Complete Index
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`- NF Monographs
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`Regeneron Exhibit 1019.001
`Regeneron Exhibit 1019.001
`
`

`

`USP
`AUTHENTICITY CERTIFICATE
`
`34-
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`29
`
`OFFICIAL
`MAY 1, 2011 - APRIL 30, 2012
`( with Supplements)
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`The United States Phannacopeia-NationaI Fonnulary
`(USP-NF) is a publication of the
`U.S. Pharmacopeia.
`
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`authentic and official print version
`of USP 34-NF 29.
`
`U.S. PHARMACOPEIA __ __,
`The Standard of QualitySM
`
`Regeneron Exhibit 1019.002
`
`

`

`2011
`
`USP 3
`F 29
`Volume 1
`
`RECEi\/ED
`
`FEB O I 2011
`
`GOODWIN PROCTER LLP
`LIBRARY
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`THE UNITED STATES PHARMACOPEIA
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`THE NATIONAL FORMULARY
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`By authority of the United States Pharmacopeia/ Convention
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`Official from May 1, 2011
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`States Pharmacopeia, Thirty-Fourth Revision, and The National Formulary, Twenty-Ninth
`Edition.
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`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
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`Regeneron Exhibit 1019.003
`
`

`

`SIX-MONTH IMPLEMENTATION GUIDELINE
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`USP 34-NF 29
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`Revises
`USP 33-NF 28 Reissue and its suoolements
`USP 33-NF 28 Reissue and its suoolements
`USP 33-NF 28 Reissue and its suoolements
`USP 33 NF 28 Reissue and its sunnlements
`USP 34-NF 29 and its sunnlements
`USP 34-NF 29 and its sunnlements
`USP 34-NF 29 and its sunnlements
`USP 34-NF 29 and its sunnlements
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`
`Regeneron Exhibit 1019.004
`
`

