Manufacturing Failures Place GMP Compliance in Spotlight

For the past 10 years, the US Food and Drug Administration has campaigned for a more efficient, risk-based approach to monitoring drug-manufacturing activities. The agency's goal has been to encourage consistent production of high-quality products while providing less routine oversight. Yet, a series of serious manufacturing breakdowns in recent months has led to plant closures and massive product recalls, raising questions about industry investment in and commitment to modern production systems able to meet established regulatory standards.

Jill Wechsler

In April, the McNeil unit of Johnson & Johnson (J&J, New Brunswick, NJ) shut its flagship facility in Fort Washington, Pennsylvania, and recalled millions of bottles of children's cold medicines due to repeated failures to meet manufacturing standards and comply with regulations. The problems, observed FDA Principal Deputy Commissioner Joshua Sharfstein at a Congressional hearing in May, appear related to the company's "pattern of noncompliance" with quality control requirements. J&J now faces potentially serious legal issues, as Congressional leaders have raised charges of stonewalling, and FDA is examining whether the firm knowingly misled the regulators.

Meanwhile, Genzyme (Cambridge, MA) continued its struggle to restore production capacity after contamination problems prompted the closure of its Allston Landing, Massachusetts, facility in June 2009. The company paid a hefty fine and invested millions in plant cleaning and renovation. Manufacturing issues also compelled KV Pharmaceutical (St. Louis, MO) to shut down operations and recall multiple generic products and vitamin therapies. And several vaccine manufacturers are working hard to eliminate extraneous viruses from cell banks and to correct manufacturing issues identified by FDA inspectors.

These situations raise questions about whether drug and biological manufacturers are cutting corners in their quality systems needed to comply with current good manufacturing practices (CGMPs). In 2002, FDA launched the Pharmaceutical CGMPs for the 21st Century initiative to modernize the regulation of drug manufacturing and to spur industry efforts to ensure product quality. After issuing several new policies and guidances to encourage a risk-based approach to quality control, FDA had to move the effort to the back burner as other issues, including these compliance crises, began to dominate the agency's agenda.

The current surge in manufacturing problems has placed drug quality and GMP compliance back in the spotlight at FDA. In a major speech last August (2009), FDA Commissioner Margaret Hamburg emphasized the importance of industry adherence to regulatory standards (see the October 2009 edition of Washington Report in Pharmaceutical Technology). Hamburg outlined initiatives to accelerate the correction of manufacturing violations identified during plant inspections and to streamline the process for issuing Warning Letters to companies that fail to address violations expeditiously.

Those policies appear to be taking hold. FDA has increased the frequency and timeliness of its "untitled" and Warning Letters that cite ongoing manufacturing problems. This approach is a reversal of the Bush administration's targeted enforcement strategy, which was based on the idea that manufacturers would take a limited number of Warning Letters more seriously. FDA enforcement efforts may gain more clout if Congress enacts long-sought legislation to strengthen the agency's legal powers, namely by providing FDA with the ability to mandate recalls, expand civil monetary penalties, and gain easier access to company records. There's more talk of FDA injunctions and consent orders, and the pharmaceutical legal community is watching closely to see whether the government brings charges against J&J and McNeil executives for not doing more to prevent company violations of food and drug laws.

In Washington this month

History of problems

The rationale behind FDA's strong action against McNeil and its leaders may have to do with the fact that McNeil's facility shutdown and product recalls are just the latest in a string of regulatory compliance failures. The May hearing before the House Oversight and Government Reform Committee did little to improve J&J's image. The only good news for the company is that FDA agreed no one had died as a result of taking the recalled adulterated products, and that McNeil's violations probably did not represent a major risk to public health.

Instead of convincing legislators that it was taking forceful action to solve its quality control problems, however, the company faced even more criticism from members of Congress. Committee Chairman Edolphus Towns (D-NY) raised questions about a "phantom" recall of the painkiller Motrin in 2008, a company strategy apparently designed to avoid an official public recall of certain Motrin products experiencing dissolution problems. McNeil hired an outside firm to retrieve thousands of convenience-size packages of the drug from retailers' shelves. When FDA discovered what was going on, it insisted on an actual recall, explained FDA's Sharfstein, adding that the agency felt the incident reflected poorly on the company.

The hearing, along with FDA documents, revealed a history of regulatory violations, failed inspections, and product recalls by the company going back several years. Inspectors found gram-negative bacteria in an ingredient in mid-2009, prompting a recall of approximately 8 million bottles that August. Soon after, FDA learned that the company had received complaints for months about a musty odor in Tylenol bottles produced at the firm's Las Piedras, Puerto Rico, plant, but had failed to report the problem to the agency. The company linked the odor to a substance used to treat wooden transport pallets, and products had to be recalled. When McNeil did not take corrective action as fast as FDA expected, the agency sent a Warning Letter in January 2010 citing concerns about the failure of McNeil and its parent J&J to assure "timely investigation and resolution of the issues."

