Porton Biopharma Limited (PBL) is a relatively new player in the pharmaceutical market. One of its main products, however, has been saving the lives of children for more than 30 years.
PBL is investing in new facilities that will enable the company to meet the growing demand for the product. An integrated filling line designed and supplied by Bosch Packaging Technology — in accordance with very challenging requirements for automation, safety and efficiency — is one of those investments.
Erwinase is used to treat acute lymphoblastic leukaemia (ALL), a type of cancer that particularly affects children. The enzyme asparaginase is used as part of the treatment protocols in conjunction with radiotherapy or chemotherapy.
Since its first registration in the UK in 1985, Erwinase has been registered in 20 countries and commercialised in more than 75 countries worldwide. It saves thousands of children’s lives globally per annum.
“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, Managing Director at PBL.
The vial-based final product is manufactured exclusively by Porton, which was established to commercialise the pharmaceutical development and manufacturing capabilities at the Porton Down site in Wiltshire, UK, which were previously part of Public Health England.
The company’s mission is to protect patient health through the quality assured development and production of biopharmaceuticals.
To improve its production processes, PBL is now investing heavily in additional resources to meet increased manufacturing demands and provide greater patient access to this essential drug. This includes the construction of a new facility and an integrated filling line, which PBL is currently implementing together with Bosch Packaging Technology.
From manual to automatic processes
To date, PBL has used a highly labour-intensive process. The vials are washed in an existing Bosch machine. However, loading and unloading, as well as transfer and inspection, are all done manually. The purpose of the PBL upgrade was to automate processes — to make them faster, easier, more reproducible and, most importantly, to remove the risk of operator contact with the product.
The production of Erwinase is an expensive and time-intensive process: the enzyme takes a long time to process, requiring a number of weeks for fermentation and purification before it is ready for filling.
“From the very beginning, it was clear that this ambitious project would include extensive design reviews to achieve compliance with regulatory requirements,” Nigel Hubbard, Senior Project Manager at PBL explains.
“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. The Bosch subsidiary, Valicare, also delivered a great deal of invaluable support regarding qualification, validation and quality engineering.”
Filling accuracy of more than 99.9%
The new line covers the entire process, from washing, depyrogenation and filling to stoppering, freeze drying and capping. Apart from the previously installed 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 an expensive product as Erwinase, it is crucial to not waste a drop. Every vial only contains one millilitre of product, which means it must be filled with the greatest accuracy. Thanks to the Bosch peristaltic pump, the PBL line achieved an accuracy level of more than 99.9% during the Factory Acceptance Test (FAT).
PBL opted for the PreVAS single-use filling system in combination with the peristaltic pump. The prevalidated, preassembled and presterilised system consists of filling needles, hoses and a product bag with a connector.
As all product contact parts are replaced after use, the risk of contamination is significantly reduced. Another very important addition for PBL is the laser-based coding of the vials. This will be done with a laser printer, which is integrated into Bosch’s VRK capping machine. It prints the batch code on the cap of the vial and a camera system is then used to verify the code.
Very high level of risk engineering
Although PBL manufactures on a batch-based campaign basis, it is essential that the equipment is available all year round and is always ready for an inspection by the 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,” Mike Raine, Director of Engineering, explains.
PBL decided to implement a very high level of risk engineering. If there was 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, lyophilisation and capping are contained, thanks to 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. In addition, 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.
Significant increase possible
Despite the many challenging requirements, Bosch had the line ready in good time for the FAT in Crailsheim, Germany, in mid-July 2018. After the successful sign-off, the machines were disassembled and prepared for shipping to the UK for the Site Acceptance Test (SAT), which will be followed by 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. It will make daily work a whole lot easier for us at Porton and, along with our other investments, enable us to scale-up the manufacture of this life-saving product.” PBL expects to have the product and facility authorised and to undertake Performance Qualification (PQ) by early 2020 — which would be right on schedule.