cGMPs / QRM Process

FDA's Pharmaceutical Inspectorate Searches for Higher Ground

FDA wants its drug investigators to go to a higher level. Can they get there? Will they really make a difference?

By Paul Thomas, Managing Editor

Twenty-six of the Food and Drug Administration’s top guns — the Agency’s most experienced drug investigators — are now in the midst of a year-long training program. Once trained, they will lead the most difficult, high-risk manufacturing plant GMP inspections. They are the new Pharmaceutical Inspectorate (PI), or, in civil servant speak, Level III Drug Investigators.

In synch with its 21st century GMPs, FDA is reinventing its entire field inspection program to make it leaner and savvier. Instead of rule-based compliance and “equal opportunity oversight,” inspectors will now be guided by scientific principles, prioritizing inspections based on processes and operations that pose the greatest potential risk to consumers.

FDA expects the new Inspectorate to be the vanguard of this brave new regulatory era, helping to spread the gospel of quality systems, risk assessment and advanced science and engineering throughout the ranks of drug investigators. Is it up to the task?

“I’m more optimistic right now that FDA is moving in the right direction than I’ve been in years,” says Jim Akers, president of the consulting firm Akers Kennedy and Associates (Kansas City, Mo.). “The key people are saying all the right things.” Akers, who has done some training for FDA in the past, believes that none of the Agency’s initiatives will matter if the core concepts don’t trickle down into the field, and this is where the Inspectorate comes in. “What we’re talking about is one of the key infrastructure elements that needs to work,” he says.

There will be challenges, though, Akers says. First, it’s no secret that the science and engineering expertise of the investigation cadre needs upgrading. The PI training will help, but perhaps not enough. It’s also no secret that the Agency has faced a chronic “brain drain,” as many of its most qualified inspectors have bolted to higher-paying consulting or industry positions. The PI title could make the most elite investigators even more attractive outside the Agency.

“This is a great, great thing FDA has done,” says Michael Anisfeld, president of Globepharm, Inc., a regulatory consulting and training firm in Deerfield, Ill. “They’ve finally recognized that their inspectors need more expertise.”

Like Akers, Anisfeld isn’t so sure the PI can have an immediate impact. “I’ve been to several of the presentations where FDA has talked about the curriculum, and it all seems good,” he says. “But when I’ve talked to several FDA inspectors, including supervisory managers, they’re basically ignorant of what’s going on. It hasn’t trickled down to the field yet.”

The training is designed to address these issues and others. While the Level III investigators will be managed and given site assignments by the Office of Regulatory Affairs in the field, the training has been a collaborative effort on the part of ORA, the Center for Drug Evaluation and Research (CDER) — including Ajaz Hussein and key members of the Office of Pharmaceutical Science — other FDA Centers, industry and academia. In addition, it follows on the heels of stepped up training programs for investigators in medical devices and food.

The Pharmaceutical Inspectorate is expected to meet several needs at once:

  • to satisfy congressional and industry demands for a stronger, tighter regulatory process;

  • to enhance integration and collaboration between the Agency’s drug review and evaluation processes, between field offices and the Centers, and between the Agency and industry in general;

  • to help address the current backlog of drug investigations and stay on top of what the Agency deems are the most critical manufacturing facilities needing a watchful eye.
The program is voluntary, and joining the PI is not tied to any promotions or pay increases. Still, FDA is confident that the PI will make a difference. “We want to do this right,” says Susan Setterberg, director of ORA’s central region, who co-chaired the Inspectorate steering committee with Janet Woodcock. “It’s a really great opportunity for the investigators. It puts them right on the cutting edge of what’s going on, so they can do their job better.”

Who are these people?

Whether the training will pay dividends depends upon the caliber of the trainees, who are being kept somewhat of a mystery. “Are they the cream of the crop?” wonders Anisfeld. “Good question.” Eventually, there will be in the neighborhood of 50 inspectors in the PI. According to Setterberg, the 26 in the pipeline right now are some of the most experienced of all drug investigators.

To be considered an entry-level FDA investigator or Consumer Safety Officer (CSO), an employee must have a GS-5 designation, requiring a college degree and at least 30 hours of coursework in the sciences. To qualify for PI training, candidates must have that and at least three years of field experience.

All of the current trainees are well beyond that, Setterberg says. Most have ten to 20 years in the field and are “product specialists” at or near the GS-12 or GS-13 level, so they have already been devoting most of their time to drug inspections. Some are even national experts from the Agency’s Centers in Rockville — namely CDER and CBER — seeking to become part of the Inspectorate. (Even with the PI, FDA will maintain its current staff of field specialists and national experts, as well as Team Biologics, a special corps managed by ORA’s headquarters.)

“We’re not bringing rookies in here,” says Gary German, who oversees all ORA training programs as its director of human resources development. “These people are already good, quality investigators. We’re not teaching them how to be investigators. What we’re talking about is this higher level of information.”

