`
`USP XXII
`NF XVII
`
`_
`1
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeiai
`Convention, Ina, meeting at Washington, D. C.,
`March 22—24, 1985. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January I, 1990
`
`ELSEm
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`\f
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`I
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`-'
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`EDI
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`_———-——
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`#_. .
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`MYLAN INST. EXHIBIT 1068 PAGE 1
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`MYLAN INST. EXHIBIT 1068 PAGE 1
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`
`NOTICE AND WARNING
`
`Concerning U. S. Patent 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 Pharmacopeial Convention. Inc.
`(D 1989
`12601 Twinbrook Parkway. Rockville, MD 20852
`All rights reserved
`Library of Congress Catalog Card Number 83-640088
`ISSN 0195-7996
`
`ISBN 0-913595-37-3 (cloth)
`0-913595-38-1 (leather)
`
`Printed by Mack Printing Company, Easton, PA 18042
`
`MYLAN INST. EXHIBIT 1068 PAGE 2
`
`
`
`Guide to GENERAL CHAPTERS
`
`(For complete alphabetic list of all general chapters in this Pharmacopeia, see under “General chapters" in the index.)
`
`General Tests and Assays
`
`General Requirements for Tests and Assays
`Injections
`1470
`USP Reference Standards .
`
`1472
`
`HA H._. vv
`
`Apparatus for Tests and Assays
`(l6) Automated Methods of Analysis .
`1
`. 1473
`(21) Thermometers .
`.
`. 1477
`(31) Volumetric Apparatus .
`(41) Weights and Balances .
`
`. 1477
`. 1477
`
`.
`.
`
`Microbiological Tests
`(51) Antimicrobial Preservatives—Effectiveness .
`(61) Microbial Limit Tests . . . 1479
`(71) Sterility Tests .
`.
`. 1483
`
`.
`
`. 1478
`
`Biological Tests and Assays
`(81) Antibiotics—Microbial Assays .. . 1488
`(85) Bacterial Endotoxins Test .
`.
`. 1493
`(87) Biological Reactivity Tests, In4vitro .
`(88) Biological Reactivity Tests, In-vivo . .
`(91) Calcium Pantothenate Assay .
`.
`. 1500
`(101) Depressor Substances Test . .
`. 1502
`(111) Design and Analysis of Biological Assays . .. 1502
`(115) Dex anthenol Assay . .. 1512
`(121)
`Insu in Assay . .. 1513
`(141) Protein—Biological Adequacy Test .
`(151) Pyrogen Test... 1515
`(161) Transfusion and Infusion Assemblies .
`(171) Vitamin 1312 Activity Assay . .. 1516
`
`.
`
`. 1514
`
`.
`
`. 1516
`
`.
`
`. 1495
`. 1497
`
`Chemical Tests and Assays
`IDENTIFICATION TESTS
`
`Identification—Organic Nitrogenous Bases .
`(181)
`Identification Tests—General .
`.
`. 1518
`(191)
`.
`Identification—Tetracyclines .
`. 1520
`(193)
`(201) Thin-layer Chromatographic Identification Test . . . 1520
`
`. 1518
`
`.
`
`LIMIT TESTS
`
`.
`
`. 1522
`
`. 1520
`.
`(211) Arsenic .
`(216) Calcium, Potassium, and Sodium .
`(221) Chloride and Sulfate .
`.
`. 1522
`(224) Dioxane .
`. . 1522
`(226) 4-Epianhydrotetracycline .
`(231) Heavy Metals .
`.
`. 1523
`(241) Iron 1524
`(251) Lead . .
`. 1525
`(261) Mercury .
`.
`. 1526
`(271) Readily Carbonizable Substances Test
`(281) Residue on Ignition .. . 1527
`(291) Selenium... 1527
`
`.
`
`. 1523
`
`.
`
`. 1527
`
`OTHER TESTS AND ASSAYS
`
`.
`
`. 1528
`
`.
`
`. 1529
`
`.
`
`. 1530
`- -'
`
`.
`
`. 1537
`. l 38
`
`.
`
`. 1544
`
`Acid-neutralizing Capacity .
`Alginates Assay .
`.
`. 1528
`Alkaloidal Drug Assays; Proximat'e Assays .
`Amphetamine Assay .
`.
`. 1530
`Antimicrobial Agents—Content .
