Flexibility has quickly become one of the most noticeable buzzwords of the bioprocessing industry. Understanding what constitutes a “flexible” process ranges from the simple application of one specific type of technology (e.g., single-use systems, automation, standard controls) to a somewhat extreme concept of a “throw-away” process. But whatever the definition, the factors leading to the need for more flexible approaches to biomanufacture are clear: Rapid, sometimes unexpected, changes in a company's business situation and/or product portfolio (whether for patients or clinical trials) require that companies adjust to meet those challenges in very short time.

Achieving Flexibility

Although blockbusters are still dominating current markets, biopharmaceutical companies have been quietly shifting from the blockbuster model to diversified portfolios with big and small products on the horizon. To develop those products, manufacturers have been forced into a position of having to introduce flexibility into their manufacturing capability that didn't exist before. Ran Zheng (executive director and plant manager at Amgen) notes three major factors in the industry's general shift toward flexible manufacturing: a volatile market with potential changes in healthcare and Medicare policies in the United States and increasing competition from emerging markets; more diverse products (particularly personalized medicines) in the pipeline and commercialization, demanding facilities to be multiproduct capable with shorter change-overs; and advances in science and process technologies providing higher potencies and titers.

Business: “The flexibility we talk about today is a new way of operating the business,” says Parish Galliher (founder and chief technology officer of Xcellerex). Galliher points to three major business factors contributing to the current need for flexibility the result of several economic, political, regulatory, and market pressures on the industry. First, the economic situation is requiring companies to do more with less money, less cash, and less economic risk. “Manufacturers have learned they need to invest in manufacturing assets much more carefully. Historically, when a company made a decision to build a plant or add capacity, it was committing large amounts of nonproductive capital for many years. Meanwhile, the plant was being built for a drug whose clinical and commercial success was still unknown. That is an enormously risky proposition that few companies are still willing to consider.”

To further mitigate such capital investment risk, Xcellerex added another dimension of flexibility to its FlexFactory biomanufacturing platform. Galliher adds, “Our CMO team can operate a FlexFactory line for a customer during the early, riskier period of a drug's clinical and commercial life, allowing the client to avoid the capital investment altogether. When appropriate milestones have been hit, we can then ‘TransPlant’ the entire operation from our facility to the client's, enabling them to take control of a prevalidated line with pretrained operators. This essentially takes the capital investment risk out of the equation for a customer by bridging over it.”

Galliher says the second factor is that companies can't take the risk of the totality of the capital cost. There's less cash available from venture capital groups and the investment community, and more companies are practicing cash preservation. The shift to smaller, targeted end-markets for drugs also contributes to this scaled-back appetite for investment. “They want to install less and yet have more capability. So spending less, doing it in less time, and not risking so much capital is forcing a more agile and less complex investment. It's really forcing the need for flexibility such that even though they're spending, they've got the kind of agility they need for their drug pipeline.”

The third factor is the increasing competition in the industry. Biosimilars are making their way to the market, and innovator companies are under increasing economic pressure to compete on price per dose. As a result, they have to be able to repeatedly modify or set up, produce drugs, more quickly and with less investment, less effort, and less labor than ever before.

“The only way they can do that is by designing in flexibility,” Galliher says. Outsourcing is another way to achieve flexibility without committing the capital and resources to produce internally. But there are limitations to that, he cautions. “It can become complicated and expensive. So you might spend less on capital to outsource, but most people would agree that it's not cheaper to outsource on an operating cost basis because you're paying a third party its profit margin. So on one hand you have the flexibility of not having to build your own; but on the other hand, once you're locked into a CMO, you lose some flexibility.”

Plant Operations: A flexible manufacturing space allows a facility to operate at different scales and/or produce multiple products without too much cost and effort in change-out. “We've had customers tell us that one day they'll get a request for running a preclinical study and need 30 grams of protein, and next day they get another request for a different molecule for 1,200 grams of protein for stability studies and clinical studies,” says Mani Krishnan (director of Millipore's Mobius single-use product line). “They will have huge swings in requirements for what molecule they need to make and how much of that molecule they need. Even the processes may be slightly different.” Krishnan says some customers may be running a traditional three-column process, but then require another column for additional purification that a particular molecule requires. “That is the flexibility customers are looking for, particularly for molecules in early phase clinical trials. That flexibility is much easier for customers in a single-use setting than in a traditional stainless steel setting.”

Processing: For Barry Holtz (cofounder of G-Con LLC) flexibility means that an operator can use multiple upstream and multiple downstream processes and convert different systems to adapt to those processes. For example, his company uses plants upstream in its Project GreenVax collaboration with the Texas A&M University system. “If I want to then be able to make a vaccine antigen or a virus-like particle,” he says, “the question becomes, ‘ How fast can I switch to a second process?’”

A flexible process can respond to challenges such as a new project that unexpectedly needs to be put through clinical trials or a project that comes from an acquisition, partnership, or merger — all without requiring many complicated adjustments in manufacturing hardware and setup, major reinvestment, major waiting times, or changes that need regulatory approval before the challenge can be addressed. “The world is full of those challenges and changes in what you might have planned,” says Günter Jagschies (senior director of strategic customer relations, biotechnologies R&D at GE Healthcare Life Sciences). “If a project failure completely changes the scheduling of everything you had planned, that should not create a problem. You never really know which of your molecules will be successful in the clinic.”However, he explains, “It doesn't mean is you are like a flag in the wind. You're not flexible in the sense that you're careless. It's still with stringent GMPs and very responsible.”