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Blueprint for Patient Safety:
How informed clean room design can promote sterility
By Barbara Petroff, MS, RPh, FASHP and David Baczewski, RPh
PHARMACISTS AND PHARMACY TECHNICIANS
This INFUSION article is cosponsored by Educational Review Systems (ERS), which is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. ERS has assigned 1.0 contact hours (0.1
CEU) of continuing education credit to this article. Eligibility to receive continuing education credit for this article begins October 22, 2015 and expires October 22, 2018. The universal activity numbers for this program are 0761-9999-15-295-H01-P
and 0761-9999-15-295-H01-T. Activity Type: Knowledge-Based.
NURSES
Educational Review Systems is an approved provider of continuing nursing education by the Alabama State Nurses
Association (ASNA), an accredited approver of continuing nursing education by the American Nurses Credentialing
Center, Commission on Accreditation. Program # 05-115-15-015. Educational Review Systems is also approved for nursing continuing education by the state of California, the state of Florida, and the District of Columbia. This program is approved for 1.0 hours of continuing nursing
education. Eligibility to receive continuing education credit for this article begins October 22, 2015 and expires October 22, 2018.
Approval as a provider refers to recognition of educational activities only and does not imply Accreditation Council for Pharmacy Education,
ERS, or ANCC Commission on Accreditation, approval or endorsement of any product. This Continuing Education Activity is not underwritten or supported by any commercial interests.
In order to receive credit for this program activity, participants must complete the online post-test and subsequent evaluation questions
available at www.nhia.org/CE_Infusion. Participants are allowed two attempts to receive a minimum passing score of 70%.
EDUCATIONAL LEARNING OBJECTIVES
1. List and describe the areas that are considered to be most problematic when designing and building a clean room.
2. Describe three scenarios in which poor clean room design could negatively affect the sterility of compounded solutions.
3. List the key considerations for using restricted access barrier systems in compliance with United States Pharmacopeia (USP) Chapter <797>.
Continuing education credit is free to NHIA members, and available to non-members for a processing fee. To apply for nursing or
pharmacy continuing education, go to www.nhia.org/CE_Infusion and follow the online instructions.
NOVEMBER/DECEMBER 2015
This continuing education article is intended for pharmacists, pharmacy technicians, nurses, and other alternate-site infusion professionals.
27
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Continuing Education
AUTHOR BIOS
Barbara Petroff, MS, RPh, FASHP, is the Pharmacy Manager at Soleo Health in Novi, Michigan. She has experienced pharmacy in many settings, including research, retail, hospital, and for many years in home infusion. In addition to patient care and pharmacy management, Petroff
has been responsible for organization-wide performance improvement activities and student mentoring. She is an adjunct faculty member
at several schools of pharmacy, serving as a preceptor for students during their experiential rotations. In addition, she serves as a surveyor for
the Accreditation Commission for Health Care (ACHC) and teaches health care management at University of Phoenix.
Petroff is a fellow of the American Society of Health-System Pharmacists and serves as the Chair of that organization’s Ambulatory Practitioners Section-Home Infusion Section Advisory Group. She is also active in NHIA, serving as Chair of the Standards and Accreditation
Committee, and co-authoring one of seven installments in the NHIA Home Infusion Therapy Module Program. Petroff received her B.S. in
Pharmacy from Ohio State University and her M.S. in Administration at Central Michigan University.
David Baczewski, RPh, is a Pharmacy Manager for Amerita in Tucson, Arizona. Throughout his career, he has specialized in infusion and
aseptic technique with an emphasis on quality assurance and performance improvement analytics, including clean room design, equipment
selection, and policy and procedure review. He has designed, engineered, and constructed or remodeled more than 30 clean rooms focusing
on process flow and USP <797> compliance.
AUTHOR DISCLOSURE STATEMENT
The authors declare no conflicts of interest or financial interest in any product or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.
