USPNF General Chapter <905> Uniformity of

Dosage Units
Type of Posting
Explanatory Note
Posting Date
20Apr2007
This explanatory note is intended to clarify the steps taken by USP to address issues
regarding the harmonization of <905> Uniformity of Dosage Units. It includes current
chapter revision status, background information, testing requirements, statistical basis,
information about the upcoming revision, and frequently asked questions.

Status of General Chapter <905>

As of January 1, 2007, the updated, harmonized revision of General Chapter <905>
published as an Interim Revision Announcement in Pharmacopeial Forum 32(6)
[NovemberDecember 2006] is official. This version also is published in the 1st
Supplement to USP 30NF 25.

Revision History and Rationale

The ICH Steering Committee considers international harmonization of about 10 specific
compendial test chapters as critical to attaining full utility of the ICH Q6A guideline. ICH
Q6A recommended the harmonization of certain tests for dosage forms, including
General Chapter <905>.
USP published a revised, harmonized General Chapter <905> on pages 25052510
of USP 28NF 23 with an implementation date of April 1, 2006. This chapter
contains the global harmonized text approved by the Pharmacopeial Discussion
Group (PDG) as well as USPspecific national text. The PDG consists of USP,
the Japanese Pharmacopeia, and the European Pharmacopeia.
In Pharmacopeial Forum 31(6) [NovemberDecember 2005], USP postponed the
implementation date of the revised, harmonized General Chapter <905> to
January 1, 2007, to allow USP to consider comments received on Weight
Variation as a test alternative in certain cases.
In USP 29NF 24, both the official and the revised, harmonized versions of <905>
appeared. The revised, harmonized version (pages 27802785) was to become
official on January 1, 2007, but was superseded by the subsequent revision in
the Sixth Interim Revision Announcement to USP 29NF 24 in Pharmacopeial
Forum 32(6) [NovemberDecember 2006].

Official Harmonized Chapter <905>

The revision of General Chapter <905> that became official on January 1, 2007, was
initially proposed in Pharmacopeial Forum 32(4) [JulyAugust 2006] and made official
through the Sixth Interim Revision Announcement to USP 29NF 24 in Pharmacopeial
Forum 32(6) [NovemberDecember 2006]. The official text includes changes based on
the comments received.

Harmonized Chapter Testing Requirements

<905> includes Content Uniformity and Weight Variation procedures and acceptance
criteria to evaluate uniformity of dosage units. These apply to both newly registered
and existing products.
Content Uniformity is the default test and may be applied in all cases. The test for
Weight Variation is applicable for dosage forms specified as W1, W2, W3, and W4.
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 greater than 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 less than or equal to L1% and all individual dosage units fall
within the ranges calculated using L2 factor.

Statistical Basis of the New Content Uniformity Criteria

The primary concept underlying the criteria in the revised <905> Uniformity of Dosage
Units is that of statistical tolerance intervals. The general idea of tolerance intervals is
to use the available data to form an interval that covers a specified proportion of the
distribution underlying the data. For content uniformity, this would be the distribution of
content and the intent is to form an interval about the label claim within which a
specified proportion of units would fall. Technically, an interval (a, b) is a 95% (the
"confidence") tolerance interval for 90% of the distribution (the "coverage") if 95% of
such intervals with repeated sampling would cover at least 90% of the distribution. The
tolerance intervals can be parametric or nonparametric. Parametric intervals are based
on an assumed distribution, usually the normal. When assuming the normal
distribution, twosided tolerance intervals are of the form, , where is the average, S the
standard deviation, and k depends on the coverage, confidence, and sample size. (The
multiplier, k, becomes smaller as sample size increases, but never to 0. For 95%
coverage, for example, it will decrease to 1.96.) This is the form of the criteria used in
General Chapter <905>.
The basic tolerance interval has been modified in four ways in constructing the criteria
of General Chapter <905>:
1. The tolerance interval is modified to correspond to the standard two-stage testing of
content uniformity; i.e., where 10 units are tested and then, if needed, an
additional 20 are tested. This requires a k1 after the first stage and then a
different k2 after the second stage, if needed, where the sample is larger.
2. The acceptance interval is allowed to be asymmetric with respect to the label claim
in those cases where the potency range specified in the monograph is not
symmetric. The T of General Chapter <905> is the center of the potency range.
3. A 1.5% interval about the label claim is included so deviations of the mean content
from the label claim count only to the extent they are greater than this
percentage. This is reflected in the calculation of M.
4. The k's are chosen so that the new procedure has operating characteristics similar to
those of the prior General Chapter <905> criteria. Having similar operating
characteristics does NOT mean that data that would pass by the prior criteria
will pass by the new criteria and similarly for data that would fail. What it means
is that is for data drawn from a distribution that is acceptable for content
uniformity, the probability of passing is similar with the old and new criteria.

