<905> applies to each drug substance in the product. <905> procedures can be applied to each substance individually so if one or more meet the conditions summarized in Table 1, it can be tested using the Weight variation procedure.
The limit for the Acceptance Value is 15.0% at both levels of the test. L2 is only used to determine the acceptable range of individual values observed when 30 units have been analyzed. Where the average result is more than 101.5% then M has the value of 101.5% and the range is calculated as in the question.
Section 5.70 of the General Notices says that when the same analytical methodology is used for the Assay and the Content uniformity with appropriate allowances made for differences in sample preparation, the average of all the individual-unit content uniformity determinations may be used as the Assay value.
The average weight of the units being tested by the Weight variation procedure is used in determining their estimated content.
The Assay is a separate test from <905>. It uses the analysis of a composite from multiple units. <905> evaluates uniformity of dose with the limit on the Acceptance Value and an acceptable range of individual values if testing proceeds to 30 units. In neither of these tests is there a requirement that individual results conform to the Assay limits, typically 90% to 110% of label claim.
The Weight variation procedure may be used to estimate the contents of the individual units under a few defined conditions. The results of a single procedure, Content uniformity or Weight variation, is sufficient to satisfy the test requirement in the chapter.
As a result of harmonization, the separate procedures and criteria for transdermal systems, suppositories and inhalations in pre-metered dosage units were removed from the chapter. These dosage forms are now classified as Others and require the use of the Content uniformity procedure. This is the same for any dosage form not meeting the conditions for the application of the Weight variation procedure.
<905> is not applied to liquids in multiple dose containers.
The value of T is used to modify the upper value of M. T represents a manufacturing target that is more than 100% (see General Notices, Section 4.10.20 Acceptance Criteria). Where the average value of the results is more than T, the Acceptance Value is calculated based on the absolute value of the difference (plus ks). Examples where T has the value of 107.5%, 10 units have been tested and SD is 3 are given in the following table.
|Mean||T||Is mean within 98.5% and T||Reference Value||Abs Value of the Difference (mean and reference value)||ks||AV|
The values observed from individual units tested by the Content uniformity procedure are in terms of the label claim. Outside of being part of the analysis of the drug substance content, the mass of the units are not considered.
The uniformity of dosage units can be demonstrated by either of the two methods. The Content uniformity procedure may be used in all cases. The Weight variation procedure can be used where permitted as detailed in Table 1. The Weight variation procedure may be used for products for which it is permitted.
Assuming L1 = 15.0 and L2 = 25.0, an example is as following:
|Content Uniformity||USP <905>||
Level 1: AV (10 units) NMT 15.0%
Level 2: AV (30 units) NMT 15.0%
Prior to harmonization, Chapter <905> contained criteria on the number of individual tablets and capsules falling outside 85.0% to 115.0% of label claim, and the zero-tolerance criterion and that no result falls outside 75% to 125% of label claim, and a criterion for the %RSD. The harmonized <905> test does not include any criteria on individual results falling outside 85.0% to 115.0% label claim but as in the previous test, does include a similar requirement that all individual results are between 75.0%–125.0% of a value, M. M is 98.5% of label claim (LC) if the sample mean is <98.5% LC, 101.5% LC if the sample mean is >101.5% LC, and the sample mean otherwise. The 98.5%-101.5% interval is termed the indifference zone. In addition, the harmonized test has a criterion on a value called Acceptance Value (AV), which must be no more than 15.0. The AV is a function of deviation of the mean from label claim by more than 1.5% (the indifference zone mentioned above) and the standard deviation of the results. The harmonized test was shown to be as, at least, conservative than the prior chapter <905>.
No, the AV criterion is always AV ≤ L1 which is 15.0% unless otherwise specified. The L2 criterion is only used to evaluate large deviations of individual results.
In this case the correct value of T will be 100%. The Target value is the intended manufacturing target for the process not the amount of drug added to the process relative to the label claim. This value does not change from lot to lot based on the actual results and is not calculated based on the apparent mean. So, you should be using the reference value from Case 1 in this situation for all lots.
The units for all the calculations are % of label claim (LC) and it is best to report the AV as either a % or as % of LC.
Here are 3 examples [Note: The units for all values in the table is % of LC]:
|Data Set #1||Data Set #2||Data Set #3|
|Level 1 Results||93.23
|Reference Value (M)||100.40||99.10||98.98|
|Acceptance Value (AV)||13.97||15.84||15.60|
|Level 2 Results||96.95
|Reference Value (M)||98.50||98.50|
|Acceptance Value (AV)||10.73||14.94|
|Large Deviation Results (Sn)||0||1|