`Assay for Steroids‘. .
`. 153-2
`Barbitu ate Assay .
`.
`. 1532
`. 1533
`r
`Cobal
`in Radiotracer Assay .
`Elasto eric Closures for Injections .
`. . 1533
`Ep' phrine Assay... 1534
`Fatsamd Fined Oils .
`.
`. 1535
`Folic ‘Acid Assay .
`.
`. 1536
`Hydroxypropoxy Determination .
`Iodometrie Assay—Antibiotics .
`.
`Methoxy Determination .
`.
`. 1538
`Niacinver Niacinamide Assay .
`.
`. 1539
`Nitrite Titration .
`.
`. 1541
`. 1542
`.
`Nitrogen Determination .
`Ordinary Impurities .
`.
`. 1542
`Oxygen Determination .
`.
`. 1543
`Oxygen Flask Combustion .
`.
`. 1543
`Penicillin G Determination .. . 1544
`Riboflavin Assay . . . 1544
`Salts of Organic Nitrogenous Bases .
`Single-steroid Assay . .
`. 1545
`Sulfonamides . .. 1545
`Thiamine Assay .
`.
`. 1546
`Titrimetry .
`.
`. 1547
`1549
`Alpha Tocopherol Assay .
`Vegetable DruHampling and Methods
`of Analysis . .
`. 1549
`Vitamin A Assay .
`.
`. 1550
`Vitamin D Assay .
`.
`. 1551
`Zinc Determination .
`.
`. 1555
`
`(301)
`(311)
`(321)
`(331)
`(341)
`(351)
`(361)
`(371)
`(381)
`(391)
`(401)
`(411)
`(421)
`(425)
`(431)
`(441)
`(451)
`(461)
`(466)
`(468)
`(471)
`(475)
`(481)
`(501)
`(511)
`(521)
`(531)
`(541)
`(551)
`(561)
`
`(571)
`(581)
`(591)
`
`(601)
`(611)
`(621)
`(631)
`(641)
`(651)
`(661)
`(671)
`(691)
`(695)
`(701)
`(711)
`(721)
`(724)
`(726)
`(731)
`(733)
`(736)
`(741)
`
`. 1557
`
`.
`
`.
`
`. 1575
`
`Physical Tests and Determinations
`Aerosols... 1556
`.
`Alcohol Determination .
`Chromatography . . . 1558
`. 1568
`Color and Achromicity .
`.
`CompleteneSs of Solution .
`.
`. 1569
`Congealing Temperature .
`. 1569
`Containers... 1570'
`Containers—Permeation .
`Cotton . .
`. 1576
`Crystallinity . .
`. 1577
`Dishltegration . .. 1577
`Dissolution .
`. . 1578
`Distilling Range .
`.
`. 1579
`Drug Release .
`.
`. 1580
`Electrophoresis... 1583
`Loss on Drying .
`.
`. 1586
`.
`Loss on Ignition .
`. 1586
`Mass Spectrometry .
`. . 1586
`Melting Range or Temperature .
`
`. 1588
`
`1468
`
`MYLAN INST. EXHIBIT 1068 PAGE 3
`
`A
`
`MYLAN INST. EXHIBIT 1068 PAGE 3
`
`
`
`
`
`LAST’lkilII
`
`Guide to General Chapters
`
`1469
`
`(751) Metal Particles in Ophthalmic Ointments . . . 1589
`(755) Minimum Fill
`1589
`(761) Nuclear Magnetic Resonance.
`(771) Ophthalmic Ointments .
`1
`. 1594
`(781) Optical Rotation .
`.
`. 1595
`(785) Osmolarity
`1595
`(788) Particulate Matter in Injections
`(791) pH... 1598
`. 1599
`.
`(801) Polarography .
`(811) Powder Fineness .
`.
`. 1602
`(821) Radioactivity... 1602
`(831) Refractive Index .
`.
`. 1609
`
`. 1590
`
`.. 1596
`
`r
`
`(841)
`Specific Gravity . . . 1609
`(851)
`Spectrophotometry and Light-scattering .
`(861)
`Sutures—Diameter .
`.
`. 1614
`(871)
`Sutures—Needle Attachment .
`(881)
`Tensile Strength .
`.
`.‘ 1615
`(891)
`Thermal Analysis .
`.
