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Uniformity of Dosage Units Using Large Sample Sizes
To ensure the consistency of dosage units, each unit in a batch should have an active substance content within a limited range around the label claim (1). Ph.Eur. General Chapter 2.9.40 on UDU addresses the recommended test to demonstrate this critical property in a batch of drug product. The general monograph was introduced in Supplement 5.2 of the Ph.Eur., and is harmonized with the Japanese Pharmacopeia (JP). The test is also included in the US Pharmacopeia (USP), but with a reservation against the possibility to demonstrate UDU by mass variation rather than content uniformity, which is allowed in Ph.Eur. and JP under certain circumstances (2). When justified and authorized, acceptable dose uniformity may be demonstrated by compliance with Ph.Eur. General Chapter 2.9.5 Uniformity of Mass of Single-Dose Preparations (2.9.5) or General Chapter 2.9.6 Uniformity of Content of Single-Dose Preparations (2.9.6) instead of the UDU test (3).
With the harmonized UDU test, acceptable and nonacceptable batches, respectively, are more precisely judged than with the 2.9.5/2.9.6 tests, as the sample size is larger (n = 30, as opposed to n = 20, and n = 10, respectively). The UDU test returns a numerical measure of the dose consistency—that is, the acceptance value (AV). In addition, UDU takes into account sample mean: a stricter standard deviation requirement applies if the sample mean is more than 1.5% off-target. The performance of the old and the new General Chapters has been discussed by Limberg and Savsek (4).
Although it is assumed that the sample is representative for the batch, it is acknowledged that the evaluation of a small sample will only provide an estimate of the batch quality. There is always a risk that a highly variable batch would pass the UDU test and be released. Likewise, there is always a risk that a good quality batch can fail the UDU test and be rejected. Increasing the sample size leads to a more precise estimate of the batch variability.
Concerns have been raised that the UDU requirements discourage the use of modern analytical techniques that are fast and nondestructive (e.g., PAT techniques) (5–10). It was unfortunate that a pharmacopoeial requirement could be regarded as a disincentive to the implementation of such analytical methods.
The main concern with the UDU test when applied to large samples was the requirement that no single result of the test sample is outside ± L2 % of the reference value M (M = "sample average"; L2 = 25.0, unless otherwise specified. For a precise definition of M, refer to Ph.Eur. 2.9.40). Such an unconditional requirement is included in both General Chapters 2.9.5/2.9.6 and the UDU chapter. The requirement was established to disclose batches with largely deviating units, even if the sample mean and the overall sample variance is acceptable. This "safety net" does not assume any distribution in the sample or in the batch (e.g., normality), and it seems reasonable enough not to allow any largely deviating unit in a small sample.
Even in normal distributed batches of good quality, a small number of largely deviating units is expected. As sample size increases, the probability to detect one of these units becomes significant. In the new General Chapter 2.9.47 (2.9.47), a small number of largely deviating units is allowed for large sample sizes. This allowance is not considered an acceptance of largely deviating units as such, but rather recognizes that the large sample has a greater probability to contain such units, even when the batch in total is considered to be of acceptable quality.
A proposal for 2.9.47 was published in Pharmeuropa 23.2 in March 2011, together with a background paper explaining the elaboration of the proposal in detail (9). During the public consultation period, several comments were submitted by industry and regulators. The feedback was fairly uniform, and the European Directorate for the Quality of Medicines (EDQM) PAT working party accordingly elaborated a revised proposal for Chapter 2.9.47. The revised text was adopted by the European Pharmacopoeia Commission in April 2012, and it will be published in Supplement 7.7 of the Ph.Eur. and implemented on Apr. 1, 2013.
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.
In practice, current technology typically returns sample sizes of a few hundred, so that if the first largely deviating unit is allowed at n = 500, it was argued by several stakeholders that such acceptance criteria would not fully resolve the main concern—the 2.9.40 zero-tolerance criteria for a largely deviating unit.
"Editorial issues." In the adopted Ph. Eur. text, the introduction to the general chapter has been rewritten to further clarify the relationship between the two alternative tests of 2.9.47 and the existing 2.9.40 (as discussed above). The tables of acceptance criteria (k, c1, c2 versus sample size n) have been expanded, and there has been no rounding of the sample sizes performed where a certain set of acceptance criteria apply.
The criteria for a "medium-sized" batch sizes (30 < n < 100) have been removed, as these were found to be less relevant for the problem statement (demonstration of UDU using large sample sizes).
Demonstration of the performance of the adopted 2.9.47 test. In the following, a series of operations characteristic (OC) curves are presented to demonstrate the performance of the new test, compared with the performance of the harmonised UDU test (Note: in the figures, Alternative 1 and 2 are denoted as "Option 1 and 2"; reference is also made to Figure 2 ).
The recently adopted Ph.Eur. General Chapter 2.9.47 should resolve the problems that have been addressed regarding the applicability of the harmonized UDU test (Chapter 2.9.40) when applied to large sample sizes. With the new test criteria, more information from the large sample is taken into account in the evaluation of dose uniformity than is available in a subset of the sample (n = 30). Thus, manufacturing processes where a large sample size is available are more precisely evaluated.
The new test does not represent new regulatory expectations. Chapter 2.9.40 represents the requirements for acceptable dose uniformity, and 2.9.47 is just an alternative means to demonstrate compliance with the 2.9.40 criteria.
The proposed test criteria are at least equally stringent as the requirements of Ph.Eur. 2.9.40, and more discriminating due to the larger sample size. Although the new test originally has been motivated by PAT applications, it is applicable also to traditional sampling and analysis.
The initial draft and adopted chapter were elaborated by the members of the Ph.Eur. PAT Working Party (Chair: Prof. G. Ragnarsson, Medical Products Agency, Sweden). We also acknowledge many helpful proposals and comments from experts from industry, industry associations, and regulatory authorities that participated in an expert hearing on Sept. 29, 2010, and contributed through the public comment process.
Ø. Holte is a scientific officer with the Norwegian Medicines Agency.
M. Horvat is a leading scientist with Lek Pharmaceuticals. Both authors are representing the European Pharmacopoeia (Ph.Eur.) PAT Working Party.
1. Ph.Eur., General Chapter 2.9.40 Uniformity of Dosage Units (European Pharmacopeia, Council of Europe, France).
2. USP, General Chapter <905> Uniformity of Dosage Units (US Pharmacopeial Convention, Rockville, Maryland).
3. See Ph.Eur. Dosage Form Monographs (e.g., <Tablets>).
4. J. Limberg and M. Savsek, Pharmeuropa Scientific Notes 2, 45–48 (2006).
5. D. Sandell et al., Drug Information Jrnl. 40 337–344 (2006).
6. M. Diener et al., Drug Information Jrnl. 43 287–298 (2009).
7. L. Foust et al., Pharm. Technol. 31 (9) 108–115 (2007).
8. J.R. Murphy and K.L. Griffiths,Pharm. Technol. 30 (1) 52–60 92006).
9. J. Bergum and K.E. Vukovinsky, Pharm. Technol. 34 (11) 72–79 (2010).
10. Ø. Holte and M. Horvat, Pharmeuropa 23.2, 286–293 (2011).