[Note—In this chapter, unit and dosage unit are synonymous.] The uniformity of dosage units can be demonstrated by either of two methods, weight variation or content uniformity. The requirements of this chapter apply both to dosage units containing a single active ingredient and to dosage units containing two or more active ingredients; unless otherwise specified in the individual monograph, they apply individually to each active ingredient in the product.
Content Uniformity requirements may be applied in all cases. The test for Content Uniformity is required for:
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coated tablets, other than film-coated tablets containing 50 mg or more of an active ingredient that comprises 50% or more (by weight) of one tablet;
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suspensions in single-unit containers or in soft capsules;
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solids (including sterile solids) that are packaged in unit-dose containers and that contain active or inactive added substances, except that the test for Weight Variation may be applied in the special situations stated below; and
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When the test for Content Uniformity is not required, the test for Weight Variation may be applied in any of the following situations:
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products containing 50 mg or more of an active ingredient comprising 50% or more, by weight, of the dosage unit or, in the case of hard capsules, the capsule contents, except that uniformity of other active ingredients present in lesser proportions is demonstrated by meeting Content Uniformity requirements;
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liquid-filled soft capsules other than soft capsules containing suspensions;
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solids (including sterile solids) that are packaged in single-unit containers and contain no added substances, whether active or inactive;
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solids (including sterile solids) that are packaged in single-unit containers, with or without added substances, whether active or inactive, that have been prepared from true solutions and freeze-dried in the final containers and are labeled to indicate this method of preparation; and
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solutions for inhalation packaged in glass or plastic ampuls, intended for use in nebulizers, oral solutions, and syrups when these articles are packaged in single-unit containers.
WEIGHT VARIATION
For the determination of dosage-unit uniformity by weight variation, select not fewer than 30 units, and proceed as follows for the dosage form designated. [Note—Specimens other than these test units may be drawn from the same batch for Assay determinations.]
Uncoated and Film-Coated Tablets—
Weigh accurately 10 tablets individually. From the result of the Assay, obtained as directed in the individual monograph, calculate the content of active ingredient in each of the 10 tablets, assuming homogeneous distribution of the active ingredient.
Hard Capsules—
Weigh accurately 10 capsules individually, taking care to preserve the identity of each capsule. Remove the contents of each capsule by a suitable means. Weigh accurately the emptied shells individually, and calculate for each capsule the net weight of its contents by subtracting the weight of the shell from the respective gross weight. From the results of the Assay, obtained as directed in the individual monograph, calculate the content of active ingredient in each of the capsules, assuming homogeneous distribution of the active ingredient.
Soft Capsules—
Determine the net weight of the contents of individual capsules as follows. Weigh accurately the 10 intact capsules individually to obtain their gross weights, taking care to preserve the identity of each capsule. Then cut open the capsules by means of a suitable clean, dry cutting instrument such as scissors or a sharp open blade, and remove the contents by washing with a suitable solvent. Allow the occluded solvent to evaporate from the shells at room temperature over a period of about 30 minutes, taking precautions to avoid uptake or loss of moisture. Weigh the individual shells, and calculate the net contents. From the results of the Assay, obtained as directed in the individual monograph, calculate the content of active ingredient in each of the capsules, assuming homogeneous distribution of the active ingredient.
Solids (Including Sterile Solids) in Single-Unit Containers—
Proceed as directed for Hard Capsules, treating each unit as described therein.
Solutions for Inhalation Packaged in Glass or Plastic Ampuls, Intended for Use in Nebulizers—
Proceed as directed for Hard Capsules, treating each unit as described therein.
Oral Solutions and Syrups Packaged in Single-Unit Containers—
Weigh accurately the amount of liquid that drains in not more than 5 seconds from each of 10 individual containers. If necessary, compute the equivalent volume after determining the apparent density. From the result of the Assay, obtained as directed in the individual monograph, calculate the content of active ingredient in the liquid drained from each of the 10 units.
CONTENT UNIFORMITY
For the determination of dosage-unit uniformity by assay of individual units, select not fewer than 30 units, and proceed as follows for the dosage form designated.
