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`USP
`NF
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`I I
`
`The Official Compendia of Standards
`
`Volume 1
`
`1 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`2007
`
`USP 30
`
`NF 25
`
`Volume I
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of The United States Pharmacopeial
`Convention, meeting at Washington, D. C., March 9-13,
`2005. Prepared by the Council of Experts and published
`by the Board of Trustees
`
`Official from May 1, 2007
`
`The designation on the cover of this publication, "USP NF
`2007," is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Thirtieth Revision, and the National
`Formulary, Twenty-Fifth Edition.
`
`Goodwin Procter LLP
`Ubrary
`The New York TfmeQ BuUdlng
`620 Eighth Avenue
`New York, NY 10018-1400
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`2 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`SIX-MONTH IMPLEMENTATION GUIDELINE
`
`Beginning with USP30-NF25, the United States Pharmacopeid-National Formulary and its Supplements will become official six months
`after being released to the public. The USP-NF, which is released on November 1 of each year, will become official on May 1 of the following
`year.
`This change was adopted to give users more time to bring their methods and procedures into compliance with new and revised USP-NF
`requirements.
`The table below describes the new official dates. The 2006 USP29-NF24, and the Supplements and Interim Revision Announcements (IRAs)
`to that edition, will be official until May 1, 2007, at which time the USP30-NF25 becomes official.
`
`Publication
`
`Release Date
`
`Official Date
`
`Official Until
`
`USP30-NF25
`
`Nov. 1, 2006
`
`May 1, 2007
`
`May 1, 2008 ( except as superceded by Supplements, IRAs, and
`Revision Bulletins)
`May 1, 2008 ( except as superceded by Second Supplement, IRAs,
`and Revision Bulletins)
`May 1, 2008 ( except as superceded by IRAs and Revision
`Bulletins)
`May 1, 2009 ( except as superceded by Supplements, IRAs, and
`Revision Bulletins)
`IRAs will continue to become official on the first day of the second month of the Pharmacopeial Forum (PF) issue in which they are
`published as final. For instance, IRAs published as final in the May-June PF (issue 3) will become official on June 1. This table gives the details
`of the IRAs that will apply to USP29-NF24 and USP30-NF25.
`
`First Supplement
`
`Feb. 1, 2007
`
`Aug. 1, 2007
`
`Second Supplement
`
`June 1, 2007
`
`Dec. 1, 2007
`
`USP31 - NF26
`
`Nov. 1, 2007
`
`May 1, 2008
`
`IRA*
`
`Release Date
`
`Official Date
`
`Revises
`
`USP29-NF24 and its Supplements
`Feb. 1, 2007
`Jan. 1, 2007
`Jan. 1, 2007 IRA, PF 33(1)
`USP29-NF24 and its Supplements
`April 1, 2007
`Mar. 1, 2007
`Mar. 1, 2007 IRA, PF 33(2)
`USP30-NF25
`June 1, 2007
`May 1, 2007
`May 1, 2007 IRA, PF 33(3)
`USP30-NF25 and First Supplement
`Aug. 1, 2007
`July 1, 2007
`July 1, 2007 IRA, PF 33(4)
`USP30-NF25 and First Supplement
`Oct. 1, 2007
`Sept. 1, 2007
`Sept. 1, 2007 IRA, PF 33(5)
`USP30-NF25 and its Supplements
`Dec. 1, 2007
`Nov. 1, 2007
`Nov. 1, 2007 IRA, PF 33(6)
`USP30- NF25 and its Supplements
`Feb. 1, 2008
`Jan. 1, 2008
`Jan. 1, 2008 IRA, PF 34(1)
`USP30-NF25 and its Supplements
`April 1, 2008
`Mar. 1, 2008
`Mar. 1, 2008 IRA, PF 34(2)
`*NOTE-Beginning January 1, 2007, USP will cease identifying IRAs numerically (First, Second, etc.) and instead will designate them by the
`date on which they are published.
`Revision Bulletins published on the USP website will continue to become official immediately upon publication, unless the Revision Bulletin
`specifies otherwise.
`General Chapters, monographs, or monograph revisions that contain a specific official date shall continue to become official upon such
`specified date, which supercedes the general official date for the publication.
`For more information about the change in official dates, please visit the USP website at http://www.usp.org.
`
`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclusion in The United States Pharmacopeia or in the National Formula,y of a monograph on any drug in respect to which patent or
`trademark rights may e?.(i1:,t _sh'clll·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_.llllcl :privileges are vested in the patent or trademark owner, and no other person may exercise the same
`without express p~rmissi~l).:,:·authority, .or)icense 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.
