Stage 4 Harmonization

Official: August 1, 2023

〈905〉 UNIFORMITY OF DOSAGE UNITS

Change to read:
This general chapter is harmonized with the corresponding texts of the European Pharmacopoeia and
the Japanese Pharmacopoeia. Portions of the general chapter text that are national USP text, and are not
part of the harmonized text, are marked with symbols (⧫⧫) to specify this fact.
[Note—In this chapter, unit and dosage unit are synonymous.⧫]
To ensure the consistency of dosage units, each unit in a batch should have a drug substance content
within a narrow range around the label claim. Dosage units are defined as dosage forms containing a
single dose or a part of a dose of drug substance in each unit. The uniformity of dosage units specification
is not intended to apply to ▲solutions, suspensions, emulsions, or gels in unit-dose
▲ (USP 1-Aug-2023)

containers intended for ▲local action following▲ (USP 1-Aug-2023) external, cutaneous administration.
The term “uniformity of dosage unit” is defined as the degree of uniformity in the amount of the drug
substance among dosage units. Therefore, the requirements of this chapter apply to each drug substance
being comprised in dosage units containing one or more drug substances, unless otherwise specified
elsewhere in this Pharmacopeia.
The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or
⧫
Weight⧫Variation (see Table 1). The test for Content Uniformity of preparations presented in dosage
units is based on the assay of the individual content of drug substance(s) in a number of dosage units to
determine whether the individual content is within the limits set. The Content Uniformity method may be
applied in all cases.
The test for ⧫Weight⧫Variation is applicable for the following dosage forms:

(W1) Solutions enclosed in unit-dose containers and into soft capsules;

(W2) Solids (including powders, granules, and sterile solids) that are packaged in single-unit contain-
ers and contain no active or inactive added substances;

(W3) Solids (including sterile solids) that are packaged in single-unit containers, with or without ac-
tive or inactive added substances, that have been prepared from true solutions and freeze-
dried in the final containers and are labeled to indicate this method of preparation; and

(W4) Hard capsules, uncoated tablets, or film-coated tablets, containing 25 mg or more of a drug
substance comprising 25% or more, by weight, of the dosage unit or, in the case of hard cap-
sules, the capsule contents, except that uniformity of other drug substances present in lesser
proportions is demonstrated by meeting the requirements for Content Uniformity.

The test for Content Uniformity is required for all dosage forms not meeting the above conditions for
the ⧫Weight⧫Variation test.1

Table 1. Application of Content Uniformity (CU) and Weight Variation (WV) Tests for Dosage
Forms
 Dose & Ratio of
Drug Substance

≥25 mg and <25 mg or

Dosage Form Type Subtype ≥25% <25%

Uncoated — WV CU

Film WV CU

Tablets Coated Others CU CU

Hard — WV CU

Suspension, emul-
sion,
or gel CU CU

Capsules Soft Solutions WV WV

Single
component — WV WV

Solution freeze-dried
in final
container WV WV
Solids in Multiple
single-unit containers components Others CU CU

Solutions in unit-dose — —
containers ⧫and into soft
capsules⧫ WV WV

Others▲a▲ (USP 1-Aug-2023) — — CU CU

a
Dosage forms not addressed by the other categories in this table including but not limited to suppositories, transdermal
systems (patches), and semisolid preparations applied cutanenously and intended for systemic distribution of the drug substance.

CONTENT UNIFORMITY
Select not fewer than 30 units, and proceed as follows for the dosage form designated.
Where different procedures are used for assay of the preparation and for the Content Uniformity test, it
may be necessary to establish a correction factor to be applied to the results of the latter.

Solid Dosage Forms

Assay 10 units individually using an appropriate analytical method. Calculate the acceptance value (see
Table 2).

Liquid or Semi-Solid Dosage Forms

Assay 10 units individually using an appropriate analytical method. Carry out the assay on the amount
of well-mixed material that is removed from an individual container in conditions of normal use, and
express the results as delivered dose. Calculate the acceptance value (see Table 2).
 Calculation of Acceptance Value

Calculate the acceptance value by the formula:

Click image to enlarge

in which the terms are as defined in Table 2.

Table 2

Variable Definition Conditions Value

Mean of individual contents (χ1, χ2, — —

…, χn), expressed as a percentage
X of the label claim

Individual contents of the units — —

χ1, χ2, …, tested, expressed as a percentage
χn of the label claim

Sample size (number of units in a — —

n sample)

If n = 10, then k = 2.4

k Acceptability constant If n = 30, then k = 2.0

Click image
to enlarge
s Sample standard deviation

Relative standard deviation (the — 100s/X

sample standard deviation ex-
pressed as a percentage of the
RSD mean)

M (case 1) Reference value If 98.5% ≤X ≤101.5%, then M = X (AV = ks)

to be ap-
plied when If X <98.5%, then M = 98.5%
T ≤101.5 (AV = 98.5 – X
+ ks)
Variable Definition Conditions Value

If X >101.5%, then M = 101.5%

(AV = X – 101.5
+ ks)

If 98.5 ≤X ≤T, then M=X

(AV = ks)

If X <98.5%, then M = 98.5%

(AV = 98.5 – X
+ ks)
M (case 2)
to be ap- If X >T, then M = T%
plied when (AV = X – T +
T >101.5 Reference value ks)

— — General
formula:

Click image
to enlarge

(Calculations
are specified
above for the
Acceptance different
value (AV) cases.)

