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Identifying issues in the factory that traditionally arise in the field minimized onsite equipment rework and subsequent qualification work.
Risk is part of biopharmaceutical development. Planning for commercialization typically starts after completion of phase 1 trials. If you wait until the end of phase 3 to build a manufacturing facility, years of profitable sales will be lost. If you build a factory too early, you risk the possibility that the factory will be idle while waiting for product approval. After all, in today's regulatory and economic climate, the odds of successfully bringing a product from discovery through clinical development to commercial success are less than 1 in 100. Companies cannot be blamed for questioning when, or even if, they should build a new facility to manufacture a product for commercial launch. However, modular design can reduce this risk by reducing construction time and increasing flexibility.
Figure 1. Service Chase in Hemosols Meadowpine Facility
In the summer of 2000, Hemosol decided to build a state-of-the-art manufacturing facility — a carefully planned strategic move to position and accelerate the commercialization of Hemolink, a hemoglobin-based oxygen carrier (HBOC). This endeavour was intended to transition the company from an R&D organization to a fully integrated manufacturing-based company poised to capitalize on the billion-dollar market for oxygen therapeutics.
Outsourcing Hemolink manufacturing was not a viable alternative. Hemolink is a large volume parenteral, requiring a significant capital investment for the large commercial manufacturing process. In addition, at that time it was not possible to find a contract manufacturer who was prepared to handle a human blood-based product.
Figure 2. Architectural Rendition of Hemosols Meadowpine Facility
The choice to proceed with the construction was risky, given that the planned facility completion date was targeted to coincide with the end of pivotal phase 3 clinical trials to permit immediate Biologics Licence Application (BLA) filings in the US, Canada, and the UK. Acutely aware that development plans don't always follow the expected path, Hemosol insisted that flexibility and adaptability be incorporated into the plant design.
When the company experienced unforeseen delays in its clinical program in 2003, this flexibility allowed necessary adjustments to be made to its business plans. Although the corporation downsized and reorganized, we were able to adapt the newly constructed facility — with its many unique and innovative design elements — to accommodate the manufacture of other products. By establishing a contract manufacturing division to serve the biopharmaceutical industry's outsourcing needs, Hemosol is leveraging its expertise and state-of-the-art manufacturing facility to generate revenues and support its own continuing R&D programs. The facility's unique design allowed it to be rapidly retrofitted for contract manufacturing. In June 2004, Hemosol announced a definitive license and strategic alliance agreement with ProMetic Biosciences regarding the Cascade technology, developed jointly by ProMetic and the American Red Cross, used for the separation of valuable therapeutic proteins from human plasma. This represents the first contract manufacturing related activity for the new facility, demonstrating its adaptability and flexibility.
Figure 3. 28-Month Project Timeline
The new 130,000-ft
building houses corporate offices, laboratories for research and quality control, warehouse space, and the manufacturing plant (Figure 2) on a seven-acre site in Mississauga, Ontario. The facility was specifically designed to meet or exceed the existing standards for the Canadian, US, and European regulatory agencies.
During the early stages of engineering design for our facility, we adopted an aggressive project schedule emphasizing process adaptability, expandability, speed of construction, and rapid start-up. Our commitment to the modular design of the plant's process units ultimately drove many of the building's unique features. By taking a "plug and play" approach to the construction and installation of process equipment, we were able to complete the $C90 million project in 28 months. The schedule is outlined in Figure 3.
Figure 4. Manufacturing Area Schematic
This innovative modular-construction style had never before been implemented with comparable scope or complexity in Canada. We met our ambitious project schedule by fabricating the process units in parallel with building construction. Conservatively, we cut between 8 to 12 months from the overall project schedule. Modular design produced further time savings in start-up and validation. Reducing build times can be a tremendous advantage for a company by permitting project approval for a new facility much later in clinical development, thus mitigating risk without sacrificing time-to-market.
It was crucial that the building design be module-friendly and well coordinated. Hemosol's project team, consisting of SNC Lavalin Pharma, Alfa Laval Biokinetics, and Levine Lauzon Architects, along with Stantec Consulting and Barnes Huntington & Associates as owners, project management, and engineering consultants respectively, used routine and frequent design review meetings to coordinate, identify, and quickly resolve issues and minimize project delays and cost overruns.
Some of the biggest obstacles to a modular-build approach relate to the discovery that the traditional design sequence used for conventional, or stick-built, plants does not work for modular facilities. Pre-construction design must be substantially more complete to ensure that module and facility interfaces are well defined. As part of the early detail design process, it was necessary to pinpoint these interfaces to allow both facility and equipment design to proceed efficiently. For example, it was necessary to quickly establish maximum footprints and elevations of the modules, identify structural and utility connection points, define routing patterns and zones to coordinate ductwork with piping, and determine installation routes sized to accommodate the largest modules and module structural loads.
The production area of the facility was constructed on three levels, as depicted in Figure 4. The large basement is 18 ft deep and houses waste treatment, five clean-in-place (CIP) systems, solution preparation, water purification systems, and buffer storage. On the main floor is the bulk of the 26,000-ft
clean production area. The ground-floor cGMP production area measures 26 ft from floor to the underside of the mechanical penthouse. This provides ample space for installation of large process modules within the 16 ft tall cleanrooms, while ensuring generous space in the interstitial areas above the ceilings.
