Utilizing o-Quinone Methide Chemistry: Synthesis of d9-Ivacaftor.

Lead time and cost are important factors for any pharmaceutical API. However, these issues become even more important when the drug substance contains an isotope such as deuterium, which has a natural abundance of only ∼0.016% of all hydrogen. Fewer suppliers and logistical barriers both play a role in driving up the cost. These factors can challenge the supply route used to manufacture d9-ivacaftor (17), requiring investigation into alternative routes. By adapting the work from Pettus et al., a synthetic approach utilizing a transient o-quinone methide allowed access to the deuterium-labeled o-tert-butylphenol moiety. This was developed and proven on pilot scale to significantly reduce the number of deuterated reagents used, leading to an overall reduction in cost by a factor of 10, while also providing the substantial benefit of applying prior process knowledge from the parent, nonisotopically enriched API ivacaftor (7).

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400.

VX-497 is a poorly water-soluble compound. It is formulated in PEG-400 and encapsulated in softgel capsules. Although the drug product is stable at refrigerated conditions, many degradation peaks have been observed at accelerated storage conditions. An investigation utilizing high performance liquid chromatography-mass spectrometry (HPLC-MS) was conducted to understand the degradation mechanism of the active pharmaceutical ingredient (VX-497) in PEG-400 formulation. Results revealed that the degradation was mainly caused by the reaction between VX-497 with moisture (hydrolysis) and PEG-400 (PEGylation). The numerous degradation peaks observed in the samples stored at accelerated conditions were PEG adducts covalently attached to portions of the VX-497 molecule, which were confirmed by comparison with synthetic markers. Investigation also found that an impurity, which was present in the VX-497 drug substance, reacted with PEG-400 following the same reaction mechanism, and generated additional impurities in the VX-497 drug product. By changing the process for drug substance synthesis, pure batches of VX-497 were obtained. Furthermore, it was found that the reaction between VX-497 and PEG-400 was temperature and time dependent. When the drug product was manufactured at 45 degrees C and the processing time was controlled, the PEG degradants and by-products were reduced to non-detectable levels, resulting in greatly improved drug product quality. This paper presents an integrated effort among analytical, process, and formulation scientists on how to develop a better drug product by understanding the fundamental issues of the drug product, namely the degradation mechanism.