THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, D. C.,
`March 8—I0, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Officiai from January 1, I995
`
`SINCE I820
`
`UNITED STATES PI-IARMACOPEIAL CONVENTION, INC."
`12601 Twinbrook Parkway, Rockville, MD 20852
`'
`Amerigen Ex. 1057, p. 1
`Amerigen Ex. 1057, p. 1
`
`

`
`NOTICE AND WARNING
`
`Concerning U.S. 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 portions of the text should request permission to do so from the
`Secretary of the USPC Board of Trustees.
`
`The United States Pharmacopeiai Convention, Inc.
`© 1994
`12601 Twinbrook Parkway, Roclcvilic, MD 20852.
`All rights reserved
`ISSN 0195-7996
`
`ISBN 0-913595-76-4 (cloth)
`0-913595-81~0 (leather)
`
`Printed by Rand McNally, 1133 County-Street, '_I'aunt_0n,
`
`02'? 80-3795
`
`I,
`
`.
`
`Amerigen
`P- 2
`Amerigen Ex. 1057, p. 2
`
`
`
`
`
`I.
`
`I.
`
`I II
`
`

`
`
`
`
`
`L and Requirementsvvffi
`1 *—Applying "to Standards,
`it
`s
`I Assays, and Other Specifications C
`of the United States ‘Pharmacopeia 6»
`
`Guide to GENERALi1\lCi)TIpCES AND REQUIREMENTS
`
`Title... 2
`
`Z
`
`“Official” and “'0fl_'icial_
`Articles”
`. 2'
`'
`
`Nutritional Supplements .. . 2
`
`Atomic Weights and'Cl1emical
`Formulas . . . 2
`-
`
`. 3 .
`Abbreviations . .
`Abbreviated Statements in
`Monographs .
`.
`. 3
`
`Significant Figures and
`Tolerances .
`. ._3
`Equivalence Statementsrin Titrimetric
`Procedures . .
`. 3 _
`Tolerances .
`.
`. 3
`
`Wcfpretation of Reqtiirernents . .
`
`. 3 -
`
`General Chapters . .
`
`. 4
`
`I
`
`Pharmacopeia] F01-um _
`
`_
`
`_ 4
`
`.
`
`. 4
`
`Pharmacopcial_Previews .
`l"‘Drocess Revision .
`. . 4
`Stimuli to the Revision Process .
`Nomenclature . _
`_ 4
`lnlcrim Revision Announcement
`Official Reference Standards .
`.
`
`.
`
`. 4
`
`4
`
`''
`
`Reagent Standards .
`
`.
`
`. 4
`
`USP Reference Standards .
`
`. . 4
`
`'5 '
`Units of Potency
`ingredients and Processes .
`Water .
`.
`. 5
`I
`.-\l::ohol .
`_
`_ 5
`Alcohol
`5
`“'~'l1t'dra't‘e1 A1
`Dcnalureii Alcggglol.
`
`.55
`
`'
`
`'AdtlcrlSubstaJIees...6
`. . 6
`Nutritional Supplements ,
`Additional Ingredients . .. 6
`Inert Headspace Gases .
`. . 6 _
`..Colors
`. 6
`_ Oi_ntmen_ts and Suppositories . . .56
`
`'
`
`Testsand Assays . .
`
`. 6
`
`~
`
`. . 8
`
`.
`
`. 8
`
`,
`. 8 '
`
`Apparatus . .. 6
`Steam Bath
`. 6
`Water.Bat.h
`6
`Foreign Substances and Impurities...6
`. 7
`Procedures . .
`Blank I_)etermination .
`Desiocator . . . 8
`Dilution .--.
`. 8 '
`Drying to Constant Weight .
`Filtration . .
`. 8
`.'
`.
`Identification Tests .
`. 8
`Ignition to‘ Constant Weight . .
`Indicators '.
`. . 8
`8
`Logarithms
`M.icrobial.Strains . .
`Negligible . .. 8
`Odor .