Figure 5. Installed Modular Process Unit
Above the production area is a 20 ft high mechanical penthouse that encloses the plant's nine HVAC units supplying the various clean suites and support spaces. In addition, two dedicated, 225-hp, oil-free air compressors supply both process and control air to the manufacturing facility. Two 400-hp boilers and three chillers with a total of 2,000 tons of capacity are located adjacent to the process area (at grade level, along the outside wall). A large explosion-vented cleanroom is also situated on the main floor (but not directly over the basement), accommodating processes using flammable solvents.
The most unique part of the design is a large service chase running down the middle of the plant, shown in Figure 1. Measuring approximately 110 ft long, 42 ft high, and 10 ft wide, this chase creates a passage from the basement to the underside of the mechanical penthouse and provides for the distribution of process and utility piping as well as main-floor HVAC-duct routing. Two additional duct shafts, one at the north end of the manufacturing space and the other at the southeast corner, allow HVAC ducts to be routed to the basement, ensuring sufficient space is reserved within the central service chase for pipe distribution.
Figure 6. Equipment Installation and Subsequent Replacement of Access Panel
The service chase allows distribution piping to be remote from the clean space and corridors while eliminating the need for piping above ceilings in the interstitial spaces. This provides easy accessibility to the utility distribution and process piping and greatly simplifies equipment installation.
All modular process equipment is "plugged" into process and utility piping at the service chase (Figure 5) using high and low wall plates, which makes connecting and starting up the process equipment very quick. Cleanroom downtime associated with maintenance, modifications, or repairs can be kept to an absolute minimum as most installation and alterations occur in the mechanical subspace within the service chase. Any downtime during modifications is limited to closing final penetrations into the cleanrooms and associated equipment connections. In the service chase, we can do independent utility changes and reroute process piping without impacting operations. Overall, it facilitates rapid requalification of manufacturing areas following changes or modifications.
Figure 7. Cleanroom Panels Removed to Accommodate Equipment Installation and Later Reinstalled
Both the main floor and mechanical penthouse floor were constructed using pre-cast concrete Ts, similar to modern bridge and parking garage construction. This enabled a 40 ft wide by 160 ft long span on each side of the central service chase to be quickly erected during the building construction. The resulting structure maximized the flexibility of the architectural layout and equipment placement by eliminating the need for extra support columns for the equipment loads. The open space also enabled large process equipment to be fully fabricated as a module at the vendor's shop and delivered as functional, assembled units ready for installation.
To accommodate the process equipment, it was critical to optimize the facility to take advantage of modular design. Two removable exterior wall sections and numerous demountable cleanroom partition walls were installed on either side of the building, and a large roll-up exterior door was installed into the mechanical penthouse. Once the construction of the cleanrooms was complete, the pre-assembled process equipment arrived onsite and was immediately transported through the specially designed openings in the building and directly connected to other process equipment and utilities through the wall plates at the service chase. These access points and the use of the clean panels made it easy to rapidly install the equipment and finish the cleanrooms in preparation for commissioning and start up activities.
Figure 8. Two of the Five Clean-In-Place (CIP) Units Installed in the Basement
The design of the building allowed process equipment to be built offsite, tested in the factory, and simply moved into place as assembled modular process units. A total of 28 modular process units were installed in the facility, including water generation and distribution, CIP, microfiltration, chromatography, ultrafiltration, concentration, diafiltration, pasteurization, virus filtration, gas exchange, sterile filtration, buffer preparation, buffer storage, and final aseptic bag filling. An added advantage of this modular approach is that process equipment can be moved, reconfigured, or removed easily without major impact on the facility. Figures 6 and 7 show how panels can be removed for equipment installation. Figures 8, 9, and 10 show clean-in-place, buffer storage, and water distribution units installed in the basement level of the facility.
Figure 9. Buffer Storage Unit
Modular construction of the process equipment enabled a large portion of the overall project to be completed off site, in a controlled manufacturing setting rather than at the job site. This simplified the field work, accelerated construction, and improved overall project quality in many ways, such as:
We saved a substantial amount of time by adopting a rigorous and controlled FAT and site acceptance-testing (SAT) regime. The project team pre- and post-approved detailed test documentation, tracked discrepancies, and controlled rework to correct problems. This ensured that process units were fully operational and functioning as intended prior to the equipment arriving onsite. SAT activities focused on site-specific requirements, such as process interconnectivity, rather than basic equipment functionality. By identifying issues in the factory that more traditionally arise in the field, we minimized costly onsite equipment rework and also ensured that subsequent qualification work proceeded with a minimum of complications.
Figure 10. Purified Water and WFI Distribution Unit
Through the use of these innovative building design elements, we were able to achieve substantial flexibility and adaptability with our new manufacturing facility while continuing to meet an aggressive project schedule and staying within a tight overall project budget.
John R. Rydall is director of operations at Hemosol Corp., 2585 Meadowpine Blvd., Mississauga, Ontario L5N 8H9, 905.286.6273, fax: 905.286.6300, firstname.lastname@example.org.