Manufacturing Compliance in the Spotlight

A number of high-profile drug and biotech manufacturing breakdowns in recent months is raising questions about industry investment in, and commitment to, modern production systems able to meet US Food and Drug Administration standards. For the past decade, the FDA has campaigned for a more efficient, risk-based approach to monitoring biopharmaceutical manufacturing activities that encourages consistent production of high-quality products.

Jill Wechsler

Yet, the massive recall in April of children's cold medicines produced by the McNeil unit of Johnson & Johnson (J&J, New Brunswick, NJ) reflects repeated failures by the company in meeting regulatory requirements. Genzyme Corp. (Cambridge, MA) continues its struggle to restore production capacity after contamination problems prompted closure of its Allston Landing, MA facility. And several vaccine makers are working hard to eliminate extraneous viruses from cell banks and to correct manufacturing issues identified by FDA inspectors. These and other situations raise questions about whether drug and biotech manufacturers are cutting corners on maintaining the quality systems needed to comply fully with current good manufacturing practices (cGMPs).

STRONGER OVERSIGHT

At a hearing before the House Oversight & Government Reform Committee in May, FDA Principal Deputy Commissioner Joshua Sharfstein said that he wanted to "send the message" to manufacturers that the FDA is significantly strengthening its oversight and criminal enforcement of manufacturing activities. In a seminal speech last August (2009), FDA Commissioner Margaret Hamburg emphasized the importance of industry adherence to regulations [see BioPharm, Regulatory Beat, October 2009]. Hamburg outlined initiatives to accelerate the correction of manufacturing deficiencies identified during plant inspections and to streamline the process for issuing warning letters to those companies that fail to address violations expeditiously. That policy appears to be taking root, as the FDA steps up the volume and timeliness of untitled and warning letters, and moves aggressively to compel industry action.

The investigation into McNeil's manufacturing problems promises to affect manufacturers more widely. Deborah Autor, director of compliance at the Center for Drug Evaluation and Research (CDER), acknowledged at the May hearing that the FDA's criminal investigative unit is examining whether there is potential criminal liability for McNeil's "phantom" recall of Motrin products in 2008 and for the company's slow response to FDA inspection citations. Sharfstein commented that the FDA plans to consider corporate structure more specifically when enforcing the law, which involves applying its experience at one facility to other operations run by the same company. Manufacturers need strong compliance programs in place, he said, adding that the FDA much prefers to see the industry adhere to the rules than for the agency to take enforcement action.

Manufacturers of older biomedical products in older facilities should take this advice to heart and invest in modernizing operations before serious difficulties arise. Quality control problems at Genzyme's outdated facility not only are proving costly to the company, but have precipitated shortages in important treatments for rare diseases. Genzyme CEO Henri Termeer nearly lost his job and had to add new members to his board of directors in June to placate investor Carl Icahn.

Genzyme's sorry saga began several years ago when the company began to receive citations for GMP violations from the FDA. The situation deteriorated when Genzyme discovered a virus in bioreactors at its Allston Landing facility last year, just when it was trying to scale up production to meet growing demand for new and existing therapies [see Regulatory Beat, February 2010]. The plant, which is more than 15 years old, had to shut down for several months in 2009 for a $9 million decontamination process.

In addition to losing millions in revenue, Genzyme has to finance a $150 million program to renovate and bring the facility into compliance. Moreover, the company has to pay $175 million in fines for GMP violations and to accept an FDA consent decree that requires third party monitoring of operations to ensure that new production complies with regulations. Potentially more damaging, the FDA speeded up review and approval of competing therapies from two other firms to alleviate product shortages, a move that may limit Genzyme's ability to regain market share.

All signs point to continued FDA emphasis on speedy and efficient responses to manufacturing violations. In June, the FDA's Center for Biologics Evaluation and Research (CBER) admonished Australian vaccine maker CSL for failing to fully correct manufacturing deficiencies found during an April 2010 inspection. In an untitled letter, the FDA cited inadequate testing of containers and closures, plus CSL's failure to investigate batch discrepancies or to establish testing procedures to ensure conformity to standards. Even though this FDA communiqué was not an official warning letter, Mary Malarkey, director of CBER's Office of Compliance and Biologics Quality, called for a meeting with CSL CEO Brian McNamee and his senior management to discuss how the company will develop a corrective action plan to address its violations and to ensure production of safe, pure, and potent vaccines.

MORE AUTHORITY

Although some members of Congress initially chastised the FDA for failing to keep McNeil's adulterated children's medications off the market, the agency came out looking pretty tough from the May hearing. The FDA was able to document a history of regulatory violations, failed inspections, and product recalls going back several years, along with multiple efforts by the agency to compel McNeil to comply with quality standards. Sharfstein cited frequent inspections and numerous warning letters, plus a meeting with corporate executives when those efforts failed to produce results.

Sharfstein also made the case for stronger FDA regulatory and recall authority. The J&J recall was voluntary because, under current policy, it's very long and difficult for the FDA to compel a company to pull products off the market. Even though most manufacturers comply with FDA recall requests, there often is a lag between when the company becomes aware of adverse events and quality problems, and when that information reaches the regulators. Several members of the House Oversight Committee indicated support for strengthening the FDA's powers, as did Rep. Rosa DeLauro (D-CT), chair of the House Appropriations subcommittee that oversees the FDA's annual budget. DeLauro sent a letter to Commissioner Hamburg complaining of McNeil's "reckless behavior" in disregarding GMPs at its facilities and suggested that the FDA might benefit from added authority to recall drugs, to require company monitoring of consumer complaints, and from more resources to conduct more frequent inspections.

The need for multiple inspections of J&J plants over the last few years also has raised the issue of whether manufacturers that require repeat site audits should pay additional fees for the extra services. Reinspection user fees have been on the FDA's wish list for several years as a way to boost revenue from those firms that create more work for agency inspectors. Some policymakers have proposed that the FDA collect fees for all field inspections, as done in Europe and many other countries. That's not likely to happen, but asking violative companies to pay more for reinspections and re-reviews may gain support.

Another outcome may be new rules from the FDA requiring more extensive pharmaceutical company monitoring of suppliers and contract manufacturers. The FDA holds the marketer of a finished drug responsible for ensuring that outside contractors comply with GMPs, but much of that oversight currently involves review of data and reports on quality control systems and product attributes. Now the agency is considering requiring biopharmaceutical companies to conduct on-site audits to ensure that contractors comply with rules and standards.

There's more talk of FDA injunctions and consent orders in the wake of examining a number of legal issues as part of the process for investigating McNeil's actions. The pharmaceutical legal community is watching closely to see if the FDA seeks charges against J&J and McNeil executives for not doing more personally to prevent company violations of food and drug laws under the FDA's "responsible corporate officer" doctrine; that could involve individual misdemeanor charges, which can carry stiff fines and even prison terms.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com