While HVAC related elements and primary engineering controls (PECs) are vital factors in cleanroom design, day-to-day operations must hold equal weight in the planning process. Optimizing door locations, placing demarcation lines, and storage and material introduction are examples of processes that require careful thought in early design stages. The July 2023 article, EM Drives Cleanroom Design Part 1: PECs, discussed how AdventHealth’s environmental monitoring program (EM) helps correlate the relationship between process controls and cleaning efficacy via EM sampling data. Similarly, using this EM data from nearly 30 compounding areas over the past several years, AdventHealth developed best practices for facilitating adherence to process controls during daily workflows. This optimized combination of cleanroom design and workflow practices helps reduce the risk of introducing contamination into compounding suites and compounded sterile preparations (CSPs).

Anteroom Guidelines

Doors, lines of demarcation (LOD), and donning and doffing areas are often interrelated (see FIGURE 1). The location of a LOD is dictated by the type and location of its affiliated door, and the donning and doffing areas are influenced by the location of LODs (or vice-versa). As such, it is imperative to consider each element’s relation to the other when designing the layout. Each of these elements will also influence how compounding staff interact with the sterile cleanroom suite.

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Options for placing the door from the non-classified general pharmacy into the anteroom may be limited by factors such as existing buildings designs, fire codes, and safety regulations. However, when possible, its placement should facilitate ease of adherence to entry and exit procedures. This includes ample room on either side of the door and, ideally, positioning in a location away from heavy traffic or storage of corrugated materials on the non-classified side.

Disinfection Process

If the building design permits, placing the door with space for a material disinfection station on the non-classified side near the entrance is favorable so long as ample space is reserved within the anteroom. While most supplies should be disinfected and transferred into the sterile compounding suite via a double-interlocking pass-through, certain equipment or supplies may not fit in the pass-through chamber. A disinfection station in proximity to any potential material transfer location promotes adherence to aseptic material transfer procedures (see FIGURE 2). A dedicated area promotes and facilitates care, attention, and taking time to perform the material disinfection process meticulously. This can simply be a carton-free area with easily cleanable surfaces. For example, one AdventHealth pharmacy facility has an unclassified room strictly used for disinfecting materials entering the cleanroom suite via a HEPA-filtered pass-through window, and this pharmacy location regularly has the lowest bioburden among almost every other facility within the health system.

Entrance and Door Considerations

When possible, a button-activated sliding door is favored for entering the anteroom from a non-classified area. Swing doors cause more turbulence than sliding doors due to the force exerted as the door swings, potentially leading to the introduction of contamination into the anteroom. Avoid hand-wave/sensor activation for the anteroom door as passersbys may unintentionally trigger activation. Timing automated doors from unclassified to classified spaces is tricky and, in our experience, is not preferred. Touch and button activation does not add much risk since entering occurs prior to the application of alcohol-based hand rub. Doors for entry between areas within the classified space (ie, after hand hygiene is fully completed) should be touch free and sliding where possible.

Pay careful attention to the door tracks during routine cleaning as crevices may accumulate and then disperse particulates when the door is activated. Set automatic doors to the shortest amount of time needed for personnel to safely enter and exit, as this reduces the risk of differential pressure loss which increases the chance for contamination. Additionally, avoid doorsweeps, as they are not necessary to maintain pressure with doors closed.

If sliding doors are not feasible due to limited wall space, a manual opening door that swings out toward the non-classified space (in the direction of the negative differential pressure) and latches is suggested to minimize the bellows effect. Studies demonstrate that doors swinging against the direction of airflow (toward positive differential pressure) create more turbulence than those that swing with the direction of the airflow and therefore increase the likelihood of contaminants entering the suite.1,2 This positioning also maximizes useable space within the anteroom. Ensure there is a latching mechanism to better protect the door-closer (swing mechanism) by alleviating the pressure applied to the door-closer from the constant positive differential pressure of the ante while the door is closed.

Buffer Room Door Considerations

When possible, a hand-wave/sensor activated sliding door is preferred for the entrance to the buffer room from the anteroom. Elbow to button-activated doors are permissible as well to avoid contaminating hands and gloves. Swing doors may be used with sensitivity-adjusted sensors to reduce unintentional activation. As mentioned previously, give tracks extra attention during routine cleaning as their inherent crevices have the potential for particle accumulation and distribution whenever the door is activated.

