”-3r'*~___
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, D. 0,
`March 8—10, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 1995
`
` THE UNITED STATES PHARMACOPEIA
`
`“51%SINCE 1820
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`SHIRE EX. 2017
`KVK v. SHIRE
`
`IPR2018—00290
`
`Page 1
`
`Page 1
`
`SHIRE EX. 2017
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`NOTICE AND WARNING
`
`Concerning US. 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
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`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 0r 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.
`© 1994
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 0-913595-76-4 (Cloth)
`0‘913595-81-0 (leather)
`
`Printed by Rand McNally, 1133 County Street, Taunton, MA 02780—3795
`
`Page 2
`
`Page 2
`
`

`

`1838
`
`.
`
`T’ = T"
`
`WEIGHT VARIATION
`
`l
`(905) Uniformity of Dosage Units / Physical Tests
`I
`quirements of this chapter apply both to dosage f
`molar heat of fusion of the major component, R = gas constant,
`
`a single active ingredient and to dosage fOI'ms c 0rIns .
`-
`and K = distribution ratio of solute betv'veen the solid and liquid
`-'
`more active ingredients.
`_
`Omal
`phases.
`
`' -
`Weight Variation requirements ma be a
`‘
`Assuming that the temperature range is small and that no solid
`uct is a liquid-filled soft capsule, or wgere $23de I
`
`solutions are formed (K = 0), integration of the van’t Hoff equa—
`contains 50 mg or more of an active ingredient cum to _-_
`
`tion yields the following relationship between mole fraction of
`
`or more, by weight, of the dosage—form unit. UomprJ-
`impurity and the melting-point depression:
`respect to other active ingredients, if present in lessmf0 '
`
`TomeAH
`-
`is demonstrated by Content Uniformity require“? Pr.
`(2)
`X2=(——m)—li
`
`Variation requirements may be applied to solids (incelms:
`
`solids) that contain no inactive or active added sub ud'
`Weight Variation requirements may be applied :ta '1'
`
`in which Ta = melting point of the pure compound, in DK, and
`° .
`eluding sterile solids), with or without inactive or
`Tm = melting point of the test specimen, in K.
`
`substances, that have been prepared from true solutiofimtw‘
`With no solid solution formation, the concentration of impurity
`
`dried in the final containers, and labeled to indicate St; Ii.
`in the liquid phase at any temperature during the melting is
`
`‘5.
`of preparation.
`inversely proportional to the fraction melted at that temperature,
`'
`~
`Content Uniformity requirements ma be a
`-
`and the melting-point depression is directly proportional to the
`The test for Content Uniformity is requiiled {03511113353
`'i'
`
`mole fraction of impurity. A plot of the observed test specimen
`including film-coated tablets, for transdermal system:d
`temperature, Ts, versus the reciprocal of the fraction melted,
`
`pensions in single-unit containers or in soft capsules and' t_I.
`l /F, at temperature TS, should yield a straight line with the slope
`
`surized metered—dose inhalers. The test for Content Um:
`equal to the melting-point depression (Ta — Tm). The theoretical
`
`is required for solids (including sterile solids) that contain 5"
`melt/ing point of the pure compound is obtained by extrapolation
`to 1 F = 0:
`or active added substances, except that the test for Wei
`I
`
`ation may be applied for special situations as stated an '3'.
`
`_ 127.2190 m
`(3)
`AH,
`
`
`
`Substituting the experimentally obtained values for To — Tm,
`AHf, and To in Equation 2 yields the mole fraction of the total
`eutectic impurity, which, when multiplied by 100, gives the mole
`percentage of total eutectic impurities.
`Deviations from the theoretical linear plot also may be due to
`solid solution formation (K 9* 0), so that care must be taken in
`interpreting the data.
`To observe the linear effect of the impurity concentration on
`the melting-point depression, the impurity must be soluble in the
`liquid phase or melt of the compound, but insoluble in the solid
`phase, i.e., no solid solutions are formed. Some chemical simi-
`larities are necessary for solubility in the melt. For example, the
`presence of ionic compounds in neutral organic compounds and
`the occurrence of thermal decomposition may not be reflected
`in purity estimates. The extent of these theoretical limitations
`has been only partially explored.
`‘
`Impurities present from the synthetic route often are similar
`to the end product, hence there usually is no problem of solubility
`in the melt. Impurities consisting of molecules of the same shape,
`size, and character as those of the major component can fit into
`the matrix of the major component without disruption of the
`lattice, forming solid solutions or inclusions; such impurities are
`not detectable by DSC. Purity estimates are too high in such
`cases. This is more common with less-ordered crystals as indi-
`cated by low heats of fusion.
