Porton Biopharma Limited (PBL) produces vaccines, therapeutic proteins and enzymes, its own licensed biopharmaceutical Erwinase, and the U.K.’s anthrax vaccine. The firm also handles contract manufacturing through all stages of product development and commercialization.
Erwinase fights leukemia and is filled in vials and manufactured exclusively by PBL, which was established to provide greater patient access to this essential drug. PBL’s Porton Down site in Wiltshire, U.K. was previously part of Public Health England.
To commercialize the pharmaceutical development and manufacturing capabilities and improve production processes, PBL is now investing heavily in additional resources, and effort that includes the construction of a new facility and an integrated filling line, which PBL is currently implementing together with Bosch Packaging Technology.
One of PBL’s main areas of focus is saving the lives of children, which is where Erwinase comes in. Used to treat Acute Lymphoblastic Leukemia (ALL), a type of cancer that particularly affects children, the asparaginase enzyme is used as part of the treatment protocols in conjunction with radiotherapy or chemotherapy. Since its first registration in the U.K. in 1985, Erwinase has been registered in 20 countries and commercialized in more than 75 countries worldwide.
Erwinase is reported to have saved thousands of children’s lives annually around the globe. “That might not sound like much at first. But if you consider that the children treated with our medicine would otherwise not stand much chance of surviving, we are proud and happy about every child we can save with Erwinase,” says Dr. Roger Hinton, PBL’s Managing Director.
From manual to automatic processes
The Bosch line is developed in accordance with challenging requirements for automation, safety and efficiency. This is especially important given that the production of Erwinase is expensive and time-intensive: The enzyme takes a long time to process, requiring weeks for fermentation and purification before it is ready for filling.
The labor-intensive process included washing vials in an existing Bosch machine. However, loading and unloading, as well as transfer and inspection, were all done manually. The purpose of the PBL upgrade was to automate processes to make them faster, easier and more reproducible. Most important, though, was to remove the risk of operator contact with the product.
“From the very beginning, it was clear that this ambitious project would include extensive design reviews to achieve compliance with regulatory requirements,” says Nigel Hubbard, Senior Project Manager at PBL. “In fact, documentation is just as important as the equipment itself. Bosch Packaging Technology not only put together a team that displayed impressive technical expertise and a great attitude, they also provided straightforward, easy-to-follow documentation that included even more information than we had expected.”
He adds, “Bosch subsidiary Valicare also delivered a great deal of invaluable support regarding qualification, validation and quality engineering.”
Filling accuracy tops 99.9%
The new line covers the entire process, from washing, depyrogenation and filling to stoppering, freeze drying and capping. Apart from the already existing freeze dryer, all machines are from Bosch Packaging Technology. The MLF 5044 vial filling and closing machine operates with a peristaltic pump and 100% in-process control.
With such a product as expensive as Erwinase, it is crucial to not waste a drop. Every vial only contains 1 mL of product, which means it must be filled with the greatest accuracy. The peristaltic pump allowed the PBL line to reach an accuracy level of over 99.9% during Factory Acceptance Testing (FAT).
PBL opted to use the PreVAS single-use filling system in combination with the peristaltic pump. The pre-validated, pre-assembled and pre-sterilized system consists of filling needles, hoses and a product bag with connector. Since all product contact parts are replaced after each batch, the risk of contamination is reduced.
Another important addition for PBL is the laser coding of the vials. This will be done with a laser printer, which is integrated into Bosch’s VRK capping machine. It prints the traceable batch code on the cap of the vial, with a camera system used to verify the code.
Risk engineering
Although PBL manufactures on a batch basis, it is essential that the equipment is available all year round and always ready for an inspection by regulatory authorities. “We perform simulation runs with our staff and undertake regular training to ensure both our people and equipment are compliant. That includes making sure that the sterility of the equipment and the environment is maintained at all times,” notes Mike Raine, the company’s Director of Engineering.
PBL decided to implement a high level of risk engineering. If there were to be a problem with any critical part of a machine, for example, in the event of a power loss, there are auxiliary back-up generator systems in place to ensure the drugs are protected and sterile.
Bosch designed the redundancy factor directly into the system. Once the vials leave the depyrogenation tunnel, the entire process is covered. Filling, lyophilization and capping are contained by three separate grade-A laminar flow groups with HEPA filters. They ensure that the laminar flow is uninterrupted, even in the unlikely event that one or more of the 14 fans stops working.
Also, a Supervisory Control and Data Acquisition (SCADA) system monitors all critical parameters for batch release, such as temperature, time and filling accuracy. The data collected and verified by the SCADA system is fully validated and ready for inspection by the authorities, whenever required.
Performance Qualification by 2020
Despite many challenging requirements, the line was ready in time for the FAT in Crailsheim, Germany in July 2018. After the successful sign-off, the machines were disassembled and prepared for shipping to the U.K. for the Site Acceptance Test (SAT), which was followed by the Installation and Operational Qualification (IQ/OQ), further types of performance qualification, test procedures, and intensive staff training.
“Thanks to the great work of the Bosch team, the new facility will feature all the process improvements we were hoping for,” says Hinton. “It will make daily work a whole lot easier for us at Porton and along with our other investments enable us to scale the manufacture of this life-saving product.”
PBL expects to have the product and facility authorized and to hold the Performance Qualification (PQ) by early 2020.
