Compounding Pharmacy and Outsourcing Facility Cleanroom Design and Construction Principles
Large scale pharmaceutical manufacturers and sterile compounders alike rely on appropriate cleanroom design and construction to produce quality drug products. While USP <797> remains the go-to cleanroom specification reference for pharmacy compounders, the pharmaceutical, biologic, and medical device industries follow CGMP guidance and 21 CFR 211. With the release of the FDA Insanitary Conditions at Compounding Facilities Guidance document along with impending changes to USP, pharmacies and hospital health systems can implement GMP concepts into their next compounding cleanroom design and construction project to build quality into their facility and to stay ahead of heightened regulations.
Cleanroom Layout Design
Cleanrooms must be purpose-built in order to achieve regulatory compliance and quality assurance over a long period of time. A retail pharmacy with plans to squeeze in a small area to prepare TPN or specialty IV compounds may find out the hard way that there was not enough space allotted to promote operational efficiencies. Similarly, a 503A pharmacy looking to convert to a 503B outsourcing facility may be in for a rude awakening to learn that cleanroom designs and space requirements are vastly different for each entity. However, the following principles hold true for most cleanroom layout design planning:
Each space constructed must be appropriate for the type of activities conducted.
Each space must be suitable in size to prevent mix-ups.
The layout must be suitable for optimal contamination control.
Materials and product must move in a straight pattern and separately from personnel when possible.
Cleanroom Specification Requirements
Hospital and pharmacy sterile compounding activities take place within a cleanroom that meets regulatory requirements and industry standards, such as USP <797> and ISO 14644. The following specification recommendations are drawn from GMP concepts that meet or exceed minimum standards as part of a robust contamination control strategy:
Building Material Choices
To achieve and maintain the desired ISO classification cleanliness specification, all surfaces in a cleanroom must be:
smooth, non-shedding, impervious
discourage contamination (e.g., won’t peel, flake, rust, corrode or support microbial proliferation, etc.)
easy to clean (e.g., all surfaces are accessible)
rigid (e.g., won’t easily pleat, shatter, dent, etc.)
There are a wide variety of suitable cleanroom material choices. For example:
Aluminum is a good choice if impact or corrosion resistance is a concern, and it is easy to add additional finishes to augment its strengths.
PVC can be reinforced with glass or metal, while its surface is resistant to frequent and intensive cleaning.
Polystyrene is lightweight and inexpensive, however it is the most prone to damage and therefore not an adequate cleanroom solution without additional reinforcement.
Plaster is a traditional cleanroom material that is no longer a first choice do to its brittleness and heaviness.
Hardened polyurethane is affordable, lightweight, customizable, easy to install, and can bend around windows; however it is not very durable.
A range of finishes are available to help materials withstand certain cleanroom conditions:
Powder coating (powder is affixed to a surface) hardens a material so it is more resistant with heavy use.
Aluminum anodizing makes a material resistant to corrosion and improves adhesion without altering the strength of the surface.
Cleanroom Construction Tips
For cleanroom build-outs with contamination control and longevity in mind, the following cleanroom construction tips will increase the lifecycle of the compounding space:
Doors
Doors should generally open into the room with higher pressure.
Choose a hands-free option to prevent cross-contamination.
Opt for alarmed or interlocking doors (avoid 2-way swing doors) to prevent cross-contamination.
Consider tempered glass material with aluminum extrusions frame for increased visibility.
Door frame seams should be sealed to allow cleaning.
A reasonable amount of airflow under a door is encouraged to promote stable pressure differentials, reduce stress on the facility as doors are opened and closed, and to keep the area in specification for longer. As such, the bottom of a door frame should be continuous with the floor for air balancing and easy cleaning.
Avoid double doors. They have a propensity to affect the pressure differential balance over time as the springs gradually weaken.
Avoid sliding doors as they can project ledges and create un-cleanable recesses.
Windows
Tempered glass windows are stronger and will lessen the chance of accidental cracking or shattering.
Opt for gas-filled and double-glazed windows that are flush to the surroundings.
Single-paned windows flush with the cleanroom side are a cost-saving option if the cleanroom window looks into a non-cleanroom space.
The bottom of the window frame should be free of areas where water could pool (e.g., avoid ledges).
Windows and frame seams should be sealed to allow cleaning.
Having lots of windows in the facility provides increased visibility for pharmacist and quality assurance oversight.
Walls
With a number of options for cleanroom walls to choose from (e.g., expensive Dagard panels, increased visibility/oversight with glass, corrosion-resistant aluminum composite with a polyester coating and anodized aluminum extrusion frames, etc.), each material has its advantages and disadvantages. The final choice depends on the purpose (e.g., what will the pharmacy compound?), supply chain availability at the time of construction, preference (e.g., facility longevity vs. speed to construct vs. cheapest materials, etc.) and budget.
