The cGMP Cell Therapy Processing Facility (CTPF) at Northwestern
Memorial Hospital is a state-of-the-art cell and tissue manufacturing
facility used by medical personnel involved in regenerative and repair
medicine collectively called cell therapy. Human cells, tissues and
cellular and tissue-based products (HCT/Ps), especially stem cell-based
products outside of the pharmaceutical industry, are collected,
processed and manufactured within an ISO-classified environment. The
facility was conceived, designed and constructed to exacting
specifications based on the requirements for cell/tissue processing
regulations promulgated by the Food and Drug Administration (FDA),
including prevailing current good manufacturing practices (cGMPs), in
addition to state and local regulations.
The facility consists of cleanroom and non-cleanroom areas. The
non-clean area consists of an 1,100 [ft.sup.2] (102 [m.sup.2])
laboratory and material staging area comprising 630 [ft.sup.2] (59
[m.sup.2]) used to support the processes occurring in the cleanroom. The
clean area, approximately 1,830 [ft.sup.2] (170 [m.sup.2]), includes
four work suites, a cold room work area, gowning and de-gowning rooms,
and a clean corridor connecting the work suites, gowning/de-gowning
areas and material staging area.
Three work suites each contain one Type B2 biological safety
cabinet (BSC), while the fourth work suite contains three Type B2 BSCs
with capacity for future equipment. Modular room construction with
epoxy-based flooring for easy cleaning and ergonomic space allocation
was used to construct the facility.
The facility was designed to meet ISO Class 7 in all cleanroom
areas except the cold room, which was designed to meet ISO Class 5.
Given the amount and grade of makeup air required, the air-handling unit
is equipped with 30% pre-, 85% intermediate- and 95% final filters. In
addition, the cleanroom ceiling diffusers are equipped with 99.997%
efficient, Type-C HEPA filters; fan filter units with HEPA filters are
installed in the cold room. Through dynamic testing and surface and
airborne particulate cultures, the cold room certified at an ISO Class 5
rating, and attained ISO Class 3 levels. The performance of the
remaining areas exceeded the design intent of ISO Class 7 or ISO Class 8
by at least one classification level.
Separate reheat coils serve each laboratory area, allowing
individualized temperature control. Humidification for the air-handling
is fed by a U.S. Pharmacopeia-grade pure water system. The system is
comprised of water softening, carbon and reverse osmosis filtration,
process holding with hydrophilic and hydrophobic filtration,
deionization and ultraviolet treatment, with pharmaceutical-grade
distribution piping. During seasonal downtime, the system is
decommissioned until the recertification, sampling and startup processes
are initiated. System turnover is sequenced with the biannual facility
certification to minimize impact on the facility.
Innovation and uniqueness in facility design originated through an
integrated delivery model, with the early stakeholders (scientists) who
envisioned the manufacturing processes to be performed within the
A major innovation was the design of the cold room for islet cell
processing. Processing of islet cells requires the product to be placed
within a 39[degrees]F (4[degrees]C), 35% RH, ISO Class 5 environment.
Prior to the facility design, the procedure required researchers to use
separate equipment placed inside a BSC, which in turn required the use
of a vigorous cleaning process and was an ill-suited method of achieving
the required conditions. To solve these problems, an ISO Class 5 walk-in
cold room was designed. The cold room was CFD modeled to perform as a
BSC, for laminar, single-pass airflow at the workbench height.
Whereas Class 7 environments derive their particulate arresting
through air-changes, ISO Class 5 environments necessitate a change to
velocity and coverage densities to ensure particle shedding and capture.
