Industry comments and applied feedback
The following section summarizes the comments received during the public consultation, and explains how the industry feedback
has been taken into account in the revised text. The primary concerns raised during the public consultation were related to
four key issues, as outlined below.
"What is the relation between the Ph.Eur. new General Chapter 2.9.47 and the existing chapters (2.9.5, 2.9.6, and 2.9.40)?"
Before the adoption of 2.9.47, there were already three general chapters in Ph.Eur. addressing dose variability. The new chapter does not represent a fourth set of acceptance criteria for the determination
of dose variability. Rather, as an alternative to demonstrating compliance with 2.9.40 with a traditional sample size n =
30, compliance with the UDU test could be demonstrated by compliance with the criteria of 2.9.47 with a large sample (sample
size ranging from n = 100 to n = 10,000). Chapter 2.9.47 should always be applied in conjunction with chapter 2.9.40, where
the relevant parameters (e.g., acceptance value, reference value) are defined and explained. In fact, 2.9.47 is meaningless
without a reference to 2.9.40. There is no formal link between 2.9.47 and the older dose variability tests described in 2.9.5
and 2.9.6.
General Chapter 2.9.47 presents two alternative sets of acceptance criteria: one parametric and one nonparametric test. It
is the user's choice which of the two sets of criteria to apply. For a given sample, the two sets may not give the same result,
due to their fundamental difference (parametric versus nonparametric). However, both alternatives are considered equivalent
in the demonstration of compliance with 2.9.40. The nonparametric test criteria for largely deviating units (L2/c2-criteria)
are identical in the two alternatives.
There is no regulatory expectation that 2.9.47 should be used by a marketing authorization (MA) applicant or a MA holder,
in the determination of compliance with 2.9.40. There is also no regulatory expectation that any of the two alternative sets
of test criteria should be favoured over the other. The new chapter does not represent a new requirement. It is the user's
decision to demonstrate compliance with 2.9.40 by any of the criteria described in the new 2.9.47.
However, it is not acceptable that a batch failing the criteria of 2.9.47 is retested by the traditional criteria of 2.9.40,
with the intention to achieve a more fortunate result. It is also not acceptable to retest a batch using the other alternative
set of criteria in 2.9.47 if a batch has produced an unsatisfactory result with any of the two alternatives.
Figure 1: Operations characteristic (OC) curves of the initial proposal for 2.9.47: Selected sample sizes (including the obsolete
sample size n = 75) are compared with the UDU test (n = 30). The red oval represents the higher probability to pass the 2.9.47
test than the UDU test for certain batch distributions. The simulated batches follow normal distribution with a certain standard
deviation (indicated along the X-axis).
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"The general acceptance criteria of the new chapter are too wide." The feedback from both industry and regulators was harmonized in that both parties argued that the new proposed acceptance
criteria of 2.9.47 were too wide. From Monte–Carlo simulations, it was evident that for certain batch distributions, with
unusually high standard deviation, a large sample fulfilling the acceptance criteria of 2.9.47 could easily fail the criteria
of 2.9.40 when evaluated on a subset of the sample (n = 30). This concern is illustrated in
Figure 1
, where the red oval represents batch characteristics where there is a larger probability to pass the test criteria for large
samples, than the UDU criteria for a small sample. For the batches with a standard deviation between 6 and 8.8 %, the probability
to pass the previously proposed version of the 2.9.47 test is greater than the probability to pass the harmonized UDU test.
Figure 2: OC curves of selected sample sizes for the adopted 2.9.47 (Alternative 1 and 2, respectively), compared with the
uniformity of dosage unit (UDU) test (n = 30). The red oval represents the higher probability to pass the 2.9.47 test than
the UDU test for certain batch distributions. The simulated batches follow normal distribution with a certain standard deviation
(indicated along the X-axis).
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Consequently, the revised criteria of the adopted 2.9.47 are such that a very small range of batch characteristics gives a
greater possibility to pass the new criteria, than the 2.9.40 criteria for n = 30. These batches already have a high probability
(> 90 %) to pass the UDU test (indicated by the red oval in
Figure 2
):
Table I: Draft proposal (Pharmeuropa 23.2): Number of largely deviating units allowed for a selection of sample sizes.
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"The specific acceptance criteria for largely deviating units in the large samples are too strict." In the original proposal for large sample test criteria, the first largely deviating unit (LDU) was allowed at sample size
n = 500 (see
Table I
). A batch that complies with these acceptance criteria for LDU when evaluated on a large sample would have a 90% probability
to pass the zero-tolerance criterion for LDU when evaluated on a small sample n = 30 (9).
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