This preface provides general information about the 28threvision of theUnited States Pharmacopeia (USP28)and the 23rdedition of theNational Formulary (NF23).Additional official information about the specific uses of these texts is provided in theGeneral Notices and Requirements (page 1).

Publications

USP28–NF23— USP28–NF23text is official as of January 1,2005,unless otherwise noted.USP–NFcontains official substance and preparation (product)monographs.An official substance is defined as an active or inactive ingredient,a nutrient,a dietary supplement ingredient,and/or a pharmaceutical ingredient or a component of an official device.An official preparation refers to the finished dosage form,device,or dietary supplement product.BecauseUSP–NFcontains practitioner-based standards for all therapeutic products,as presented by decisions of the Council of Experts,USPmonographs are also useful to compounding practitioners.The standards of a monograph for a named official article include its definition;packaging,storage,and other requirements;and a specification.The specification consists of a series of universal (description,identification,impurities,assay)and specific tests,one or more analytical procedures for each test,and acceptance criteria.Ingredients are defined as either active ingredients or excipients.An excipient is any component,other than the active substance(s),intentionally added to the formulation of a dosage form.It is not necessarily inert.USP28–NF23contains approximately 4000monographs and over 160General Testsand Assays(á1000ñand below)and General Information Chapters(above á1000ñ).General Chaptersprovide frequently cited procedures,sometimes with acceptance criteria,to conserve text.Compared toUSP27–NF22,USP28–NF23contains 103new monographs,613revised monographs,9new General Chapters,and 25revised General Chapters.Obsolete matter deleted from this edition is indicated on page xxxiii in the Admissions section.

Organization of the Compendia— Monographs for active ingredients and preparations with the exception of dietary supplements appear in the first section of USP.Monographs for dietary supplements appear in a separate section of USPand no longer appear in NF.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 NFbut also may appear in USP,with suitable cross-referencing.Atabulation of excipients by functional category appears on page 2941.

Revisions— USP–NFis continuously revised.Revisions are presented annually,in twice-yearlySupplements,and inInterim Revision Announcements (IRAs).

Supplements— TheFirst Supplement toUSP28–NF23will be published in February 2005and will become official in April 2005.TheSecond Supplement will be published in June 2005and will become official in August 2005.Users of USPprint products must retain bothSupplements and keep their subscriptions current in order to have up-to-date information.The Index in eachSupplement is cumulative and includes citations to the annual revision and,for the Second Supplement,citations to the First Supplement.The contents of the twoSupplements are integrated into the annual edition of the following year,along with new official revisions since the Second Supplementto the previous compendia.

Interim Revision Announcements— IRAs contain revisions that become official in the interval between publication ofSupplements.They appear in USP's bimonthly journal,Pharmacopeial Forum (PF),with the official date noted in the publication.They are subsequently incorporated into the nextSupplement or annual revision.One reprint of eachIRAis available toUSP–NFsubscribers on request.Additional copies may be ordered from USP.

Pharmacopeial Forum— The following sections regularly appear in each issue ofPF,in the order listed:

Reference Standards Catalog— The catalog listing the collection of officialUSP–NFReference Standards is kept up-to-date through bimonthly publication inPF.It also can be accessed via the USPwebsite at www.usp.org and is available in print form by contacting USPsales and marketing staff at 301-816-8237.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.USPadvances this unofficial material to official status via careful characterization studies and collaborative testing,followed by review and,if appropriate,approval by the Reference Standards Committee of the Council of Experts.Use of these officialUSP–NFReference Standards promotes uniform quality of drugs as an aid to the public health.

Chromatographic Reagents— This comprehensive reference provides detailed information needed to conduct chromatographic procedures found inUSP–NF.Chromatographic Reagents 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 inPFsince 1980.Chromatographic Reagents 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 throughPF.

Chemical Names and CAS Registry Numbers— The 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 the CAS.This is presented in accordance with the rules established over the years by the International Union of Pure and Applied Chemistry (IUPAC)and the International Union of Biochemistry,and is employed in the current issues ofChemical Abstracts (CA).The second subtitle,given in uninverted form,is of a systematic type formerly used inCA.It is identical with,or closely resembles,the chemical name sanctioned and employed by the IUPACand by the World Health Organization (WHO).The IUPACnames make generous use of nonsystematic and semisystematic (often referred to as “trivial”)names and qualifying terms,all of which impede electronic manipulation.In contrast,the CASnames are fully systematic for most substances and are amenable to search and retrieval.The two subtitles referred to above are frequently identical,and a CASsynonym is occasionally supplied as a third subtitle.Monographs with chemical subtitles generally also carry CASregistry numbers.These italicized,bracketed numbers function independently of nomenclature as invariant numerical designators of unique,unambiguous chemical substances in the CASregistry and thus find wide,convenient use.

