Operational Compliance Drives Cleanroom Design

November 2020 - Vol.17 No. 11 - Page #4
Category: Cleanrooms/Modular Cleanrooms

Maintaining a state of control in a sterile compounding cleanroom can be challenging, making it imperative that pharmacy staff understands the proper design considerations for engineering controls in a cleanroom suite. It is essential that staff be able to identify when designers and architects may be creating a compliant, but unrealistic, cleanroom. The goal is to create a cleanroom suite that complies with the requirements of USP <797>, but also ensures that a state of control will be maintained based on how the environment will be used. In other words, the cleanroom suite should be designed to achieve operational as well as regulatory compliance.

Pharmacy leaders are continually challenged with ensuring the cleanroom is compliant and suitable for preparing compounded sterile preparations (CSPs). Key to this goal is maintaining an appropriate state of control, which is determined by how well the cleanroom suite maintains operational functionality through engineering control design, such as room pressurization and proper air cleanliness levels. Beyond being compliant on paper, the ultimate goal is to maintain compliance during any worst-case conditions that could be encountered while compounding.

See the SIDEBAR for information about the evolution of operational compliance in a cleanroom suite.

Designing a Cleanroom

Designing and building a cleanroom requires a multidisciplinary team with demonstrated expertise. Pharmacy leadership must be highly involved. There is a risk at this point that the details of operational functionality may be overlooked. Architects and designers must consider the following:

  • Current operational workload
  • Number of pharmacy personnel
  • Future growth plans and service expansions
  • Inventory and storage capacity
  • Current and projected technology use

Evaluating current operations can clarify key requirements for the design of the new space. Are you having trouble maintaining a proper state of control? Was the cleanroom suite designed specifically for your current workflows and the number of staff typically in the cleanroom? There are plenty of cases where a new cleanroom is compliant with both USP and building codes, passes certification testing, and yet experiences repeated microbial excursions over time because the design team failed to account for the number of people and equipment occupying the environment.

This problem occurs in growing operations as well. When staff and equipment are added to the cleanroom with no concurrent changes to the engineering control design parameters, microbial excursions often ensue. Thus, the introduction of additional staff and equipment must prompt a re-evaluation of the space and the HVAC system to ensure the cleanroom can maintain a microbial state of control.

In addition to regularly scheduled meetings with the design team, once construction has begun, schedule regular walk-throughs to discuss the project’s progress. Initially, meeting frequency could be once a month and then become more frequent as the cleanroom construction phases progress.

Energy Conservation Challenges

Architects and designers face a daunting challenge in meeting the myriad building code and regulatory requirements while constructing a functional cleanroom suite. Perhaps the thorniest matter is resolving cost and energy efficiency issues related to the cleanroom’s environmental controls. Because cleanroom suites are not inherently energy efficient, architects and designers may struggle to balance energy and cost savings against the need to build a high-performing cleanroom.

It is important to communicate that sterile compounding cleanrooms should never be expected to follow energy conservation guidelines for conventional HVAC ventilation and environmental air quality. HVAC nightly set-backs, ACPH reductions, and overall reduced airflow design parameters must be avoided. Cleanroom suites are meant to run 24 hours a day, 7 days a week at high volumes of supply, return, and airflow pressures. Furthermore, HD cleanrooms require the external ventilation of conditioned air, which is a key component of ensuring worker safety.

Simply designing a cleanroom to the minimum standards in USP <797> is insufficient to ensure operational compliance. USP requires cleanrooms be designed to maintain air cleanliness levels under dynamic conditions specific to an ISO class. However, the ideal approach is to understand the specific ISO classification that will be needed to maintain environmental control under the worst case operational conditions and then design environmental controls to ensure that ISO classification can be met. Taking this more comprehensive approach ensures an organization will not end up with a compliant, but ineffectual, cleanroom suite.

