The most common way of administration of medicine is the oral route with a solid dosage form (tablet formulation). For example, the three most widely prescribed medicines in U.S market in 2019 were tablet formulations (Statista, 2019). The importance of tablet formulation technology has increased considerably. One reason is the huge market of generic products and their cost effective production (Ierapetritou et al., 2016; Robinson, 2019). However, the manufacturers are under social and economic pressure to lower the costs of production and increase effectiveness to achieve better competitiveness in global markets (Barton and Emanuel, 2005). Thus the emphasis is moving toward to solid oral dosages, tablet formulations, from batch to continuous manufacturing and its technology by applying methods like direct compression, wet granulation and dry granulation (Vervaet and Remon, 2005). One option is hot-melt extrusion (HME), if the above-mentioned technologies are not possible (Maniruzzaman et al., 2015). The FDA defines a continuous process as ´a process consisting of at least two connected Unit Operations to which material is continuously fed and from which material (product) is continuously removed´.
According to the FDA, conventional batch processes consist of a sequence of individual process steps (FDA, 2019). The main processing steps include feeding, blending and tableting. The additional unit processes e.g. the dry granulation consists of roller compaction with milling, while the wet granulation consists of drying system with granule milling. Direct compaction does not have any granulation process prior to tableting. The main routes of a continuous manufacturing process (Rogers et al., 2013) are shown in Figure 5.
29
Figure 5. The main routes of the continuous manufacturing process (Adapted from Rogers et al., 2013).
2.4.1 Continuous direct compression (CDC) process
The most simple way of producing a tablet formulation is direct compression manufacturing, where the blended materials are fed directly into the tablet press (Galbraith et al., 2019; Ervasti et al., 2015). High standards have been set for the materials used in direct compression (Jivraj et al., 2000; JRS, 2016), as the common challenges encountered are segregation of the material (Lakio et al., 2010; Lakio et al., 2017; Mateo-Ortiz et al., 2014), its cohesiveness and poor flowing properties (Allenspach et al., 2020;
Mehrotra et al., 2009). However, the studied CDC line was shown to be able to handle challenging materials and different formulations e.g. low-dose formulations, which make CDC lines a very attractive alternative to batch processing (Ervasti et al., 2020; Galbraith et al., 2019; Lakio et al., 2017; Van Snick et al., 2017), even for a formulation not normally deemed suitable for direct compression (DC) (Palmer et al., 2020). One more significant aspect is that the CDC process is more tolerant of disturbances during manufacturing.
However, Karttunen et al., 2020 showed that the production rate and the particle size of APIs have an effect on the capacity of the process to smoothen out disturbances. The larger particle size and increased production rate may be limiting parameters in achieving a product that fulfills the quality requirements. A schematic illustration of CDC line (Singh et al., 2013) is shown in Figure 6. As seen in Figure 6, the unit processes are installed in top-down configurations, which is the most common way to build the CDC
30
line. The other way is a horizontal set-up with conveyers (Promis Lab, University of Eastern Finland, School of Pharmacy, Kuopio, Finland).
Figure 6. Schematic illustration of continuous direct compressible manufacturing line flow sheet (Adapted from Singh et al., 2013).
An understanding of the material throughput time and especially residence time distribution (RTD) is essential in understanding the details of the CM process, and thus has been widely studied in CM powder mixing processes (Gao et al., 2011; Gao et al., 2012; Marikh et al., 2008; Pernenkil and Cooney, 2006; Portillo et al., 2008; Ziegler and Aguilar., 2003). RTD is a typical parameter being evaluated in the CM processes; it is the probability time distribution of the material component travelling through the process, and is based on the tracebility of the materials, the batch definition and development of a control strategy (Billups and Singh, 2018; Engisch and Muzzio, 2016). RTD is described as a critical tool for quality assurance and a prerequisite for RTR of the batch (FDA, 2019).
There are many different strategies which have been adopted to determine the RTD in powder formulation in CM processes e.g. by studying different trace materials (Dülle et al., 2019; Escotet-Espinoza et al., 2019; Karttunen et al., 2019a; Kruisz et al. 2017; Mangal and Kleinebudde, 2017) or material variations utilization (Gao et al., 2011; Martinez et al., 2018). Vanarase et al., (2013) has demonstrated that certain material properties such as bulk density, and process parameters e.g. the mixer impeller speed, have an effect on RTD.
31
2.4.2 Continuous wet granulation process
Granulation is the unit process, where the desired feature is an enlargement of the particles to improve their properties like powder flow, compressibility, uniformity of content and dissolution, and a reduction of dusting and segregation (Parikh, 2005). This is an alternative method if the API or excipients are not suitable for a direct compression process (Meena et al., 2017). Currently, the batch based wet granulation dominates the pharmaceutical tablet production, but efforts are underway to switch towards continuous wet granulation processes (Bandari et al., 2020; Beer et al., 2014; Li et al., 2015; Pauli et al., 2018; Schmidt et al., 2018; Singh et al., 2014; Zomer et al., 2018). The principle of high-shear continuous granulation is the same as in the batch production (Meng et al., 2019).
However, the alternative most often commonly used method in wet granulation, twin-screw granulation (TSG), is typical for CM processes, and commonly integrated with a continuous fluid-bed drying system (Pauli et al., 2018; Silva et al., 2017). The usability of the TSG process towards industrial scale processes has been widely studied (Menth et al., 2020; Osorio et al., 2017; Pawar et al., 2020; Vercruysse et al., 2015). There are commercial applications for pharmaceutical use of TSG e.g. GEA ConsiGma® GC Lines, which involve integrated continuous wet granulation, fluid bed drying and tablet compression into one efficient continuous production system.
