FDA's Pharmaceutical Inspectorate Searches for Higher Ground

Uneven inspections are the greatest source of antagonism between industry and, says Aegis Corp.’s Neway. “Too often we hear, ‘My inspector had a bad day.’ If the inspector has been inspecting a toothpaste facility and then comes to an injectable facility, of course there are going to be problems.”

This shouldn’t be an issue with the PI, if it is allowed to devote itself to drug work and has the time and wherewithal to utilize its support system of specialists and experts.

Daunting challenges

Even with some of the right conditions in place, the Inspectorate’s real success will hinge upon some key questions. First, can they truly master the scientific and technical intimacies of the modern pharmaceutical plant? FDA investigators are often compared to their counterparts within the European Union, who tend to come from within industry with backgrounds in science and manufacturing.

“Inspectors here don’t have the heritage of actually making the product,” Anisfeld notes. This continues to be a knock against American inspectors and doesn’t figure to disappear.

Let’s say, for the sake of argument, that the members of the Pharmaceutical Inspectorate do have a comprehensive know-how of pharmaceutical science and technology. Is it still not enough in an industry that gets more complex and technical by the day? Will three weeks and change of training make an ounce of difference in their ability to do their job?

In a way, modern investigations are becoming a near-impossible challenge, says Jerry Vince, a senior consultant with AAC Group, Inc. (Rockville, Md.). Vince is better recognized for his 37 years in FDA, the last few as director of regional operations, where he advised the Agency on all matters relating to ORA field activities.

“In the not too distant future, it’s going to reach that point of being an extremely daunting challenge,” he says. “For example, if Biotech breaks through with some product approvals and procedures which I’ve been hearing about, it would put me to shame. It would take another five or six years of continuing experience just to understand them.

“I see that as a possible future roadblock,” Vince continues. “How does one validate or evaluate the adequacy of a highly technical process that has no previous common factor?”

Process Analytical Technologies (PAT) may serve as a case in point. How is it possible to arm investigators with the unique technical and philosophical challenges that PAT presents, given limited training time and so much other important territory to cover? In the Level III training, PAT is just one element of the entire technology module, and that module is one of three to be taught in one week’s training.

And yet PAT is at the core of FDA’s quality initiatives, and the PIs will have to spread the word throughout the ranks of investigators. “Industry is way, way ahead of where FDA is on PAT,” says one regulatory consultant, who believes key technical concepts readily understood by the industry are not trickling down to FDA field staff. “I have spoken to at least 20 inspectors at the field level, and not one of them knows what PAT is. I’ve spoken to lower-level people and middle-level people, and they didn’t know what I was talking about. They’ve heard rumors, but that’s about it. The only one who truly understands PAT within FDA is Ajaz Hussein,” he jokes.

Setterberg says it’s not an issue. “Our belief right now is that we want them to have enough training for some basic ability in Process Analytical Technology,” she says. “They can use the experts and a few people trained specifically for PAT.” FDA has in fact trained a half-dozen or so PATriots to serve as specialists and resources for the entire Agency.

And, in any case, there just isn’t much PAT to look at in the industry right now, Setterberg adds. “If we trained 50 people on PAT right now, most of them would not have any cause to use it, and we’d have to go back and retrain them again.”

It’s a moot point, says Wayne A. Mazanec, a regulatory consultant with Bright Associates (Charlotte, N.C.) who spent 33 years in FDA as a field investigator and supervisor. Industry will always be ahead of regulators, and the challenge of the FDA teams is to admit ignorance and then figure out how to ask the right questions and deal with new technologies. “Even if the investigators haven’t had specific training, they can easily pause what they’re doing and call headquarters to get an expert,” he says. “If necessary, they can have someone from headquarters come out to the field.”

“When I started out, I learned that you go in with a reasonable degree of knowledge and have an idea of what you’re looking for, but profess some degree of being a novice with management,” says Vince. “In many cases, they’ll go out of their way to explain what to look for and what criteria to use to explain their compliance status.”

These are the kind of ideas being bandied about in the current training, Setterberg says. She’ll be the first to admit that the trainees and course advisory board are making some things up as they go along. “We’re doing this bit by bit,” she says, “building blocks and trying to give people enough understanding to know when they need to go to the experts for help and to know who to go to.”

Old dogs, new tricks?

Another issue is whether or not these inspectors can really “get” the paradigm shift that is taking place within the Agency. Neway sums it up this way: “FDA wants to stop being the police and start being the coach,” he says. “But 20 to 30 years of being the police has left its mark. Change might take ten years. But if we don’t get started, it’ll never happen.”

Investigators need to rethink the way they have been doing inspections for their entire careers. Ludwig Huber, a worldwide compliance fellow with Agilent Technologies (Palo Alto, Calif.), believes FDA’s troops are well-trained and have a handle on pharmaceutical science and manufacturing processes. He wonders whether inspectors truly understand the risk-related concepts associated with the new initiatives, even though they’ve been around for a few years. The inspectors are “totally helpless” in this regard, he says.