“Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability”. The statement has recently been included in USP 37. The question is then, which characteristic/parameter do the tests reflect, and how?

In a recent posting on the USP site, under the heading of (USP–NF General Notices; Updated: 08–Aug–2013) it is stated that the following text will be added to the USP 37 GENERAL NOTICES AND REQUIREMENTS (http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/2013-07-09_general_notices_usp37-nf32_final.pdf (link not working) [try this one]

“4.10.11. Dissolution, Disintegration, and Drug Release Tests

Multiple Dissolution, Disintegration, or Drug Release tests may be present in the monograph. The order in which the tests are listed in the monograph is based on the order in which they are approved by the relevant Expert Committee for inclusion in the monograph. Test 1 is not necessarily the test for the innovator or for the reference product. Compliance with any of the tests does not assure bioequivalence or bioavailability” [emphasis is mine].

So what good are these testers/methods then? Furthermore, if their use is to be continued as usual then one requires knowing which characteristic/parameter of the product these compendial dissolution tests are measuring and how. In addition, some supporting evidence should also be provided showing how the current dissolution testers/methods have been qualified and validated for the suggested characteristic/parameter.

On the other hand, if these tests are not linked to the bioequivalence/bioavailability characteristics then there is no reason that these tests be conducted using bio- or physiologically relevant experiments conditions e.g. 37 ºC or aqueous buffers. A dissolution test should be considered equally valid if conducted using non-physiological experimental conditions, for example:

Using a beaker/flask containing 1000 mL of solvent (50/50 mixture of water and alcohol) maintained at room temperature with a rotating magnetic stirrer. Such experimental conditions should be as good, if not better, as currently used testers and methods.

Unfortunately, however, the reality is that USP statement regarding dissolution testing is not accurate. A dissolution test is an important and useful test and indeed linked to the bioavailability and bioequivalence evaluation of a product. This linkage forms the basis for the use of this test during the product development stage (IVIVC, SUPAC, etc.), and later at manufacturing for assessing/establishing the quality of the product (i.e. as quality control tool for compendial purposes, bio-waivers etc.).

The lack of success of [compendial] dissolution tests is not that a dissolution test lacks relevance, but the tests have been conducted using non-qualified and non-validated apparatuses. Significant literature is available showing that the [compendial] apparatuses, in particular paddle and basket, are flawed and provide highly variable, unpredictable and irrelevant dissolution results. It appears that this is what the current USP position refers to i.e. compendial dissolution testing/results are not relevant. Therefore, it can be argued that if these [compendial] dissolution testers/methods are not relevant then these should be removed from the compendial requirements.

On the other hand, there are suggestions in the literature that if modified dissolution testers (e.g. with crescent-shape spindle) are used for dissolution testing, then appropriate dissolution characteristics of a product can be determined and established. Furthermore, in reality, coupled with convolution technique an improved dissolution test can be used even to predict/estimate plasma drug level fairly accurately.

Therefore, it is requested that USP should re-evaluate its recommendation and requirement for the use of current compendial testers, in particular paddle and basket. The USP should seek and encourage suggestions for new testers and/or methods which should be predictable for bioequivalence and bioavailability, thus the quality of products.

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