`8'
`Pressure Measurements .
`Solutions...9-'
`Specific Gravity .
`.
`Temperatures .. . 9
`Time -limit . .
`. 9
`Vacuum .
`.
`. 9
`Water .
`. .' 9 -
`Water and Loss on Drying... 9-
`Tesl Results, Statistics an! '
`,
`Standards . .
`. 9
`.
`Description . .
`. 9
`' Solubility .
`.
`. 10
`
`. 8
`
`. 9
`
`.
`
`_
`. 9
`'-
`
`_
`
`‘
`
`.
`
`. 5
`
`Prescribing and Dispensing .
`
`.
`
`. 10
`
`Preservation, Packaging, Storage,
`-andLalJel_ing...'10 '
`
`.
`Containers . . . 10
`. . 10
`Tamper_-resistant Packaging .
`Light-resistant Container .
`. . 10
`
`'
`
`.
`
`-
`
`13
`
`Well-closed Container .. . 10
`. Tight Container 10
`l_1
`Hermetic Container .
`. 11
`Single-tmit Container . .
`. 11
`.
`Single~dose Container ‘.
`‘Unit4iose.Conta'iner . .. 11
`Multiple-unit Container_ . .. ll-= '
`.Multiple-dose Container. . ..1 1
`Storage Temper-atur
`.
`.
`. 11
`Freezer .
`.
`. 11
`'
`Cold... 11
`1
`11
`. 11
`.
`Room Temperature .
`Controlled Room Temperature .
`Warm .
`. 1]
`.
`. 11
`.
`Excessive Heat .
`Protection from Freezing . ;-. 11'
`Storage under Nonspecific
`' Conditions .
`. . 11
`Labeling .
`.
`. ll
`.'
`Amount of Ingredient per Dosage
`Unit .
`. . 11
`Labeling of Salts of Drugs .
`Labeling Vitamin-containing
`_Products ..
`.
`. 12
`. Labeling Parenteral and Topical
`Preparations‘... 12
`' Labeling Electrolytes... 12"
`' Labeling Alcohol . .
`. 12
`' Special Ca sules and Tablets .
`- .Expiration
`ate -. .. 12
`-
`‘Vegetable and Ale' al
`' Substances
`13
`_ Foreign Matter
`. 13
`.
`.
`Weights and Measures .
`I Concentrations . .. 1.3
`-
`Percentage Measurements .
`Percent weight in weight
`Peroentweight in yolume . .
`Percentvolurne in volume . .
`
`
`
`.
`
`. ll
`
`12
`
`.
`
`.- 12 '
`
`_
`. 13
`
`14 '
`. 14
`. 14
`. 14
`
`Amerigen Ex. 1057, p. 3
`Amerigen Ex. 1057, p. 3 1
`
`

`
`
`
`,
`
`The General Notices and Requirements (herein-
`' after referred to as the General Notices) provide in
`.. summary form the basic guidelines forlthe interpre-
`'
`tation and application of the standards, tests,_assays,
`__and other specifications of the United States Phar-
`macopeia, and obviate the need to" rep_eat-_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 exceptions do exist, the General Notices employ
`'-'---"where indicated 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.
`'
`
`'
`
`2
`
`General Notices
`
`USP 23
`
`'
`
`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 monographs apply to them only when
`_ thefclrticles are intended or labeled for use as drugs,
`as nutritional supplements, or as medical devices and
`t, sold, or dispensed for these purposes or
`when bough
`_ 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~ 5
`ognized nutrient, or a pharmaceutic ingredient (see
`also NF 18) or a component of a finished device for E
`which the monograph title includes no indication of
`i
`the nature of the finished form; an ofliciat
`repa- ;
`ration is a drug product, a nutritional supp ement,
`9
`or a fin_ished_ device. It is the finished or partially -
`finished (e.g., as in the case, of a sterile solid to be -
`constituted into a solution for administration) prep-
`Z
`aration or product of one or more official" substances
`formulated for use on or for the patient or consumer‘,
`an article is an item for which a monograph is pro 3
`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-
`ment 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 suct-
`article that is not recognized in the pharmacopeia and
`for which nutritional value is" claimed, shall not be
`represented not imply that it is of USP quality 01
`recognized, by USP. If a preparation does not compl)
`with applicable requirements butcontains nutrients
`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.