`. 1615
`(901)
`Ultraviolet Absorbance of Citrus Oils .
`(905)
`Uniformity of Dosage Units .
`.
`. I617
`\uscosny... 1619
`(911)
`. 1619
`(921) Water Determination
`(941) X-ray Diffraction . .. 1621
`
`.
`
`. 1609
`
`.
`
`. 1614
`
`.
`
`. 1617
`
`General Information
`
`. 1624
`.
`. 1625
`
`(1001)
`(1035)
`(1041)
`(1051)
`(1061)
`(1071)
`(1076)
`
`(1077)
`
`Antacid Effectiveness .
`Biological Indicators .
`.
`Biologics .
`.
`. 1627
`.
`. 1627
`.
`Cleaning Glass Apparatus .
`. 1627
`.
`Color—Instrumental Measurement .
`Controlled Substances Act Regulations .
`.
`. 1629
`Federal Food, Drug, and Cosmetic Act Requirements
`. Relating to Drugs for Human Use .
`.
`. 1655
`Good Manufacturing Practice for Finished
`Pharmaceuticals .
`.
`. 1671
`1
`(1081) Gel Strength of Gelatin .
`.
`.‘ 1682
`(1086)
`Imgurities in Official Articles . .. 1682
`(1091) La eling of Inactive Ingredients .
`.
`. 1684
`(1101) Medicine Dropper . .. 1684
`(1111) Microbiological Attributes of Nonsterile
`Pharmaceutical Products .
`. . 1684
`
`(1121)
`(1141)
`(1151)
`(1171)
`(1176)
`
`(1181)
`(1191)
`
`(1211)
`
`1685
`Nomenclature .
`. 1685
`.
`Packaging—Child-safety .
`Pharmaceutical Dosage Forms .
`.
`. 1688
`Phase-solubility Analysis . .
`. 1697
`Prescription Balances and Volumetric
`Apparatus... 1699
`'
`.
`Scanmng Electron Microscopy .
`. 1700
`Stability Considerations in Dispensing
`Practice. .
`. 1703
`Sterilization and Sterility Assurance of Compendial
`Articles .
`.
`. 1705
`(1221) Teas 00111710
`(1225) Vali ation of Compendial Methods . .. 1710
`(1231) Water for Pharmaceutical Purposes . .. 1712'
`(1241) Water-solid Interactions in Pharmaceutical
`Systems... 1713
`
`
`
`MYLAN INST. EXHIBIT 1068 PAGE 4
`
`
`
`MYLAN INST. EXHIBIT 1068 PAGE 4
`
`
`
`GENERAL CHAPTERS
`
`General Tests
`
`and Assays
`
`General Requirements
`for Tests and Assays
`
`
`
`(1)
`
`INJECTIONS
`
`red-
`Every care should be exercised in the preparation of all
`ucts intended for injection, to prevent contamination wit mi-
`croorganisms and foreign material. Good pharmaceutical prac-
`tice requires also that each final container of Injection be subjected
`individually to a physical inspection, whenever the nature of the
`container permits, and that every container whose contents show
`evidence of contamination with visible foreign material be re-
`jected.
`Definitions—In this Pharmacopeia, the sterile preparations for
`parenteral use are grouped into five distinct classes, defined as
`follows: (1) medicaments or solutions or emulsions thereof suit-
`able for injection, bearing titles of the form, __ Injection; (2)
`dry solids or liquid concentrates containing no buffers, diluents,
`or other added substances, and which, upon the addition of suit—
`able solvents, yield solutions conforming in all respects to the
`requirements for Injections, and which are distinguished by titles
`of the form, Sterile '_; (3) preparations the same as those
`described under (2) except that they contain one or more buffers,
`diluents, or other added substances, and which are distinguished
`by titles of the form, _ for Injection: (4) solids which are
`suspended in a suitable fluid medium and which are not to be
`
`injected intravenously or into the spinal canal, distinguished by
`titles of the form, Sterile
`Suspension; and (5) dry solids
`which, upon the addition of suitable vehicles, yield preparations
`conforming in all respects to the requirements for Sterile Sus-
`pensions, and which are distinguished by titles of the form, Sterile
`._ for Suspension.
