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When does an ingredient merit a public standard (monograph)?
Public standards, such as United States Pharmacopeial Convention monographs, help companies verify the integrity of food and dietary supplement ingredients, globally and industry-wide. While companies are not required to use monographs, there are many reasons why a company would want to.
While the United States, Europe, and other countries with strong regulatory agencies promote Good Manufacturing Practices (GMPs) for foods and dietary supplements, and take appropriate action against regulatory infractions that put public health at risk, there are still, however, numerous countries with less robust regulatory frameworks that operate primarily on the public’s trust in the safe production and distribution of foods and dietary supplements. For that reason, manufacturers and formulators of foods and dietary supplements around the world with a serious desire to protect their brands and build trust in the quality of their ingredients have adopted science-based quality standards (monographs) such as those in the Food Chemicals Codex (FCC) and the United States Pharmacopeia (USP). These standards serve as a safety net in a marketplace inundated with a continuous flow of new ingredients. USP dietary supplement monographs are also published in the Dietary Supplements Compendium (DSC), an industry-directed resource featuring relevant documentary standards, along with industry and regulatory guidance documents, supplemental information, and reference tools.
Engaging manufacturers and other stakeholders in the supply chain early on is the best way to create public standards. Intense and extensive participation ensures that standards benefit from broad input and are also likely to be widely accepted.
The process of developing quality standards with an organization such as USP may seem obscure and sometimes intimidating. In this article, we break down the process, from start to finish. In doing so, we hope to encourage stakeholder interest in “sponsoring” (helping to create) monographs for food ingredients and dietary supplements.
Stakeholder input throughout the development process is crucial to ensure that, when a monograph is ready for adoption, it is written in such a way that it does not inadvertently exclude applicability to other relevant, potentially high-quality ingredients-i.e., that it does not prevent other ingredients that should fall under the monograph’s scope from being able to comply with the monograph’s standards. After all, the end goal is to create fit-for-purpose standards that encourage quality for as many companies as possible, also thereby leveling the playing field in increasingly global supply chains.
Breaking Down Monograph Development
It may sound trivial at first, but one of the first hurdles an ingredient has to clear in order to be considered a potential candidate for a USP monograph is the answer to the question, “Is there proof that this food or dietary supplement ingredient meets regulatory requirements to be legally marketed?”
For food ingredients, there are several legal pathways that would green-light USP to start the monograph development process. Usually, USP scientists will accept a GRAS notification (Generally Recognized as Safe) for which the U.S. FDA has issued a “no questions” letter. A successful food-additive petition, or sometimes even a self-GRAS determination of a food ingredient with appropriate documentation from manufacturers, may also count.
For dietary ingredients, NDI (New Dietary Ingredient) notifications without FDA objection also meet the initial requirement for creating a monograph. NDI notifications apply to ingredients marketed in the United States after October 15, 1994, when the Dietary Supplement Health and Education Act (DSHEA) established conditions for dietary supplements to be marketed in the United States. USP also evaluates dietary supplement ingredients that were in the market before 1994, for the sole purpose of determining whether an ingredient should be admitted and published as a monograph in a USP compendium. This activity is performed by a USP Expert Committee, which conducts a literature-based review of clinical studies, adverse events, and regulatory status,
USP works with 22 Expert Committees, which comprise the very core of USP’s standards-setting activities. Expert Committees are groups of volunteer experts from academia, industry, and regulatory bodies selected every five years to guide USP’s work. This is one of the early levels of engagement available to interested parties. USP is currently taking applications for the next cycle of Expert Committees, which starts in 2015. We encourage experts in foods and dietary supplements to learn more and apply for the next cycle.
Additional information that USP seeks from manufacturers when deciding if an ingredient warrants a monograph are:
A full list of acceptance criteria and submission information can be found at www.usp.org/dietary-supplements/development-process/dietary-supplements-donor-program (for dietary supplements) and www.usp.org/food-ingredients/development-process/food-ingredients-donor-program (for food ingredients).
Once a new ingredient is identified as a monograph contender, and one or more sponsors has committed to working on developing quality standards, the sponsors and USP scientists work hand-in-hand to ensure all necessary tests and procedures are in place to establish the identity, purity, and quality of that ingredient. Physical samples of the ingredient (reference standards) are also developed whenever possible to accompany the monograph. Reference standards provide companies that adopt a standard with an opportunity to test their own procured ingredients against a physical quality benchmark.
