:

3.1. Avoid condensation

To minimize the risk of condensation and heat losses by transmission, we should avoid the standard panel thickness for conventional air handling units. Usually, manufacturers offer 50 or 60 mm. For our purposes, 60 mm should be the minimum thickness, and ideally, 80 mm.

We should also apply general construction characteristics for cleanroom applications, as we described in our post, Air Handling Unit Factory Acceptance Test (FAT). Special attention we should pay to the thermal bridge, source of the most condensation issues, with minimum classification TB1.

3.2. Avoid coils freezing

As mentioned, supplying air at a temperature close to 0ºC, and using as refrigerant fluid glycol water at negative temperatures, freezing of the coils is a risk quite probable. To avoid that we can use the following:

• Always install a temperature transmitter after the coils. This temperature will limit the cooling capacity of the coils.
• Always install a differential pressure transmitter to monitor the pressure drop across the coil. When the pressure drop is over 100 Pa, we can be sure that the coil is frozen, and we can get an alarm on the BMS, or proceed according to the following point.
• Install a double coil system in parallel with dampers. With this solution, when freezing is detected by the pressure transmitter, the system can change over the second coil. After each coil, we will install a damper that would close when the coil is frost.

The frosted inactive coil can then start the defrosting process. This is achieved thanks to an electrical resistance installed on it. This is the same principle performed in traditional cold rooms evaporators.

We will need to keep the glycol flowing through the coil. To avoid excessive heating a separate circuit will need a dedicated pump to maintain the loop temperature at the supply temperature set point (read from the temperature transmitter located after the coils before mentioned).

Also, be sure to install a stem heating element in the glycol water valve to avoid freezing!

4. Stratification Issues

Everybody knows that the air density increases at lower temperatures. In low temperature cleanroom design we have to take this into account. This is important because validation activities usually include testing of temperature uniformity. It is a good practice to locate the transmitter used for temperature control in the location where the uniformity study showed the highest temperature.

In the same way that in a normal temperature cleanroom (say 20 ºC) we require low level air returns for good air distribution throughout the room. This is the same for low temperature cleanrooms. Nevertheless, due to the higher air density, the upper level of the room air does not distribute conveniently.

Thus, the solution consists of installing air return grilles in the upper section of the air return column:

5. Duct insulation

The next point to consider is the duct insulation. We usually specify that the air supply is insulated for energy savings purposes and avoiding condensations. This is important still in low temperature cleanroom design, but even more.

Nevertheless, the designer does not always specify the air return ductwork insulation. The temperature is close to the room setpoint, and the risk of condensation decreases.

At last, in low temperature cleanrooms, we shall specify always air return insulation. The thickness recommendation is 60 mm for standard Armaflex type insulation, for instance.

6. Terminal HEPA housing insulation

Another important specification is the insulation of the terminal HEPA filter housings. We recommend installing stainless steel type, more resistant to corrosion than painted steel ones.

In the same way that the ductwork, it’s absolutely necessary to insulate the housing located in the technical area. Condensation in this point is more critical due to the housing is in contact with the cleanroom.

7. Humidity Control

If you have decided not to control humidity in a low temperature cleanroom (🤞), this chapter is not interesting for you. But you should be aware of such a decision. At lower temperatures, the risk of condensation is extremely high. On the other hand, the relative humidity could achieve values above 80%, which brings on the possibility of microorganism growth.

7.1 Use of dessiccant wheel

If the generated internal latent heat is not high (procured by just a few people inside the room), our main concern is to remove the humidity coming from the fresh air. In this case, the installation of a dedicated air dryer (with precooling) would decrease the fresh air humidity to a desirable handly value. We will consider this option depending on the condition of the existing fresh air existing in the plant, and the airflow.

Note that if there is present a dehumidification system for normal temperature AHU (up to 7-8 g/Kg), this is not enough for low temperature humidity control (2.5-3 g/Kg) and we will require an additional dehumidification system.

7.2 Use of a reheating system

Finally, with this system, we will control the room humidity in a similar way we control normal temperature cleanrooms. Leading the air stream close to the dew point and condensate the requested amount of water to satisfy the room humidity conditions. After that, the air passes through a heating coil to reach the supply temperature set point. See the post Cooling and dehumidification in Excel for more details.

Equally important is to pay attention to the possibility of heating fluid freezing when there is no request for reheating. The freezing could cause the breaking of the heating coil and we shall take the necessary measures to avoid that:

• Using a secondary loop using glycol. This will require a pump, expansion vessel, valves, etc.
• The same secondary circuit without glycol, but limiting the temperature of circulating water at a minimum of 1 ºC.

The first option is safer but more expensive.

8. Energy savings considerations

Cleanroom HVAC has traditionally a high energy consumption. This consumption even increases when the use is for low temperature applications. In order to mitigate this consumption, we can apply the following in the low temperature cleanroom design:

• If the process which requires low temperature is not being carried out in the room, the process BMS can communicate to the HVAC system a second higher temperature setpoint. When the signal is reversed, the system will go back to the first low temperature setpoint.

• In a similar way, if the airflow required is higher than the necessary per classification air changes per hour, the same BMS signal can automatically decrease the airflow reducing the fan energy consumption and enlarge HEPA filters life.

The transition between both setpoints takes place quickly for the airflow. But it’s slower for the temperature. To reduce the setpoint switch time, we can use both cooling coils described in section 3.2.