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Efforts to solicit new monographs have fallen behind the rate of NDA approvals, while analytical techniques have become outdated because of advances in analytical technologies.
The United States Pharmacopeia's (USP) mission statement notes that USP "promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other health care technologies, and related practices used to maintain and improve health and promote optimal health care" (1). Since the publication of the first United States Pharmacopeia (USP) in 1820, one of USP's abiding strategies for advancing this mission has been the continuous revision and improvement of USP and, since 1975, USP–NF.
The growth of the compendia has been remarkable: the 1820 edition of USP contained 621 monographs, but USP 29 includes more than 4000 ingredient and drug, dietary supplement, and other product monographs for therapeutic articles legally marketed in the United States, and NF 24 now includes more than 355 excipient monographs.
USP cannot compel pharmaceutical manufacturers to submit a monograph, technically known as a request for revision to USP–NF. Because of confidentiality agreements between a new drug application (NDA) sponsor and the US Food and Drug Administration, the agency also cannot publicly release information about the private specification that it concludes with the sponsor during the approval of the sponsor's NDA (2). Many companies understand and support public standards for pharmaceutical articles (e.g., the availability of compendial standards for identity, strength, purity, and quality of articles in public commerce; public standards for labeling, shipping, and storage; and many more). USP has worked diligently to gain the cooperation of these pharmaceutical manufacturers who understand and support public quality standards (3). USP has posted a guideline on its Web site to help sponsors submit a request for revision for a new monograph or a revision of an existing one (4).
Nonetheless, these efforts to solicit new monographs have fallen behind the rate of NDA approvals. At the same time, analytical techniques such as thin-layer chromatography in many older monographs have become outdated because of advances in analytical technologies, including high-performance liquid chromatography and mass spectrometry. Before USP convened its most recent five-year convention in 2005, it was clear that USP–NF was missing monographs: approximately 2000 new monographs were needed, and approximately 800 existing monographs required updating.
As part of an organized plan to reduce the number of missing monographs in USP–NF, each Expert Committee was asked to review the monographs within its purview at the end of the 2000–2005 revision cycle and to develop a list of those that were in need of revision and new monographs that should be developed during the 2005–2010 cycle. In some cases, revision could include extensive rewrites or even subdivision into several distinct chapters (e.g., the possible division of Chromatography ‹621› into several smaller, possibly easier to use, chapters). USP soon will publish an article about the revision of General Chapters and other initiatives and has posted a table showing the status of existing and proposed General Chapters and revisions (www.usp.org/USPNF/submitMonograph/generalChapterWorkplans.html) (5).
In a parallel activity, USP staff consulted numerous databases and identified a list of high-priority monographs, defined as drug substances and products, as well as excipients that are or soon will be off patent. These have been organized into lists that are posted on USP's Web site at www.usp.org/USPNF/submitMonograph/newMon.html. The Web site indicates when a monograph proposal has been received. When the request for revision has been published in USP's bimonthly journal of standards development and pharmacopeial review, Pharmacopeial Forum (PF), the monograph name is removed from the list. The list of high-priority monographs also is published in PF.
Revised processes and new approaches
The July–August 2006 PF Policies and Announcements column included "Recent Modifications to the USP Standards-Setting Process," a notice that USP's Council of Experts approved changes to its Rules and Procedures to expedite the monograph approval process and to expand the scope of the monographs that USP publishes (6). These changes were effective Sept. 1, 2006.
New authority to evaluate comments. One provision in particular is designed to reinforce the ability of an Expert Committee to finalize and approve revisions to USP–NF without republication in PF. Previously, any change made to a proposed revision published in PF automatically triggered republication of the monograph in PF, frequently necessitating multiple publication cycles. In some cases, second-entry manufacturers complained that the system was being exploited to delay approval of their monograph and, thus, entry of their product into the US marketplace.
Under the new provision, an Expert Committee will be given authority to evaluate comments on their scientific merits, to modify the submitted monograph if supporting scientific and validation information so warrant, and to move the monograph to official status in the next Interim Revision Announcement, Supplement, or USP–NF. The Expert Committee would be required to summarize and respond to public comments about the revision, much like the comment and response section at the beginning of Federal Register notices. In other words, the current Briefings that introduce monograph revisions in PF would be greatly expanded and would be more informational.
An essential point is that the Expert Committee will be allowed to decide whether it has sufficient information to modify the draft monograph if necessary and make it official or to send it back to PF for another round of public review and comments. In either case, the Expert Committee, as always, will make its decisions based on sound scientific principles.
Communicating changes. Expert Committees also will use the USP Web site and other vehicles more extensively to communicate proposed revisions. In addition, the revised Rules and Procedures allow a new group, FDA Observers, to more fully participate in USP Expert Committee meetings. Once confidentiality issues have been resolved, FDA Observers can contribute their compendial and scientific knowledge to the monograph review process.