Questions or comments regarding this article should be directed to
Barbara Petroff at [email protected] or to David Baczewski at [email protected]
A
NOVEMBER/DECEMBER 2015
poorly functioning clean room can contribute to
lapses in product sterility and jeopardize patient
safety. But, once in place, design-build errors can
be challenging and costly to overcome—and are typically
associated with an interruption in pharmacy operations.
While it’s clearly advantageous to design and build a facility
with adequate engineering controls from square one,
understanding the variables and common mistakes makes it
easier to address performance issues when they arise.
Compounding pharmacies have recently experienced a
renewed focus on clean room design and function. In 2013,
the US Pharmacopeial Convention (USP) published new
proposed standards for the handling of hazards drugs in health
care settings (USP <800>) and this fall it proposed the next
round of revisions to its guidelines for sterile compounding
(USP <797>). [Editor’s Note: Proposed revisions to USP <797>
are available for public comment until January, 2016. See
“Sterile Compounding in the Future: How Newly Proposed
USP Standards Could Affect Your Practice” on p. 22 for details.
The contents of both documents address patient safety by
detailing the processes and safeguards that should be in place
in all compounding pharmacy operations.
The new proposed standards—along with stepped up
regulatory and inspection efforts at the state board of
pharmacy level—are prompting many providers to assess
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the status of their current clean room design. In addition, as
the industry grows, new entrants are planning construction
and established organizations may move or upgrade their
clean room facilities. This article encourages pharmacy
organizations to “measure twice and cut once” by examining
how clean room design affects sterility, investigating common
mistakes, and preempting potential pitfalls.
How Poor Design Can Affect Sterility
Clean rooms are designed to keep patients safe by
reducing particulate contamination and controlling other
environmental parameters such as pressure, temperature, and
humidity. The primary components are HEPA (high efficiency
particulate air) filters that trap particles as air enters the room.
Air may be filtered to specified particle counts in different
areas of the facility depending on the tasks and processes
undertaken there (see Exhibit 1). In a poorly designed clean
room, particle counts can exceed targets and affect the
sterility of the final products compounded within.
Unidirectional airflow is air that flows in one direction only.
It moves at a fast enough speed that it keeps contaminants
away from the compounding area. This reduces the chances
that compounded sterile preparations (CSPs) will become
contaminated during compounding and helps maintain
Ask the Experts
Using a consultant or clean room designer may not guarantee that the design and construction will be without any issues, but
it can make the process more efficient. The pharmacy provider is ultimately responsible for the project; therefore, the point
person(s) must be very familiar with the requirements. Be sure to ask questions and don’t be afraid to speak out when the design
does not look right or the contractors do not follow the design. Including an infection control specialist can be a good idea as
well. You can ask your clean room designer or certifier for references or consult a nearby university microbiology department.
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Exhibit 1
International Organization for Standardization (ISO) Classifications for Clean Rooms
ISO CLASS
PARTICLE COUNT (per m3)
WHERE USED
5
3,520
Primary engineering control
7
35,200
Buffer (clean) room
Ante Room
8
3,520,000
Ante Room
of 68° F or cooler to allow personnel to comfortably work
while wearing the required garb, which increases the body
temperature. Aside from creating discomfort, higher
temperatures can cause the compounder to sweat, which could
compromise the sterility of the CSPs he or she is preparing. USP
<797> also recommends that the humidity be less than 60%.
High humidity not only supports microbial growth but can
speed the formation of rust on metal surfaces (e.g. grates over
the HEPA filters) and drop particulate matter onto the work
surfaces. These conditions could also affect the sterility of CSPs.
It is important to consider the traffic flow and placement
of the PEC when designing the clean room. The PEC should be
away from air currents so as not to interfere with the airflow of
the entire room. During the compounding process, operator
movement in the clean room should be minimal because
it too can disrupt airflow. Even though there are minimal
supplies in the clean room area, placement should be planned
to maximize the efficiency of the traffic flow.
Currently, USP <797> allows the use of compounding low
volumes of hazardous medications as long as a closed system is
used in the compounding process. In the proposed USP <800>
this allowance will be eliminated. The change is expected to
eliminate any cross contamination that could occur from the
process and contribute to patient and personnel safety.
