Process safety groups in the pharmaceutical industry are important components of active pharmaceutical ingredient (API) development through its life cycle from discovery to commercial scale. The pharmaceutical process safety laboratory staff conduct a series of tests to identify chemically unstable reagents, intermediates and solvents, and mixtures to ensure that the proposed operating conditions provide a sufficient safety margin from the onset of undesired and potentially catastrophic thermal decomposition. Across several pharmaceutical companies, the methods used for these assessments and how results and conclusions are made are widespread (vide infra). A working group was created with members from several pharmaceutical companies within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the goal of precompetitive collaboration and to understand each of the participating companies’ procedures and assessment regarding process safety. Each company was invited to provide input using a blind survey format. This was done in the interest of making this knowledge accessible for the participating companies and the wider community of other pharma and chemical companies and even academic institutions in the US and throughout the world. This article provides the results of this in-depth survey of the members of the IQ Consortium thermal hazard working group. General issues around different tools used to assess thermal hazard risk and questions regarding staffing and tech transfer of process safety data/information from development to manufacturing were addressed. A snapshot of how various assessment strategies are employed as a function of stage of development (early, mid, and late) is also presented.
Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt (1-HCl). Initial research lots and the first delivery batch yielded form I of 1-HCl; however, during process optimization to support a second delivery, form II was identified. This discovery left limited time to map the thermodynamic relationship between the two phases prior to the second production, and based on limited knowledge at the time, form I was selected and successfully scaled even though it was determined to be the room temperature metastable phase. Case study II: 2 is a process intermediate for a novel toll-like receptor 8 (TLR8) agonist. Applying lessons learned from case study I, polymorph screening identified unsolvated forms I and II, whose relative stabilities were mapped so that a crystallization could be designed to ensure phase control for the thermodynamically most stable form at room temperature prior to production, which ultimately benefited superior impurity rejection.
Compound 1 is a densely functionalized iminohydantoin that possesses a quaternary stereocenter and is under development as an HIV protease inhibitor. Key challenges that are discussed include the preparation of a neopentyl Grignard reagent via magnesium insertion, development of a one-pot Curtius reaction that generated a volatile isocyanate and was trapped with an alcohol, and removal of a CBz protecting group to isolate a succinate salt. This study describes process development efforts that enabled the first scale-up of 1.
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