While epoxy-painted plaster board is perhaps the most economical option, it can cost more in the long run to maintain these walls (e.g., frequent dent and chip patching, etc.). In this case, it may be ideal to have stainless steel facings installed at exposed corners in high traffic areas as well as on lower wall surfaces (e.g., floor to 4-ft. height) to prevent impact damage to the walls.
One of the more important considerations in cleanroom walls is how the wall panels are framed together. Watch out for visible gaps between panels, the use of rivets or grooved nuts and bolts to join panels, sloppy silicone sealant application, etc.
There should be no sharp corners or ledges (e.g., corners are rounded).
The wall seams should be sealed to allow adequate cleaning.
Floors
The flooring must be continuous and sealed to allow cleaning.
The floors must be coved (at least 4” in height) in the corners and sealed to the walls.
No drains can be located in the ISO 7 where sterile compounding takes place.
Ceiling
The ceiling seams must be sealed to allow cleaning and so panels do not move when mopped.
HEPA filter coverage must be sufficient to meet the specified ISO classification.
Lighting
There must be adequate lighting (LED lights are preferable). Contamination becomes easy to miss when cleaning if the cleanroom is not well lit. Conversely, glare and excessive heat loads are the result of an over-lit cleanroom.
Light fixtures should have gaskets and be sealed.
Top maintenance access is preferred.
Lighting control modules are preferably located outside the cleanroom.
Sinks
The sink can be constructed of 304 or 316 stainless steel to discourage corrosion.
Sinks should be sealed to allow cleaning.
Sinks should be hands-free for hand-washing but not hands-free for glassware washing.
A sink for hand-washing should be sufficient in size and depth to wash to the elbows and to avoid splashing.
Sinks should be located in at least ISO 8.
No sinks can be placed within 1 meter of the cleanroom door.
No sinks can be placed within 1 meter of the PEC.
Pass-Throughs
The materials of construction of the pass-throughs are 304 or 316 stainless steel.
Seams are sealed to allow cleaning.
Pass-Throughs are interlocking.
In a purpose-built cleanroom, pass-throughs are not located between a non-classified area and the ISO 7 sterile compounding cleanroom.
The pass-throughs are flush with the ISO 7 cleanroom suite where sterile compounding occurs (not protruding into the area). This enhances airflow, reduces dead zones, and makes the space quicker and easier to clean.
Edges and Ledges
There should not be any ledges in a cleanroom because this is where dust or water can pool.
There should not be any recesses in a cleanroom because they may be difficult to clean and may not routinely receive clean air.
Sharp corners and crevices should be avoided in the cleanroom because these areas are harder to clean and therefore dust particles, dirt, bacteria, and other debris collect. Water or cleaning agents can also build up in these areas. The pathways for air flow at sharp corners are not as streamlined, causing a disruption in air flow, temperature control, humidity, and pressurization.
Coving all major cleanroom crevices and corners (e.g., wall/floor junctions, wall/ceiling junctions, wall corners, etc.) eliminates 90-degree angles and helps maintain a sterile work environment by minimizing the risk of contaminant accumulation and maximizing the cleaning of the space (e.g., a coved shape is easier to saturate than a crevice).
Miscellaneous
There must be adequate power to handle all cleanroom and equipment utilities at all times.
All services (e.g., pipes, ducting, electrical conduit, cable, ethernet, etc.) should be concealed or installed in a way such that they don’t create recesses.
Sealant application is an art. Sealant should be applied in a clean environment and in a long sweeping motion to reveal a smooth finish. Smeared or sloppy silicone sealant application will peel off or flake over time and be cause for contamination.
Since cleanroom HVAC engineering is designed to remove particles (including smoke), smoke detectors should be located in places where any smoke generated is likely to find them.
Since cleanroom materials need to be smooth and impervious, internal insulation is not advised in cleanroom HVAC ductwork. Internal insulation material shed fibers that shorten the life of HEPA filters or blow directly into the cleanroom.
Ready to Get Started?
Restore Health Consulting’s advisors can help your health system, compounding pharmacy or 503B outsourcing facility develop a cleanroom user requirements specification document to ensure appropriate installation operation qualification, outline an efficient sterile compounding workflow, design the cleanroom layout to control contamination, recommend equipment needed to produce the product(s) of interest, and develop or customize standard operating procedures you will need to produce high quality compounded sterile preparations.
The information provided on this website does not, and is not intended to, constitute legal advice; instead, all information, content, and materials available on this site are for general informational purposes only. Information on this website may not constitute the most up-to-date legal or other information. Readers of this website should contact their attorney to obtain advice with respect to any particular legal matter.