With PAT, much of the focus has switched to the broader concept of quality by design (QBD). “It is difficult to do PAT without QBD,” says Duncan Low, Ph.D., scientific executive director at Amgen (www.amgen.com). This suggests that biotech companies might continue to put off deploying PAT if they can meet their QBD objectives through more traditional means, for example through cell engineering.
Dr. Low has been working with the ASTM E55 Committee on Manufacture of Pharmaceutical Products, which is developing standards for PAT. He expects the standards will provide greater flexibility for, and help streamline systems validation and verification. In particular, the standard will allow manufacturers to use more of their vendors’ data and information for systems verification—including for analytical instrumentation—rather than repeating verification/validation work that has already been documented.
“This amounts to a more risk-based approach to systems verification,” Dr. Low says. The FDA and EMEA are involved in developing this consensus standard, but it is not a guidance or directive. Nor does it absolve biomanufacturers from validating the scientific validity of their tests and measurements, for example if an assay correctly reflects protein titer. “You still must qualify that as part of your assay.”
Professor Carl-Fredrik Mandenius, who heads the biotechnology division at Linköping University, dismisses the notion that bioprocessors have too much data, or that real-time data acquisition will overwhelm.
“All relevant analytes are normally well-known and -characterized,” he says. Methods exist for measuring them, and many have already been correlated with product quality, either during manufacturing or at release. It is a simple matter, he says, to rank process attributes by relevance to product quality, and apply some algorithm for assessing them during processing.
The problem is that adapting proven analytical methods to real-time monitoring has been difficult. “Existing methods, for example LC, are tedious and laborious when applied to real-time monitoring.
“It will take substantial effort to modify and improve analytics to make them sensitive, rapid, or automated for a PAT setting. A goal of PAT would be not only to render existing methods PAT-able, but to improve on them.”
Dr. Mandenius’s group works on optical sensors, particularly near-infrared for smaller molecules (below 1,000 Da), and surface plasmon resonance for measuring protein interactions. Both techniques have the advantage of being near-instantaneous (for example, no waiting for a protein to elute from a gel or column). Their drawbacks include a much smaller user base and less familiarity among analytical scientists than, say, chromatography.
So is process monitoring, in the FDA-inspired PAT sense, doomed to remain in the 20th century? It may be best to think of PAT as a goal—something to shoot for but not to obsess over. “Clearly, PAT is not going to save us,” says Dr. Page. “Pharmaceutical plants will likely never have the continuous tweaking we see in chemical plants. For new processes, PAT is becoming more common, and under the right conditions and with the right base information it can help modernize bioprocesses by making them faster and less expensive to run. But it will take a lot of time to produce real-time data that either a manufacturing or quality person can use.”