NOVEMBER/DECEMBER 2015
product sterility. The airflow in the Primary Engineering
Control (PEC) is also unidirectional and this keeps the
compounding area free of airborne particulate contamination.
The number of times the HEPA filtered air flows through
the rooms maintains the cleanliness of the room. USP <797>
requires a minimum of 30 air changes per hour (ACPH)
in the anteroom and in the clean room. If there is an ISO 5
recirculating device (i.e. PEC) in the room it can be used to
augment the number of air changes. It’s important to consider
factors that affect the number of air changes needed in the
design process so the filters are not over-taxed. When the
HVAC personnel set the air changes in the rooms, they must
make allowances for any particle-shedding entities—from
the number of people working in the room to the type of
equipment and supplies stored there.
The placement of the room exhaust openings is also an
important element of the design. The openings should be low
to the floor to enable the downward flow of the air to keep
contaminants away from the compounding area and CSPs. It
is also important that the size of the returns is large enough to
handle the room and the devices that are in it.
Temperature and humidity affect a number of conditions in
the compounding of sterile products. The temperature should
be comfortable. Current <797> recommends a temperature
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A Review of Restricted Access Barrier Systems
David Baczewski, RPh
Restricted Access Barrier Systems (RABS) are engineering control
devices used in aseptic compounding. Their closed architecture—
the working environment is not opened during operating
conditions—and a supply of HEPA-filtered, ISO Class 5 air through
defined openings prevent the external transfer of contamination.
Often referred to as “glove boxes,” two common examples of RABS
include Closed Aseptic Isolators (CAIs) and Compounding Aseptic
Containment Isolators (CACIs).
Closed Aseptic Isolators (CAIs) are designed for compounding
pharmaceuticals. An aseptic environment is maintained within the
isolator throughout the material transfer and compounding process.
Room air surrounding the CAI must first pass through a HEPA filter
to ensure the interior of the isolator is providing an ISO 5 working
environment. Compounding Aseptic Containment Isolators
(CACIs) are designed to provide an ISO 5 aseptic environment
for materials transfer and compounding as well as a level of user
protection when volatile or hazardous pharmaceuticals are handled.
This is achieved by exhausting internal isolator air via a properly
designed and installed building ventilation system. See the quick
comparison of RABS features in the table below. Following are a
few key considerations for selection and use of RABS in home and
specialty infusion.
Quick Comparison of Restricted Access Barrier Systems
Device
Full Enclosure
Pressure
Gradient
Unidirectional HEPA
Material
Transfer
System
External
Venting
Closed Aseptic
Isolators (CAIs)
Yes
Into device
Yes
Yes
Yes
No
Compounding
Aseptic Containment
Isolators (CACIs)
Yes
Out of device
Yes
Yes
Yes
Yes
NOVEMBER/DECEMBER 2015
Device Selection
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Understanding RABS engineering designs, functions and limitations, and the pharmacy’s compounding requirements will assist in
selection. All CAIs and CACIs are RABS but not all RABS meet the requirements for aseptic compounding. For a RABS to be either
a CAI or CACI, it must isolate the air, maintaining an ISO 5 environment during all phases of operations. The pass-through is a
critical feature and can be accomplished through three basic designs: static air, dilution air, and unidirectional airflow. The material
transfer process is one of the greatest potential sources of contamination, so selection of a device with unidirectional, purged passthrough air should meet USP criteria. There are multiple manufacturers of these devices and appropriate due diligence is always warranted when investing in new
equipment. The evaluation of the various designs starts with understanding which device best suits your compounding needs.
If your pharmacy compounds hazardous or volatile pharmaceuticals, it should invest in a CACI, because CAIs are only used for
sterile admixture of non-hazardous pharmaceuticals.
