Since the FDA released its final guidance on process analytical technology (PAT) last autumn, there's been a flurry of conference activity focusing upon implementation. If the lists of speakers are any indication, however, the activity is almost exclusively coming from Big Pharma.
"The whole industry is at an early adoption stage," notes Janice Abel, director of marketing, Invensys Validation Technologies (www.invensys.com). She likens the situation to that of implementing 21CFR regulations, which were on the books in 1997, but became an important industry consideration only years later.
This, according to Abel, will be a big driver as well, as the industry sees real gains in manufacturing efficiency and a reduction regulatory burden.
Within the biopharma sector industry, however, PAT appears to be very low on companies' priority lists. "On the subject of PAT, biotech is very quiet," Brian Davies, Ph.D., director of PAT for Thermo Electron (www.thermo. com) says. "Look at the PAT conferences. They're mainly attended by people from old pharma. There's very little public information from biotech."
Phone calls to biotech companies engaged in drug development or manufacturing showed a remarkable lack of concern or knowledge about PAT. Typically, companies not yet in manufacturing said PAT didn't affect their operations.
Valient Pharmaceuticals' office of strategic manufacturing was unaware of PAT. It wasn't alone. Jay Johnson, spokesman for Quintiles (www.quintiles.com), cited no activity to implement PAT, pointing out that "we're a clinical trials company."
Karen White, spokesman for Celera Genomics and Celera Diagnostics (www.celera.com), also said there was no PAT activity, "because we're still in clinical trials."
BIO, in comments on the FDA's Draft Guidance in November 2003, notes that, "many of the principles of PAT are currently practiced in portions of biotechnology processes (such as buffer preparation, fermentation/cell culture, and product recovery/purification)."
It is, therefore, understandable if many in the industry think they're up to speed with PAT. That belief, however, isn't entirely accurate. Although the biotech industry does rely upon many analytical technologies, they fall short of the FDA's vision of PAT as a system-wide implementation that allows real-time monitoring and process control.
The FDA has a different view. The final PAT guidance states, "Ideally, PAT principles and tools should be introduced during the development phase."
As FDA spokesperson Christine Parker, says, "PAT will be useful in research phase and will assist in identification of critical variables and develop control strategies. This information can be very useful in justifying regulatory specifications." Nonetheless, Parker says, "Utility of the PAT guidance is the decision of a companynot a requirement."
Furthermore, Parrish Galliher, president and CTO, Xcellerex (www.xcellerex.com), points out, "PAT's guidance applies to drugs, not to biologics," except for those regulated under CDER or the Center for Veterinary Medicine.
"PAT directors at the FDA are enrolling CBER in the value and benefits of a more extensive application of PAT," with the possibility of expanding the guidance to biologics in the next year or so. The biologics industry is quietly tracking this development and talking with the companies currently affected by PAT.
PAT activity isn't totally lacking, however. "PAT has been implemented at some of the big pharmaceutical companies, at various stages of manufacturing," Dr. Davies says. And, Tina Larson, senior engineer, Genentech (www.gene.com), adds, "Several companies are forming PAT core teams to monitor the situation and come up with a strategy."
Invitrogen (www.invitrogen. com) is in the vanguard. It has been working toward PAT for about three years. "PAT actually marries up nicely with what Invitrogen is doing as a company," says David Onions, Ph.D., CSO.
"We're taking a series of disparate companies and realizing they have great synergy, and so are developing a series of integrated tools and systems to measure and control process to yield faster product releases with increased understanding and control of what actually happens in those processes."
For example, he says, "BioReliance, a division of Invitrogen, has set up a process center to take clients' genes into gene expression systems and through the manufacturing process, with the goals of PAT designed into the project at the beginning. In this model, removal of adventitious agents is considered at the beginning, rather than waiting until scaleup," says Dr. Onions.
"The result is an optimal system that, early in the process, takes account of all issues that may affect the clinical phase (of development)."
The testing side of the company is developing the 14-day HyMy test to replace the 28-day assays currently used. "It offers the advantage of cell cultures and the speed of PCR," Dr. Onions says. Another rapid detection method is being developed for Invitrogen's Zeotron nucleic acid chip to provide near-real-time detection of contaminants before a company commits the product to down-stream processing.
Grand Island Biologics (GIBCO), an Invitrogen division that supplies cell banks and media, is developing systems using molecular probes to monitor the physiological state of the cells by looking for apoptosis and related intracellular signaling. In a similar vein, Invitrogen is engineering cells for better performance in fermentors.
