RX0575
`
`2009
`
`USP 32
`
`NF 27
`Volume 1
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention meeting at Washington DC March 913
`2005 Prepared by the Council of Experts and published
`by the Board of Trustees
`
`Official from May 1 2009
`
`The designation on the cover of this publication USP NF
`2009 is for ease of identification only The publication
`contains two separate compendia The United States
`Pharmacopeia Thirty Second Revision and The National
`Formulary Twenty Seventh Edition
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway Rockville MD 20852
`
`REGITC00139018
`RX05750001
`
`Regeneron Exhibit 1082.001
`
`

`

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`requirements
`the new official dates The 2008 USP31NF26 and the Supplements and Interim Revision Announcements
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`and its Supplements
`and its Supplements
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`Revises
`USP31NF26
`USP31NF26
`USP32NF27
`USP32NF27 and First Supplement
`USP32NF27 and First Supplement
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`Copyright 0 2008 The United States Pharmacopeial Convention
`12601 Twinbrook Parkway Rockville MD 20852
`
`All rights reserved
`
`ISSN 01957996
`ISBN 1889788692
`
`Printed in the United States by United Book Press Baltimore Maryland
`
`REGITC00139019
`RX05750002
`
`Regeneron Exhibit 1082.002
`
`

`

`312
`
`K788 Particulate Matter in Injections
`
`Physical Tests
`
`USP 32
`
`Evaluation
`
`For preparations supplied in containers with a nominal volume of
`more than 100 mL apply the criteria of Test 2A
`For preparations supplied in containers with a nominal volume of
`less than 100 mL apply the criteria of Test 2B
`For preparations supplied in containers with a nominal volume of
`100 mL apply the criteria of Test 2B NOTETest 2A is used in
`the Japanese Pharmacopeia
`Test 2A Solutions for parenteral
`infusion or solutions for in
`jection supplied in containers with a nominal content of more than
`100 mLThe preparation complies with the test
`the average
`if
`in the units tested does not exceed 12
`number of particles present
`per mL equal
`to or greater than 10 1tm and does not exceed 2 per
`mL equal
`to or greater than 25 11M
`Test 2B Solutions for parenteral
`infusion or solutions for in
`jection supplied in containers with a nominal content of less than
`100 mLThe preparation complies with the test
`the average
`number of particles present
`in the units tested does not exceed 3000
`than 10 pm and does not exceed
`per container equal
`to or greater
`300 per container equal
`to or greater than 25 11m
`
`if
`
`789 PARTICULATE MATTER IN
`OPHTHALMIC SOLUTIONS
`
`Particulate matter consists of mobile randomly sourced extrane
`other than gas bubbles that cannot be quantitated
`ous substances
`by chemical analysis because of the small amount of material
`they
`and
`because
`of
`represent
`their heterogeneous
`composition
`Ophthalmic solutions should be essentially free from particles that
`inspection The tests described herein are
`can be observed on visual
`tests performed for the purpose of enumerating extraneous
`physical
`particles within specific size ranges
`Every ophthalmic solution for which the monograph includes a
`for Particulate matter is subject
`to the particulate matter limits
`test
`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 prepara
`tions that are suspensions emulsions or gels are exempt from these
`to the specific mono
`as are medical devices Refer
`requirements
`graph when a question of test applicability occurs
`Light obscuration and microscopic procedures
`for the determina
`tion of particulate matter
`in ophthalmic solutions are identical
`to
`those for injections therefore where appropriate Particulate Mat
`ter in Injections 788 is crossreferenced This chapter provides a
`test approach in two stages The ophthalmic solution is first
`tested
`by the light obscuration procedure stage 1 If
`to meet the
`stage 2
`prescribed limits it must pass the microscopic procedure
`limits Where
