Shire, the leading global biotechnology company focused on serving people with rare diseases and other highly specialized conditions, recently completed construction and commissioning of a new pharmaceutical manufacturing facility located 35 miles east of Atlanta, Georgia. The plant is a one-million-square- foot complex built on a 100-acre green field site. Operations are dedicated to the manufacture of human plasma-derived protein therapies used to treat patients with immune disorders and other rare diseases. Laboratory professionals can learn from Shire’s design and start-up experiences because the plant includes a 60,000 square-foot laboratory building.

Laboratory design

The three-level laboratory building was designed with the same open-space concept as the entire facility. Floor-to-ceiling windows cover two full sides of the building, allowing generous amounts of natural light into the workspace. The first floor consists of chemistry and immunology laboratories for quality control testing of product and raw materials, a sample control suite, and rooms for consumables storage and waste staging. The second floor includes a method remediation laboratory, microbiology laboratories, and rooms for cold storage and document control. The third level houses a building- specific purified water system and equipment for nitrogen, vacuum, and air distribution.

The laboratory building was designed for maximum visibility

The laboratory building was designed for maximum visibility.The facility was designed to meet regulatory requirements for pharmaceutical production in the U.S., Europe, and other markets. To that end, the laboratories are tour friendly due to the large windows separating office and laboratory areas. This makes the work being done highly visible, easier to manage, and safer.

Design of the laboratory building also meets occupational safety and environmental regulations with state-of-the-art features. Unique safety features include eyewash stations embedded in the walls that operate automatically when pulled down, and safety showers at color-coded floor sections for ease of location during an emergency.

Laboratory drains flow directly to the facility’s wastewater treatment plant, and automated fire walls can isolate buildings and floors throughout the facility as needed. The sterility isolator includes visual and audible alarms for the control of vaporized hydrogen peroxide.

Sterility testing at Shire’s new manufacturing facility.

The laboratory building includes its own reverse osmosis (RO) water generator and distribution loop. The loop provides RO-quality water to 17 points of use throughout the building. Eleven of these points supply water polishers that further purify the water used for analysis.

All critical equipment throughout the facility, including controlled temperature units (CTUs), the RO water system, and the air handling system, is monitored by a building automation system (BAS). Set points in the BAS control these systems and define operating ranges for alarm notifications.

Unique features

The laboratory design facilitates sample flow. Samples come in via a drop-off station at one end of the building and flow through the testing process toward the other end where waste disposal is managed. In the areas between, rooms are dedicated to chemical weighing, glass washing, sample incubation, and CTU storage. The building also has conveniently located copy rooms, office areas, conference rooms, restrooms, and elevators.

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Seven stability chambers qualified to conditions defined by the International Council for Harmonization are located in the warehouse just a short walk down the hallway that connects all of the facility’s buildings. The temperature and humidity of stability chambers is monitored by the BAS and displayed on real-time monitoring screens in the laboratory.

Another unique feature of the laboratory space is mobile benches that can be redistributed as needed. Additionally, overhead service carriers provide gases and power to each workstation and can be customized for current needs. Argon, helium, oxygen, hydrogen, and nitrogen are routed to the carriers from specialty gas cabinets and generators located throughout the building. Power options can be configured via color-coded outlets at each workstation, and supply up to 300 V and uninterrupted power where needed.

Mobile benches and overhead service carriers make the laboratory highly configurable.

On the first level, testing is performed using approximately 100 product-specific analytical methods. Raw materials and utilities are tested by way of USP-NF and EP compendia. All methods were validated, transferred from other sites, or verified according to a detailed method implementation plan.

Prior to occupation of the building, analyses of specific analytical work flows were performed to ensure optimal placement of equipment and supplies. These reviews included spaghetti diagrams to evaluate work cell movement and 5S planning for placement of tools and consumables.

In the microbiology laboratories on the second level, samples are tested in designated areas for bioburden, endotoxin, and sterility. Additionally, there is a specialized microbial identification suite utilizing MALDI-TOF mass spectrometry. The second level also includes an autoclave suite and a large walk-in cooler for media and sample storage.

