01 December 2023

Pharmaceutical Cleanroom Design & ISO 14644-16

Cleanrooms and controlled contamination environments are increasingly being used across many industrial sectors, including the pharmaceutical industry. An important issue is the operating cost associated with cleanroom energy consumption and, consequently, the identification of applicable energy containment measures. This article reviews pharmaceutical cleanroom calculations for non-unidirectional airflow against energy consumption with known sources of contamination and type of air diffusion used. It proposes alternative cases to compare potential economic savings from applying energy-saving measures proposed by ISO 14644-16.1

Pharmaceutical cleanrooms can consume up to 15 times more energy than commercial building systems, with more than 50% of electricity being consumed by plant HVAC cleanroom systems.2 This level of energy consumption is driven by the high air change rates required to ensure the air quality of pharmaceutical production.

Typically, there are two ways to control airborne contamination: a displacement system with unidirectional airflow (UDAF) or a system providing dilution, non-UDAF. Because systems that use UDAF systems have very high airflows, they are not considered here.

When designing a cleanroom with non-UDAF flow, it is important to ensure:

Environmental contamination is below the limits defined in the user requirement specification (URS).
The HVAC system is able to control thermal loads to meet temperature and relative humidity environmental requirements.
The external airflow rate is adequate to maintain space pressurization to compensate for leakage from/to the cleanroom and to account for process air discharge/consumption.
The airflow rate is sufficient to ensure that the time of cleanroom cleanup is below defined limits. (This requirement is applied to the pharmaceutical cleanroom to ensure compliance with European GMP.)3

The energy efficiency of the cleanroom, including the HVAC system, is subordinate to the reliability and performance of the pharmaceutical process. During the design phase of the cleanroom, the extent of the contaminant source is unknown. To define the airflow rate, designers often rely on industry guidelines. This choice can lead to oversizing the HVAC system, which results in high capital and operating costs.

ISO 14644-16, Part 16, “Energy Efficiency in Cleanrooms and Separative Devices,”1 prescribes a set of recommendations for energy efficiency in cleanrooms and the optimization techniques applicable in every stage of cleanroom life, including airflow rate design.

ENERGY-SAVING METHODS

The following methods can be applied to reduce energy consumption in cleanrooms:

Minimizing cleanroom size.
Avoiding over specification of the contamination class.
Installing low-pressure drop HEPA filters.
Reducing make-up air due to air leakage between two rooms at different pressures, sealing the cleanroom structure (walls, terminal HEPA filters, lamps), and sealing and testing air ducts.
Minimizing the number of people in the cleanroom. This can be accomplished with technologies that require the presence of a reduced number of operating personnel, such as processes with closed systems, restricted access barrier systems (RABS), and isolators. (A comparison between RABS and isolator technology and relevant operating cost was presented during an Associazione per lo Studio e il Controllo della Contaminazione Ambientale [Italian Association of Contamination Control] conference.)4
Properly selecting consumables used in cleanrooms and operator clothing.
Reducing the airflow during the at-rest condition of the cleanroom.
Avoiding overdesign of airflow rates.

REFERENCE STANDARDS FOR AIR CHANGES

Many cleanroom regulations and standards do not specify air changes and leave it to the project designer to analyze and define these values, which are important cleanroom design parameters. However, research of regulations and standards documents found a guidance value of 20 air changes per hour (ACH) and a guidance time of 15–20 minutes for cleanup (also called recovery) time. (Table 1 shows the recommended values of air changes across various standards.)3 ,5 ,6 ,7

For Class 100,000/ISO 8 supporting rooms, airflow that is sufficient to achieve at least 20 ACH is typically acceptable. Significantly higher ACH rates are normally needed for Class 10,000/ISO 7, Class 1,000/ISO 6, and Class 100/ISO 5 areas.5

The World Health Organization (WHO) 2019 technical report for nonsterile drugs states, “The number of air changes or air-exchange rates should be sufficient. A guidance value is between 6 and 20 air changes per hour.” It further outlines that manufacturers should establish “how much time it takes for a room that is out of its classification to return within the specified class,” which is often referred to as cleanup or recovery time, and offers a guidance period of 15–20 minutes.7

In the latest revision of the EU GMP,4 the indication on minimum air changes was removed, but the guide retained the requirement of a “cleanup period” of 15–20 minutes.

The ISPE Baseline Guide, Vol. 3, Sterile Product Manufacturing Facilities7 makes explicit reference to the ISPE Good Practice Guide: Heating, Ventilation, and Air Conditioning.8 The latter publication defines the air changes to be applied during the conceptual design phase with the intention to revise and reduce them in the next phase—detail design—when more detailed information about process operation and personnel (number of opera-tors, type of garments worn) will be available.