To date, there has not been a study on the standards which monitor negative cleanrooms for compounding sterile preparations (CSPs). As 503b facilities grow in popular use, how can we have assurances on limiting the exfiltration of hazardous materials and vapors exiting the cleanroom and the infiltration of potentially harmful particles and contaminates from ceiling plenums or common spaces that adjoin our single wall cleanrooms into our stored drugs? We can rethink how negative cleanrooms can be constructed to both increase clean assurances, while standardizing construction details and the systems that monitor and control the cleanroom.
A negative cleanroom is a certified room — tested for particulate counts, airflow direction, and airflow volume against federal or nationally recognized standards — that has a negative pressure relative to surrounding spaces. To avoid contamination, the supply air must be filtered prior to entering the room via HEPA/ULPA filters or fan filter units. The air flow direction for all classified space should be varying degrees of laminar (straight) flow from the ceiling to a point at or near the floor.
In compounding facilities, negative cleanrooms are used to isolate both the hazardous drug ingredients and compounded drugs from personnel and surrounding spaces which may be other clean environments, pharmacy spaces, or general public areas.
The pressure differential can vary widely from standard to standard. USP 797 recommends a minimum of 0.01” W.C.1 of difference between the negative cleanroom environment and the surrounding areas, with up to 0.05” W.C.2 referenced by other standards.
Compounding: The environment of CSP and hazardous drugs
Compounded drugs are classified into several microbial risk categories: low risk, medium risk, high risk, and immediate use. USP 797 separates the drugs (not referring to the room design) from the contamination risk, stating, “Hazardous drugs shall be prepared for administration only under conditions that protect the healthcare workers and other personnel in the preparation and storage areas.”3 The standards of US Pharmacopeia as well as supporting documents from the FDA and American Society of Health-System Pharmacists (ASHP) point to specific architectural element requirements for the required separation of drugs/compounds/agents from public and personnel.
Where high risk drugs are compounded, the compounding room is isolated from the general areas by means of an ante room. The compounding room consists of the buffer room and the primary engineering control (PEC). The PEC, which could be a Class II biosafety cabinet or compounding aseptic containment isolator (conventionally a glove box with HEPA filtration), is where the drugs are compounded. The buffer room is one of two lines of defense between the physical compounded drug and the general public. The room has HEPA filtered air as noted above, with thirty air changes per hour of room air, and the PEC generally filters that air prior to entering the compounding chamber.
In most installations, the ante room does not fully isolate the buffer area/room from general public space. The walls and ceiling of the general space may be directly adjacent to the buffer area. This particular construction issue is where some of the particulate transfer can occur and is the most difficult to assess and correct when the problem is found.
The Standards and Reference Material
Pharmacists, hospital administrators, state/city regulators, and the architects and engineers who design compounding facilities and rooms rely on standards including the United States Pharmacopoeia standard USP 797, with additional guidance from the International Society for Pharmaceutical Engineering (ISPE) and ASHP guidelines, as well as the American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) and local/state agencies. USP 797 is the standard upon which most regulatory agencies and hospitals base the design and certification of compounding areas. Depending on the specifics of each compounding facility, certifiers and administrators may adopt the more stringent or explicit recommendations of the other standards. This article focuses on the two items in USP 797 that are the basis of most facilities: 0.01” W.C. of negative room differential pressure at certification, and the guidelines for the room requirements and construction. USP 797 standards have been enforced since its introduction on Jan. 1, 2004, when USP 27 officially introduced it as part of a revision. One of USP 797’s foci of compounding hazardous drugs in negative cleanrooms set minimum standards in order to protect personnel both in the general hospital environment as well as those doing the compounding. The 0.01” W.C. differential pressure was established as the minimum differential to maintain a level of safety and was adopted from an FDA standard.4
Issues with construction of NCs
The ASHP: Guidelines on Compounding Sterile Preparations outline recommendations for the frequency of cleaning and monitoring of compounding facilities: cleaning of walls and ceiling a minimum of once per month, daily cleaning of floors
and surfaces, and monitoring tests a minimum of once every six months checking for nonviable particles, surface sampling, and electronic sampling for viable particles by qualified personnel.5 In light of the limitation in the required frequency of cleaning and monitoring facilities, it should be noted there are some areas in the design of these rooms requiring thoughtful review with owners and administrators prior to, during, and after construction:
1. Single wall separation
Except for tested manufacturer wall systems, very few methods of single wall construction can withstand pressurization over several cycles of HVAC fluctuation after the initial space test. While the paints or coatings on the wall generally have elasticity to maintain adherence without splitting at the drywall seams, most wall baseplates and ceiling-to-wall joints do not maintain tight seals.
2. Controlling pressure
As is often the case in cleanroom construction, most facilities rely on cascade control to provide buffers between dirty areas and clean areas. Where a negative cleanroom exists, the ante room is maintained at a positive pressure, pumping clean air into the room to bleed out into the cleanroom and the pharmacy workroom, to buffer the cleanroom from the workroom’s dirty air. However, often the workroom is directly adjacent to the negative cleanroom and if pressures fluctuate in each space, matter can be transferred, especially if the negative cleanroom pressure decreases to a point where the differential pressure between the workspace and cleanroom is significantly greater (more than 0.01” W.C.) than when the suite was first tested.
