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The dietary supplement industry's GMP compliance is a work in progress. How the industry is living with-and learning from-FDA Form 483s
That jittery air of tension hovering over the post-audit environment of an FDA current Good Manufacturing Practices (cGMP) facility inspection can feel a lot like report-card time, and for many of the star pupils in our industry, nothing but a 4.0 will do.
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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Even Good Companies Get 483s
But not every company who gets a 483 is bad. As Luther points out, “Even very good companies may receive a Form 483.”
Gary Swanson, senior vice president, global quality, Herbalife (Los Angeles), maintains that a 483 “shouldn’t be interpreted as necessarily negative by other parties.” Echoing Prochnow and Luther, he stresses that “It’s not uncommon for an audit to result in a Form 483” and that “the issuance or non-issuance is not a measure of compliance.”
In other words, just because a company doesn’t get a 483 doesn’t mean that it’s compliant; likewise, the receipt of several 483s doesn’t mean that it’s not concerned about quality.
In fact, many companies are doing their best to comply with the high standards of recordkeeping and raw-material and finished-product testing prescribed in the cGMPs, which requires not only “resources, time, and money,” Luther points out, “but, more importantly, company personnel willing to implement and maintain them on a day-to-day basis.”
Still, FDA’s expectations are rising alongside the number of inspections it conducts. So what are the major problems still persisting?
Observers say that among the enforcement trends emerging are an uptick in warning letters covering new dietary ingredients (NDIs) and ingredients generally recognized as safe (GRAS), as well as problems with ingredient identification. As Wong points out, “Information gaps about raw materials hamper the manufacturer’s ability to perform appropriate tests to verify the identity, strength, purity, composition, and limits on contaminants of the finished product.”
Loren Israelsen, president, United Natural Products Alliance (UNPA; Salt Lake City), adds that the widespread use of botanical raw materials presents “specific problems with identification, the likelihood of adulteration, and understanding of which analytical techniques and tools can assure identity to rule out adulteration.”
“This, to me,” he says, “ranks as the top priority for improvement.”
Lengthening supply lines only complicate the matter, making proper qualification of an ingredient’s supplier and origins all the more important. Recognizing an unmet need, several trade associations, including CRN, UNPA, and the Consumer Healthcare Products Association (CHPA), formed the Standardized Information on Dietary Ingredients (SIDI) Work Group to develop voluntary best practices for ingredient procurement, documentation, and supplier qualification. The resources, Wong notes, “are free for industry to use to improve quality-management systems and improve cGMP inspection results.”
Focus Is Primarily on Quality and Manufacturing
One could be forgiven for wondering how many of the most common infractions actually put consumers at risk and how many merely reflect a box unchecked or a spec sheet that someone forgot to produce in triplicate. Prochnow notes that while a 483’s bill of particulars may include “the occasional mention of someone’s lunch being left in a work area or some technical facility upkeep requirements,” the overall focus, he insists, “remains on the manufacturing and quality of the product.”
And as to the question of which violations rank as “serious” versus “minor” from FDA’s viewpoint, Prochnow says “there’s technically no such thing as a minor or serious violation. Each violation of the cGMPs would constitute an unlawful act under the Federal Food, Drug, and Cosmetic Act, and the failure to comply with the cGMPs could cause any products manufactured to be adulterated.”
Swanson adds that although FDA doesn’t rate 483 observations by severity, “they do have categories that are considered important because of safety, such as microbial excursions, foreign material contamination, raw-material identification, and quality oversight.”
And for her part, Luther cautions that any 483 observation may trigger an FDA warning letter and subsequent enforcement action “if the documented violations aren’t promptly and adequately corrected. Many companies this year have been issued warning letters as a result of not properly addressing previously issued 483s.”
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So You’ve Gotten a 483…
The lesson is that if FDA hands you a Form 483, don’t let it paralyze you into inaction. Prochnow points out that while “there’s no legal or regulatory obligation to respond” to a 483, its position as the first step in a potentially escalating enforcement process demands a thorough and timely response.
“And the emphasis is on thorough,” Prochnow says. “Many of the letters over the last two years note that the company responded to the letter, but in an inadequate fashion.” FDA wants evidence of change: copies of revised standard operating procedures (SOPs), photographs of repaired equipment or facility conditions, batch-record copies, you name it. “Failure to provide such documentation,” he says, “has been cited often in recent warning letters.”
This is where leaning on the wisdom of a regulatory veteran comes in handy. CRN’s Wong notes that legal counsel or consultants experienced in dealing with 483s-and in communicating with FDA on cGMP issues-“can be very helpful.” Professionals “who understand how FDA works,” she says, have unique insight into how to resolve such issues before they rise to the level of a warning letter.
Cynthia A. Ipach, president, Compliance Insight Inc. (Fairfield, OH), is one such professional. She and her team work with manufacturers on quality and regulatory matters and have helped many turn a 483’s findings into a workable plan for improvement. The key to doing so, she says, is “to set up a complete understanding for FDA of what steps you’re taking, with as much proof as possible that you’re in the process of taking them.”
