`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopet'al
`Convention, Ina, meeting at Washington, DC,
`March 8—10, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January I, 1995
`
` SINCEIL'IO
`
`SHIRE EX. 2018 'Pan 1
`KVK v. SHIRE
`IPR2018—00293
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`p. 1
`p.1
`
`.rtmmgraphs
`
`
`
`SHIRE EX. 2018 Part 1
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`NOTICE AND WARNING
`
`Concerning US. Parent or Trademark Rights
`
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any
`drug in respect to which patent or trademark rights may exist shall not be deemed, and is
`not intended as. a grant of, or authority to exercise, any right or privilege protected by such
`patent or trademark. All such rights and privileges are vested in the patent or trademark
`owner. and no other person may exercise the same without express permission. authority. or
`license secured from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and
`others wishing to use portioris of the text should request permission to do so from the
`Secretary of the USPC Board of Trustees.
`
`The United States Pharmacopeial Convention, Inc.
`o 1994
`1260] Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`
`ISBN 0-913595-76-4 (cloth)
`0-913595-81-0 (leather)
`
`”
`
`r
`‘
`
`,
`
`-
`
`Printed by Rand McNally. 1133 County-Street,- Taunton, MA 02780-3795
`
`p. 2
`
`

`

`_ "General.- Notices
`and Requirements
`' Applying to Standards, Tests,
`Assays, and Other Specifications
`of the United States Pharmacopeia
`
`Title ‘
`
`_
`
`. 2
`
`it
`
`"
`
`2
`
`'
`’1
`“
`‘
`Officgilleggd Ozfl'itnal
`r
`t:
`-' °
`Nutritional Supplements
`_
`.
`_
`Atonnc Weights and Gnomes]
`Formulas...2
`Abbrenattons .
`.
`. 3
`Abbreviated Statements in
`Monographs .
`.
`. 3
`_
`_
`Significant Figures and
`Tolerances ,
`,
`_ 3
`
`-
`
`.
`
`'
`
`.
`
`-
`
`- 5
`
`,
`
`.
`
`. 6
`
`. 8
`s
`
`.
`
`. 4
`
`8
`
`.
`
`' 9
`
`.
`
`'
`
`,
`
`.
`
`'
`
`. 9-
`
`.
`
`“I
`0
`otenc
`y. 5
`Ingredients and Pr
`Wm
`tr 5
`Alcohol 5
`Alcohol
`Dehydrated Alcohol. 5
`Denatured AlcohoL '5
`
`.5 .5
`
`“him?“
`'
`.
`_
`. 10
`.
`Prescribing and Drspensmg .
`.
`.
`Preservahou, Packaging, Storage,
`and Labelin
`10
`3 ‘
`'
`'
`Containers . .. 10
`. 10
`Tamper-resistant Packaging . .
`Light-resistant Container . .. 10
`
`Well-closed Container .. . 10
`Eight (Epmcfllflfl'; .. 10 11
`MG 16
`on “In!!! -
`-
`-
`_
`Singieunit Centainer .. . 11
`Single-dose Container
`11
`Univ-dose Container. .
`. ll
`Multiple-uthontsiner... Il‘
`guittplciéosc Cotiem -1-1- 11
`Enigma?” I
`Cool :J: 11;
`. ll
`Room Tern ersture . .
`Controlled
`corn Temperature .
`Warm...ll
`Excessive Heat . .. ll
`Protection from Freezing .
`St
`under Nompecifie
`dons
`_
`_
`1
`hW---
`-
`-'
`mogglffIngtiedtent per Dosage
`L beling
`5 ts
`[$653)]: awmg..12
`Pmduets.
`12
`-
`-
`labeling Parenteral and Topics!
`Preparations. .
`. 12
`Labeling Electrolytesii12"
`Labeling Alcohol.
`SpecialSCH. stiles. and Tablets.
`- Expiration
`.12
`Vegas??? and
`Proseryatbn..i13
`“M95:-
`Foreign Matter . .. 13
`
`.
`
`'
`'.
`-
`Weights and Measures .
`.
`.
`_
`.
`Concentrations . .. 13
`. . 14 '
`Percentage Meamrements .
`Percent weight in weight . .. l4
`Percent weight in volume . .