Three weeks, seven modules

The Level III training faculty are, without question, top notch — renowned technical experts in their fields, many from the Center for Pharmaceutical Process Research (CPPR), the Measurement and Control Engineering Center (MCEC) and the Center for Process Analytical Chemistry (CPAC).

And the training program itself is ambitious. The curriculum (see sidebar below) aims to deliver seven modules in three one-week sessions — one last August, one just ending in early February, and one later this spring. That’s a lot of ground to cover in a very short span. Trainees will be familiar with most of the material, though in all likelihood this will be the first time they will have had formal classroom training in cutting edge technologies, such as Process Analytical Technology (PAT), or in the more abstract aspects of quality systems, process knowledge and risk management integral to the Agency’s current initiatives.

Following the classroom work, trainees will return to Rockville in the fall to spend from two to six weeks in one-on-one contact with experts in CDER and other Centers, cementing relationships and filling in the knowledge gaps each may have.

By FDA’s account, the training has gone smoothly to date. While the first session in August was predominantly lecture-based, trainees requested more “hands on” work emphasizing group exercises, case studies and problem solving. The Pharmaceutical Inspectorate prospects have been joined in study by an equal number of FDA product and technical specialists, drug evaluation scientists and compliance officers seeking advanced training, but only the inspectors will receive certification.

There was an “a-ha!” experience when the group realized how much they had to gain from each other, Setterberg says. “They realized that this kind of collaboration could really build strong decisionmaking by the Agency while we’re in the midst of our inspections,” she adds.

German says the pupils are hungry. “Their eyes and ears are open,” he says. “We see people getting in there, engaging in the class, challenging the material. I can’t say enough about the group.”

Barring a surprise dropout or two, the first 26 of the Pharmaceutical Inspectorate should be certified during the last quarter of this year. They will continue their work out of their district offices and devote at least 80 percent of their time to drug inspections, domestic and foreign, and will serve as lead investigators on most inspection teams. Lessons learned from the PI class of 2005 will guide future continuing education for the entire inspection cadre top to bottom.

Good vibrations

According to FDA, there are currently more than one thousand CSOs devoted to manufacturing operations in drugs, devices and food. At any given time, the Agency plans to have 140 CSOs working on drug quality. The 50 or so investigators expected to have Level III certification in the next few years should have an immediate impact on inspection teams and the overall quality of inspections performed.

But can they really make a difference? To begin with, is three weeks of classroom work and a few weeks of communing with experts enough to ensure a higher level of performance? If so, will the wisdom and good vibes that came out of the training rub off on the rest of the field staff? And will industry notice a difference and recognize the inspection teams as more authoritative and technically competent?

At this point, some of the conditions for success are in place. For one thing, the industry is receptive to change. It is craving it, in fact. Initial response to FDA’s 21st Century transformation has been positive, and industry insiders are upbeat about a more savvy corps of investigators.

“It is a leap forward,” says Justin Neway, founder and executive vice president of Aegis Corp. (Lafayette, Colo.), a manufacturing process solutions firm. Neway attends as many FDA subcommittee meetings as he can, and keeps close tabs on Agency activities. He’s impressed with what he’s seen, particularly the movement towards more regulatory consistency, and believes that training in risk analysis methods and PAT will pay off. “We’re going to find that this works better than what we had before,” Neway says. “And we’re going to want more of it.”

FDA seems genuine in its commitment to greater Agencywide teamwork and consistency in its drug oversight. Until now, the expertise of research scientists, product specialists and compliance and drug experts in Rockville and district offices has been underutilized. They will now serve as an invaluable resource for the PI.

The Agency has also taken steps to tighten its internal controls in order to encourage greater regulatory consistency. It has already shifted to a more centralized review process of inspection documentation, ensuring, for instance, that all warning letters regarding GMP issues at plants go through Center experts and headquarters for review before they are sent to manufacturers. The Agency has expressed willingness to enter into dispute resolution with firms regarding any and all compliance issues. So far, only one company has taken the Agency up on its offer, as Janet Woodcock noted at last fall’s ISPE conference, but the dialogue represents an important break from the past.

FDA doesn’t want any firm to suffer from a bum inspection, or any egregious noncompliance to be overlooked. Everyone in the pharmaceutical world, it seems, has a war story of an inspection gone wrong or an inspector out of his or her league.

“I’ve met some real good field inspectors,” says Maik Jornitz, group VP of global product management, bioprocess, for Sartorius North America (Edgewood, N.Y.). “It’s wonderful to talk with them. They listen to you, and you want to listen to them.” However, there’s one exception, he says: an inspector he bumps into on a regular basis. “It’s painful and embarrassing when you listen to him,” he says.

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.

“When I look at inspection reports from the past few years, they always describe what questions were asked, and I haven’t seen anything said about risk in any of them,” Huber says. “There’s a big difference between the theoretical and practical and this is what the training should focus on.”

