The Caliber Biotherapeutics manufacturing facility in Bryan, Texas offers an interesting look at the development and integration of Plant Made Pharmaceuticals. This commitment to new and innovative drug development strategies has led to it being recognized as one of Pharmaceutical Processing’s Facility Excellence Award winners for 2014.
The Caliber facility provides 128,000 square feet for growing up to 2.2 million Nicotiana benthamiana plants, and came into being as the result of a Technology Investment Agreement between the Defense Advanced Research Projects Agency (DARPA) and Caliber’s parent company, G-Con.
The agreement was part of Project Blue Angel, an H1N1 acceleration project designed to show that Plant Made Pharmaceuticals (PMP) can be scaled-up to deliver biotherapeutic proteins at a lower cost. While there is already strong research data supporting the use of plant-based technology, this project represented the first in which production levels were scaled-up to support military and government needs.
The facility began initial production in late 2011, with the goals of proving that a plant-based system offers the advantages (compared to mammalian cell systems) of higher throughput development and screening of monoclonals and easier manipulation of primary amino acid sequence and glycosylation patterns.
The hydroponic plant production system begins with pre-soaking rockwool Kiem plugs and placing them in 240-count Styrofoam trays with a pH-adjusted hydroponic nutrient solution. Following this procedure, seed is distributed via a Bouldin & Lawson compact needle seeder. After three weeks plants are transplanted into grow trays and placed on flow racks. These trays are loaded and unloaded by custom-built wire-guided forklifts.
The Styrofoam trays are then placed in a specially-designed aluminum germination flat that, when fitted with drip irrigation, delivers a re-circulating hydroponic solution of growth nutrients. Germination trays are then placed in a room where a laminar flow wall disburses air at a constant temperature of 27 degrees Celsius and relative humidity of approximately 50 percent. Under these conditions, germination typically occurs within 3-5 days, with plants remaining in the germination room for 21 days.
Fully developed plugs are then transplanted to grow trays that are fitted with a vacuum infiltration lid. The plants reach their optimum size in approximately seven days. LED lighting is used throughout the facility instead of standard fluorescent lights because fluorescent lighting proved to require more maintenance, produced too much heat and could not deliver the type uniformity in plant development that is required. The customized LED lighting developed by G-Con also reduces energy costs by 44 percent.
All upstream plant production, which takes 35 – 38 days, is done in specialized pods, also created by G-Con. These flexible, scalable, modular bio-processing clean-rooms contain a working space of 450 square feet and can be moved into place by floating on a layer of compressed air. Utilities are connected via umbilicals, with the cleanrooms attached to an access corridor that provides an interface to the building and another level of pressure cascade for containment.
The pods have onboard inlet and exit filtration, in addition to HEPA filtration, to effectively isolate the cleanroom and allow the pod to be used in either positive or negative pressure modes and in constant volume or variable volume mode. The pods also have built-in fire suppression so hard connections to sprinkler systems are not necessary.
Additionally, they are equipped with a control system featuring Rockwell Control Logix PLC controllers. All sensors and control systems are IP addressable, with the pod connected to the local area network via Ethernet and a single cable. Each Pod is served by its own redundant HVAC system, with two air handlers.
Banks Integration provided the control systems for individual process components, as well as the data monitoring and control GUI interface for the pods and building management system. This system completely monitors and fully controls processes from seeding and germination to filling purified product into bulk vials.
The PlantPAx solution is comprised of an Allen-Bradley 1756-L73 ControlLogix Programmable Automation Controller (PAC), backed up with an HMI server running FactoryTalk View SE. All the devices were connected on EtherNet/IP and configured with RSLogix 5000 software.
The solution also included Rockwell’s Global Engineering Modularity Standard control modules as the basis of the control architecture. They were implemented in ControlLogix add-on instructions with associated HMI faceplates. The process sequencing was programmed using Rockwell’s Phase Manager Software and a custom sequence manager, which followed the ANSI/ISA-88.01 standard for modular programming.
- The facility is designed under the premise that the largest single utility unit can be down for maintenance, but the loads will be maintained with redundant equipment, which includes:
- A heating capacity of two million BTUH.
- Chilled water cooling capacity consisting of two 400-ton independent chillers.
- The existing PFW system can generate 150 LPM with a storage capacity of 7,500 liters.
- A liquid-handling bio waste inactivation system where heat is utilized to inactivate all BSL 1-designated liquid waste streams.
- A standby, diesel-powered electric generator can produce up to two megawatts of emergency power.
According to Caliber, at commercial scale their facility can produce 100 million doses of H1N1 PMP product in 16-20 weeks, whereas similar tank-based bioreactor systems can take 6-9 months to produce the same quantity. This time-savings combines with upstream capital costs that are 10 percent lower and typically contain less automation.