The case of disappearing/late-appearing stable polymorphs and their impact is well-understood by scientists in the pharmaceutical industry. This paper discusses an instance where a more stable crystal form was discovered during the development of a fast-track drug candidate. Challenges in adapting to the discovery of the new crystal form during this accelerated drug development program and approaches to develop a robust crystallization process are discussed.

The issue of sulfonate ester formation is one that has been of significant concern to regulatory authorities since the start of the millennia. These concerns, focused primarily on the risk of ester formation where sulfonic acid salts are formed in alcoholic solvents, has led to the need for specific analysis for such species in the final API in any product containing a sulfonic acid counterion. This concept article examines the growing experimental data that exist showing how this risk can be negated through the application of simple process controls that effectively eliminate this risk. These data are also compared to specific product data, illustrating the practical experience of organizations. The article also reflects on the Viracept incident and how the mechanistic understanding of the reaction between sulfonic acids and alcohols readily predicts the observed outcome. It is the conclusion of the authors that the continued need for exhaustive analytical testing should be replaced instead by a scientific riskbased approach, taking into full consideration the specific process conditions.

ICH M7 provides several risk-based control options to manage mutagenic and potentially mutagenic impurities (MI and PMIs) in the manufacture of pharmaceuticals. A Working Group in the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org) performed a survey of pharmaceutical manufacturers to gain insight into the use and regulatory acceptance of mutagenic impurity control strategies and control options across the industry. Information on the regulatory acceptance of ICH M7 control strategies was collected on late-stage clinical and commercial programs with regulatory feedback from the FDA, EMA, and PMDA. The data show a preference for ICH M7 Option 4 as it allows the utilization of process knowledge to reduce analytical testing without any compromise on patient safety. This approach appeared globally acceptable when appropriately applied. The survey data collected show that the ability of a manufacturing process to purge impurities is a strong indicator of purity control, and the data provide additional evidence that the purge factor calculation as proposed by Teasdale et al. produces a conservative prediction of the purging ability of a process. As such, the use of predicted purge factors and purge ratio assessments relative to the required process purge provides a sound framework for mutagenic impurity controls. Experimental purge data may be generated to support Option 4 strategies when predicted purge factors offer insufficient assurance for process control.

BMS-317180 (1) is a potent, orally active agonist of the human growth hormone secretagogue (GHS) receptor. This manuscript details the process research and development efforts that enabled the synthesis of the phosphate salt of 1 on a multi-kilogram scale. Key considerations in the development of this process focused on safe execution and the requirement for telescoped synthetic transformations (i.e., without isolation of intermediate products) to contend with a lack of suitably crystalline products.

(R)-N-(3-(7-Methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (1) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of the hydrochloride salt of 1 and demonstrated the synthesis on a multikilogram scale. Two different routes to the chiral indazolyl amino ester subunit were developed utilizing either a Rh-catalyzed asymmetric hydrogenation or a biocatalytic process to install the single chiral center. The advantages and disadvantages of each of these process routes are discussed, as are challenges addressed in the assembly of the final drug substance.