`A Pharmacy bulk package is a container of a sterile prepa-
`ration for parenteral use that contains many single doses. The
`contents are intended for use in a pharmacy admixture program
`and are restricted to the pre aration of admixtures for infusion
`or, through a sterile transfer evice, for the filling of empty sterile
`syringes.
`'The closure shall be penetrated only one time after constitution
`With a suitable sterile transfer device or dispensing set which
`allows measured dispensing of the contents. The Pharmac bulk
`package is to be used only in a suitable work area sue
`as a
`11170
`
`laminar flow hood (or an equivalent clean air compounding area).
`Designation as a Pharmacy bulk package is limited to prep-
`arations from classes 1, 2, or 3 as defined abcve. Pharmacy bulk
`packages, although containing more than one single dose, are
`exempt from the multiple-dose container volume limit of 30 mL
`and the requirement that they contain a substance‘or suitable
`mixture of substances to prevent the growth of microorganisms.
`Where a container is offered as a Pharmacy bulk package, the
`label shall (a) state prominently “Pharmacy Bulk Package—Not
`for direct infusion,” (b) contain or refer to information on roper
`techniques to help assure safe use of the product, and (c bear
`a statement limiting the time frame in which the container may
`be used once it has been entered, provided it is held under the
`labeled storage conditions.
`Where used in this Pharinaeopeia, the designation Large-vol-
`ume intravenous solution applies to a single-dose injection_that
`is intended for intravenous use and is packaged in containers
`labeled as containing more than 100 mL. The designation Small-
`volumc Injection applies to an Injection that is packaged in con-
`tainers labeled as containing 100 mL or less.
`The Pharmacopeial definitions for sterile preparationslfor par-
`enteral use generally do not apply in the case of the biologics,
`because of their special nature and licensing requirements (see
`Biologics (1041)).
`Aqueous Vehicles—The vehicles for aqueous Injections meet
`the requirements of the Pyrogen Test (151) or the Bacterial
`Endotoxins Test (85), whichever is specified. Water for It‘ll?"
`tion generall
`is used as the vehicle, unless otherwise spectfled
`in the indivi ual monogra h. Sodium chloride may be added In
`amounts sufficient to ren er the resulting solution isotonic; and
`Sodium Chloride Injection, or Ringer's Injection, may be us
`in whole or in part instead of Waterfor Injection unless otherwise
`specified in the individual monograph. For conditions applying
`to other adjuvants, see Added Substances, in this chapter.
`Other Vehicles——Fixed oils used as vehicles for nonaqueOIls
`injections are of vegetable origin, are odorless or nearly so. an
`have no odor or taste suggesting rancidity. They meet the 1'?
`quirements of the test for Solid paraffin under Mineral Oil, the
`cooling bath being maintained at 10°, have a Saponificanon value
`of between 185 and 200 (see Fats and Fixed Oils (40%)). have
`an Iodine value of between 79 and 128 (see Fats and Fixed 0‘13
`(401)), and meet the requirements of the followrng tests:
`Unsaponifiable Motter—Reflux on a steam bath 10 mL of the
`oil with 15 mL of sodium hydroxide solution (1 in 6) and 30 mL
`of alcohol, with occasional shaking until the mixture becomt'is
`clear. Transfer the solution to a shallow dish, evaporate the ap-
`coho] on a steam bath, and mix the residue with 100 mL of water:
`a clear solution results.
`
` 'FI'H-u—s
`
`MYLAN INST. EXHIBIT 1068 PAGE 5
`
`MYLAN INST. EXHIBIT 1068 PAGE 5
`
`
`
`USP XXII
`
`General Requirements / Injections
`
`(l)
`
`1471
`
`Free Fatty Acidsh'l'he free fatty acids in 10 g of oil require
`for neutralization not more than 2.0 mL of 0.020 N sodium hy-
`droxide (see Fats and Fixed Oils (401)).
`Synthetic mono- or diglycerides of fatty acids may be used as
`vehicles, provided they are liquid and remain clear when cooled
`to 10° and have an Iodine value of not more than 140 (see Fats
`and Fixed Oils (401)).
`These and other nonaqueous vehicles may be used, provided
`they are safe in the volume of injection administered, and also
`provided they do not interfere with the therapeutic efficacy of
`the preparation or with its response to prescribed assays and tests.
