Biologics producer MedImmune won a Facility of the Year Award for Project Execution in 2011 for the build of a large-scale mammalian cell culture-based production facility in Maryland, US. This article highlights its winning concepts
In the world of biologics, MedImmune has one of the most robust pipelines. The company currently has approximately 100 biologics in R&D; including 16 in clinical development and 11 in preclinical stage. The challenge of having a robust product pipeline is the need for operational flexibility to manufacture a diverse group of products with a wide range of titres.
To enable production of forthcoming products, the company chose to build and license a flexible, large-scale mammalian cell culture-based production facility adjacent to its existing Frederick Manufacturing Center, Building 636, in Maryland, US.
The new facility, Building 633, will initially house 337,000ft2 of administrative, production, warehouse, lab, and utility space. To cater for future growth, MedImmune allowed for a 100,000ft2 expansion of internal production space.
The company wanted a flexible facility that could accommodate a product titre range of 0.5 to 7.0g/litre. This would arguably make it the first large-scale facility in the industry able to produce a 14x process range up to 7.0g/litre.
The company implemented a best in class Process Control System (PCS) to allow for the flexibility required to enable operators to control all processes efficiently. The design called for the extensive use of the S88 model, (which defines a complete process in terms of process actions, but without regard to the equipment) which was provided to each skid manufacturer for implementation.
To verify that these skids would flawlessly integrate into its PCS infrastructure, the company developed a FAT PAC – a portable package of servers that replicated the company’s high-level process network and allowed it to test the equipment in its environment, at each vendor site.
MedImmune also developed a complete, isolated replica of the PCS to allow validation activities to be performed at the same time as equipment validation and shakedown (test runs). Replication of the manufacturing equipment operation, using PLC controllers in a virtual environment, proved to be an effective method for PCS validation.
The company planned for successive shakedown runs several years before the start of qualification and planned other activities with support of shakedown as a top goal. Shakedown activities, which commenced during commissioning and qualification, were planned early on and took precedence in the project schedule.
This approach maximised operator on-the-job training, as well as opportunities to identify issues. The shakedown phases were designed to use equipment progressively through the manufacturing process.
Design model
The plant was designed around several specific requirements:
- The company used a closed system approach, where feasible, to allow simultaneous production of multiple batches or multiple similar products within process areas. This design will allow for concurrent manufacturing in cell culture and campaigned manufacturing in purification. This design also allows for staged product changeover to maximise equipment uptime.
- Manufacturing capacity was based on a production module of four 15,000L production bioreactors with a 12,500L working volume, and the supporting purification capacity to provide bulk substance output.
- Three independent inoculum expansion labs were provided to allow for concurrent expansion of up to three different cell lines. Each inoculum lab is self-contained, with single-pass airflow to eliminate cross contamination.
- The seed bioreactors are arrayed in redundant trains, with the flexibility to use any given seed bioreactor in seed train development. Either final seed bioreactor may be used to inoculate any of the four production bioreactors. The seed train allows operation at full capacity, even at minimum design cycle times, while allowing for backup seeds at reduced capacity.
- The purification process areas are designed to support the wide range of production scenarios. As installed, the purification equipment includes the process capability for three chromatography steps and a variety of viral inactivation, viral filtration, and ultrafiltration scenarios.
- To support quick turn-around time in purification, two sets of chromatography skids, chromatography columns, and purification vessels are installed. The facility provides the ability to install and remove columns with a clear path from purification process areas to the loading dock. Chromatography transfer panels were built with the flexibility to configure chromatography control skids with any of eight buffer inlets, two product inlets as well as WFI, 0.1N, and 1.0N sodium hydroxide. In addition, multi-port valves were installed on the chromatography control skids to allow time-saving stacking of buffer and product line CIP and SIP through transfer panels and chromatography skids.
- All ultrafiltration equipment was sized to accommodate the wide range in possible final bulk substance volumes.
Three model processes were selected as a design basis, including the company’s existing product, Synagis (palivizumab), and two pipeline products that were chosen because of their extended range of process requirements. All three processes were modelled using Excel-based process flow diagrams with mass balances. The spreadsheets were set up to allow simple and rapid “what if” analysis of process variables.
This analysis yielded not only a preliminary equipment list and sizing basis, but also forced certain process decisions.
After completing IOQ, the company performed a process capability study to verify the as-built plant capabilities. The sheer magnitude of the facility dictated the high complexity of the Process Control System (PCS). The team decided that the PCS platform would be based on the Rockwell family of hardware and software. The PCS is a fully integrated, custom installation, designed as a GAMP5-Category 4 system.
