With new 9/11 security chores squeezing its limited manpower, the FDA turned to the pharma industry in September 2004 and said, “Ok, you asked for it. You can have your manufacturing innovation—in fact, we insist on it.”
The pharmaceutical industry’s response was, “Now what?” Welcome to the FDA’s Process Analytical Technology (PAT) initiative and the brave new world of pharmaceutical manufacturing.
Under the PAT initiative, the FDA wants pharma manufacturers to adopt a system for “designing, analyzing and controlling manufacturing through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.” In short, to adopt 21st century manufacturing technology that can cut waste and improve quality.
This new manufacturing technology outline in PAT is old hat to industries such as food and beverage, petrochemicals and semiconductors. But to pharma—with its paper-based control systems—this is alien technology. You can’t really blame pharmaceutical companies for their backward manufacturing habits. In the past, the FDA hasn’t been friendly to process innovation. The FDA itself admitted, “Unfortunately, the pharmaceutical industry has been hesitant to introduce new technologies and innovative systems into the manufacturing sector for a number of reasons.” The reason most often cited is that—again in the FDA’s own words—“The existing regulatory system is rigid and unfavorable to the introduction of new technology.”
Not surprisingly for a bureaucracy with deep big-brother habits, when the FDA released restrictions on new technology, it didn’t stop there. Though PAT is not regulatory law, the FDA pretty much insists that it be adopted. “The FDA can simply put out guidelines, which are not legal documents, but they want you to follow the guidelines,” says John Blanchard, principal analyst, ARC Advisory Inc., in Dedham, Mass. “The FDA is effectively saying, ‘There’s no legal requirement, but you’d better do it.’ ”
Advanced manufacturing technology seems like a no-brainer for pharmaceutical manufacturing. The adoption of process analytical tools will almost certainly reduce manufacturing waste and improve capital asset utilization. Pharma executives have admitted to analysts and vendors that the return on investment (ROI) from PAT is virtually certain. Even so, the pharmaceutical industry is resisting changes to its manufacturing processes. Because the FDA initiative is new, there are no industry leaders yet demonstrating the value of PAT, so pharma companies are approaching PAT with uncertainty.
For one thing, drug companies are more accustomed to waste than they are to new technology. “U.S. drug companies have had the ability to use process control for 20 years, but they have not used it because it’s expensive, and they can absorb waste better than other industries,” says Alison Smith, senior research analyst, AMR Research Inc., in Boston. “It’s cheaper to throw stuff out than it is to develop new processes.”
Competition is also a factor. If your competitor uses wasteful manufacturing processes, there is little incentive to change your own wasteful processes, especially since those antiquated processes pass regulatory inspection easily. The PAT initiative, however, effectively mandates manufacturing innovation. “Drug companies won’t be able to sustain the waste,” says Smith. “The technology is there and the FDA has said, ‘wake up.’ ” With the FDA giving its go-ahead to new technology, the issue of change management is all that’s keeping pharmaceutical companies from adopting technology. “The FDA is supportive and willing to help any company willing to adopt advanced ideas,” says Smith. “At this point, the cultural issues far outweigh the technology issues.”
Part of the pharmaceutical industry’s resistance to change comes from the industry’s view of change itself. “Historically, pharma would develop a product, describe the product, describe the process materials and methods in great detail in the regulatory filing, and validate the process through consecutive batches,” explains Dave Radspinner, PAT development director at instrumentation vendor Thermo Electron Corp., in Waltham, Mass. “The expectation was that the quality would remain consistent as long as nothing was changed. So change was seen as a sign of problems, not improvement.”
Not all of those in the pharmaceutical industry are resistant to change. At the executive level, PAT is a welcome development. “The acceptance of PAT depends somewhat on where you are in the company,” says Troy Logan, pharmaceutical segment manager at Siemens Energy and Automation Inc., an automation supplier based in Alpharetta, Ga. “On the technical level, people see it as extra work. For those in risk assessment, it’s just more work. But for those in leadership, PAT is seen as enabling a new way of operating.”
Is anyone adopting?
