Challenges and Opportunities in the Continuous Manufacturing of Pharmaceuticals

The pharmaceutical industry is a large, high value added manufacturing sector, with annual worldwide sales of nearly $1 trillion. The traditional manufacturing mode in this sector has been batch operation. However, recent advances in technologies, changes in the regulatory climate and continuously drivers for cost reduction have provided a unique opportunity for the introduction of advanced manufacturing technologies.  

Continuous processing is considered to be one of the key technologies that can provide significant innovation in the pharmaceutical sector also motivated by the vision of developing “on demand” personalised medicines. In addition to offering better product consistency, and overall process efficiency, continuous manufacturing has the potential to provide more distributed and even mobile manufacturing systems that could be located at the point of use, improving access to novel medicines, opening new market

opportunities, reducing costs, driving innovation and speeding time to market. However, to be able to exploit the advantages of continuous manufacturing processes in an industry characterised by high value, high variety and low volume products obtained through a network of distributed manufacturing systems, advances are required in fundamental process understanding, continuous processing and equipment in particular for chemical solids and in measurement, modeling and control methodologies.

The presentation will provide an overview of the advantages and challenges, including regulatory aspects, related to the continuous manufacturing of pharmaceuticals, from synthesis to formulation of the final product. We will provide a brief overview of aspects related to continuous production of active pharmaceutical ingredients (API) and then focus on methodologies for the continuous processing of slurries and solids, which present key challenges in enabling the overall continuous manufacturing process. Crystallization is the key unit operation that connects the primary (API synthesis) and secondary (design of delivery form) manufacturing processes.

The solid properties such as shape and crystal size distribution (CSD) of the API obtained at the crystallization step will strongly influence the efficiency of the secondary manufacturing process. Modeling and control approaches for continuous crystallization will be presented that allow better control of the product CSD.

Continuous secondary manufacturing of the final product from the API isolated at the crystallization step has also received quite a bit of

attention in the industry and been the focus of research in the NSF

Engineering Research Center for Structured Organic Particulate Systems, a multi-university collaboration with industry. The focus here again is on innovative use of on-line measurement, process modelling and control, exceptional events management and real time process management. Process configurations including the full range of unit operations from powder feeding to tablet coating are under active consideration. The rudiments of process flowsheet modelling for such operations are beginning to be assembled offering the potential for design optimization. The presentation

will conclude with a brief overview of some additional manufacturing

innovations targeting small scale manufacturing configurations suitable for delivery of individualized medicine.