One of our biotech clients recently approached us with an interesting process challenge. They were in the middle of a scale-up of a multi-step manufacturing operation that involved the formulation of the active in a solvent mixture, removal of the solvent, addition of an aqueous buffer and sterile filtration. The active is temperature sensitive and expensive. Laboratory preparation was performed using a small explosion-proof spray dryer, but the product losses were much higher than anticipated due to thermal degradation and carryover of product into the exhaust filtration system. It was anticipated that, although the spray dryer had the capability of removing the solvent, the losses due to thermal degradation and carryover would persist in the scaled-up process. Clearly, spray drying technology was not an optimum selection.
There are dozens of ways to remove solvents from a solution and end up with a dry powder. We wanted one that would minimize material transfer, eliminate thermal degradation and reduce the handling of dust and solvent vapors. Our first attempt was to employ a scraped-surface heat exchanger equipped with a vacuum system and appropriate controls to gently remove the solvent at a reduced temperature while minimizing the carryover of the active. Theoretically, both thermal degradation and carryover would be minimized and most of the solvent could be condensed limiting the environmental exposure. Unfortunately, during the solvent removal process, the active/solvent formed a thick paste that was incompatible with the mechanical operation of the scraped-surface heat exchanger. A gummy mess was created that was undesirable.
We suspected that the physics of the process was right, but we needed a better mechanical solution. One of the technologies used extensively in the cosmetics and personal products industry for the manufacture of creams, ointments and thick topical preparations is a jacketed, pressure and vacuum-rated vessel equipped with multiple agitation features including a scraped wall agitator to prevent sub-cooling of the product during the process. Analogy LLC suggested that a slight modification of this technology could result in a multi-purpose processor that would meet and exceed the process requirements.
- The formulation of the active in the solvent solution can be performed in the vessel
- Vacuum is created, temperature is maintained and solvent is removed in a very controlled manner to eliminate thermal degradation and loss of active.
- Since this is a batch operation, the scraped wall agitation could be discontinued and the residual solvent could be removed using vacuum and gentle addition of heat as required. The formation of a sticky product was not an issue.
- When solvent is totally removed, buffer can be added directly to the vessel and the active can be returned to solution with minimal losses.
- The buffer/active can then be directly connected to the sterile filtration skid.
- The entire system is contained and easily cleanable.
This is an example where selecting the right technology results in significant cost avoidances, reduced loses, increased yields, better quality, minimal environmental issues and improved safety. Great project!