Though it has been more than a year since the FDA released the details of its PAT initiative, few, if any, pharmaceutical companies are willing to talk about their efforts to implement PAT. Technology vendors acknowledge that many of their pharma customers are in the planning stages of adopting PAT, but few have actually implemented new manufacturing technology.
AMR’s Smith notes that some companies are beginning to try out new manufacturing technology, but so far, these companies are still in the testing phase. “One company—Novartis—is running sensor technology side-by-side with the old process,” says Smith. “That plant does a lot of pioneering, cutting-edge work. I also wouldn’t be surprised if Genentech wasn’t messing around with new technology.”
There may be a few companies initiating the adoption of process control technology, but according to analysts, most pharma companies don’t know where to start. “The pharmaceutical industry is very conservative. They’re looking around to see who has successfully implemented PAT, and they’re not seeing anything,” explains Smith. “If you want to know what PAT is, you have to look outside pharma to the chemical industry. They’ve been doing simulation and in-line sensing forever, and they know how to model their processes. Pharmaceutical companies don’t know how to get basic variability out of their processes.”
Even the large drug producers with considerable resources are just now coming out of the planning stage in adopting PAT, says Mark Albano, life sciences product manager at technology vendor Honeywell Automation and Control Systems in Phoenix. “There are some thought leaders who are embracing PAT and putting resources into it, but that is mostly the large companies.”
The process analytical technology that falls under PAT is being used by a number of industries, including petrochemicals, food manufacturing and semiconductor plants. Many of the PAT tools will come directly from these industries. “The petrochemical and food manufacturing industries offer the best examples of the technology in PAT,” says Siemens’ Logan. “A third industry to look at may be semiconductors. That industry has innovated in developing quality systems and quality metrics. The FDA refers to semiconductors as an industry for drug producers to watch.”
Drive to survive
AMR’s Smith notes that part of the reason the semiconductor industry has advanced in manufacturing technology is because of intense competition, which has been missing in the pharmaceutical industry. “Innovation at semiconductor companies was driven by survival. They were getting put out of business by Asia,” says Smith. “Pharmaceutical companies have not been in imminent danger, so they didn’t innovate.”
As well as learning process control technology from other industries, pharma companies may also turn to their manufacturing control vendors for guidance in successfully adopting the technology. “The pharmaceutical industry should be looking to vendors to see what they’re doing with customers in petrochemicals and refining,” says Smith. “Vendors like Aspen Technology and Pavilion Technologies have a great play on the pharma side with analysis tools.”
Pavilion Technologies, of Austin, Texas, has been working with Thermo Electron to develop PAT tools that combine Thermo’s analytics and Pavilion’s process control software. The companies developed their expertise in petrochemical and food manufacturing. “The technology for PAT has been successfully used in the petrochemical industry for 30 years,” says Zafar Kamal, strategic development director for the Process Instruments Division of Thermo Electron. He notes that the analytical technology Thermo has used in the petrochemical and food industries can be deployed successfully in pharmaceutical manufacturing.
On the technician level, PAT is widely viewed as an imposed headache. But those in the executive suites see the adoption of PAT as an ROI winner. “Effective implementation of PAT can lower the cost of goods, improve capital asset utilization and increase the speed of change,” says Radspinner, of Thermo Electron. “Pharmaceuticals have a limited patent life, so the faster the improvement can be implemented, the better.”
Where’s the return?
ROI is always a consideration when manufacturers adopt new technology. But in addition to ROI, pharmaceutical manufacturers expect PAT to deliver improved quality and safety. “Yes, PAT comes with an ROI, but it’s difficult to always quantify ROI,” says ARC’s Blanchard. “So it’s not just the ROI, but it’s also issues of product quality and safety that make PAT attractive. In the business sense, PAT offers risk mitigation.”
With the push from the FDA and the incentive of clear ROI, the adoption of PAT is certain. The only force holding back adoption is the cautious example being set by pharmaceutical leaders. Analysts believe wide-scale PAT adoption will happen once companies such as Genentech, Novartis, Pfizer and Eli Lilly show the way with demonstrated—and replicable— tools and standards.