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Exclusive Life Science Feature But what really made this a bit of a gamble was that when the plant was designed and construction began, it was with the knowledge that the technology necessary to operate the facility, namely a 2,000L SUS commercially available bioreactor, did not exist! "The closest thing we had was a prototype by one of the vendors," says Bill Ciambrone, executive sponsor of the project. The EVP of global technical operations and 20-year industry veteran, Ciambrone recounts Shire's decision-making approach, the process of gaining buy-in from the team and regulatory bodies, and the various risk mitigation strategies employed. NECESSITY — THE MOTHER OF DECISION MAKING In 2005 Ciambrone was working for Transkaryotic Therapies (TKT), which was acquired that year by Shire. He says even back then while he was at TKT the need for a Project Atlas-like facility was evident. "We were a small biotech focused on orphan diseases," he explains. "We knew we would be dealing with mammalian cell cultures, operating largely in perfusion, but there was uncertainty about which products in development would successfully come forward." This uncertainty about which product would get FDA approval proved to be a driving factor for the type of plant to build at Shire. "How do you best deal with uncertainty?" he asks rhetorically. "It is hard to deal with uncertainty if you build a bunch of hard-pipe reactors of a certain size when you aren't sure which products will be approved and will require commercial manufacturing capabilities. If you do create a hard-pipe configuration, you may be operating suboptimally with higher costs than the product really needs." Because Shire was faced not with the prospect of manufacturing blockbuster products for millions of patients but with specialty drugs, the need for increased manufacturing capacity was superseded by an even bigger need — manufacturing flexibility. "The flexibility we needed was for producing multiple products, possibly even multiple scales, but all within a small scale," Ciambrone explains. In addition, the company had a tremendous need for getting the plant up and running quickly. It was even more important to do so considering Shire's competitor, Genzyme, was experiencing manufacturing deficiencies at its Allston, MA plant. An FDA warning letter in March 2009 led Genzyme to shut down the plant just three months later — resulting in a severe drug shortage for two life-sustaining, rare-disease medicines (Cerezyme and Fabrazyme). In addition, the Cerezyme shortage resulted in Shire getting FDA fast-track designation for its experimental Gaucher treatment, VPRIV (velaglucerase alfa for injection). "We thought we had an accelerated schedule of bringing a plant up and running by going with SUS," he states. "The competitor's supply crisis resulted in our having to accelerate everything even faster." When the Shire team looked at the various approaches to building a new plant, the positives of single-use technology were significant. "There were almost no negative points except for the uncertainty of the technology not yet being in existence," he affirms. "If you believed in what the technology promised, you could build 'a box' [a building with an open floor plan] that could support perfusion over a variety of scales. And then you could decide which reactors to install later without changing the speed at which the plant could be built." To support the decision-making process of building such a flexible plant, Ciambrone's team conducted an algorithm analysis of a number of potential product-mix scenarios. "The algorithm showed the impossibility of the solution," he explains. "There was no hard-and-fast outcome saying, 'install two 2,000s and two 500s, and those reactors will cover enough capacity.'" Further, none of the configurations addressed the speed question. For example, when you build a traditional plant, install utilities, reactors, and equipment, only then can you begin the WHY NOT SIMPLY OUTSOURCE MANUFACTURING TO A CMO? Given the rise in popularity of outsourcing pharma manufacturing, it would be natural to ask Bill Ciambrone, EVP of global technical operations at Shire, if using a CMO was considered instead of building its cell-culture manufacturing facility in Lexington, MA. "I don't think there was a single CMO that would have fit the bill because of the small volume of multiple products," he states. "It is very costly to partner with a CMO when you cannot promise exactly what is coming." Ciambrone notes prior to the recent formation of Gallus BioPharmaceuticals, there wasn't a CMO with the SUS capability he was seeking. "We would have had to invest a lot with any CMO, and economically it would not have made sense," he states. "They get different margins on small volumes. With perfusion, you are occupying whatever space they have for a long period of time. No one was able to cost effectively meet the demands our product lines required." Even though it could not find one CMO with the actual capacity for the time period required, Shire conducted a 20 LifeScienceLeader.com December 2013 detailed financial analysis to assess outsourcing as an option to further support the decision to build. "Even with the investment of building a $210-million plant, we were able to more cost effectively produce the range of products we needed on a cost per liter, cost per gram basis when compared to CMOs." Another option considered involved developing a strategic partnership with a CMO. "When we looked at potential partners, they already had a lot of clients occupying space," he states. "In some cases the best deal we could get was to build something for them. This was how we decided having control justified the expansion and expenditure." According to Ciambrone, when it came to trying to broker a strategic partnership, there was not enough willingness for an equitable sharing of costs and risks on the part of CMOs to make a strategic partnership economically feasible. In the end, the need for flexibility became the ultimate deciding factor. "Because the CMO is not the client, you never really have complete flexibility when outsourcing," he notes.