This was accomplished using fan filter units (FFUs) with HEPA filters at
a density of 90% ceiling coverage and filtered-return grilles located
opposite the work tables near the floor. Additional cooling was
accomplished through a secondary process system for the space: processes
discharge the room's recirculated and makeup ventilation air
through desiccant moisture removal following a depressed suction
temperature by direct expansion, producing a frosted-coil condition and
38[degrees]F (3.3[degrees]C) leaving-air temperature. Makeup ventilation
air is supplied from the facility unit to maintain the required space
The ISO Class 5 cold room was designed and developed as a
manufacturing enhancement for the islet cell transplantation program. It
is unique because it permits precise and rapid manufacturing steps to be
completed in a low-temperature environment (39[degrees]F to 43[degrees]F
[4[degrees]C to 6[degrees]C]), resulting in better product manufacturing
yields as compared with conventional hoods retrofitted with bulky and
poor ergonomic equipment layouts. In fact, because of the cold room
design, scientists in the CTPF need only one pancreas to harvest the
same amount of islet cells that others require two pancreases to
achieve. The cold room design (flat walls with coved corners,
cold-cathode lighting, point-of-use HEPA filtration, movable, locking
stainless steel workbenches and seamless flooring) also permits easy,
rapid cleaning and allows for establishment of immediate product
[FIGURE 1 OMITTED]
In addition to streamlining cell processing procedures,
constructing the project-specific cold room permitted the presence of
multiple scientists in the room as required for different procedures.
Previously the process was performed in BSCs with limited space,
increasing processing time and limiting the ability to efficiently
prepare the product. The design permits optimal numbers of personnel to
participate in the cell processing, reducing overall processing time.
The cold room design significantly improved the tissue manufacturing
process and results in consistently high quality final cell products.
Space restrictions were a major constraint to be overcome during
design of the facility. After accounting for the equipment,
approximately 5 ft (2 m) of interstitial space was available to
accommodate the systems serving the facility, as well as the biological
waste piping and systems of the deck and spaces above. By application,
excessive systems' distribution, supply, return and exhaust valves
for zoning, transformer locations and access for maintenance dictated
careful trade management to prevent interference and collision.
Integrated design, in conjunction with the installing trades, required
building information modeling (BIM) to coordinate all services to
tolerances within less than an inch (25.4 mm) for installation.
Another unique aspect of the facility design was the establishment
of positive-pressure cascades, allowing multiple cell/tissue
manufacturing procedures to be simultaneously conducted without the
potential of product cross contaminations.
CTPF Laboratory construction phase activities were conducted under
a clean build protocol that included quality control measures (e.g.,
using only cleaned tools, wiping down the worksite each evening
following construction, controlling entry and requiring work personnel
to partially gown to enter worksite). At completion of the construction,
the entire facility, systems, and interstitial spaces were cleaned.
Surface microbial samples and air particle counts were taken to
establish a cleaning monitoring program.
Maintenance and redundancy were of critical importance to facility
operation. Any interruption that may result in a breach of the cleanroom
environment requires the facility to be shut down, and a complete
cleaning process of the facility must occur before the space can be
operated again. To reduce, if not altogether eliminate the likelihood of
an event, the design allows for non-invasive maintenance activities to
be performed without compromising the integrity. The custom air-handling
unit, dedicated to the CTPF, uses a fan array to supply 40,000 cfm (18
878 L/s) that is variable speed, with pressure-independent air valves
controlling supply, return and exhaust air, tracking duct pressure. The
"clean" compartments of the unit and all distribution were of
pharmaceutical-grade construction, with adjacent service corridors for
equipment control systems, security and maintenance provisions. The fan
sections consist of multiple, plug-plenum fans, each independently back
drafted, as well as electrically isolated and monitored through motor
overload current transformers. The unit was designed with N + 2 fan
systems redundancy such that should several supply or return fans fail,
the loss of pressure will be isolated across non-operational fans,
allowing the remaining fans to increase speed to maintain the required
airflow via pressure within the duct systems. The supply and return fans
each have redundant drives such that if one variable frequency drive
(VFD) fails, the second has a parallel run signal enabling the backup
VFD to catch the fans mid-rotation, maintaining minimal interruption to
[FIGURE 2a OMITTED]
All caustic air within the process BSCs is exhausted; all other
facility air is returned to the central system. Heat recovery of exhaust
air was not viable due to economic and potential biological
considerations. Following filtration, a high-plume, induction exhaust
system was used to prevent reentrainment of the air. The system consists
of two exhaust fans, both on VFDs, again with one fan operating and the
other fan in standby, serving a common exhaust plenum. The redundant
fans, similar to the air-handling unit, use parallel run signals,
independently isolated. Both the air-handling unit and the exhaust
systems were designed for excess capacity, affording future expansions
of the CTPF. The equipment is designed and presently operating to allow
for half of the non-clean laboratory to be converted and certified to
FDA validated processing space in the future.