Position buffer room doors at least 1 meter away from hand-hygiene stations in the anteroom. Doors should be located at least 1 meter away from garbing areas. If possible, install a system of interlocking doors, including the door adjacent to the non-classified area, to help maintain differential pressure and reduce the likelihood of less-than-ISO 7 air from reaching the buffer rooms and the “clean side” of the anteroom.

Anteroom HEPA and Return Placement

Ensuring there is at least one HEPA filter and return near the main entrance of anterooms is an important consideration. Each time the suite is entered from the non-classified area, less-than-ISO 7 air and contaminants may enter the suite with the temporary loss of some of the differential pressure. A terminal HEPA filter placed above area(s) of the anteroom where donning and doffing of garbing will occur, or material transfer will be performed, will also aid in improving contamination control.

The combination of introducing HEPA-filtered air and a nearby return can better protect the suite by quickly facilitating the dilution and exchange of any potential non-classified air and pushing possible contaminants down and out. Experience shows that campuses with thorough HEPA-filtered air coverage and returns near the entrance do not typically recover viable growth or actionable levels of contamination even if compounding personnel from an unclassified area enter, exit, don, or doff in the area while a viable air sample is actively being collected.

Line of Demarcation

For sterile compounding, LODs typically denote the “clean” side of an anteroom from the “dirty” side, or separate the start of the hazardous area within a negative pressure buffer room from the nonhazardous area. Although often colloquially referred to as a “dirty” side, space nearest the anteroom door should remain as clean as possible and should be cleaned and disinfected with the same frequency and thoroughness as the “clean” side of the LOD. Thus, it can be helpful during training to make the distinction that despite being referred to as the “clean” side and the “dirty” side, this is truly a clean and a cleaner side of the anteroom.

The LOD should provide enough space to don garb while preserving most of the anteroom for “clean side” operations. If space permits, a larger “dirty” side may provide some advantages, such extra space for a trash can or a bench by the LOD to aid in the garbing process. Storing compounding supplies on the “dirty” side should be avoided to deter ungarbed or partially garbed personnel from using the space unnecessarily or remaining there for extended periods to stock supplies or perform material transfer. This also eliminates the lure of reaching across from the “clean” side to the “dirty” side to grab supplies.

Minimize Communication-induced Exposure

Communication between garbed and ungarbed compounding staff in the anteroom should be avoided, as speaking can expel up to 50 particles per second and may contaminate the sterile cleanroom suite and garbed staff.³ There is no magic curtain that keeps activities on the “dirty side” of the anteroom from affecting those on the clean side. Holding doors open between unclassified and classified spaces to have conversations should be strictly prohibited.

Educating staff and providing a reliable means of communication, such as a clear intercom, makes it less likely that people will use the anteroom to communicate between ungarbed and garbed personnel. EM results frequently show pharmacies with unreliable communication means (eg, a quiet intercom) have more air and surface recoveries than those with reliable modes of communication (see the CASE STUDY).

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The “dirty” side of an anteroom is a transitional area that prepares us to go from clean to cleaner and should be dedicated solely to the pre-garbing process before entering the “clean” side. It should not be used to have conversations or even perform visual observations of processes for an extended period. If performed, extended visual audits should occur from outside of the cleanroom through a window. When occupying the classified area for more than a transitional period, auditors should perform hand hygiene and garb.

Hand Hygiene and Garbing Area

In addition to denoting anteroom sides, the LOD indicates where donning and doffing garb for non-HD compounding begins and ends. Ideally, the anteroom “clean” side where donning and doffing occur should have at least one HEPA filter overhead and a nearby return, as these activities tend to produce more particles than other cleanroom practices since personnel are at least partially ungarbed during the process.

Garb, especially when donned prior to hand hygiene (eg, mask, beard cover, bouffant, boot covers), is often donned and doffed in the same general area. If HEPA filters and space allow, a separate area, further from the LOD, for donning sterile and other garb that comes after hand hygiene is preferable. Of note, always avoid personnel donning and doffing garb simultaneously.

