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.
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).
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
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
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