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:
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.
The following methods can be applied to reduce energy consumption in cleanrooms:
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.
ISO 14644-161 dedicates chapter 6 to the calculation of the airflow rate, highlighting that the airflow contributes significantly to the cleanroom’s energy consumption. Therefore, a reduction of airflow rate leads to significant energy savings. In fact, the ventilation power by fans depends on the cube of the airflow rate:
Where P is power in watts and Q is flow rate in m 3 /s.
The standard introduces the types of air diffusion, the UDAF that removes the airborne contamination by displacement, and the non-unidirectional flow (air mixing, non-UDF) that reduces airborne contamination by dilution. It also describes the method to calculate the airflow for non-UDAF to dilute the airborne contaminants. The equation adopted for the calculation is reported in Annex A:1
Where Qs is flow rate (m 3 /s); D is the rate of emission of particles or microbe-carrying particles (MCPs) from sources of contamination (counts/s); C is the limit of particles/m 3 or MCPs/m 3 in the environment, and ε is ventilation efficiency.
| Source | Sterile Production | Nonsterile Production |
|---|---|---|
| • USA FDA aseptic guidance 5 | • 20 ACH | |
| • EU GMP 3 | • Cleanup period 15–20 min | |
| • ISPE Good Practice Guide: Heating, Ventilation, and Air Conditioning 6 | • 6–20 ACH for CNC (EU Grade D) spaces • 20–40 ACH for Grade 8 (EU Grade C) spaces • 40–60 ACH for Grade 7 (EU Grade B) spaces | |
| • WHO 7 | • 6–20 ACH |
Due to the uncertainty of the data at the design stage, the standard suggests adopting a compensation factor, expressed in paragraph 6.3.3 as follows:1
a) as a margin for particle concentration limit alert levels, for example, ISO 7 class limit, Cclass, is 352,000 particles/m 3 for particles ≥ 0.5 μm, but, for process reasons, its alert level, Clim, can be chosen as 100,000 particles/m 3 , or even 50,000 particles/m 3 ; and b) as a margin for particle removal effectiveness by lowering the predicted CRE [contamination removal efficiency] or ACE [air change effectiveness] to values less than 1.0 if air distribution is deemed to be not good enough.
Several studies regarding the sources of contaminant emissions were carried out by Ljungqvist and Reinmuller. In an interesting article, Romano and colleagues9 evaluate emissions from personnel, determine the main source of contamination, test different types of clothing worn by operators, and simulate different movements of the operator in a cleanroom. Chapter 5.2 of ISO 14644-16 establishes that “the required cleanroom garment levels should also be specified in the URS since they play a vital role in controlling particulate contamination.” 1
The emission of MCPs from process equipment is usually considered negligible. However, the process equipment supplier should provide data for the emission of nonviable contaminants. If this information is not available, ISO 14644-16 mentions that ISO 14644-1410 describes a method to determine the emission of particles from equipment. (The literature provides measured values of particle emissions from some process equipment.)11
In relation to ventilation efficiency, ISO 14644-16 specifies two types of ventilation efficiency: CRE and ACE. ACE is determined according to AN-SI/ASHRAE 129-1997,12 which relates the nominal time constant to the age of the air at a point:
Where Tn is the nominal time constant, equal to 1/N (room air changes), and Ai is the air age at measuring point, equal to 1/ni (local time changes).
Whyte13 demonstrated that the ACE value can also be calculated as the ratio between the air changes at the measuring point and the nominal air changes in the room. The air changes can be calculated from the particle decay as follows:
Where t is the time to switch from initial concentration, C0, to final concentration, C.
Then the value of ACE is calculated as:
The CRE ventilation efficiency is calculated as follows:
Though the ASHRAE standard defines how to measure and calculate the ACE value, there is no standard for the CRE value.
The CRE coefficient is used when the contamination comes from a precise, fixed source. The CRE index gives information about the ability of the ventilation system to control the contaminants emitted from a specific source but does not provide any information about the efficiency of the cleanroom's ventilation system, and it cannot be used to predict the level of airborne contamination that could be reached in the cleanroom.
Considering that the source of contamination in a cleanroom is not always located at a fixed point (for example, the operators in cleanroom), the suggestion is to use the ACE index to calculate the airflow rate.
