Mission and Preface USP 35NF 30
This section provides background information on the United States Pharmacopeial Convention (USP), as well as general information about the 35th revision of the United States Pharmacopeia (USP 35) and the 30th edition of the National Formulary (NF 30). Text in USP 35NF 30 is official May 1, 2012, unless otherwise noted.
USPNF is published in continuing pursuit of the mission of USP: To improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.
On January 1, 1820, 11 physicians met in the Senate Chamber of the U.S. Capitol building to establish a pharmacopeia for the United States. These practitioners sought to create a compendium of the best and most fully established medicines, give them useful names, and provide recipes for their preparation. Nearly a year later, on December 15, 1820, the first edition of The Pharmacopoeia of the United States was published. Over time, the nature of the United States Pharmacopeia (USP) changed from being a compendium of recipes to a compendium of documentary standards for identity and quality that typically involve reference materials used as comparison standards in specified tests and assays. The publishing schedule of the USP also changed over time. From 1820 to 1942, the USP was published at 10-year intervals; from 1942 to 2000, at five-year intervals; and beginning in 2002, annually.
In 1888, the American Pharmaceutical Association published the first National Formulary under the title The National Formulary of Unoficinal [sic] Preparations (NF). Both the USP and the NF were recognized in the Federal Food and Drugs Act of 1906 and again in the Federal Food, Drug, and Cosmetic Act of 1938 (FD&C Act). In 1975, USP acquired the National Formulary (NF), which now contains excipients standards that also call for reference materials. USP continues to develop USP and NF, through the work of the Council of Experts, into compendia that provide standards for articles based on advances in analytical and metrological science. As these and allied sciences evolve, so do USP and NF.
CONTENT OF THE USPNF
USPNF contains official substance and preparation (product) monographs. The terms official substance and official preparation are defined in the General Notices and Requirements (General Notices). With few exceptions, all articles for which monographs are provided in USPNF are legally marketed in the United States or are contained in legally marketed articles.
A USPNF monograph for an official substance or preparation may consist of various components, including the article's name; definition; packaging, storage, and other requirements; and a specification. The specification consists of a series of universal tests (description, identity/identification, impurities, assay) and specific tests, one or more analytical procedures for each test, and acceptance criteria. Ingredients are defined as either drug substances or excipients. An excipient is any component, other than the active substance(s), intentionally added to the formulation of a dosage form. Excipients are not necessarily inert. Drug substances and excipients may be synthetic, semi-synthetic, drawn from nature (natural source), or manufactured using recombinant technology. Drugs that consist of larger molecules and mixtures requiring a potency test are usually referred to as biologicals or biotechnological articles.
General chapters provide frequently cited procedures, sometimes with acceptance criteria, in order to compile into one location repetitive information that appears in many monographs. New and revised monographs and general chapters and obsolete matter deleted from this edition are indicated in the Admissions section.
USPNF Organization USPNF is printed as a three-volume set. Volume 1 includes front matter (Mission and Preface, People, Governance pages and websites, and Admissions/Annotations). It also includes USP General Notices, general chapters, Dietary Supplement general chapters, Reagents, Reference Tables, Dietary Supplement monographs, NF Admissions, Excipients, and NF monographs. Volume 2 includes USP monographs AI, and Volume 3 includes USP monographs JZ. To facilitate convenient use and reference, all three volumes include the full index, as well as the USP General Notices and the Guide to General Chapters. General chapters specific to dietary supplements are included in numerical order with the rest of the general chapters in USP. Excipient monographs usually are presented in NF but also may appear in USP with suitable cross-referencing when they are also drug substances. The Excipients section (Volume 1) presents a tabulation of excipients by functional category.
Revisions to USPNF USPNF is continuously revised. Revisions are presented annually as Standard Revisions in USPNF and in twice-yearly Supplements, and as Accelerated Revisions, on USP's website (Errata, Interim Revision Announcements (IRAs), and Revision Bulletins).
Standard Revisions USP's Standard Revision Process calls for publication of a proposed revision in the Pharmacopeial Forum (PF) for a 90-day notice and comment period and, after the revision is approved by the relevant USP Expert Committee, publication in the next USPNF or Supplement, as applicable.