To be fair, Huber says that FDA is actually ahead of industry in its emphasis on risk-management techniques, and more companies need to develop and improve their risk-management master plans to keep pace with FDA.

“It’s wrong to say investigators haven’t been concerned about risk,” says FDA’s German. “We have had for two, three, four years a work plan for inspections based on risk. So it’s not a foreign term. We’re just nurturing, building and cultivating that concept.” The latest risk analysis models and tools are a key focus of the second module of training, and are already working their way down to the field level.

Experience drain

Despite progress, it's likely that not all of the PI will rise to the challenges, and some turnover is inevitable, says Aegis Corp.’s Neway. The more critical concern, he says, is whether or not the Agency can keep its best and brightest investigators, especially the most highly trained. “You see a migration of FDA-trained people out into the industry,” says Neway. “What a loss! The FDA is just less attractive to them as a career.”

There is a “major deficiency” in the ranks of investigators, Anisfeld agrees. “You could overcome it by hiring people from industry, but the salary would have to change dramatically and that’s not going to happen.”

The new training and certification program exacerbates the problem. Those who join the Pharmaceutical Inspectorate will become eminently more desirable to private industry. “The real problem is that if inspectors don’t earn more, they will have even more motivation to leave,” Huber says. He estimates that an experienced, reputable FDA investigator could earn two to five times an FDA salary in the private sector.

According to FDA’s salary table for 2003, a beginning investigator at the GS-5 level can expect to earn up to about $30,000 annually. A GS-12 specialist earns between $50,000 to $70,000, and a GS-13 between $60,000 and $80,000. There are, of course, plenty of perks with government service. But when recruiters from major pharmaceuticals or consultancies come calling, promising six figures, what is to keep Inspectorate members from jumping ship?

Commitment, says Mazanec of Bright Associates, who notes that the swinging door goes both ways: As a trainer, he frequently gets inquiries from industry personnel interested in joining the Agency. “Some are enamored with the concept of being an investigator,” he says.

History repeats

In his 33 years with FDA, Mazanec served as a drug investigator in Seattle and Philadelphia, supervised in Chicago and Los Angeles, directed investigations in San Francisco, and ended his Agency career six years ago as assistant regional director in the Pacific regional office.

Speaking from vast experience, Mazanec says the new training initiative is merely history repeating itself. “I view it as someone trying to lay claim to inventing the wheel,” he says. In other words, this isn’t the first time FDA has tried to remake itself and revamped its drug training initiatives.

There was a time, Mazanec recalls, when FDA recognized experts and highly trained personnel with what were known as 200C credentials. He spent three weeks at the University of Rhode Island, and later two weeks at the University of Pittsburgh, after which he received what he received what he calls his “racing stripes.”

A few years later, he had them taken away. “The Agency eventually decided it’s not a good idea to have people with special credentials,” he says. “When investigators had other kinds of work to do, like in the medical device area, they said, ‘No, I have special credentials.’" Unions supported this stance, Mazanec says. This led the Agency eventually to designate some of its investigators as specialists in the field.

The Pharmaceutical Inspectorate might not be anything new, in Mazanec’s view, but that doesn’t mean it’s such a bad thing. “A rose is a rose is a rose,” he says. “The motive is still the same. You’re always going to try to have people appropriately trained to do their jobs.”

Will firms notice any changes in the way inspections are done, with a member of the PI leading the proceedings? Not really, says the Agency. “I don’t think there’ll be much difference in the inspections,” says FDA’s Doug Ellsworth, director of the New Jersey district office and chair of FDA’s Field Drug Committee, “but when firms begin to use more of the advanced technologies and techniques, the Pharmaceutical Inspectorate will understand what industry is doing and be able to apply their normal inspection approach. The training is preparing them for the future of the pharmaceutical industry.”

THE PHARMACEUTICAL INSPECTORATE CURRICULUM

The following curriculum outlines the training for the Pharmaceutical Inspectorate. Trainees will visit FDA headquarters in Rockville for just three week-long sessions over the course of a year to complete the seven modules.

The first session, which took place last August, covered the first three modules. The second session, in late January and early February of this year, tackled Modules 4 and 5, while the last session, later this spring, will be devoted to the final two modules.

Following the three sessions, trainees will be assessed for additional wants and needs, then return to Rockville in the fall to spend time — from one week to more than one month, depending on the individual — in close contact with experts in the Centers in order to reinforce lessons learned in training and fill in knowledge gaps investigators may still have.

A certification board comprising Center experts, experienced field investigators and others will then review the candidates for certification. The exact means of final evaluation have yet to be determined, but will likely include written tests and performance audits.

  • Module 1 – Regulating Pharmaceutical Quality and the Relationship to FDA’s Mission
  • Module 2 – Risk Management
  • Module 3 – Advanced Quality Systems
  • Module 4 – Pharmaceutical Science
  • Module 5 – Current Regulatory Programs and Procedures
  • Module 6 – Technology
  • Module 7 – Investigational

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