Contractors ready for FDA systems-based inspections.

FDA's switch to systems-based inspections for GMP compliance and pre-approvals has resulted in considerable hand-wringing in the pharmaceutical industry, but contractors seem to be more sanguine about the change. The switch took effect Feb. 1.

The approach has been used occasionally during the last decade but has not been institutionalized, according to Fred Blumenschein, chief of the case management and guidance branch in CDER's Office of Compliance. Nor has FDA made much use of the big stick it always had at its disposal--the power to shut down manufacturing operations companywide or to put a hold on any product under review by the agency until a violation is remedied to FDA's satisfaction.

This power has both pharmaceutical manufacturers and contractors on edge. Big pharma companies could lose crucial marketing time to a rival while a potential billion-dollar seller is held in limbo. Contractors found in violation would have to idle all their capacity. The out-migration of clients during the downtime could be deadly.

Yet contractors say FDA's sword of Damocles is less of a worry. With multiple clients subjecting them to multiple audits, they tend to be hypervigilant about quality control.

"I don't want the FDA telling us anything we haven't caught already," says Michael Harding, senior VP of quality and technical affairs for Toronto-based Patheon, a manufacturing-oriented contractor that has six sites in and around the city and four others in Europe.

To recruit and maintain clients, "we always have to stay above the bar," he notes. Harding and other contractor executives say they're looking forward to the new FDA approach, hoping it will shorten inspection time and give the whole process a more logical tinge.

Agency officials are aiming for similar results, especially with a mounting backlog of GMP inspections. By law, FDA must inspect all registered drug sites for GMPs every two years. It must also conduct pre-approval inspections. Both types of inspection are carried out by CDER's compliance office.

Joe Phillips, a former deputy director of FDA's Central Region Office in Philadelphia, who now is VP of pharmaceutical quality systems at Rockville, MD-based Quintiles Consulting, estimates that the agency's total inspectional obligation--including imports, medical devices, and pharmaceuticals--increased from 85,000 sites to 115,000 sites during the last decade. Yet the number of inspectors has remained level at about 1,000.

Blumenschein says the systems-based approach aims to alleviate the staffing pinch. "Instead of trying to cover every single thing at a firm, which is just not possible for us to do, we hope to do more of an audit," he explains. "We nearly were becoming consultants for these firms." Companies should do the heavy lifting before FDA arrives, according to the branch chief.

In the past, GMP inspections have focused on profile classes--the type of finished product, such as tablets, liquids, or capsules. This meant that every time a company needed a preapproval inspection, and it was for a new profile class, FDA would have to return, notes Blumenschein. The agency might be conducting three or four inspections of the same site in a year. More importantly, companies would only fix problems for that particular class at that particular facility. Larger problems wouldn't be addressed.

Wes Neumann, vice president of business development for Lancaster Laboratories, says with a narrow focus, "there is a tendency to get hung up on individual data idiosyncrasies or human error." The old approach ignores a company's overriding philosophy and encourages patchwork solutions, he asserts.

Now, for a full inspection, FDA staffers will be instructed to review at least four out of six systems that have been defined as crucial to ensuring GMPs. The quality system is always inspected. The other five systems are facilities and equipment, materials, production, packaging and labeling, and laboratory control.

All registered drug establishments, including contractors, will be subject to the systems approach. Foreign facilities will have full inspections only, says branch chief Blumenschein. Domestically, inspectors can opt for an abbreviated inspection. An abbreviated inspection will focus on two systems, of which quality is one.

If the system looks good at one facility, and for one product, then it's probably fine globally, Blumenschein says. Similarly, if violations are found in a system, it's likely to be a facilitywide and companywide problem, according to the FDA branch chief.

Significant violations mean the agency can shut down every facility owned by a company and put a hold on any product under review. The industry has complained about this, but Blumenschein notes that FDA reviewers can overrule his division if they deem the therapy under review as lifesaving or medically necessary. But, he adds, the overlying threat "will behoove them to get into compliance."

Blumenschein also says the systems-based approach won't turn up more violations. In the pilot last year, 35 of 155 inspections were considered "official action-indicated inspections," he notes. Ten of those 35 were compliance inspections--follow-ups to previous inspections that identified violations.

Even so, Quintiles Consulting's Phillips believes the systems approach is going to have a large impact. "It's going to demand that top management get involved earlier and get committed to identifying and taking care of the problems," he says. Companies may claim that a systems-based inspection is not a true picture, but Phillips disagrees. "If the system is broken, it's broken."

"It's definitely a valid snapshot," says Claire Courtemanche, director of regulatory affairs and quality assurance at Rockville, MD-based BioReliance. The company uses a systems approach to inspect its four Rockville-area facilities, plus one in Scotland and one in Germany. BioReliance conducts toxicology, biologics, raw material, and lot-release testing, and it has manufacturing and filling operations.

The company has not had a systems-based inspection by FDA. Yet, as a result of serving 600 clients per year, BioReliance has plenty of audits--usually several times per week and mostly systems-based, says Courtemanche. The approach "allows an inspector to cover a lot of ground in a shorter amount of time," she says.

Patheon's Harding says FDA has already been using a systems approach for preapproval inspections at his company. Consequently, Patheon does not expect radical changes to its process. A systems-based inspection is an improvement over a profile class inspection because it forces broader solutions, claims Harding. He adds: "If it's a system or quality-related problem, we'll take a look at that for all our sites in Canada."

Patheon has 65 to 70 client audits per year. The Canadian Therapeutic Products Directorate, the MCA [U.K. Medicines Control Agency] and European Medicinal Evaluations Agency in Europe evaluate the company. "Clients expect us to be at the top of our game for compliance," says Harding.

Lancaster Labs' Neumann agrees. Noting that his contract lab has three audits per week he says, "We get to practice a lot, so we have some pretty serious experience." He doesn't anticipate major changes to his QA operations, but thinks "it's a never-ending progression."

Reprinted, with permission, from Bio/ Pharmaceutical Outsourcing Report, available from Pharmsource Information Services Inc., www.PharmSource.com.