Identification of Critical Process Impurities and Their Impact on Process Research and Development

Abstract

The identification of low-level critical process impurities and degradants encountered during pharmaceutical development is crucial to the process development, but can often be challenging and can negatively impact the timeline of the developmental program. This is demonstrated during the early stage of process research and development of a Factor Xa inhibitor, the caprolactam 1. Details focusing on rapid identification of impurities in the active pharmaceutical ingredient (API), recognition of their root causes of formation, and the impact on process development are described.

The Boulton–Katritzky rearrangement of isocarboxazid

“…At 100 C in the ionic liquid, [bmin]HSO À 4 , close to the temperature of refluxing toluene, the reaction is essentially complete in 3 h as determined by HPLC analysis. Isocarboxazid (1) melts between 103 and 107 C and a 24% conversion to triazole 9 was observed when isocarboxazid (1) was heated at 105 C in a reaction vial for 2 h. For this drug substance, a validated HPLC method showed limits of detection (LOD) of 15 lg for the triazole 9 and 7.5 lg for the pyrazole 6 and no triazole 9 or pyrazole 6 was detected in the crude isocarboxazid (1).…”

“…[23]. Pyrazole 6 was freely soluble in IPA, the recrystallization solvent for isocarboxazid (1). The addition of hydrochloric acid causes the hydrochloride 6a to precipitate from solution.…”

“…Current guidelines by the ICH (International Committee on Harmonization) state that known impurities in the drug substance are acceptable at levels of 0.2%. Satisfactory levels of unknown impurities are 0.1% [1]. The melding of a mechanistic knowledge of impurity pathways coupled with solid process development has led to a generalized approach for statistical process control and control of impurity formation [2].…”

Consolidating and Managing Data for Drug Development within a Pharmaceutical Laboratory: Comparing the Mapping and Reporting Tools from Software Applications

“…In other words, each synthetic variation is part of a process aimed at exploring various routes to improve the product yield and reduce process impurities from starting materials, reagents, solvent, product degradation, etc. The amount of analytical data collected is quite substantial, and the data are stored in multiple locations, including the instrument computer ( e.g. , in a CDS), an ELN, or a LIMS.…”

“…In other words, each synthetic variation is part of a process aimed at exploring various routes to improve the product yield and reduce process impurities from starting materials, reagents, solvent, product degradation, etc. 7 The amount of analytical data collected is quite substantial, and the data are stored in multiple locations, including the instrument computer (e.g., in a CDS), an ELN, or a LIMS. To further complicate the matter, the data can exist separately on more than one vendor type of CDS across multiple company sites, in addition to the use of ELNs and LIMSs from multiple vendors because of the utilization of contract research organizations (CROs).…”