`Impurity levels calculated from thermograms are reproducible
`and probably reliable within 0.1% for ideal compounds. Melting—
`point determinations by scanning calorimetry have a reproduci-
`bility with a standard deviation of about 0.2°. Calibration against
`standards may allow about l° accuracy for the melting point, so
`that this technique is comparable to other procedures.
`Compounds that exist in polymorphic form cannot be used in
`purity determination unless the compound is completely con-
`verted to one form. On the other hand, DSC and DTA are in—
`herently useful for detecting, and therefore monitoring, poly-
`morphism.
`Procedure—The actual procedure and the calculations to be
`employed are dependent on the particular instrument used. Con-
`sult the manufacturer’s literature and/or the thermal analysis
`literature for the most appropriate technique for a given instru-
`ment. In any event, it is imperative to keep in mind the limitations
`of solid solution formation, insolubility in the melt, polymorphism,
`and decomposition during the analysis
`
`(905) UNIFORMITY OF
`DOSAGE UNITS
`
`The uniformity of dosage units can be demonstrated by either
`of two methods, weight variation or content uniformity. The re-
`
`For the determination of dosage-form uniformity bv '-
`variation, select not less than 30 units, and proceed as f6]
`
`the dosage form designated.
`[NOTE—Specimens other that ..
`
`test units may be drawn from the same batch for Assay 3'
`minations.]
`'
`UNCOATED TABLETS—Weigh accurately 10 tablets i. -
`ually, and calculate the average weight. From the result
`
`Assay, obtained as directed in the individual monograp'
`
`culate thc~content of active ingredient in each of the 10 n '
`
`'
`assuming homogeneous distribution of the active ingrcdi .
`
`HARD CAPSULES—Weigh accurately 10 capsules individ -
`
`'
`taking care to preserve the identity of each capsule. Remo
`
`contents of each capsule by a suitable means. Weigh accu
`
`the emptied shells individually, and calculate for each caI
`
`the net weight of its contents by subtracting the weight is "
`
`shell from the respective gross weight. From the results :-
`
`Assay, obtained as directed in the individual monograph,
`
`culate the content of active ingredient in each of the ca
`
`assuming homogeneous distribution of the active ingredie
`
`SOFT CAPSULEsiDetermine the net weight of the come} .
`
`_
`individual capsules as follows. Weigh accurately the 10..
`
`capsules individually to obtain their gross weights, taking caI .
`preserve the identity of'each capsule. Then cut open the ca-
`
`by means of a suitable clean, dry cutting instrument su_-
`
`scissors or a sharp open blade, and remove the contents by -
`ing with a suitable solvent. Allow the occluded solvent to .
`
`orate from the shells at room temperature over a period ofIa ._
`
`30 minutes, takin precautions to avoid uptake or loss of m019
`,
`'.
`Weigh the indivi ual shells, and calculate the net contcfltS-I
`
`the results of the Assay, obtained as directed in the Indivl
`
`monograph, calculate the content of active ingredient In 635
`
`the capsules, assuming homogeneous distribution of the a '
`
`-
`ingredient.
`'
`SOLIDS IN SINGLE-UNIT CONTAINERS and STERILE 50‘“
`
`.
`FOR PARENTERAL USE—Proceed as directed under Hard
`sules, treating each unit as described therein.
`
`
`
`
`For the determination of dosage-form uniformit
`
`individual units, select not less than 30 _Iunits, an
`I .
`follows for the dosage form designated.
`
`UNCOATED AND COATED TABLETS, HARD AND SOFTS.
