Pfizer Biotechnology Ireland has constructed the Monoclonal Antibodies (MAbs) Small Scale Facility (SSF) at Shanbally, Ringaskiddy, Co. Cork, Ireland. The facility, which is Pfizer’ s first biotechnology greenfield development, is a phase 2B/3 clinical trial product facility designed to manufacture, purify, formulate and bulk fill mammalian cell culture derived proteins. It was purpose built for cGMP small scale manufacturing for transfer, scale-up and clinical supply and represents a critical business need for Pfizer. The facility also serves to establish a strategic biotechnology manufacturing center of excellence and is planned to support the rapid development of new biotechnology products.
The SSF was a truly global project, with design undertaken by Fluor Inc. (based in Greenville, South Carolina, USA), Construction Management by Jacobs Engineering Ltd. (based out of Cork, Ireland) and equipment sourced from various locations around the globe including the United States, Europe and Asia.
The overall site is approximately 29 acres, of which the SSF site occupies approximately 10 acres. The facility includes 5,500 liters of bioreactor capacity that are capable of concurrent mono-product production.
The manufacturing basis of design is for a specific g/L titer, downstream purification (MAbs platform technology) with one batch processed at a time, and up to 38 batches per year and up to four products per year. The facility is designed to operate in a campaigned multi-product manufacturing mode with each programmed change-over utilizing a rolling shutdown basis.
The facility was designed with a strong emphasis on a ‘green’ approach and use of the use of best available technology. Aspects of this include re-use of existing assets, waste minimization and recycling (in construction and operations), energy efficient fixtures and equipment, occupancy sensored lighting, minimized air change rates to meet comfort conditions and classification standards, amongst many others.
For their efforts in designing and building a facility that truly ascribes to green philosophies, the project has been awarded the Facility of the Year Award (FOYA) for Sustainability. The annual FOYA program honors the “best-of-the-best” and hands out awards in several categories. The program is sponsored by ISPE, INTERPHEX and Pharmaceutical Processing magazine. An overall winner is announced at ISPE’s Annual Meeting.
The Path to Sustainability
“Sustainability was a key facet of the project from inception and was borne in mind through the project implementation,” says Helen Walshe, Site Leader for the project. “For example, the choice of Shanbally as the site for the project and the fact that it was a previous manufacturing site with ready adjacency to the Pfizer API facility presented significant opportunity for asset re-use. 5,000 cubic meters of crushed rubble from an old adjacent facility were used in the building substructure. 4,000 cubic meters of rock and stone which were excavated in the course of the works were crushed on site and used as backfill beneath the building and roads.”
“Utilizing best practice and Pfizer’s Green Building guidelines, a large number of energy efficient features were applied in the design. As well as items which were commonly applied across the majority of utility systems, specific measures undertaken include economizers on boilers, heat recovery from blow down to pre-heat make-up water, automatic oxygen trim, gas boilers and low NOx burners, and all condensate systems are designed for the return of condensate to a central receiver/deaerator. Cooling water systems were designed such that the RO waste water stream, regeneration and reject, can be used as feed-water for make-up. For clean water system sanitization purposes, ozone is used on RIW (Reduced Ion Water) rather than heat/steam, and final treatment on purified water systems is electro-deionized, with meters provided to monitor all water use. Point of use coolers are utilized rather than loop coolers.
The electrical distribution system is metered for every area and major use point. All utility meters and instrumentation are tied into an Energy Monitoring System in order to monitor and control the major utility systems for the site. In addition, a lighting management system has been installed in the facility across all floors. This ensures lighting is only operational in occupied areas. This has a projected cost saving of 61,000 per year compared to a traditional switched system. And of course energy efficient light fixtures and motors are used throughout the facility.”
Disposable Technology
There can be no denying that in recent years disposable technologies have shown that they are up to the task for pharmaceutical manufacturing. In particular, biological products are well-suited for disposable technologies.
Disposable technologies employed at Pfizer’s Shanbally facility include disposable cartridge filtration and disposable bags (for media/buffer hold, intermediate product hold, seed bioreactor and final bulk product storage applications). The rationale behind employing single use/ disposable technology for these applications included:
• Clean Room optimization – clean room classifications can be downgraded.
