Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design

Abstract

Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research.

Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms

“…A recent paper by Nandi et al [ 77 ] discusses advances in TSG and includes details of applicable PAT, while a paper by Portier et al [ 78 ] discusses TSG from the perspective of the formulation and raw material properties.…”

“…Merck Sharp and Dohme, together with GEA, ran a ConsiGma™ for 120 h, and during that time, produced 15 million tablets with a yield of 99.5% [ 88 ]. Pictures and diagrams of GEA’s ConsiGma™ equipment can be found in [ 77 , 78 ].…”

“…A number of suppliers have produced excipients tailored to CM, and in particular BASF, DFE Pharma, DOW, JRS Pharma and Roquette, have been mentioned in this regard [ 78 ].…”

Analysis of the Effects of Process Parameters on Start-Up Operation in Continuous Wet Granulation

“…For the granule size-based definition, the start-up time t start was set as 10 min regardless of the values of process parameters. The optimization problem of cost in wet granulation was defined as shown in Equation ( 7): min r,α C WG subject to 500 ≤ r ≤ 900 0.12 ≤ α ≤ 0.16 (7) where objective function C WG can be calculated by Equations ( 4)- (6). Figure 7 represents the economic assessment when using stabilized (a) process parameters (i.e., torque profiles) and (b) product quality (granule size distribution) as the criterion to define the boundary of the start-up process.…”

“…Examples of technical challenges are a lack of the understanding of material attributes and process parameters, and high requirements for process analytical technologies (PAT) [4,5]. Among unit operations in continuous manufacturing, wet granulation is one of the critical unit operations, which aims to improve the uniformity and flowability of premixed materials [6,7]. Numerous studies have performed design of experiments (DoE) to characterize key parameters in continuous wet granulation in terms of torque [8][9][10][11], residence time distribution [10,[12][13][14], granule properties [8][9][10][11][13][14][15][16][17][18][19][20][21][22][23], and tablet quality [10,[16][17][18][19]21,23].…”