Often, many of the lower cost solutions (VAV/CAV, manually set fan filter units, low pressure packaged rooftop units) that do not have high speed air control will allow elevated pressure fluctuations, if only temporarily, because of the slow reaction of the controllers.
3. Holes in the negative room construction
Similar to the single wall issue, often the construction cannot consistently maintain a tight seal in the room perimeter. Holes and gaps are normally present where conduits, pipes, and network cable are routed over the negative cleanroom through the perimeter wall. This poses an issue when maintaining consistent pressure control.
4. Low pressure HVAC equipment
Conventional HVAC selections for hospitals and compounding facilities often have limited external static pressure capability and may not be able to provide sufficient and consistent make-up air pressurization, depending on the room requirements. This can cause the designers and administrators to design towards the lower thresholds of the USP 797 standard, which leads to increased issues with pressure control as noted above.
Studies by Ahmed, Mitchell, and Klein6, as written in a 2003 article in the ASHRAE Journal: Room Pressure For Critical Environments by Brian Wiseman, P.E., used (-)0.05” W.C. differential for their tests; the Journal concluded, based on several additional studies, that (-)0.01” W.C. is a suggested floor for pressure differential between rooms and (-)0.05” W.C. or higher differential is preferred to be maintained.7 As such, solutions that are proposed should be able to maintain these parameters without deviations that could pose an issue.
Are there solutions?
There are solutions, but the risks versus the rewards should be understood, because alternates will generally increase project budgets. A thorough understanding of the return on investment (ROI) should be part of every analysis.
1. Double wall room construction, where the negative cleanroom becomes a room within an outer pressurized shell. Clean air is forced into the outer shell wall closest to the dirty rooms, providing a buffer to overcome pressure fluctuations on either the dirty or clean side.
2. Utilize high speed terminal units/air valves and high speed controllers. Combining a proper control scheme and pressure monitoring, many construction issues can be overcome to keep the compounding room negative while maintaining the set differential pressure level.
3. Provide the negative cleanroom with more air changes to decrease the contamination potential by limiting contact time of foreign particles in the cleanroom.
4. Change the sterilization and cleaning procedures to maintain sterile containers throughout the compound’s lifecycle. As part of any high risk compounding procedure, sterilization and cleaning could be increased to limit any impacts that the HVAC system cannot overcome.
The USP 800 draft document Hazardous Drugs — Handling in Healthcare Settings outlines proposed recommendations for compounding, handling, and protection in healthcare facilities.8 When this guidance document is published, one of its goals, as published in the draft document, will be to require CACIs/BSCs used for hazardous drug preparation to be in a negative cleanroom.
USP 797 and other standards fall short of offering architectural or mechanical means or methods to maintain a clean compounding buffer zone. As drug compounding becomes more prevalent and budgets for construction dwindle, the risk of contamination will ultimately rise. Some issues can be limited with the means of sterilization; however, constant pressure cycling can be assumed to lead to increases in particulate transfer from dirty to clean spaces, especially when dealing with a negative cleanroom for hazardous drug compounding.
A discussion to consider changing USP 797 could and should be done, both to offer increased protocols and to set minimum standards/recommendation for room construction for each drug risk application. Furthermore, cross collaboration and coordination with standards-setting organizations should be broached to develop lasting procedures and standards of construction for hazardous compounding facilities. State certifiers and regulators can reference these standards in their advisory documentation and expect architects and engineers to adhere to these standards in the design documents.
1. US Pharmacopeia, 36th edition, Chapter 797, 2013
2. 1999 ASHRAE Handbook, HVAC Applications, Chapter 15 as noted in ASHRAE Journal: Room Pressure in Critical Environments, Brian Wiseman P.E., Feb. 2003.
3. US Pharmacopeia, 36th edition, Chapter 797, 2013
4. American Society of Health-System Pharmacists, ASHP Guidelines on Compounding Sterile Preparations, Drug Distribution and Control: Preparation and Handling — Guidelines, pg 75.
5. American Society of Health-System Pharmacists, ASHP Guidelines on Compounding Sterile Preparations, Drug Distribution and Control: Preparation and Handling — Guidelines, 79-80.
6. Ahmed, O., e al. 1993. “Dynamics of laboratory pressurization.” ASHRAE Transactions 99(2): 223-229
7. Wiseman, Brian, P.E., ASHRAE Journal: Room Pressure For Critical Environments, Feb. 2003, pg. 35-37, 39
8. US Pharmacopeia, Corr Number—C151881, Chapter 800, May-June 2013
Todd Somerset, PE engineers building systems for SMRT Architects and Engineers, serving clients in the technology worlds of life sciences, electronics, higher education, and healthcare. www.smrtinc.com
This article appeared in the April 2015 issue of Controlled Environments.