• Optimization of Clean Utilities – less CIP solutions/WFI/Clean steam required.
• Time to Start-Up – reduced construction time, validation can be carried out in parallel with construction.
• Flexibility – process changes/scale-up are simpler and easier to reconfigure to accommodate new technologies.
• Reduced initial project cost and reduced operating costs (for the seed bioreactor and final bulk product storage applications).
• Flexibility to accommodate process development and new product production requirements.
Specifically, disposable bags have developed a reliable track record for use in media hold, buffer hold and intermediate product hold applications in place of traditional stainless steel vessels.
For the upstream steps, disposable wave bioreactors are used up to and including the 100 L working volume cell culture. Media for these early stages is prepared in a fixed media vessel and various lots are “bagged off’ into multiple bags using a single bridging part connected to the bags. The bridging part uses a single filter and Y-piece connectors for the multiple bags downstream of the filter, thereby reducing the number of filter integrity tests. The filtered media is considered sterile and can be held for extended periods of time. In addition, this sterile filtering of media removes the need for the media preparation vessels to be steam sanitized, thus reducing the capital cost of these vessels.
The media preparation suite. Media is prepared in a fixed vessel and various lots are “bagged off’ into multiple bags using a single bridging part connected to disposable bags
“Disposable bags have significant advantages for clinical trial and initial commercial launch facilities,” says Walshe. “These facilities tend to operate at a scale (100 to 1,000 L) and frequency (once per week or less) ideally suited to disposable bags. Additionally, these facilities undergo frequent reconfiguration to accommodate different product manufacturing requirements as existing products undergo process development and new products are manufactured. This reconfiguration is significantly easier and less costly than that required for facilities designed around fixed vessels. The key factor for the Shanbally facility was the flexibility it provides for immediate and future process needs. Disposable bag technology is widely used in the facility for both upstream and downstream stages.”
“While there are risks associated with implementing single-use/disposable technology. supply chain management risk can be mitigated by qualifying at least two different single-use/disposable technology vendors. This risk can also be mitigated with a larger warehouse inventory to allow time to investigate suitable alternatives in the event of a supply chain disruption. Of the risks associated with the various process applications, the breach of container integrity and failure of aseptic connections present the most serious. Integrity testing disposable bags before use is very important for applications with potential high-value product loss. Operator training and selection of robust connections are very important for applications requiring aseptic operation.”
Like the media preparations, the buffers are also prepared in fixed vessels, and then transferred into disposable bags. A significant proportion of these buffers have high chloride content at varying pH levels and are known to attack/corrode 316L stainless steel when left in contact with the metal for relatively short periods of time. This is a common problem with fixed hold vessels and often the solution is to use higher grades of stainless steel (higher % of Molybdenum). These alloys add significantly to the capital cost of the equipment. Here again, the disposable technology surmounts the problem of corrosion. Specific bags are not required for these buffers and the material of the tote is not exposed to attack as it is not in contact with the buffer. The buffer preparations can be completed and staged well in advance of their process requirement to give more flexibility to the preparation and to level out operational loadings. The Buffer Hold area to support the downstream process steps is simplified to a staging area for these totes. Disposable connections on the outlet of the bags are passed through from the HVAC Controlled Non Classified (CNC) staging area in to the higher HVAC classification downstream suites.
Within these downstream suites, the product pool is typically collected and held in disposable bags between each of the purification steps. Portable stainless steel vessels are only used for pH excursion steps and pressure transfers. Sampling is catered for in the design of the bags by having a sample bag as part of the main disposable bag. Mixing of combined chromatography elutions can also be undertaken in the bags with an option for up to two recirculation lines on the disposable bag - a peristaltic pump is used to re-circulate the contents. The final buffers are mixed using a proprietary Levtech disposable bag and agitator. From this point, the final product pool is sterile filtered into a generic disposable bag and can be held sterile before being transferred and frozen in the final product bags.
A Flexibility Facility
The manufacturing environment was designed with a high degree of flexibility, consisting of a number of reconfigurable rooms, in tune with the multi-product charter for the facility. Downstream suites were designed around ‘plug and play’ operations with movable processing skids. Each generic station within the suite is supported by buffers from disposable bags, with transfer panels, utility panels and ceiling hubs utilizing flexible connections.
Walshe explains, “The two downstream suites in the facility are principally empty rooms each containing a number of equipment stations. Each station has the capability to cater for any of the purification operations. Future process platforms may vary significantly in the downstream purification steps and, because of the potential for these variations, a modular approach was taken to downstream elements of the facility and equipment. The equipment stations allow for the equipment to be moved so that the process flow follows the sequential equipment stations for all processes. Each of the equipment stations contain a transfer panel that links the process from one station to the next and can supply CIP to the equipment. Pass-throughs to the buffer hold staging area, clean and plant utilities, power and communications are provided at each of the stations. Downstream equipment is modular and the concept of roll-in/roll-out equipment has been incorporated into the layout and operation of this equipment. The main equipment is set at a particular station for an entire process campaign but it has the ability to be disconnected and moved to a different station to suit future processes. The principal benefits of the modular approach to the design is the need to be ‘fast and flexible” given the potential for changing technologies and the likelihood that shorter product campaigns will be a hallmark for future product demand.”
Equipment Selection
While the facility design is highly flexible in nature, Pfizer sought to standardize equipment for various business reasons. “At the outset of the project, a number of goals were set in relation to standardization within all the vendor packages across the project, Walshe notes. “This led to successful standardization of most of the instruments, manual valves, pumps, seals etc. across all vendor packages. This helped in the overall reduction of the site spares inventory and will have future benefits for site maintenance costs. An added bonus of this approach was the earlier availability of vendor data to feed into the 3D model design, which expedited the isometric generation, facilitated the early off-site fabrication of piping and allowed construction mechanical and electrical installation to drive ahead.”
Tying it All Together
An Emerson DeltaV distributed control system (DCS) was selected for the control and monitoring of the plant equipment. Vendor package control systems and quality critical HVAC monitoring instruments interface with the DeltaV DCS. The project automation team utilized the Pfizer PA1 (Process Automation Initiative) library of software standards thereby reducing the need for a development phase of the control modules (CM) and bottom layers of the automation structure.
The project used fully tested control module class-based templates including the Graphic dynamos and faceplates from the PA1 library. This reduced the development and testing time needed to populate the database and have fully functioning control modules to interface with the equipment.
Wireless communication between the DCS and the waste water treatment analyzers eliminated the requirement to run a 500 meter multicore cable between the DCS and these environmental monitoring analyzers. This advance in technology also eliminated the need to construct a 300 meter underground cable duct to contain this communication link.
PAT Applications
Process Analytical Technology (PAT) is utilized throughout the facility from clean utility generation to CIP to bioreactor controls to chromatography. On-line TOC and conductivity are utilized to continuously monitor the status and control the feed forward of all the clean utilities generation and distribution systems. These measures are applied to the RIW, WFI (Water for Injection) and clean steam systems.
On the bioreactors, DO (Dissolved Oxygen) and pH are monitored and controlled by on-line instruments that remove the requirement to take multiple samples for off-line testing and manual adjustment of air, oxygen, carbon dioxide or base flowrates. On-line turbidity on the centrifuge is used to set the ejection frequency of solids for the centrifuge. The chromatography systems have on-line UV on the line out of the chromatography columns that determine and control the collection of the product elution.
The CIP (clean in place) systems have on-line conductivity that controls the final rinse cycle completion.
A Bruker NIR system is available in the QC laboratory and this is being used to replace external raw material ID testing with a simple to use and quick NIR method which dramatically reduces the time to ID raw materials.
The Team Approach
Beyond the physical aspect of the plant, a lot of time and effort was put in by a core team at Pfizer, as Walshe explains. “The overall team approach to the delivery of the project reflected a strong belief in the experience, strength and capability of the core project team. This team believed that they could meet and exceed industry performance standards in project safety, quality, cost, and delivery. The team formed at project inception and carried on through the full lifecycle of the project into early operations. In the later stages of the project, there was full integration of the start-up resources and the sustaining operations team. Rarely, if ever, has such a cohesive unit been established, and maintained such a clarity of purpose over an extended period of time to deliver such success.”n