New supplement regulations most important for industry since passage of DSHEANew supplement regulations most important for industry since passage of DSHEA

The dietary supplement industry experienced two once-in-a-decade events in 2007: the implementation of a serious adverse event reporting (SAER) law and the publication of the long-awaited final rule on good manufacturing practices (GMPs) for supplements. These are the most significant regulatory events to hit the dietary supplement industry since the passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994.

Supplement companies' compliance with the serious adverse event reporting requirements of the Nonprescription Drug and Dietary Supplement Consumer Protection Act recently surpassed the six-month mark. And on June 25, 2008, manufacturers, packers, labelers and holders of dietary supplements with 500 or more employees became the first in the industry to be subject to the final GMPs. An enormous amount of time has been invested by companies and trade groups in preparation for compliance with both of these rules, and a large part of that preparation has involved the deciphering of gray areas of the rules.

Now that the new GMPs have gone into effect for the largest companies in our industry, we will begin to see the impact of our preparation. The industry has also begun to see the U.S. Food and Drug Administration's (FDA) own commentary on these gray areas. It is of some concern that on more than one occasion the agency, in offering guidance on these rules, has created confusion with misstatements that later require correction.

GMPs: Ensuring Quality and Other Big Ideas

The June 25, 2007, Federal Register notice in which the final GPM rule was published consisted of 219 pages: 17 pages of the actual rule, now codified as 21 CFR 111, preceded by 202 pages of “preamble.” As is the standard practice in publishing federal regulations, it is in the preamble that the FDA explains its thinking behind the regulation, answers comments received since the publication of the proposed rule in 2003 and estimates the cost of compliance for the industry.

Within the text of the final rule, the phrase “ensure the quality” is repeated 17 times. This points to the overarching goal of the regulation: that manufacturers establish operations which are specifically designed to ensure the quality of the products they make. The rule defines the word “quality” to mean that a dietary supplement “consistently meets the established specifications for identity, purity, strength, and composition, and [for] limits on contaminants, and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration.” To meet this requirement, manufacturers must set clear specifications for the products they make and stay focused on ensuring that these specifications are met throughout all production and process stages — all the way to the finished products themselves.

If “ensuring quality” is the heart of the new GMP rule, then “written procedures” are its skeleton. In the 16 subparts of 21 CFR 111 and in the hundreds of pages of the preamble, the phrase “written procedures” is repeated countless times. Furthermore, the number of written procedures a U.S. company might need to create to comply with the new GMP law is in the many dozens to many hundreds, depending on the number of products a company produces.

Those companies that already use written procedures throughout their operations — including for personnel; plants, grounds and equipment; production and process controls; returned goods; and product complaints — will have less work to do in the next two years to comply with the new GMP. Those companies that conduct these many operations without written procedures will have much more work to do to get in line with the new requirments.

Another key element of the GMP is its requirement for supplement manufacturers to conduct “at least one appropriate test or examination to verify the identity” of each dietary ingredient that goes into its products. Some confusion has surfaced around this requirement because an alternative identity testing petition process was described in an interim final rule (IFR) published in the Federal Register by the FDA on the same day that the agency published the final rule on GMPs. As currently written, supplement manufacturers, but not ingredient suppliers, may submit petitions for exemptions from the GMP requirement, in which they must demonstrate “that there is no material diminution of assurance, compared to the assurance provided by 100% identity testing, of the identity of the dietary ingredient.”

In October 2007, the American Herbal Products Association (AHPA) requested that the FDA also allow ingredient suppliers to submit petitions to the FDA under the IFR, so their manufacturer customers could use an alternative to 100% identity testing for ingredients. AHPA's comments asked for some additional reasonable flexibility in the mechanisms that should be used to assure ingredient identity, but no response from the FDA has been received yet.

De-Bugging the Rule

A month after the publication of the GMP rule, the AHPA submitted another petition asking the FDA to reconsider aspects of the new law. Several of the issues addressed in the petition hinge on the fact that only finished product manufacturers — and not ingredient suppliers — are subject to the rule, a decision that some in the industry strongly disagree with. In explaining this exclusion, the FDA declared that supply companies could become subject to the rule based on the way their customers use their ingredients. For example, if any downstream company were to “simply package” the ingredient — and the FDA has stated publicly that it considers encapsulation to be a packaging operation — then the supplier would need to be in compliance with the GMP. In other words, the actions of a customer would have a retroactive effect on a supplier's regulatory obligations.