Nomenclature— In the U.S.,the FDAhas authority to establish names for drug ingredients and determine proper names for biologics.FDAexecutes this work in part through efforts of the United States Adopted Names (USAN)Council.USPparticipates in this activity together with the American Medical Association,the American Pharmaceutical Association,and the FDA.Drug product names can be established by FDAbut more often are developed cooperatively with USPin activities of the Council of Experts'Nomenclature and Labeling Committee.Oversight of brand names is the responsibility of FDA,working with applicants.The USAN Council's program began in 1961by providing ingredient names for drugs prior to their marketing.The Council's output is incorporated,along with other names for drugs (including generic,proprietary,and chemical names and code-designations),in theUSP Dictionary of USANand International Drug Names.Since 1988this publication has been recognized by federal regulation as being the source of established names for drugs in the United States (see above).The USP Drug Nomenclature Committee was formed in 1986to supplement the Executive Committees of the Drug Standards Division and the Information Division,and to prevent any inconsistency regarding nomenclature.Following the 2000meeting of the USP Convention,the responsibility for devising and,where necessary,revising labeling requirements has been delegated to this Committee,which is now termed the Expert Committee on Nomenclature and Labeling.The Committee's work does not overlap that of the USAN Council.Rather,it is complementary and is concerned with standardization of compendial names,particularly dosage form names,and names for combination drug products.

USP Dictionary— The USP Dictionary of USANand International Drug Names provides the most up-to-date United States Adopted Names of drugs;officialUSP–NFnames;nonproprietary,brand,and chemical names;graphic formulas;molecular formulas and weights;CASregistry numbers and code designations;drug manufacturers;and pharmacologic and therapeutic categories—all in a single volume.TheDictionary helps to ensure the accuracy of product labeling;reports,articles,and correspondence;FDAregulatory filings;and pharmaceutical package inserts.It is published annually (last edition April 2004)and is recognized by FDAas the official source for established drug names.

Print and Electronic Presentations— All USPpublications are available in print form.In addition,USP–NFand its two annualSupplements are available in compact disc (CD)and Internet versions.The CDversion makesUSP–NFaccessible to users on their computer hard drives.The Internet format allows individual registered users to access the online format through the World Wide Web.Both electronic formats provide fast and easy access to officialUSP–NFcontent,along with extensive search options.The electronic formats are cumulatively updated to integrate the content ofSupplements.Searchable electronic versions ofPFand of the Dictionary are also available.

Symbols Indicating Change to Official Text— Symbols identify the beginning and end of each revision.ForSupplements,a black square superscript marks the beginning of each revision,and a black square subscript marks the end.For the six yearlyInterim Revision Announcements,black circles are used.Next to the subscript is a number that links the official date of the revision with the correspondingSupplement orInterim Revision Announcement.For example,a black square subscript with the numeral 1next to it indicates that the revision will become official via theFirst Supplement.[NOTE—WhenInterim Revision Announcements are incorporated into the nextSupplement or annual edition,the black circles will be replaced with either the appropriateSupplement black square and number or annual edition triangle and number.]The following table shows symbols and official dates forInterim Revision Announcements andSupplements toUSP28–NF23:

Revision Process

The Council of Experts— The Council of Experts is the standards-setting body of USP.It is composed of 62Expert Committee chairs elected to five-year terms at USP's Convention in April 2000.A Nominating Committee,consisting of the Chair of the Council,Convention President,and the Vice-Chair of the Nominating Committee for the Council of Experts,proposes committee members who are subsequently elected by the members of the Council.The chairs and committee members consist of over 650volunteers drawn from all parts of the world.The Expert Committees are organized into four Divisions (Figure 1),each of which has its own Executive Committee.The Council's Executive Committee provides overall direction,is an appeals body,and performs other functions that support the Council's operations.Thirty-one of the 62Expert Committees are responsible for creation of the content ofUSP–NFand associated publications (see below).A Multidisciplinary Coordinating Group for dietary supplements allows better coordination between the Expert Committees responsible for dietary supplements.

