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One of the specific challenges of the guideline was that it also potentially applied to applicants for generic versions of existing products. On one level, an applicant for a generic medicine might assume that the active substance in their medicine is “out of scope,” as clearly such a medicine has a significant preexisting period of use such that its safety is known. However, this assumption relies upon the generic active pharmaceutical ingredient and medicinal product having the same quality and impurity profile as the existing drug substance and drug product. This may on many occasions not be the case, as even if similar chemistry is used, subtleties of manufacture or formulation can lead to potentially significant differences in impurity profile, especially when “significant” is no longer being considered as reflecting levels commensurate with that of the ICH unspecified impurity control limits [2] (e.g. in the order of 0.1% – i.e. parts per thousand) but at the levels of TTC‐based controls (which can be in the order of parts per million and indeed for those impurities defined by the cohort of concern, parts per billion).

A particular challenge in terms of development of generic products relates to how can a generic applicant assure themselves they have introduced no new risk factors with respect to previously approved materials? Could this be achieved by simply meeting the preexisting European Pharmacopoeia (EP) monograph for the active substance (if one exists)? In reality even now it is likely that this will not be sufficient: monographs rarely include controls on potential MIs at low levels. Thus, many of these potential risks may be “invisible” in terms of the public quality standard; indeed, the recent issues surrounding N‐nitrosamines clearly highlight this. Maybe the generic applicant could simply test their drug substance against the previously approved drug substance? But what analytical methods should be used? Of course, this lack of transparency relates not only to the generic manufacturer, the regulator charged with assuring the suitability of the new product faces a similar challenge.

Of course, if the generic applicant decided to do a comprehensive and independent risk assessment of their drug substance or drug product and their manufacturing processes and establish TTC‐based controls for any potentially MIs (on the basis of structural alerts, etc.), then no doubt the regulatory agencies will be presented with a potentially approvable drug substance, associated specification, and manufacturing process. What even now remains unclear is how will the agency view the previously approved marketing application holders. Issues surrounding valsartan and N‐nitrosamines show that certainly where the risk is deemed to be a general risk this will very likely lead to a request to test all current approved products for the MIs that the subsequent applicant has determined to be potentially present.