The only constant in today’s world is change, and this could not be truer for the current state of pharmaceutical manufacturing. “Right now the manufacturing experts from the 1950s would easily recognize processes today. In 25 years these same processes will be obsolete,” said Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration in her keynote address at the AAPS annual conference in 2011. Continuous manufacturing will be a significant component in the future of pharmaceutical manufacturing.
The advantages of continuous manufacturing over batch manufacturing are well established. When properly implemented, continuous processes are almost completely steady, can be designed at scale, and can be used reliably to minimize segregation and agglomeration of ingredients. Moreover, a continuous process is also the perfect scenario for implementation of Process Analytical Technology (PAT) methods, which are required to ensure closed-loop control of the continuous process. The business case for continuous manufacturing is very robust. In product development, continuous manufacturing systems allow the user to perform complex DOE matrices in just a few days, and using a tiny fraction of the material required to perform a comparable study in batch mode  , thus enabling enormous savings in labor, analytical costs and capital .
If recent investments by large pharmaceutical companies in researching and developing continuous processes for manufacture of solid oral dosage forms are any indicators, then we are very likely see rapid change in this arena, taking much less than 25 years.
Interestingly, some of the unit operations that are involved in the process of making tablets and capsules today are intrinsically continuous in nature, namely, milling, spray drying, roller compaction, extrusion, capsule filling, tableting and packaging. This implies that an existing batch process can be transformed into a continuous process with relatively minimal change in most processing steps. A crucial unit operation that is usually practiced in “intrinsically batch” mode, and that captures the essence of the batch approach is powder mixing. The typical batch powder mixing process involves the addition of all ingredients to a large bin, double cone or V-blender, and the vessel is then tumbled for a predetermined number of revolutions to enact a time-dependent process, where the challenge is to determine a suitable end point. Similarly, wet granulation is performed in batch mode using either a high shear blender or a fluid bed system (both batch). Irrespective of the manufacturing route (direct compaction or granulation), powder mixing is involved in all manufacturing routes, often multiple times in the same process. In addition, pharmaceutical powders often display segregation and agglomeration tendencies as well as poor flow properties, and therefore the development of robust and reliable powder mixing processes is one of the main challenges in batch process development.
EXPECTED TO BE CHALLENGING
Given this situation, the development of continuous powder mixing processes ought to be expected to be challenging as well. Surprisingly, this is largely not the case, and a rapidly growing body of experience indicates that continuous powder mixing processes are much more reliable, easier to develop, and easier to monitor and control than their batch counterparts.
Continuous granular mixing is not really new to the process engineering community. Continuous mixers have been widely used in the food, mineral processing, detergents and the catalyst industry for decades. However, in a recent review on continuous powder blending by Pernenkil and Cooney, the following statement highlights the state of continuous mixing for pharmaceutical applications: “It is interesting to observe that pharmaceutical powders have not been reported in continuous blenders.” This is understandable because very few powder mixing processes used in the pharmaceutical manufacturing today are continuous and hence the dearth of published research in the area. However, in the past decade or so, both the pharmaceutical industry and academia have begun to investigate and publish on continuous powder blenders with pharmaceutical materials.
The objective of the article is to provide a brief overview of the current state of technology of continuous blenders for pharmaceutical applications. The article focuses on a popular class of blenders, herein called tubular blenders. Four tubular blenders are reviewed in detail, with a description of their physical characteristics, capabilities and general performance. Other common continuous blenders are described in brief to provide a broad view of the state of the technology. The article concludes with the authors’ view on the main open scientific questions in continuous powder blending, seeking to identify areas where future efforts could be useful.
Portillo et al.(2008 and 2009) characterized in detail two continuous blenders that were built by GEA. The first blender was fitted with 2.2 KW motor and rotation rates of the impeller of range from 16 rpm to 78 rpm. The mixer is 0.74 m in length and 0.15 m in diameter. An adjustable number of flat blades can be fitted in the mixing zone of the blender. The powder is discharged through an outlet weir, which can be fitted with screens of desirable holes. The size of the holes controls not only the size of the largest agglomerate exiting the blender, but also the powder holdup in the blender, which in turn dictates residence time and thus mixing performance. It was found that the residence time and number of blades passes experienced by the powder was strongly affected by the impeller rotation rate and the processing angle. The longest residence time resulted from upward processing angle and low impeller rotation rates, which also produced superior mixing performance.