Quality of OTC Medicines, Ingredients Critical to Patients; Modern Scientific Standards Needed to Support Globalized Industry

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FDA, Industry and USP Identify Current Gaps and Needs, Map Paths Forward to Help Ensure Public Health, Support Innovation

Top officials from the U.S. Food and Drug Administration (FDA), the pharmaceutical industry and the U.S. Pharmacopeial Convention (USP) expressed the need for modern scientific standards to help ensure the quality of over-the-counter (OTC) monograph medicines and their ingredients at a workshop, September 8-9. Widely relied upon by consumers every day, these products are regulated differently than FDA-approved medicines. OTC medicines are available in a wide variety of dosage forms, colors and flavors, and are self-administered by patients without required oversight of healthcare providers. With rapid globalization occurring across the pharmaceutical industry—roughly 80 percent of the active pharmaceutical ingredients used in U.S. medicines are produced abroad—it is vital to undergird OTC monograph medicines with sound public testing and process standards (the USP monograph coupled with adherence to current Good Manufacturing Practices) that help ensure their identity, strength, quality and purity.

Opening the workshop, Dr. Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, noted that the public expects the same quality of OTC medicines as it does of prescription medicines. Having enjoyed a high-quality drug supply, Americans expect to encounter no problems with the medicines they take, and, collectively, “we have an obligation to keep it that way,” she said. Among the safety nets protecting OTC and all medicines are USP quality standards, which are developed under an open public process that includes industry participation and FDA input and guidance. USP, a nonprofit scientific body, develops standards published in two official compendia, the U.S. Pharmacopeia and National Formulary (USP–NF), that manufacturers marketing products in the United States are required to meet, and which are enforceable by FDA.

Monographs are written specifications for a medicine or its ingredients: USP monographs address identity, quality, purity and strength, while FDA monographs address safety and efficacy. Many OTC medicines are marketed without having been individually licensed and approved by FDA—for example, those marketed under FDA-specified categories such as “cough and cold,” which have only an FDA monograph. However, all OTC drugs, regardless of monograph type, are subject to applicable USP quality standards, and the USP standards are particularly important for those classes of FDA monograph OTCs that do not require an individual FDA license prior to marketing.

The FDA OTC monograph approach coupled with quality standards in USP–NF offer the opportunity for manufacturers to produce low cost, good quality medicines. Yet, given that some OTC monograph medicines have been on the market for decades, many standards in USP–NF are in need of modernization to assure that the tests, procedures and acceptance criteria in these monographs are optimal. This may be true of other medicines as well, not only those having USP public testing standards but also of the private testing standards submitted by manufacturers in drug-approval applications to FDA.

A subset of a larger modernization project addressing all USP pharmaceutical standards, FDA, USP and industry initiated a partnership over the past year to close quality gaps that could increase the vulnerability of OTC monograph medicines specifically. These gaps include missing or outdated tests for impurities (including degradation impurities that may occur over manufacturing or shelf-life) and non-specific testing for the identification of a pharmaceutical product or ingredient. Because USP standards are used by all manufacturers, such standards create a level playing field for the ultimate protection of the consumer. Last year, FDA provided USP with a list of OTC priorities, focusing first on acetaminophen (pain reliever and fever reducer) and diphenhydramine (antihistamine, sleep aid), as well as a number of inactive ingredients.

FDA’s OTC monographs are supported in most cases by USP quality standards. The USP monographs are further supported by general chapters produced by USP, which contain methods, procedures or other information that apply to many different individual products or ingredients. USP–NF contain more than 4,500 individual quality standards. These all require updating over time, but keeping pace with OTC monograph medicines is particularly challenging, given that manufacturers may introduce new dosage forms, colors and flavors to meet consumer preferences without submitting an application to FDA and/or providing information and materials to assure an up-to-date USP monograph. There are 37 individual quality monographs for acetaminophen in the USP–NF, for example. How to approach updates comprehensively was a major workshop theme.

Representing the nation’s manufacturers of OTC products, Mr. Scott Melville, president and CEO of the Consumer Healthcare Products Association (CHPA), pointed out that quality is critical given the prevalence of these medicines in the marketplace. Touching “millions of consumers each and every day,” six of the 10 most widely used medicines are OTC products. He noted that “safe and effective products stem from sound science,” and that this science does indeed evolve over time.

Addressing the unique needs of the OTC market, a key area of discussion among FDA, USP and manufacturers were options to forge a new path for updating standards for these products. Responding to the challenge posed by the sheer number of monograph dosage forms (in contrast to prescription medicines), attendees considered keeping pace through increased reliance on USP general chapters. A general chapter on impurities in acetaminophen products, for instance, would be more efficient than updating 37 individual monographs. However, attendees noted difficulties in this approach as well, particularly involving products with multiple active ingredients (e.g., cough and cold products) as well as interfering inactive ingredients.

The workshop also provided the opportunity for a progress report on modernization of the initial list of priority medicines from FDA. USP has advanced work on all the listed ingredients, and it unveiled its proposal for diphenhydramine for public review and comment over the summer. Among the USP monograph updates were the addition of a specific identification test and an organic impurities test. Next steps include revising the dosage form monographs. Critical work on the acetaminophen monograph has also advanced, with next steps including final determination of acceptable limits for known acetaminophen impurities, such as p-aminophenol, in solid and liquid forms. At a broader level, USP is initiating work on revising its standards for impurities across all OTC products, and is advancing work on an additional 10 priority ingredients identified by FDA in August.

Dr. Roger L. Williams, chief executive officer of USP, signaled the work at-hand “could be a new era for all of us as we work towards a modern cohort of standards to support end-product testing. We have an exciting opportunity to improve standards, support the critical regulatory work of FDA and help protect public health, while gaining flexibility to address the speed and innovation of the OTC industry. The use of modern analytical approaches, coupled with key general chapters, could rapidly advance solutions that otherwise might take years to accomplish.”

For more information, please email mediarelations(at)usp(dot)org.


USP – Advancing Public Health Since 1820
The United States Pharmacopeial Convention (USP) is a scientific, nonprofit, standards-setting organization that advances public health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods. USP’s standards are relied upon and used worldwide. For more information about USP visit http://www.usp.org.

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Francine Pierson
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