Garb donned prior to hand hygiene should be stored on the “clean” side but accessible from the “dirty” side of the LOD so that donning may occur just before, as, or after crossing the LOD to the classified area. Wall mounted dispensers provide a solution for storing the pre-hand hygiene garb while preserving table or floor space. Table, cart, or shelving unit storage is also an acceptable option if wall space is limited. Storage on the “dirty” side of the ante area is permissible when necessary, such as if a sink is located on the outside of the classified area or there is limited space.

Properly transfer supplies into the suite and properly clean and disinfect storage locations at the appropriate intervals. When staging garb, appropriately placed items help ensure personnel don the right items in the correct order and place. For example, when waste bins are not readily available near a hand washing sink, personnel may walk from one side of the anteroom to the other to dispose of hand wipes, or if alcohol-based hand rub is not installed near where personnel should be drying hand and applying the product, these steps may occur in the wrong order or are more likely to be skipped altogether.

Anteroom Bench Placement

Position the bench either straddling the LOD or just within the classified area to aid in the garbing process. If space permits, provide an additional bench for added convenience during the donning and doffing process. If two benches are utilized, one should be dedicated to donning post-hand hygiene garb/sterile garb, and the other dedicated to doffing garb and donning pre-hand hygiene/non-sterile garb (generally on the “dirty” side bench if located on the LOD). Position benches at least 1 meter away from the sink whenever possible. In addition to routine cleaning and disinfection, disinfect the bench seating surface after each use. Station disinfectant wipes on or near the bench to promote this best practice.

Post-Hand Hygiene Non HD Garbing

Since donning the rest of a compounder’s garb (frocks, coveralls, etc) should occur just after performing hand hygiene, that donning area should be near the sink to limit walking within the anteroom while ungarbed, but at least 1 meter from the sink so garb is donned away from water (if space allows). Place a waste receptacle in proximity to the donning/doffing area(s) to make discarding used garb or garb-packaging convenient and to limit personnel movements. Perform all actions under a HEPA filter and with a return nearby.

HD PPE Placement

Outside of the HD buffer room, place a cart containing HD PPE (ie, chemo-rated sterile gloves; chemo-rated, rear-opening gowns; boot covers, etc) and sterile 70% IPA (for glove sanitization prior to entry). A waste receptacle may be located on the side of the cart furthest from the chemo room door for non-HD waste disposal.

Anteroom air will flow into the chemo room due the negative pressure direction. If space allows, place the HD buffer room entrance away from the non-HD garb donning and doffing areas and a HEPA-filtered supply and exhaust just inside the HD buffer room door. This placement aids in controlling particle introduction into the buffer room during donning and doffing of additional PPE required for HD compounding. Don the additional PPE just prior to entering the HD buffer room to restrict the potential for particle generation within a buffer room. If anteroom space is limited, the additional HD PPE may be donned within the chemo room but before crossing the LOD to the HD side.

Exiting the Suite

Each facility’s SOPs should dictate the process for exiting the suite post-compounding. When leaving the HD buffer room, doff the outer PPE (eg, gloves, chemo gowns, shoe covers, etc) prior to exiting the room. Place a trace chemo waste bin near the LOD for PPE disposal. Doff inner garb (eg, frock and inner gloves) in the anteroom in a designated doffing zone near the hand hygiene area to facilitate hand washing before exiting the cleanroom. Doff pre-garb (eg, inner boot cover, face mask, bouffant, beard cover, etc) after crossing the LOD within the anteroom and dispose of it in a trash can on the “dirty” side of the LOD or in a trash can outside the compounding suite.

Cleanroom Storage

With cleanroom storage, less is more. Minimizing the quantity of items stored within the cleanroom facilitates cleaning and adherence to cleaning policy, lessening the bioburden risk. AdventHealth’s internal data demonstrates the majority of bioburden recovery takes place in the material storage area, particularly when there are many items stored therein. As outside cartons are stored within boxes that are more likely to facilitate the proliferation of microorganisms that should be prevented from entering the compounding area.