Accelerated Revisions The Accelerated Revision Process is used to make revisions to USPNF official more quickly than through USP's Standard Revision Process. Accelerated Revisions, which include Errata, IRAs, and Revision Bulletins, are posted on USP's website and do not always require notice and comment and allow for a revision to become official prior to the next USPNF or Supplement. See the USP Guideline on Use of Accelerated Processes for Revisions to the USPNF, which is posted on USP's website.
Errata An Erratum/Errata is content erroneously published in a USP publication that does not accurately reflect the intended official or effective requirements as approved by the Council of Experts. These typically are changes that do not have a broad impact on the standards. Errata are not subject to public comment and become official when posted to the USP website. Errata are incorporated into the next available USPNF or Supplement.
Interim Revision Announcements (IRAs) An IRA appears in PF first as a Proposed Interim Revision Announcement with a 90-day comment period. If there are no significant comments, the IRA becomes official in the New Official Text section of USP's website, with the official date indicated. IRAs are incorporated into the next available USPNF or Supplement.
Revision Bulletins If circumstances require rapid publication of official text, a revision or postponement may be published through a Revision Bulletin. Revision Bulletins are posted on USP's website with the official date indicated. Revision Bulletins are incorporated into the next available USPNF or Supplement.
Pharmacopeial Forum (PF) The PF is USP's official publication for public notice and comment. Proposals for revision are presented in the In-Process Revision or the Proposed Interim Revision Announcement (see above) sections and represent draft revisions that are expected to advance to official status pending final review and approval by the relevant Expert Committee.
On January 3, 2011, PF transitioned to an online-only publication that is available free of charge. The print version is no longer available. The new online-only PF includes proposed changes and additions to the USPNF, including Stage 4 Harmonization, and Stimuli articles for which USP is seeking public comments. All proposals, including IRAs, will have a 90-day comment period. Other information that was contained in PF, including official text (final IRAs) is now published solely on USP's website or moved into other USP publications.
This change to make PF freely available will help facilitate open and public participation when revisions are proposed to the USPNF.
Supplements Supplements to USPNF follow a standard schedule each year: The First Supplement is published in February and becomes official August 1. The Second Supplement is published in June and becomes official December 1. Users of USP print products must retain Supplements and check the New Official Text section of USP's website in order to have up-to-date official text. The USPNF online version is updated with each Supplement or annual revision. Each time a new edition or Supplement is released during the subscription period, a new electronic version is issued. The Index in each Supplement is cumulative and includes citations to the annual revision and, for the Second Supplement, citations to the First Supplement. The contents of the two Supplements are integrated into the annual edition of the following year, along with new official revisions that have been adopted since the Second Supplement to the previous compendia.
USPNF Spanish Edition In 2006, USP began providing a Spanish edition of USPNF. Maintenance of this edition follows the same revision approaches as the English edition.
USP Reference Standards When approved for use as a comparison standard as a component of a USP monograph or other compendial procedure, use of USPNF Reference Standards promotes uniform quality of drugs and supports reliability and consistency by those performing compliance testing, and other users of USPNF, including manufacturers, buyers, and regulatory authorities. The USP Catalog, which lists the collection of USPNF Reference Standards, can be accessed on the USP's website at www.usp.org. The listing identifies new items, replacement lots, lots of a single item that are simultaneously official, lots deleted from official status, and a preview of items eventually to be adopted. Purchase order information is included, and the names of distributors who can facilitate international availability of these items are suggested. This program benefits from the widespread voluntary contribution of suitable materials and test data from pharmaceutical manufacturers. USP advances this material via careful characterization studies and collaborative testing, followed by review and approval of the compendial use of the reference material by Expert Committees of the Council of Experts.
Symbols Symbols identify the beginning and end of each revision, or non-harmonized text. The following table summarizes the types of symbols and the associated subscripts used in USP publications:
The following table shows symbols and official dates for IRAs and Supplements to the USP 35NF 30.