— L1 = 15.0 unless
Maximum allowed acceptance otherwise
L1 value specified

On the low side, no dosage unit L2 = 25.0 unless

result can be less than [1– otherwise
(0.01)(L2)]M, while on the high specified
side, no dosage unit result can
Maximum allowed range for devia- be greater than [1 + (0.01)
tion of each dosage unit tested (L2)]M. (This is based on an L2
L2 from the calculated value of M value of 25.0.)

Target content per dosage unit at — —

the time of manufacture, ex-
pressed as a percentage of the la-
bel claim. Unless otherwise stated,
T is 100.0%, or T is the
manufacturer's approved target
T content per dosage unit.
 ⧫WEIGHT VARIATION
⧫
Carry out an assay for the drug substance(s) on a representative sample of the batch using an
appropriate analytical method. This value is result A, expressed as percentage of label claim (see
Calculation of Acceptance Value). Assume that the concentration (weight of drug substance per weight of
dosage unit) is uniform. Select not fewer than 30 dosage units, and proceed as follows for the dosage
form designated.

Uncoated or Film-Coated Tablets

Accurately weigh 10 tablets individually. Calculate the content, expressed as percentage of label claim,
of each tablet from the ⧫weight⧫ of the individual tablet and the result of the Assay. Calculate the
acceptance value.

Hard Capsules

Accurately weigh 10 capsules individually, taking care to preserve the identity of each capsule. Remove
the contents of each capsule by a suitable means. Accurately weigh 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⧫. Calculate the drug substance content of each capsule from the ⧫net weight⧫
of the individual capsule ⧫content⧫ and the result of the Assay. Calculate the acceptance value.

Soft Capsules

Accurately weigh 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. Calculate the drug substance content in each capsule from the ⧫weight⧫ of
product removed from the individual capsules and the result of the Assay. Calculate the acceptance value.

Solid Dosage Forms Other Than Tablets and Capsules

Proceed as directed for Hard Capsules, treating each unit as described therein. Calculate the acceptance
value.

Liquid Dosage Forms

Accurately weigh the amount of liquid that is removed from each of 10 individual containers in
conditions of normal use. If necessary, compute the equivalent volume after determining the density.
Calculate the drug substance content in each container from the mass of product removed from the
individual containers and the result of the Assay. Calculate the acceptance value.

Calculation of Acceptance Value

Calculate the acceptance value as shown in Content Uniformity, except that the individual contents of
the units are replaced with the individual estimated contents defined below.

χ1, χ2, …, χn = individual estimated contents of the units tested, where χi = wi × A/W

w1, w2, …, = individual ⧫weights⧫ of the units tested

wn
 A = content of drug substance (% of label claim) obtained using an appropriate analyti-
cal method

W = mean of individual ⧫weights⧫

(w1, w2, …, wn)

CRITERIA
Apply the following criteria, unless otherwise specified.

Solid, Semi-Solid, and Liquid Dosage Forms

The requirements for dosage uniformity are met if the acceptance value of the first 10 dosage units is
less than or equal to L1%. If the acceptance value is > L1%, test the next 20 units, and calculate the
acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is ≤
L1%, and no individual content of ⧫any⧫ dosage unit is less than [1 − (0.01)(L2)]M nor more than [1 +
(0.01)(L2)]M ⧫as specified⧫ in the Calculation of Acceptance Value under Content Uniformity or under
⧫
Weight⧫ Variation. Unless otherwise specified, L1 is 15.0 and L2 is 25.0.

1 ⧫European Pharmacopoeia and Japanese Pharmacopoeia text not accepted by the United States Pharmacopeia:
Alternatively, products listed in item (4) above that do not meet the 25 mg/25% threshold limit may be tested for uniformity
of dosage units by Mass Variation instead of the Content Uniformity test if the concentration relative standard deviation
(RSD) of the drug substance in the final dosage units is not more than 2%, based on process validation data and
development data, and if there has been regulatory approval of such a change. The concentration RSD is the RSD of the
concentration per dosage unit (w/w or w/v), where concentration per dosage unit equals the assay result per dosage unit
divided by the individual dosage unit weight. See the RSD formula in Table 2.
⧫

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