The range where the content of the active substance varies by 60% is way to wide in every country.
In most of the world's pharmacopoeias, both national and international, the allowed variability in the amount of the active substance can be tested either as uniformity of mass or, if the amount of labeled substance is lower than a certain predefined value, as uniformity of content. For certain dosage forms, testing the uniformity of content is a must, no matter the labeled mass of the active substance (e.g. soft capsules filled with emulsions, suspensions or gels).
Pharmacopeias prescribe the testing procedure and the acceptance criteria. Appropriate regulatory authority requests those pharamcopoeial criteria to be met.
As for the uniformity of mass, in the European Pharmacopoeia, Ph. Eur. 7.0. (the newest that can be accessed via browser search) the test is given in the monograph 2.9.5. Uniformity of mass of single-dose preparations.
Weigh individually 20 units taken at random or, for single-dose preparations presented in individual containers, the contents of
20 units, and determine the average mass. Not more than 2 of
the individual masses deviate from the average mass by more
than the percentage deviation shown in Table 2.9.5.-1 and none
deviates by more than twice that percentage.
For capsules and powders for parenteral administration,
proceed as described below. [emph. mine]
Content mass of capsules and powders for parenteral administration is weighed by difference (the whole preparation is weighed, than the empty shell/primary package and the difference is the content mass).
The table mentioned states that for tablets, e.g:
- average mass is 80 mg or less (allowed) percent deviation is 10
- average mass is more than 80 mg and less than 250 mg percent deviation is 7.5
- average mass is 250 mg or more, percent deviation is 5
As for the uniformity of content, the same source (Ph. Eur. 7.0.) gives the test in the monograph 2.9.6.Uniformity of content of single-dose preparations where, again, the test and acceptance criteria vary by dosage form. To take tablets as an example, we can look at "test A" (for tablets, powders for parenteral administration, ophthalmic inserts, suspensions for injection):
The preparation complies with the test if each individual content is between 85 per cent and 115 per cent of the average content. The preparation fails to comply with the test if more than one individual content is outside these limits or if one individual content is outside the
limits of 75 per cent to 125 per cent of the average content.
If one individual content is outside the limits of 85 per cent to
115 per cent but within the limits of 75 per cent to 125 per cent,
determine the individual contents of another 20 dosage units
taken at random.The preparation complies with the test if not
more than one of the individual contents of the 30 units is
outside 85 per cent to 115 per cent of the average content and
none is outside the limits of 75 per cent to 125 per cent of the
average content. [emph. mine]
As for the other countries, the European pharmacopoeia also gives the test for Uniformity of dosage units in monograph 2.9.40. This test (or most of it) was harmonized between the three pharmacopoeias Ph. Eur. (European), USP (for the US) and JP (Japanese). This test is slightly more complicated than the previous, because it calculates the acceptance value based on the mean of the measured samples, standard deviation of these measurements and a coefficient based on the number of measurements. There are 6 different cases of this formula, but the simplest one is where the acceptance value is the standard deviation multiplied by the given coefficient. This value should not be greater than 15% of the prescribed content.
Regulatory authorities in these countries acknowledge this harmonisation, see the documents issued by EMeA and FDA.
So, finally, which of these is to be used in Europe? EMeA states:
[...] the decision on what approach to take is left to the applicant.
In the U.S. most of the tests are harmonised, and all are given in the USP, monograph 905 Uniformity of dosage units.