The mechanism of granule growth in the TSG processes can be divided into four steps:
nucleation, consolidation, coalescence and breakage (Dhenge et al., 2012). These steps occur in a successive way due to the setup of the equipment; its function is based on the length of the screw, unlike in high-shear or fluid-bed granulation where the steps occur simultaneously (Iveson et.al, 2001). As stated, it is essential to have a good knowledge of all process parameters and their impact on the final product. The granule growth can be affected by varying the process parameters like the powder feed rate, L/S ratio, binder viscosity of granulation liquid and liquid type (Seem et al., 2015). Another typical feature of CM processes is the mean residence time. The effect of process parameters on the mean residence time in the wet granulation process has been studied systematically (Dhenge et al., 2010, 2011, 2012); increasing the flow rate has been shown to decrease the mean residence time. The opposite features occur with low feed rates causing so-called ´back-mixing´.
It is also worth noting that green pharmaceutical efforts have increased in the 2010s.
The transition of industrial scale batch based wet granulation to continuous wet granulation has been shown to improve environmental sustainability and reduce carbon footprints significantly (De Soete et al., 2013). The schematic illustration of a continuous wet granulation process (Bandari et al., 2020) is shown in Figure 7.
32
Figure 7. Schematic illustration of continuous wet granulation process (Adapted from Bandari et al., 2020).
2.4.3 Hot-melt extrusion process
The hot-melt extrusion (HME) is a process with an abundance of opportunities for pharmaceutical process applications e.g. continuous process, 3D printing, manufacturing protein products, controlled-released taste masking and solubility enhancement of poorly soluble API´s (Maniruzzaman, 2019). In fact, the use of this technology in pharmaceutical applications has significantly increased since the 1980s (Crowley et al., 2008). The process is based on a technology where the API and polymer are melted together into a solid dispersion, the molten mass is cooled and milled into granules or cut into pellets, and subsequently compressed into tablets (Maniruzzaman, 2015). Critical process parameters e.g. feed rate, screw speed, melting and cooling temperature have an impact on the final product and are easily monitored (Baronsky-Probst et al., 2016). Equally, material attributes e.g. polymer type and API-polymer solubility and miscibility may affect the properties of the final product (Lang et al., 2014). From the continuous process point of view, the scaling-up can be easily implemented by increasing either the feed rate or running the process for a longer time, increasing screw speed or its diameter (Maniruzzaman and Nochodchi, 2017). Thus, it is evident that HME represents an attractive choice for an industrial scale continuous process. The schematic illustration of a continuous HME process and its downstream processes is shown in Figure 8.
33
Figure 8. An example of a continuous HME extrusion process and its downstream processes (Adapted from Markl et al., 2013).
2.4.4 Continuous dry granulation process
Dry granulation is inherently a continuous granulation method in which there is no liquid utilized; it is a suitable method for heat and moisture sensitive materials (Kleinebudde, 2004). Therefore, the possibility to implement this cost reducing method into the continuous line has been noted (Vervaet and Remon, 2005). Dry granulation is an alternative method if the materials make a poor contact with binders or if they are too cohesive to form granules. However, the selection of binder type and concentration of binders have an effect on tablet quality in the dry granulation method e.g. the dissolution profile (Inghelbrecht and Remon, 1998; Mangal et al., 2016), tensile strength of the tablets (Herting and Kleinebudde, 2008, Santl et al, 2011; Sun and Kleinebudde, 2016) and disintegration time, friability and granule size (Arndt and Kleinebudde, 2018). It has been found that the fine grades of binders exert an effect on granule size and furthermore the disintegration time is dependent on the viscosity of binders. In addition, the starting material’s properties e.g. particle size, material hardening and addition of lubricant are known to have an effect on tablet quality attributes (Grote and Kleinebudde, 2018; Mosig and Kleinebudde, 2015).
From a tableting perspective, the disadvantage of the dry granulation is the loss of tablet strength after tableting compared to direct compression of the blend (Herting and Kleinebudde, 2008; Mosig and Kleinebudde, 2015; Santl et al, 2011; Sun, 2008; Sun and Himmelspach, 2006; Sun and Kleinebudde, 2016). Sun and Himmelspach (2006) produced 34
carefully evidence of this phenomenon, an enlargement of granules reduced the compactability. Despite the major role of lubrication noted in that investigation, there is evidence of the impact of granule size enlargement in dry granulation processes (Herting and Kleinebudde, 2008; Patel et al, 2011; Sun and Kleinebudde, 2016; Wu and Sun, 2007);
the size enlargement is highly material dependent, for example having an impact on density or brittleness (Mosig and Kleinebudde, 2014). Sun and Kleinebudde (2016) highlighted the two main features in the dry granulation process affecting the tablets:
bonding area and bonding strength. In summary, the porosity of the granules exerts an impact on the tensile strength of the tablets (Nordström and Alderborn, 2015). All these phenomena are summarised in Figure 9.
Figure 9. Factors in the dry granulation process, which have an impact on properties of the final tablets (Adapted from Sun and Kleinebudde, 2016).
The roller compaction equipment consists of three main units: feeding unit, compaction unit and granulation unit (Mangal and Kleinebudde, 2018). The blended mass is fed from the feeding unit by the ´top-down´ principle into the compaction unit, and subsequently the mass is compacted in between two high-pressure rolls producing ribbons, which are milled to desired granule size in the milling unit. Process parameters have an impact on both the properties of the granules and tablets. With in-line monitoring system, Wilms and Kleinebudde (2020) demonstrated how the compaction force could influence granule hardness. A schematic illustration of roller compaction (Saintyco, 2020) is shown in Figure 10.
mixing tableting
dry granulation
roll compaction
35
Figure 10. A schematic illustration of dry granulation (Adapted from Saintyco, 2020).