"Close Collaboration Maximizes Value of Engineered Solutions and Saves Time in Start-Up" (La Vague 53)
The case study of BioMarin Fast Track project with Verdot Ips²
This paper reports a very fruitful collaboration between a Biopharmaceutical company, BioMarin International Ltd and a manufacturer of purification equipment, VERDOT Ips², which contributed to a fast start-up of an installation for manufacturing a recombinant human tripeptidyl peptidase 1 (rhTPP1), for the treatment of neuronal ceroid lipofuscinosis Type 2 (CLN2) disease, also known as Batten Disease.
The successful start-up of every manufacturing process depends on:
• Design and building of equipment, engineered for purpose and qualified to deliver the quality and efficacy attributes of the product;
• Validated procedures for operating, cleaning and maintaining operations, which must be optimized according to the installation;
• Trained and competent engineering and technical staff for operating, maintaining, and supporting the operation;
• Continued support by supplier-partners who maintain understanding of the equipment, application and project history through the qualification and start-up phases and handoff to operations.
Since 1987, VERDOT Ips² (www.verdotips2.com) is a worldwide supplier of purification solutions, especially in Low Pressure Liquid Chromatography, for applications in Biopharmaceutical and Nutraceutical manufacturing.
BioMarin (www.biomarin.com) is a world leader in developing and commercializing innovative biopharmaceuticals for rare diseases driven by genetic causes. In that respect, Children with CLN2 disease typically begin to present symptoms between the ages of two and four, with the majority of affected children losing their ability to walk and talk by approximately six years of age. During the later stages of the disease, feeding and tending to everyday needs become very difficult, and death often occurs between 8 and 12 years of age. Saving months on the market release of such therapy can save years of life expectancy for the young patients. Thus, after positive results obtained during clinical phase, BioMarin accepted to launch an early access program to provide experimental drug prior to marketing phase.
The collaboration between BioMarin Shanbally Ireland and VERDOT Ips² in this project started in September 2015. The goal was to start up a large scale process chromatography installation within eight months to respect the timing of the early access program.
In addition to the stringent planning, the project also involved difficult space constraints, as the new installation had to fit in existing production suite dimensioned for smaller scale. Smart chromatography column design, capable to reduce volume of consumables for its preparation (packing/unpacking/cleaning) was thus considered as a strong advantage for minimizing the impact on utilities, such as the WFI installation.
Excellent team work and communications was critical to responding to the challenge. The engineering teams of BioMarin and VERDOT Ips² worked closely together to address the space & utilities constraints with consideration of operational requirements and work ergonomics.
The project managers of both companies met weekly through the project completion to satisfy the milestones of the planning, and respond to challenges in coordinating the supply chain of equipment and fabrication.
Standard Operating Procedures (SOPs) are the most important documents available to operators, engineers and maintenance technicians. They describe very precisely the implementation of the design intention with the installation, and ensure the consistency of quality and efficacy in batch, whatever the operator. Very often this document is drafted by a process expert alone, who writes it based on his own experience and following template procedures close to the ongoing application. The specificities of the installation and the current application can thus not be fully considered. This approach does not allow us to integrate new know-how from external experts, such as suppliers of consumables (chromatography resins, filtration membranes) or equipment suppliers. Useful tips can be found in the instruction manuals of each one, but these being generic are rarely applicable as described.
Based on successful experience between the two partners, BioMarin and VERDOT Ips² implemented an intensive collaborative approach to speed up the preparation for installation and commissioning of the equipment. This approach was based on the co-writing and covalidation of the SOPs. Following BioMarin’s standard format and based on the existing installation and quality attributes defined for the new product, BioMarin and VERDOT Ips² very openly shared their experience to write the detailed procedures for equipment preparation: packing, unpacking and pre- and post -packing cleaning.
The new procedures were pilot tested in generic and non-GMP conditions, just after the Site Acceptance Test. This early procedure walk-through allowed optimization of parameters settings and sequence of operations. The revised procedures were tested again in cGMP conditions with the set of buffers and stationery media defined for each purification step. The static phases, i.e.: chromatographic media, were supplied from various international suppliers. One also provided his assistance during the packing.
BioMarin and Verdot Ips² also know from experience that important design features can often be left behind in the hand-off of equipment from supplier to customer engineering to operations. Without critical communication, awareness, and training, operational practices quickly default to familiar techniques developed on obsolete equipment. The opportunity provided by a new manufacturing process with purpose engineered equipment and an aggressive timeline means everyone involved can be hyper-focused on the details of change.
Results and Discussion
The column was sanitized with 1N NaOH (sodium hydroxide), injected via suction using the motorized adapter as a large syringe. The adapter equipped with an inflatable seal was fully soaked in Sodium hydroxide with seal deflated. After 2 hours of soaking, an alternated circulation of NaOH between down flow and up flow performed a full sanitization of the distributors and bed support. The design of the adapter ensured that the mobile phase was distributed everywhere, enclosing the border of the dynamic seal to avoid risk of bioburden.
Figure 2: picture and cut-away view of the InPlace top adapter
The InPlace™ column of VERDOT Ips² being equipped with slurry valves, the media was transferred in “close” conditions minimizing the risk of contamination. The media transfer performed via suction with a controlled stroke allowed transferring a precise amount of media, for ensuring packing reproducibility. The column degassing was instantaneously obtained by actuating the embedded column tilter while deflating the dynamic seal. The media was simply packed in axial compression by lowering the adapter at controlled speed and automatic height monitoring for precise compression control.
This ensured a high performance packing. For instance, an agarose based media bed gave a reduced HETP (Height equivalent to theoretical plate divided by mean particle size) of 2.16, with 4400 plates/m and an asymmetry of 0.96, all within BioMarin acceptance criteria.
The packed bed was re-slurried in place by injecting one column volume of water alternatively in up flow and down flow, followed with a 20 minutes air-sparging by simply injecting low pressure air through the bottom process connection. For emptying the column, the column was tilted and the slurry valve located at the lowest point of the tilted column was opened to the slurry tank. Air sparging was maintained during the slurry transfer to keep the media suspended, maintain slight pressurization and help the media flow toward the slurry valve.
Only small traces of media were left in the column, easily removed with a few liters of water. As result, less than 2.5 columns volume were required to reslurry the bed transfer the slurry back into the tank (maintaining a 50/50 slurry) and completely rinse the column, leaving no trace media.
After validation by VERDOT Ips² and BioMarin process experts, BioMarin Operating teams took over and repeated the procedures without assistance to ensure documentation was sufficiently detailed and precise to ensure reproducible results with the different teams working around the clock.
This experience has confirmed that the equipment intrinsic performance is only one success factor of a successful new process implementation. A thorough collaboration between the users and the equipment supplier all along the project, and especially at the project start-up is also paramount for the success.
The very open discussion and confident share of information between the different parties, under non-disclosure agreement, has finally made the collaboration efficient.
As result, it contributed to the timely manufacture of the first lots of rhTPP1 under the early access program and smooth step-up to the forth-coming manufacturing phase.
By Sébastien Lefebvre - Verdot Ips²
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