IRAs and Supplements to USP 35NF 30
Official Dates and Symbols
Commentary In accordance with USP's Rules and Procedures of the Council of Experts, USP publishes all proposed revisions to the USPNF for public review and comment in the PF, USP's bimonthly journal for public notice and comment. After comments are considered and incorporated as the Expert Committee deems appropriate, the proposal may advance to official status or be republished in PF for further notice and comment, in accordance with the Rules and Procedures. In cases when proposals advance to official status without republication in PF, a summary of comments received and the appropriate Expert Committee's responses are published in the Commentary section of the USP website at the time the revision is published.
The Commentary is not part of the official text and is not intended to be enforceable by regulatory authorities. Rather, it explains the basis of the Expert Committee's response to public comments. If there is a difference between the contents of the Commentary and the official text, the official text prevails. In case of a dispute or question of interpretation, the language of the official text, alone and independent of the Commentary, shall prevail.
Chemical Names and CAS Registry Numbers Chemical subtitles given in the monographs are index names used by the Chemical Abstracts Service (CAS) of the American Chemical Society. They are provided only in monographs in which the titles specify substances that are definable chemical entities. The first subtitle is the inverted form of the systematic chemical name developed by CAS for the purpose of the Collective Index (CI). The second subtitle, given in uninverted form, is a preferred IUPAC name (PIN) sanctioned and used by the International Union of Pure and Applied Chemistry (IUPAC). Preferred IUPAC names are also used by the World Health Organization (WHO). Occasionally a third subtitle is supplied for historical reasons or when the synonym uses an alternative, but equivalent, naming convention. Monographs with chemical subtitles also generally carry CAS registry numbers. These bracketed numbers function independently of nomenclature as invariant numerical designators of unique, unambiguous chemical substances in the CAS registry and thus are convenient and widely used.
Print and Electronic Presentations All USPNF publications are available in print form (with the exception of the Pharmacopeial Forum and Accelerated Revisions, discussed above, which are posted on USP's website until incorporation into the next USPNF or Supplement). In addition, USPNF and its two annual Supplements are available in USB flash drive and online versions. The USB flash drive version makes USPNF accessible to users on their computer hard drives. The online format allows individual registered users to access the online format through the Internet. Both electronic formats provide access to official USPNF content, along with extensive search options. The electronic formats are cumulatively updated to integrate the content of Supplements. A searchable electronic version of the USP Dictionary also is available.
USP GOVERNING, STANDARDS-SETTING, AND ADVISORY BODIES
USP's governing, standards-setting, and advisory bodies include the USP Convention, the Board of Trustees, the Council of Experts and its Expert Committees, Expert Panels (formerly known as Advisory Panels), and staff. Additional volunteer bodies include Stakeholder Forums, Project Teams, and Advisory Groups, which act in an advisory capacity to provide input to USP's governing, standards-setting, and management bodies.
USP Convention The composition of the USP Convention membership is designed to ensure a global representation from all sectors of health care, with an emphasis on practitioners, given USP's practitioner heritage (see the History section). Voting Delegates of Convention member organizations elect USP's President, Treasurer, other members of the Board of Trustees, and the Council of Experts. They also adopt resolutions to guide USP's strategic direction and amend USP's Bylaws. The 2010 meeting of the USP Convention occurred in April 2010 in Washington, DC. A listing of all current Voting Delegates of the USP Convention is included in the People section.
Board of Trustees USP's Board of Trustees is responsible for the management of the business affairs, finances, and property of USP. During its 5-year term, the Board defines USP's strategic direction through its key policy and operational decisions. A listing of the members of the 20102015 Board of Trustees is included in the People section.
Council of Experts The Council of Experts is the standards-setting body of USP. For the 20102015 cycle it is composed of 21 members, elected to 5-year terms by USP's Convention, each of whom chairs an Expert Committee. These Chairs in turn elect the members of their Expert Committees. The Expert Committees are responsible for the content of USP's official and authorized publications (see Figure 1). The Executive Committee of the Council of Experts includes all Expert Committee Chairs and provides overall direction, is an appeals body, and performs other functions that support the Council of Experts' operations.
Expert Panels to the Council of Experts The Chair of the Council of Experts may appoint Expert Panels to assist the Council of Experts by providing advisory recommendations to particular Expert Committees in response to a specific charge consistent with the Expert Committee's Work Plan. Expert Panels are continuously formed; their topics and membership appear in the People section.
