Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issues such as waste container overpressurization or fire. In this study, multiple module calorimeter (MMC) testing along with micro-GC tests of small scale (1−2 mL) representative lab samples were performed to detect and predict the potential safety hazards associated with the scale-up of an ATH process. Due to the safety concern discovered in the early safety screening tests, methanesulfonic acid (MSA) quench was implemented at the end of the ATH reaction to suppress hydrogen generation, avoiding possible overpressurizing the waste drum and the need to use special hydrogenrated equipment at pilot-and production-scale. A safety assessment was performed to ensure that the subsequent vacuum distillation poses no risk of hydrogen combustion caused by using a standard pump/system. The process improvements and rigorous safety assessments enable the ATH reaction to be scaled-up using standard pilot plant equipment without the need for special handling and monitoring requirements for hydrogen gas. This study provides useful guidance and recommendations for safer scaling-up of similar organic synthetic reactions which may also generate flammable gas.

Process safety testing performed on a batch process for making a pharmaceutical intermediate revealed that one process stream, a reaction in dimethyl sulfoxide, had a significant undesired reaction that could lead to catastrophic vessel failure as a result of a single process deviation. Comprehensive testing identified the worst case process stream with the lowest exotherm initiation temperature and most severe pressure consequences, for which corrective actions must be taken. With this information in hand, hazard assessments were performed to support processing, to determine the appropriate safeguards needed to mitigate the consequences, and to reduce the likelihood of reaching this activity to a tolerable level.

Pharmaceutical operations often require inertion or other suitable explosion protection systems when handling highly ignition sensitive materials. Regulating bodies typically require full inertion, which may be difficult and expensive to maintain. This work measured the influence of oxygen concentration on the values of the minimum ignition energy (MIE) as well as the explosion severity (Kst and Pmax) for several of the most easily ignitable pharmaceutical powders. We found a significant increase in the MIE and decreases in the Kst and Pmax by reducing the oxygen level to 12% to 15% v/v. The changes in MIE and explosion severity mean that partial inertion along with control of static should provide a satisfactory basis of safety for most unit operations handling these powders. We share these results to encourage others to examine the behavior of similar organic powders. Further, we have used the adiabatic flame temperature from combustion calculations to model the Pmax, limiting oxygen concentration, and MIE at reduced oxygen concentrations, and find very good agreement with the experimental values. This modeling can be a useful tool as a safe and economical alternative to testing when material is not available or for highly potent/toxic materials where testing is not preferred to avoid personnel exposure.

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Process safety testing is critical for small molecule active pharmaceutical ingredient (API) scale-up and manufacturing by proactively identifying any process safety hazards, including environmental and industrial hygiene issues. The intent of this contribution is to describe how Merck & Co., Inc. Kenilworth, NJ (known as MSD outside of the U.S. and Canada) manages process safety testing for pilot plant and manufacturing scale operations with a stagewise approach. Several case studies will be discussed.