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Tablets & Capsules May 2015 21 "The pharmaceutical industry is going through a period of dramatic change, and incremental improvement to the decades-old batch manufacturing paradigm is no longer sufficient," said Phillip Nixon, the executive director of Pfizer's PharmaTherapeutics PharmSci Technology & Innovation Group. He said it is no longer a question of if the pharmaceutical industry will adopt continuous manu- facturing, only of when, how, and to what extent. Those were the ideas Nixon and nearly 150 attendees discussed at the 50th Arden House conference, held March 16-18 in Baltimore, MD. The event focused on oral solid dosage forms and featured 21 speakers, each of whom gave 45-minute presentations and answered ques- tions. There was also a poster session. Nixon, who chaired the event, spoke first. The busi- ness factors driving companies to adopt continuous man- ufacturing include the need to accelerate development and lower costs, address changes in the markets, and find better ways to make low-volume products. Continuous processing allows manufacturers to use the same equip- ment for product development and commercial manufac- turing, which reduces the effort, cost, time, and risk asso- ciated with technology transfer (Figure 1). While continuous manufacturing may seem "disrup- tive," Nixon said, it doesn't require new or unknown tech- nologies. Much of the uncertainty centers on process integration, process control, and regulatory acceptance. It also requires the use of predictive computational models and other analytical tools. Pfizer's approach is to use con- tinuous "mini-factories"—an approach dubbed "portable, continuous, miniature, and modular," or PCMM—that replace large fixed-size batches and reduce manufacturing time to minutes. Scaling up production would no longer entail using larger equipment, only running the process longer. With PCCM, the process equipment is enclosed in an autonomous "pod" that can be shipped to any loca- tion and quickly installed in a "gray-space" warehouse to create a fully functional GMP space. The need to raise quality also favors continuous manu- facturing, and most solid dosage operations operate at two or three sigma quality, Nixon said. "We optimize our settings and then don't move them. Thus the variability of the inputs, such as excipients, lead to variable results." A better idea is to use a process that can adjust to variable inputs. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER) and acting direc- tor of CDER's new Office of Pharmaceutical Quality, was next to speak. Her talk was mostly about the FDA's drive to modernize the industry and itself. She addressed con- tinuous manufacturing specifically at a 2014 event [1]. After her remarks, an attendee noted that continuous manufacturing generates a large amount of data and asked how much of it the FDA will want to see. "FDA shouldn't ask for all the data that you generate on continuous," she replied. "Tell us your algorithms and how well you're doing with that. We will have to decide how much con- trol data we will want to see, so there will be a struggle over that." She said that any company that attains six- sigma quality would face less scrutiny. "But for those that don't shift over [to six sigma], we can't insist on that." She said the FDA was still considering how continuous manu- facturing would affect recalls, specifically on "how to put boundaries on where the problem lies." She said that the biggest problem with batch processes is that the Agency "can't find out what went wrong." Jim Wetzel, director of global reliability at General Mills, discussed how his company moved to continuous production of Cheerios. Until 1966, every box of Cheerios was made in batches using an explosive process that puffed the cereal. He said it took 20 years of R&D for the company to develop a continuous process to do that. And while it continues to operate garage-sized dryers, the continuous puffing equipment is only as big as two conference tables, he said. It saves the company many millions of dollars each year. Wetzel said one the "biggest leaps" in managing its processes and plants around the world was standardizing on the company's information technology platforms instead of its engineering or other platforms. It now gath- ers information about the variability of its ingredients before they reach the factory, enabling the facility to pre- pare for them. He said General Mills handles 700 billion data points a day and, thanks to its sophisticated con- trols, attains 0.25 percent accuracy on operations that process a million pounds per day. Kris Schoeters is in charge of the continuous manu- facturing business of GEA, a multinational supplier of equipment and systems to the process industries. He said the company began developing its ConsiGma continuous processing equipment in 2007, when two major manufac- turers inquired about continuous wet granulation. That process was developed in cooperation with the Unive r - sity of Ghent. Since that time, the company has added feeders, mixers, mills, dryers, tablet presses, and film coaters to its continuous portfolio. Today, the company has 35 different projects installed worldwide, Schoeters said, most of which are R&D opera- tions. But some customers are manufacturing commer- Figure 1 Evolving business needs of the pharmaceutical industry Accelerated development Cost pressures Changing markets • Unprecendented pace of technology and informatics • Importance of uniformly high quality and supply reliability Breakthrough therapy More, lower volume products Reduce inventory Oncology Acess to emerging markets Reduce development costs Courtesy of Phillip Nixon, Pfizer