In 2014 we were approached to prepare an intermediate in bulk. Our customer had specific issues finding suppliers for this product.
The question was not the availability of the commercial product, but the analytical data provided by the different suppliers. In this case the analytical data was critical, since the intermediate was going to be used in the last reaction step to manufacture an API under GMP.
We evaluated the information available on the product, and we identified 7 different synthetic strategies. We selected 2 routes as the most convenient, taking into account several critical parameters. First, since the intermediate was to be used in the n-1 step of the GMP synthesis, no genotoxic impurities were allowed. Second, solvent selection according to the ICH Q3C avoiding the introduction of a new solvent. Third, no use of some catalysts to avoid heavy metal contamination in the final product. And fourth, we also decided to go for cheap raw materials.
After the client approval the development was started. The selected routes were tried in the lab and the potential impurities identified and duly reported to the customer. One route was then selected and scaled up to deliver the first batch of 1 kg according to the schedule.
The analytical controls (both for process and product) were also developed during the scale up. The final product presented an unexpected turbidity in the distilled product. The issue was solved by a simple filtration over a layer of Celite. Afterwards, it was demonstrated that the turbidity was caused by the presence of an impurity. The impurity was then identified and quantified. After some assesment we decided, in accordance with the customer, that the impurity was not critical, so the filtration step can be removed and the synthesis cost reduced. The client will request additional product batches in the near future.