The AHPA is not aware of any GMP regulation for any type of food that includes a mechanism whereby an ingredient company can be required to conform to a specific finished food product GMP based on how its customers use the supplied ingredient. Therefore, the association has asked that the FDA clarify that an ingredient manufacturer or supplier cannot be made subject to the rule based on the way its customers use its ingredients.

Another obvious oversight of the new GMP rule is that, while it is a requirement that batch, lot or control numbers be assigned to products, these identifiers do not need to appear on finished products. As such, a product recall would result in the pulling of more products than would likely have been pulled had there been batch, lot or control numbers on the products. This, of course, would cost manufacturers far more money.

Clearly, there are important issues that need to be sorted out in the very near future. As previously mentioned, guidance thus far from the FDA has been lackluster. Companies that attended an FDA conference call in October 2007 entered with a good idea of their specific compliance date, and left with confusion and uncertainty in regard to this crucial issue. This is because FDA misinformed its audience on how to determine company size — the only factor involved in determining compliance date — and it was only weeks later that the FDA corrected its misstatement.

In summary, companies engaged in any dietary supplement operations — whether it is manufacturing, packing, labeling or holding — must be immediately attentive to the final GMP rule. There is a significant emphasis on written procedures, and manufacturers must make sure that they establish specifications that they know they can meet, and that they identify the tests or examinations that will be used to confirm ingredient identity. Although it can be argued that this new rule would not have been necessary if the FDA had actually enforced the prior GMP food rule — after all, it was never legal to fail to meet label claims — it should be assumed that the FDA has a sense of ownership in this newly established GMP, and that the agency will be more attentive to manufacturing operations in the dietary supplement trade, at least in the short term.

The Other Bookend: SAER

The passage of the SAER bill in December 2007 by the 109th U.S. Congress was the culmination of a cooperative effort by the industry and its Congressional allies and critics. While GMPs ensure the quality at the front end, SAERs give us a reporting mechanism at the back end. In this way, the GMPs and SAERs provide regulatory bookends for the industry and should at least dampen the cry that supplements represent an unregulated industry.

Since December 2007, marketers of dietary supplements and nonprescription drugs have been required to report to the FDA any serious adverse events they receive, and to maintain records of all adverse event reports. The law includes a definition of “serious” that is closely modeled after the prescription drug industry's SAER rule. A serious adverse event is defined as an event that results in death, a life-threatening experience, inpatient hospitalization, disability or incapacity, or birth defects, as well as situations where medical or surgical intervention is required to prevent these outcomes.

The definition also borrows from the drug model appropriate protections for industry. For example, the law specifically states that the submission of an SAER “shall not be construed as an admission that the dietary supplement involved caused or contributed to the adverse event.” And importantly, the law is preemptive against any state or local law, so the industry will not encounter a proliferation of duplicative or contradictory laws around the country.

The SAER law also requires that company contact information be disclosed on product labels to allow consumers to report adverse events. The SAER bill and accompanying report language were very clear on these requirements of the new law. For instance, the Senate's committee of jurisdiction included language in its report on the law which stated that it “does not require the label to make any statement other than providing the address or phone number.”

However, the FDA issued a draft guidance document on the purported “labeling requirements” of the SAER law and “recommended” that product labels identify the required contact information with a statement such as, “To report an adverse event….” AHPA has requested the agency withdraw this unnecessary guidance. Additionally, several trade associations initiated communications with the Small Business Association (SBA), which prompted SBA's Office of Advocacy to write a letter to the FDA suggesting the agency “better analyze the possible effects” of the draft guidance to industry.

But regardless of how this semantic argument is resolved, marketers of dietary supplements (generally the company whose name is on a product label) must be completely familiar with the SAER law. Responsibility starts with product labels, so that a domestic phone number or address at which adverse event reports can be received must be included on all product labels. And each responsible company must have programs in place to receive calls, sort reports into serious and non-serious events, submit SAERs to the FDA on the required MedWatch form, and maintain records in accordance with the law. Although this sounds somewhat tedious at the current stage of initiation, it is likely that in the near and long term the industry will be able to confirm that dietary supplement products are a remarkably safe class of consumer goods.

Michael McGuffin is a member of NBJ's editorial advisory board and president of the AHPA, the only national trade association devoted to herbal issues.