Type of Posting: Explanatory Note
Posting Date: 20–Apr–2007
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) [November–December 2006] is official. This version also is published in the 1st Supplement to USP 30–NF 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 2505–2510 of USP 28–NF 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 USP–specific national text. The PDG consists of USP, the Japanese Pharmacopeia, and the European Pharmacopeia.
- In Pharmacopeial Forum 31(6) [November–December 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 29–NF 24, both the official and the revised, harmonized versions of <905> appeared. The revised, harmonized version (pages 2780–2785) was to become official on January 1, 2007, but was superseded by the subsequent revision in the Sixth Interim Revision Announcement to USP 29–NF 24 in Pharmacopeial Forum 32(6) [November–December 2006].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) [July–August 2006] and made official through the Sixth Interim Revision Announcement to USP 29–NF 24 in Pharmacopeial Forum 32(6) [November–December 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, two–sided 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>:
- 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.
- 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.
- 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.
- 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.
- Katori. N, Aoyagi N, Kojima S, A Proposal for Revision of the Content Uniformity Test and Weight Variation Test, PF 23(6), 5325–5333, 1997.
- Content Uniformity—Evaluation of the USP Pharmacopeial Preview, Members of the Statistics Working Group PhRMA, PF 24(5), 7029–7044, 1998.
- Content Uniformity—Alternative to the USP Pharmacopeial Preview, Members of the Statistics Working Group PhRMA, PF 25(2), 7939–7948, 1999.
- Recommendation for a Globally Harmonized Uniformity of Dosage Units Test, Members of the Statistics Working Group PhRMA, PF 25(4), 8609–8624, 1999.
- Recommendations for a Globally Harmonized Uniformity of Dosage Units Test, Members of the Statistics Working Group PhRMA, PF 25(4), 8609–8624, 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.
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Example 1: Pass on First |
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95 |
lower monograph limit |
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110 |
upper monograph limit |
102.5 |
T value |
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15.0 |
L1 (use 15.0 unless monograph specifies a different value) |
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25.0 |
L2 (use 25.0 unless monograph specifies a different value) |
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Step 1 –– content (or weight) of 10 units –– X1, ..., X10 |
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102.00000 |
Average of the 10 values expressed as % of the label claim (do not round) –– AVERAGE(X1, ..., X10) |
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4.60000 |
Standard deviation of the 10 values expressed as % of the label claim (do not round) –– STDEV(X1, ..., X10) |
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102.00000 |
M value |
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11.04000 |
AV |
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Result: |
Pass, stop here |
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(USP rounding applied) |
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Step 2 –– content (or weight) of 20 additional units –– X11, –, X30 |
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Average of the 30 values expressed as % of the label claim (do not round) –– AVERAGE(X1, –, X30) |
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Standard deviation of the 30 values expressed as % of the label claim (do not round) –– STDEV(X1, –, X30) |
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Minimum value of the 30, expressed as % of the label claim |
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Maximum value of the 30, expressed as % of the label claim |
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M value |
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AV |
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Minimum allowed value of 30, expressed as % of label claim |
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Maximum allowed value of 30, expressed as % of label claim |
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Result: |
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(USP rounding applied) |
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Example 2: Fail–Pass |
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90 |
lower monograph limit |
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110 |
upper monograph limit |
100.0 |
T value |
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15.0 |
L1 (use 15.0 unless monograph specifies a different value) |
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25.0 |
L2 (use 25.0 unless monograph specifies a different value) |
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Step 1 –– content (or weight) of 10 units –– X1, ..., X10 |
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107.00000 |
Average of the 10 values expressed as % of the label claim (do not round) –– AVERAGE(X1, ..., X10) |
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4.60000 |
Standard deviation of the 10 values expressed as % of the label claim (do not round) –– STDEV(X1, ..., X10) |
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101.50000 |
M value |
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16.54 |
AV |
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Result: |
Does not pass; proceed to step 2 |
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(USP rounding applied) |
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Step 2 —content (or weight) of 20 additional units –– X11, –, X30 |
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106.50000 |
Average of the 30 values expressed as % of the label claim (do not round) –– AVERAGE(X1, –, X30) |
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4.60000 |
Standard deviation of the 30 values expressed as % of the label claim (do not round) –– STDEV(X1, –, X30) |
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78.00000 |
Minimum value of the 30, expressed as % of the label claim |
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118.20000 |
Maximum value of the 30, expressed as % of the label claim |
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101.50000 |
M value |
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14.20000 |
AV |
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76.1 |
Minimum allowed value of 30, expressed as % of label claim |
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126.9 |
Maximum allowed value of 30, expressed as % of label claim |
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Result: |
Passes |
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(USP rounding applied) |
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Example 3: Fail–Fail |
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90 |
lower monograph limit |
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110 |
upper monograph limit |
100 |
T value |
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15.0 |
L1 (use 15.0 unless monograph specifies a different value) |
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25.0 |
L2 (use 25.0 unless monograph specifies a different value) |
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Step 1 –– content (or weight) of 10 units –– X1, ..., X10 |
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107.00000 |
Average of the 10 values expressed as % of the label claim (do not round) –– AVERAGE(X1, ..., X10) |
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4.60000 |
Standard deviation of the 10 values expressed as % of the label claim (do not round) –– STDEV(X1, ..., X10) |
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101.50000 |
M value |
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16.54000 |
AV |
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Result: |
Does not pass; proceed to step 2 |
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(USP rounding applied) |
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Step 2 –– content (or weight) of 20 additional units –– X11, –, X30 |
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106.50000 |
Average of the 30 values expressed as % of the label claim (do not round) –– AVERAGE(X1, –, X30) |
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5.20000 |
Standard deviation of the 30 values expressed as % of the label claim (do not round) –– STDEV(X1, –, X30) |
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94.70000 |
Minimum value of the 30, expressed as % of the label claim |
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127.10000 |
Maximum value of the 30, expressed as % of the label claim |
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101.50000 |
M value |
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15.40000 |
AV |
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76.1 |
Minimum allowed value of 30, expressed as % of label claim |
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126.9 |
Maximum allowed value of 30, expressed as % of label claim |
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Result: |
Fails |
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(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 Extended–Release 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 film–coated 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 two–component 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.