Heating, ventilation, and air conditioning (HVAC) systems must perform myriad functions for a pharmacy cleanroom, including providing compounders with a comfortable environment while maintaining appropriate levels of humidity and temperature, as well as facilitating compliance with USP standards for ISO-classified spaces such as differential pressures, ACPHs, particle counts, and bioburden limits of the air. In an effort to optimize cleanroom design and workflow practices, AdventHealth utilizes the data from its robust environmental monitoring (EM) program to evaluate how HVAC needs vary across different pharmacies (see the SIDEBAR). Though all AdventHealth’s cleanroom construction projects (including those that happened before the EM program was centralized) employ a team of engineers, architects, and designers, the data derived from our EM program provides further direction to help drive the HVAC decisions for both new design projects and renovations. To maintain compliance and prevent HVAC systems from contributing to environmental failure of required parameters, it is important that all components of the system are customized to each particular cleanroom space.

Size Considerations

Many factors influence appropriate HVAC size (see the FIGURE). The design of a cleanroom HVAC system is particularly complex in that it must have the ability to change air at rates around 30 air changes per hour (ACPH), whereas in comparison, the average home has a rate of .35 ACPH, and an office typically has 3 to 5 ACPH.1 While cleanroom design companies and HVAC providers understand these considerations, an HVAC engineer, preferably with cleanroom expertise, can be helpful in making the right selection. This individual is often separate from a standard cleanroom design or construction company and is skilled in ensuring that ducting and electricity (including any transfer switches for emergency power) are properly designed for efficiency and reliability. As the client, it is important to provide information such as the square footage of the cleanroom space, the maximum occupancy of the suite, and the usage of the suite. In this context, usage refers to how often the cleanroom will be in use (eg, 24 hours a day for 7 days a week versus a single shift on weekdays only) and how many people will be in the cleanroom on average.

Maximum suite occupancy and the function of each room is another key factor in HVAC selection, as these factors can increase the amount of expected bioburden. Since cleanrooms are always “on,” the expected run time may not seem relevant; however, the number of hours a day that the room will be truly operational is important since this represents when the room will be burdened with people and materials. Once operational hours are established, HVAC engineers will request target ACPH which drives the appropriate airflow needed. While air change formulas and interactive calculators are available online, it is important to remember that these determinations are complex and may not be easily determined by a single formula. Engineers will take many factors into account to identify the best ACPH for each space. Beware of advice to simply reference another cleanroom of similar size to determine ACPH without considering each facility’s unique needs and operations.

Temperature Considerations

The most common issue the PMQS detects with HVAC is temperature. Compounding personnel, especially those following best practices and covering almost all their skin with coveralls and face shields or goggles, may find that temperatures which are “cool” for an office feel sweltering and uncomfortable when wearing PPE. Warm and uncomfortable personnel sweat, shed more rapidly, and are more likely to touch their face and body during their time in the cleanroom. This means more risk to shedding on a surface and spreading touch contamination due to adjusting garbing and touching their faces.

USP <797> specifies a temperature of 68°F or cooler is appropriate for the cleanroom.2 How much cooler than that minimum standard a facility might need will depend largely on garbing and how much movement and traffic there will be. Older HVAC systems that were not originally designed to meet the current specifications may only meet temperatures at the minimum ranges of these requirements. When selecting a new or replacement HVAC system, identifying the target temperature for the area (and the number of hours per day the HVAC needs to produce that consistent temperature) will help your engineers select the right system capacity.

Without knowing the target temperature or justification for why a minimum should be exceeded, facilities may run into the following challenges:

• Design teams may assume the minimum standard of 68°F is the target.
• Finance teams may have a harder time approving added cost without a clear understanding of the justification.

Our EM data has shown positive correlations with facilities using more coverage, like coveralls, combined with appropriate temperatures. Ultimately, the best combination is that which keeps your operators comfortable.

Air- vs Water-Chilled Units

There are two types of HVAC units available for consideration: air-chilled and water-chilled. AdventHealth utilizes both air- and water-chilled HVAC units at various locations across the system and has found each system performs equally. This similar efficacy may be due to the preventative maintenance (PM) schedules employed at each hospital. While someone may have their home HVAC system looked at once or twice a year, the systems at AdventHealth are inspected and preventatively maintained monthly or even more frequently, including measures such as filter inspection, filter changes, cleaning, etc. This rigorous PM program applies whether a facility has air-chilled or water-chilled units.

Determining the appropriate system involves many factors such as space availability and whether running water to the system is possible. Of note, at free-standing locations without a dedicated engineering department and where PMs are more difficult, we tend to see more frequent temperature issues.