`.
`
`ATOMIC WEIGHTS AND CHEMICAL FORMULAS
`
`The atomic weights used in computing moleculai
`weights and the factors in the assays and elsewhere
`are those recommended in 1991 by the IUPAC Com-
`mission on Atomic Weights and Isotopic Abun-
`dances. Chemical formulas, other than those in the
`Definitions, tests, and assays, are given for purpose.‘
`of information and calculation. The format within 5
`given monograph is such that after the official title
`the primarily informational portions of the text ap-
`
`Amerigen Ex. 1057, p. 4
`Amerigen Ex. 1057, p. 4
`
`TITLE
`
`The full title of this book, including its supple-
`ments, is The Pharmacopeia of the United States of
`America, Twenty-tliird 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 supp1ement(s) thereto.
`
`“OFFICIAL” AND. “OFFICIAL ARTICLES”
`
`The word “official,” as used in this Pharmacopeia
`or with reference hereto, is synonymous with “Phar-
`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, endorsem_ent, 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 ingredients in official titles,
`whether or not the added designation “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-
`
`

`
`
`
`USP 23
`
`Bar first, followed by the text comprising require-
`llincnts, the latter section of the monograph being in-
`troduced by a boldface double-arrow symbol
`33.
`{Gr-a hie formulas and chemical nomenc1ature-pro-
`videdp 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
`Nance; (see also USP Reference Standards (11)).
`The terms .CS and TS refer t-o 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 Pharmacopeial Forum, the
`journal of standards development and official com-
`pendia revision (see Pharmacopeial Forum in these
`General Notices). .
`C
`_
`_
`_
`_
`Abbreviations for the names of many institutions,"
`organizations, and publications_ are used for conven-
`ience throughout USP and NF. An alphabetized tab-
`ulation follows.
`_
`_
`'
`
`Abbreviation '
`AA Ml
`
`'
`
`Institution, Organization, or Publication
`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
`U.S. Code of Federal Regulations
`' U.S.'.Environmental Protection Agency
`' Food Chemicals Codex
`- U.S. Food and Drug Administration
`Health Industry Manufacturers Association
`_ International Standards Organization
`International Union of Pure and Applied
`Chemistry
`'
`-
`. National Bureau of Standards
`National "Institute of Standards and
`Technology (formerly NBS)
`_
`USAN
`United States Adopted Names
`WHO
`World Health Organization
`Abbreviated Statements in Monographsm-Incom-
`Dlete 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
`brackets) designate the respective procedures to be
`followed, and that the values specified after the colon
`3“? the required _limits.
`
`ACS
`ANSI
`AOAC
`
`ASTM
`ATCC
`CA3
`CFR
`EPA
`FCC
`FDA
`HIMA
`I30
`IUPAC
`
`NBS
`NIST
`
`_
`
`3-pain\.u1’
`
`SIGNIFICANT FIGURES AND TOLERANCES
`U Where limits are expressed numerically herein, the
`vPPcr and lower limits of a range include the two
`“"65 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 Titrimetric 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 Titrimetry
`
`(541) .
`
`'
`
`Tolerances-—The 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 designate the chemical entity or
`entities, as given in the com lete chemical name of
`the article, having absolute (I00 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—AnaJytical re-
`sults observedin 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 ljmit expression by the following pro-
`Amerigen Ex. 1057, p. 5
`Amerigen Ex. 1057, p. 5
`
`

`
`
`
`4
`
`- General Notices
`
`cedure.._ -[NOTE—Limits, which are fixed-numbers,
`are not rounded offl]
`.
`-
`When rounding off is required, consider only one
`digit in the decimal place to the right of the last place
`in the limit expression.