USP Chapter <797> requires a compounding isolator to maintain ISO 5 conditions during dynamic operations AND maintain
ISO 5 during material transfer. Compounding isolator performance must be documented and validated following CETA-0022006 standards as well. Equipment must be tested to appropriate standards at installation, and again every six months and
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certified to CETA standards. The following CETA standards must be met to qualify as a compounding isolator:
• High integrity transfer ports are used to move supplies/components into and out of the isolator.
• The isolator is decontaminated using a generator that distributes a sporicidal agent throughout the isolator chamber.
• The isolator maintains a constant overpressure of at least 0.05-inch water column.
• CACIs must maintain a minimum of 0.1 WIC (water inch column) negative pressure with 100% external exhaust.
• The manufacturer provides documentation that the compounding isolator will continuously meet ISO 5 Class conditions
including material transfer.
Ergonomics are an essential consideration during the evaluation and selection of a compounding isolator. A thorough understanding
of equipment design and use will help assure functionality as well as adherence to USP <797> requirements and organizational
policies for aseptic compounding. It’s wise to involve the employees performing aseptic compounding in the evaluation process.
Consider how a device’s design elements help manage steps in the compounding process. Steps performed easily when using
a traditional workbench can be challenging when performed in a CAI. Materials staging, trash removal, and sharps use must be
considered to ensure the device can meet organizational policies. Soliciting feedback from peers can help narrow the selection
process as well. Manufacturers should be willing to provide the contact information of past customers for reference.
Be sure to review manufacturer guidelines for gauntlet glove replacement. Good questions to ask might include: “How are
replacement gloves installed?” Who can install them? How often do they need to be replaced?” Disinfection considerations are
also critical during the evaluation and selection of a CAI. Manufacturer recommendations for cleaning and disinfection should
align with USP <797> requirements. Interior surfaces and seams should be designed for easy cleaning and be accessible through
the gloves; some devices require aftermarket cleaning aids.
Placement
Currently, as long as the CETA CAG-002-2206 certification ascertains that the ISO Class 5 environment is maintained during
material transfer, a CAI can be placed in an unclassified area. However, the newly proposed revision to USP <797> requires that
isolators meeting all ISO 5 Class criteria and standards (above), be placed in at least an ISO 8 environment. If the above conditions
are not met, then the isolator is considered a RABS and must be located in a ISO Class 7 area.
Additionally, the room should accommodate hand washing and garbing, be designed and sized appropriately to support the
proper use of the equipment, allow space for material storage, and be appropriate for the hazard level being compounded.
When compounding hazardous materials, CACIs should be located in a negative pressure room with 0.01-WIC of negative
pressure with 12 ACPH allowing for inventory storage that is then segregated from non-hazardous materials.
Disinfecting and Cleaning
Disinfection must follow USP <797> guidelines. An isolator must be cleaned after each opening then disinfected once closed,
between batches and after any suspected spills. Cleaning can be done with sterile water and lint-free wipes after removing
particulate matter and disinfecting completed with sterile 70% isopropyl alcohol (IPA).
Currently, pharmacists and technicians should follow the same gowning and hand sanitation as outlined in USP <797> as they
would in any clean room operation—unless the manufacturer provides written documentation, including validated environmental
testing, that components of personal cleaning or personal protective equipment (PPE) are not required. The pending revision to
USP <797> removes this exemption. Requirements for staff process validation, finger tip testing, and media fill requirements must
be followed to standards established by USP <797> regardless of the equipment selected.
Equipment like CAIs and CACIs are tools and should never be expected to replace a thorough understanding of USP <797>,
proper techniques, adherence to strict professional standards and organizational policies including robust staff training, validation
and testing. Knowledge of the requirements with an appreciation for equipment design elements, including limitations, drives the
proper selection and use of these critical pieces of equipment.
KEY
CETA: Controlled Environment Testing Association
HEPA: High-efficiency particulate air
ISO: International Organization for Standardization
USP: United States Pharmacopeial Convention
NOVEMBER/DECEMBER 2015
Gowning
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Consider the Air First
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Whether you will be undertaking new construction
or renovating an existing facility, the HVAC (heating,
ventilation, air conditioning) system will be very important.
