Be careful of “validation” traps: At present, these may, in fact, require accepting scientifically irrelevant and non-reproducible apparatuses (or methods)

It is often suggested that to use an apparatus (or method) for dissolution testing, it must first be validated. There is nothing wrong with this statement or requirement. One should follow this requirement.

The question, however, is how should one validate a dissolution apparatus? This is where the problem is! In principle, validation means establishing that an apparatus is capable of measuring required characteristics. Here capability means ability of measuring relevant dissolution characteristics or results.

In the case of current practices of dissolution testing, however, there is an interesting twist in the validation requirement. Here, promoted validation means obtaining dissolution results similar to those one would obtain using one of the compendial apparatuses, in particular paddle or basket apparatus. It is important to note that the requirement is not that  of relevant and/or reproducible results, but similarity of results obtained using compendial apparatuses (read similar practices with vibration and de-aerations aspects). This would have been acceptable if compendial apparatuses were validated themselves against some relevant reference product or value. Unfortunately, the compendial apparatuses have never been validated. In fact, these apparatuses have been shown repeatedly to provide irrelevant and irreproducible results. As per current practices or requirements any new or different apparatus also become non-validated, by default, if it provide similar results as those of the compendial apparatuses. Therefore, current recommendations require developing and using non-validated apparatuses and methods.

Not only are the current requirements and practices scientifically invalid, they also create serious hindrance in developing new and improved apparatuses and methods. For example:

(1) Current recommendations will allow using only those apparatuses which will be as bad as the current ones which are known to be flawed (in particular paddle and basket).

(2) In reality, the requirement/practice will not allow using any comparable method as it will be argued that if one is obtaining similar results using current apparatuses, then why to introduce new variations. In fact, it is a clever way of maintaining the status quo or the use of flawed apparatuses and methods.

(3) It is very important to note that any new or improved apparatuses will have to provide different results which will be the only reason for their development or use. However, considering the current mindset, these improved variations will be considered non-validated as the results obtained will be different than the ones obtained using current recommended approaches. Therefore, improved apparatuses (or methods) would be rejected against current practices.

The implication of the above mentioned practices may be explained as follows: Suppose someone would like to develop a physiologically or bio-relevant apparatus. Such an apparatus would be based on simulating physiological environment. As the physiological environment is product independent and consistent across products (e.g. IR and ER), the new and improved method will be based on a single set of product independent experimental conditions. However, current requirements promote and stress product dependent experimental conditions. Therefore, if one will compare results based on current requirements with those obtained with improved method, those will not be equivalent or comparable, therefore, the results obtained will be considered non-validated and will be rejected (even those obtained using an improved method simulating the physiological environment). Therefore, there is a limited chance of developing an improved and physiologically relevant dissolution method, apparatuses or obtaining dissolution results, if current promoted validation practices continue.

The only option available to develop physiologically or bio-relevant and reproducible apparatuses and/or methods is to validate these against their intended purpose and not against results obtained using arbitrarily selected apparatuses, methods and experimental conditions.

In conclusion, one should be watchful of current validation recommendations and requirements. These requirements are logically and scientifically invalid. The validation should be performed against the intended objective, and not by comparing results obtained from non-validated or irrelevant apparatuses and/or using arbitrary experimental conditions.

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