[FIGURE 2b OMITTED]
As the CTPF is located within the hospital's institutional
occupancy, the electrical requirements were segregated to their own
critical branch: redundant to both a utility primary and a secondary,
they are also connected to an emergency generator. As such, 100% of the
facility's loads attain emergency power restoration within 10
seconds of failure, per the National Fire Protection Association (NFPA).
The facility was designed with a utility corridor surrounding the
perimeter of the cleanroom space to allow access to critical air valves,
which are installed close to the facility perimeter for easy access, and
to provide access to the process cooling system for the cold room. A
walkable ceiling grid was installed throughout the space so that
maintenance personnel may access any valves, coils or equipment that
cannot be reached from the utility corridors without interrupting the
The hydronic reheat system uses high pressure steam from the
building plant that is reduced through dual-stage regulating from 165
psig to 15 psig (1239 kPa to 204 kPa) for two parallel steam-to-hot
water exchangers. Two distribution pumps, of variable-primary control,
operate in a lead-lag sequence to circulate water through reheat coils
and each exchanger. The pump and exchanger systems are further
independently coupled for redundant backup.
Cold cathode lighting was selected to eliminate the need for bulb
changes within the facility. The cold cathode technology does not
require replacement for approximately 20 years. The ballasts for the
cathode devices were also located at the perimeter of the laboratory and
the utility corridor for external access and maintenance without need to
enter classified space. A custom 2 in. (55 mm) ceiling grid and cold
cathode application were developed for this project. The cathode
lighting is recessed in the hollowed-"T," with acrylic lens.
This type of lighting was installed to reduce the energy required to
illuminate the laboratory.
The facility uses direct digital controls for operational and
historical trending and electronic record. The systems are comprised of
a standalone building automation system (BAS) that serves as a
controlled, private-network environmental monitoring system (EMS), which
is validated as the facilities log, and compliant with federal
requirements under 21 C.F.R. Part 11. The BAS/EMS systems are used as an
historical checksum of environmental integrity, tracking energy and
critical parameters for trending and alarming to assure product quality.
Access to and within the BAS/EMS systems are restricted within the
facility as well as by authorized, administrative privileges. Alarming
systems are integrated to a callout system for all-hours paging to
provide rapid notification via a chain of authority.
Energy reducing systems and procedures were used wherever
applicable. However, inherent in a laboratory requiring high air-change
rates, filtration and makeup air, is large energy expenditure. Air
systems are equipped with comparative enthalpy economizing and variable
speed control of the fans. Hydronic systems have VFDs as well. Given the
low leaving-air temperatures required within the facility, for comfort
and process, depressed enthalpy ranges for economizing were achieved
affording greater seasonal range of free-cooling. Off-peak ice storage
and variable speed chilled-water systems are to be considered for future
expansions of the facility's infrastructure.
The integrated design/use approach resulted in a compact,
efficient, state-of-the-art facility that is easy to maintain and
provides cell and tissue products of the highest quality following
pharmaceutical-based engineering best practices and controls.
Building at a Glance
Name: cGMP Cell Therapy Processing Facility at Northwestern
Memorial Hospital in Chicago
Location: Olson-McGaw Pavilion, 7th Floor
Owner: Northwestern University/Northwestern Memorial Hospital
Principal Use: Stem cell processing for transplantation
Includes: Bone marrow stem cell, islet stem cell (for diabetes),
cardiological stem cell, and neurological stem cell programs
Gross Square Footage: 6,095
Conditioned Space: 5,694
Substantial Completion/Occupancy: October 2007
By Brett J. Kelley, P.E., CEng., Member ASHRAE, and Charles T.
Meagher, J.D., P.E., Associate Member ASHRAE
Brett J. Kelley, P.E., CEng., is former vice president/project
manager, and Charles T. Meagher, J.D., P.E., is project
manager/mechanical engineer at Henneman Engineering in Chicago.