Speed and Efficiency in Designing and Building a Monoclonal Antibodies Pilot Plant

Over the past several years, biopharmaceuticals have taken their place among the promising therapies approved for human use. Between 2000 and 2004, for example, regulators in the US and Europe approved 75 biopharmaceuticals, including hormones, therapeutic enzymes, vaccines, antibodies, and other therapeutics. The growing importance of biotherapeutics is further evidenced by the market's estimated size: $40 billion and still growing.¹

Desmond Fitzgerald

THE NEED FOR A SPECIALIZED FACILITY

Among the leading life sciences companies that have announced intentions to stake out a position in biologics is Pfizer, which is investing $237 million in a monoclonal antibody (MAb) process development and clinical-scale pilot production plant in Shanbally, Ireland, adjacent to its existing facility in Ringaskiddy. Becoming a top-tier provider of biotherapeutics is one of Pfizer's priorities.

Currently, Pfizer ranks 19th in the world in biotherapeutics but the company has announced its intentions to be among the top five by 2015. Central to Pfizer's achieving this leadership position is the recent creation of a new research and development (R&D) division, the Biotherapeutics and Bioinnovation Center, which will advance leading edge biologic technologies and new biotherapeutics into Pfizer's biotherapeutics pipeline and product portfolio. With five biological-based products on the market and a strong, growing biotherapeutics-based pipeline, adequate capacity and capability to manufacture the new compounds will be critically important to the company's growth strategy.

The MAb pilot-plant site at Shanbally, Ireland, before any construction activity (circa 1969). The tree still blossoms there every year.

Designing and building a facility for the production of MAb drug substance is a major undertaking. Not only is the investment substantial, but also the various elements of facility design must be carefully tailored to accommodate processes that may still be developing. Pfizer's Shanbally project offers an excellent illustration of the complex facility design challenges and requirements dictated by the flexibility, speed, and economic value now required by a competitive business environment.

FROM COW PASTURE TO MONOCLONAL ANTIBODIES

Under construction on a 30-acre site adjacent to the Ringaskiddy facility, and on target for completion in late 2009, Shanbally sits 10 miles from the city of Cork in what used to be a cow pasture. Pfizer chose Ireland as the site for the facility because of the favorable business climate, accessibility of an experienced biotechnology talent pool, and close proximity to the company's drug product plant in Dublin, which formulates products produced in mammalian cell culture. The adjacent Ringaskiddy plant was one of the first pharmaceutical plants established in Ireland, initially making citric acid in the 1970s, and shortly afterwards adding an active pharmaceutical ingredient (API) manufacturing facility. Today, it has expanded both its API and drug product presence in Ireland.

Aerial view of the site under construction, from the first pour of the Pfizer small-scale facility in October 2007 to the ongoing progress of steel erection of the main production area and laboratory administration block in February 2008.

The new site in Shanbally will provide MAb drug substance for Phase 2b and Phase 3 clinical studies and perform process validation studies, drug substance and drug product release testing, and stability program testing. Shanbally will play a pivotal role for Pfizer's network in applying MAb platform technologies and producing small-volume commercial supplies for potential therapies in oncology, chronic pain, diabetes, and autoimmune diseases.

FACILITY DESIGN CONSIDERATIONS

Because of the unpredictability of the development portfolio, two of the most important design considerations include the need for maximum operational flexibility and the speed at which changes can be made. Because site operators will be working with a number of processes in the course of a year, the ability to easily and quickly reconfigure operations and equipment is vital. These two factors affect nearly all design decisions at Shanbally—from how automation is initially configured to how buffers and media are dispensed.

The Use of Disposable Bags

Assessing project requirements was a critical initial step that covered a sweep of key factors and design and build elements carefully mapped to Shanbally's future use. Again, speed and flexibility topped the list of requirements. Designing in the ability for rapid changeover from one product to another meant the use of less hard piping in the facility. Instead, the project team opted for the use of disposable bag technology for both buffer and media, where possible. This greatly reduced the amount of piping that needs clean in place (CIP) and steam in place (SIP) treatment, which will make changeover faster and easier.

Single Downstream Processing Equipment Train

The relatively small production capacity needed for clinical quantities of drug substance dictated that the facility include two 2,500 L bioreactors and a single downstream processing equipment train. Much of the downstream equipment is mobile and the skids can be configured to suit differing product needs.

Completion of cladding and roofing in September 2008.

A key factor that influenced the plans for Shanbally was the need to achieve a design similar to the company's Phase 1 and Phase 2a pilot plant in St. Louis, MO. Because St. Louis is the focal point supporting Pfizer's biologics research and development efforts, plant similarities will permit colleagues at the two facilities to more easily share workload, improve technology transfer, and work to develop new technology as required. This will help ensure smooth technology transfer in the future from the St. Louis Pfizer Global Research & Development site to Shanbally for MAb therapeutics.

