Unfortunately, in the five-odd years since dietary supplement cGMP practices went into full effect under 21 CFR Part 111, FDA has continued doling out Form 483s—the equivalent of a “needs improvement” grade—frequently enough to put at least one in almost every company’s file.
But a grade of “needs improvement” is no sign that a supplement maker is about to flunk out. And companies can learn a lot from a 483 if they think of the process as a progress report that supplement makers can use to stay on the dean’s list—and keep their products out of detention.
No Doubt about It: Take a 483 Seriously
Despite their ubiquity, Form 483s still sting, and manufacturers are right not to let the notices roll off their backs. For while it’s not necessarily a black mark on a company’s permanent record, a 483 is serious business.
For those readers arriving late to class, an FDA Form 483 is the official “Inspectional Observations” document the agency issues to a manufacturer’s management following an investigation in which the inspector observes conditions that might amount to a violation of dietary supplement cGMPs as established in 21 CFR Part 111.
There has been an increase in the pace of 483 issuances. “It’s a rare occasion when a Form 483 is not handed out at the close of an inspection,” notes Justin J. Prochnow, shareholder, Greenberg Traurig LLP (Denver, CO).
Alas, the precise number of 483 issuances remains something of a black box, as FDA doesn’t make the documents public. Inquirers can access them through a Freedom of Information Act (FOIA) request, but even the documents thus obtained are redacted to shield the identity and privacy of the companies involved.
Following a Form 483, the next, more serious, step in FDA’s disciplinary chain—absent further action or remedy by the manufacturer—is an FDA warning letter. “And these seem to be increasing in number every year,” says Gary Swanson, senior vice president, global quality, Herbalife (Los Angeles).
In contrast to the protocol with 483s, FDA does publicly post warning letters, and the Council for Responsible Nutrition (CRN; Washington, DC) has built a searchable database of such letters pertaining to products marketed as dietary supplements. The goal of the database, says Andrea Wong, PhD, CRN’s vice president, scientific & regulatory affairs, is “to help industry understand FDA’s enforcement priorities and activities” concerning cGMPs. This way, they can better anticipate and avoid the missteps that lead to the warnings in the first place.
483s: Where Are We Today?
Wong reports that as of August 2015, FDA had issued 14 warning letters related to potential cGMP violations, “nearly all” of which noted “a failure to establish specifications for dietary supplement components and/or finished products,” she says. “As FDA has previously stated, ‘If it wasn’t written down, it didn’t happen.’”
Other common infractions cited in both warning letters and 483s, those privy to the documents say, run to problems with written procedures, testing of raw materials and finished products, supplier qualifications, product complaints, holding and distribution operations, returned products, reserve samples, and master manufacturing records (MMRs) and batch production records (BPRs).
Dr. Cheryl Luther, general manager, NSF Dietary Supplement Program (Ann Arbor, MI), adds that citations related to stability testing have been on the rise, as well, and that FDA is increasingly conducting website audits, which have the advantage for inspectors of dispensing with on-site visits. Such virtual audits might examine promotional materials, research support for online claims, blogs, drug claims, and ingredient safety and identity issues, among others, which is why Luther “strongly recommends that companies develop policies for routinely monitoring their websites.”
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