`If this digit 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.
`
`Illustration of Rounding Numerical Values for Comparison
`'
`with Requirements
`-
`Rounded '
`
`Compendial
`Requirement '
`
`' Unrounded
`Value
`
`Result
`
`C()I1f0l‘1'l'1S-
`
`USP «23 '_
`
`NF and to afford opportunity for comment thereon.
`The organization of PF includes, but is not limited I
`to, the following sections. Subsections occur where
`needed for Drugs and Pharmaceutic Ingredients and
`for Nutritional Supplements.
`'
`.
`'
`Pharmacopeial Previews—Possib1e 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.
`Stimuli-to the Revision Process-——-Reports, state-
`ments, articles, or commentaries relating to compen-
`dial issues.
`'
`-
`-
`
`i
`
`I
`
`Nomenclature—Articles' and announcements rel-
`evant to compendial nomenclature issues and listings
`of proposed and new United States Adopted Names
`(USAN) and International Nonproprietary Names
`(INN).
`.
`s
`,
`r
`e
`Interim Revision‘ Announcement (if present)—Of-
`ficial revisions and the_ir_e_ffective dates, announce-
`ment of the availability of new USP Reference Stan-
`dards, and announcement of assays or tests that are
`held in abeyance pending availability of required USP_
`Reference Standards.
`'
`
`Ojficial Reference Standards——-Catalog o_f current
`lots of USP Reference Standards with ordering in-
`formation and names and addresses of worldwide sup-
`pliers.
`.
`.
`
`REAGENT STANDARDS
`
`The proper conduct of the_Pharmacopeial tests. and
`assays and the reliability of the results depend, "in
`part, upon the quality of thereagents 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,”
`'
`'
`
`Assay limit 298.0%
`
`'
`_
`Assay limit 5101.596 I
`
`_
`
`Limit test 50.02%
`.
`
`'
`
`-
`
`Limit test 53 ppm
`
`97.96%
`97.92%
`91.95% 1
`101.55%
`101.46%
`101.45% "
`0.025%
`0.015%
`0.027%
`
`0.0003596
`0.0002596
`0.000128%
`
`.
`
`93-0%
`97.9%
`98.0%
`101.6%
`101.5%
`- 101.5%
`. 0.03%
`0.02%
`0.03%
`
`0.0004%
`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 (1) to (999), chapters that _are informational
`are numbered from_ (1000) 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. It is especially helpful
`where monograph" section headings and chapter names
`are not the same (e.g., Ultraviolet absorption (I9'lU)
`in a monograph refers to method (197U) under gen-
`eral tests chapter (197) Spectrophotometric Identi-
`fication Tests; Specific rotation (TSIS) in a mono-
`graph refers to method (?81S} under" general tests
`chapter (781) Optical Rotation; and Calcium (191)
`in a_ monograph refers to the tests for Calcium under '
`gene'ra_l'test_s chapter (191) Identification Tests—
`General).
`'
`'
`
`PHARMACOPEIAL FORUM
`
`. USP REFERENCE STANDARIB
`
`P-harmacopeial Forum (PF) is the USP journal of .
`standards development and official compendia revi-
`sion. Pharmacopeta! 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
`standards in USP or NF tests and assays. {See USP
`Reference Standards (11).) Currently official-lots of
`USP Reference. Standards are published in Phar-
`macopeial Forum.
`'
`
`Amerigen Ex. 1057, p. 6
`Amerigen Ex. 1057, p. 6
`
`

`
`
`
`General Notices
`
`5
`
`signed to assure that the resultant substances meet
`the requirements of the compendial monographs (see
`also Foreign Substances and 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'_not._bc dried prior to use if due
`allowance is made for the.water or other volatile sub-
`stances present in the qu_antity taken.
`_.