`with its own set of test
`reasons
`for technical
`the
`ophthalmic solution cannot be tested by light obscuration micro
`scopic testing may be used exclusively Documentation is required
`the light obscuration procedure
`of
`demonstrating that
`is incapable
`invalid results
`testing the ophthalmic solution or that
`it produces
`is expected that most articles will meet the requirements on the
`It
`basis of the light obscuration test alone however
`it may be neces
`sary to test some articles by the light obscuration test
`followed by
`to reach a conclusion on conformance to re
`the microscopic test
`quirements Any product that
`is not a pure solution having a clarity
`and a viscosity approximating those of water may provide errone
`ous data when analyzed by the light obscuration counting method
`
`fails
`
`it
`
`Such materials may be analyzed by the microscopic
`counting
`method In some instances the viscosity of a material
`to be tested
`may be sufficiently high so as to preclude its analysis by either test
`method In this event a quantitative dilution 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 examining a
`discrete unit or group of units for particulate matter cannot be extra
`remain untested Thus
`polated with certainty to other units that
`sampling plans based on known operational factors must be devel
`oped if valid inferences are to be drawn from observed data to char
`the level of particulate matter
`in a large group of units
`acterize
`Sampling plans need to be based on consideration of product vol
`ume particle numbers historically found to be present
`in compari
`son to limits particle size distribution of particles present and vari
`ability of particle counts between units
`
`LIGHT OBSCURATION PARTICLE COUNT
`TEST
`
`This test applies to ophthalmic solutions including solutions con
`stituted from sterile solids for which a test for Particulate matter is
`specified in the individual monograph The test counts
`suspended
`particles that are solid or liquid
`Instrument
`Apparatus
`Test
`Test
`Standardization
`Environment Test Procedure and CalculationsProceed as di
`rected for Light Obscuration Particle Count Test under Particulate
`in Injections 788
`Matter
`InterpretationThe ophthalmic
`solution meets the require
`the average number of particles present
`ments of the test
`in the
`units tested does not exceed the appropriate value listed in Table
`the average number of particles exceeds the limit
`If
`test
`the article
`by the Microscopic Particle Count Test
`
`if
`
`Table 1 Light Obscuration
`
`Test Particle Count
`
`Number of particles
`
`Diameter
`
`10 ttm
`50 per mL
`
`25 rim
`5 per mL
`
`MICROSCOPIC PARTICLE COUNT TEST
`
`Some articles cannot be tested meaningfully by light obscuration
`In such cases individual monographs clearly specify that only a mi
`is to be performed The microscopic parti
`particle count
`croscopic
`cle count
`test enumerates
`subvisible essentially solid particulate
`matter
`in ophthalmic solutions after collection on a microporous
`membrane filter Some ophthalmic solutions such as solutions that
`readily because of their high viscosity may be ex
`do not
`filter
`empted from analysis using the microscopic test
`When performing the microscopic test do not attempt to size or
`enumerate amorphous semiliquid or otherwise morphologically in
`distinct materials that have the appearance of a stain or discolora
`tion on the membrane surface These materials show little or no sur
`face relief and present a gelatinous or film like appearance Because
`1 pm or
`in solution this material consists of units on the order of
`or deformation
`less which may be counted only after aggregation
`on an analytical membrane interpretation of enumeration may be
`aided by testing a sample of the solution by the light obscuration
`particle count method
`Test Procedure and
`Test Apparatus Test Environment
`Enumeration of ParticlesProceed as directed for Microscopic
`in Injections 788
`Particle Count Test under Particulate Matter
`
`REGITC00139020
`RX05750003
`
`Regeneron Exhibit 1082.003
`
`

