〈905〉 UNIFORMITY OF DOSAGE UNITS

Stage 6 Harmonization

Official December 1, 2011 〈905〉 Uniformity of Dosage Units 1

The test for Content Uniformity is required for all dosage

〈905〉 UNIFORMITY OF DOSAGE forms not meeting the above conditions for the

✦

Weight

✦

Variation test.

■1

■2S (USP34)

UNITS

Table 1. Application of Content Uniformity (CU) and Weight

Variation (WV) Tests for Dosage Forms

Dose & Ratio of

Drug Substance

Change to read:

≥25 <25

mg mg or

This general chapter is harmonized with the correspond-

and <25%Dosage

ing texts of the European Pharmacopoeia and the Japanese

≥25%Form Type Subtype

Pharmacopoeia. Portions of the general chapter text that are

national USP text, and are not part of the harmonized text, Uncoated WV CUTablets

are marked with symbols (

✦

) to specify this fact.

Film WV CU

✦

OTE

—In this chapter, unit and dosage unit are

Others CU CUCoated

synonymous.

✦

Hard WV CUCapsules

To ensure the consistency of dosage units, each unit in a

Suspension,

batch should have a drug substance content within a nar-

emulsion,

row range around the label claim. Dosage units are defined

or gel CU CU

as dosage forms containing a single dose or a part of a dose

Solutions WV WVSoft

of drug substance in each unit. The uniformity of dosage

units specification is not intended to apply to suspensions, Single com-Solids in sin-

emulsions, or gels in unit-dose containers intended for ex- ponent WV WVgle-unit

ternal, cutaneous administration. containers

Solution

The term “uniformity of dosage unit” is defined as the

freeze-

degree of uniformity in the amount of the drug substance

dried in fi-

among dosage units. Therefore, the requirements of this

nal

Multiple

chapter apply to each drug substance being comprised in

container WV WV

compo-

dosage units containing one or more drug substances, un-

Others CU CUnents

less otherwise specified elsewhere in this Pharmacopeia.

Solutions in

The uniformity of dosage units can be demonstrated by

unit-dose

either of two methods, Content Uniformity or

✦

Weight

✦

Varia-

containers

tion (see Table 1). The test for Content Uniformity of prepa-

✦

and into

rations presented in dosage units is based on the assay of

soft cap-

the individual content of drug substance(s) in a number of

sules

✦

WV WV

dosage units to determine whether the individual content is

Others CU CU

within the limits set. The Content Uniformity method may be

applied in all cases.

The test for

✦

Weight

✦

Variation is applicable for the follow-

ing dosage forms:

Change to read:

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

capsules;

CONTENT UNIFORMITY

(W2) Solids (including powders, granules, and sterile solids)

that are packaged in single-unit containers and contain

Select not fewer than 30 units, and proceed as follows for

no active or inactive added substances;

the dosage form designated.

(W3) Solids (including sterile solids) that are packaged in sin-

Where different procedures are used for assay of the prep-

gle-unit containers, with or without active or inactive

aration and for the Content Uniformity test, it may be neces-

added substances, that have been prepared from true

sary to establish a correction factor to be applied to the

solutions and freeze-dried in the final containers and are

results of the latter.

labeled to indicate this method of preparation; and

Solid Dosage Forms—Assay 10 units individually using

(W4) Hard capsules, uncoated tablets, or film-coated tablets,

an appropriate analytical method. Calculate the acceptance

containing 25 mg or more of a drug substance compris-

value (see Table 2).

ing 25% or more, by weight, of the dosage unit or, in

Liquid

■

or Semi-Solid

■2S (USP34)

Dosage Forms—

■

Assay 10

the case of hard capsules, the capsule contents, except

units individually using an appropriate analytical

that uniformity of other drug substances present in

method.

■2S (USP34)

Carry out the assay on the amount of well-

lesser proportions is demonstrated by meeting the re-

mixed material that is removed from an individual container

quirements for Content Uniformity.

■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 Uniform-

ity 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 ap-

proval of such a change. The concentration RSD is the RSD of the concentra-

tion 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.

✦■2S (USP34)

Stage 6 Harmonization

2 〈905〉 Uniformity of Dosage Units Official December 1, 2011

in conditions of normal use, and express the results as de- in which the terms are as defined in Table 2.

livered dose. Calculate the acceptance value (see Table 2).