There are some general pros and cons to either type that are important to note when choosing a unit (see the TABLE).

Compatibility of Valves and Controllers

Ensure valves and controllers are compatible with the building’s automation and monitoring systems. At a handful of AdventHealth sites, vendors recommended a brand of controllers and sensors that differed from our system’s standard. Before the effort to centralize projects under a set of standards established by our PMQS Team, there were sometimes decisions like these that had preventable, lasting effects. The implementation of these controllers and sensors led to compatability issues with our building automation and control system every time there was an update or a patch to the system. Consequently, the health system has spent tens of thousands of dollars replacing the valves with compatible products.

Utilizing Dedicated Systems

If the budget permits, utilizing a dedicated HVAC system for the cleanroom space that is separate from the general pharmacy and hospital system can be advantageous. A dedicated HVAC system for the cleanroom space allows for easier balancing of pressures and maintenance scheduling compared to those systems shared throughout various areas of the facility. When sharing an HVAC system, often times compounding operations are interrupted, and other hospital operations may be affected. This is particularly common for pharmacies located on multiple floors (a common practice for multi-tower hospitals) and for pharmacy systems that are interconnected with other departments, such as labs. In these instances, outages or adjustments can have significant downstream effects.

Fan Filter Units

HEPA filters with dedicated fans, often referred to as fan filter units, can control airflow directly at the outlet of the HVAC system. These units are not necessary for a well-functioning cleanroom, but they can make it easier to achieve and maintain the velocities and ACPHs needed to reach ISO classification requirements. Many of the cleanrooms in our system do not have these, and the viable air recoveries have been minimal to nil. If the budget allows it, and you have an in-house engineering team with the expertise to support it, these may offer added benefit, but they are not necessary in all spaces.

UV and Ozone Systems

Germicidal ultraviolet wavelengths (UV-C: Peak Effectiveness 240 nm – 280 nm) have been used for decades in air and surface disinfection.3 They may be employed within a room to improve air quality by disinfecting the air above room occupants and for surface disinfection. UV-C can also be employed within HVAC systems, disinfecting the air and internal HVAC surfaces. While UV-C disinfection has limited efficacy against fungi and bacterial spores unless extended exposure is achieved, it is effective against viruses and bacteria.3 Terminal HEPA filtration at the supply vent will theoretically remove 99.97% of contamination within the HVAC system before it enters the cleanroom if the HEPA filters are intact and properly installed.3,4 To maximize these benefits, it is important to regularly test HEPA filters for leakage, inspect for damage, and replace the filters on a regular schedule.

Conversely, disinfecting surfaces using a sporicidal agent has a faster contact time and is easily applied to all surfaces requiring disinfection; UV-C can only disinfect surfaces that it can “shine” onto. Thus, we recommend that design considerations for air and surface cleaning be centered on HEPA filter integrity, maintaining appropriate ACPH, and routine cleaning and disinfecting. If a system is functioning as it should but air contamination issues persist, it is important to address the root cause of the contamination.

Air Cleaning Devices

Air cleaning devices are free-standing devices that use HEPA filtration to remove air microbial contaminants (sometimes called air scrubbers). Some may also include UV-C and other disinfection methods to inactivate microbial contaminants. These systems are typically deployed in hospital settings in critical care environments that serve severely immunocompromised patients. They are portable making it possible to move the device between patient rooms.

These devices have limited application in pharmacies with cleanrooms that work as intended. Cleanrooms should be designed and built in a way that they achieve the standards without the need for devices like this. In instances when repeated viable air results are recovered from a cleanroom space where engineering controls and HVAC are found to be contributing, there may be some use of these devices to additionally filter the air, but even then, resources are better served to correct the issue. In a new cleanroom design, even if it is tempting to use these devices due to their portability or cost as compared to a well-engineered HVAC system, our data shows that they are not a cure-all. During a remediation attempt of above action-level viable air recoveries, it is important to identify the root cause and remediate to that root cause. If a facility has not invested, or there is not a justification to invest in a cleanroom based on the type of compounding/volume/dating needs, that compounding is happening in a segregated compounding area. Air scrubbers may offer additional risk mitigation in these environments.

Redundancy and Contingency Plan

In addition to local and state requirements, HVAC engineering and construction partners can be your best guide for HVAC redundancy planning if operational leaders can effectively explain what “down-time” would mean for your facility. If your facility cannot afford down-time and down-time could mean catastrophic interruptions to patient care, this would call for a different plan than one where immediate compounding may be an option.

