Continuous Granulation Technology Trends


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By Dilip M. Parikh, DPharma Group

Seeking a smooth path and avoiding dead ends

Over the past few years and especially during 2014-2015, it seems the pharmaceutical industry is now excited about continuous manufacturing. For one, equipment vendors are providing modular systems to manufacture solid dosage products. There are also numerous conferences/symposium conducted by AAPS Arden House, Europe pharma industry, ISPE India affiliate and other technical meetings. At the same time, some of the major pharmaceutical companies have committed a substantial amount of investment with universities in the U.S. and Europe. Of note, a continuous direct compression tableting system is about to be validated and submitted to the FDA by a major pharmaceutical organization. Continuous processing has long received support from FDA, which has been interacting with the European Medicines Agency (EMA) and aligns well with FDA’s process analytical technology (PAT) and process validation guidance.

The term “continuous” is applied to all production or manufacturing processes that run with a continuous flow. With that definition, continuous processing of solid dosage products in the pharmaceutical industry means starting the process from the synthesis of API to the final packaging of tablets or capsules 24/7 all year round.

The pharmaceutical industry has been slow to adopt or even consider the concept of continuous processing, even though its value has already been proven in other industries—polymer, food, dairy, electronics, automobile and petrochemical/chemical—which have implemented fully continuous production processes for many years.

Drivers for continuous manufacturing in the pharmaceutical industry include the fact that NCE’s are getting more potent/toxic; small, dedicated suites are suitable to serve as “containments” for highly potent drugs; investment costs for multi-product facilities for highly potent oral solid dosage products are exaggerated due to segregation measures; FDA initiative; the recent availability of compact integrated systems from equipment and software suppliers; and the perceived operational and labor savings for high volume products.

In the September 3, 2003 edition of the Wall Street Journal, the publication sated: “The pharmaceutical industry has a little secret: Even as it invents futuristic new drugs, its manufacturing techniques lag far behind those of potato-chip and laundry-soap makers.”

The pharmaceutical industry is also dominated by batch processes due to the smaller amounts that must be processed compared to other industries. The small material quantities available during the development stage also dictate the use of a batch process during the design phase of the formulation and manufacturing process, and these same batch-wise processes are often scaled up to production. Batch-processing equipment is the most flexible and convenient to use. There is reluctance from the industry to embrace continuous manufacturing because of the additional capital investment required along with the prospect of the current vast disposition of batch process equipment and staff training that would be required.

Currently however, the limited number of unit operations such as API synthesis, roller compaction, extrusion, milling, blending and compression are somewhat continuous but dependent upon upstream and downstream processing that will render the operation semi-continuous.

Continuous granulation
The granulation aspect is defined as “A unit operation of mechanical process engineering characterized by a combination with a change in particle size using pressure, solvent or binder.”

There are different techniques employed in the industry to produce granulated product depending on the physico-chemical properties of the composition, intended product attributes required, and the access to the process technology required to produce the dosage form (see Figure 1).

In the 1980s, Koblitz and Ehrhardt1 reported on continuous wet granulation and drying. The article focused on continuous variable frequency fluid bed drying.  Berkovitch in a Manufacturing Chemist article2 quoted some researchers presenting these concepts in a symposium. Continuous processing of pharmaceuticals, including a process for solid oral dosage form manufacturing, was also discussed by Kawamura.3

Dry granulation
The roller compaction process is well established as a dry granulation continuous process as long as the blended composition of powders are supplied and post compaction process is aligned to produce subsequent blending and compression/encapsulation operation.

Wet granulation
Manufacturing solid dosage forms with the classic wet granulation in a continuous manner is not easy. There are a number of steps involved in the wet granulation process.
A continuous manufacturing process relies on the ‘one in, one out’ principle as new materials are continuously added to the process and finished products are continuously removed at the same rate to ensure a constant material volume in the process chamber. The quality is assured by incorporating at-line, on-line or in-line measurements into the process stream, which allow continuous monitoring of critical process parameters as well as continuous inspection of quality attributes of raw materials, intermediates and end product.

On the other hand, if in-house batch process equipment is required to be integrated, connecting existing equipment for solid dosage manufacturing is not enough. An integrated system loses its flexibility unless a product dedicated system is planned. Some of the questions faced by the industry include the following:

  • Is the product dedicated or multi-purpose? If not dedicated, then how do we evaluate the economic advantage? If it is dedicated, can we justify losing the flexibility offered by batch processes?
  • What to do when one piece of equipment breaks down while the product flow from upstream units continues?
  • How do you address physical/chemical consistencies of API and excipients?
  • How do you characterize the homogeneity of the mix and residence time distribution?
  • If the process is developed on a continuous system, and the system is dedicated, how long will you be waiting for regulatory approval without the use of facility and or system?
  • Will a hybrid system (semi-automatic) be more cost effective?
  • What will be the capital investment and commissioning timeline?