`
`Copyright © 2006 The United States Pharmacopeial Convention
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0 195-7996
`ISBN 1-889788-47-3
`Printed in the United States by Port City Press, Baltimore
`
`3 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`single
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`USP 30
`
`Physical Tests I (788) Particulate Matter in Injections
`
`321
`
`(788) PARTICULATE MATTER IN
`INJECTIONS
`
`Particulate matter consists of mobile, randomly-sourced, extrane(cid:173)
`ous substances, other than gas bubbles, that cannot be quantitated by
`chemical analysis due to the small amount of material that it
`represents a~d to its_ heteroge~eous composi~ion. ~je~table solu(cid:173)
`tions includmg solut10ns constituted from stenle solids mtended for
`pare~teral use, is essentially free from particulate matter that can be
`observed on visual inspection. The tests described herein are
`physical tests performed for the purpose of enumerating subvisible
`extraneous particles within specific size ranges.
`Microscopic and light obscuration procedures for the determina(cid:173)
`tion of particulate matter are given herein. This chapter provides a
`test approach in two st~ges. The injection is first tested by the light
`obscuration procedure (stage 1). If it fails to meet the prescribed
`limits, it must pass the microscopic procedure (stage 2) with its own
`set of test limits. Where for technical reasons the injection cannot be
`tested by light obscuration, microscopic testing may be used
`exclusively. Documentation demonstrating that the light obscuration
`procedure is incapable of testing the injection or produces invalid
`results is required in each case. It is expected that most articles will
`meet the requirements on the basis of the light obscuration test alone;
`however, 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.
`All large-volume injections for single-dose infusion and those
`small-volume injections for which the monographs specify such
`requirements are subject to the particulate matter limits set forth for
`the test being applied, unless otherwise specified in the individual
`monograph. Excluded from the requirements of this chapter are
`injections intended solely for intramuscular and subcutaneous
`administration.
`Not all injection formulations can be examined for particles by
`one or both of these tests. 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 method. Emulsions, colloids, and liposomal prepara(cid:173)
`tions are examples. Similarly, products that produce air or gas
`bubbles when drawn into the sensor, such as bicarbonate-buffered
`formulations, may also require microscopic testing. Refer to the
`specific monographs when a question of test applicability occurs.
`Higher limits are appropriate for certain articles and will be specified
`in the individual monographs.
`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 for large-volume and small-volume
`injections, the results obtained in examining a discrete unit or group
`of units for particulate matter cannot be extrapolated with certainty
`to other units that remain untested. Thus, statistically sound
`sampling plans based upon known operational factors must be
`developed if valid inferences are to be drawn from observed data to
`characterize the level of particulate matter in a large group of units.
`Sampling plans should be based on consideration of product volume,
`numbers of particles 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
`
`USP Reference Standards ( 11 )-USP Particle Count RS.
`The test applies to large-volume injections labeled as containing
`more than 100 mL, unless otherwise specified in the individual
`mo_nograph. It counts suspended particles that are solid or liquid.
`This test applies also to single-dose or multiple-dose small-volume
`
`injections labeled as containing 100 mL or less that are either in
`solution or in solution constituted from sterile solids, where a test for
`particulate matter is specified in the individual monograph. Products
`for which the individual monograph specifies that the label states
`that the product is to be used with a final filter are exempt from these
`requirements.
`
`Test Apparatus
`
`The apparatus is an electronic, liquid-borne particle counting
`system that uses a light-obscuration sensor with a suitable sample(cid:173)
`feeding device. A variety of suitable devices of this type are
`commercially available. It is the responsibility of those performing
`the test to ensure that the operating parameters of the instrumentation
`are appropriate to the required accuracy and precision of the test
`result, and that adequate training is provided for those responsible
`for the technical performance of the test.
`It is important to note that for Pharmacopeial applications the
`ultimate goal is that the particle counter reproducibly size and count
`particles present in the injectable material under investigation. The
`instruments available range from systems where calibration and
`other components of standardization must be carried out by manual
`procedures to sophisticated systems incorporating hardware- or
`software-based functions for the standardization procedures. Thus, it
`is not possible to specify exact methods to be followed for
`standardization of the instrument, and it is necessary to emphasize
`the required end result of a standardization procedure rather than a
`specific method for obtaining this result. This section is intended to
`emphasize the criteria ·that must be met by a system rather than
`specific methods to be used in their determination. It is the
`responsibility of the user to apply the various methods of
`standardization applicable to a specific instrument. Critical opera(cid:173)
`tional criteria consist of the following.
