Inside USP: Monograph Makeover Requires Industry Input

The cover story of this issue of Pharmaceutical Technology is devoted to over-the-counter (OTC) medications—how they're regulated, and what safeguards are in place to help ensure their quality and safety. These complex issues have been in the news quite a bit lately. Consumer confidence has been shaken by multiple recalls of common products. The US Pharmacopeial Convention (USP) plays a specific role in ensuring the quality of OTC drugs by setting standards for drug formulators and manufacturers in the US Pharmacopeia–National Formulary (USP–NF). The adulteration and misbranding provisions of the 1938 Food, Drug, and Cosmetic Act establish USP–NF in US law and are enforceable by FDA.

USP cannot create and update standards—whether written monographs or physical reference materials—without a close partnership with industry as well as FDA. Currently, USP is working on an ambitious project that it started more than a year ago to update key monographs to incorporate modern analytical methods and technologies. FDA has provided valuable guidance to this project by identifying priority monographs, based on exposure to the population and relative risk of quality concerns (e.g., inadvertent contamination or economically motivated adulteration). The Consumer Healthcare Products Association (CHPA) is also collaborating on the project. Most of the priority monographs are used for nonprescription products, although some (e.g., acetaminophen with codine) are prescription as well. CHPA's participation in the effort highlights the unique collaboration taking place in industry to ensure the quality of OTC medications for the marketplace.

FDA Commissioner Margaret Hamburg exressed support for USP's standards modernization project during her remarks at the USP Convention meeting in April 2010. She cited the effort as one of the most pressing tasks facing USP and FDA given the disturbingly frequent incidents of poor-quality products in the OTC and prescription arenas.

The project thus far has involved identifying and prioritizing a master list of existing monograph procedures of interest as candidates for modernization. A list of the top 300 (200 are for drug substances, 100 are for excipients) monographs selected for modernization was posted on the USP website in February 2011. Of the initial list of monograph candidates, about 25% are OTC-related. It is important to note that the same product or ingredient can be OTC, for example, in low doses, and available as a prescription at high doses or in a different dosage form.

USP has begun to seek external (primarily from industry) and internal support (primarily from USP laboratories around the world) for the project. The convention is focusing on: replacing outdated technology and methodology with current procedures; adding critical tests to monographs (e.g., for impurities); and deleting tests that are no longer relevant, such as those for odor or melting point. A primary challenge is obtaining the best procedures and acceptance criteria from the manufacturing community. To address this challenge, USP has launched several outreach programs, including a public webinar.

USP has traditionally relied on donated procedures with supporting documentation from industry as the primary basis for its standards. The proposals are put through USP's rigorous, public, and transparent vetting process, involving many volunteer experts who evaluate the standards and seek input from industry, regulators, and other interested stakeholders. The resulting public standards (as compared with a manufacturer's private specifications, which are a component of the drug-approval process for new drug and biologics license applications) are beneficial to the donor and the public in following ways:

• Public standards level the playing field for buyers and sellers by helping to establish the identity and quality of medicines

• A public standard defines an "article of commerce" and is accessible to everyone

• USP monographs provide a legal standard of quality for the United States and international markets

• USP monographs help ensure product quality across manufacturers, contributing to public confidence in the medicine supply.

By donating a monograph modernization procedure, the donor has a direct impact on setting the resulting USP standard, which provides an appropriate standard to be enforced by regulatory authorities. To acknowledge the generosity of donors, USP recently enhanced and expanded its Donor Recognition Program. Elements include a Certificate of Appreciation; public recognition (for those donors who wish to be recognized) in formats such as the USP–NF or during scientific meetings; donor-specific progress reports; and complementary or discounted USP products and services.

To maintain consistency with FDA–approved specifications and control strategies, USP prefers to receive submissions from manufacturers of FDA–approved products (including drug substances and excipients used in FDA–approved products) or manufacturers seeking FDA approval. The latter category of submissions will be considered for publication as Pending standards. Submissions, especially new impurity procedures, from other sources (e.g., contract laboratories, academic institutions, analytical instrumentation or equipment manufacturers) will be accepted on a case–by–case basis and should follow the International Conference on Harmonization's Q3 guideline. Some modernization proposals may generate new USP Reference Standards, and USP invites the sponsor of the proposal to donate the necessary bulk reference materials.

Manufacturers may be concerned that updated monographs will lead to added costs for correspondingly upgraded equipment and processes. However, many manufacturers of the medications involved have already, of their own initiative, improved tests since the monograph was first published. These updates occur regularly as technologies and methods advance. In fact, USP is hoping to take advantage of these types of initiatives and growth so that they may be reflected in the compendia through updated tests and limits.

The partnership among USP, FDA, and CHPA represents a united front in the effort to safeguard public health. USP appreciates and strongly encourages widespread industry participation early in the monograph-modernization process.

For more information

• Details about the monograph modernization initiative, including FDA's priority list, can be found online at www.usp.org/hottopics/monographs.html.

• Details about the Donor Recognition Program are available online at www.usp.org/referenceStandards/participate.html.

• Details about submitting revision requests can be found in the USP Guideline for Submission of Request for Revision and in the USP Submission Checklist, available at www.usp.org/USPNF/participate.html and www.usp.org/USPNF/submitMonograph/subGuide.html, respectively.

• Details about submitting reference standards can be found in the USP Guideline for Suppliers of Reference Standard Materials at www.usp.org/referenceStandards/participate.html.

• To review and comment on the proposed revisions, including proposals for revisions not listed, see the latest edition of the Pharmacopeial Forum.

Karen Russo, PhD, is vice-president of small molecules, and Shawn Dressman, PhD, is vice-president of standards acquisition, both at the US Pharmacopeial Convention (USP), kar@usp.org, sfd@usp.org.