Construction and start-up challenges

The start-up challenge facing the laboratory team was to be ready to support all critical utilities, cleaning validation, environmental monitoring, raw material release, and product testing for three separate manufacturing buildings. The timeline for readiness was 11 months from the day of entering an empty QC building. In this timeframe, the team had to install and qualify 600 pieces of equipment and analytical instrumentation, hire and train approximately 50 new employees, implement hundreds of procedures, and transfer or validate 100 analytical methods.

Perhaps the most unprecedented aspect to the start-up challenge was the need to qualify 22 different computerized laboratory systems to the requirements of 21CFR Part 11, Electronic Records. The team followed strict quality system guidance to satisfy these federal requirements. Doing this for so many systems in such a short time period called for an intensive team effort with a detailed plan for each system.

Each computerized system had to go through a multistage series of assessments, from design qualification to user requirement specifications to risk assessment. Each then required qualifications for installation, operation, and performance. Typically, a fully functioning laboratory would consider it a success to complete these requirements for one new computerized system in a period of six months. The start-up of the Shire Georgia laboratories required qualification of 22 computerized systems in approximately nine months. Lessons learned

Overall, the laboratory building start-up was an unprecedented effort, and lessons were learned that warrant sharing with the laboratory management community, including the following:

When a laboratory start-up is part of an overall facility start-up, it is important for planners to realize the broad impact of laboratory operations. In order to support critical utilities like water and air supplies or environmental monitoring for the facility, the laboratory must be prioritized in the sequence of implementation.

Laboratory representatives must closely coordinate with construction contractors to finish construction, including all punch list items. This coordination should include agreement on ownership of qualification and training tasks for all contractor-furnished equipment such as glass washers, fume hoods, sterility isolators, and autoclaves.

Building design should be reviewed for changes in regulatory requirements as the project proceeds, because facility usage can be impacted. For example, rooms that were originally designed for waste accumulation might no longer meet the requirements at time of occupation, and late-stage room or process modifications may be needed.

Contractors for commissioning and qualification are beneficial in cases where highly specific expertise is needed. However, the plan for how employees and contractors work together should be carefully considered, given inherent differences in business objectives. Contractors should never lead the project, and should have clearly outlined deliverables.

Weekly sanitization of the building’s RO water loop involves an automated cycle that closes valves at all points of use while super-heated water passes through for a period of hours. The parameters of the sanitization cycle must be carefully considered with respect to the operation of water polishing units installed at the points of use. Incorrect usage can cause malfunction of the polishers.

Any equipment, no matter how simple, can pose difficulties in installation and qualification if care is not taken to review manufacturer’s recommendations for use. Temperature mapping of laboratory refrigerators that operate via forced air circulation, for example, can present challenges with set point configurations and probe placements.

Risk assessments for computerized systems that do not meet all 21CFR Part 11 requirements off the shelf must drive mitigation actions. For example, when a system does not have electronic signature capability, result records should be printed and signed by the analyst and reviewer, and such mitigations need to be captured in operational procedures.

To reduce the number of software systems used, a chromatography data system (CDS) was chosen to operate five different instrument types: GC, HPLC, ion chromatography, capillary electrophoresis, and LC-MS (TQD). The team quickly learned that implementation of the CDS for third-party instruments marketed as compatible was a challenge, as neither the CDS supplier nor the instrument supplier was prepared to take responsibility for making the combination work. Details of the lessons learned in this regard could be very valuable to laboratory managers in similar situations.

Automated workstations that control operation of multiple analytical instruments in sequence can be difficult to bring on line and operate reliably. Workstations focused on ELISA or endotoxin methods include software and robotics that control automated liquid handling, bar code reading, sample dilutions, plate washing, and plate reading. Although careful coordination with the supplier can make it all work together, qualification of the system and associated methods requires extensive time and labor. In such cases, use of an experienced contractor helps.

Shire strives to develop best-in-class products for patients living with rare diseases, and to do so requires high-functioning, state-of-the-art laboratories. The Covington, Georgia, laboratories provide an excellent work environment, both functionally and esthetically. Successful implementation has resulted in quality control functions that put the new manufacturing plant in a good position to supply patients with much-needed protein therapies. Sharing the experiences and lessons learned with other laboratory professionals is another step toward helping patients worldwide.