Some of the technical challenges include:

  • PAT challenges: Different unit operations/equipment have their own proprietary software. There needs to be one single control panel to control the process. It should be able to collect data from all of the unit operations.
  • More precise measurement and control
  • Continuous flow and level measurement
  • Modulating flow and level control valves
  • On-line quality measurement
  • Real-time quality control
  • Tight control systems integration of each process step
  • Extensive personnel training, particularly for operators
  • Redundant controls and instrumentation
  • Quick corrections to all process variations
  • Advanced process control

According to FDA, “effective process control we must understand interaction between unit operations, support feedback/feed forward controls, characterize propagation of changes and disturbances through system, understand interface between different lots of raw material, be able to isolate bad material from disturbances, should have an integrated data acquisition system over all unit operations, and manage data from all on-line/in-line measurement systems.”4

The transition from batch to continuous pharmaceutical operations can facilitate the development of processes within the Quality by Design (QbD) framework. To achieve equipment coordination and predictive capabilities, the relationships between critical quality attributes (CQAs), critical material properties (CMPs) and critical process parameters (CPPs) need to be correlated sequentially between the multiple unit operations in product manufacturing. Inline monitoring of process can be accomplished at various stages in the manufacture, i.e. by spectroscopic (NIR, FTIR, Raman), laser light scattering for particle size, NIR for moisture, NMR for weight and GC for solvent detection.

One of the requirements for continuous solids processing is the implementation of real-time online sensing for control and optimization in order to ensure its safety and efficiency.5,6 However, some of the critical variables are difficult to detect due to the limitation of economy and technology.7 Therefore, soft sensors as opposed to physical sensors provide a convenient solution to eliminate this bottleneck. Soft sensors serve the same function as physical sensors, except that values for the variable are not measured directly, but are obtained from a mathematical model of the physical sensor using other known variables as inputs.

Process modeling is a tool that can be used to answer questions such as how material mixes. Because continuous processes are integrated, an integrated model is needed to describe the system. Modeling saves money and time by evaluating processes in a computer-modeling environment, which can then be verified in the laboratory.

Continuous granulation systems
A number of equipment manufacturers have offered integrated wet granulation systems where the raw material is granulated and dried. The following is a list of just some of the suppliers of continuous wet granulation systems and their brief description.

GEA Pharma Systems offers the Consigma integrated granulation/drying and tableting system. Based on the twin screw wet granulation and the fluid bed drying, this integrated system is capable of producing between 0.5-200 kg of product depending on the size of the system. In twin screw continuous wet granulation, powdered solids and binder pass through a twin-screw extruder, usually with co-rotating screws, resulting granulated product is dried continuously, milled and blended and compressed.

Bohle offers the BCG System with screw configuration of the twin screw. Granulation uses twin screw extruder and drying is performed using infrared (IR) and vacuum. The throughput of 8 kg/h to 30 kg/h is controlled by a dosing unit. The residence time varies according to the throughput required and product attributes desired.

Glatt Pharma Systems offers a continuous granulation system in which the product is granulated in a continuous fluid bed granulator/dryer. The composition to be granulated is fed at one end of the unit and the binder liquid is added to the product as it travels through the fluid bed unit with continuously granulating and drying until dry product is discharged.

Loedige offers a continuous granulation system in which a premixed mixture of composition is fed in the system and by a very high rotation speed the product is moved through the horizontal drum as ring layer. Liquid addition is done by injectors or hollow shaft. The granulated product is then fed in to continuous fluid bed dryer with a varying fluidization velocity as the product is transferred through the dryer and further processed as required.

Achieving the vision of continuous manufacturing of solid dosage, where product starting as API and ending up as a finished dosage form via wet granulation, will not happen immediately. To start you need to ensure that the necessary technology and skills are sufficiently available.

Much of the product quality should be achieved by designing an effective process at the design stage and supplemented, as needed, by additional in-process controls, monitoring and end product testing.

Many unit operations are intrinsically continuous and are well understood. For all remaining unit operations, equipment is available. Experiences with continuous wet granulation have been positive. Opportunities to a adopt continuous process exist and should build on QbD approach, for that it will require more advanced control systems with simple and more complex PATs. It must be realized that not all products or processes will be manufactured with continuous granulation approach. Every API will have to be evaluated for its capability to be a candidate for continuous granulation and a pertinent process will have to be developed for it.


  1. Koblitz T. and Ehrhardt L. “Continuous Variable-Frequency Fluid Bed Drying of Pharmaceutical Granulations.” Pharmaceutical Technology, March 1985.
  2. Berkovitch I. “From Batch to Continuous Pharmaceutical Engineering.” Manufacturing Chemist, August 1986, 43-45.
  3. Kawamura K. “Continuous Processing of Pharmaceuticals.” In Encyclopedia of Pharmaceutical Technology 3rd Edition, Eds. Swarbrick J. and Boyle J. 1990, Marcel Dekker.
  4. S. Chatterjee,  FDA -IFPAC Annual Meeting, Baltimore, January , 2012
  5. Zeng PC, Lovett D, Morris J. Process analytical technologies (PAT)—the impact for process systems engineering. Comp Aided Chem Eng. 2010;25:967–72.
  6. Wu H, Heilweil EJ, Hussain AS, Khan MA. Process analytical technologies (pat)—effects of instrumental and compositional variables in terahertz spectral data quality to characterize pharmaceutical materials and tablets. Comp Aided Chem Eng. 2007;343:148–58.
  7. Xiong ZH, Huang GH, Shao HH. Soft sensor modeling based on Gaussian processes. J Cent South Univ Technol. 2005;12:469–71.

Dilip M. Parikh is president, DPharma Group Inc., a pharmaceutical technology development and consulting group located in Ellicott City, MD. As an industrial pharmacist he has more than 40 years of experience in product development, manufacturing, FDA remedial execution, plant operations, process engineering and troubleshooting, at various major pharmaceutical companies in Canada and the U.S.

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