44 ASHRAE Jour nal ashr ae.

or g Sept ember 2010

ASHRAEs BEST
T
he 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-classied
environment. The facility was conceived, designed and constructed to exacting specications 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
2
(102
m
2
) laboratory and material staging
area comprising 630 ft
2
(59 m
2
) used
to support the processes occurring in
the cleanroom. The clean area, approxi-
mately 1,830 ft
2
(170 m
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 ooring for easy clean-
ing and ergonomic space allocation was
used to construct the facility.
stem cell lab
By Brett J. Kelley, P.E., CEng., Member ASHRAE, and Charles T. Meagher, J.D., P.E., Associate Member ASHRAE
About the Authors
Brett J. Kelley, P.E., CEng., is former vice presi-
dent/project manager, and Charles T. Meagher,
J.D., P.E., is project manager/mechanical engineer
at Henneman Engineering in Chicago.
SECOND PLACE: INSTITUTIONAL BUILDINGS, EXISTING
I ntegrated design of the Cell Therapy Processing Facility involved scientists early on. Left: QA/QC support lab. Right: Materials staging.
This article was published in ASHRAE Journal, September 2010. Copyright 2010 American Society of Heating, Refrigerating and Air-Conditioning
Engineers, Inc. Posted at www.ashrae.org. This article may not be copied and/or distributed electronically or in paper form without permission
of ASHRAE. For more information about ASHRAE Journal, visit www.ashrae.org.
Sept ember 2010 ASHRAE Jour nal 45
technology award case studies
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 diabe-
tes), cardiological stem cell, and
neurological stem cell programs
Employees/Occupants: 15
Gross Square Footage: 6,095
Conditioned Space: 5,694
Substantial Completion/Occupancy:
October 2007
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% nal lters. In
addition, the cleanroom ceiling diffus-
ers are equipped with 99.997% efcient,
Type-C HEPA lters; fan lter units with
HEPA lters are installed in the cold room.
Through dynamic testing and surface and
airborne particulate cultures, the cold
room certied at an ISO Class 5 rating,
and attained ISO Class 3 levels. The per-
formance of the remaining areas exceeded
the design intent of ISO Class 7 or ISO
Class 8 by at least one classication level.
Separate reheat coils serve each labo-
ratory area, allowing individualized tem-
perature control. Humidication for the
air-handling is fed by a U.S. Pharmaco-
peia-grade pure water system. The system
is comprised of water softening, carbon
and reverse osmosis ltration, process
holding with hydrophilic and hydropho-
bic ltration, deionization and ultraviolet
treatment, with pharmaceutical-grade
distribution piping. During seasonal
downtime, the system is decommissioned
until the recertication, sampling and
startup processes are initiated. System
turnover is sequenced with the biannual
facility certication to minimize impact
on the facility.
Innovation and uniqueness in facility
design originated through an integrated
delivery model, with the early stake-
holders (scientists) who envisioned the
manufacturing processes to be performed
within the facility.
A major innovation was the design
of the cold room for islet cell process-
ing. Processing of islet cells requires
the product to be placed within a 39F
(4C), 35% RH, ISO Class 5 environ-
ment. 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 airow at the
workbench height.
Whereas Class 7 environments de-
rive 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 accom-
plished using fan filter units (FFUs)
with HEPA lters at a density of 90%
ceiling coverage and filtered-return
grilles located opposite the work tables
near the oor. Additional cooling was
accomplished through a secondary
process system for the space: processes
discharge the rooms recirculated and
makeup ventilation air through desiccant
moisture removal following a depressed
suction temperature by direct expansion,
producing a frosted-coil condition and
38F (3.3C) leaving-air temperature.
Makeup ventilation air is supplied from
the facility unit to maintain the required
space pressurization.
The I SO Class 5 cold room was
designed and developed as a manufac-
turing 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 (39F
to 43F [4C to 6C]), resulting in bet-
ter product manufacturing yields as
compared with conventional hoods ret-
rotted 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
Left: Cold room process cooling unit. Right: Work suite 4 for islet cells.
46 ASHRAE Jour nal ashr ae. or g Sept ember 2010
cold room design (at walls with coved corners, cold-cathode
lighting, point-of-use HEPA ltration, movable, locking stain-
less steel workbenches and seamless ooring) also permits
easy, rapid cleaning and allows for establishment of immediate
product changeover procedures.
In addition to streamlining cell processing procedures,
constructing the project-specic 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 efciently prepare the product. The
design permits optimal numbers of personnel to participate
in the cell processing, reducing overall processing time. The
cold room design signicantly improved the tissue manu-
facturing process and results in consistently high quality
nal 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 conjunc-
tion 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.
Roof Line
Exhaust Air
Supply Air
Return Air
Exhaust Air
Supply Air
Return Air
Exhaust Air
Supply Air
Return Air
Exhaust Air
Supply Air
Return Air
Exhaust Air
Supply Air
Return Air
East Corridor
De-Gowning
Work Suite 1 Work Suite 2
Gowning Material Staging
Pass
Through In
(Airlock)
OA/QC Room North Corridor
Work Suite 3
Work Suite 4
Receiving
West Corridor
Cold
Room
Return Air
E
x
h
a
u
s
t

A
i
r
Supply Air
Pass
Through Out
(Airlock)
Exhaust Air
Return Air
Supply Air
Figure 1: Cell Therapy Processing Facility airow diagram.
Another unique aspect of the facility design was the establish-
ment of positive-pressure cascades, allowing multiple cell/tis-
sue manufacturing procedures to be simultaneously conducted
without the potential of product cross contaminations.
CTPF Laboratory construction phase activities were con-
ducted 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 clean-
ing 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 facil-
ity 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
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48 ASHRAE Jour nal ashr ae. or g Sept ember 2010
Figure 2b: Cold room section.
Figure 2a: Partial seventh oor mechanical plancold room.
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 redun-
dancy 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 airow
via pressure within the duct systems.
The supply and return fans each have
redundant drives such that if one vari-
able frequency drive (VFD) fails, the
second has a parallel run signal enabling
the backup VFD to catch the fans mid-
rotation, maintaining minimal interrup-
tion to airow.
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 expan-
sions 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.
As the CTPF is located within the hospitals institutional oc-
cupancy, 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 facilitys 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 surround-
ing 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
ISO-classied areas.
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 paral-
lel steam-to-hot water exchangers. Two distribution pumps,
of variable-primary control, operate in a lead-lag sequence to
Sept ember 2010 ASHRAE Jour nal 49
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 pe-
rimeter of the laboratory and the utility
corridor for external access and main-
tenance without need to enter classied
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 re-
quired to illuminate the laboratory.
The facility uses direct digital con-
trols 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 fa-
cilities 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 privi-
leges. Alarming systems are integrated
to a callout system for all-hours paging
to provide rapid notication via a chain
of authority.
Energy reducing systems and proce-
dures were used wherever applicable.
However, inherent in a laboratory re-
quiring high air-change rates, ltration
and makeup air, is large energy expen-
diture. 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 com-
fort 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 facilitys
infrastructure.
The integrated design/use approach resulted in a compact,
efcient, 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.
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