`Sensor Concentration Limits-Use an instrument that has a
`concentration limit (the maximum number of particles per mL)
`identified by the manufacturer that is greater than the concentration
`of particles in the test specimen to be counted. The vendor-certified
`concentration limit for a sensor is specified as that count level at
`which coincidence counts due to simultaneous presence of two or
`more particles in the sensor view volume comprise less than 10% of
`the counts collected for 10-µm particles.
`Sensor Dynamic Range-The dynamic range of the instrument
`used (range of sizes of particles that can be accurately sized and
`counted) must include the smallest particle size to be enumerated in
`the test articles.
`
`Instrument Standardization
`The following discussion of instrument standardization empha(cid:173)
`sizes performance criteria rather than specific methods for calibrating
`or standardizing a given instrument system. This approach is
`particularly evident in the description of calibration, where
`allowance must be made for manual methods as well as those
`based on firmware, software, or the use of electronic testing
`instruments. Appropriate instrument qualification is essential to
`performance of the test according to requirements. Since different
`brands of instruments may be used in the test, the user is responsible
`for ensuring that the counter used is operated according to the
`manufacturer's specific instructions; the principles to be followed to
`ensure that instruments operate within acceptable ranges are defined
`below.
`·
`The following information for instrument standardization helps
`ensure that the sample volume accuracy, sample flow rate, particle
`size response curve, sensor resolution, and count accuracy are
`appropriate to performance of the test. Conduct these procedures at
`intervals of not more than six months.
`
`SAMPLE VOLUME ACCURACY
`
`Since the particle count from a sample aliquot varies directly with
`the volume of fluid sampled, it is important that the sampling
`accuracy is known to be within a certain range. For a sample volume
`
`4 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`322
`
`(788) Particulate Matter in Injections / Physical Tests
`
`USP 30
`
`[}SP 3l
`
`determination, determine the dead (tare) volume in the sample feeder
`with filtered distilled or deionized water that has been passed
`through a filter having a 1.2-µm or finer porosity. Transfer a volume
`of filtered distilled or deionized water that is greater than the sample
`volume to a container, and weigh. Withdraw through the sample
`feeding device a volume that is appropriate for the specific sampler,
`and again weigh the container. Determine the sample volume by
`subtracting the tare volume from the combined sample plus tare
`volumes. Verify that the value obtained is within 5% of the
`appropriate sample volume for the test. Alternatively, the sample
`volume may be determined using a suitable Class A graduated
`cylinder (see Volumetric Apparatus (31) ). [NOTE-Instruments of this
`type require a variable tare volume. This is the amount ot: sample
`withdrawn prior to counting. This volume may be determmed for
`syringe-operated samplers by setting the sample vol~me to zer? and
`initiating sampling, so that the only volume of solut10n drawn 1s the
`tare. Subtract the tare volume from the total volume of solution
`drawn in the sampling cycle to determine the sample volume.]
`
`SAMPLE FLOW RATE
`
`Verify that the flow rate is within the manufacturer's specifications
`for the sensor used. This may be accomplished by using a calibrated
`stopwatch to measure the time required for the instrument to
`withdraw and count a specific sample volume (i.e., the time between
`beginning and ending of the count cycle as denoted by instrument
`indicator lights or other means). Sensors may be operated accurately
`over a range of flow rates. Perform the Test Procedure at the same
`flow rate as that selected for calibration of the instrument.
`
`CALIBRATION
`
`Use one of the following methods.
`Manual Method-Calibrate the instrument with a minimum of
`three calibrators, each consisting of near-monosize polystyrene
`spheres having diameters of about 10, 15, and 25 µ1?1, in an aqu~o~s
`vehicle.* The calibrator spheres must have a mean diameter ofw1thm
`5% of the 10-, 15-, and 25-µm nominal diameters and be
`standardized against materials traceable to NIST standard reference
`materials. The number of spheres counted must be within the
`sensor's concentration limit. Prepare suspensions of the calibrator
`spheres in water at a concentration of 1000 to 5000 particles per mL,
`and determine the channel setting that corresponds to the highest
`count setting for the sphere distribution. This is determined by using
`the highest count threshold setting to split the distribution into two
`bins containing equal numbers of counts, with the instrument set in
`the differential count mode (moving window half-count method).