Stakeholder Forums and Project Teams USP has formed several domestic and international Stakeholder Forums and Project Teams to exchange information on USP's standards-setting activities. Stakeholder Forums may form Project Teams to work on selected topics. The following lists the current USP Stakeholder Forums.
North American Stakeholder Forums (United States and Canada)
International Stakeholder Forums
USP also conducts Scientific and Standards Symposia (formerly Annual Scientific Meetings) in the United States, India, China, Latin America, Middle East/North Africa, and other regions of the world.
Staff USP maintains a staff of over 700 scientists, professionals, and administrative personnel at its Rockville, Maryland headquarters and throughout the world, including an account management office in Basel, Switzerland, and laboratory facilities in Hyderabad, India; Shanghai, China; and São Paulo, Brazil.
RULES AND PROCEDURES
Governing Documents USPNF standards are recognized widely because they are authoritative and science-based and are established by a transparent and credible process. See the Articles of Incorporation section in this book; the Bylaws and the Rules and Procedures of the Council of Experts are available on USP's website (www.usp.org). Collectively, these documents serve USP volunteers and staff as the governing principles for USP's standards-setting activities.
Conflicts of Interest USP's Conflict of Interest provisions require all members of the Council of Experts, its Expert Committees, Expert Panels, Board of Trustees, and key staff to disclose financial or other interests that may interfere with their duties as USP volunteers. Members of the Board of Trustees, Council of Experts, and its Expert Committees are not allowed to take part in the final discussion or vote on any matter in which they have a conflict of interest or the appearance of a conflict of interest. Members of Expert Panels may participate and vote, so long as any conflicts have been adequately and promptly disclosed and are communicated to the relevant Expert Committee along with any Expert Panel recommendations.
Confidentiality and Document Disclosure Members of the Council of Experts, Expert Committees, and Expert Panels sign confidentiality agreements, in keeping with USP's Confidentiality Policy and the confidentiality provisions of the Rules and Procedures of the Council of Experts. The USP Document Disclosure Policy, available on USP's website, contributes to the transparency of the standards-setting process by making information available to the public, yet provides protection to manufacturers and others who submit confidential information to USP.
Authority for Publication USPNF is published in accordance with Article II, Purposes, of the USP Bylaws, which states, The purposes for which the Convention is formed are as set forth in the Articles of Incorporation and include developing and disseminating public standards for medicines and other articles, and engaging in related public health programs.
USPNF REVISION PROCESS
Public Participation Although USP's Council of Experts is the ultimate decision-making body for USPNF standards, these standards are developed by an exceptional process of public involvement and substantial interaction between USP and its stakeholders, both domestically and internationally. Participation in the revision process results from the support of many individuals and groups and also from scientific, technical, and trade organizations.
Requests for Revision of the USPNF, whether new monographs or general chapters or those needing updating, contain information submitted voluntarily by manufacturers and other interested parties. At times USP staff and Expert Committees may develop information to support a Request for Revision. USP has prepared a document titled Guideline for Submitting Requests for Revision to USPNF (available at www.usp.org; search on Submission Guidelines). Via PF, USP solicits and encourages public comment on these revision proposals. Comments received are considered by the Expert Committees, who determine whether changes should be made to the proposed revisions based on such comments. Proposed standards are finalized when Expert Committees vote to make them official text in USPNF. Thus, the USP standards-setting process gives those who manufacture, regulate, and use therapeutic products the opportunity to comment on the development and revision of USPNF standards. Figure 2 shows the public review and comment process and its relationship to standards development.
Working with the Food and Drug Administration (FDA) As specified in U.S. law, USP works with the Secretary of the Department of Health and Human Services in many ways. The principal agency in the Department for this work is the Food and Drug Administration. The FDA Liaison Program allows FDA representatives to participate in Expert Committee and Expert Panel meetings, enabling interactions between FDA scientific staff and Expert Committees. Staff in the FDA Centers who are responsible for review of compendial activities provide specific links and opportunities for exchange of comments. Dr. Paul Seo in the Center for Drug Evaluation and Research provides a primary compendial point of contact between FDA and USP.