Rollout of the first Invitrogen component is expected in about one year, with full implementation in about three years.
At Genentech, "We've had a manufacturing science department for decades but the PAT initiative formalized our efforts," Larson says. At Amgen (www. amgen.com), "PAT is in its infancy. We plan to be proactive, but it's too early to report anything," according to spokesperson Mary Klem. "It's a great opportunity, and we've initiated conversations with the FDA." Johnson & Johnson (www.jnj.com) says its PAT work is proprietary.
Implementation isn't as simple as adding a few sensors or even controls to critical processes. Regulatory harmonization is lacking. Consequently, companies may need to maintain parallel validation processes to meet the requirements of other regulatory bodies, both abroad and within the U.S.
Whether the necessary tools have been developed is also open to debate. Dr. Onions says the physical tools are available, but the inline statistical analysis tools may be lacking. At Invitrogen, "we started three years ago and it will take more time to get the tools into the right bundle." As Genentech's Larson points out, "The petrochemical industry went through this 20 years ago, and still has some technological hurdles."
For biotech, direct characterization of critical attributes are challenging. "The industry is striving to replace offline product quality measurements, like HPLC and mass spectrometry, with techniques that produce real-time measurements.
Spectroscopic techniques like near infrared (NIR) spectroscopy, which have been at the core of Big Pharma's PAT efforts, are difficult to apply in the aqueous process streams that dominate biopharmaceutical manufacturing," says Larson.
Beyond that, Xcellrex' Galliher says, are the engineering issues of validating products inline and maintaining the sensors and controls, as well as determining which of the 20 quality assays (for biologics) for each product to use inline.
Transferring knowledge from the lab to manufacturing, and implementing process optimization technologies are two areas in which PAT will play an important role. "Biotech and pharma both can use advanced controls," Invensys' Abel says. "Even simple batch controls can be used, but often aren't, because the company started with just one batch," and is loath to undergo revalidation.
A New Paradigm
With PAT, "we're moving away from an environment in which a compound is validated with three qualification lots and you're done," Larson says, to an environment in which the drive to learn more and more about each process is continual. That requires a different mindset.
The pharma culture attracts cautious individuals, and rightly so, Dr. Davies says. But that means, "as an industry, we have to overcome the inertia of culture, organizational barriers, turf wars and history," notes Ron Miller, Ph.D., director of new technologies, manufacturing technologies, Bristol-Myers Squibb (www.bms.com). That appears to be happening. "Initially, there was some resistance to change, but it's falling away," Dr. Davies says.
Yet, Dr. Miller maintains, regulatory uncertainties and fears that PAT may slow the advance through the regulatory cycle can inhibit adoption. "That's what the FDA PAT Patriot team is supposed to minimize," he says. "There are still questions in some minds because only a few drugs have gone through the regulatory process with PAT tools hooked to them. GlaxoSmithKline is the first company to do so," he says.
Return On Investment
Nonetheless, "the FDA is trying to lessen regulatory hurdles to implementing new technologies," Larson says. "It enables us to re-evaluate technologies we've considered and the perception that they're impossible to implement," because of validation concerns.
"It's ideal to bring new technology through process development, to get experience before scale-up. "However," Larson says, "the PAT initiative should also ease concerns about updating technology on existing manufacturing processes."
Return on investment is an open question. "There are no figures," Dr. Miller says, and many questions. His list includes whether PAT would be used on existing processes and, if so, why; whether PAT would reduce costs and mitigate risks with the additional process understanding; and whether, if used with a new drug, PAT could mitigate the risk of poor manufacturing. Those decisions, he predicts, will be made on a case-by-case basis.
Benefits, so far, are anecdotal. One company got a release test dropped by eliminating the release assay activity, making it possible to start the new batches earlier and ship the product sooner, according to Galliher.
"The real benefit is process understanding," Genentech's Larson emphasizes. "The idea is that, eventually, you can plan manufacturing much better and not get surprised. You can constantly produce high quality products at the levels you're expecting."
"The pharma industry may be state-of-the-art in discovering new therapies and medicine, but it needs to get better at manufacturing them," Dr. Davies adds.
"Basic industries such as soap powders, food, and petroleum have highly science-based, efficient manufacturing processes that can teach pharma a lot about product development, process understanding, and control and quality strategies."
Individuals haven't yet understood the potential of PAT, Dr. Onions says.
"It's a very bold and useful initiative," which the industry needs to embrace. It offers more latitude by offering "real-time control versus a lock-down, which can result in faster product development and faster release of drugs."