Regulatory vs Operational Compliance

As we know, USP’s regulations simply establish the minimum requirement at which a facility can function. It is important to note that USP’s intent is not for individual facilities to operate at the bare minimum requirements only. Furthermore, USP does not state what steps to take if you follow minimum requirements and compliance cannot be achieved. So why not exceed the minimum requirements at the outset? This way you can ensure both regulatory and operational compliance. Operational compliance is achieved through a recognition of the many challenges a cleanroom suite will face, including:

  • Seasonal challenges
  • Personnel activity levels
  • Design concept and cleanroom furnishings
  • Inevitable aging and obsoletion
  • Mixed cleanroom suites requiring external ventilation

Determining the right amount of airflow is hard to predict even if you can accurately project future compounding operations. As such, organizations that achieve only the minimum USP requirements may find their regulatorily compliant design does not work, once actual operations begin. To offset this challenge, raising the minimum bar slightly will get airflow closer to the desired result.

Cleanroom suites containing both hazardous and nonhazardous buffer rooms that share a single ante-room must achieve ISO 7 classification for the entire cleanroom suite. However, the environmental controls may struggle to maintain the requirements of this ISO-classified environment. Because the ante-room serves as an ingress and egress space with garbing activity and a water source, a high number of microorganisms sourced from people and waterborne microorganisms will be present. This room must work hard to remove contaminants and keep them from migrating to adjacent ISO-classified spaces, so 30 air changes per hour (ACPH) may be insufficient. Further dilution of HEPA-filtered airflow and room-to-room pressurization will facilitate faster and more efficient contaminant reduction through strategically placed ceiling HEPA-filtration and returns/exhausts that are sited low on the wall.

The same HEPA-filtration and return/exhaust placement principles are utilized for ISO Class 7 buffer rooms. For nonhazardous buffer rooms, because the ISO Class 5 primary engineering controls (PECs) are recirculating HEPA-filtered devices, they add supplemental HEPA airflow to the environment, which helps filter and reduce particulates in the air. This supplemental engineering control combined with the facility engineering control provides a much greater total of ACPH for the ISO-classified buffer room. Therefore, this space is less likely to experience airflow issues. Nevertheless, requiring a higher HVAC airflow than the minimum requirements provides flexibility should issues arise. There is no maximum rate of ACPH that can be engineered for a particular buffer room. However, the importance must be set on ventilation of return airflow once it has been supplied to the space. Adding more air in a cleanroom space without considering how it will be exchanged increases turbulence that kicks up particulates and debris, which further challenges a microbial state of control.

Hazardous buffer rooms are more complicated as they must maintain both a microbial state of control and HD containment. Because the HD buffer room will be negative to the adjacent space, it is likely that contaminants and particulates will be drawn in from the activities occurring in the anteroom. This makes it crucial that the airflow engineering controls exceed the minimally required design in all HD buffer rooms in order to properly equip the room to maintain a microbial state of control while being externally vented. Proper airflow delivery and room pressure balance is critical to the success of this particular room design.

Addressing Aging Equipment

Like all equipment, HVAC systems will age and eventually become obsolete. The HEPA filters in the ceiling that filter the HVAC supply air age as well. Because filters collect dust, pollen, and particulates that contain microorganisms, filter loading is inevitable. HEPA filters will load to a degree where they no longer provide their original airflow supply rates.

HEPA filters lose the ability to deliver the airflow design within the first year of a newly built facility because of the effect the collection of particulates and debris have on HEPA filtration. Because of this, airflow rates of a new facility experience a strong decline from the original design within that first year. The evidence of this gradual airflow decline will be found within the first two certifications. This can be a major issue if the HVAC and facility parameters are built to the minimum airflow design. Within the first year, the cleanroom may not be able to meet the minimum ACPH or the airflow pressurization it was designed to have, due to the loading of the HEPA filters with no way to increase airflow or find balance in the system to accommodate the airflow decline. There are a few ways to combat this naturally occurring, aging facility issue:

  • Cleanroom suites must have a dedicated HVAC system separate from the system used in the main pharmacy or other departments. This allows for full control over the cleanroom’s environmental parameters, avoiding instances where neighboring departments need airflow balance, temperature, and humidity elements that conflict with the cleanroom suite’s needs.
  • Design the HVAC system benchmark to provide airflow delivery that achieves at least three-quarters of the maximum airflow required when all the HEPA filters are loaded consistently. Generally, when air flow rates decline, HVAC systems that have been designed for this occurrence can be adjusted to meet the original design parameters. This allows for an increase of airflow to balance the spaces that experience HEPA filter loading.
  • Implement a timeframe in which cleanroom suite HEPA filters will be replaced to regain lost airflow delivery. HEPA filters typically provide effective airflow delivery for 5-7 years, depending on the preventative maintenance schedule and seasonal effects on the HVAC system.

