Advancing Unit Operations for Continuous Processing in Solid-Dosage Manufacturing

March 1, 2012
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-03-01-2012, Volume 2012 Supplement, Issue 2

The article examines some recent developments for this process step and for continuous manufacturing overall.

The pharmaceutical industry, equipment and machinery companies, and academic researchers are investing to develop applications in continuous processing for drug production. Supported by quality-by-design principles, a regulatory environment that is encouraging the industry's move to continuous manufacturing, and lured by the promise of improved production economics and greater operating efficiencies, the industry is moving forward with select projects in continuous solid-dosage manufacturing.


Continuous granulation

Although pharmaceutical production is a batch-processing operation, specific unit operations in solid-dosage manufacturing, such as milling or tablet compression, may be run in semicontinuous and continuous processing steps (1). The feasibility of developing continuous processes for specific unit operations requires advances in pharmaceutical equipment design and operation. For example, to make continuous mixing, granulation, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems need to be developed with limited or no start-up and shutdown waste to enable reaching steady state in an extremely short time (2). A commercial example is GEA Pharma Systems' ConsiGma continuous granulation, and drying system. Designed in a modular way, the system consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and a granule-conditioning unit to prepare granules for a tablet press (2).

One advantage of continuous operations is the elimination of scale-up, which may be difficult overall and in specific operations, such as granulation (1). As hot-melt extrusion is gaining popularity for solubilization of insoluble drugs, twin-screw extrusion also is gaining attention as a continuous alternative to traditional high-shear granulation. This continuous process enables faster throughput and easier scale-up. Ashland Specialty Ingredients recently presented results on how hydroxypropylcellulose (Krucel), povidone (Plasdone), and hypromellose (Benecel) performed in continuous low-temperature extrusion granulation as compared with traditional wet granulation. The results showed twin-screw extrusion as a promising method for high-dose formulations and highlighted how tablets made by means of extrusion showed improved strength and low friability compared to traditional wet granulation, according to an Oct. 13, 2011, company press release.

Researchers at Ghent University in Belgium and Complutense University in Madrid recently evaluated the strengths and weaknesses of several complementary process analytical technology (PAT) tools implemented in a continuous wet-granulation process, which was part of a fully continuous from powder-to-tablet production line (3). The use of Raman and near infrared spectroscopy and a particle-size distribution analyzer was evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline-lactose blend. The solid-state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the API. The researchers reported that a higher barrel temperature and a higher powder feed rate resulted in larger granules (3).

Researchers at Pfizer and the University of Cincinnati recently reported on work regarding optimization for a continuous extrusion wet-granulation process (4). Three granulating binders in high drug-load acetaminophen blends were evaluated using high-shear granulation and extrusion granulation. The researchers reported that a polymethacrylate binder enhanced tablet tensile strength with rapid disintegration in simulated gastric fluid, and polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was evaluated with respect to the effects of granulating liquid, injection rate, and screw speed on granule properties. Response variables considered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle-size distribution, tablet hardness, friability, disintegration time, and dissolution (4).

Academic–industrial partnerships

Continuous manufacturing also is being advanced by industrial, public, and academic partnerships. For example, in October 2011, FDA awarded a $35-million, five-year grant to the National Institute for Pharmaceutical Technology and Education (NIPTE), a nonprofit research center focused on pharmaceutical product development and manufacturing, to improve drug manufacturing standards. NIPTE's goal is to increase science and engineering-based understanding, so technologies can be developed and science-based regulations can be implemented. The FDA grant will in part by used to promote continuous manufacturing as well as other issues, such as improving small-batch production, reducing the environmental impact of manufacturing pharmaceutical products, and rectifying other drug-development and manufacturing problems.

NIPTE is partnered with 10 US universities involved in the pharmaceutical sciences and engineering. The member universities are Duquesne University, the Illinois Institute of Technology, Purdue University, Rutgers University, the University of Puerto Rico, the University of Connecticut, the University of Iowa, the University of Kentucky, the University of Maryland–Baltimore, and the University of Minnesota.

In April 2011, the United Kingdom's Engineering and Physical Sciences Research Council (EPSRC) established the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization. EPSRC is the main UK government agency for funding research and training in engineering and the physical sciences. The University of Strathclyde is leading the EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization, which also involves the Universities of Bath, Cambridge, Edinburgh, Glasgow, Heriot-Watt, and Loughborough. Industry partners include GlaxoSmithKline, Pfizer, AstraZeneca, Fujifilm, Croda, Genzyme (now part of Sanofi), NiTech Solutions, Phoenix Chemicals, Solid Form Solutions, and British Salt.

The EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization has identified several key research challenges:

  • Achieving precise control over manufacturing of solid particles using continuous-manufacturing technologies

  • Understanding the control of nucleation and growth of particles by means of crystallization under continuous flow

  • Developing continuous crystallization platforms, process analysis tools, and strategies to manufacture particles for different applications

  • Delivering the tools to control crystal structure, particle shape, and particle-size distribution

  • Facilitating continuous manufacture of medicines and nanomaterials with kinetic, cocrystallization, and impurity control (5).

In 2007, Novartis formed a $65-million, 10-year research collaboration with the Massachusetts Institute of Technology (MIT) to launch and fund the Novartis–MIT Center for Continuous Manufacturing to develop new technologies to replace the pharmaceutical industry's conventional batch-based system with continuous manufacturing processes.

The Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez, is another academic-partnership involved in continuous processing. The center, which is funded by National Science Foundation and industrial partners, includes 35 pharmaceutical manufacturers and equipment producers involved in R&D for continuous processing (2).

Researchers at Rutgers University recently reported on an enhanced model-based control of a continuous direct-compression pharmaceutical process. The control-loop performance was assessed in silico, and results obtained will be incorporated into the pilot-plant facility of the continuous direct-compaction process at the National Science Foundation's Engineering Research Center at Rutgers University. The models used in the study were obtained by means of a system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The purpose of the study was to formulate an effective control strategy at the basic/regulatory level for the integrated continuous operation of the direct-compaction process and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances (6).


1. B.L. Trout et al., Ind. Eng. Chem. Res. 50 (17), 10083–10092 (2011).

2. P. Van Arnum and R. Whitworth, Pharm. Technol. 35 (9), 44–47 (2011).

3. M. Fonteyne et al., "Real-time Assessment of Critical Quality Attributes of a Continuous Granulation Process," Pharm. Develop. & Technol., online, DOI 10.3109/10837450.2011.627869, Oct. 24. 2011.

4. L. Tan et al., Pharm. Develop. & Technol. 16 (4), 302–305 (2011).

5. EPSRC, "EPSRC Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization,", accessed Feb. 13, 2012.

6. R. Ramachandran et al. , J. Pharm. Innov. 6 (4), 249–263 (2011).