`Use only the central portion of the distribution in this calculat_ion to
`avoid including asymmetrical portions of the peak. The port10n of
`the distribution, which must be divided equally, is the count window.
`The window is bounded by threshold settings that will define a
`threshold voltage window of ± 20% around the mean diameter of
`the test spheres. The window is intended to include all single
`spheres, taking into account the standard deviation of the spheres
`and the sensor resolution, while excluding noise and aggregates of
`spheres. The value of 20% was chosen based on the W?r~t-case
`sensor resolution of 10% and the worst-case standard deviation of
`the spheres of 10%. Since the thresholds are proportional to the area
`of the spheres rather than the diameter, the lower and upper voltage
`settings are determined by the equations:
`Vr = 0.64V5
`in which Vr is the lower voltage setting and V5 is the voltage at the
`peak center, and
`
`in which Vu is the upper voltage setting.
`
`Vu= 1.44Vs
`
`Once the center peak thresholds are determined, use these
`thresholds for the standards to create a regression of log voltage
`versus log particle size, from which the instrument settings for the
`10- and 25-µm sizes can be determined.
`Automated Method-The calibration (size response) curve may
`be determined for the instrument-sensor system by the use of
`validated software routines offered by instrument vendors; these may
`be included as part of the instrument software or used in conjunction
`with a microcomputer interfaced to the counter. The use of these
`automated methods is appropriate if the vendor supplies written
`certification that the software provides a response curve equivalent to
`that attained by the manual method and if the automated calibration
`is validated as necessary by the user.
`Electronic Method-Using a multichannel peak height analyzer,
`determine the center channel of the particle counter pulse response
`for each standard suspension. This peak voltage setting becomes the
`threshold used for calculation of the voltage response curve for the
`instrument. The standard suspensions to be used for the calibration
`are run in order, and median pulse voltages for each are determined.
`These thresholds are then used to generate the size response curve
`manually or via software routines. The thresholds determined from
`the multichannel analyzer data are then transferred to the counter to
`complete the calibration. If this procedure is used with a comparator(cid:173)
`based instrument, the comparators of the counter must be adjusted
`accurately beforehand.
`
`SENSOR RESOLUTION
`
`The particle size resolution of the instrumental particle counter is
`dependent upon the sensor used and may vary with individual
`sensors of the same model. Determine the resolution of the particle
`counter for 10-µm particles using the 10-µm calibrator spheres. The
`relative standard deviation of the size distribution of the standard
`particles used is not more than 5%. Acceptable methods of
`determining particle size resolution are (1) manual determination
`of the amount of peak broadening due to instrument response; (2)
`using an electronic method of measuring and sorting particle sensor
`voltage output with a multichannel analyzer; and (3) automated
`methods.
`Manual Method-Adjust the particle counter to operate in the
`cumulative mode or total count mode. Refer to the calibration curve
`obtained earlier, and determine the threshold voltage for the 10-µm
`spheres. Adjust 3 channels of the counter to be used in the
`calibration procedure as follows:
`Channel 1 is set for 90% of the threshold voltage.
`Channel 2 is set for the threshold voltage.
`Channel 3 is set for 110% of the threshold voltage.
`Draw a sample through the sensor, observing the count in Channel
`2. When the particle count in that channel has reached approximately
`1000, stop counting, and observe the counts in Channels 1 and 3.
`Check to see if the Channel 1 count and the Channel 3 count are
`1.68 ± 10% and 0.32 ± 10%, respectively, of the count in Channel
`2. If not, adjust Channel 1 and Channel 3 thresholds to meet these
`criteria. When these criteria have been satisfied, draw a sample of
`suspension through the counter until the counts in Channel 2 have
`reached approximately 10,000, or until an appropriate volume (e.g.,
`10 mL) of the sphere suspension has been counted. Verify that
`Channel 1 and Channel 3 counts are 1.68 ± 3% and 0.32 ± 3%,
`respectively, of the count in Channel 2.
`Record the particle size for the thresholds just determined for
`Channels 1, 2, and 3. Subtract the particle size for Channel 2 frorn
`the size for Channel 3. Subtract the particle size for Channel 1 fro~
`the size for Channel 2. The values so determined are the observe
`standard deviations on the positive and negative side of the m~an
`count for the 10-µm standard. Calculate the percentage of resolution
`of the sensor by the formula:
`
`· ASTM standard F658-87 provides useful discussions pertaining to
`calibration procedures applying near-monosize latex spheres.