Significant Operational Elements

Effective work practices are key to maintaining a microbial state of control; those most likely to cause excursions are:

  • Hand hygiene and garbing
  • Material handling and transfer
  • General cleanroom behavior

If the microorganisms do not enter the facility, they are not problematic. This is where staff training becomes critical. Sterile compounding personnel must not only understand how to perform tasks like garbing and material transfer, but they also must grasp their importance, and recognize how inappropriate performance can negatively impact the cleanroom suite. A great way to demonstrate the impact of contamination is to share sampling results and the outcomes of excursion investigations with the cleanroom staff.


A well-functioning cleanroom that maintains a microbial state of control typically exceeds minimum regulatory compliance requirements. A pharmacy team culture that buys in to the principle of operational compliance is crucial to successfully maintaining a microbial state of control. While a complete state of control starts with a cleanroom carefully designed well above the USP <797> minimum requirements, it is ultimately maintained by a well-informed pharmacy team with a desire for both operational and regulatory compliance, rather than a box-checking mentality.

Adam J. West, NSF-49, RCP-SCF, is the environmental monitoring and training specialist for CriticalPoint, LLC.


Evolution of Operational Compliance

The fundamental element to achieving a complete state of control in the cleanroom is maintaining the microbial state of control. Nevertheless, pharmacy culture often focuses solely on regulatory compliance, too often asking: What is the least I need to do to be compliant with USP? Such an approach can be counterproductive as illustrated by many pharmacies’ initial response to the 2008 USP <797> requirement to perform viable environmental monitoring.

Many pharmacies turned to their cleanroom certifiers in response to the requirement to perform air and surface sampling in the primary and secondary engineering controls (PECs and SECs). It was not uncommon for hospital pharmacies to have repeated microbial excursions exceeding action levels, which caused those organizations to panic and desperately seek to recover zero colony forming units (CFUs); repeated microbial excursions exceeding action levels also made them think there were issues with their engineering controls. This was because viable sampling was now seen as part of certification and a direct indicator of engineering control functionality, as opposed to being an indicator of the overall state of control, including staff work practices.

Prior to this requirement for viable air and surface sampling, engineering control compliance was primarily achieved through certification. Certification compliance is simple: A failed device or room can be evaluated, repaired, and retested to confirm compliance. But microbial excursions are much harder to remediate, as the solution may require adjustments to both engineering controls and work practices.

At the time, many sterile compounding organizations did not understand what the exceeded levels really meant. Most facilities were cleaned and re-cleaned in an attempt to achieve compliant levels. Often, organizations would show exceeded results and would then wait until the next certification interval to see what the new results yielded. This inaction left state boards of pharmacy with no choice but to crack down on all sterile compounding organizations that had exceeded levels. This evolution of events created a culture focused on achieving zero CFUs; with zero CFUs, there is no state board scrutiny and facilities maintain compliance simply by passing certification. Unfortunately, this is not the microbial state of control USP had in mind by adding viable sampling to the Chapter.

The engineering control requirements in USP Chapter <797> (2008) for a sterile compounding cleanroom is a minimum design standard, essentially a watered down cGMP design. This challenges cleanroom suite functionality even before a facility is built. Minimum compliance cleanroom design reveals that engineering controls, furnishings, and fixtures contribute to the lack of desired operational compliance, a microbial state of control. However, there is more to being compliant than simply meeting the requirements of USP <797>. Effective engineering controls and work practice design are essential to reaching the desired state of control. It is the responsibility of pharmacy leadership to share with the design team what is needed to accomplish operational compliance.


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