As FDA continues to inspect dietary supplement manufacturers under the new CGMP framework, it is clear that many manufacturers share similar deficiencies.  Recent FDA warning letters show that many manufacturers are still struggling with structure function claims, the required pre- and post-production qualitative and quantitative testing requirements, and strong quality control units that have the necessary authority and resources needed to comport with CGMPs.  (See, e.g., here, here, here, here, here, and here.)  When coupled with recent administrative guidance suggesting FDA may resort to reprimanding non-complying firms under the Park Doctrine, which imposes strict criminal liability for non-compliance with CGMPs, it is imperative that dietary supplement firms understand the potential consequences arising from serious CGMP violations.

Indeed, last year FDA sent a letter to Senator Charles Grassley (R-IA) explaining its intention to reintroduce the possibility of imposing criminal charges for misdemeanor violations of the Federal Food, Drug and Cosmetic Act (“FFDCA”) under the Parks Doctrine.  The Park Doctrine imposes strict liability, which means that the violating firm’s senior management need not have intent or knowledge of the violations to be found guilty.  Therefore, given FDA’s publicly stated intention of imposing harsher punishments for CGMP non-compliance, are future violations similar to those recorded thus far likely to result in criminal sanctions under the Park Doctrine?

The Park Doctrine is derived from United States v. Park, 421 U.S. 628 (1975), a landmark case decided by the Supreme Court.  In Parks, the president of Acme Markets, Inc., a large national food retailer, was convicted of violating sections of FFDCA for failing to sufficiently rectify unsanitary conditions at some of Acme’s warehouses, and for allowing adulterated food to be distributed in interstate commerce.  The Court reasoned that “[t]he requirements of foresight and vigilance imposed on responsible corporate agents are beyond question demanding, and perhaps onerous, but they are no more stringent than the public has a right to expect of those who voluntarily assume positions of authority in business enterprises whose services and products affect the health and well-being of the public that supports them.” Parks, 421 U.S. at 672.  A dietary supplement is considered adulterated if it is prepared, packed or held in conditions that do not comply with CGMPs, or if it contain poisonous or unsafe ingredients.  21 U.S.C.A. 342.

While FDA has enumerated several “serious” violations of FFDCA during routine CGMP audits, the severity of the violations found do not necessarily pose a serious public health risk as seen in Parks.  For example, FDA’s recent warning letter to Gaspari Nutrition cites several deficiencies in the company’s customer complaint recording procedures.  While the absence of customer complaint recordation procedures may (substantially) delay the recall of an adulterated dietary supplement product that poses a public health risk, it is not aconduct that is necessarily an imminent public health risk.

In fact, the majority of violations found in dietary supplement firms—as recorded in FDA’s published warning letters—stem from a lack of documentation, validation, or pre- and post-production testing.  In Parks, however, the violations were more obviously deleterious; FDA inspectors found chronic rodent infestations in some of Acme’s warehouses.  However, this is not to say that deficiencies in documentation, validation, and testing cannot result in the manufacture or distribution of dietary supplements that pose a public health risk.  On the contrary, such deficiencies may simply be telltale indicators of more substantive public health risks.  For example, if a dietary supplement firm cannot confirm the identity or purity of an ingredient through documentation, it is logically plausible to conclude that the dietary supplement may contain ingredients that are injurious to public health.

Dietary supplements that are processed in operations that do not comport with CGMPs are more likely to be contaminated by virtue of the fact that such operations lack the necessary infrastructure and procedural controls necessary to prevent cross-contamination and adulteration.  Smaller dietary supplement firms are less likely to have made the necessary investments in air handling and water purification systems, both of which are potential sources of adulteration.  If a cleaning procedure is not validated though quantitative testing, how can the manufacturer verify that the equipment has been sufficiently cleaned to prevent potential microbial growth or product cross-contamination?  To be sure, firms that lack validated operating procedures risk improperly cleaning equipment and facilities without sufficiently eliminating the potential for adulteration.

Despite these deficiencies, anecdotal consensus suggests that any future Parks Doctrine enforcement will stem from gross violations of FFDCA and CGMPs that are so pervasive that they pose a substantial and imminent risk to public health.  And, using Parks’ factual circumstances as a guide, habitual or repeated violations will likely be a prerequisite for a Parks Doctrine prosecution.  From a procedural vantage, if FDA intends to pursue criminal sanctions under the Park Doctrine, it must notify its Office of Criminal Investigations accordingly, which is then required to conduct further due diligence.  Unfortunately, FDA has not supplied a bright-line rule articulating what kinds of violations will warrant criminal sanctions.  Instead, firms are left with a series of factors, which includes repeated violations and illegal conduct, inter alia.