Process control study
The design of the PCS encompasses the following capabilities:
- Control, monitoring, alarming and data collection of more than 40 production skids, of all process piping and transfer panels, and holding tanks, Clean In Place equipment, Steam In Place equipment, and of critical utilities.
- Integrated communications with the Building Management System
- Design to allow future expansion to implement a second full manufacturing module in Building 633
- Design to allow for ease of transfer to Electronic Batch Record (EBR) methodology
- Design for plug and play integration with Manufacturing Execution Systems (MES)
- Use of a common Human-Machine Interface (HMI).
The use of an automated configuration management tool quickly proved valuable during commissioning and start-up because many changes were identified and implemented during this phase. For example, at one point 15 control engineers were accommodating various change requests to the PCS code. This configuration management system provided a systematic method for control and organisation.
This process continued through validation, with a parallel test system configured as a mirror image of the production system that was being validated. Both systems utilised a common AssetCentre server. Following validation of each skid or process area, the associated code was versioned again and an automatic schedule for upload and compare was established.
This schedule provided for automatic comparison of the actual code running in the production system with the locked, effective master version. Any deviations between the two versions initiated an automatic email to key team members. In addition to control of PCS code, this automated configuration management system has also been used to control batch file configuration management.
An issue that all facilities start-up teams deal with is the time required to start up and debug applications, train production operators and run test batches. These steps in the process are always competing for time on equipment. They typically overlap each other and the start-up of Building 633 was no different. However, with the time constraints dictated by the aggressive schedule, each group needed to run specific tasks 24 hours a day, seven days a week, concurrently.
Using a Rockwell SoftLogics solution the company created a complete, all-inclusive duplicate of the production system. Work instructions were created describing the steps to maintain the code and applications exactly the same as that on the production system. AssetCentre was used to provide evidence that the changes made between the production system and test systems were identical. This duplicate system was used extensively in the following areas:
Development and testing of changes prior to loading live: Changes that were identified during shakedown runs and other testing could be modified and then loaded on the simulator and verified that they worked properly prior to actual use.
Pre-Qualification testing: Test protocols were written and verified on the test system. Validation protocols for use in the production system were also pre-executed on the test system. This process reduced the time needed for making production system changes and the risk of introducing errors into the production system.
The operational qualification of the S88 system was performed extensively on the simulator. This allowed commissioning and shakedown runs to be done on the actual equipment, freeing up valuable time. Since both the production system and the simulator were being utilised 24/7 in parallel, this dramatically reduced the overall time required to execute the project.
Clean build
The company also planned early to implement a successful Clean Build programme, with increasingly restrictive cleaning requirements as construction progressed into ICQ and start-up. Implementing Clean Build early in the process provided a controlled environment in which to construct mechanical, electrical, process piping and cleanroom finishes.
All personnel assigned to Building 633 activities were required to receive Clean Build training, which specified cleaning requirements for building areas, and identified specific responsibilities in main-taining the required cleanliness level for each area of the building. Implementation of the Clean Build programme resulted in a successful Environmental Monitoring Process Qualification (EMPQ), which was executed without significant excursions or contaminations.
The shakedown methodology used reduced the risk of a failed PV run, but it did have other collateral effects. First, by beginning shakedown runs during ICQ, the scheduling complexity for the job increased. The company needed daily co-ordination meetings to plan activities on every piece of equipment in the facility, forcing ICQ, Process Qualification (PQ), Preventative Maintenance (PM), and calibration activities to defer to shakedown activities.
The most important impact was the need to drive GMP area release earlier in the project to support GMP column-packing. This decision required moving Environmental Monitoring Performance Qualification (EMPQ) up in the schedule. This approach benefited the overall process by allowing the project team to leverage shakedown activities to support cleaning validation, sterilisation validation, and mixing studies. Most important, however, was the ability to reduce the risks to starting up the centrifuges. The centrifuges could not be tested effectively without using live cells and the shakedown methodology maximised the number of runs through to centrifuge to aid in start-up and cleaning validation.
The shakedown process was more successful than hoped. From the first vial thaw, the company successfully grew cells and made product that met all established metrics and criteria.
Fluor Corp. of Irving, Texas, partnered the original contractor, Parsons Commercial Technology Group to assist with ‘‘the scope, the scale and the complexity” of the biologics building project. Coakley & Williams Construction of Gaithersburg won the contract for the interior architectural work for the Frederick manufacturing facility.