Public Participation— While USP's Council of Experts is the ultimate decision-making body forUSP–NFstandards,these standards are developed by an exceptional process of public involvement and substantial interaction between USPand its stakeholders (Figure 2).Proposals for drug monographs contain information submitted voluntarily by manufacturers and other interested parties.In this cycle,USPhas prepared a document entitled Guideline for Submitting Requests for Revision to USP–NF(available online at www.usp.org),to which interested parties are referred.Via thePF,USPsolicits and encourages public comment on these monographs and other draft documents.The Council of Experts reviews these responses and approves draft proposals,which then become official inUSP–NF.Thus,the USPstandards-setting process gives those who manufacture,regulate,and use therapeutic products the opportunity to comment on the development and revision ofUSP–NFstandards.The chart displayed in Figure 2shows the public review and comment process and its relationship to standards development.

Participants in the Revision Process

Advisory Bodies to the Council of Experts— The Chair of the Council of Experts,Dr.Roger Williams,periodically appoints expert advisory panels and special committees to assist the Council of Experts in reaching scientific decisions and implementing new USPdirectives relating to the USP–NF.The following groups are currently assisting or recently have assisted the Council of Experts:the Expert Panel on the Equivalence of Complex Active Ingredients (Resolution 2from the 2000Convention);the Advisory Panel on Good Agricultural Practices under the Dietary Supplements:Botanicals Expert Committee;and five advisory panels under the Biopharmaceutics Expert Committee to begin development of performance tests based on the evolving taxonomy.In addition,Dr.Williams,as Executive Vice President and CEO,formed an Implementing Panel to oversee the publication of USP–NFin Spanish.USPacknowledges the contribution of the individuals participating in these panels and others who contribute to the USP–NFprocess.

Stakeholder Forums— In this five-year cycle,USPhas formed several Stakeholder Forums as a means of enlisting the active participation of stakeholders interested in a specific area of focus.Depending on the topic,a Stakeholder Forum may form Project Teams to work more intensively on selected topics in an advisory capacity.As part of its efforts to work internationally with users of USPproducts and services,USPhas also formed country-oriented quality communication groups.Following are lists of the current Stakeholder Forums,Project Teams,and quality communication groups.

Food and Drug Administration (FDA)— USPworks with FDAin many ways to promote good communications and optimal interactions.Senior management of both organizations can meet to provide oversight to these activities.FDA's ad hoc reviewer program that places FDArepresentatives in Expert Committees allows continuing interactions between FDAscientific staff and these Committees.FDAstaff may also participate on their own time as members of Expert Committees.Staff in the Centers responsible for review of compendial activities provide specific links and opportunities for exchange of comments.Larry A.Ouderkirk in the Center of Drug Evaluation and Research provides a primary link between FDAand USP.

Organizations— Revision ofUSP–NF,particularly in development of new monographs,General Chapters,and specifications for specialized products,continues to progress through the strong and proactive participation of manufacturers,compounding professionals,and many others.USPacknowledges the importance of this participation that occurs not only through the Stakeholder Forums but also through collaborative activities,work on Project Teams,and many other points of contact.

Staff— USPmaintains a staff of approximately 380scientists,professionals,and administrative staff at its Rockville offices (see Figure 3).Aprimary activity of many of these staff members is to assist the Council of Experts in producing USP's publications (see Figure 4).Afull listing of all USPemployees is provided,beginning on page xix after the names of Expert Committee members.Users of the USP–NFwho have questions about the organization,its publications,USP Reference Standards,or general questions are referred to listings inPF,which are updated bimonthly.

Legal Recognition

Drugs— USP's goal is to have substance and preparation (product)monographs for all FDA-approved drugs.USPalso develops monographs for therapeutic products not approved by FDA;e.g.,pre-1938drugs,dietary supplements,and compounded preparations.The complex set of procedures that result in validation of private regulatory procedures submitted in regulatory filings and the subsequent transition to a public official procedure inUSP–NF,coupled with availability of a verified reference standard material,has been described elsewhere (T.Layloff,et al.,The U.S.FDA Regulatory Methods Validation Program for New and Abbreviated New Drug Applications,Pharm.Tech.and Biopharm.,January 2000).While submission of information needed to develop a monograph by the Council of Experts is voluntary,compliance with aUSP–NFmonograph,if available,is not.

Biologics— In the United States some biologics are regulated under the provisions of the Public Health Service Act (PHSA).Biologic products regulated under the PHSAare required to bear “proper”names not “established”names,like drugs.Provisions of the FD&C Act apply to biological products regulated under the PHSA.For this reason,products approved under the PHSAshould comply with the adulteration and misbranding provisions of the FD&C Act at Section 501(b)and 502(g)and,thus,should conform to official monographs if available.

