Sign up

Stem cell lab.
Subject:
Hospital laboratories (Design and construction)
Hospital laboratories (Heating, cooling and ventilation)
Authors:
Kelley, Brett J.
Meagher, Charles T.
Pub Date:
09/01/2010
Publication:
Name: ASHRAE Journal Publisher: American Society of Heating, Refrigerating, and Air-Conditioning Engineers, Inc. Audience: Academic Format: Magazine/Journal Subject: Construction and materials industries Copyright: COPYRIGHT 2010 American Society of Heating, Refrigerating, and Air-Conditioning Engineers, Inc. ISSN: 0001-2491
Issue:
Date: Sept, 2010 Source Volume: 52 Source Issue: 9
Geographic:
Geographic Scope: United States Geographic Code: 1USA United States

Accession Number:
257352858
Full Text:
[ILLUSTRATION OMITTED]

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.

[ILLUSTRATION OMITTED]

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 facility.

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 pressurization.

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 changeover procedures.

[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 airflow.

[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 ISO-classified 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 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

Employees/Occupants: 15

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.
Gale Copyright:
Copyright 2010 Gale, Cengage Learning. All rights reserved.