`
`in which S0 is the highest observed standard deviation determined
`for the sphere; S5 is the supplier's reported standard deviation for the
`
`spheres;
`the supp
`Autor
`deterrnin
`This sol
`conjunct
`of these
`written
`determin
`resolutio
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`
`Deter
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`(total) n
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`discard
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`suspens
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`Proper
`counts
`counte
`
`5 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`'P 30
`
`USP 30
`
`Physical Tests I (788) Particulate Matter in Injections
`
`323
`
`these
`oltage
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`andard
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`in the
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`:hannel
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`± 3%,
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`ermined
`1 for the
`
`spheres; and D is the diameter, in µm, of the spheres as specified by
`the supplier. The resolution is not more than 10%.
`Automated Method-Software that allows for the automated
`determination of sensor resolution is available for some counters.
`This software may be included in the instrument or used in
`conjunction with a microcomputer interfaced to the counter. The use
`of these automated methods is appropriate if the vendor supplies
`written certification that the software provides a resolution
`determination equivalent to the manual method and if the automated
`resolution determination is validated as necessary by the user.
`Electronic Method-Record the voltage output distribution of
`the particle sensor, using a multichannel analyzer while sampling a
`suspension of the 10-µm particle size standard. To determine
`resolution, move the cursor of the multichannel analyzer up and
`down the electric potential scale from the median pulse voltage to
`identify a channel on each side of the 10-µm peak that has
`approximately 61 % of the counts observed in the center channel.
`Use of the counter size response curve to convert the m V values of
`these two channels to particle sizes provides the particle size at
`within 1 standard deviation of the 10-µm standard. Use these values
`to calculate the resolution as described under Manual Method.
`
`PARTICLE COUNTING ACCURACY
`
`Determine the particle counting accuracy of the instrument, using
`Method 1 (for small-volume injections) or Method 2 (for large(cid:173)
`volume injections).
`Method 1-
`Procedure-Prepare the suspension and blank using the USP
`Particle Count RS. With the instrument set to count in the cumulative
`(total) mode, collect counts at settings of greater than or equal to 10
`µm and greater than or equal to 15 µm. Mix the blank by inverting
`25 times within 10 seconds, and degas the mixture by sonicating ( at
`80 to 120 watts) for about 30 seconds or by allowing to stand.
`Remove the closure from the container, and gently stir the contents
`by hand-swirling or by mechanical means, taking care not to
`introduce air bubbles or contamination. Stir continuously throughout
`the analysis. Withdraw directly from the container three consecutive
`volumes of not less than 5 mL each, obtain the particle counts, and
`discard the data from the first portion. [NOTE-Complete the
`procedure within five minutes.] Repeat the procedure, using the
`suspension in place of the blank. From the averages of the counts
`resulting from the analysis of the two portions of the suspension at
`greater than or equal to 10 µm and from the analysis of the two
`portions of the blank at greater than or equal to 10 µm, calculate the
`number of particles in each mL by the formula:
`
`(Ps - Po)! V
`in which Ps is the average particle count obtained from the
`suspension; P0 is the average particle count obtained from the blank;
`and Vis the average volume, in mL, of the 4 portions tested. Repeat
`the calculations, using the results obtained at the setting of not less
`than 15 µm.
`Interpretation-The instrument meets the requirements for
`Particle Counting Accuracy if the count obtained at greater than
`or equal to 10 µm and the ratio of the counts obtained at greater than
`or equal to 10 µm to those obtained at greater than or equal to 15 µm
`conform to the values that accompany the USP Particle Count RS. If
`the instrument does not meet the requirements for Particle Counting
`Accuracy, repeat the procedure using the remaining suspension and
`blank. If the results of the second test are within the limits given
`above, the instrument meets the requirements of the test for Particle
`Counting Accuracy. If on the second attempt the system does not
`meet the requirements of the test, determine and correct the source of
`the failures, and retest the instrument.
`Method 2-
`. Procedure-Using standard calibrator spheres having a nominal
`diameter of 15 to 30 µm, prepare a suspension containing between
`50 and 200 particles per mL. Degas the suspension by sonicating (at
`80 to 120 watts) for about 30 seconds or by allowing to stand.
`Properly suspend the particles by stirring gently, and perform five
`counts on 5-mL volumes of the suspension, using the particle
`counter 10-µm size threshold. Obtain the mean cumulative particle
`
`count per mL. Pipet a volume of this suspension containing 250 to
`500 particles into a filter funnel prepared as described for Filtration
`Apparatus under Microscopic Particle Count Test. After drying the
`membrane, count the total number of standard spheres collected on
`the membrane filter. This count should be within 20% of the mean
`instrumental count per mL for the suspension.