It is preferable that the clean room complex has its own
dedicated system. Sharing a system with other parts of the
organization’s facility makes it too difficult to control the
temperature, humidity, and airflow, which are all critical
components in maintaining the ideal environment for sterile
compounding. It has been my experience as a pharmacy
manager and as an accreditation surveyor that the HVAC
units in modular clean rooms are not large enough to
maintain the proper conditions. In one case, an organization
tried to retrofit an air conditioning unit into a modular unit
because they could not keep the temperature below mid80s. Even with the retrofitting, the organization could not
keep the temperature below 70°, which still exceeds USP
standards. In addition, by circumventing the air flow, there
was no direct flow of HEPA filtered air into the clean room.
Issues related to HVAC and HEPA filtered air are very
difficult to remedy after the fact—it is highly advised that they
be addressed during the design of the room. HVAC specialists
can help with the correct equipment choice. Even when
building a new clean room in an existing space, the HVAC
system choices are important. There must be room above the
ceiling for all the components and “open space” required for
air circulation.
Maintaining a room temperature below 68° can create
additional challenges. Since it is the air conditioning that
is running most of the year, the unit may freeze in winter in
the colder states. Melting ice from the unit can cause water
leakage into or near the clean room complex. If the ceiling tiles
get wet, the complex is at risk for bacterial and fungal growth,
and they must be replaced, causing a delay in compounding
operations. Similarly, damage sustained to a ceiling that is
hard-wall construction would also shut down a clean room
for repairs and recertification. Enlisting the advice of an HVAC
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specialist can help prevent this situation and the loss of
business and revenue that could occur.
HVAC systems also include equipment to regulate humidity.
By investing the additional money during construction, costly
changes can be avoided later. In one organization I surveyed,
the clean room lacked humidity control and moisture built
up in the ceiling until it actually “rained” in the clean room
complex. This caused the room to be shut down for several
days while the ceiling was replaced, everything was cleaned
and disinfected, and the room was re-certified.
Look at the Layout
Some organizations make the mistake of treating their
anterooms as if they are storage rooms. Anterooms are
meant to be a clean area for staging materials that will be
used in the clean room; donning proper garb; and performing
proper hand hygiene. To stress this concept, the layout of the
anteroom might include a designated clean side and dirty
side. Operators enter on the dirty side and don their garb on
the clean side just prior to entering the clean room to work.
Many providers use a strip of colored tape to designate the
clean and dirty sides of the anteroom. If a line of demarcation
is utilized, consider installing a permanent strip of flooring in
a different color. This will make cleaning easier and eliminate
the buildup of dirt and dust on the tape itself and under its
sticky edges. Lines of demarcation are not required in the
proposed revision of USP <797>.
Closets, shelves, and cabinets are magnets for dust and dirt
and interfere with the anteroom cleanliness. Likewise, storing
excess supplies and medication in the anteroom can interfere
with the required number of air changes. Before transferring
supplies into the anteroom, they need to be wiped down (if
using a spray bottle of sterile alcohol, wipe the items with a
lint free cloth after spraying) to remove contaminants.
Sinks used for handwashing should have hands-free controls.
Sinks should be freestanding rather than placed in cabinets
to reduce the buildup of dust, dirt, and bacteria. Tacky mats
placed just outside the door to the anteroom are used to
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Think and Plan
As previously stated, there are a minimum number of air
changes per hour required by USP <797>. If your engineering
plans don’t account for people working in the room, other
devices (e.g. compounding pumps), and supplies, you will
not meet the minimum requirement. Most organizations will
design for air changes at a much higher rate than required
to accommodate for these variables. Your room certifier can
help when you have the certification done for the first time.
The clean room should be as free as possible of computers
and printers, which produce both particles and heat. Some
automated compounding devices have printers. While it is not
ideal to have printers in the complex, some accommodations
can be made to reduce their impact, such as placing the
printer near an exhaust vent.