`Added Substancesfiguitable substances may be added to in-
`crease stability or usefulness, unless proscribed in the individual
`monograph,dprovided they are harmless in the amounts admin-
`istered and 0 not interfere with the therapeutic efficacy or with
`the responses to the specified assays and tests. No coloring agent
`may be added, solely for the purpose of coloring the finished
`reparation, to a solution intended for parenteral administration
`see also Added Substances under General Notices, and Anti—
`microbial Preservatives—Effectiveness ( 5 1 ) ).
`Observe special care in the choice and use of added substances
`in preparations for injection that are administered in a volume
`exceeding 5 mL. The following maximum limits prevail unless
`otherwise directed: for agents containing mercury and the cat-
`ionic, surface-active compounds, 0.01%; for those of the types of
`chlorobutanol, cresol, and phenol, 0.5%; and for sulfur dioxide,
`or an equivalent amount of the sulfite, bisulfite, or metabisulfite
`of potassium or sodium, 0.2%.
`"A suitable substance or-mixture of substances to prevent the
`growth of microorganisms must be added to preparations in-
`tended for in'ection that are packaged in multiple-dose con-
`tainers, regar less of the method of sterilization employed, unless
`otherwise directed in the individual monograph, or unless the
`active ingredients are themselves antimicrobial. Such substances
`are used in Canoentrati‘ons that will prevent the growth of or kill
`microorganisms in the preparations for injection (see also Anti-
`microbial Preservatives—Ej'f‘eCtiveness (51) and Antimicrobial
`Agents+Content (341)). Sterilization processes are employed
`even though such substances are used (see also Parenteral and
`Topical Preparations in the section, Added Substances, under
`General Notices, and Sterilization and Sterility Assurance of
`Compendial Articles (1211)). The air in the container may be
`evacuated or be displaced by a chemically inert gas.
`Containers for Injections—Containers, including the closures,
`for preparations for injection do not interact physically or chem-
`ically with the preparations in any manner to alter the strength,
`quality, or purity beyond the official re uirements under the or-
`dinary or customary conditions of han 'ng, shipment, storage,
`sale, and use. The container is made of material that permits
`inspection of the contents. The type of glass preferable for each
`parefiteral preparation is usually stated in the individual mono-
`grap .
`For definitions of single-dose and multiple-dose containers, see
`Containers under General Notices. Containers meet the require-
`ments under Containers (661).
`Containers are closed by fusion, or by application of suitable
`closures, in such manner as to prevent contamination or loss of
`contents. Closures for multiple-dose containers permit the with-
`drawal‘of the contents without removal or destruction of the
`closure. The closure permits penetration by a needle, and, upon
`withdrawal of the needle, at once recloses the container against
`contamination.
`
`Containers for Sterile Solids—Containers, including the clo-
`sures, for dry solids intended for parenteral use do not interact
`physically or chemically with the preparation in any manner to
`alter the strength, quality, or purity beyond the official require-
`ments under the ordinary or customary conditions of handling,
`shipment, storage, sale, and use.
`.
`A container for a sterile solid permits the addition of a suitable
`solvent and withdrawal of portions of the resulting solution or
`suspension in such manner that the sterility of the product is
`maintained.
`'
`-
`
`Where the Assay in a monograph provides a procedure for
`4ssay preparation in which the total withdrawable contents are
`to be withdrawn from a single-dose container with a hypodermic
`needle and syringe, the contents are to be withdrawn as com-
`pletely as possible into a dry hypodermic syringe of a rated ca-
`pacity not exceeding three times the volume to be withdrawn and
`
`fitted with a 21—gauge needle not less than 2.5 cm (1 inch) in
`length, care being taken to expel any air bubbles, and discharged
`into a container for dilution and assay.
`Volume in Container—Each container of an Injection is filled
`with a volume in slight excess of the labeled “size” or that volume
`which is to be withdrawn. The excess volumes reconmmnded in
`the accompanying table are usually sufficient to permit with-
`drawal an administration of the labeled volumes.
