Continuous manufacturing: the future in pharmaceutical solid dosage form manufacturing

Abstract

The highly conservative pharmaceutical industry is now approaching an era of renewal, transforming from batch manufacturing to continuous manufacturing, to convert seamlessly in fast continuous sequence, raw materials into high-quality final products [1,2]. This transformation is significant, to meet demands on solid dosage forms manufacture through cost savings by simplifying processes, reduced space and energy footprints, reduce product failures and yet, provide even better quality products for patients [3,4]. Full automation allows for consistent product quality produced under 24 h production capabilities [5]. However, high initial investment cost, vagueness on the long-term capability of the manufacturing system and the uncertainty of regulatory requirements for continuously manufactured products are some initial hurdles creating reluctance to adopt this highly required transformation. Currently, the most common pharmaceutical solid dosage form, tablets are manufactured by batch manufacturing. First, active pharmaceutical ingredients (APIs) are manufactured in upstream steps which mainly involve chemical synthesis, reaction engineering, crystallization, separation and purification. Almost 70% of the upstream reaction steps are in batch mode [6]. Many companies are now trying to change these batch reactions with flow reactions to generate API with minimal losses. In the next stage, isolated APIs are further treated by different downstream steps to formulate the dosage form, tablets. In a perfect future world, fully end to end continuous manufacturing, which is also coined as homogeneous processing, will take root and terms such as upstream and downstream processing may not exist anymore [7]. Homogeneous processing requires the incorporation or development of new technologies. However, before the dream of homogeneous processing becomes a reality, a transformative transitional phase, in which heterogeneous continuous processing involving the streamlining of upstream processing and downstream processing as continuous phases, has to be initiated. GEA Pharma Systems is a leading group of companies involved in developing these continuous processing systems, particularly for downstream processing and some of their systems are discussed here to provide recent updates in this emerging area. The downstream steps for batch manufacturing of tablets involve one of the three common methods: wet granulation, dry granulation and direct compression [7]. Blending and milling are also the parts of the downstream processes and are carried out as according to the requirements. In this aspect, recently developed downstream processing methods such as melt extrusion, thin film casting and electrospinning can be considered as continuous processing with less powder handling [8]. Major limitation to prepare tablets via batch manufacturing is the requirement of very good flowing feed materials. Wet granulation is the popular method to convert free particles into aggregates with the aim to improve flow properties, compressibility and homogeneity of materials and become suitable for high-speed tableting. Continuous twin Continuous manufacturing: the future in pharmaceutical solid dosage form manufacturing