Statistical References
Further information regarding the statistical basis of the chapter is available in the
references noted below.
1. Katori. N, Aoyagi N, Kojima S, A Proposal for Revision of the Content Uniformity
Test and Weight Variation Test, PF 23(6), 53255333, 1997.
2. Content UniformityEvaluation of the USP Pharmacopeial Preview, Members of the
Statistics Working Group PhRMA, PF 24(5), 70297044, 1998.
3. Content UniformityAlternative to the USP Pharmacopeial Preview, Members of the
Statistics Working Group PhRMA, PF 25(2), 79397948, 1999.
4. Recommendation for a Globally Harmonized Uniformity of Dosage Units Test,
Members of the Statistics Working Group PhRMA, PF 25(4), 86098624, 1999.
5. Recommendations for a Globally Harmonized Uniformity of Dosage Units Test,
Members of the Statistics Working Group PhRMA, PF 25(4), 86098624, 1999.

Calculation Examples
On the following pages are 3 examples involving different outcomes.
Please submit comments or further inquiries on this topic to William Brown, Senior
Scientist at web@usp.org or +1-301-816-8380.
Example 1: Pass on First

95

lower monograph limit

110

upper monograph limit

15.0
25.0

L1 (use 15.0 unless monograph specifies a

different value)
L2 (use 25.0 unless monograph specifies a
different value)

Step 1 content (or

weight) of 10 units X1,
..., X10
102.00000

4.60000

Average of the 10 values expressed as % of

the label claim (do not round)
AVERAGE(X1, ..., X10)
Standard deviation of the 10 values
expressed as % of the label claim (do not
round) STDEV(X1, ..., X10)

102.00000
11.04000

M value
AV

Result:

Pass, stop here

(USP rounding applied)

Step 2 content (or

weight) of 20 additional
units X11, , X30
Average of the 30 values expressed as % of
the label claim (do not round)
AVERAGE(X1, , X30)
Standard deviation of the 30 values
expressed as % of the label claim (do not
round) STDEV(X1, , X30)
Minimum value of the 30, expressed as % of
the label claim
Maximum value of the 30, expressed as % of
the label claim
M value
AV
Minimum allowed value of 30, expressed as
% of label claim
Maximum allowed value of 30, expressed as
% of label claim
Result:

10
2.5

T
val
ue

(USP rounding applied)

Example 2: FailPass
90

lower monograph limit

110

upper monograph limit

15.0
25.0

L1 (use 15.0 unless monograph specifies a

different value)
L2 (use 25.0 unless monograph specifies a
different value)

Step 1 content (or

weight) of 10 units X1,
..., X10
107.00000
4.60000

Average of the 10 values expressed as % of

the label claim (do not round)
AVERAGE(X1, ..., X10)
Standard deviation of the 10 values
expressed as % of the label claim (do not
round) STDEV(X1, ..., X10)

101.50000
16.54

M value
AV

Result:

Does not pass; proceed to step 2

(USP rounding applied)

