From Lab to Plant: Managing Operational Environment During Scale-Up
By Katie Anderson, Chief Editor, Pharmaceutical Online
Scale-up comes with its challenges, with adaptations to the process, materials and equipment often anticipated. Though these challenges can result from equipment, raw material differences, and process variability, operational environments must be a major focus during lab trials, as Yuhei Yamamoto and his team at Takeda learned in a recent experience.
Yamamoto and his lab team took their Suzuki-Miyaura coupling reaction to new heights (literally), and published the lessons they learned from their scale-up with a contract manufacturing organization (CMO) at a higher altitude. CMOs at higher elevations are certainly not the norm; however, the research can help those with palladium-catalyzed reactions recognize early considerations and avoid unforeseen complications during scale-up.
Troubleshooting Cause and Solutions
Palladium is sensitive to temperature and oxygen. To maintain the internal conditions of the reaction, the CMO (at a higher altitude) needed to use a pressure reactor.
“Reaction temperature was an important factor and needed to be maintained at 85–95 °C. At high altitude, the solvent refluxed at 80°C, and the reaction would not go to completion at this temperature. The CMO used a reactor that could be pressurized, allowing the internal temperature to reach 85–95 °C, explained Yamamoto.
The researchers established solid reaction conditions in their lab; however, when the CMO performed the reaction at a higher altitude using the pressure reactor, the crystals had elevated levels of palladium. “The release test of the compound included impurity levels and residual palladium, and this was identified by checking the master batch record and comparing it to the laboratory procedure and data to identify any differences,” added Yamamoto.
Impurities are not uncommon with Suzuki-Miyaura coupling, according to Yamamoto. Dehalogenation, homo-coupling and oxidation can all produce impurities, but the out-of-expectation (OOE) levels of related substances led to concern. “Many parameters can affect impurity formation. If we consider which conditions cause impurity issues during scale-up, they include the presence of air (or oxygen), mixing efficiency, nitrogen flow, heating efficiency, and reaction temperature,” explained Yamamoto.
His team investigated stirring efficiency, jacket temperature, reaction pressure and presence/absence of oxygen to determine the cause of the excess palladium.
The research team deduced that the elevated impurities from the reaction were caused by a high external temperature. They found that there were local hot spots near the high-temperature jacket.
To tackle the crystal quality, the scientists noted that the jacket temperature needed to be below 105 °C. This measure helped to reduce impurities from the reaction. However, the strict aerobic conditions prevented them from removing the palladium after the reaction, and they needed to add air.
Since adding air directly was not advisable, the team added air via 02N2 bubbling. This was integrated after the reaction to facilitate palladium removal and enhance crystal quality.
Lessons Learned
In their research, the scientists emphasized the importance of mimicking the equipment and environments to be used for manufacturing. In this case, having utilized the pressure reactor in the process would have highlighted impurities that led to earlier process refinement.
Yamamoto continued that other reactions at high altitude should take heed. “This issue is not limited to the S-M reaction and can occur with any reaction if the decrease in boiling point at high altitude is not considered. Therefore, it is recommended that, when running reactions at reflux or high temperature, a pressure reactor should be used in the lab and relevant data should be collected,” he furthered. Altitude is not a concern for reactions that do not require high temperatures or reflux.
Good communication is the key, according to Yamamoto, concluding, “For manufacturers at high altitude, I recommend maintaining good communication with laboratory chemists, especially if the lab chemists are located at normal altitude.”