Active pharmaceutical ingredient primary processes

Figure 40 Primary process of active pharmaceutical ingredients at company B.

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodriguez-Hornedo and Murphy, 1999 Shekunov and York, 2000 Rodriguez-Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purihcation during the intermediate and hnal stages of drug synthesis. Moreover, solution crystallization determines the hnal solid-state modihcation of the API namely polymorphs, solvates, and hydrates. 

Characterization starts once the synthetic route has been selected, although there will be opportunities to modify the route if the changes do not impact the final solid state or impurity profile of the final active pharmaceutical ingredient. The primary objective is to understand, through experimentation, the chemical and physical chemical processes involved in the transformation of raw materials to intermediates and products. The primary outcome is a process definition that includes the order of manufacturing steps, process parameter control methodology, process parameter limits, raw material specification, and diagnostic metrics. 

We have embraced this relatively modem definition of PAT for the purposes of this chapter. In particular, PAT in this context includes any analytical technique that provides data in real time to manufacturing processes involved in making bulk active pharmaceutical ingredients (APIs) with the primary intent to ensure process control and thus product quality. 

Primary recovery of the active ingredient from the solid or liquid phase to remove large quantities of unwanted waste materials, which may themselves be processed further. Suitable techniques include solvent extraction, precipitation by chemical or physical changes to the product-containing solution, and ultrafiltration or microfiltration to separate products above a particular size. Work done on combined biomass separation-primary product recovery processes such as expanded-bed adsorption are now being commercialized in the pharmaceutical industry. 

Bulk pharmaceuticals and generally the active ingredient in a pharmaceutical product, are more often than not produced in primary pharmaceutical plants which are very similar to fine chemicals plants. They arc capital intensive, are relatively large and work on a three-shift system. There is a tendency for pharmaceutical companies to locate their primary plants near to their home base. On the other hand, secondary pharmaceutical plants process the ingredients of the product, and fill and pack the medicinal item. These plants are not so capital intensive and work mainly on day shift. 

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