Observed trends in regulatory expectations for the qualification of pharmaceutical container/closure systems from an extractables and leachables perspective

摘要

A first observation you bring to the table is that - from a regulatory perspective - there is still a strong bias towards concerns about the quantitative aspect of E&L studies. Can you elaborate a bit more on this? When assessing the impact of extractables or leachables from a safety perspective, there are two important pieces of information that will allow completing an in-depth toxicological assessment: the compound's identity and its concentration or dose to the patient. The compound's correct identification allows making the link to relevant toxicological information (e.g. literature). Alternatively, it can also be derived from in silico information (e.g. QSAR) if no relevant literature is available. Armed with this toxicological information, PDE's or other relevant toxicological thresholds can be derived. In a second step, you can verify the impact for the patient by confirming if the patient's exposure is above or below this PDE value, or you can calculate "Margin of Safety" values. While it is a valid concern that a "screening methodology", often used for the discovery, identification, and quantification of extractables and leachables may only lead to estimated or semi-quantitative results, the obtained concentration "estimates" can still be used, in combination with well-defined uncertainty factors, which account for the lack of accuracy of the result. However, only a few questions are asked about the correctness of the identification of the compound, while identifications - e.g. based upon "mass spectral matching"- can lead to flawed identities, which will irreversibly compromise the overall risk assessment.