Active pharmaceutical ingredients continuous processes

Thomas, P.W. and Ramsay, A. (2004) Continuous manufacturing of a bulk active pharmaceutical ingredient. Presented at Switching from Batch to Continuous Processing Conference,... 

Active pharmaceutical ingredients are most often manufactured in batch or semicontinuous process since most APIs are potent and normally used in relatively small amounts in each batch of drug product, especially during the early phase of drug product introduction. With the advent of many new APIs, the capital investment for continuous operation is not economically feasible. In a batch process, the product is often made from a well-identified, approved raw material supply, which is usually present at the start of the reaction. 

Cervera-Padrell, A. E., Morthensen, S. T., Lewandowski, D. J., Skovby, T., Kill, S., Gemaey, K. V. (2012). Continuous hydrolysis and liquid-liquid phase separation of an active pharmaceutical ingredient intermediate using a miniseale hydrophobic membrane separator. Organic Process Research Development, 16, 888-900. 

Hot Melt Extrusion (HME) is a continuous solvent- and dust-free manufacturing process that requires the use of only a limited number of excipients and low-cost instrumentation. The purpose of HME is to create a dispersion of the Active Pharmaceutical Ingredient (API) in a polymer matrix in order to achieve solubility enhancement, release rate modulation, taste masking, or to develop a new dosage form. However, polymers must fulfill a number of requirements in order to be suitable for HME processing. 

It is of worthy of note that the International Conference on Harmonization (ICH, Guideline Q6A of the October of1999) includes under the heading of polymorphs single entity polymorphs molecular adducts (solvates, hydrates), amorphous forms . The FDA currently requires that pharmaceutical manufacturers investigate the polymorphism of the active ingredients before clinical tests and that polymorphism is continuously monitored during scale-up and production processes [42], The... 

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