Medical Devices— Section 201(h)of the FD&C Act defines a device as an article/instrument,apparatus,or component recognized in theUSP–NF.Section 502(e)defines the established name of a device in the absence of an FDAdesignation of the official name as the official title in an official compendium.Despite these statutory provisions,there is no comparable recognition of USP's standard-setting authority and ability to define the medical device as exists for other FDA-regulated therapeutic products.Under the Food and Drug Administration Modernization Act,CDRHrecognizes national and international standards,including someUSPtests and assays for medical devices.

Dietary Supplements— As with drugs and biologics,the Dietary Supplement Health and Education Act amendments to the FD&C Act name theUSP,theNF,and theHomeopathic Pharmacopeia as official compendia for dietary supplements.For this reason,a dietary supplement may be deemed misbranded if it is covered by the specification in an official compendium,is represented as conforming to this specification,and fails to conform.Therefore,the dietary supplement must assert conformance to theUSP–NFmonograph in order for the compendial standards to apply.Compliance with aUSP–NFmonograph is thus voluntary on the part of a dietary supplement manufacturer.

Compounded Preparations— Preparation monographs may also provide information or standards applicable in compounding.Compounding means the preparation,mixing,assembling,packaging,or 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.Standards inUSP–NFfor compounded preparations may be enforced at both the Federal and State levels.

Governance

Convention— USP's direction and priorities are determined by more than 400credentialed Convention members divided into nine categories (page xxvi).Within each membership category,eligible organizations are invited to appoint their representatives.Membership composition is determined to ensure suitable representation of those sections of the health care system that are impacted by,and in turn impact,USP's activities.D.Craig Brater,M.D.,Dean of the Indiana University School of Medicine,is the USP Convention president for 2000–2005.Convention members elect USP's officers and trustees and the Council of Experts.They also vote on resolutions to guide USP's scientific policy and public health initiatives.

Board of Trustees— USP's Board of Trustees is entrusted with management of the business affairs,finances,and property of USP(Figure 5).During its five-year term,the Board defines USP's strategic direction through key policy and operational decisions.

International Activities

World Health Organization (WHO)— USPworks with the WHOin many of its normative and other activities that promote the availability of safe,effective,and good quality medicines.By invitation,USPstaff participate as members or observers of WHO's expert advisory committees,including the Expert Committee for Specifications for Pharmaceutical Preparations and the Biological Standards Expert Committee.

Pan American Health Organization (PAHO)— USPworks with PAHOin many of its activities.USPparticipates actively in PAHO's Pan American Network for Drug Regulatory Harmonization (PANDRH).In this activity,USPattends meetings of the PANDRH Steering Committee as a nongovernmental observer (NGO).USPis coordinator for the Pharmacopoeial Working Group (PWG)and a member of the Bioavailability/Bioequivalence Working Group in PANDRH.The PWGis composed of representatives from the Argentine,Brazilian,Mexican,and United States pharmacopeias.

Pharmacopeial Discussion Group (PDG)— USPharmonizes pharmacopeial excipient monographs and General Chaptersin the PDG,which includes representatives from the European and Japanese Pharmacopoeias,and WHO(observer).According to the PDGdefinition,a pharmacopoeial general chapter or other pharmacopoeial document is harmonized when a pharmaceutical substance or product tested by the procedure yields the same results,and the same accept/reject decision is reached.Harmonization for a particular monograph or General Chapter may be complete,but more likely is partial.As an example,excipient monographs may be harmonized by attribute,which means that some tests but not others may be harmonized.Similarly,some General Chapters may be partially harmonized.Harmonization is not achieved until all active participants present official text in their pharmacopeias.The status of harmonization is provided in General Chapter Pharmacopeial Harmonization á1196ñ.

United States Agency for International Development (USAID)— USPworks to support USAID's global health objectives by providing leadership in drug quality assurance to international efforts to improve the availability of safe,effective,and good-quality essential medicines.Through a cooperative agreement with USAID,USP's Global Assistance Initiatives program develops conferences and regional meetings on approaches to improving drug quality in collaboration with other organizations.At the country level,USPevaluates quality assurance systems and provides training to strengthen drug quality control labs and improve drug quality surveillance.USPalso provides technical assistance in good manufacturing practices to targeted manufacturers in collaboration with WHO.

Miscellaneous

Fellowships and Internships— USPoffers a number of year-long fellowships to doctoral candidates.Aselection committee composed of USP Council of Experts members or Expert Committee Members and USPscientists evaluates candidates.Six awards for standards-related studies were made for the period of July 1,2004through June 30,2005.The purpose of the USP Fellowships is to promote postgraduate research in areas related to compendial standards.Recognition is also given to sponsoring university faculty members elected to the USP Council of Experts or serving as a member of an Expert Committee or advisory panel.This year's fellows were selected from over 50applicants.