There’s Something in the Air – Cleanroom Technology in the Pharmaceutical Industry

Excerpt from the 60th episode of the webcast GMP & TEA

6 min. reading time | by Thomas Peither 
Published in LOGFILE 11/2026

In pharmaceutical manufacturing, clean air is not a subjective perception but a precisely controlled technical condition that is essential for product safety. Heating, ventilation and air-conditioning (HVAC) systems ensure, through airflow management, air filtration and pressure control, that particles and microorganisms are kept away from critical areas. This is based on clearly defined requirements for air changes, cleanliness classes, airflow patterns and pressure concepts, all of which are designed according to the manufacturing process and contamination risk involved.

In everyday life, clean air is mainly a subjective sensation. In pharmaceutical manufacturing, however, it is an exactly defined and controlled condition. The quality of the room air has a direct impact on the safety of pharmaceutical products.

Cleanroom and ventilation technology are intended to prevent particles or microorganisms from entering critical production areas. Behind this task lies a complex interaction of airflow management, air filtration, pressure control and system design.

In the latest episode, “There’s Something in the Air – Cleanroom Technology in the Pharmaceutical Industry”, of our GMP & TEA webcast, I discuss the fundamental structure of HVAC systems, as well as their design and configuration. Further valuable information can be found in Chapter 3.I Air Handling Technology in our GMP Compliance Adviser.

In this article, I address some of the questions answered during the webcast.

How do HVAC systems work?

In principle, they distribute cleaned air evenly throughout the room with as little turbulence as possible, with the aim of not stirring up contaminants but instead removing them in a controlled manner. Strong deflections of the airflow are therefore avoided.

One central function of HVAC technology is ventilation, in which room air is replaced by pre-conditioned and filtered outside air. This process is referred to as the air change or air change rate. This should be distinguished from the air change rate used in cleanroom technology, which indicates how often the total air volume of a room is recirculated by the supplied airflow.

What must the system achieve in the specific manufacturing process?

In addition to the functional description, user requirements must also be known, including the external conditions and site-specific circumstances, the premises, production parameters, room climate and particle/microbial emissions, and finally the requirements resulting from the layout.

All these points are documented in the User Requirements Specification (URS) and form the binding basis for planning and plant construction. On this basis, the Functional Design Specification (FDS) containing specific technical performance data is developed.

Three factors are particularly decisive for the future economic efficiency of an HVAC system: the required air volume flow, the proportion of outside air and the thermal loads of the individual rooms.

Another important parameter in the technical design is the degree of turbulence in the cleanroom, i.e. fluctuations in air velocity. If this is too high, it may prevent the rapid removal of airborne contaminants.

One point is crucial in all these considerations: only when all conditions and requirements are known and specified can an optimal HVAC system be designed. For this reason, it is best practice to compile all relevant data in a room data sheet or room book and share it with the entire planning and implementation team. If this compilation is updated at every stage of the project, it can serve as the basis for subsequent calculations and qualification activities.

Based on the defined requirements and conditions, a room-specific performance table is generally prepared, summarising all important data required for the engineering design of the air-handling system. In addition to general data such as room number, designation, area, height and volume, it should contain at least the following information:

• the intended use,
• the maximum permitted number of personnel,
• design values for supply air, exhaust air and outside air volumes,  
• air volumes of special ventilation systems and transfer air volumes, and  
• finally, the required cleanliness classes.

From this, thermal loads – meaning heating and cooling requirements – as well as the required outside air proportion are calculated. The air volume flow is derived from the contaminant concentration, whereby particle and microbial emissions from personnel may also be taken into account.

As mentioned, the design and structure of an HVAC system depend on the cleanroom requirements and the prevailing conditions.

Several criteria play a role in the selection process:

• the influence of outside air,
• the use of recirculated air,
• climatic conditions,
• energy efficiency and CO₂ emissions,
• life-cycle cost considerations,
• cleanliness requirements, and
• the desired flexibility.

In pharmaceutical manufacturing, four systems are primarily used:

• 100% fresh-air systems,
• central recirculation/mixed-air systems,
• decentralised recirculation/mixed-air systems with central fresh-air treatment, and
• pure recirculation systems.

The choice of system depends on the risk of possible airborne contamination pathways described in the Contamination Control Strategy (CCS). For example, airborne transmission is only relevant if a stable aerosol is generated that can be transported through the air.

In principle, HVAC systems consist of three components:

• air treatment in an air-handling unit,
• air distribution, and finally
• air delivery via supply and exhaust air terminals.

The clean area lies between the supply and exhaust air terminals. This means that the cleanliness of the supply air and the airflow pattern within the cleanroom or production area can influence the product.

Components located outside the cleanroom are generally less critical. A possible influence from the surrounding air only exists when the product is exposed to the ambient atmosphere. Potential contamination depends on the size of the “contamination surface”, the duration of exposure and the subsequent process steps.