`. l4
`Percent volume in volume . .. l4
`'
`
`Guide to GENERAL NOTICES AND REQUIREMENTS
`
`Added Sfism. .6
`NggtiontilISnpcéernents .6
`A tiona
`r
`ients
`6
`{Mt Headggfcc Gases 5
`c0195 5
`Ointments and Suppositories .
`'
`.
`Tests and Assays .
`. 6
`gmgmngfi
`- _
`'
`“(£9er
`5
`FWB“ Substances and [mourning -
`“MIKE ; 7 ,
`BlankDetenmnatton...8
`1)!“th ' ‘
`' 8
`.
`D'J‘Elwn -
`- - 3
`Drying to Constant Weight .
`_
`Filtration . r. 8
`Equtvalcnce Statements in Titrimetric
`m immerse-est
`n cs_. ..
`gnitinn to
`onstant
`eig t ...
`"ucrpretauon of Requirements . .
`. 3
`Indicators .
`.
`. 8
`logarithms ‘
`-
`. 3
`General Chapters .. . 4
`Microbial Strains
`.
`.
`NESIIE‘911313
`.
`Pharmacopelnl Fonnn .
`Odor.
`Pharmacopeia! Previews 4
`Pressure Measurements ‘ '
`Inprocess Revision 4
`501“?” m?
`Stimuli to the Revision Process.
`5 ”fl“ Gram? - .. 9
`Nomenclature .4
`emperatttres -- - 9
`Interim Revision Announcement} .4
`Tm“ mt " ' 9
`Official Reference Standards.
`$211.1"! ' 9 9
`a r. .
`.'
`Reagent Standards
`Water and LOSS on During . .
`u-ts {P
`Standarils...4
`g?!“ptinn 1'05;
`USP
`TeflRaflmStatisficsufl‘,
`RBference
`Sundards.
`.9
`.
`
`-
`
`.
`
`ll
`
`. ll
`
`12
`
`.
`
`Am‘
`18;
`
`. 13
`.
`
`p. 3
`p. 3 1
`
`

`

`2
`
`General Notices
`
`USP 23
`
`
`
`The General Notices and Requirements (herein-
`after referred to as the General Notices) provide in
`summary form the basic guidelines for the interpre—
`tation and application of the standards, tests, assays,
`and other specifications of the United States Pizar-
`macopeia and obviate the need to repeat throughout
`the book those requirements that are pertinent in nu—
`merous instances.
`-
`_, Where exceptions to the General Notices are made,
`'the wording in the individual monograph or general
`test chapter takes precedence and specifically indi-
`cates the directions or the intent. To emphasize that '
`, such exce tions do exist, the General Notices employ
`where in 'cated a qualifying expression such as “un-
`less otherwise specified.” Thus, it is understood that
`the specific wording of standards, tests, assays, and
`other specifications is binding wherever deviations
`from the General Notices exist. By the same token,
`where no language is given specifically to the con-
`trary, the General Notices apply.
`
`'
`
`TITLE
`
`The full title of this book, including its supple-
`ments, is The PharmacOpeia of the United States of
`America, Twenty—third Revision. This title may be
`abbreviated to United States Pharmacopeia, Twenty-
`third Revision, or to USP 23. The United States
`Pharmacopeia, Twenty-third Revision, supersedes all
`earlier revisions. Where the term" USP is used, with-
`out further qualification, during the period in which
`this Pharmacopeia is official, it refers only to USP
`23 and any supplement(s) thereto.
`
`“OFFICIAL” AND "OFFICIAL ARTICLES”
`
`The word “official," as used in this Pharmaco eia
`or with reference hereto, is synonymous with “P ar-
`macopeial,” with “USP,” and with “compendial.”
`The designation USP in conjunction with the of—
`ficial title on the label of an article means that the
`article purports to comply with USP standards; such
`specific designation on the label does not constitute
`a representation, endorsement, or incorporation by
`the manufacturer’s labeling of the informational ma-
`terial contained in the USP monograph, nor does it
`constitute assurance by USP that the article is known
`to comply with USP standards. The standards apply
`equally to articles bearing the official titles or names
`derived by transposition of the definitive words of
`official titles or tranSposition in the order of the names
`of two or more active in redients in official titles,
`whether or not the added esignation “USP" is used.
