Advancing Unit Operations for Continuous Processing in Solid-Dosage Manufacturing

The article examines some recent developments for this process step and for continuous manufacturing overall. This article is part of a special issue on solid dosage and excipients.
Mar 01, 2012

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).