`SULES, SUPPOSITORIES, TRANSDERMAL SYSTEMSi 52E?“
`
`SIONS IN SINGLE—UNIT CONTAINERS, PRESSURIZED ME C
`
`[NHALATIONS IN SINGLE-UNITIN ,
`DOSE INHALERS,
`TAINERS, and SOLIDS (INCLUDING STERILE SOLIDS) dire
`
`GLE-UNIT CONTAINERS—Assay 10 units individually as .56 S '
`
`in the Assay in the individual monograph, unless otherW1 unl-
`ified in the test for Content uniformity. Where the “no
`
`CONTENT UNIFORMITY
`
`
`
`Page 3
`
`Page 3
`
`

`

`
`
`
`
`.23
`
`Physical Tests / Uniformity of Dosage Units
`
`(905)
`
`1839
`
`. grEdient in a single dose unit is less than required in the
`Indjust the degree of dilution of the solutions and/or the
`
`| . 1f aliquots so that the concentration of the active ingre-
`
`: in the final solution is of the same order_ as that obtained
`
`" 145m}; procedure; or, in the case of a titrimetric assay, use
`
`9‘ dilute titrant, if necessary, so that an adequate volume
`rent is required (see Titrimetry (541)); see also Procedures
`
`3Tests and Assays .in the General Notices and Require-
`If any such modifications are made in the Assay pro-
`
`set forth in the indiVidual monograph, make the appro-
`', corresponding changes in the calculation formula and,
`
`"'on factor. .
`.
`-.
`.
`.
`
`- are a speClal procedure is spec1fied in the test for Content
`
`ntin in the individual monograph, make any necessary cor-
`
`iis
`in of the results obtained as follows.
`.
`-
`II) Prepare a compOSite speCimen of a sufficient number
`
`.1 all -
`”age units to provide the amount of speCimen called for in
`
`:ed t..
`__ my in the indiVidual monograph plus the amount required
`6 special procedure given in the test for Content uniformity
`
`‘; mon0graph by finely powdering tablets or mixing the_con-
`of capsules or suspenSions or solids in Single-unit containers
`
`min a homogeneous mixture.
`If a homogeneous mixture
`
`.i be obtained in this manner, use suitable solvents or other
`
`dues to prepare a solution containing all of the active in-
`
`.nt, and usevappropriate aliquot portions of this solution for
`
`'pecified procedures.
`.
`l2) Assay separate, accurately measured portions of the
`
`,,5ite specimen of capsules or tablets or suspensions or in-
`i by
`,
`-
`
`sfoll-n'
`ions or solids in single-unit containers, both (a) as directed
`:rthanL-
`- Assay, and (b) using the special procedure given in the
`
`or Content uniformity in the monograph.
`4ssay '
`'r
`(3) Calculate the weight of active ingredient equivalentto
`
`Ilets in-'
`._. page dosage unit, by (a) using the results obtained by the
`result :.'r
`' procedure, and by (b) using the results obtained by the
`I.al procedure.
`'
`
`iograph,‘
`ie 10 ta- '
`4] Calculate the correction factor, F, by the formula;
`igredie.
`individ
`
`ich A is the weight of active ingredient equivalent to 1
`Rfimo "_
`
`sh 30°“ '
`qr: dosage unit obtained by the Assay procedure, and P is
`6th car__
`'weightof active ingredient equivalent to 1 average dosage
`
`.
`resu
`M31812: 3)?
`obtained by the special procedure.
`
`.
`.nograph.
`
`the
`ngredicn
`
`he come; _
`
`e of a correction factor is not valid.
`the 10
`
`taking 0 -
`) A valid correction may be applied only if F is not less
`
`' 1.03 nor greater than 1.10, or, not less than 0.900 nor greater
`:n the ca-
`
`imentbsyu .' '
`,0-(9170, and if F is between 0.970 and 1.030 no correction is
`"C ,
`:
`items
`
`_ 6)
`alvent t0
`If F lies between 1.03 and 1.10, orbetween 0.900 and
`
`)eriod 0f?"
`'« Calculate the weight of active ingredient in each dosage
`)ssoflg01'_ uInugtiplying each of the weights found using the special
`.
`'
`.
`ten -
`re
`
`(the illle .
`y F.
`
`iii 63 ‘
`‘
`.
`.
`.
`.
`36:; the a
`. alculation of the Relative Standard Devration
`
`.
`b11156 0f preprogrammed calculators or computers is ac-
`IERILE Sd ,
`e- A manual mathematical method is as follows:
`
`1 05ample standard deviation.
`,dei H1”
`
`n T relative standard deviation (the sample standard de-
`
`;
`:Xpressed as a percentage of the mean).
`
`'. . mean of the values obtained from the units tested, ex-
`g as a percentage of the label claim.
`' nulIlber of units tested.
`
`_X2’d"3
`x,, = individual values (xi) of the units tested,
`e
`as a percentageof the label claim.
`
`F = A/P,
`
`If(ioolA—Pl) >1
`
`Y
`“m, by a
`
`"‘1
`
`-‘D§‘l_ggiX .
`
`Criteria
`.
`Apply the following criteria, unless otherwise specified in the
`individual monograph.