`Names considered to be synonyms of the official titles
`may not be used for official titles.
`Where an article differs from the standards of
`strength, quality, and purity, .as determined by the
`application of the assays and tests set forth for it in
`the Pharmacopeia, its difference shall be plainly stated
`on its label. Where an article fails to comply in iden-
`tity with the identity prescribed in the USP, or con-
`tains an added substance that interferes with the pre-
`
`,
`
`scribed assays and tests, such article shall be
`designatedby a name that is clearly distinguishing
`and differentiating from any name recognized in the
`PharmaCOpeia.
`Articles listed herein are official and the standards
`set forth in the mon0graphs apply to them only when
`thearticles are intended or labeled for use as drugs,
`as nutritional supplements, or as medical devices and
`when bought, sold, or dispensed for these purposes or
`when labeled as conforming to this Pharmacopeia.
`An article is deemed to be recognized in this Phar-
`macopeia when a monograph for the article is pub-
`lished in it, including its supplements, addenda, or
`other interim revisions, and an official date is gen-
`erally or specifically assigned to it.
`The following terminology is used for distinguish-
`ing the articles for which monographs are provided;
`an official substance is an active drug entity, a rec-
`ognized nutrient, or a pharmaceutic ingredient (see
`also NF it?) or a component of a finished device for
`which the monogra h title includes no indication of
`the nature of the mished form; an official
`repa-
`ration is a drug product, a nutritional supp ement,
`or a finished device.
`It is the finished or
`artially
`finished (e.g., as in the caseof a sterile so id to be
`constituted into a solution for administration) prep-
`aration or
`roduct of one or more official substances
`formulatedPfor use on or for the patient or consumer,
`an article is an item for which a monograph is pro-
`vided, whether an official substance or an official
`preparation.
`Nutritional Supplements—The designation of an
`official preparatiOn containing recognized nutrients
`as “USP" or the use of the designation “USP" in
`conjunction with the title of such nutritional supple
`meal preparation may be made only if the article
`contains two or more of the recognized nutrients and
`the preparation meets the applicable requirements
`contained in the individual Class Monograph and
`General Chapters. Any additional ingredient in such
`article that is not recognized in the pharmacopeia and
`for which nutritional value is claimed, shall not be
`represented nor imply that it is of USP quality 0]
`recognizedby USP. If a preparation does not comply
`with applicable requirements but contains nutrientt
`that are recognized in the USP, the article may not
`designate the individual nutrients as complying witl
`USP standards or being of USP quality without des-
`ignating on the label that the article itself does not
`comply with USP standards.
`
`ATONIIC WEIGHTS AND CHEMICAL FORMULAS
`
`The atomic weights used in computing molecular
`weights and the factors in the assays and elsewhere
`are those recommended in 1991 by the IUPAC Com-
`mission on Atomic Weights and Isoto ic Abun'
`dances. Chemical formulas, other than t ose in the
`Definitions, tests, and assays, are given for purpose
`of information and calculation. The format within 2
`given monograph is such that after the official title
`the primarily informational portions of the text ap-
`p. 4
`p.4
`
`

`

`
`
`USP 23
`
`pear first, followed by the text comprising require-
`ments, the latter section of the monograph being in-
`troduced by a boldfaCe double-arrow symbol a,
`[Graphic formulas and chemrcal nomenclature-pro-
`sided as information in the 1nd1v1dual monographs
`are discussed in the Preface.)
`
`ABBREVIATIONS _
`
`The term RS refers to a USP Reference Standard
`as stated under Reference Standards in these General
`Notices (see also USP Reference Standards (11)).
`The terms CS and TS refer to Colorimetric So-
`lution and Test Solution, respectively (see under Re-
`agents, Indicators, and Solutions). The term VS re-
`fers to Volumetric Solution as stated under Solutions
`in the General Notices.
`,.
`The term PF refers to Pharmacogieial Forum, the
`journal of standards deve10pment and official com-
`pendia revision (see Pharmawpeiai Forum in these
`General Notices).
`.
`Abbreviations for the names of many institutions,
`organizations, and publications are used for conven-
`ience thrOughout USP and NF. An alphabetized tab-
`ulation follows.