To make sure that FDA's message was reaching top J&J executives, FDA took what Sharfstein described as an "extraordinary step" of holding a meeting with senior executives from the parent company as well as from McNeil to spell out the agency's concerns. At this meeting in February 2010, FDA officials questioned J&J's oversight of McNeil, noting that its subsidiary failed to report material information to FDA, misstated product risks and benefits, and took a reactive—not proactive—approach to product quality problems. FDA expressed its concerns about "whether the company's corporate culture was appropriately focused on product quality issues," Sharfstein added.

Despite efforts to address these issues, McNeil continued to experience manufacturing and quality problems. A product recall in March 2010 was caused by defective bottles and labels. And when McNeil found particulates in some of its products, along with other manufacturing and quality problems, it shut down the Ft. Washington facility and launched a recall of some 136 million bottles of children's medicines. Although the company initially expressed optimism about quickly correcting its problems, J&J acknowledged in June that the Pennsylvania plant would not reopen this year. The long-term shutdown affects products that generate more than $600 million in annual sales and prompted negative financial assessments on Wall Street. The company also expanded its recall to include additional over-the-counter products made in Puerto Rico.

At the same time, House Oversight Committee Chairman Towns moved to schedule a second hearing to query J&J chairman William Weldon directly about the company's manufacturing problems and phantom recall activity. Weldon sent a substitute to the May hearing, claiming he was still recuperating from back surgery. But Towns and his colleagues want to hear directly from Weldon as to the nature of and responsibility for the company's violations and compliance missteps. After the May hearing, Towns complained that J&J was not cooperating with the committee's investigation, and suggested he might issue subpoenas or take other action to obtain complete information.

Broader effects

Sharfstein used the Congressional hearing to "send the message" to manufacturers that FDA is significantly strengthening its oversight and criminal enforcement. Deborah Autor, director of compliance at the Center for Drug Evaluation and Research (CDER), said FDA's criminal investigative unit is examining whether J&J is criminally liable for McNeil's phantom recall and for the company's slow response to FDA inspection citations. Sharfstein added that FDA plans to consider corporate structure when enforcing the law, which would involve applying its experience at one facility to other operations run by the same company. Companies need strong compliance programs in place, he said, noting that FDA prefers to see industry adhere to the rules than to take enforcement action.

Manufacturers of older drug products in outdated facilities should take this advice seriously and modernize operations before difficulties arise. Quality control problems that emerged at Genzyme last year led to a plant shutdown, dangerous shortages in important treatments for rare diseases, and a contentious fight for control of the company. Genzyme CEO Henri Termeer almost lost his job and had to add new members to his board of directors in June to placate investor Carl Icahn. Genzyme had already been hit with FDA citations for GMP violations when the company discovered a virus in the bioreactors of its Allston Landing facility last year, just when it was trying to scale up production to meet growing demand for new and existing therapies. Additional fill-and-finish problems emerged later. The plant, which is more than 15 years old, had to close for several months to undergo a $9-million decontamination process.

In addition to losing millions in revenue, Genzyme also has to finance a $150-million program to renovate and bring the facility into compliance. Moreover, the company had 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, FDA sped up its 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 company responses to citations of product quality violations. In June, 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, FDA cited inadequate testing of containers and closures as well as 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 the production of safe, pure, and potent vaccines.

More authority

Although some members of Congress initially chastised FDA for failing to keep McNeil's adulterated children's medications off the market, the agency came out looking pretty tough from the May Oversight Committee hearing. FDA was able to document multiple efforts to compel McNeil compliance with quality standards, including frequent inspections of company facilities, numerous reports and Warning Letters, and the meeting with corporate executives when previous 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 difficult for FDA to compel a company to pull products from the market. Although most manufacturers comply with FDA recall requests, there is often is a lag between when the company becomes aware of adverse events and quality problems, and when that information reaches regulators. Several members of the House Committee indicated support for strengthening FDA's powers, as did Rep. Rosa DeLauro (D-CT), chair of the House Appropriations subcommittee that oversees FDA's annual budget. DeLauro sent a letter to Commissioner Hamburg complaining of McNeil's "reckless behavior" in disregarding GMPs at its facilities and in marketing inconsistent and noncompliant cold medications for children. The Congresswoman suggested that FDA might benefit from added authority to recall drugs and 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 past few years 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 FDA's wish list for several years as a way to boost revenue. Some policymakers have proposed that FDA collect fees for all field inspections as is done in Europe and many other countries. Such fees are not likely to be approved in the US, but asking violators to pay more for reinspections and secondary reviews may gain support.

One likely possibility is for FDA to require more extensive pharmaceutical company monitoring of suppliers and contract manufacturers. 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 asking pharmaceutical companies to conduct on-site audits to confirm that contract manufacturers comply with rules and standards.

As these options are being debated, the legal issues exposed by FDA attorneys could have a broad impact on industry. Pharmaceutical companies are watching to see whether the agency brings criminal charges against J&J and McNeil, as well as enforcement action under its "responsible corporate officer" doctrine. The latter could involve individual misdemeanor charges, which can carry stiff fines and even prison terms.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com.