Generally, an N+1 approach to HVAC redundancies helps facilitate seamless operations if/when components fail over time. Determine the number of a particular component needed to meet minimum requirements and include one additional redundant unit within the HVAC system as a backup. Redundancy considerations include but are not limited to chillers, steam boilers, heat exchangers, water pumps, air handling units, and fans. There are some workarounds and alternatives that may be available if the redundancies are cost-prohibitive. Because of the lead time on mechanical parts, including those involving the HVAC system, having backup parts of critical components can minimize dreaded down-times. In large health systems, standardizing brands and models makes it so these backup parts can be used in any site that follows the standards.

If a cleanroom experiences issues with the HVAC system, there are options available for continued safe compounding to ensure patient care continuity without increasing the risks to patients. One such option is temporarily classifying a cleanroom space as an SCA with immediate use to 12-hour BUDs. This ensures that patients receive necessary medication with minimal interruption. Because of issues with the HVAC in this instance, we recommend conducting viable environmental sampling, including viable air, as soon as possible to confirm that the room is still maintaining a clean environment. Each facility should perform a risk assessment to formulate the right plan and assess the different options. There is not a one-size fits all plan since many variables introducing different levels of risk exist depending on the severity and scope of an excursion.

If HVAC issues create unsafe compounding environments, consider renting a mobile compounding pharmacy for temporary compounding while the suite is out of commission or under construction. Options include self-contained trailers or modular cleanrooms set up with another room temporarily providing an ISO-certified compounding space.

Conclusion

HVAC systems comprise numerous components that function in harmony to ensure comfort and compliance within a cleanroom space. While all cleanrooms require an HVAC system, each space has unique needs and considerations to avoid environmental failure. It is important to work in tandem with design and HVAC experts to ensure a smooth operation within each space.

References

1. Ventilation in Buildings. Centers for Disease Control and Prevention. Published February 11, 2020. https://www.cdc.gov/coronavirus/2019-ncov/community/ventilation.html
2. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding – Sterile Preparations. USP 42-NF 37, 2023.
3. Rutala WA, Weber DJ, and the Healthcare Infection Control Practices Advisory Committee. Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008. Centers For Disease Control; 2008;55. www.cdc.gov/infectioncontrol/pdf/guidelines/disinfection-guidelines-H.pdf
4. US EPA. What is a HEPA filter?. Published February 19, 2019. www.epa.gov/indoor-air-quality-iaq/what-hepa-filter

Christine Hong, BS, is the pharmacy quality assurance manager at AdventHealth, where she led the development of AdventHealth’s Pharmacy Microbiological Quality Services (PMQS) program and oversees the program’s services including viable sampling and analysis, investigations, cleanroom design review, and contamination control studies. Christine graduated from the University of Central Florida with a bachelor’s degree in microbiology and molecular biology (biomedical sci-ences) and health services administration.

Michael Maynard, BS, is a senior pharmacy environmental microbiology analyst at AdventHealth. As a subject matter expert in aseptic technique and cleanroom quality, Michael aided in the development of AdventHealth’s PMQS program. He earned his bachelor of science degree in biotechnology from the University of Central Florida.

Brandon Duncanson, MS, is a senior pharmacy environmental microbiology analyst at AdventHealth. Brandon has 7 years of experience working in cleanrooms and biosafety level 2 & 3 containment laboratories and plays a vital role in the continuing evolution of the PMQS services at AdventHealth. He earned his bachelor of science in microbiology from the University of Florida and his master of science in microbiology from Georgetown University.

SIDEBAR

AdventHealth’s Cleanroom Design Series

AdventHealth is committed to continuously reviewing its sites to identify potential quality improvement opportunities, thereby increasing patient safety. The health system currently includes 52 hospitals and numerous infusion centers with pharmacies across the country; a large number of these facilitie are located Florida where the team is based. In 2019, AdventHealth standardized its environmental monitoring (EM) program across 28 pharmacy locations and soon expanded the scope of their specialized team beyond environmental monitoring, calling it Pharmacy Microbiological Quality Services (PMQS). This dedicated team regularly collects and analyzes samples and trended data, working collaboratively with other members of the pharmacy department including operations, infection prevention leaders, the office of design and construction, and the engineering department to execute improvement projects informed by the EM data. For more information on this topic, see the following Pharmacy Purchasing and Products’ articles from the AdventHealth team:

• Part 1: PECs (July 2023)
• Part 2: Design for Contamination Control (November 2023)
• Part 3: Optimize Airflow in Cleanroom Design (January 2024))