`
`'
`
`ACS
`ANSI
`AOAC
`
`
`Abbreviation
`Institution, Organization, or Publication
`AA M1
`Association for the Advancement of Medical
`Instrumentation
`American Chemical Society
`American National Standards Institute
`AOAC International (formerly Association
`of Official Analytical Chemists)
`American Society for Testing and Materials
`American Type Culture Collection
`-
`Chemical Abstracts Service
`US. Code of Federal Regulations
`U.S. Environmental Protection Agency
`Food Chemicals Codex
`US. Food and Drug Administration
`Health Industry Manufacturers Association
`_ International Standards Organization
`International Union of Pure and Applied
`Chemistry
`-
`National Bureau of Standards
`National'lnstitute of Standards and
`Technology (formerly NBS)
`United States Adopted Names
`USAN
`
`WHO World Health Organization
`
`ASTM
`ATCC
`CAS
`CFR
`EPA
`FCC
`FDA
`HIMA
`130
`IUPAC
`
`NBS
`NIST
`
`Abbreviated Statements in Monographsglncom-
`Plete sentences are employed in various portions of
`the monographs for directness and brevity. Where
`the limit tests are so abbreviated, it is to be under-
`stood that the chapter numbers (shown in angle
`braclcets) designate the resriective procedures to be
`followed, and that the values specified after the coIOn
`are the required limits.
`
`vwinu
`
`1
`
`SIGNIFICANT FIGURES AND TOLERANCES
`
`Where limits are expressed numerically herein, the
`upper and lower limits of a range include the two
`Values themselves and all intermediate values, but no
`
`General Notices
`
`3
`
`values outside the limits. The limits expressed in
`monograph definitions and tests, regardless of whether
`the values are expressed as percentages or as absolute
`numbers, are considered significant to the last digit
`shown.
`
`Equivalence Statements in Tt’trt'metric Proce-
`dures-”The directions for titrimetric procedures con-
`clude with a statement of the weight of the analyte
`that is equivalent to each mL of the standardized
`titrant. In such an equivalence statement, it is to be
`understood that the number of significant figures in
`the concentration of the titrant corresponds to the
`number of significant figures in the weight of the
`analyte. Blank corrections are to be made for all
`
`titrim)etric assays where appropriate (see Titrt'metry
`
`(541) .
`
`'
`
`Tolerancesw'l'he limits specified in the mono—
`graphs for Pharmacopeial articles are established with
`a view to the use of these articles as drugs, except
`where it is indicated otherwise. The use of the mo-
`lecular formula for the active ingredient(s) named in
`defining the required strength of a Pharmacopeial
`article is intended to design ate the chemical entity or
`entities, as given in the com lete chemical name of
`the article, having absolute dos percent) purity.
`A dosage form shall be formulated with the intent
`to provide 100 percent of the quantity of each ingre-
`dient declared on the label. Where the content of an
`ingredient is known to decrease with time, an amount
`in excess of that declared on the label may be intro-
`duced into the dosage form at the time of manufac-
`ture to assure compliance with “the content require—
`ments of the monograph throughout the expiration
`period. The tolerances and limits stated in the def-
`initions in the monographs for Pharmacopeial articles
`allow for such overages and for analytical error, for
`unavoidable variations in manufacturing and com-
`pounding, and for deterioration to an extent consid-
`ered acceptable under practical conditions.
`The specified tolerances are based upon such at-
`tributes of quality as might be expected to charac-
`terize an article produced from suitable raw materials
`under recognized principles of good manufacturing
`practice.
`'
`.
`The existence of compendial limits or tolerances
`does not constitute a basis for a claim that an official
`substance that more nearly approaches 100 percent
`purity “exceeds” the Pharmacopeial quality. Simi-
`larly, the fact that an article has been prepared to
`closer tolerances than those specified in the mono-
`graph does not constitute a basis for a claim that the
`article “exceeds” the Pharmacopeial requirements.
`Interpretation of Requirements—Analytical re-
`sults observed'in the laboratory (or calculated from
`experimental measurements) are compared with
`stated limits to determine whether there is confor-
`mance with compendial assay or test requirements.
