Development of a Continuous Flow Grignard Reaction to Manufacture a Key Intermediate of Ipatasertib

This article outlines the development of a continuous flow process for the manufacture of a key intermediate of the active pharmaceutical ingredient ipatasertib for the treatment of metastatic castration-resistant prostate cancer and triple-negative metastatic breast cancer. The reaction sequence incorporates multiple telescoped unit continuous operations, including a Br/Mg exchange reaction leading to intramolecular cyclization of the magnesium species onto a neighboring nitrile group to form a five-membered ring in 5-exo-dig fashion. The product from the reaction mixture is obtained after continuous aqueous acidic hydrolysis, neutralization/extraction, water wash, and phase separation. Each of these unit operations took place in a cascade of continuous stirred tank reactors. The control strategy was refined via a series of continuous lab studies at 20 g/h using a Design of Experiments approach to define process parameter ranges and to help identify any criticality therein. The learnings from this laboratory study served as a basis for the construction of a suitable pilot-plant facility, where the control strategy was verified at a representative manufacturing scale of about 1.0 kg/h

Supplementary Table 1 from Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in <i>EGFR</i> Wild-Type Non–Small Cell Lung Carcinoma Cell Lines

XLSX file - 144K, Protein identifications in eluted fractions from erlotinib-Sepharose and gefitinib-Sepharose</p

Supplementary Figure 2 from Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in <i>EGFR</i> Wild-Type Non–Small Cell Lung Carcinoma Cell Lines

XLSX file - 24K, Statistics of proteins that significantly decrease in their relative abundance with increasing compound concentration, in at least one of the two compounds</p

Supplementary Figure 1 from Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in <i>EGFR</i> Wild-Type Non–Small Cell Lung Carcinoma Cell Lines

PDF file - 60K, Schematic diagram of the experimental framework applied to perform label-free, quantitative chemical proteomics on erlotinib and gefitinib</p

Supplementary Methods from Quantitative Chemical Proteomics Profiling Differentiates Erlotinib from Gefitinib in <i>EGFR</i> Wild-Type Non–Small Cell Lung Carcinoma Cell Lines

PDF file - 96K</p

QbD Approach to Process Characterization and Quantitative Criticality Assessment of Process Parameters

The quality-by-design (QbD) approach is widely utilized for developing and validating manufacturing processes for drug substances as well as drug products. This paper discusses the application of the risk-based QbD approach used at F. Hoffmann-La Roche Ltd. for development, optimization, and characterization of drug substance manufacturing processes for small molecules. It presents the evolution of the QbD concept into statistical thinking and development of a quantitative tool, namely, the impact ratio concept, for its successful implementation. The utilization of this approach is illustrated with a case study from the taselisib drug substance manufacturing process