Correct pressure differentials will keep your rooms clean. If
you have both a negative pressure room and a positive pressure
room being serviced from the same anteroom be sure your
pressures are set correctly. The object is to keep air from coming
out of the negative pressure room into the anteroom and to
keep anteroom air from entering the clean (buffer) room and
to keep air from the pharmacy from entering the anteroom. The
certifier will check for this, so be sure that your HVAC contractor
correctly adjusts the settings prior to the certification date.
Few organizations have the ability to add to an existing clean
room complex. Most of the time there just isn’t space to add on.
When possible, it’s advisable to build for the business lines and
workload you expect in the future rather than the workload
you have today. For example, if you are not going to compound
hazardous drugs now, consider what you will do in the future.
It is far more cost-effective to prepare an area for future
hazardous drug compounding during the initial construction
than it is to add one later. Modular units are usually set up for
future expansion, but if you don’t have the features in a place
that allow expansion, you will lose that option.
Consider how you will monitor all your temperatures,
humidity, and pressures. It’s advisable to place meters to allow
them to be monitored from outside the complex. Work with
your designer and contractor to determine the placement
that will work best for you at the cost you have in your budget.
Conclusion
Building a clean room complex is very expensive and time
consuming. By planning in advance, you can avoid most of the
common mistakes. I have yet to see a clean room complex
construction project that was completed according to the
initial schedule. Issues with design, building codes, architects,
equipment, and deliveries cause many delays. Something as
simple as hunting season that takes workers out of the project
for a week can wreak havoc to your timeline.
Plan ahead and supervise the project closely. It is possible to
construct a clean room that promotes sterility of compounded
preparations and therefore promotes patient safety.
Resources
•
•
•
•
•
USP Chapter <800> Hazardous Drugs—Handling in
Healthcare Settings. www.usp.org/sites/default/files/
usp_pdf/EN/m7808_pre-post.pdf
USP Chapter <797> Pharmaceutical Compounding-Sterile Preparations (proposed revision) www.usp.org/
sites/default/files/usp_pdf/EN/USPNF/usp-gc-797proposed-revisions-sep-2015.pdf
Controlled Environment Testing Association (CETA)www.cetainternational.org
National Home Infusion Association Sterile Compounding
Resource Center - www.nhia.org/resource/sterile/
American Society of Health-System Pharmacists
Sterile Compounding Resource Center - www.ashp.
org/sterilecompounding
NOVEMBER/DECEMBER 2015
remove dirt and debris from the bottom of shoes as operators
enter. The type that stick directly to the floor can become
hiding places for dirt and bacteria—just as the colored tape
line of demarcation can. It’s better to use the tacky mats that
come in a “frame” and can be moved for cleaning.
Other areas that can be problematic and should be considered
during construction include the use of pass throughs, ceiling
tile choices, light covers, electrical outlets, and switches. Review
the blueprints and the product specifications and understand
what is being ordered, and expected delivery dates. Windows
should have no ledges because they collect dust. Tempered glass
doors are great for entries because they allow light to pass and
people to observe without entering. However, some municipal
building codes require a metal plate at the bottom to prevent
the door from shattering if struck by something hard, such as
a wheelchair or hand cart. Doorways must be wide enough to
allow clearance for equipment that will be installed in the clean
room complex. Remember that equipment breaks, and plan for
its safe removal and/or replacement.
Many materials used in clean room construction, such as
ceiling tiles, must be special ordered. Be sure that the delivery
dates are appropriate for the flow of construction and allow
time for unanticipated problems. If your entire palette of
ceiling tiles arrives damaged, do you have enough time to
get another shipment before they are needed? Waiting for
materials and having workers idle will be expensive.
Know what is in your blueprints and regularly check the
progress. Recognizing issues as they happen—electrical outlets
or data ports in the wrong place, a floor that’s not coved, or a
wall surface that’s rough enough to tear mop heads—before
the room is finished prevents delays and additional costs later.
More than one organization has had to make adjustments
after the fact, which holds up the certification process and the
opening of the facility.
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