`The observed or calculated values usually will contain
`more significant figures than there are in the stated
`limit, and an observed or calculated result is to be
`rounded off to the number of places that is in agree-
`ment with the limit expression by the following pro-
`p. 5
`p.5
`
`
`
`
`
`
`.54;“I-_"2-'.n';.-:__-Ig£=.,_..‘.;,t--,.._-._,..
`
`,,:-__:,,-._,_;.-:-....-..-."_.:__
`
`
`
`
`
`
`-.__._—--_.....--"-2-...”--—:',.-~'.—-.--:_ra_-.-_-_:'_-'_-:_
`
`

`

`4
`
`General Notices
`
`USP «23
`
`cedure... [NOTE—Limits, which are fixed numbers,
`are not rounded off-.]
`When rounding offis required, consider only one
`digit in the decimal place to the right of the last place
`ingthe limit expression. If this diggit is smaller than
`5, it is eliminated and the preceding digit
`is un-
`changed. . If this digit is greater than 5, it is eliminated
`and the preceding digit is increased by one. If this
`digit equals 5, the S is eliminated and the preceding
`digit is increased by one.
`
`NF and to afford opportunity for comment thereon.
`The organization of PF includes, but is not limited
`to, the following sections. Subsections occur where
`needed for Drugs and Pharmaceutic Ingredients and g
`for Nutritional Supplements.
`'
`Pharmacopeial Previews—Possible revisions that
`are Considered to be in a preliminary stage of devel-
`opment.
`In-process Revision—New or revised monographs
`' or chapters that are proposed for adoption as official
`USP or NF standards.
`
`Illustration of Rounding Numerical Values for Comparison
`with Requirements
`
`-
`
`Stimuli to the Revision ProcessuReports, state-
`ments, articles, or commentaries relating to compen-
`dial issues.
`
`Nomenclature—Articles and announcements rel-
`evant to compendial nomenclature1ssues and listings
`of proposed and new United States Adopted Names
`
`EUSAF) and International Nonproprietary Names
`
`INN
`
`Interim Revision Announcement (if present)—0f—
`ficial revisions and theireffective dates, announce-
`ment of the availability of new USP Reference Stan-
`dards and announcement of assays or tests that are
`held1n abeyance pending availability ofrequired USP
`Reference Standards
`
`Official Reference Standards—'Catalog of current
`lots of USP Reference Standards with ordering in-
`formation and names and addresses of worldwide sup-
`pliers.
`.
`_
`
`REAGENT STANDARDS
`
`The proper conduct of theIPharmacopeial tests and
`assays and the reliability of the results depend, in
`part, upon the quality of the reagents used in the
`performance of the procedures. Unless otherwise
`specified, reagents are to be used that conform to the
`specifications set forth in the current. edition of Re-
`agent Chemicals published by the American Chem-
`ical Society. Where such ACS reagent specifications
`are not available or where for various reasons the
`required purity differs, compendial specifications for
`reagents of acceptable quality are provided. (See Re-
`agents, Indicators, and Solutions.) Listing of these
`reagents, including the indicators and solutions em-
`ployed as reagents, in no way implies that they have
`therapeutic utility; furthermore, any reference to USP
`or NF in their labeling shall include also the term
`“reagent” or “reagent grade.”
`
`Compendisl
`Requirement
`
`-
`
`' Unrounded
`Value
`
`Rounded
`Result
`
`Conforms
`
`Assay limit 298.0%
`
`_
`Assay limit 5.101.596
`
`Limit test 50.02%
`.
`
`-
`Limit test 53 ppm
`
`97.96%
`97.92%
`97.95%
`101.55%
`,101.46%
`101.45% '
`0.025%
`0.015%
`0.023%
`0.0003593
`0.0002596
`0.00028%
`
`.
`
`98.0%
`97.9%
`98.0%
`101.6%
`101.5%
`- 101.5%
`0.03%
`0.02%
`0.03%
`0.000496
`0.0003%
`0.000393
`
`'
`
`Yes
`No
`Yes
`No
`Yes
`Yes
`- No
`Yes
`No
`No
`Yes
`Yes
`
`GENERAL CHAPTERS
`
`Each general chapter is assigned a number that
`appears in brackets adjacent to the chapter name (e.g.,
`(601) Aerosols). General chapters that include gen-
`eral requirements for tests and assays are numbered
`from (I) to (999) chapters that are informational
`are numbered from (100.0) to (1999), and chapters
`pertaining to nutritional supplements are numbered
`above (2000).