`,
`DETERMINATION 0]" VOLUME OF INJECTION IN CON-
`TAINERS—Select l or more containers if the volume is 10 mL
`or more, 3 or more if the volume is more than 3 mL and less
`than 10 mL, or 5 or more if the volume is 3 mL or less. Take
`up individually the contents of each container selected into a dry
`hypodermic syringe of a rated ca acity not exceeding three times
`the volume to be measured, an fitted with a 21-gauge needle
`not less than 2.5 cm (1 inch) in length. Expcl any air bubbles
`from the syringe and needle, and then discharge the contents
`of the syringe, without emptying the needle, into a standardized,
`dry cylinder (graduated to contain rather than to deliver the
`designated volumes) of such size that the volume to be measured
`occupies at least 40% of its rated volume. Alternatively, the
`contents of the syringe may be discharged into a dry, tared beaker,
`the volume, in mL, being calculated as the weight, in g, of In-
`jection taken divided by its density. The contents of two or three
`l-mL or 2-mL containers may be pooled for the measurement,
`provided that a separate, dry syringe assembly is used for each
`container. The content of containers holding 10 mL or more may
`be determined by means of opening them and emptying the con-
`tents directly into the graduated cylinder or tared beaker.
`
`Recommended Excess Volume
`For Mobile
`For Viscous
`Liguids
`Liguids
`0.10 mL
`0.12 mL
`0.10 mL
`015mL
`0.15 mL
`U 25 mL
`0.30 mL
`0.50 mL
`0.50 mL
`0.70 mL
`0.60 mL
`0.90 mL
`0.80 mL
`1.20 mL
`
`Labeled Size
`0.5 mL
`1.0 mL
`2.0 ml.
`5.0 mL
`10.0 mL
`20.0 mL
`30.0 mL
`50.0 mL
`
`or more 3% 2%
`
`
`
`The volume is not less than the labeled volume in the case of
`containers examined individually or, in the case of I-mLand 2-
`mL containers, is not less than the sum of the labeled volumes
`of the containers taken collectively.
`For Injections in multiple-dose containers labeled to yield a
`specific number of doses of a stated volume, proceed as directed
`in the foregoing, using the same number of separate syringes as
`the number of doses specified. The volume is such that each
`syringe delivers not less than the stated dose.
`For Injections containing oil, warm the containers, if necessary,
`and thoroughl
`shake them immediately before removing the
`contents. 000 to 25° before measuring the volume.
`Particulate Mutter—A11 large-volume Injections for single-dose
`infusion, and those small-volume Injections for which the mono-
`graphs specify such requirements, are subject to the particulate
`matter limits set forth under Particulate Matter in Injections
`(788). An article packaged as both a large-volume and a small-
`volume Injection'meets the requirements set forth for Small-
`volume Injections where the container is labeled as containing
`100 mL or less if the individual monograph includes a test for
`Particulate matter: it meets the requirements set forth for Large-
`volume Injections for Single-dose Infusion where the container
`is labeled as containing more than 100 mL. Injections packaged
`and labeled for use as irrigating solutions are exempt from re-
`quirements for Particulate matter.
`Sterility Tests—Preparations for injection meet the require-
`ments under Sterility Tests (71).
`Labeling—-[NOTE—See definitions of “label” and “labeling”
`under Preservation, Packaging, Storage, and Labeling—Label-
`ing in the General Notices.
`.
`The label states the name of the preparation; in the case of a
`liquid preparation, the percentage content of drug or amount of
`drug in a specified volume; in the case of a dry preparation, the
`
`MYLAN INST. EXHIBIT 1068 PAGE 6
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`MYLAN INST. EXHIBIT 1068 PAGE 6
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`
`
`1472
`
`(ll)
`
`USP Reference Standards / General Requirements
`
`USP XXII
`
`amount of active ingredient; the route of administration; a state-
`ment of storage conditions and an expiration date; the name of
`the manufacturer and distributor; and an identifying lot number.
`The lot number is capable of yielding the complete manufacturing
`history of the specific package, including all manufacturing, fill-
`ing, sterilizing, and labeling operations.
`Where the individual monograph permits varying concentra-
`tions of active ingredients in the large-volume parenteral, the
`cancentration of each ingredient named in the official title is
`stated as if part of the official title, e.g., Dextrose Injection 5%,
`or Dextrose (5%) and SodiumIChloride (0.2%) Injection.