`

`328 (788) Particulate Matter in Injections / Physical Tests
`
`USP
`
`transparent graticule reference circles is used to size white
`and transparent particles, while dark particles are sized by
`using the outer diameter of the black opaque graticule ref(cid:173)
`erence circles.
`In performing the Microscopic Particle Count Test, do not
`attempt to size or enumerate amorphous, semiliquid, or
`otherwise morphologically indistinct materials that have the
`appearance of a stain or discoloration on the membrane
`filter. These materials show little or no surface relief and
`present a gelatinous or film-like appearance. In such cases,
`the interpretation of enumeration may be aided by testing a
`sample of the solution by the Light Obscuration Particle
`Count Test.
`
`Evaluation
`
`For preparations supplied in containers with a nominal
`volume of more than 100 ml, apply the criteria of Test 2.A.
`For preparations supplied in containers with a nominal
`volume of less than 100 ml, appl)( the criteria of Test 2.B.
`For preparations supplied in containers with a nominal
`volume of 100 ml, apply the criteria of Test 2.B. [NOTE-Test
`2.A is used in the Japanese Pharmacopeia.]
`Test 2.A (Solutions for parenteral infusion or solutions for
`injection supplied in containers with a nominal content of more
`than 7 00 mL)-The preparation complies with the test if the
`average number of particles present in the units tested does
`not exceed 12 per ml equal to or greater than 10 µm and
`does not exceed 2 per ml equal to or greater than 25 µm.
`Test 2.B (Solutions for parenteral infusion or solutions for
`injection supplied in containers with a nominal content of less
`than 7 00 mL)-The preparation complies with the test if the
`average number of particles present in the units tested does
`not exceed 3000 per container equal to or greater than 10
`µm and does not exceed 300 per container equal to or
`greater than 25 µm.
`
`(789) PARTICULATE MATTER IN
`OPHTHALMIC SOLUTIONS
`
`Particulate matter consists of mobile, randomly sourced,
`extraneous substances, other than gas bubbles, that cannot
`be quantitated by chemical analysis because of the small
`amount of material they represent and because of their het(cid:173)
`erogeneous composition. Ophthalmic solutions should be
`essentially free from particles that can be observed on visual
`inspection. The tests described herein are physical tests per(cid:173)
`formed for the purpose of enumerating extraneous particles
`within specific size ranges.
`Every ophthalmic solution for which the monograph in(cid:173)
`cludes a test for Particulate matter is subject to the particu(cid:173)
`late matter limits set forth for the test being applied, unless
`otherwise specified in the individual monograph. When
`higher limits are appropriate, they will be specified in the
`individual monograph. Ophthalmic preparations that are
`suspensions, emulsions, or gels are exempt from these re(cid:173)
`quirements, as are medical devices. Refer to the
`monograph when a question of test applicability occurs.
`light obscuration and microscopic procedures for the de(cid:173)
`termination of particulate matter in ophthalmic solutions are
`identical to those for injections; therefore, where appropri(cid:173)
`ate, Particulate Matter in Injections (788) is cross-referenced.
`This chapter provides a test approach in two stages. The
`ophthalmic solution is first tested by the light obscuration
`procedure (stage 1 ). If it fails to meet the prescribed limits,
`1t must pass the microscopic procedure (stage 2) with its
`
`own set of test limits. Where for technical reasons the
`ophthalmic solution cannot be tested by light obscuration.
`microscopic testing may be used exclusively. Documenta-.'
`tion is required; demonstrating that the light obscuration
`procedure is incapable of testing the ophthalmic solution
`that it produces invalid results.
`It is expected that most articles will meet the require(cid:173)
`ments on the basis of the light obscuration test alone; how..
`ever, it may be necessary to test some articles by the light
`obscuration test followed by the microscopic test to reach a
`conclusion on conformance to requirements. Any product
`that is not a pure solution having a clarity and a viscosity
`approximating those of water may provide erroneous data
`when analyzed by the light obscuration counting method.
`Such materials may be analyzed by the microscopic count(cid:173)
`ing method. In some instances, the viscosity of a material
`be tested may be sufficiently high so as to preclude its
`ysis by either test method. In this event, a quantitative dilu
`tion with an appropriate diluent may be made to decrease
`viscosity, as necessary, to allow the analysis to be
`·
`performed.
`In the tests described below, the results obtained by ex(cid:173)
`amining a discrete unit or group of units for particulate
`matter cannot be extrapolated with certainty to other units
`that remain untested. Thus, sampling plans based on k
`operational factors must be developed if valid inferen
`to be drawn from observed data to characterize the I
`particulate matter in a large group of units. Sampling plans
`need to be based on consideration of product volume, par:
`tide numbers historically found to be present in comparison
`to limits, particle size distribution of particles present, and
`variability of particle counts between units.
`
`LIGHT OBSCURATION PARTICLE COUNT TEST
`
`This test applies to ophthalmic solutions, including solu(cid:173)
`tions constituted from sterile solids, for which a test for Par(cid:173)
`ticulate matter is specified in the individual monograph. The
`test counts suspended particles that are solid or liquid.
`Test Apparatus, Instrument Standardization, Test
`Environment, Test Procedure, and Calculations-Proceed
`as directed for Light Obscuration Particle Count Test under
`Particulate Matter in Injections (788).
`Interpretation-The ophthalmic solution meets the re(cid:173)
`quirements of the test if the average number of particles
`present in the units tested does not exceed the appropriate
`value listed in Table 7. If the average number of particles
`exceeds the limit, test the article by the Microscopic Part/de
`Count Test.
`
`Table 1. Light Obscuration Test Particle Count
`Diameter
`~25 m
`5 er ml
`
`Number of articles
`
`MICROSCOPIC PARTICLE COUNT TEST
`
`Some articles cannot be tested meaningfully by light
`scuration. In such cases, individual monographs clearly
`ify that only a microscopic particle count is to be per-
`formed. The micros
`particle count test enumerates
`subvisible, essential!
`d, particulate matter in
`mic
`solutions, after collection on a microporous me
`ter.
`Some ophthalmic solutions, such as solutions that do not
`filter readily because of their high viscosity, may be ex(cid:173)
`empted from analysis using the microscopic test.
`When performing the microscopic test, do not attempt
`size or enumerate amorphous, semiliquid, or otherwise mor(cid:173)
`phologically indistinct materials that have the appearance of.
`a stain or discoloration on the membrane surface. These
`
`Regeneron Exhibit 1019.005
`
`