These changes will expedite monograph development and approvals, but USP again emphasizes that Expert Committees always have the option to republish monographs in PF for further public review when the circumstances warrant. USP believes that speeding up approvals should not impose a compliance burden on industry, and, thus, the implementation period between publication of new monographs and revisions and the date on which they become official generally is being expanded to six months. Each issue of PF contains a chart indicating the dates on which comments are due, the targeted official publication, the latter's date of publication, and the official date.
New ways to develop monographs. In addition to revising its processes, USP is expanding the approaches used to acquire and develop monographs. For example, USP is developing procedures to identify monographs that are published in other major pharmacopeias of the world but not in USP–NF. Some of these candidate monographs may be submitted to the Council of Experts for review and possible adoption as alternative-source monographs. USP's Monograph and Reference Standards Development Department will work with partners whenever possible to conduct inter- and intra-laboratory collaborative tests using sound metrological procedures to evaluate candidate reference standard materials as appropriate. USP's new office in India will collaborate and may help provide candidate reference standards for articles approved as generics in the United States.
USP also is undertaking the development of monographs for medicines pending approval at FDA (Standards for Articles Pending FDA Approval or SAPFA) so that such monographs can be made available and official upon FDA approval. Before FDA approval, a SAPFA monograph will be posted on USP's Web site, but once approval is granted (and FDA is allowed an opportunity to comment on the monograph), it will be moved to USP–NF and have official status.
Finally, the Council of Experts endorsed and USP's Board of Trustees has approved an initiative titled Standards for Articles Legally Marketed Outside the US (SALMOUS). Under this program, USP will develop monographs for medicines legally marketed outside the United States to treat neglected diseases such as malaria (7), provided that such medicine has been approved and is legally marketed in a country with a stringent regulatory authority. These monographs will be posted on USP's Web site (first in draft for public comment and then in final form), but they will not appear in USP–NF.
USP continues to make information available to a wide variety of constituents in user-friendly formats. For example, USP is undertaking a major redesign and simplification of the format of monographs (8), and USP–NF will soon be offered in three volumes to accommodate the increasing content. USP already has launched two new publications and is planning others:
For compounding pharmacists, the USP Pharmacists' Pharmacopeia contains both legally enforceable official text from USP–NF and authorized text of supporting information. A scientifically exact translation of USP 29–NF 24 into Spanish is available. The process of developing this book has provided USP with experience that facilitates other translations. For example, USP is working on a Russian-language translation of USP–NF and anticipates that other translations will follow.
This article has reviewed some of the new and unique approaches USP is taking toward the development of monographs and General Chapters as well as the launch of some new publications. USP has established a vigorous work plan for the 2005–2010 revision cycle and is making the necessary procedural changes to expedite the realization of these goals. USP welcomes the extraordinary contributions of its volunteer constituents as the organization strives throughout the remaining years of this cycle to fulfill its mission of improving public healthcare.
Todd L. Cecil, PhD, is the vice-president of the Department of Standards Development at the US Pharmacopeia. Roger L. Williams, MD, is a member of Pharmaceutical Technology's Editorial Advisory board and the executive vice-president and CEO of the US Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8255, firstname.lastname@example.org
1. United States Pharmacopeia 29–National Formulary 24 (US Pharmacopeial Convention, Rockville, MD, 2006), p. v.
2. T. Layloff et al., "The FDA Regulatory Methods Validation Program for New and Abbreviated New Drug Applications," Pharm. Technol. 24 (1), 30–42, 84 (2000).
3. L. Bhattacharyya et al., USP Council of Experts Executive Committee, "The Value of USP Public Standards for Therapeutic Products," Pharm. Res. 21 (10), 1725–1731 (2004).
4. USP, USP Guideline for Submitting Requests for Revision toUSP–NF. Available at: www.usp.org/pdf/EN/USPNF/revisionGuide.pdf, accessed Sept. 14, 2006.
5. USP Council of Experts, Expert Committee Members, and USP Staff, "The United States Pharmacopeia's Council of Experts 2005–2010: Work Plans, New Revision Approaches, and Other Enhancements," The AAPS J. Accepted for publication.
6. USP, "Recent Modifications to the USP Standards-Setting Process," Pharm. Forum. 32 (4), 1010 (2006), Available at: www.usp.org/USPNF/notices/uspStandardsSetting.html, accessed Sept. 14, 2006.
7. Council of Experts Executive Committee, Ad Hoc Council of Experts Committee, and USP Staff, "Development of a New Official Compendium, Separate from USP–NF, for Articles Not Legally Marketed in the US," Pharm Forum. 30 (5), 1877–1883 (2004).
8. T. Cecil. "Monograph Redesign Proposal," Pharm. Forum. 32 (6), in press (2006).