`Unless. specifically exempted elsewhere in "this
`-Ph aimacopeia, the identit-y, strength, quality, and pu-
`rity of_. an official article are determined by the def-
`inition, physical properties, tests, assays, and other
`specifications relating to the article, whether incor-
`porated in the monograph itself, in the Generaf No-
`tices, or in the section General Chapters.
`-W_ater—Water used as an ingredient of - official
`preparations meets the requ_irements for Purified
`Water-, for Waterfor Injection, or for one of the sterile
`forms of water covered by a monograph in this Phar-
`ma_copeia. .
`'
`-
`_
`_
`_
`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 Alcohoi -content refer to
`percentage, by volume, of C2H5OH at 15.56“. Where
`reference is made to ..“-C2H5OH,” the cliemicalentity
`possessing absolute (100 percent) strength is in-
`tended.
`
`
`
`Afcoholm-\lVhere “alcohol”_ is called for in for-
`mulas, tests, and assays, the monograph article A!-
`cohof is‘ to be used.
`I
`-
`'
`
`Dehydrated AIcohoI—Wh'ere “dehydrated alco-
`hol” (absolute alcohol) is called for in tests and as-
`says, the monograph article Dehydrated Alcohol-is
`to be used.
`.
`
`Denatured AIcoho!—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
`internaluor 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, provided_ that the denaturant is either a 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
`Amerigen Ex. 1057, p. 7
`Amerigen Ex. 1057, p. 7
`
`
`
`USP 23
`
`Where a US? 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
`coinpendial 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 USP'Reference
`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 i=o1'ENcir,
`
`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.
`-
`Units of biological otency defined by the World
`Health Organization WHO) for International Bio-
`logical Standards and International Biological Ref-
`erence Preparations are termed International Units
`(IU). 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 Internatio_nal Units,
`where such exist. Such equivalence is usually estab-
`lished on the basissolely of the compendial assay for
`the substance.
`'
`'
`"
`For antibiotics (see Antibiott'cs-—.Mt'crobia! Assays
`(31)). USP Units are defined by the_ corresponding
`USP_Reference Standards in terms of the units of
`activity established by the FDA. Each -unit is'estab-
`lished through the corresponding antibiotic master
`standard, 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. necessary, and their activity is_ expressed
`in metric units (micrograms or milligrams) in terms
`_0l the chemically defined substances described in the
`l1'ldlVlCl1l'c-ll 1]'1(j_pnQgI-aphS_
`.
`.
`.-
`-
`t_ For biological products, whether or not Interna-
`(iltiglal Units or USP Units do exist (see Biologics
`41)), units of potency are defined by" the correr
`5P°“d1I1g US Standard established by the FDA.
`
`INGREDIENTS AND -Piaocassns
`thgfgcial Preparations are prepared from ingredients
`gmphsetiit the F“-'fll11_reme_nts of the compendial mono-
`mono I’ 0t] those individual ingredients for which
`Offacfual S are provided (see also NF 18.).
`-
`Ognized 4 _311lDStances are prepared according to rec-
`from inggmclples of good manufacturing practice and
`edients complying with specifications de-
`
`

`
`
`
`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-
`tinguished from an official preparation, c0ntain_s'no
`added 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,
`reservatives, stabiliz-
`ers, and vehicles may be adde
`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, (c) their presence does not im-
`pair‘ the bioavailability or the therapeutic efficacy or
`safety of the official preparation, and ((1) they do not
`interfere with the assays and tests prescribed for de-
`Itierrsliining compliance with the Pharmacopeial stan_-
`ar s.
`Nutritional Supplements—Unless otherwise spec-
`ified in the individual monograph, orelsewhere 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-
`ment 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 plicable regulatory require-
`ments, provided that (all 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 those 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
`y a mixture-of these gases, which fact need not be
`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 S'uppositories—In the preparation
`of ointments and suppositories, the proportionsof the
`
`substances constituting the base may be varied to
`maintain a suitable consistency under different cli-
`matic conditions, 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
`given solely as a recommendation. Where volumetric
`flasks 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 _propo'rtionately
`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 apparatus 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 chro