While surfing the net, I came across a response to a query, published in Dissolution Technologies, (see issue of February 2011 Volume 18 Issue 1, Question & Answer Section), regarding product specific dissolution testing. It is quite disturbing to read that such poor and irrational scientific reasoning can be provided, for multiple and product dependent, dissolution tests in the pharmacopeia. The suggested reasons are not only scientifically invalid, but also provide a strong case for removing the tests and standards from the compendia which by definition is expected to set un-biased and product independent standards. For example:
It is stated that “We may find tempting the notion that because products may have similar doses and dosing intervals, they should have the same dissolution test. In the present state of the art, that is simply not the case for extended-release products.” On the other hand, such a practice is valid for immediate-release (IR) products, because the same dissolution tests are recommended for IR products (e.g. generics) having similar doses and dosing intervals. It is not clear how a dissolution tester and/or test will differentiate between IR and extended-release (ER) products and will start behaving differently by providing unacceptable results for ER products only.
It is stated that “While bioequivalence is used to establish generic status, the release mechanisms of reference listed drugs and generics may not produce adequately similar profiles in the dissolution test conditions to satisfy one quality control performance test.” A “generic status” means that drug release characteristics of the reference and generic products are the same. The composition, manufacturing and/or mechanism attributes of the reference and generic products are always different. That is why bioavailability/bioequivalence studies are required, and conducted, to establish that given the differences in products, their drug release characteristics MUST be the same. So, if products are bio-equivalent i.e. having the same drug dissolution/release profiles in vivo, and another test, in vivo or in vitro, shows differences in drug release, how relevant or useful would such a test be? The responder, in fact, appears to be arguing for developing an irrelevant dissolution test, for ER products, which would show differences in vitro dissolution/release profiles for products having the same or similar in vivo profiles.
It is further stated that “Depending on your use of the dissolution test, you may need to develop a test specifically for the product in hand.” If that is that case, what should be the basis (or criteria) for developing the test for products having similar in vivo dissolution profiles? If it is accepted that dissolution tests are to be developed as product dependent, and not necessarily linked to in vivo characteristics of the product, then a test having the attributes of 80% drug dissolved in 45 minutes using water with 50% alcohol as the dissolution medium with the paddle (250 rpm) has to be considered satisfactory. Otherwise, current requirements for pharmacopeial drug dissolution testing may be considered as based on the principle of “follow the instructions” and not science and/or logical reasoning.
It appears that the responder has provided a strong case for the discontinuation of the pharmacopeial dissolution standards and/or requirements, at least for the ER products. This may be explained as follows: (1) if the tests and tolerances are linked to a specific product as suggested, then such standards may become proprietary, and may be difficult for others to meet and/or duplicate; (2) if the reported tests or standards in the pharmacopeia are not required or expected to be met then why are these in the pharmacopeia; (3) in the absence of such requirements, obviously one is free to develop any tests and/or tolerances, with or without the relevance to in vivo drug release. The question is then again, what is the use of setting public standards?
In short, it may be argued that the current practices of setting multiple and product dependent dissolution tests are scientifically invalid and provide no useful purpose thus should be discontinued.
