Compounding hazardous drugs is a chemically volatile process, which means that tight control of air pressure, temperature, and humidity is required. Thus, when designing compounding areas, it is critical to determine an acceptable time delay before alarming and when and how often to report these values when out of compliance. Most mechanical systems are not capable of operating perfectly in all conditions due to many factors, including weather conditions, occupant demands, and maintenance, which affect the system’s operation and ability to provide consistent airflow and temperature. Heating, Ventilating, and Air Conditioning (HVAC) Systems can be designed to minimize this effect, often at a trade-off of added first cost for more complicated equipment.
Prior to the pending adoption of the latest version of United States Pharmacopeia (USP) <797> and <800>, it was adequate to periodically test the differential pressure manually and record it once daily. USP <797> and <800> now indicate that pressure differential monitoring must be performed continuously with a monitoring device, and then the results must be reviewed and documented at least once daily. It should be noted that there is a difference between alarming and reporting: alarming concerns about non-compliance and reporting concerns about documenting that non-compliance. In the strictest sense of the word, continuous alarming and reporting is impractical, as these spaces have occupants that move through interconnecting doors, compromising pressure relationships in the process, which causes inherent variations of the mechanical system delivering airflow. Using more sophisticated control systems can reduce the impact of the mechanical fan system variation but not eliminate it entirely. The sophisticated controls come at a cost that is much more significant than a standard classroom or office building control system. In practical terms, there will be a range of acceptable operating pressures and a time delay to account for the fluctuations before an alarm indicates the system is out of compliance.
USP <797> and <800> do not give any guidance on a time delay that is acceptable prior to initiating an alarm. The Controlled Environmental Testing Association (CETA), which outlines a guide for the certification process of compounding facilities, also does not give a specific time delay prior to alarming compliance. The setpoint and range of differential pressure must be discussed with the pharmacy and facility staff to determine the acceptable values above or below the required pressures before an alarm occurs. In addition, a time delay will also need to be discussed and documented in the facility’s standard operating procedures and reviewed as compounding operations continue. A 5 to 15-minute delay of the pressures being out of range is generally a reasonable delay built into the monitoring system. While monitoring the differential pressures is continuous, the intent does not appear to be to maintain and document an exact pressure all the time but more to identify systemic errors if there are extended periods out of compliance.
A sterile hazardous drug compounding buffer room has a maximum differential pressure requirement in addition to the minimum for a sterile, non-hazardous buffer room. As USP <800> requires, the differential pressure must be between the range of negative 0.01 and negative 0.03 inches of water column. Again, a discussion with the staff about a reasonable setpoint and delay until an alarm is set is a suitable means to avoid nuisance alarms that could delay or stop thesafe operation of the pharmacy.
The USP <797> version that is being officially released November 1, 2023 allows manually recording the temperature and humidity values once a day but gives the users the option for a continuous recording device where results are retrievable. USP <797> indicates that the results need to be reviewed according to the facility’s standard operating procedure but gives no guidance. Similar to the discussion above about differential pressures, the space temperature and associated relative humidity are subject to fluctuation from occupant movement, operation of doors, and mechanical system variations. Again, more sophisticated, and expensive equipment and controls can reduce the occurrence but not eliminate the variations. Discussions with the user groups are critical to determining the parameters for a functional pharmacy suite. An acceptable range of values or deadband should be discussed with a setpoint below the 68 degrees F and 60% relative humidity maximum recommended by USP <797>. Similar to the differential pressure, a time delay for temperature and relative humidity should be established.
Just as continuously perfect pressure, temperature, and relative humidity conditions will never be reached at all times, zero contamination is also not achievable. Disinfection and pressurization protocols are recommended by USP <797> and <800> to keep occupants and patients safe while temperature and humidity maximums are in place for the comfort of occupants, to preserve pharmacy products, and to prevent microbial growth. USP currently defines no acceptance limits for microbial contamination, nor is environmental monitoring required, but contamination in any amount indicates a lack of containment. If microbial contamination above an acceptable level is found, the recommendations beyond cleaning and disinfection include making practice changes such as re-training personnel, microbial environmental monitoring, certification of the biosafety cabinets and classified spaces, and finally, documentation of what occurred and what has been implemented. Once addressed with these practice changes, while the next set of surface samples willnotlikely detect zero contaminants, a decrease in the levels should be noticed if the remediation efforts are effective.
A major challenge of classified pharmacy spaces is to keep them within the established ranges of pressure, temperature, and humidity and limit contamination. Establishing reasonable delays in alarms and reporting can aid in a smooth operation. If you are reviewing your current installation or have a new compounding pharmacy, contact Douglas Barnhart, PE, at dcb@ba-inc.com or 717-845-7654 to discuss the guidelines we have helped clients establish on other projects.