Although the likelihood of FDA imposing criminal sanctions to owners and senior decision-makers of dietary supplement firms for minor violations of CGMPs is unlikely, repeated violations that engender public health risks will certainly be candidates for the draconian consequences that arise from the Parks Doctrine.  Accordingly, it is in the dietary supplement industry’s best interest to adopt super-adequate quality control and quality assurance protocols.  Instead of waiting for FDA’s inexorable audit, dietary supplement firms should be conducting regular internal audits to ensure compliance with CGMPs and other relevant regulatory rules.  Such measures will engender good will with consumers of dietary supplement products as well as government agencies.

Shafiel A. Karim earned a B.A. from California State University, Fullerton and an M.A. from California State University, Long Beach.  He is currently a J.D./M.B.A. candidate at Southwestern University School of Law and the Peter F. Drucker and Masatoshi Ito School of Management at Claremont Graduate University.

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Jonathan W. Emord, Esq.

This is Part II of the Post that began here in which we discuss the three important suits filed this summer by supplement lawyer Jonathan Emord challenging FDA administrative action on first amendment grounds.

The cGMP Challenge – FDA Overreaching?

The FDA supplement cGMP regulations were anticipated from the time that DSHEA was passed in 1994 since the statute delegated authority to the Secretary of Health and Human Services to prescribe good manufacturing practices for dietary supplements.¹ The FDA’s dietary supplement GMPs were to “be modeled after current good manufacturing practice regulations for food and may not impose standards for which there is no current and generally available analytical methodology.”²

Of course, any regulation the FDA would promulgate under DSHEA would need to be consistent with the statute. DSHEA created a system of regulation where dietary supplements are deemed safe unless the FDA proves that a particular supplement presents a significant or unreasonable risk of illness or injury. As the cGMP Challenge Complaint correctly notes, “the express purpose of DSHEA was to ensure that ‘the Federal Government erects no regulatory barriers that impede the ability of consumers to improve their nutrition through the free choice of dietary supplements.’”³. Therefore, Congress placed “the burden of proof . . . on the Food and Drug Administration to prove that a product is unsafe before it can be removed from the marketplace.”⁴

FDA dragged its feet on the cGMP regulations until finally in 2003 the FDA published its Proposed Rule for dietary supplement GMPs.⁵ FDA published the Final Rule on June 22, 2007.⁶

The cGMP Challenge takes on the Final cGMP Rules on three separate fronts. First it argues that the cGMP Rules are contrary to DSHEA because under the regulations no longer is the burden on the FDA to prove a supplement is dangerous before it can be yanked from the market. Second it argues that the cGMP Rules create excessive burdens on small business and society. Third it argues that the cGMP Rules are unconstitutionally vague.

All these arguments appear sound. Emord argues convincingly that FDA has granted itself wide discretion to declare a dietary supplement adulterated for any violation of the Final Rule, without proof that a dietary supplement was prepared, packed, or held under conditions that violate the GMPs.

FDA concludes that it has no duty to prove a finished product to present a risk of illness or injury before deeming it adulterated and pulling it from the market for cGMP Rule violations. This is because under the GMPs, FDA can declare inadequate any record required to be kept and to deem on that basis alone a dietary supplement adulterated without meeting the statutory requirements of DSHEA.

The decisions that emerge from these cases could determine whether the courts will stand by the principles in DSHEA and protect the public’s access to supplement products in the future.

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1. See 21 U.S.C. § 342(g
2. Id.
3. See 140 Cong. Rec. S11705-06, at S11706 (Aug. 13, 1994
4. Id.
5. See Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary Supplements; Proposed Rule, 68 Fed. Reg. 12158 (Mar. 13, 2003
6. See Final Rule, 72 Fed. Reg. 34752 (June 25, 2007

Hamburg

The FDA has put supplement companies on notice that violators can expect earlier detection and prosecution. Remarks by commissioner Margaret Hamburg on Aug. 6 strongly suggest that the agency has shifted to a policy of less talk and more action. In a speech to the Food and Drug Law Institute, Hamburg said the FDA will be more vigilant, strategic, quick and visible.