The opportunities for other stakeholders (regulators, academics, other manufacturers) do not stop with the ingredient selection or the sponsor commitment; they continue even after the monograph is drafted.
Once drafted, each and every monograph is proposed in a discussion forum for public comment. At this time, stakeholders also have the opportunity to suggest other complementary tests and materials for inclusion. The FCC Forum (for food ingredients) and the Pharmacopeial Forum (for dietary supplements) are free, online tools that allow stakeholders to interact with scientists developing monographs. Through the forums, stakeholders can submit supporting evidence to increase the confidence in a proposed monograph and also help to ensure that the monograph does not exclude other potentially authentic ingredients and products.
Public comment is open for a period of 90 days, after which all comments are compiled and considered. After review and consideration of the comments, Expert Committees dedicated to either food ingredients or dietary supplements vote on whether the proposed monograph is ready for adoption. If they decide significant changes must be made, it may initiate another opportunity for public comment.
Even after a monograph is published in the USP or FCC, stakeholders can send their comments and suggestions for changes, which may trigger a review process for that particular monograph. During a review, evidence is once again collected and, in case the monograph needs a revision, the process restarts with new opportunities for input from all interested parties.
Case Study: Krill Oil Monograph
While USP staff will always guide the sponsor through the submission process, developing a monograph may still be a complex process. Sometimes, validation data is insufficient; tests and materials are not available, or the process to develop a reference standard is complicated; or stakeholders and scientists take longer than expected to formulate the monograph. The following case study illustrates the development of FCC and USP monographs for krill oil, an ingredient used by the industry in foods as well as dietary supplements.
USP’s krill oil monograph for food (for the FCC) began development in 2009, after previous attempts failed to bring consensus on what to include and how to conduct quantification tests, especially for omega-3 fatty acids EPA and DHA, which are linked to purported heart health benefits, among others.
In recent years, krill oil has been increasingly used as a food ingredient and a dietary supplement because of its higher concentration of omega-3 phospholipids compared to most animal or plant sources. Increased usage not only raises krill oil’s profile; it opens a window for adulteration with phospholipids from other sources. Sponsors of the FCC krill oil monograph focused on establishing a unique profile of the phospholipids present in krill oil using nuclear magnetic resonance (NMR) analysis. They also worked on quantification of those phospholipids, since health effects associated with this ingredient depend largely on the type and amount of those phospholipids. Finally, sponsors also established limits for heavy metal contaminants: not more than 0.1 mg/kg for arsenic, lead, and mercury.
USP’s monograph for krill oil as a dietary supplement ingredient was proposed in July 2013 and was well received by major stakeholders, who actively participated in the development process. In addition to the ingredient monograph, dietary supplement product monographs for krill oil capsules and delayed-release capsules were also proposed. These three monographs are scheduled to become official in the USP-NF in December 2014.
Reason to Participate
While FDA does not require manufacturers to conform to FCC or USP standards for food ingredients (unless they are referenced in FDA regulations) or dietary supplements (unless they are labeled as USP), manufacturers that adopt these standards can offer their customers the confidence that their ingredients are authentic. Science-based evidence of an ingredient’s integrity is at the core of increasing consistency and trust in the food and dietary supplement supply chains.
While USP does not play a direct role in establishing the safety and efficacy of foods and dietary supplements, its rigorous quality standards can help. That alone should provide market value to manufacturers that want to stand out in a crowd of new ingredients and products. And this should make it worthwhile for industry members to participate in the monograph process.
Markus Lipp, PhD, is the senior director of food standards, and Nandakumara Sarma, PhD, the director of dietary supplements standards, for the U.S. Pharmacopeial Convention (USP), which is responsible for publishing the Food Chemicals Codex and the Dietary Supplements Compendium. Other USP staff that contributed to this article are Gabriel Giancaspro, PhD; Carla Mejia, PhD; Anton Bzhelyansky, PhD; Donna Kaye Wilson, PhD; and Claudia Costabile, M.A. Visit www.usp.org.
USP is seeking sponsors to help develop monographs for ingredients that are not part of the Food Chemicals Codex and the Dietary Supplements Compendium. Below is a current list of the ingredients USP has prioritized for monograph development. Contact USP at email@example.com for more information.
Food Chemicals Codex
Dietary Supplements Compendium