For its efforts, the LSM facility and the team behind its construction and implementation have won the Operational Excellence award in the annual Facility of the Year Award competition sponsored by ISPE, INTERPHEX and Pharmaceutical Processing magazine. The facility is now a contender for the overall Facility of The Year Award to be announced at ISPE’s Annual Meeting in November.
About The Company
Biogen Idec is an industry leader in engineering, process science and manufacturing. The company's capabilities and capacity for protein manufacturing are world-class in quality and scale. Biogen Idec has expertise in protein expression in mammalian cells and process sciences capability for cell culture and downstream processing. Biogen Idec is one of a few biotechnology companies with three licensed and dedicated biological bulk-manufacturing facilities. One of these facilities is the 250,000sf LSM plant located in Research Triangle Park (RTP), North Carolina.
With 90,000 liters of bioreactor capacity LSM is one of the largest biologic manufacturing facilities of its kind in the world. This facility has already received industry recognition for its exceptional design, innovative modular construction methods, and strong safety record. Within the LSM, significant investments have been made by bio-pharm suppliers and subsequently tremendous advances in new equipment and technologies have been introduced. Combined with advances in R&D and high titer process, higher yields are being developed.
Reasons for Winning/Project Highlights
The facility, process and equipment improvements deliver an increase in titer capabilities from 1 g/L to >3g/L. The result is a >300% increase over previous capacity.
When the project team compared what it would cost to build a new >3g/L facility versus renovating the LSM to deliver >3g/L the equivalent capital outlay of the new facility would have been in the range of approximately $500M and would take approximately 60 months to design, build, validate and license. In contrast the agreed upon project leveraged what was already operational and executed it in 18 months (with only a 4 month shutdown) at a cost of $39.1M.
Bioreactor feed tanks
The renovation also provides capability to establish late stage clinical/commercial capabilities and also provides harmonization between Biogen Idec’s other global Large Scale Manufacturing facilities.
A Lean Transformation
This lean transformation resulted in an overall increase in capacity by de-bottlenecking the process operations and addressed the downstream process operations and made significant efficiency improvements.
The project incorporated lean project delivery methods utilizing 3D Building Information Modeling (BIM) of the process equipment layouts. The equipment was designed and modeled to within ¼" tolerance. The model was reviewed using real-time online software allowing stake holders in Denmark, Cambridge, RTP and Somerset, NJ to review for technical content, accessibility, ergonomics, and maintenance and operations.
In addition, the "3D Model" was developed in conjunction with the equipment vendors and fabricators thus leveraging their expertise and eliminating duplication of efforts. The model was given to the contractors who then in turn utilized it to generate hundreds of isometric drawings saving several weeks of isometric submittal drawing time.
Commenting on the input and value of the equipment vendors, Mitch Lower, Biogen Idec’s, Director, Global Engineering commented, "Custom equipment vendors were an important component to design and engineer equipment to meet transportation, rigging and other challenges associated with the renovation. These vendors were critical to ensure the equipment was delivered on time. The particularly tight timeframe of the project demanded precise timing."
Lean fabrication using modular skids and super skids were utilized. Components were assembled off site to speed installation, improve quality, and minimize environmental disruption.
Modular 1000 liter and 6000 liter buffer hold tanks
Utilizing a Lean philosophy the concept of "rolling shutdowns" reduced facility down time to a minimum. This optimized the production and eliminated the need to keep areas out of production when they didn’t need to be.
According to Lower, "The rolling shutdown was critical to the project’s success. The rolling shutdown entailed keeping GMP production going while construction activities started. For example, on the front end, product was coming through purification while construction work began in upstream areas. The rolling shutdown, coupled with lean project delivery methods and skid fabrication and a highly integrated team, allowed us to minimize our commercial production outage to a mere 16 weeks.
A facility the size and complexity of our Large Scale Manufacturing building has P&L impact greater than $100,000 per day when not in operation. Biogen Idec has used a rolling shutdown strategy in the past, but not to the same magnitude and not with a plant-wide scope including nearly all processing areas. The widespread scope introduces risk to successfully return to commercial GMP manufacturing, but we had a high degree of confidence in our ability to execute.
Our experiences and knowledge of other biopharm companies suggest that while some firms will leverage rolling shutdowns, few will attempt one of this scale, duration and impact. It was one of the primary "buzz" factors at the recent INTERPHEX conference."
Innovative Project Delivery
After a comprehensive execution plan was developed the execution called for the acceleration of what would normally be a fast-track project. The hybrid approach of stick built and modular construction methods along with contractor and vendor collaboration demanded a well-organized and coordinated effort among all parties involved to deliver a successful project.
Commenting on the factors that decided which skids were to be modular and which were to be stick-built, Lower says, "The primary factors in determining stick-built vs. modular were: current status of the process equipment, cost, schedule, accessibility/working space and various risk considerations holding potential impacts to ongoing manufacturing, cost, schedule, etc.
The final breakdown was ~50/50 from a cost and work load perspective."
A Flexible Facility
One of the biopharm industry's newest buzzwords is "flexibility". With recent economic and market drivers in mind - companies are looking to get more out of their facilities than ever before. The LSM is no different in this regard, as Lower explains, "Without question, the renovated facility is highly flexible. As Biogen Idec’s product pipeline has grown tremendously over the past few years, flexibility has become a must. The LSM facility in RTP is capable of producing a range of titers, is licensed for concurrent production and is used for early clinical supply campaigns through commercial, mature products."
Details, Details, Details
A technically advanced facility such as the LSM is made of numerous parts, components and equipment. Yet, it's the details that make it all work together. When asked about this - and what details and features of the facility he's most proud of Lower responded, "The combination of a low cost, multi-product licensed facility with a high degree of flexibility is what makes the LSM facility a highly valuable asset to the company. Beyond the bricks and mortar of the LSM facility itself, Biogen Idec has run this plant with an excellent audit history and safety record."
What puts all of this into motion is of course the people, the team behind the project, as Lower explains, "We’re most proud of the project team. Many in the industry would view the project team as a small subset of company engineers and the contracted firms working on the particular project. We view the team more broadly to encompass Biogen Idec’s RTP staff, including operations, engineering, facilities, quality and support functions. More than 400 employees, representing over 75% of the employee base, were involved directly in the execution of this project. This team has been focused on attaining and retaining a world-class biopharmaceutical manufacturing status. This project was conceptualized, planned and executed with this focus of team in mind. All staff functions were part of the planning process and were tasked with carrying out activities to ensure the project’s success. Continuous review of business processes and procedures as well as project management and execution strategies were challenged to encourage a value added mentality."
Industry Reaction And The All Important Judging Process
"The industry has shown great interest in the accomplishments of this project," says Lower. "We’ve received multiple inquires about our successes from project management and planning through technologies and processing capabilities."
On the subject of judging, and why the facility garnered the attention of the judges, and ultimately led to the award, Lower says," We believe the exceptional planning utilizing lean, integrated, cross functional and operational excellence approaches facilitated an outstanding effort to a recognized world-class manufacturing facility, staff and site. Increasing processing capacity by more than 300 percent in a multi-product, licensed facility with minimal downtime is critical to producing pharmaceutical products for patients."