To that end, Hamburg said the FDA has instituted six policy changes:

• Fewer, if any warnings. “If we find that we must move quickly to address significant health concerns or egregious violations, we will consider immediate action – even before we have issued a formal warning letter,” Hamburg said.
• Greater emphasis on swift enforcement. “When the public health is at risk, the FDA will reach out to our partners to take rapid action while we alert the public and prepare longer-term responses,” she said.
• Fewer warning letters. The letters are now limited to significant legal issues. “Most enforcement letters will be able to move forward through a more streamlined process.,” Hamburg said.
• Shorter post-inspection deadlines. “When the FDA finds that a firm is significantly out of compliance, we expect a prompt response,” she said. “The firm will generally have no more than fifteen working days in which to respond before the FDA moves ahead with a warning letter or enforcement action.”
• More follow-up on enforcement actions. “After a warning letter is issued or a major product recall occurs, we will make it a priority to follow up promptly with appropriate action, such as an inspection or investigation to assess whether or not a company has made required changes in its practices,” Hamburg said.
• Public notice of completed corrections. “We will provide to the firm a ‘close-out’ letter, indicating that the issues in the warning letter have been successfully addressed.”

In sum, a supplement maker can expect a knock on the door before getting a letter in the mail. If the FDA perceives a significant risk to public health, it will ask enforcement agencies to take immediate steps. In some circumstances, there will be no warning and no negotiation before a plant is shut down or a product is recalled.

Why is the change in policy needed? Hamburg, who has been on the job just 90 days,  pointed to slow action on serious violations regarding product quality; adulteration and misbranding; false, misleading, or otherwise unlawful labeling; and misleading advertising. Agencies took to long to respond because of procedures and policies, she said.

The industry response must be to get better or get out. Get better at controlling ingredient quality; get better at manufacturing; get better at documentation; get better at advertising and marketing; get better at legal representation. Otherwise, get out of the business.

While the actions may seem harsh, they increase the public’s confidence in the dietary supplement industry, Hamburg said.  “The solution is a commitment to compliance backed by a strong compliance program. Now is a good time to reassess whether you have such an effort in place.”

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The companies facing legal action are American Sports Nutrition Inc., Quality Formulation Laboratories, Inc. and Sports Nutrition International LLC, all in Paterson, N.J. The FDA says that Mohamed S. Desoky  manages all three companies. The FDA had warned Desoky in July 2007 that there were problems both with cleanliness in the Quality Formulation manufacturing plant and with unlisted ingredients in some products. Desoky has had a problem with inspectors in May 1998, according to FDA records.

The FDA complaint filed July 10 of this year says that management of the companies did not live up to promises to correct problems. In the latest inspection, “the company failed to clean processing equipment between batches and control allergens in the facility. FDA investigators also discovered live and dead rodents and rodent urine, feces and gnaw holes on bags of product.”

Gross. Attorneys for the FDA have asked the federal court for a permanent injunction that would halt manufacturing and distribution until all problems are corrected. In essence, the FDA wants a shutdown that could last weeks, even months depending on the amount of work needed to trap animals, disinfect equipment and eliminate unlisted ingredients.

Can a brand name survive such a scandal over the quality and safety of its products? Desoky and the three companies face that and other challenges. If the judge grants the FDA’s request, they will spends tens of thousands of dollars putting operations back in order. Responding to regulators’ legal actions will also be very costly. And customers and distributors may defect en masse.

The lesson for other manufacturers is that the FDA is getting tougher on food safety. While the agency gave Doseky two years to correct problems, when time ran out, the hammer came down. It is likely to strike again and again this year.

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Anne Hart has lots of questions about the quality and safety of nutritional supplements, 19 questions to be exact. They revolve around product integrity, contamination, mislabeling (think sibutramine), FDA oversight and so on.  A nutrition columnist for Examiner.com, Ms. Hart has several ideas for matching products to their labels,  all of which create more questions about the testing of every pill, powder, gel and liquid that could be considered a nutritional supplement.

The basic premise of her column is that a lab — probably a lot of labs — should test each nutritional supplement to see if it contains what the label says. The test results should be made available free of charge to consumers whether they are buying online, in a store or from a friend. Who owns the labs and who pays for all those assays and the like? And what entity maintains the databases that must constantly be updated?

Ms. Hart would like the nutrition supplement industry to underwrite the testing costs, but that poses an ethical problem: Just how independent and trustworthy can the labs be if their clients are the  manufacturers? For the answer, look at the uneven history of research firms on Wall Street. The Council for Responsible Nutrition is off the list, too, says Ms. Hart. We can rule out the FDA because it does not have the funding and cannot tax the manufacturers to pay the costs.  Universities have lots of labs and student researchers, but not the money to conduct tests.

“What about forming a group of consumers that would watch the government agency, the independent testing labs, and the manufacturers?” asks Ms. Hart? The idea may be laudable but it is not realistic. America’s social and economic structure does not have a place for such an entity unless it is underwritten by a foundation. The closest model is the Insurance Institute for Highway Safety. It tests how well vehicles fare in crashes, but insurance companies — not consumers — pay for the publicly available research.

Is there a solution that gives consumers peace of mind that what they buy is what they get?

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Manufacturers beware. Your regulatory problems may not be over when you pull a product from the store shelves. Matrixx Initiatives Inc. recalled its Zicam products on June 16 and three days later the Securities & Exchange Commission sent a letter of inquiry. The company said that it did not know what the regulatory agency wanted, according to an article in the Wall Street Journal.

Mattrix is a public company, so it serves many masters, including the SEC and shareholders. The company’s stock lost 70 percent of its value the day the recall was announced. Shares closed at $4.83 on June 23, down another 95 cents from the June 16 close.

As might be expected, users of Zicam products have sued Mattrix. Among the latest is a Fort Lauderdale attorney who defends homeowners against foreclosures. Not a likely plaintiff based on his practice, his claim is based on the fact that he lost his sense of smell in 2007. He attributes that to the use of Zicam and now he wants compensation for damages.

The SEC focuses not on customer, but shareholder losses. A letter of inquiry can be a first step into an investigation that can lead to civil and criminal charges. Or it can lead to nothing; the SEC does not comment on its actions until they are final.

Matrixx stock had survived the downturn in the general market. It was trading near a 52-week high of $19.74 when the Food and Drug Administration issued a warning about certain Zicam products. In May, the company reported that 2009 revenues had hit a record level and annual earnings per share had jumped 40 percent from fiscal 2008 levels. In the earnings press release, acting company president Bill Hemelt said, “The 11% increase in fiscal 2009 net sales was driven primarily by increased sales within our core Zicam Cold Remedy and Allergy/Sinus products.”

Zacks Investment Research had rated the company a strong buy, saying in a release dated May 8 that “The Zacks #1 Rank (Strong Buy) company has now topped the consensus forecast in each of the last 4 quarters with an average upside surprise of 28.48%.”

When a stock on a big upswing suddenly goes into a tailspin, the SEC takes notice. Even if the reason for the decline is obvious, there are questions to be answered.

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Get ready for the not-so-kind-and-gentle FDA when it comes to food safety. The agency took abuse from politicians and consumer advocates over its handling of peanut and pistachio contamination earlier this year. Possibly to avoid a third hit, the agency moved swiftly and without warning on May 7 when it sent U.S. marshals into a warehouse of Memphis-based American Mercantile to seize $1.5 million in food ingredients.

The FDA found evidence in March of extensive rodent and insect infestation throughout the company’s warehouse, the agency said in a news release. American Mercantile did not clean up the mess, the agency said, so it obtained a court order to send federal agents to the company’s warehouse. They hauled away food products including sarsaparilla, spearmint leaves, cornstarch, sweet orange peels powder, licorice powder, sassafras and salt.

“FDA will not tolerate a company’s failure to adequately control and prevent filth in its facility,” said Michael Chappell, the FDA’s acting associate commissioner for regulatory affairs, said in the release. “The FDA is prepared to use whatever legal means are necessary and appropriate to keep potentially contaminated products out of the marketplace.

Tough action matched the words. Functional Ingredients reports that the FDA did not issue a warning letter to American Mercantile before the raid.

The door-kicking has rattled some in the ingredients industry. “If there is anything to be learned from this, it’s that this is a very visible example of a system that needs improvement. Better communication is needed from FDA, third-party certifiers and the National Organic Program and vice-versa,” says Marty Mesh, executive director of Quality Certification Services told Functional Ingredients. QCS was due to re-inspect American Mercantile for organic certification, according to the article.

“The food and supplements industry can expect a lot more of this,” says Loren Israelsen, executive director of the supplements trade group United Natural Products Alliance, told the publication. “This is the new FDA, so wake up everybody.”

Now that the FDA has everyone’s attention, what are the best courses of action?

• Take health inspections seriously. Ignore an FDA or state agency evaluation and armed men may come through your door.
• Keep warehouses and manufacturing facilities squeaky clean. Check vendors and demand documentation, not assurances, that they are following certified good manufacturing practices.
• Communicate. Tell customers, regulators and certification agencies what steps you are taking to make sure that your food ingredients are uncontaminated. Post documents online that show your company and its vendors passed inspections.
• Trust, but verify, as the Russian saying goes. American Mercantile says on its Web site that its manufacturing plant is GMP/FDA and pharmaceutical compliant, but Functional Ingredient could find no evidence to support those claims.

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Looking to promote the safety of your product? Tout the fact that your children’s bath and shampoo products do not contain formaldehyde. In a recent test, the Campaign for Safe Cosmetics found 23 children’s bath products that that may cause cancer and skin allergies. Another product, 1,4-dioxane, was found in 32 of 48 products. The EPA considers 1,4-dioxane a probable human carcinogen. National media including USA Today and The Washington Post picked up on the report and giant consumer companies such as Johnson & Johnson had to turn up their PR machines to counter the negative press.

A number of environmental and health groups including the Breast Cancer Fund and the Environmental Working Group, are behind the Campaign for Safe Cosmetics. They hired Analytical Sciences to perform the tests. The California lab found formaldehyde and 1,4-dioxane in a wide variety of products. Among the brand names were Baby Magic, L’Oreal and  Aveeno.

A number of companies that operate in the organic sphere are already wise to the potential health threats. USA Today reported that Earth Friendly Products, Life Tree, Nature’s Gate, Planet Ultra and Seventh Generation have all reduced levels of 1,4-dioxane since the previous Campaign report. A representative for Whole Foods told the paper that it was reformulating its 365 Everyday Value products to be free of 1,4-dioxane by July.

The European Union has banned 1,4-dioxane as an ingredient in personal care products, the Post reported, and Congress may direct the FDA to take action. “The fact that we are bathing our kids in products contaminated with carcinogens shows how woefully out of date our cosmetics laws are and how urgently they need to be updated,” said Rep. Jan Schakowsky of Illinois told the Post. “The science has moved forward; now the FDA needs to catch up and be given the authority to protect the health of Americans.”

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Jessica Hardy

A swimmer who missed the Olympics says she doesn’t have a drug problem: A Texas supplement company does.  Jessica Hardy claims in a lawsuit that AdvoCare International Co. caused her to be disqualified from the U.S. team because the products Arginine Extreme and Nighttime Recovery were contaminated with clenbuterol, an anti-asthma medication similar to albuterol, that is banned. The legal battle could have far-reaching effects on company liability.

Advocare has taken the unusual step of suing Hardy for defamation, saying that her claims are infringing on the company’s ability to do business, especially with swimmers. In an article in the Dallas Morning News, company attorney Allison Levy says that Advocare wants to clear its name.

The two sides have conducted laboratory tests with conflicting results. Informed-Choice says Advocare’s products are clean; Anti-Doping Research says that the products contain clenbuterol. The back and forth in court could take years. If there is a trial, the outcome could have a ripple effect on the supplement industry. A win by Advocare might help companies that face civil charges from other athletes who claim that poor manufacturing practices damaged their careers and incomes.

If Hardy prevails, supplement makers might face higher product-liability insurance costs. They may also have to shy away from lucrative athlete markets and could lose valuable endorsements. Even if the matter is privately settled, the legal entanglement again highlights the need for have a good manufacturing process. Advocare’s defense could depend mightily on demonstrating that it took appropriate care.

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What do sibutramine, rimonabant, phenytoin and phenolphthalein have in common? You can find them spread among the 69 brands of weight-loss pills identified by the FDA. The weight-loss segment of the industry will likely see even more scrutiny of its manufacturing practices now that the FDA has targeted products that it considers harmful or illegal. Among the name-brand products were StarCaps, which has all but shut down its Web site.

Of the four ingredients, the FDA says that sibutramine is a Schedule IV controlled substance, rimonabant is a pharmaceutical ingredient not approved in the United States, phenolphthalein has also been found to be genotoxic, and phenytoin poses a risk to consumers who are allergic or hypersensitive to the pharmaceutical ingredient.

Just how seriously does the FDA take this matter? In a release, the agency says, “More and more products tainted with prescription drugs, including drugs for erectile dysfunction, diabetes, and obesity, are finding their way into the U.S. marketplace.  Many are labeled as dietary supplements or supplements.  FDA takes this escalating issue very seriously, and is committed to doing all that it can to identify and remove these dangerous products from the market.”

Distributors and sellers would be well advised to stay ahead of the FDA. The first step is to review your good manufacturing practices. The federal rule that went into effect in June 2007 describes in detail the required steps. An overview can be found at the FDA Web site. Amendments were published in September of last year.

As you might expect, manfacturers are required to check their products so that they are not mislabeled. In the case of the 69 supplements, there were undeclared products. Discovery of those ingredients in part prompted agency action.

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