Physical Design

The physical design includes a single building consisting of a manufacturing plant with a laboratory and administration block and a warehouse block configured at each end. The laboratories include a quality control (QC) laboratory and a dedicated technical services laboratory where process development work using small-scale bioreactors and purification equipment will take place. The manufacturing block has a ground floor where all utilities are located. The first floor is the main cleanroom suite where the inoculum laboratories, cell culture, harvest, purification, buffer and media prep, bulk fill, and various support activities are located. The cleanroom suite has an interstitial area over the walk-on ceiling. The third floor contains the main heating, ventilation, and air conditioning (HVAC) units.

Final construction phase of the facility with the installation of utility equipment in October 2008.

Another consideration was effective planning for warehousing space that would be adequate for storage needs of the raw materials used in manufacturing. Storage was assessed based on the inventory requirements for our products and benchmarks with other Pfizer sites.

FLEXIBILITY THROUGH AUTOMATION

Perhaps the most significant element of the plant's design is the high degree of automation, an approach driven by the need for operational flexibility, and allowing for easy changeover on a batch-by-batch basis. The complex and sophisticated process for identifying appropriate automation elements addressed the following:

• Distributed control system (DCS) software was developed with flexibility in mind—in small operating blocks associated with unit operations rather than large recipes that would control the complete process.

• The programmable logic controller (PLC) associated with specific vendor skids were an important part of the automation solution.

• Definition of a user requirement specification (URS) before the software bid process, enabling a more tailored approach in matching requirements with software solutions.

• An overall philosophy of seeking out value-added automation when selecting what and how to automate key functions.

• Use of the global automation solutions core modules from the Pfizer Global Manufacturing IT software library. These standard units of automation code can be drawn down and used by any site, minimizing software development and testing efforts.

• A multistep approach in separating the functional and detailed design specification documents into a functional specification and a detailed design specification (DDS). This enabled the process subject matter experts to develop process requirements upfront; it also allowed the automation resources to ensure the functional requirements are met in the DDS and relayed on to the software.

• Conducting a thorough Pfizer quality audit of the automation integrator quality systems, enabling use of their quality system and resources. This means that the team can use supplier test methods and documentation without the need to develop project-specific documentation.

• Planning ahead for postproject system support by tapping a nearby Pfizer Ireland Pharmaceuticals Operations support group for colleagues that could be assigned to key project positions and developed for ongoing support. (This group is a central automation and information technology function that supports all Pfizer manufacturing sites in Ireland.)

BEST TEAM, BEST PRACTICES

The Shanbally project is a complex coordination of interdependent considerations that must balance a variety of inputs: strategic considerations for Pfizer's biologics infrastructure; operational requirements needed for future clinical-scale production work; and logistical elements that center on time, space, and budgetary constraints. To meet the challenge, Pfizer assembled an approach based on best practices in facility planning, cross-functional team input, and company-wide initiatives in design and operational excellence.

From the start, the new facility drew on multiple disciplines. The design and build process required global input from a project team of individuals with specialized backgrounds. The project leverages the know-how of specialists in technical services and production, quality and regulatory issues, laboratory operations, and engineering. Various subject matter experts from corporate support groups and operating plants in the Pfizer network are also involved to provide input on key design disciplines ranging from quality control laboratory size and design, to the specifics of downstream processing platform technology.

This core team of 10 people will work through design construction, commissioning, and qualification, and will stay through the whole process, right up to the point where the plant is making its first batches. At every step, Pfizer needed the involvement of people who understood the project processes and what is required to deliver an operating plant. Rounding out the project team are seven key stakeholders, representing Pfizer Global Manufacturing, Pfizer Global Research & Development, Quality functions, and appropriate Pfizer manufacturing plants.

Because the Shanbally plant will form a key component in the company's global biologics infrastructure, the design and build process had to address a number of important Pfizer-wide operational excellence initiatives.

Among these is Right First Time (RFT), the company's program for encouraging colleagues to apply Six Sigma and other tools to the task of understanding and improving key processes—with the goal of reducing process variations, making them stable, and allowing for future optimization.

Together, RFT and Lean manufacturing were used for assessing the facility layout. For example, the laboratory area was evaluated in depth to ensure its layout supported the test cell philosophy for efficiently carrying out future activities, requiring optimization that affected availability of utilities, sinks, storage space, and instrument location. Process equipment was designed with the use of process analytical technology (PAT) systems in mind.

Quality risk management tools were used to assess the facility design with regard to European Union (EU) and US regulatory requirements. The team worked to ensure the plant design complies with requirements of the EU Annex 2 Guidance on Manufacture of Biological Medicinal Products for Human Use and with all relevant FDA requirements. Shanbally also will meet the requirements of the Irish Medicines Board. The project team concentrated on reviewing the 3D model to ensure it met the quality expectations for the overall design.

ENVIRONMENTAL CONCERNS

Another worldwide Pfizer initiative, called the Green Buildings program, helped guide the planning of the Shanbally facility.

The program seeks to reduce the environmental impact of business operations through the innovative design, construction, and operation of Pfizer facilities, and seeks opportunities to apply these best practices to additional company locations worldwide. Key areas scrutinized in Shanbally's design include energy performance, water conservation, renewable resources, recycling plans, waste management, indoor air quality, and innovation.

TEAM MEMBERS MATTER

One key tenet of the project team was the need to recognize and manage the different project phases, and never to get out of sequence with the design effort. For example, proceeding with the detailed design of a system before the plant piping and instrumentation diagram (P&ID) development has advanced enough would not be allowed because past experience shows the time and cost of rework far outweighs any delay in getting to the appropriate standard before proceeding. Benchmarking also played a role in the design. The team analyzed other biologics facilities, both within the company's manufacturing network and outside it, for key parameters such as cost, schedule, equipment size, and other parameters.

A few other considerations in Shanbally's design process are worth mentioning, especially the fact that good design requires a project team culture oriented around solid design principles. A key principle in this case was to plan for more than simply the ongoing operation of the site. With this facility, design considerations also take construction and commissioning requirements into account. The fact that the designer will commission and qualify the systems ensures that the appropriate high- and low-point vents and system isolation breaks are built into the design, not engineered-in late, after construction is complete. Layouts that maximize construction trade access to equipment are another benefit of designers' being familiar with how construction can be made easier.

In the early phases of the project, the team enacted a formal process for soliciting input and reviews, and then froze the design to allow for consideration of project details. This cycle of review, approval, and design freeze to allow for detail development was followed during both the design and construction phases. A team mindset developed to resist changes as the project moved forward. After a system was deemed safe and in compliance with quality and performance standards, on-the-fly changes would be highly discouraged.

STREAMLINING THE PROCESS

A challenge that was evident from the start was the aggressive schedule, which called for a project timeline of 27 months from start of detailed design to making the first engineering batch. One example of how the team mitigated this issue was by involving the automation team early on, and by working to achieve crossfunctional agreement between the process users, the project team, and the integrator on the design elements. To ensure that the approach was well understood, the team invested time by selecting and preparing a vertical slice of one automation element, the bioreactor pH control system. Process users, project team members, and the integrator made a number of fundamental decisions about major features, including graphic displays, module faceplates, pipe lines and colors, operator prompts, and security access on control modules.

Starting with a clean slate for this facility on a green field site brought advantages and challenges. For the team, this meant that decisions would be based on current good practices and not on site traditions. This is highlighted by how the automation team was handled; most automation team members in Pfizer are located in the offices of the integrator to ensure the quality, functionality, and other standards are built-in throughout the automation systems.

Pfizer Global Manufacturing currently has no MAb commercial or pilot-scale facility in its operating plant network. The project team created its own virtual customer group that included people from different parts of Pfizer who would serve to provide input as an end-user would. This virtual customer included staff members from R&D, from other manufacturing sites, and from central technical groups.

CONCLUSION

Currently, the Shanbally plant construction is more than 60% complete and the commissioning and qualification activity is just starting. Project team members who were formerly involved with the project design phase have transitioned to commissioning activities. Recently hired Shanbally plant colleagues will participate in equipment commissioning activities as part of their education and development program.

Other teams are developing plant manufacturing and quality systems in preparation for plant start up, with engineering batches planned for 2009. There is a detailed operation readiness plan in place and we are currently 30% complete in this area. The laboratories will come online in March 2009, and will be ready to support testing of the initial production batches.

As Shanbally's finishing touches come together and the plant nears completion, the hard work of hundreds of people, inside and outside the company, brings Pfizer another step closer to its objective.

Desmond Fitzgerald is the project leader of the Shanbally project and Ken Bradley is the site leader at the Shanbally plant, both of Pfizer Inc, Shanbally, Ireland, +353 21 500 7947, bradlk@pfizer.com

REFERENCES

1. Wagenigen University [homepage on the Internet]. Wagenigen, the Netherlands: Innovation in Biopharmaceutical Process Development and Manufacturing; 2006 [cited 2009 Jan]. Available from: http://www.bionovations.org.