ISO 14644-16 Appendix A.2.2 states that, “in the majority of cleanrooms, the main contamination problem is caused by personnel who move freely about the room. In that situation, the aim should be to ensure that sufficient contamination-free air reaches the critical location(s) to ensure the required concentration of contamination.”1
The air diffusion system should be designed to reach an ACE index as close as possible to 1, the perfect mixing. If the value is less than 1, it means that less “clean” air reaches the point of measurement, whereas if the value is greater than 1, it means that more “clean” air reaches that point.
The ACE index depends on the type of air diffuser. Figure 1 shows a HEPA filter with and without a diffuser. (ISO 14644-16 defines a diffuser as a “device placed on inlet air supply terminal to improve distribution of incoming air with room air. A mesh grille or a perforated screen is not considered to be a diffuser.” )1
In a diffusion air system with a HEPA filter without a diffuser, most of the air is supplied directly under the HEPA filter, where the cleanliness level is greater than in the rest of the room. Accordingly, the ACE index under the filter shall be greater than 1, whereas in the rest of the room it will be less than 1. In this situation, the air diffusion shall not be homogenous with consequent nonhomogeneous particle concentration in the cleanroom, and nonhomogeneous room volume temperature. The nonhomogeneous room temperatures may cause discomfort for operators and, more importantly, may lead to uncontrolled air currents in the cleanroom, increasing the risk of product contamination.
If the same degree of cleanliness is required throughout the room—a necessary condition when the emission sources of contaminants are not fixed in space and time—air diffusion with a HEPA filter without a diffuser would not be the most suitable option. Air diffusion with a HEPA filter without a diffuser creates a sort of unidirectional flow, which is required when a higher cleanliness class is necessary to protect a zone locally—for example, the point of the vessel loading in a preparation room.
In summary, in a cleanroom with non-UDAF, the supply airflow is calculated with equation 1, where the ACE index is determined with consideration given to:
It is also worth considering Eaton’s analysis of cleanroom contamination measurements,16 where, after verifying the contamination class of the room according to ISO 14644-1 (2015 version),17 it was found that the contamination value was above the limit at a point. Following this, the ACE index was verified at each point of the cleanroom, and at the point where the contamination was very high, the ACE index was much lower than 1, meaning there was bad air distribution in proximity of a source of particle emission [16]. In conclusion, it is reasonable for the calculation of the airflow to consider an ACE value of 0.7 when the air is supplied in the cleanroom with high-induction diffusers and is extracted through floor-level return.
Thus far, the airflow rate has been calculated using equation 1, which considers cleanroom contamination sources. But pharmaceutical cleanrooms must also satisfy the “cleanup” period requirement, as indicated in the EU GMP Guide, Annex 1.3 The cleanup period can be calculated using equation 3, integrated with the ACE index, as follows:
Having defined the cleanup period, this equation can also be used to calculate the airflow for an air lock, material, or personnel.
Table 2 presents the results of the airflow calculated with equation 1 (dependent on the source of contamination) and equation 4 (dependent on cleanup period). The airflow due to cleanup period is greater than the airflow due to contamination sources (airflow is expressed as air changes).
| Cleanroom surface (m 2 ) | 100 | ||
| Cleanroom volume (m 3 ) | 300 | ||
| Nonviable 0.5 m | Viable MPCs | Cleanup Time | |
| EU GMP Grade C limit (operational): Airborne contamination, cleanup time | 3,520,000 part/m 3 | 100 MCP/m 3 | 15–20 min |
| Alert limit/m 3 (considering a compensation factor of 30% of the limit) | 1,000,000 | 35 | |
| Cleanup period limit | 15 min C = 352,000 C0 = 3,520,000 | ||
| Total particle and MPS dispersion rate per second, due to 10 people (emission rate per person: 15,000 part/s of 0.5μm, and 2MCP/s) | 150,000 | 20 | |
| ACE | 0.7 | 0.7 | 0.7 |
| Calculated air change, ACH | 2.6 | 9.8 | 13.2 |
Note: The higher air change shown in the table (13.2 ACH) is lower than the minimum US FDA–required ACH (20 ACH).5