`

`USP 32
`
`Physical Tests I 791 pH 313
`
`Interpretation The ophthalmic
`solution meets the require
`the average number of particles present
`ments of the test
`in the
`units tested does not exceed the appropriate value listed in Table 2
`
`if
`
`pension the ionization constant of the acid or base the dielectric
`constant of the medium the liquid junction potential which may
`1 pH unit and the hydrogen
`give rise to errors of approximately
`are all changed For these rea
`ion response of the glass electrode
`sons the values so obtained with solutions that are only partially
`can be regarded only as apparent pH values
`in character
`aqueous
`
`BUFFER SOLUTIONS FOR
`STANDARDIZATION OF THE pH METER
`
`as di
`Buffer Solutions for Standardization are to be prepared
`rected in the accompanying table Buffer salts of requisite purity
`Institute of Science and Technol
`can be obtained from the National
`ogy 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 carbon dioxide free water The table indicates
`the
`pH of the buffer solutions as a function of temperature The instruc
`tions presented here are for the preparation of solutions having the
`designated molal m concentrations For convenience
`and to facili
`tate their preparation however
`instructions are given in terms of
`dilution to a 1000mL volume rather than specifying the use of
`1000 g of solvent which is the basis of the molality system of solu
`The indicated quantities cannot
`tion concentration
`be computed
`simply without additional
`information
`005 mDissolve 1261 g of
`Potassium Tetraoxalate
`2E20 in water to make 1000 mL
`KH3C2042
`005 mDissolve 1012 g
`Potassium Biphthalate
`of
`for 1 hour in water to make
`KHC811404previously dried at 1100
`1000 mL
`Equimolal Phosphate 005 mDissolve 353 g of Na2HPO4
`and 339 g of KH2PO4 each previously dried at 120° for 2 hours in
`water to make 1000 mL
`Sodium Tetraborate 001 mDissolve 380 g of Na2B407
`to make 1000 mL Protect
`10H20 in water
`from absorption of car
`bon dioxide
`Calcium Hydroxide saturated at 25° Shake an excess of
`calcium hydroxide with water and decant at 25° before use Protect
`from absorption of carbon dioxide
`Because of variations in the nature and operation of the available
`pH meters it
`is not practicable to give universally applicable direc
`tions for the potentiometric determinations of pH The general prin
`ciples to be followed in carrying out
`the instructions provided for
`each instrument by its manufacturer are set
`forth in the following
`paragraphs Examine the electrodes and if present
`the salt bridge
`prior to use If necessary replenish the salt bridge solution and ob
`indicated by the instrument or electrode
`serve other precautions
`manufacturer
`
`available buffer solutions for pH meter standardization
`Commercially
`Institute of Standards and Technology NIST
`by methods traceable to the National
`labeled with a pH value accurate
`to 001 pH unit may be used For standardization
`solutions having a pH lower than 4 a labeled accuracy
`of 002 is acceptable Solutions
`prepared from ACS reagent grade materials or other suitable materials in 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
`
`standardized
`
`Table 2 Microscopic Method Particle Count
`Diameter
`25 gm
`5 per mL
`
`Number of
`
`10 tm
`50 per mL
`
`50 Itm
`2 per mL
`
`particles
`
`791 pH
`
`For compendial purposes pH is defined as the value given by a
`instrument pH
`suitable properly standardized
`potentiometric
`meter capable of reproducing pH values to 002 pH unit using an
`sensitive to hydrogen ion activity the glass elec
`indicator electrode
`trode and a suitable reference electrode The instrument should be
`capable of sensing the potential across the electrode pair and for
`pH standardization purposes applying an adjustable potential
`to the
`circuit by manipulation of standardization zero asymmetry
`or calibration control and should be able to control
`the change in
`millivolts per unit change in pH reading through a temperature
`andor slope control Measurements are made at 25 ± 2° unless
`otherwise specified in the individual monograph or herein
`The pH scale is defined by the equation
`pH = pHs + E Es I k
`in which E and Es are the measured potentials where the galvanic
`represented by pH and the ap
`the solution under test
`cell contains
`represented by pHs
`propriate Buffer Solution for Standardization
`The value of k is the change
`in potential per unit
`respectively
`in pH and is theoretically 005916 + 0000198t
`25°
`change
`volts at any temperature t
`the definitions of pH the pH scale
`It should be emphasized that
`and the values assigned to the Buffer Solutions for Standardization
`are for the purpose of establishing a practical operational system so
`between laboratories The pH values
`that results may be compared
`thus measured
`do not correspond exactly to those obtained by the
`definition pH =
`log all So long as the solution being measured is
`sufficiently similar in composition to the buffer used for standardi
`zation the operational pH corresponds
`fairly closely to the theoreti
`cal 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 related to the activity of the hydro
`gen ion in aqueous solutions
`a pH meter is standardized by use of an aqueous buffer
`Where
`and then used to measure the pH of a nonaqueous
`solution or sus
`
`Tempera
`ture °C
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`Potassium Tetraoxa
`late 005 in
`167
`167
`168
`168
`168
`169
`169
`170
`171
`
`pH Values of Buffer Solutions for Standardization
`Sodium Tetraborate
`001 in
`933
`928
`923
`918
`914
`910
`907
`904
`901
`
`Equimolal Phosphate
`005 m
`692
`690
`688
`686
`685
`684
`684
`683
`683
`
`Potassium Biphtha
`late 005 m
`400
`400
`400
`401
`402
`402
`404
`405
`406
`
`Calcium Hydroxide
`Saturated at 25°
`1300
`1281
`1263
`1245
`1229
`1213
`1198
`1184
`1171
`
`REGITC00139021
`RX05750004
`
`Regeneron Exhibit 1082.004
`
`