I would now like to present the four different HVAC system concepts in somewhat greater detail.

100% fresh-air systems

In a pure fresh-air system, the supply air consists of 100% outside air, conditioned to the defined values for temperature, humidity and cleanliness.

Such a system eliminates the possibility of contaminants entering the supply air system via the exhaust air system. They are used when different production areas are supplied by a common HVAC system or when the exhaust air from rooms is so heavily contaminated that the filtration stages cannot guarantee safe elimination of pollutants.

Pure fresh-air systems are highly flexible. At any time, a production facility can be supplied for another product group with different requirements without any risk of cross-contamination. The only exception is penicillin production, which always requires a dedicated ventilation system.

Central recirculation or mixed-air systems

In central recirculation or mixed-air systems, the supply air consists of outside air and recirculated air. The respective proportions may be fixed or variably controlled, for example depending on outside temperature or the CO₂ content of the room exhaust air.

In cleanroom areas with constant room conditions, however, variable control of the outside air rate usually offers little energy-saving benefit, as the number of days per year on which outside air conditions correspond to supply air conditions is low.

Depending on the number of people working in a room or the pollutant load, the legally compliant minimum proportion of outside air must of course not be undershot.

Central recirculation or mixed-air systems are used in mono-production facilities when pollutant concentrations in the exhaust air are so low that they can be safely eliminated, or when no contamination risk exists and direct heat recovery is possible without additional heat exchangers.

What are the disadvantages of these systems? Their flexibility is limited, because product changes always require a renewed assessment of the cross-contamination risk.

Decentralised recirculation/mixed-air systems with central fresh-air treatment

In decentralised recirculation/mixed-air systems with central fresh-air treatment, the supply and exhaust air of a room or zone are circulated via a recirculation unit. The outside air is centrally conditioned, thereby ensuring the required outside air proportion for personnel in accordance with workplace regulations or pollutant loads.

The recirculation unit is generally equipped with a heat exchanger and an additional filtration stage for return air from the production area.

These systems are frequently installed where different production areas are supplied by a common fresh-air treatment system and where pollutant concentrations in the exhaust air are low enough for the contaminants to be safely eliminated through the cleaning/filter stages of the decentralised recirculation system.

These systems do not present any cross-contamination risk between different production zones and offer energy advantages at minimal outside air proportions, as only the outside air portion requires thermal treatment.

Pure recirculation systems

Pure recirculation systems exclusively recirculate room air without additional outside air.

Typical applications include locally high-grade cleanroom zones within a cleanroom, partially separated areas with restricted access, so-called RABS, isolators or clean benches.

Special applications also exist for rooms with controlled temperature or humidity conditions that differ from the surrounding room conditions, such as storage, refrigerated or deep-freeze rooms.

Pure recirculation systems are only suitable for areas where personnel are not permanently present or where an existing room ventilation system ensures the supply of outside air.

Recirculation systems can be implemented using an air-handling unit, filter-fan modules or stand-alone modules. The latter allow easy retrofitting, for example to increase the air change rate within a room or to supply areas with elevated particle generation.

Which concepts exist for the protection of clean areas?

Material transport and personnel movement between adjacent clean areas always increase the risk of transferring contaminants. Therefore, a well-designed layout and the organisation of material and personnel flows are particularly important.

Annex 1 of the EU GMP Guide therefore refers to separate airlocks for personnel and materials. Unidirectional personnel airlocks for entry into and exit from Grade B areas are desirable but not mandatory.

Where physical separation is not possible, at least temporal separation is required – defined on a risk basis and documented in the Contamination Control Strategy.

In principle, there are three ways of reducing the risk of airborne contamination from adjacent areas:

•  Physical separation: walls, airlocks, isolators or RABS systems create clear barriers between rooms with different requirements.
• Displacement airflow concept: here, a directed airflow – typically between 0.2 and 0.6 m/s – protects the cleaner area. This concept is used when a higher-grade clean zone is required within a cleanroom or when two clean areas of different classifications are connected via a transfer or sterilisation tunnel. In such cases, an overpressure concept is technically not practical.
• Pressure differential concept: this is probably the most commonly used method in pharmaceutical facilities. Higher pressure in the cleaner area causes air to flow in a controlled manner towards adjacent areas with lower cleanliness classifications. In facilities with several rooms of different cleanliness classes, a so-called pressure cascade is created.

The often-cited guideline values of 10 to 15 pascals pressure difference are historical reference values. Technically, airflow transfer already functions with a positive pressure differential.

Far more important than high values is stable control and reliable door functionality. Excessive pressure levels can cause turbulence, noise and operational problems.

Pressure differentials should always be defined on a risk basis rather than according to fixed standard values. Modern airtight construction methods significantly reduce infiltration, and even short-term pressure reversals generally have little influence on the process area provided that room airflow remains stable.

Do you have any questions or suggestions? Please contact us at: redaktion@gmp-verlag.de