`(A)
`If the Average of the Limits Specified in the Potency
`Definition in the Individual Monograph is 100.0 Percent or Less—
`COMPRESSED TABLETS (COATED OR UNCOATED), SUPPOSI-
`TORIES, SUSPENSIONS IN SINGLE-UNIT CONTAINERS, SOLIDS
`(INCLUDING STERILE SOLIDS) IN SINGLE-UNIT CONTAINERS,
`and STERILE SOLIDS FOR PARENTERAL USE—Unless otherwise
`specified in the individual monograph, the requirements for dose
`uniformity are met if the amount of the active ingredient in each
`of the 10 dosage units as determined from the Weight Variation
`or the Content Uniformity method lies within the range of 85.0%
`to 115.0% of the label claim and the Relative standard deviation
`is less than or equal to 6.0%.
`If 1 unit is outside the range of 85.0% to 1 15.0% of label claim
`and no unit is outside the range of 75.0% to 125.0% of label
`claim, or if the Relative standard deviation is greater than 6.0%,
`or if both conditions prevail, test 20 additional units. The re-
`quirements are met if not more than 1 unit of the 30 is outside
`the range of 85.0% to 115.0% of label claim and no unit is outside
`the range of 75.0% to 125.0% of label claim and the Relative
`standard deviation of the 30 dosage units does not exceed 7.8%.
`CAPSULES, TRANSDERMAL SYSTEMS, INHALATIONS, AND
`MOLDED TABLETS—Unless otherwise specified in the individual
`monograph, the requirements for dose uniformity are met if the
`amount of the active ingredient in not less than 9 of the _10 desage
`units as determined from the Weight Variation or the Content
`Uniformity method lies within the range of 85.0% to 115.0% of
`label claim and no unit is outside the range of 75.0% to 125.0%
`of label claim and the Relative standard deviation of the 10
`dosage units is less than or equal to 6.0%.
`If 2 or 3 dosageiunits are outside the range of 85.0% to 115.0%
`of label claim, but not outside the range of 75.0% to 125.0% of
`label claim, or if the Relative standard deviation is greater than
`6.0% or if both conditions prevail, test 20 additional units. The
`requirements are met if not more than 3 units of the 30 are outside
`the range of 85.0% to 115.0% of label claim and no unit is outside
`the range of 75.0% to 125.0% of label claim, and the Relative
`standard deviation of the 30 dosage units does not exceed 7.8%.
`PRESSURIZED METERED—DOSE INHALERS—[NOTE—A dos-
`age unit is defined as the discharged spray obtained by actuation
`of the valve that number of times defined in the labeling as the
`recommended dose. Follow the labeled instructions for shaking
`and firing the inhaler. For collection of the dosage unit from the
`inhaler, proceed as directed in the test for Uniformity of Unit
`Spray Content under Aerosols (601).] Unless otherwise speci-
`fied in the individual monograph, the requirements for dose uni-
`formity are met if the amount, of the active ingredient discharged
`in not more than 1 of the 10 dosage units as determined from
`the Content Uniformity method lies outside the range of 75.0%
`to 125.0% of the label claim and no unit is outside the range of
`65.0% to 135.0% of the label claim. If 2 or 3 dosage units are
`outside the range of 75.0% to 125.0% of label claim, but not
`outside the range of 65.0% to 135.0% of label claim, test 20
`additional units. The requirements are met if not more than 3'
`units of the 30 are outside the range of 75.0% to 125.0% of label
`claim and no unit is outside the range of 65.0% to 135.0% of
`label claim.
`
`If the Average of the Limits Specified in the Potency
`(B)
`Definition in the Individual Monograph is Greater than 100.0
`Percent—
`
`If the average value of the dosage units tested is 100.0
`(1)
`percent or less, the requirements are as in (A).
`(2)
`If the average value of the dosage units tested is greater
`than or equal to the average of the limits specified in the potency
`definition in the individual monograph, the requirements are as
`in (A), except that the words “label claim” are replaced by the
`words “label claim multiplied by the average of the limits spec-
`ified in the potency definition in the monograph divided by 100.”
`(3)
`If the average value of the dosage units tested is between
`100 percent and the average of the limits specified in the potency
`definition in the individual monograph, the requirements are as
`in (A), except that the words “label claim” are replaced by the
`words “label claim multiplied by the average value of the dosage
`units tested (expressed as a percent of label claim) divided by
`100.”
`
`Page 4
`
`Page 4
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`