So her team may conduct brainstorming sessions with a company’s management to address the observations in a 483, the options available for reaching compliance, and those that “best suit that company based on the resources they have,” she says. Then they’ll compile a list of short- and long-term actions for achieving results. The former get going right away “so that when we submit our response in 15 days, we’ve taken some steps to show FDA that we’re serious about and committed to resolving the issues-and we provide proof,” she says. To demonstrate action on longer-terms corrections-new equipment or facilities modifications, say-“we report what we’re doing to mitigate the risk in the short term and provide maybe an invoice for equipment on order to prove that we’re moving in the right direction.”
It’s a process that both FDA and her company’s clients appreciate. “Every company I’ve worked with is doing the best they can with what they know,” Ipach says. “It’s just a matter of continuous learning about their products, the regulations, and the latest technologies. I really find them to be very cooperative. They really want to make good products. And who doesn’t?”
Behind the Numbers
That sentiment-more than the frequency with which FDA issues 483s or the infractions it enumerates therein-may be the best indicator of where industry stands vis-Ã -vis cGMPs. “The number of 483s only tells a small part of the cGMP-compliance story,” Swanson declares, “and does not necessarily reflect an industry commitment or trend in terms of quality.”
Israelsen says that any verdict on quality compliance should account for “how long a sector’s cGMPs have been in place.” For while the dietary supplements industry has only operated under the new standards for 5–8 years, food manufacturers have been operating with cGMPs for decades, as has the prescription-drug industry. And when you look at the seafood industry, whose cGMPs “are about twice as old as dietary-supplement cGMPs,” he says, that field also “struggled in the first 5–8 years with compliance.” So patience is in order.
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Room for Improvement
That said, the nature of the infractions that wind up on 483s “reveals we should focus industry efforts on training, education, and improvement in operational competence,” Israelsen says.
“As time passes, we’d expect to see general improvements in these areas, but for now, they remain a problem,” he concurs.
Prochnow believes that “bigger companies are doing well,” while smaller players, “in my experience, have been slower to get compliant.” The culprit, he says, is “the huge cost associated with the additional testing” that cGMPs require. “I think many companies take the position, certainly not recommended, that they’ll do the best they can and make adjustments when FDA comes for an inspection and points out violations,” he says. “But this is not a great way to move forward, as some companies have found that you don’t always get a free pass.”
Opportunity in Disguise
Besides, seen from a certain light, a 483 is a terrible thing to waste. As Swanson says, “A company should view a 483 as an opportunity to improve processes and systems.” By that same token, they should embrace the standards laid out in the cGMPs.
“I really do think that the cGMPs are highly beneficial to manufacturers,” Ipach says. “The more consistently they make their products, the more money they save in scrap. They can run a leaner organization because they become more efficient in how they produce their product. So I think it’s been a benefit, even if companies cry foul when they have to comply.”
And even if companies cry foul when they get a 483, they should know it’s not the end of the world-or of them. “Every dietary supplement company’s objective is a no-483 inspection,” Israelsen says. But sometimes, that’s just not realistic.
“The goal,” he says, “should be continuous improvement. And if a company does receive a 483, that offers a fast-track improvement opportunity.”
Sidebar: Contracting Compliance
Who’s Responsible: the Marketer or the Manufacturer?
Those familiar with FDA enforcement of dietary supplement cGMPs note that industry’s growing reliance on contract manufacturers is creating unintended consequences for quality control. As Justin J. Prochnow, shareholder, Greenberg Traurig LLP (Denver, CO), says, “The obligation of private-label distributors to ensure that their products are being manufactured pursuant to cGMPs continues to be one of the more frequent observations and-still-one of the areas that industry has failed to get up to speed on.”
The problem lies with the dynamics of the supplement marketer/contract manufacturer relationship. As Prochnow explains, “There’s a reason many companies hire third parties to manufacture products: they don’t have the experience or know-how to do it themselves. That being the case, how are they supposed to have the experience or know-how to check with their contract manufacturer to see that they’re complying with the laws?”
Meanwhile, Loren Israelsen, president, United Natural Products Alliance (UNPA; Salt Lake City), underscores the “primary responsibility” that supplement marketers bear for shepherding their brands.
“Brand holders have been slow to understand that they, too, are responsible for cGMP compliance and cannot just hand it over to contract manufacturers,” he says. “Contract manufacturers are under tremendous pressure to enhance quality systems, increase testing, and still hold down costs. This is an unrealistic demand. Industry needs to understand this and accept that if we want and expect significant improvements in quality, there’ll be increases in costs, which will ultimately surface in the supply chain and to the consumer.”
Sidebar: Step-by-Step to Recovery
Hitting All the Right Notes in a 483 Action Plan
There’s no one-size-fits-all plan for addressing the observations in an FDA Form 483. But those in the know, like Dr. Cheryl Luther, general manager, NSF Dietary Supplement Program (Ann Arbor, MI), agree: “The best approach for dietary supplement companies is to address all cGMP violations quickly, implement robust quality-management systems, improve training programs, and invest in continual improvements.” That sounds like great advice. But can she get even a bit more specific? She can. In fact, says Luther, “I’d recommend that to increase compliance with 21 CFR 111, firms must” do the following: