In Search of Consistency

With the possible exception of the semiconductor industry, the pharmaceutical business is the most scientifically innovative industry at the R&D stage. By contrast, pharmaceutical manufacturing relies on processes and information technologies that are decades--in some cases centuries--old.

At Biogen's manufacturing facility in Research Triangle Park (RTP), N.C., new technology deployments are allowed when they provide significant productivity improvements. Everywhere else, the firm prefers proven methods that minimize the risk of failure and delays.

"Process variability affects your success rate for new drugs and usually means longer approval times," says Nicolas Barthelemy, vice president and general manager of the RTP site. "The advantages of reducing variability and batch failure rate dwarf any potential savings from acquiring a new piece of equipment or re-inventing a process."

And while the high quality and safety of the pharmaceutical industry's end products remain unquestioned, 20 to 30 percent of unit costs typically are tied up in non-value-adding activities needed to ensure that quality, adds Velumani Pillai, global technology leader for automation and plant solutions, Pharmacia (Kalamazoo, Mich.).

"On average, the pharmaceutical industry operates at one-sigma quality levels," he says, in reference to the popular Six-Sigma standard for limiting process variability to within acceptable standards (3.4 times out of a million tries).

"An electronics manufacturer who operated at one-sigma would be out of business in no time," Pillai explains.

In all fairness to drugmakers, changing a validated process is no easy undertaking. Biotechnology companies in particular, which spend years optimizing fermentations that produce labile, high-value products, are understandably wary of changing anything. Even at innovative biotech firms, new technologies may be impractical or simply unavailable.

Innovation woes often are blamed on the FDA and its labyrinthine drug development regulations (formulated, more often than not, with industry's blessing or at its request). Recognizing this, the agency has begun to encourage innovation through its Process Analytical Technology Committee (PAT) and Advisory Committee for Pharmaceutical Science (ACPS) with the hope of creating for manufacturers a win-win environment for innovation.

"There is a significant room for improvement in pharmaceutical manufacturing operations," says Ajaz Hussain, deputy director, Office of Pharmaceutical Science at the FDA's Center for Drug Evaluation and Research (CDER). "With today's emphasis on drug discovery, development and marketing, manufacturing has become a stepchild. Companies believe their opportunity for improving processes is limited, so they tend to stick with what they are already doing."

According to Hussain, industry has adopted a "hear no evil, see no evil" approach to manufacturing innovation, meaning they are inclined either not to use new technologies or, if they use them, not to tell the agency.

"There's the perception that regulatory uncertainty is holding back new technologies, and that NDAs [new drug applications] would be delayed or denied because FDA reviewers may not understand the underlying science," Hussain says. "We hope to address that through our PAT initiative."

By encouraging the application of process analytical technologies, the FDA hopes to quell the oft-stated sentiment that it is to blame for technologic stagnation. With the help of university-based pharmaceutical manufacturing experts, the FDA is training teams on what to look for in new process technologies and to encourage their use. Eventually the FDA plans to issue guidances based on its experiences.

Techniques for improving first-time quality are currently available. The aim is to assure that companies "manufacture right the first time"--a phrase used by the FDA's PAT subcommittee. Rapid, real-time, in-line analysis is one way to achieve this.

Example 1: Where research mass spectrometry (MS) analyzes complex chemical mixtures through hybrid separation/mass measurement techniques, process MS keeps it simple, concentrating on low-molecular weight off-gases.

"QA/QC [quality assurance/quality control] and process engineers don't understand how you can have an in-process MS without liquid or gas chromatography up front," says Tony Slapikas, product manager for process MS at Ametek (Paoli, Pa.). Process MS derives the mass balance in a biochemical reactor from the composition of the feed air going in and the air coming out of the process. According to Slapikas, off-gases provide simpler, more accurate indications of what is going on in the process than sampling and analyzing offline.

In small-molecule manufacture, process MS can measure moisture or solvent levels in batches by monitoring masses corresponding to the solvent of interest. Slapikas estimates that MS can reduce drying time by at least 10 percent by eliminating the need to pause the operation, remove a sample and analyze it offline. For a 20-hour drying process used a hundred times a year, process MS pays for itself through higher productivity, lower electricity use and less wear and tear on equipment.