You don’t want to miss the special issue of Organic Process Research & Development, dedicated to analytical control strategies in quality assurance and reaction monitoring. There are few articles dedicated to potential mutagenic impurities. Enjoy the read
Access link: https://pubs.acs.org/page/oprdfk/vsi/analytical-control-strategies-2025
Enabling Data-Driven Solubility Modeling at GSK: Enhancing Purge Predictions for Mutagenic Impurities
Abstract:
In the pharmaceutical industry, solubility is a critical parameter influencing various stages of drug development, from early discovery to commercial manufacturing. This work showcases a high-throughput solubility screening workflow and describes the steps required to standardize and curate data suitably to allow automated data flow. Using the high-quality data, we developed a quantitative structure–property relationship model using gradient boosting and molecular descriptors, requiring only a 2D molecular structure to generate predictions. The accuracy of the model is competitive with alternative approaches where additional physical data is not required. A key use case for solubility predictions made in this way is in developing control strategies for mutagenic impurities, allowing for a data-driven and consistent method for calculating the solubility contribution to purge calculations. Further perspective is given on the future of the application of the model as a solubility prediction algorithm and on the approach to data-driven methodologies supporting drug development in general, highlighting the potential for federated learning approaches which use technological approaches to overcome the barrier to cross-industry data sharing.
Veliparib: Analytical Tools and Process Design Strategies for the Control of Mutagenic Impurities and Other Drug Substance Critical Quality Attributes
Abstract:
(R )-Veliparib (ABT-888) is a poly(ADP-ribose)polymerase (PARP) inhibitor that is being investigated for the treatment of a broad spectrum of oncology indications, including BRCA1/2-mutated breast cancer and other solid tumors. The (R )-veliparib process consists of three stages utilizing two proposed regulatory starting materials, (R )-Boc-2-methylproline and 2,3-diaminobenzamide dihydrochloride, with two isolated intermediates. The drug substance control strategy, which was established based on a combination of analytical tools and uniquely designed manufacturing process and unit operations, provides robust controls for mutagenic and other impurities and ensures that (R )-veliparib drug substance consistently meets all critical quality attributes (CQAs) and acceptance criteria. The purpose of this article is to provide details of how the (R )-veliparib control strategy for the selected CQAs was cross-functionally developed using analytical measurement tools and specially designed unit operations.
Quality Control for Incoming Raw Materials Beyond Identity and Purity: Case Studies from Recent Merck API Manufacturing Processes
Abstract:
The development of robust manufacturing processes for active pharmaceutical ingredients (APIs) is paramount to ensure a supply of safe and effective medications. Implementation of a holistic control strategy, including quality control of incoming raw materials, is a key element in meeting this goal. This paper describes several examples from recent Merck API manufacturing routes, in which impurities in raw materials affected the processes in various ways, including giving rise to new process impurities, jeopardizing process safety and causing damage to reaction vessels, and─sometimes unexpectedly and counterintuitively─suppressing formation of process impurities. In all of these examples, analytical characterization plays a critical role in identifying these impurities and enabling their control to ensure consistent process performance and product quality