Recognition of USPNF USPNF is recognized by law and custom in many countries throughout the world. In the United States, the FD&C Act defines the term official compendium as the official USP, the official NF, the official Homeopathic Pharmacopeia of the United States, or any supplement to them. As noted below (and in General Notices section 2.30), USPNF standards play a role in the adulteration and misbranding provisions of the FD&C Act (which apply as well to biologics, a subset of drugs, under the Public Health Service Act). USP has no role in enforcement of these or other provisions that recognize USPNF standards, which is the responsibility of FDA and other government authorities in the United States and elsewhere.
Under the relevant FD&C Act provisions, a drug will be deemed misbranded unless its label bears to the exclusion of any other nonproprietary name the established name, which ordinarily is the compendial name (see discussion of Nomenclature, below). A drug with a name recognized in USPNF must comply with the identity/identification requirements of its monograph, or be deemed adulterated, misbranded, or both. Drugs also must comply with compendial standards for strength, quality, and purity (tests for assay and impurities), unless labeled to show all respects in which the drugs differ. FDA requires that names for articles that are not official must be clearly distinguished and differentiated from any name recognized in an official compendium. Drugs with a name recognized in USPNF also will be considered misbranded unless they meet compendial standards for packaging and labeling.
Drugs USP's goal is to have substance and preparation (product) monographs in USPNF for all FDA-approved drugs, including biologics, and their ingredients. USP also develops monographs for therapeutic products not approved by FDA, e.g., pre-1938 drugs, dietary supplements, and compounded preparations. Although submission of information needed to develop a monograph by the Council of Experts is voluntary, compliance with a USPNF monograph, if available, is mandatory.
Biologics In the United States, all biologics are considered a subset of drugs, whether they are approved by FDA under the FD&C Act (and receive a new drug application [NDA]) or under the Public Health Service Act (PHS Act, where they receive a biologics license application [BLA]). As a result, all PHS Act biologics are subject to the drug regulatory requirements of the FD&C Act, which means they are required to comply with the adulteration and misbranding provisions of the FD&C Act, including USPNF compendial requirements. This is equally so for biologics approved under the longstanding PHS Act 351(a) pathway, as well as the new 351(k) pathway for biosimilars added by the 2010 healthcare reform legislation.
Medical Devices Section 201(h) of the FD&C Act defines a device as an instrument, apparatus, similar article, or component thereof recognized in USPNF. Section 502(e) of the FD&C Act defines the established name of a device in the absence of an FDA designation of the official name as the official title in an official compendium. Despite these statutory provisions, there is no comparable recognition of USP's role in establishing compendial standards for medical devices as exists for drugs and biologics. Under authority granted by the Food and Drug Administration Modernization Act of 1997, the Center for Devices and Radiological Health recognizes national and international standards, including some USP tests and assays, for medical devices.
Dietary Supplements The Dietary Supplement Health and Education Act of 1994 amendments to the FD&C Act name USP and NF as official compendia for dietary supplements. The amendments also provide that a dietary supplement may be deemed misbranded if it is covered by a monograph in an official compendium, is represented as conforming to this monograph, but fails to so conform. The dietary supplement must be represented as conforming to a USPNF dietary supplement monograph for the compendial standards to apply. This contrasts with pharmaceutical products, wherein conformance to the monograph is mandatory, whether or not the product claims to conform.
Compounded Preparations Compounding means the preparation, mixing, assembling, altering, packaging, and labeling of a drug or device or other article, as the result of a practitioner's order or in anticipation of such an order based on routine, regularly observed prescribing patterns. USP provides both general chapters and monographs for compounded preparations. Compounded preparation monographs include formulas (ingredients and quantities), specific directions to correctly compound the particular preparation, packaging and storage information, labeling information, pH, beyond-use dates based on stability studies, and detailed assays (majority of monographs). Standards in USPNF for compounded preparations may be enforced by both the states (as pharmacy practice/compounding is traditionally regulated by state boards of pharmacy), and FDA (as compounded preparations subject to FDA regulation as drugs remain subject to the adulteration and misbranding provisions of the FD&C Act, which require conformance to USPNF standards).