UNCOATED AND COATED TABLETS, HARD AND SOFT CAPSULES, SUPPOSITORIES, TRANSDERMAL SYSTEMS, ORAL SOLUTIONS IN SINGLE-UNIT CONTAINERS, SUSPENSIONS IN SINGLE-UNIT CONTAINERS, SYRUPS IN SINGLE-UNIT CONTAINERS, INHALATIONS PACKAGED IN PREMETERED DOSAGE UNITS, AND SOLIDS (INCLUDING STERILE SOLIDS) IN SINGLE-UNIT CONTAINERS—
Assay 10 units individually as directed in the
Assay in the individual monograph, unless otherwise specified in the
Procedure for content uniformity. For oral solutions, suspensions, and syrups in single-unit containers, conduct the
Assay on the amount of well-mixed material that drains from an individual container in not more than 5 seconds, and express the results as delivered dose. Where the amount of active ingredient in a single dosage unit differs from that required in the
Assay, adjust the degree of dilution of the solutions and/or the volume of aliquots so that the concentration of the active ingredients in the final solution is of the same order as that obtained in the
Assay procedure; or, in the case of a titrimetric assay, use a titrant of a different concentration, if necessary, so that an adequate volume of titrant is required (see
Titrimetry 
541
); see also
Procedures under
Tests and Assays in the
General Notices and Requirements. If any such modifications are made in the
Assay procedure set forth in the individual monograph, make the appropriate corresponding changes in the calculation formula and titration factor.
Where a special Procedure for content uniformity is specified in the test for Uniformity of dosage units in the individual monograph, make any necessary correction of the results obtained as follows.
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Prepare a composite specimen of a sufficient number of dosage units to provide the amount of specimen called for in the Assay in the individual monograph plus the amount required for the special Procedure for content uniformity in the monograph by finely powdering tablets or mixing the contents of capsules or oral solutions, syrups, suspensions, or solids in single-unit containers to obtain a homogeneous mixture. If a homogeneous mixture cannot be obtained in this manner, use suitable solvents or other procedures to prepare a solution containing all of the active ingredient, and use appropriate aliquot portions of this solution for the specified procedures.
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Assay separate, accurately measured portions of the composite specimen of capsules or tablets or suspensions or inhalations or solids in single-unit containers, both (a) as directed in the Assay, and (b) using the special Procedure for content uniformity in the monograph.
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Calculate the weight of active ingredient equivalent to 1 average dosage unit, by (a) using the results obtained by the Assay procedure, and by (b) using the results obtained by the special procedure.
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Calculate the correction factor, F, by the formula:
F = A/P,
in which A is the weight of active ingredient equivalent to 1 average dosage unit obtained by the Assay procedure; and P is the weight of active ingredient equivalent to 1 average dosage unit obtained by the special procedure. If
is greater than 10, the use of a correction factor is not valid.
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A valid correction may be applied only if F is not less than 1.030 nor greater than 1.100, or, not less than 0.900 nor greater than 0.970, and if F is between 0.970 and 1.030 no correction is required.
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If F lies between 1.030 and 1.100, or between 0.900 and 0.970, calculate the weight of active ingredient in each dosage unit by multiplying each of the weights found using the special procedure by F.
Calculation of the Relative Standard Deviation
The use of preprogrammed calculators or computers is acceptable. A manual mathematical method is as follows:
s = sample standard deviation.
RSD = relative standard deviation (the sample standard deviation expressed as a percentage of the mean).
bar(X ) = mean of the values obtained from the units tested, expressed as a percentage of the label claim.
n = number of units tested.
x1, x2, x3 . . . xn = individual values (xi) of the units tested, expressed as a percentage of the label claim.
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), SUPPOSITORIES, ORAL SOLUTIONS IN SINGLE-UNIT CONTAINERS, SYRUPS IN SINGLE-UNIT CONTAINERS, 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 dosage 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 115.0% 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 requirements 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 PACKAGED IN PREMETERED DOSAGE UNITS, AND MOLDED TABLETS—
Unless otherwise specified in the individual monograph, the requirements for dosage uniformity are met if the amount of the active ingredient in not less than 9 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 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 dosage units 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%.
(B) If the Average of the Limits Specified in the Potency Definition in the Individual Monograph is Greater than 100.0 Percent—
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If the average value of the dosage units tested is 100.0 percent or less, the requirements are as in Limit A.
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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 specified under Limit A, except that the words “label claim” are replaced by the words “label claim multiplied by the average of the limits specified in the potency definition in the monograph divided by 100”.
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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 Limit 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”.
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