Hamburg's most high-profile initiative so far is to streamline the process for issuing Warning Letters and for taking enforcement
action against manufacturers that fail to comply with good manufacturing practices (GMPs) and other agency rules. Many serious
violations "have gone unaddressed for far too long," including manufacturing violations, product adulteration, and false and
misleading labeling and advertising, Hamburg commented at an August meeting sponsored by the Food and Drug Law Institute.
The commissioner wants to limit the wrangling with regulated companies that delays compliance. And if a situation raises serious
health and safety issues, FDA may launch a recall or seizure before even issuing a Warning Letter, she said.
Under the new policy, a manufacturer has 15 working days after receiving a 483 inspection report to provide information about
how it will address cited violations to prevent enforcement action. If FDA doesn't receive an adequate response in that time,
the agency may issue a Warning Letter or take other steps to enforce compliance. The 15-day policy went into effect for violation
notices issued after Sept. 15, 2009, and it may prove a challenge for manufacturers to meet, points out former FDA regulatory
official David Chesney, vice-president of Parexel Consulting. Although manufacturers are not legally required to respond to
483s, and only about 10% of inspection problems traditionally lead to Warning Letters, Chesney considers a timely response
advisable to avoid a more serious regulatory action.
Hamburg also aims to issue Warning Letters more promptly by ending an extra internal legal review of the documents before
they are sent out. The Bush administration required the FDA chief counsel to examine all proposed Warning Letters, a policy
that was criticized for delaying and reducing agency enforcement actions. "This created very cumbersome practices without
a lot of benefit," observed Hamburg. Now the chief counsel will review only proposed Warning Letters that raise "novel, complex,
and sensitive issues" such as an activity at the center of a lawsuit or a requirement recently established by legislation.
For its part, FDA is offering a carrot to encourage industry to take corrective actions quickly. The agency aims to promptly
reinspect or evaluate a company's remedial efforts and not leave manufacturers wondering whether a corrective action is adequate.
If a review indicates that problems have been corrected, FDA will issue a formal close-out letter and make an announcement
on its website. This policy provides manufacturers with an official statement to show investors and customers that they're
back in FDA's good graces and that a facility or product is no longer tainted by quality or safety concerns.
"There's a lot of room to improve FDA's side of the equation," Chesney comments, noting that the agency often fails to follow
up with companies for months, or even years, after issuing violation notices or Warning Letters. Conversely, if reinspection
shows that cited problems have not been corrected, FDA says it won't just issue another Warning Letter, but may initiate product
seizures, shut down plants, or impose additional penalties.
Even before announcing these changes, FDA officials were stepping up GMP enforcement and making compliance actions more visible.
Earlier this year, for example, FDA banned the import of Ranbaxy products from two plants in India following a series of Warning
Letters and inspections. KV Pharmaceuticals (St. Louis, MO) received a consent decree in March 2009 after years of inadequate
responses to inspection reports and letters citing GMP violations. More recently, FDA instigated a high-profile seizure of
drugs produced at the Michigan facilities of Sun Pharmaceutical's (Mumbai) Caraco subsidiary because of the company's failure
to fully address earlier inspections that revealed variation in the size of digoxin tablets, among other problems. FDA quickly
imposed a permanent injunction in July 2009 to halt the manufacturing and distribution of products from Teva Animal Health's
(St. Joseph, Missouri) facility. FDA recently froze imports from Apotex (Toronto) because of inadequate correction of manufacturing
violations cited in a June 2009 Warning Letter.
Biotechnology companies face particular scrutiny because of the high risks of toxicity from substandard injectables. Genzyme
(Boston) has been struggling for more than a year to address serious manufacturing problems. It had to shut down its Allston
Landing, Massachusetts, facility in June 2009 because of viral contamination, thus leading to serious shortages of enzyme-replacement
therapies such as Cerezyme (imiglucerase). A threat to revoke Immucor's (Norcross, GA) biologics license for poor quality
control of blood-diagnostic products prompted fast development of a corporate remediation plan and quality-process improvements.
Hamburg expects that FDA's enforcement campaign will increase the volume of Warning Letters initially, as already seen this
year. However, she anticipates that the volume will level off over the long run as industry recognizes that a strong compliance
program is good for business and for consumers. FDA's success in spurring compliance "should be measured not by the number
of Warning Letters or injunctions or seizures," she said, but by "our impact on the health and welfare of the public." Failure
to meet FDA standards means that a company is "putting the public at risk" and also "jeopardizing the public's confidence
in your industry." Conversely, speedy corrective efforts and broader compliance throughout industry will increase public confidence
in FDA and better educate patients and consumer about potential risks in medical products.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org
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