Nomenclature In the United States, FDA generally defers to USP to create established (nonproprietary) names for drug products, including proper names for biologics. USP, as a member of the United States Adopted Names (USAN) Council, works to determine names for drug and biological substances. USP's authority to develop official nonproprietary names is identified in section 502(e) of the FD&C Act. FDA's policy on established names is set forth in 21 CFR 299.4. FDA-approved nonproprietary names are considered by FDA and the courts to be interim names that exist only unless and until USP designates a name. In contrast to USP's role in designating nonproprietary names, the designation of proprietary names is solely the responsibility of FDA, working with applicants.
The USP Nomenclature Expert Committee was formed in 1986 to create appropriate established names for dosage forms and combination drug products, and to develop naming policies. The Nomenclature Expert Committee coordinates its work with the USAN Council, and it establishes the Pronunciation Guide, which is utilized by USAN.
The USAN Council began in 1961 by providing ingredient names for drugs prior to their marketing. USP participates in this activity, together with the American Medical Association, the American Pharmacists Association, and FDA. The Council's output is incorporated, along with other names for drugs (including generic, proprietary, and chemical names and code designations), into the USP Dictionary of USAN and International Drug Names (the Dictionary). Since 1988, the current compendial name (which in most cases is consistent with the USAN name) has been recognized by federal regulation as the source of established names for drug substances in the United States.
Pharmacopeial Discussion Group USP harmonizes pharmacopeial excipient monographs and general chapters through the Pharmacopeial Discussion Group (PDG), which includes representatives from the European, Japanese, and United States pharmacopeias, and WHO (as an observer). According to the PDG definition, a pharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the document's harmonized procedure yields the same results, and the same accept/reject decision is reached. General information chapter 1196, Pharmacopeial Harmonization, provides (1) the PDG Policy Statement, (2) the PDG Working Procedures and a definition of each stage of harmonization, (3) a discussion, (4) a status report, and (5) a glossary. More information regarding PDG is available on USP's website.
OTHER USP PUBLICATIONS
Chromatographic Columns This comprehensive reference, previously titled Chromatographic Reagents, provides detailed information needed to conduct chromatographic procedures found in USPNF. Chromatographic Columns lists the brand names of the column reagents cited in every proposal for new or revised gas- or liquid-chromatographic analytical procedures that have been published in PF since 1980. Chromatographic Columns also helps to track which column reagents were used to validate analytical procedures that have become official. The branded column reagents list is updated bimonthly and maintained on USP's website.
USP Dictionary The USP Dictionary of USAN and International Drug Names provides in a single volume the most up-to-date United States Adopted Names of drugs; official USPNF names; nonproprietary, brand, and chemical names; graphic formulas; molecular formulas and weights; CAS registry numbers and code designations; drug manufacturers; and pharmacologic and therapeutic categories. The Dictionary helps to ensure the accuracy of the following: product labeling; reports, articles, and correspondence; FDA regulatory filings; and pharmaceutical package inserts. It is published annually and is recognized by FDA as the official source for established drug names. (See Nomenclature.)
USP Dietary Supplements Compendium The Dietary Supplements Compendium combines, in a single volume, USPNF standards for dietary supplements, standards and information from the Food Chemicals Codex, regulatory and industry documents, and other tools and resources. It is published every 2 years, as a hardcover print edition.
Food Chemicals Codex The Food Chemicals Codex (FCC) is a compendium of internationally recognized monograph standards and tests for the purity and quality of food ingredients, e.g., preservatives, flavorings, colorings, and nutrients. FCC is published every 2 years with supplements every 6 months, and is available in print and electronic formats.
USP Medicines Compendium The USP Medicines Compendium (MC) includes monographs, general chapters, and reference materials for suitable chemical and biological medicines and their ingredients approved by national regulatory authorities. The purpose of the MC is to help ensure that these medicines are of good quality by providing up-to-date, relevant public standards and reference materials. MC standards are available to manufacturers, purchasers, national regulatory authorities, and others to ensure conformity of a medicine to MC standards through testing. The MC does not include standards for foods or for traditional medicines/dietary supplements.