`The use of the general chapter numbers is en-
`couraged for the identification and rapid access to
`general tests and information. Itis especially helpful
`where monograph section headings and chapter names
`are not the same (e.g., Ultraviolet absorption (19TU)
`in a monograph refers to method (197U) under gen-
`eral tests chapter (19'?) Spectrophotometrtc Identi-
`fication Tests; Specific rotation (7818) in a mono-
`graph refers to method {7818) under general tests
`chapter (781) Optical Rotation; and Calcium (191)
`in a monograph refers to the tests for Calcium under '
`general—tests chapter (191) Identification Tests;
`General).
`'
`
`PHARMACOPEIAL FORUNI
`
`. USP REFERENCE STANDARDS
`
`Pharmacopeial Forum (PF) is the USP journal of .
`standards development and official compendia revi—
`sion. Pharmacopeiai Forum is the working document
`of the USP Committee of Revision. It is intended to
`provide public portions of communications within the
`General Committee of Revision and public notice of
`proposed new and revised standards of the USP and
`
`USP Reference Standards are authentic specimens
`that have been approved by the USP Reference Stan-
`dards Committee as suitable for use as comparison
`standards1n USP or NF tests" and assays. (See USP
`Reference Standards (1 1).) Currently official lots of
`USP Reference Standards are published in Phar-
`macopeial Forum.
`
`p. 6
`p.6
`
`
`
`

`

`
`
`
`Generai Notices
`5
`
`USIP 23 d”.
`
`Where a USP Reference Standard is referred to
`in a monograph or chapter,
`the words “Reference
`Standard" are abbreviated to “RS” (see USP Ref-
`erence Standards (11)).
`.
`Where a test or an assay calls for the use of a
`compendial article rather than for a USP Reference
`Standard as a material standard of reference, a sub-
`stance meeting all of the compendial monograph re-
`quirements for that article is to be used.
`The requirements for any new USP or NF stan—
`dards, tests, or assays for which a new USPReference
`Standard is specified are not in effect until the spec-
`ified USP Reference Standard is available. The
`availability of new USP Reference Standards and the
`official dates of the USP or NF standards, tests, or
`assays requiring their use are announced via Supple—
`ments or Interim Revision Announcements.
`
`UNITS OF POTENCY
`
`For substances that cannot be completely charac-
`terized by chemical and physical means, it may be
`necessary to express quantities of activity in biological
`units of potency, each defined by an authoritative,
`designated reference standard.
`defined by the World
`Units of biologiCal oten
`Health Organization WHO for International Bio-
`logical Standards and International Biological Ref-
`erence Preparations are termed International Units
`(Ill). Units defined by USP Reference Standards
`are USP Units, and the individual monographs refer
`to these. Unless otherwise indicated, USP Units are
`equivalent to the corresponding International Units,
`where such exist. Such equivalence is usually estab-
`lished on the basis solely of the compendial assay for
`the substance.
`For antibiotics (see Antibiotics—Microbial Assays
`(31)). USP Units are defined by the corresponding
`US‘P_Reference Standards in terms of the units of
`actmty established by the FDA. Each unit is'estab—
`Itshed through the corresponding antibiotic master
`Slandafd. which in many instances is the basis also
`for the definition of the WHO International Unit.
`For most antibiotics, however, biological units of po-
`tency are not nosessary, and their activity is expressed
`111 metric units (micrograms or milligrams) in terms
`9f the chemically defined substances described in the
`lflleldutll monographs.
`. F01" biological products, whether or not Intema~
`“Iona! Units or USP Units do exist (see Bioiogt'cs
`( 041)), units of potency are defined by the corre-
`Smndlng US Standard established by the FDA.
`
`INGREDIENTS AND PROCESSES
`”,3Theta] Preparations are prepared from ingredients
`meat ”“3 re(ltlll'ements of the compendial mono-
`$3132; for
`those ifldividual ingredients for which
`landfill“ are provided (see also NF I3).
