The Influence of the USP on the Drug Approval Process
INTRODUCTION The objective of this chapter is to provide the reader with an overview of the United States Pharmacopeia/National Formulary (USP/NF) and its formal and legal role in the Food and Drug Administration’s (FDA) drug regulatory process in the United States (1). When considering the history of the USP and NF, once separate drug standards compendia originate from two different sectors of the health care delivery system, it is interesting to note in parallel the key milestones of U.S. Food and Drug Law History (2,3). The role of the USP (inception 1820) and NF (inception 1888) has always been to establish public standards for purity, quality, and strength for medicinal articles, and compounding information. The role of the FDA formally established in 1938, and all of its predecessor organizations, starting with the Bureau of Chemistry of the Department of Agriculture in 1862, has always been involved with the enforcement of purity and potency standards for drug materials, in addition to other stipulated regulatory responsibilities (2,3). The earliest recorded interface between the USP, as a private, nongovernmental drug standards-setting organization, and the federal government regarding enforcement of public standards for strength and purity of drugs occurred in 1848. Congress passed the Drug Importation Act in 1848 to prevent the importation of adulterated and spurious drugs and medicines into the United States. The U.S. Customs Service was empowered to test or have tested drugs and determine if they were inferior in strength and purity to the “standard established in the United States Pharmacopoeia, and therefore improper, unsafe, or dangerous to be used for medicinal purposes, the articles shall not pass the custom house” (4). Currently the USP/NF is recognized in Federal statutes as a drug standards setting body, which in turn mandates that all marketed medicinal articles in the United States, which are the subject of USP/NF monographs, must be fully compliant with all standards established in the monograph for the medicinal article. Noncompliance of the medicinal article with the USP/NF monograph standards makes the article adulterated. Marketing of adulterated articles is illegal and subjects the marketer to FDA compliance actions. While still the benchmark for quality and purity, the above comments regarding compliance of all compendial articles with monograph requirements, the FDA Office of New Drug Quality Assessment has recently issued guidance for new drug development submissions to FDA, MAPP 5310.7, “Acceptability of Standards from Alternative Compendia (BP/EP/JP).” The effective date for this document is November 3, 2007. The policy applies only to original NDA submissions. What the document offers NDA sponsors is the option of using standards from the alternative compendia provided that the rigor and acceptance criteria are equivalent to or better than USP/NF monograph requirements. This option applies to excipients, drug
substances, or drug products. Further, if there is no USP/NF monograph in place but there is a BP/EP/JP monograph for the article(s) employed in the drug product submission, the NDA sponsor is authorized to employ the alternative compendial procedure provided that it is equivalent to or better than the corresponding procedures stipulated in USP general chapters. Full details for the new MAPP 5310.7 can be found on the FDA Web site [www.fda.gov/cder/map/5310.7R.pdf]. In addition to the formal monographs in USP/NF, there are sections termed General Notices and Requirements and General Chapters which contain information applicable to all drug substances, inactive ingredients (excipients), drug products, and all other official articles (5).