Step 2 content (or

weight) of 20 additional
units X11, , X30

106.50000
4.60000

78.00000
118.20000
101.50000
14.20000
76.1
126.9

Average of the 30 values expressed as % of

the label claim (do not round)
AVERAGE(X1, , X30)
Standard deviation of the 30 values
expressed as % of the label claim (do not
round) STDEV(X1, , X30)
Minimum value of the 30, expressed as % of
the label claim
Maximum value of the 30, expressed as % of
the label claim
M value
AV
Minimum allowed value of 30, expressed as
% of label claim
Maximum allowed value of 30, expressed as

10
0.0

T
val
ue

% of label claim
Result:

Passes
(USP rounding applied)

Example 3: FailFail
90

lower monograph limit

110

upper monograph limit

15.0
25.0

L1 (use 15.0 unless monograph specifies a

different value)
L2 (use 25.0 unless monograph specifies a
different value)

Step 1 content (or

weight) of 10 units X1,
..., X10
107.00000
4.60000

Average of the 10 values expressed as % of

the label claim (do not round)
AVERAGE(X1, ..., X10)
Standard deviation of the 10 values expressed
as % of the label claim (do not round)
STDEV(X1, ..., X10)

101.50000
16.54000

M value
AV

Result:

Does not pass; proceed to step 2

(USP rounding applied)

Step 2 content (or

weight) of 20 additional
units X11, , X30

106.50000

5.20000

94.70000
127.10000
101.50000
15.40000

Average of the 30 values expressed as % of

the label claim (do not round)
AVERAGE(X1, , X30)
Standard deviation of the 30 values expressed
as % of the label claim (do not round)
STDEV(X1, , X30)
Minimum value of the 30, expressed as % of
the label claim
Maximum value of the 30, expressed as % of
the label claim
M value
AV

1
0
0

T
val
ue

76.1
126.9
Result:

Minimum allowed value of 30, expressed as %

of label claim
Maximum allowed value of 30, expressed as %
of label claim
Fails
(USP rounding applied)

Frequently Asked Questions

Question: What is meant by the term "special procedure" as found under
Content Uniformity in the official chapter?
Answer: Typically, the Content Uniformity determination is made on individual dosage
units using the procedure found in the Assay. For certain products, a separate
procedure is given in the monograph. Where that is the case, the monograph
procedure would be considered a special procedure for content uniformity.
Theophylline ExtendedRelease Capsules is an example of a monograph requiring a
special procedure for content uniformity.
Question: The harmonized <905> Uniformity of Dosage Units became official on
January 1, 2007. Does the harmonized chapter completely replace the current
text?
Answer: Yes. As of January 1, 2007, only the revised, harmonized chapter text is
official.
Question: I have heard from European colleagues that existing products may be
exempt from the requirements of the harmonized chapter and that it will only
apply to new formulations. Will the USP allow such grandfathering?
Answer: The harmonized chapter text applies to any monograph, new or existing, that
includes a test for Uniformity of Dosage Units.
Question: What is the maximum allowable acceptance value for Content
Uniformity testing at level 2, where a total of 30 dosage units have been tested?
Our confusion is in the use of the L1 and L2 values (15.0 and 25.0, respectively).
Answer: Content Uniformity testing can be performed in two stages. The first stage has
a total of 10 dosage units tested, and an additional 20 dosage units are tested to
complete testing at the second stage. L1 is used as the limit for the acceptance value
for both stages of test. L2 is used only in the second stage of testing where a total of
30 dosage units have been tested, and it is only used in the calculation of the allowed
limits for individual dosage unit content.
Question: Weight Variation is allowed for hard capsules, uncoated tablets, and
filmcoated tablets containing 25 mg or more of the drug substance comprising
25% or more of the weight of the dosage unit. If a product, such as an uncoated
tablet, contains two drug substances but only one of them meets the
requirement for weight variation, how can the requirement be met?
Answer: Weight Variation is generally seen as requiring less lab work than the
procedure for Content Uniformity. Thus, the allowance to substitute Weight Variation
for Content Uniformity may be seen as offering a benefit to manufacturers. In the case
of a twocomponent tablet, the Uniformity of Dosage Units test requirement will be met
by the Weight Variation procedure for the component that is present at 25 mg or more
and also comprising 25% of the total dosage unit mass. The other component will
require the Content Uniformity procedure.