`Ognized Srisubstances are prepared according to rec-
`rom i
`nciples of good manufacturing practice and
`"Bredlents complying with specifications de-
`
`signed to assure that the resultant substances meet
`the requirements of the com endial monographs (see
`also Foreign Substances on impurities under Tests
`and Assays).
`Preparations for which a complete composition is
`given in this Pharmacopeia, unless specifically ex-
`empted herein- or in the individual monograph, are to
`contain only the ingredients named in the formulas.
`However, there may be deviation from the specified
`processes or methods of compounding, though not
`from the ingredients or proportions thereof, provided
`the finished preparation conforms to the relevant
`standards laid down herein and to preparations pro-
`duced by following the specified process.
`Where a monograph on a preparation calls for an
`ingredient in an amount expressed on the dried basis,
`the ingredient need nothe dried prior to use if due
`allowance is made for the.Water or other volatile sub—
`stances present in the quantity taken.
`.
`Unless specifically exempted elsewhere in this
`Pharmacopeia, the identity, strength, quality, and pu-
`rity of an official article are determined .by the def-
`inition, physical preperties, tests, assays, and other
`specifications relating to the article, whether incor-
`porated in the monograph itself, in the General No-
`tices, or in the sectiou Genera! Chapters.
`Water—Water used as an ingredient of official
`preparations meets the requirements for Purified
`Water, for Waterfor Injection, or for one of the sterile
`forms of water covered by a monograph in this Phar-
`macopeia. .
`'
`_
`Potable water meeting the requirements for drink-
`ing water as set forth in the regulations of the federal
`Environmental Protection Agency may be used in the
`preparation of official substances.
`
`Alcohol—All statements of percentages of alcohol,
`such as under the heading Alcohol-content refer to
`percentage, by volume, of CZHSOH at 15. 56°. Where
`reference is made to “-CzHSOH,” the chemical entity
`possessing absolute (100 percent) strength is
`in-
`tended.
`'
`
`Alcohol—Where “alcohol" is called for in for-
`mulas, tests, and assays, the monograph article A!-
`coiroi is to be used.
`
`Dehydrated Alcohol—Where “dehydrated alco-
`hol” (absolute alcohol) is called for in tests and as-
`says, the monograph article Dehydrated Aicoho‘i is
`to be used.
`
`Denatured Alcohol—Specially denatured alcohol
`formulas are available for use in accordance with fed-
`eral statutes and regulations of the Internal Revenue
`Service. A suitable formula of specially denatured
`alcohol may be substituted for Alcohol in the man—
`ufacture of Pharmacopeial preparations intended for
`internal -or topical use, provided that the denaturant
`is volatile and does not remain in the finished product.
`A finished product that is intended for topical ap-
`plication to the skin may contain specially denatured
`alcohol, providedlthat the denaturant is either 3 nor-
`mal ingredient or a permissible added substance; in
`either case the denaturant must be identified on the
`label of the topical preparation. Where a process is
`p. 7
`p.7
`
`
`
`

`

`
`
`6
`
`General Notices
`
`USP 23
`
`given in the individual monograph, the preparation
`so made must be identical with that prepared by the
`given process.
`
`Added Substances—An official substance, as dis-
`tin
`ished from an official preparation, contains no
`adgeld substances except where specifically permitted
`in the individual monograph. Where such addition
`is permitted,
`the label
`indicates the name(s) and
`amount(s) of any added substance(s).
`Unless otherwise specified in the individual mono-
`graph, or elsewhere in the General Notices, suitable
`substances such as antimicrobial agents, bases, car-
`riers, coatings, colors, flavors, preservatives, stabiliz-
`ers, and vehicles may be added to an official prepa-
`ration to enhance its stability, usefulness, or elegance
`or to facilitate its preparation. Such substances are
`regarded as unsuitable and are prohibited unless (a)
`they are harmless in the amounts used, (b) they do
`not exceed the minimum quantity required to provide
`their intended effect, (0) their presence does not im-
`pair the bioavailability or the therapeutic efficacy or
`safety of the official preparation, and (d) they do not
`interfere with the assays and tests prescribed for de-
`termining compliance with the Pharmacopeial stan-
`dards.