Based on this data, limiting storage to the day’s or week’s compounding needs is a better approach, with the ideal situation being the introduction of supplies on demand/as needed. Avoid storing supplies in bulk quantities within the compounding space, as this can lead to underutilization of appropriate disinfectant and inadequate contact times as staff may rush to complete this task. Additionally, high volumes of compounding supplies stored on shelving may lead to improper disinfecting and insufficient cleaning due to the sheer volume of surfaces that need to be cleaned and disinfected.

On-Demand Storage Method

The on-demand storage method allows for the appropriate amount of disinfectant and requisite contact time before introducing supplies into the compounding space. If your staffing model permits, assign a pharmacy staff member to material transfer duty in order to complete the material transfer as orders come in to facilitate consistent material disinfection. This staff member should manage the contact time and relay to the compounding staff when supplies are ready for use after disinfecting is complete.

If the on-demand storage model is unattainable, reduce the number of supplies to the day’s or week’s requirements. This helps facilitate proper material transfer processes and supports the routine cleaning process.

Locating Supply Storage

Place storage off to the side, away from returns and doorways and be mindful of airflow from horizontal laminar air flow workbenches (LAFWs). When the air exits the filters, it provides first air during sterile preparation and then washes over the compounding personnel and continues until it is either pushed down by the HEPA-filtered air supply in the ceiling or encounters other surfaces. Even with garbing (eg, frock, bouffant, face mask, etc), shed particles may be deposited onto the surface of supplies stored behind the compounder. Thus, it is important to avoid storing supplies behind compounding staff when possible.

Also be mindful of the level where supplies are stored. If supplies are stored low to the ground, the natural shedding from personnel and disrupted ground contaminants may collect on the items. If items are stored too high, personnel will have to reach and lean over supplies on lower shelves causing additional shed onto the lower supplies. Ideally, supplies should be placed at an accessible height that avoids the path of natural particulate shedding.

Work Surface Best Practices

According to USP <797>, “Only furniture, equipment, and other materials necessary for performing compounding activities are permitted in a classified area or SCA, and they should be low-shedding and easily cleaned and disinfected.”4 Any tables, carts, and work surfaces should be easily cleaned and disinfected with a facility’s regularly used cleaning, disinfection, sporicidal, and decontaminating agents. Stainless steel satisfies these requirements as it is resistant to most disinfectants, though it is important to note that stainless steel comes in different grades and durability. Remove all cleaning and disinfecting agents using sterile water or IPA after manufacturer recommended contact times. Check the agents used for material compatibility with surfaces within the cleanroom and with the gloves worn by compounding staff.

Just as the placement of carts and shelving that house garb and PPE can facilitate best cleanroom workflows, the same is true for the tables, carts, and work surfaces within the buffer rooms. Place these items in proximity to compounding supplies or material transfer points and include low-lint wipers, sterile alcohol, and disinfectants for material transfer and disinfection of sterile gloves. When disinfection materials are easily accessible, compounding personnel are more likely to disinfect gloves at increased frequencies, thus reducing the risk of growth within the PEC. Also, providing surfaces within quick reach prevents staff from placing supplies in less than desirable areas, such as hanging IPA spray bottles from garbage cans.

Conclusion

Daily workflow considerations should involve tracking how personnel and particulates move throughout the suite. Design the physical space and the workflows in conjunction to ensure the cleanroom suite facilitates best practices for reducing contamination throughout. EM data can help you confirm that the design and engineering as well as process controls are working in harmony to deliver contamination control.

References

1. Tang JW, Eames I, Li Y, et al. Door-opening motion can potentially lead to a transient breakdown in negative-pressure isolation conditions: the importance of vorticity and buoyancy airflows. J Hosp Infect. 2005;61(4):283-6.
2. Hendiger J, Chludzińska M, Ziętek P. Influence of the Pressure Difference and Door Swing on Heavy Contaminants Migration between Rooms. PLoS One. 2016;11(5):e0155159.
3. Asadi S, Wexler AS, Cappa CD, et al. Aerosol emission and superemission during human speech increase with voice loudness. Sci Rep. 2019;9.
4. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding – Sterile Preparations. USP 42-NF 37, 2023.

Christine Hong, BS, is the pharmacy quality assurance manager at AdventHealth, where she led the development of AdventHealth’s Pharmacy Microbiological Quality Services 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 sciences) 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 pharmacy microbiological quality services 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.