`The labeling includes the following information, if the complete
`formula is not specified in the individual monograph: (1) In‘ the
`case of a liquid preparation, the percentage content of each in-
`gredient or the amountof each ingredient in a specified volume,
`except that ingredients added to adjust to a given pH or to make
`the solution isotonic may be declared by name and a statement
`of their effect; and (2).in the case of a dry preparation or other
`preparation to which a diluent is intended to be added before
`use, the amount of each ingredient, the composition of recom-
`mended diluent(s) [the name(s) alone, if the formula is specified
`in the individual monograph], the amount to be used to attain a
`specific concentration of active ingredient and the final volume
`of solution so obtained, a brief description of the physical ap-
`pearance of the constituted solution, directions for proper storage
`of the constituted solution, and an expiration date limiting the
`period during which the constituted solution may be expected to
`have the required or labeled potency if it hasbeen stored as
`directed. ‘
`l
`Containers for Injections that are intended for uSe as dialysis,
`hemofiltration, or irrigation solutions and that contain a volume
`of more than 1 liter are labeled to indicate that the contents are
`not intended for use by intravenous infusion.
`Injections intended for veterinary use are labeled to that effect.
`The container is so. labeled that a sufficient area of the con-
`tainer remains uncovered for its'full length or circumference to
`permit inspection of the contents.‘
`'
`Packaging and StoragFThe volume of Injection in single-dose
`containers provides the amount specified for parenteral admin-
`istration at one time and in no case is more than sufficient to
`permit the withdrawal and administration of 1 liter.
`Preparations intended for intraspinal, intracisternal, or peri-
`dural administration are packaged only in single-dose containers.
`Unless otherwise specified in the individual monograph, no
`multiple-dose container contains a volume of Injection more than
`sufficrent to permit the withdrawal of 30 mL.
`'
`Injections (packaged for use as irrigation solutions or for hemo-
`filtration or
`ialysis or for parenteral nutrition are exempt from
`the l-liter restriction of the foregoing requirements relating to
`packaging. Containers for Injections packaged for use as hemo-
`tiltration or-irrigation solutions may be designed to empty rapidly
`and may contain a volume of more than 1 liter.
`'
`Injections labeled for veterinary use are exempt from pack—
`aging and storage requirements concerning the limitation to sin-
`gle-dose containers and the limitation on the volume of multiple-
`dose containers.
`
`CONSTITUTED SOLUTIONS
`
`Sterile dosage forms from which'constituted solutions are pre-
`pared for injection bear titles of the form, Sterile _ or _
`for Injection. Since these dosage forms are constituted at the
`time of use by the health—care practitioner, tests and standards
`pertaining to the solution as constituted for administration are
`not included in the individual monographs on sterile dry solids
`or liquid concentrates. However, in the interest of assuring the
`quality of injection preparations as they are actually adminis-
`tered, the following nondestructive tests are provided for dem-
`onstrating the Suitability of constituted solutions when they are
`prepared just prior to use.
`'
`Completeness and Clarity of Solution—Constitute the solution
`as directed in the labeling supplied by the manufacturer for the
`sterile dry dosage form.
`.
`A: The solid dissolves completely, leaving no visible residue
`as undissolved matter.
`B: The constituted solution is not significantly less clear
`than an equal volume of the diluent or of Purified Water con-
`tained in a similar vessel and examined similarly.
`
`Particulate Matter—aConstitute the solution as directed in the
`labeling supplied by the manufacturer for the sterile dry dosage
`form:
`the solution is essentially free from particles of foreign
`matter that can be observed on visual inspection.
`
`(11) USP REFERENCE
`STANDARDS
`USP Reference Standards are established and released under
`the authority of the USPC Board of Trustees upon recommen-
`dation of the USP Reference Standards Committee, which passes
`on the selection and suitability of each lot. The critical char-
`acteristics of each lot of specimen selected for the standard are
`usually determined indefiendently in three or more laboratories.
`The USP Drug Researe and Testing Laboratory (see Preface)
`and the Food and Drug Administration laboratories participate
`in testing almost all new Standards and replacements for existing
`Standards. In addition, laboratories throughout the nation, both
`academic and industrial, participate in the testing.
`- Reference Standards are specifically required in many Phar-
`macopeial assays and tests and are provided solely for such use;
`suitability for other non-official application(s) rests with the pur-
`chase. Originally introduced for the biological assays of USP X,
`reference standards are now required for numerous other pro-
`cedures as well. This reflects the extensive use of modern chro-
`matography and spectrophotometry, which require measurements
`relative to a reference standard to attain accurate and reprodu-
`cible results.
