Simulation and modeling practices for establishing quality of pharmaceutical products – valid intentions but invalid outcomes

Dear experts:

In the area of simulation and modeling, including developers of commercial software, note that I may not be able to argue with you regarding your methodologies of data analysis, modeling and/or simulation aspects as this is not my area of expertise. However, I know with certainty that you would require valid and accurate data for your analysis purposes. The difficulty is that you would not have access to such valid and accurate data, at least for evaluating tablet or capsule products for predicting plasma drug levels or profiles.  The in vitro drug dissolution results represent or simulate in vivo dissolution and, by extension, plasma drug levels or profiles.

You would require such data to validate your simulation or modeling outcome at least for the product development and manufacturing stages. Unfortunately, no one, at present, is generating or can generate valid in vitro dissolution data. Thus, your efforts of conducting simulation/modeling are regrettably of no use and would not help the industry, regulatory authorities, or anyone else. Please, do not make claims about the successes and usefulness of such exercises.

One of the main reasons for not being able to obtain valid in vitro dissolution or drug release data is that the recommended and required (e.g., from USP and FDA) dissolution testers for such purposes have never been shown to provide valid and accurate dissolution results. These testers have never been validated for their intended use or purpose. Vendors/manufacturers make extraordinary efforts and take pride in providing “compliant” testers, i.e., meeting or exceeding “physical or fixed” specifications according to the pharmacopeial (such as USP) requirements; however, they are unable to validate the testers as dissolution testers. For example, no present vendor can provide valid in vitro dissolution results if given a blinded sample of a tablet/capsule product. Therefore, in this respect, claims made by the vendors are also not accurate that they are selling or manufacturing dissolution testers. At best, the only claim they can, or should, make is that they are selling simple stirrers. Perhaps more disturbing is that these stirrers, when used as required for dissolution evaluations, cannot provide valid and accurate dissolution results, which are documented extensively in the literature because of their design and operation limitations and flaws.

In short, please use and promote the simulation and modeling techniques with care and certainly use extra caution in making claims about future expectations and successes.

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