`
`Nutritional Su plements—Unless otherwise spec»
`ified in the individiral monograph, or elsewhere in the
`General Notices, consistent with applicable regula—
`tory requirements, suitable added substances such as
`bases, carriers, coatings, colors, flavors, preservatives,
`and stabilizers may be added to a nutritional supple-
`merit preparation to enhance its stability, usefulness,
`or elegance, or to facilitate its preparation. Such
`added substances shall be regarded suitable and shall
`be permitted unless they interfere with the assays and
`tests prescribed for determining compliance with
`Pharmacopeial standards.
`Additional Ingredients—Additional ingredients,
`including excipients, may be added to nutritional sup-
`plement preparations containing recognized nu-
`trients, consistent with a plicablc regulatory require—
`ments, provided that (a they do not interfere with
`the assays and tests prescribed for determining com-
`pliance with Pharmacopeial standards, and (b) that
`such additional ingredients are listed separately on
`thelabel from these ingredients recognized in the
`definition of the USP article.
`
`Inert Headspace Gases—The air in a container of
`an article for parenteral use may be evacuated or be
`replaced by carbon dioxide, helium, or nitrogen, or
`by a mixture of these gases, which fact need not he
`declared in the labeling.
`Colors—Added substances employed solely to im-
`part color may be incorporated into official prepa—
`rations, except those intended for parenteral or oph—
`thalmic use, in accordance with the regulations
`pertaining to the use of colors issued by the FDA
`provided such added substances are otherwise appro—
`priate in all respects.
`(See also Added Substances
`under Injections (1).)
`Ointments and Suppositories—In the preparation
`of orntments and suppositories, the proportions of the
`
`substances constituting the base may be varied to
`maintain a suitable consistency under different cli-
`matic cenditions, provided the concentrations of ac-
`tive ingredients are not varied.
`
`TESTS AND ASSAYS
`
`Apparatus—A specification for a definite size or
`type of container or apparatus in a test or assay is
`fiiven solely as a recommendation. Where volumetric
`asks or other exact measuring, weighing, or sorting
`devices are specified, this or other equipment of at
`least equivalent accuracy shall be employed.
`(See
`also Thermometers (21), Volumetric Apparatus (31),
`and Weights and Balances (41)). Where low-actinic
`or light—resistant containers are specified, clear con-
`tainers that have been rendered opaque by application
`of a suitable coating or wrapping may be used.
`Where an instrument for physical measurement,
`such as a spectrophotometer, is specified in a test or
`assay by its distinctive name, another instrument of
`equivalent or greater sensitivity and accuracy may be
`used. In order to obtain solutions having concentra-
`tions that are adaptable to the Working range of the
`instrument being used, solutions of proportionately
`higher or lower concentrations may be prepared ac-
`cording to the solvents and proportions thereof that
`are specified for the procedure.
`Where a particular brand or source of a material,
`instrument, or piece of equipment, or the name and
`address of a manufacturer or distributor,
`is men—
`tioned (ordinarily in a- footnote), this identification is
`furnished solely for informational purposes as a mat-
`ter of convenience, without implication of approval,
`endorsement, or certification. Items capable of equal
`or better performance may be used if these charac-
`teristics have been validated.
`Where the use of a centrifuge is indicated, unless
`otherwise specified, the directions are predicated upon
`the use of ap aratus having an effective radius of
`about 20 cm 8 inches) and driven at a speed suffi-
`cient to clarify the supernatant layer within 15 min-
`utes.
`
`Unless otherwise Specified, for chromatographic
`tubes and columns the diameter specified refers to
`internal diameter (ID); for other types of tubes and
`tubing the diameter Specified refers to outside di-
`ameter (OD).
`Steam Bath—Where the use of a steam bath is
`directed, exposure to actively flowing steam Or to an-
`other form of regulated heat, corresponding in tem-
`perature to that of flowing steam, may be used.
`Water Bath—Where the use of a water bath is
`directed without qualification with respect to tem-
`perature, a bath of vigorously boiling Water is in-
`tended.
`
`Foreign Substances and Impurities—Tests for the
`presence of foreign substances and impurities are pro-
`vided to limit such substances to amounts that are
`unobjectionable under conditions in which the article
`is customarily employed (see also Impurities in Of-
`ficr'al Articles (1086)).
`
`p. 8
`p.8
`
`

`

`
`
`USP 23
`
`While one of the primary objectives .of t