`USP Reference Standards are substances selected for their
`high purity, critical characteristics, and suitability for the in-
`tended purpose. Heterogeneous substances, of natural origin, also
`are designated “Reference Standards” where needed. Usually
`these are the caunterparts of international standards.
`Antibiotic reference standards distributed by the USPC have
`been designated by the US. Food and Drug Administration as
`identical to FDA working standards under the FDA certification
`prOCedures. ,USPC distributes both US. Reference Standards
`and USP Reference Standards for antibiotic substances. This
`difference in labeling the Standards is in effect only temporaril ,
`and eventually all vials will bear the same title. Where a U P
`ReferenceStandard is called for, the corresponding substance
`labeled as a “US. Reference Standard” may be used, and vice
`versa.
`.
`.
`Reference Standards currently labeled as “NF Reference Stan-
`dards” will eventually all be designated and labeled as “USP
`Reference Standards’ pursuant to the consolidation of USP and
`NF within the USPC as of January 2, 1975. Meanwhile, where
`a USP Reference Standard is called for, the corresponding sub-
`stance labeled as an “NF Reference Standard" may be used.
`
`Other Reference Substances
`As a service, the USPC tests and distributes additional au-
`thenticated substances not currently required as USP or NF Ref-
`erence Standards. These also are provided under the supervision
`of the USP Reference Standards Committee. These additional
`substances fall into three groups:
`(1) former USP and NF Ref-
`erence Standards, not required in the current USP or NF but
`for which sufficient demand remains; (2) FCC Reference Stan-
`dards, specified in the current edition of the Food Chemicals
`Codex; and (3) Authentic Substances (AS), which are highly
`purified samples of chemicals, including substances of abuse, that
`are collaboratively tested and made available as a service pri-
`marily to analytical, clinical, pharmaceutical, and research lab-
`oratories.
`The distribution of controlled substances is subject to the reg-
`ulations and licensing provisions otthe Drug Enforcement Ad-
`ministration of the Department of Justice.
`As an additional service, the USPC distributes several non-
`commercial reagents required in certain USP monographs. These
`reagents are specially prepared for their intended use and will be
`dliasltributed by USPC only until they become commercially avail-
`a e.
`A program to provide international biological standards and
`chemical reference substances is maintained by the World Health
`Organization, an agency of the United Nations. The WHO {'0'
`gram is cencemed with reference materials for antibiotics,
`10'
`
`MYLAN INST. EXHIBIT 1068 PAGE 7
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`MYLAN INST. EXHIBIT 1068 PAGE 7
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`
`
`USP XXII
`
`Apparatus / Automated Methods of Analysis
`
`(16)
`
`1473
`
`logiCals, and chemotherapeutic agents. As a rule, an Intema-
`tio'nal Standard for a material of natural origin is discontinued
`once the substance responsible for its characteristic activity has
`been isolated, identified, and lprepared in such form that it can
`be completely characterized y chemical and physical means.
`The USP Reference Standards Committee collaborates closely
`with the WHO in order to minimize unavoidable differences in
`the actual units-of potency, and in some cases to share in the
`preparation of a reference standard. Since some USP Reference
`tandards are standardized in terms of the corresponding Inter-
`national Standards, the relevant USP Units and the International
`Units of potency are generally identical.
`.
`.
`.7
`- Proper, Use of USP Reference Standards—To serve its intended
`purpose, each USP Reference Standard must bedprqperl
`stored,
`,andled, and used. Generally, Reference Stan ar s shyould. be
`stored in their original stoppercd containers away from heat and
`protected from light. Avoidfhumid storage areas in particular.
`Where special storage conditions are necessary, directions are
`given on the label.
`.
`.
`Neither Reference Standards nor Authentic, Substances are
`intended for use as drugs or as medical devices.
`_
`_
`,-
`. Many Pharmacopeial tests and assays are based on comparison
`of a test specimen with a USP Reference Standard.
`In such
`cases, measurements are made on preparations of both the test
`specimen and the Reference Standard. Where it is directed that
`a Standard solution or a Standard preparation be prepared for
`a quantitative determination by stepwise dilution or otherwise, it
`is intended that the Reference Standard substance shall‘be ac-
`curatelyweighed (see Weights and Balances (41) and Volu—
`metric Apparatus (31)). Due account should also be taken of
`the relatively large errors associated