`
`Test Environment
`Perform the test in an environment that does not contribute any
`significant amount of particulate matter. Specimens must be cleaned
`to the extent that any level of extraneous particles added has a
`negligible effect on the outcome of the test. Preferably, the test
`specimen, glassware, closures, and other required equipment are
`prepared in an environment protected by high-efficiency particulate
`air (HEPA) filters, and nonshedding garments and powder-free
`gloves are worn throughout the preparation of samples.
`Cleanse glassware, closures, and other required equipment,
`preferably by immersing and scrubbing in warm, nonionic detergent
`solution. Rinse in flowing tap water, and then rinse again in flowing
`filtered distilled or deionized water. Organic solvents may also be
`used to facilitate cleaning. [NOTE-These steps describe one way to
`clean equipment; alternatively, particulate-free equipment may be
`obtained from a suitable vendor.] Finally, rinse the equipment in
`filtered distilled or deionized water, using a hand-held pressure
`nozzle with final filter or other appropriate filtered water source, such
`as distilled or deionized water passed through a capsule filter having
`a 1.2-µm or finer porosity.
`To collect blank counts, use a cleaned vessel of the type and
`volume representative of that to be used in the test. Place a 50-mL
`volume of filtered distilled or deionized water in the vessel, and
`agitate the water sample in the cleaned glassware by inversion or
`swirling. [NOTE-A smaller volume, consistent with the article to be
`counted, can be used.] Degas by sonicating (at 80 to 120 watts) for
`about 30 seconds or by allowing to stand. Swirl the vessel containing
`the water sample by hand or agitate by mechanical means to suspend
`particles. Withdraw and obtain the particle counts for three
`consecutive samples of not less than 5 mL each, disregarding the
`first count. If more than 10 particles of 10-µm or greater size, or
`more than 2 particles of 25-µm or greater size are observed in the
`combined 10-mL sample, the environment is not suitable for
`particulate analysis: the filtered distilled or deionized water and
`glassware have not been properly prepared or the counter is
`generating spurious counts. In this case, repeat the preparatory steps
`until conditions of analysis are suitable for the test.
`
`Test Procedure
`
`TEST PREPARATION
`
`Prepare the test specimens in the following sequence. Outside of
`the laminar enclosure, remove outer closures, sealing bands, and any
`loose or shedding paper labels. Rinse the exteriors of the containers
`with filtered distilled or deionized water as directed under Test
`Environment. Protect the containers from environmental contamina(cid:173)
`tion until analyzed. Withdraw the contents of the containers under
`test in a manner least likely to generate particles that could enter the
`sample. Contents of containers with removable stoppers may be
`withdrawn directly by removing the closures. Sampling devices
`having a needle to penetrate the unit closure may also be employed.
`Products packaged in flexible plastic containers may be sampled by
`cutting the medication or administration port tube or a comer from
`the unit with a suitably cleaned razor blade or scissors.
`Dry or lyophilized products may be constituted either by
`removing the closure to add diluent or by injecting diluent with a
`hypodermic syringe having a 1.2-µm or finer syringe filter. If test
`specimens are to be pooled, remove the closure and empty the
`contents into a clean container.
`The number of test specimens must be adequate to provide a
`statistically sound assessment of whether a batch or other large group
`of units represented by the test specimens meets or exceeds the
`limits. If the volume in the container is less than 25 mL, test a
`solution pool of 10 or more units. Single small-volume injection
`units may be tested if the individual unit volume is 25 mL or more.
`
`6 of 22
`
`Fresenius Kabi
`Exhibit 1028
`
`

`

`324
`
`(788) Particulate Matter in Injections / Physical Tests
`
`USP 30 USP 30
`
`For large-volume injections, individual units are tested. For large(cid:173)
`volume injections or for small-volume injections where the
`individual unit volume is 25 mL or more, fewer than 10 units may
`be tested, based on the definition of an appropriate sampling plan.
`
`per mL would be multiplied by 10 to obtain the test result based on
`the 10-mL maximum dose. [NOTE-For the calculations of test
`results, consider this maximum dose portion to be the equivalent of
`the contents of one full container.]
`
`PRODUCT DETERMINATION
`
`Calculations
`
`Depending upon the dosage form being tested, proceed as directed
`under the appropriate category below.
`Liquid Preparations-
`Volume in Container Less than 25 ml-Prepare the containers a