Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques

Abstract

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.

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir

“…The reaction mixture was evaluated by DSC and showed an onset of decomposition at 105 °C with a mild exothermic event of 127.25 J g –1 . Since the MTSR value is well below the MTT (boiling point of solvent), it showed low severity as per Stoessel’s Rules . Moreover, no thermal accumulation of heat was observed.…”

“…Since the MTSR value is well below the MTT (boiling point of solvent), it showed low severity as per Stoessel’s Rules. 9 Moreover, no thermal accumulation of heat was observed. The overall data project this to be a potentially safe process for scale-up operations.…”

Precompetitive Collaborations in the Pharmaceutical Industry: Process Safety Groups Work Together to Reduce Hazards, from R&D Laboratories to Manufacturing Facilities

“…Group members represented the major pharmaceutical companies in the United States and Europe. In 2020, the group published a paper 22 on companies' different approaches to thermal hazard evaluation that was well received by the community and won the ACS Editor's Choice Award. Future work will focus on platforms used to carry these important testing methodologies.…”

Quantum Mechanical Methods for Thermal Hazard Risk Assessment in Early Phase Pharmaceutical Development

“…The development often involves new reactive building blocks, reagents, intermediates, and nitrogen containing heterocycles which are present in 59% of new pharmaceutical entities . However, lack of understanding of the potential safety hazards associated with the newly designed reactions/materials can lead to serious consequences. − To understand the safety hazards associated with a chemical process, thermal stability analysis of compounds involved in the reaction and thermal runaway potential of the reaction are required . The severity of exothermic reactions can be quantified with adiabatic temperature rise (Δ T ad ), and the probability of thermal decomposition.…”