`

`Physical Tests I (791) pH 329
`
`Potassium
`Tetraoxalate 0.05 m
`1.67
`1.67
`1.68
`1.68
`1.68
`1.69
`1.69
`1.70
`1.71
`1.72
`1.72
`
`pH Values of Buffer Solutions for Standardization
`Potassium
`Equimolal
`Sodium Tetraborate,
`Bi hthalate 0.05 m
`Phos hate 0.05 m
`0.01 m
`4.00
`6.92
`9.33
`4.00
`6.90
`9.28
`4.00
`6.88
`9.23
`4.01
`6.86
`9.18
`4.02
`6.85
`9.14
`4.02
`6.84
`9.10
`4.04
`6.84
`9.07
`4.05
`6.83
`9.04
`4.06
`6.83
`9.01
`4.08
`6.83
`8.99
`4.09
`6.84
`8.96
`
`Calcium Hydroxide,
`Saturated at 25°
`13.00
`12.81
`12.63
`12.45
`12.29
`12.13
`11.98
`11.84
`11.71
`11.57
`11.45
`
`show little or no surface relief and present a gelati-
`1lm-like appearance. Because in solution this mate-
`. of units on the order of 1 µm or less, which may
`d only after aggregation or deformation on an
`membrane, interpretation of enumeration may be
`testing a sample of the solution by the light obscu(cid:173)
`· c1e count method.
`paratus, Test Environment, Test Procedure,
`meration of Particles-Proceed as directed for Mi(cid:173)
`Particle Count Test under Particulate Matter in lnjec•
`8).
`elation-The ophthalmic solution meets the re(cid:173)
`of the test if the average number of particles
`t in the units tested does not exceed the appropriate
`listed in Table 2.
`
`Table 2. Microscopic Method Particle Count
`Diameter
`~25 m
`5 er ml
`
`~ 10 m
`50 er ml
`
`(791) pH
`
`r c~mpendial purposes, pH is defined as the value given
`suitable, properly standardized, potentiometric instru(cid:173)
`t(pH !lleter) capable of reproducing pH values to 0.02
`um! ~sing an indicator electrode sensitive to hydrogen(cid:173)
`acttv1ty, the glass electrode, and a suitable reference
`ro~e. The instrument should be capable of sensing the
`ent.1al across the electrode pair and, for pH standardiza(cid:173)
`purposes applying an adjustable potential to the circuit
`~n of "standard
`," "zero," "asymmetry,"
`' control, and sh
`be able to control the
`livolts per unit change in pH reading through
`e" and/or "slope" control. Measurements are
`at 25 ± 2°, unless otherwise specified in the individual
`or herein.
`scale is defined by the equation:
`
`pH = pHs + (E Es)/k
`
`which E and Es are the measured potentials where the
`cell contains the solution under test, represented
`d the appropriate Buffer Solution for Standardiza(cid:173)
`_resented by pHs, respectively. The value of k is the
`m potential per unit change in pH and is theoreti-
`
`cally [0.05916 + 0.000198(t - 25°)] volts at any tempera(cid:173)
`ture t.
`It should be emphasized that the definitions of pH, the
`pH scale, and the values assigned to the Buffer Solutions for
`Standardization are for the purpose of establishing a practi(cid:173)
`cal, operational system so that results may be compared
`between laboratories. The pH values thus measured do not
`correspond exactly to those obtained by the definition, pH
`= - log aH+, So long as the solution being measured is suffi(cid:173)
`ciently similar in composition to the buffer used for stan(cid:173)
`dardization, the operational pH corresponds fairly closely to
`the theoretical pH. Although no claim is made with respect.
`to the suitability of the system for measuring hydrogen-ion
`activity or concentration, the values obtained are closely re(cid:173)
`lated to the activity of the hydrogen-ion in aqueous
`solutions.
`Where a pH meter is standardized by use of an aqueous
`buffer and then used to measure the ' pH" of a nonaqueous
`solution or suspension, the ionization constant of the acid or
`base, the dielectric constant of the medium, the liquid-junc(cid:173)
`tion potential (which may give rise to errors of approxi(cid:173)
`mately 1 pH unit), and the hydrogen-ion response of the
`glass electrode are all changed. For these reasons, the values
`so obtained with solutions that are only partially aqueous in
`character can be regarded only as apparent pH values.
`
`BUFFER SOLUTIONS FOR STANDARDIZATION
`OF THE pH METER
`
`. Buffer ~olutions for Standardization are to be prepared as
`directed m the accompanying table.· Buffer salts of requisite
`purity can be obtained from the National Institute of Sci(cid:173)
`ence and Technology. Solutions may be stored in hard glass
`or polyethylene bottles fitted with a tight closure or carbon
`dioxide-absorbing tube (soda lime). Fresh solutions should
`be prepared at intervals not to exceed 3 months using car(cid:173)
`bon dioxide-free water. The table indicates the pH of the
`buffer solutions as a function of temperature. The instruc(cid:173)
`tions presented here are for the preparation of solutions
`having the designated molal (m) concentrations. For conve(cid:173)
`nience, and to facilitate their preparation, however, instruc(cid:173)
`tions are given in terms of dilution to a 1000-mL volume
`rather than specifying the use of 1000 g of solvent, which is
`the basis of the molality system of solution concentration.
`The indicated quantities cannot be computed simply with(cid:173)
`out additional information.
`Potassium Tetraoxalate, 0.05 m-Dissolve 12.61 g of
`KH3(C2O4)2 · 2H2O in water to make 1000 ml.
`· Commercially available buffer solutions for pH meter standardization, stan(cid:173)
`dardized by methods traceable to the National Institute of Standards and
`Technology {N1sn, labeled with a pH value accurate to 0.01 pH unit may be
`used. For standardization solutions having a pH lower than 4, a labeled accu(cid:173)
`racy of 0.02 is _acceptable. _Solutions prepared Iron: _ACS reagent grade matf!!r•
`1als or other suitable materials, 1n the stated quantities, may be used provided
`the pH of the resultant solution is the same as that of the solution prepared
`from the NIST certified material.
`
`Regeneron Exhibit 1019.006
`
`