Calculation of Acceptance Value—Calculate the accep-

tance value by the formula:

Table 2

Variable Definition Conditions Value

Mean of individual contents (χ

, … , χ

), expressed as a per-

X centage of the label claim

, χ

, … , χ

Individual contents of the units

tested, expressed as a percentage

of the label claim

n Sample size (number of units in a

sample)

If n = 10, then k = 2.4k Acceptability constant

If n = 30, then k = 2.0

s Sample standard deviation

RSD Relative standard deviation (the 100s/X

sample standard deviation ex-

pressed as a percentage of the

mean)

If 98.5% ≤X ≤101.5%, then M = X (AV = ks)M (case 1) to be applied when T Reference value

≤101.5

M = 98.5%

If X <98.5%, then (AV = 98.5 – X + ks)

M = 101.5%

If X >101.5%, then (AV = X – 101.5 + ks)

M = XM (case 2) to be applied when T Reference value

If 98.5 ≤X ≤T, then

(AV = ks)>101.5

M = 98.5%

If X <98.5%, then

(AV = 98.5 – X + ks)

M = T%

If X >T, then (AV = X – T + ks)

Acceptance value (AV) general formula:

(Calculations are specified above

for the different cases.)

L1 Maximum allowed acceptance L1 = 15.0 unless otherwise speci-

value fied

Stage 6 Harmonization

Official December 1, 2011 〈905〉 Uniformity of Dosage Units 3

Table 2 (Continued)

Variable Definition Conditions Value

L2 Maximum allowed range for On the low side, no dosage unit L2 = 25.0 unless otherwise speci-

deviation of each dosage unit result can be less than fied

tested from the calculated value [1–(0.01)(L2)]M, while on the

of M high side no dosage unit result

can be greater than [1 +

(0.01)(L2)]M. (This is based on

an L2 value of 25.0.)

T Target content per dosage unit at

the time of manufacture, ex-

pressed as a percentage of the

label claim.

■

Unless otherwise

stated, T is 100.0 per cent, or T

is the manufacturer’s approved

target content per dosage

unit.

■2S (USP34)

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

✦

WEIGHT

✦

VARIATION

equivalent volume after determining the density. Calculate

the drug substance content in each container from the mass

Carry out an assay for the drug substance(s) on a repre-

of product removed from the individual containers and the

sentative sample of the batch using an appropriate analyti-

result of the assay. Calculate the acceptance value.

cal method. This value is result A, expressed as percent of

label claim (see Calculation of Acceptance Value). Assume that Calculation of Acceptance Value—Calculate the accep-

the concentration (weight of drug substance per weight of tance value as shown in Content Uniformity, except that the

dosage unit) is uniform. Select not fewer than 30 dosage individual contents of the units are replaced with the indi-

units, and proceed as follows for the dosage form vidual estimated contents defined below.

designated.

Uncoated or Film-Coated Tablets—Accurately weigh 10

, χ

, ... , χ

= individual estimated contents of the units

tablets individually. Calculate the content, expressed as %

tested, where χ

= w

× A/W

of label claim, of each tablet from the

✦

weight

✦

of the indi-

, w

, ... , w

= individual

✦

weights

✦

of the units tested

vidual tablet and the result of the Assay. Calculate the ac-

A = content of drug substance (% of label claim)

ceptance value.

obtained using an appropriate analytical

Hard Capsules—Accurately weigh 10 capsules individu-

method

ally, taking care to preserve the identity of each capsule.

W = mean of individual

✦

weights

✦

Remove the contents of each capsule by a suitable means.

, w

, … ,w

)

Accurately weigh the emptied shells individually, and calcu-

late 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

Change to read:

each capsule from the

✦

net weight

✦

of the individual cap-

sule

✦

content

✦

and the result of the Assay. Calculate the

acceptance value.

Soft Capsules—Accurately weigh 10 intact capsules indi-

CRITERIA

vidually to obtain their gross

✦

weights

✦

, taking care to pre-

serve the identity of each capsule. Then cut open the cap-

Apply the following criteria, unless otherwise specified.

sules by means of a suitable clean, dry cutting instrument

Solid,

■

Semi-Solid,

■2S (USP34)

and Liquid Dosage Forms—

such as scissors or a sharp open blade, and remove the

The requirements for dosage uniformity are met if the ac-

contents by washing with a suitable solvent. Allow the oc-

ceptance value of the first 10 dosage units is less than or

cluded solvent to evaporate from the shells at room temper-

equal to L1%. If the acceptance value is > L1%, test the

ature over a period of about 30 minutes, taking precautions

next 20 units, and calculate the acceptance value. The re-

to avoid uptake or loss of moisture. Weigh the individual

quirements are met if the final acceptance value of the 30

shells, and calculate the net contents. Calculate the drug

dosage units is ≤ L1%, and no individual content of

✦

any

✦

substance content in each capsule from the

✦

weight

✦

dosage unit is less than [1 − (0.01)(L2)]M nor more than [1

product removed from the individual capsules and the result

+ (0.01)(L2)]M

✦

as specified

✦

in the Calculation of Acceptance

of the assay. Calculate the acceptance value.

Value under Content Uniformity or under

✦

Weight

✦

Variation.

Solid Dosage Forms Other Than Tablets and

Unless otherwise specified, L1 is 15.0 and L2 is 25.0.

Capsules—Proceed as directed for Hard Capsules, treating

each unit as described therein. Calculate the acceptance

value.