Continuous Processing in Pharmaceutical Manufacturing

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Matthew J. Mollan Jr., Ph.D. and Mayur Lodaya, Ph.D., Pfizer Inc.

Drug Product Manufacture

The general process involved in the manufacture of drug products consists of a series of unit operations, each intended to modulate certain properties of the material being processed. Several of these commercially used unit operations are already continuous by design. For example, tableting is commercially used in unattended operation “lights out mode” and is a continuous compaction operation, run in batch mode. Milling is another common unit operation where the equipment operates in a continuous fashion but is utilized in batch mode. Essentially, any equipment that operates on a first in/first out principle can be considered continuous by design. Equipment that operates in a continuous manner has the issue of start-up and shutdown, but operates at a steady state for the great majority of the processing time. Materials processed through such equipment experience the same level of energy input, regardless of batch size. From the standpoint of unit operations involved as practiced today, there are some that are inherently continuous in nature while there are others that are conducted in batch mode. Table 1 shows the list.

One of the advantages of continuous processing equipment is that the scale, or physical size, of the equipment does not change anywhere near the magnitude that batch equipment changes with increasing scale. Batch manufacture involves the changing of the scale of the equipment as batch size increases. Usually, dramatic changes in equipment surface area to volume occur during scale-up, leading to significant differences in what the product experiences in the manufacturing vs research environments. For example, in blending with V-blenders or bin blenders, research size equipment

may be 1-2 feet tall, while a production size V-blender can be 1-2 stories high. Additionally, as bin blenders are increased in capacity, they usually only get taller as the manufacturing plants generally have only 1 holder for all size bins. In another example, for suspension manufacture, the mixing tank size increases and the residence time of the material being processed also changes with scale. A laboratory size mixing tank may have heat and shear distribution kinetics so that the “time in the tank” of the product may be in the order of minutes, while a manufacturing scale batch mixing tank will require the same materials to be in the tank for hours to achieve the same endpoint. This residence time can be a major issue for chemical and physical degradation, as well as raising potential microbial concerns. Overall, equipment designed for continuous operation is much smaller than its batch counterpart in order to process an equivalent amount of product. This difference is often translated into two or more orders of magnitude in size. A roller compactor is a good example of equipment engineered to be continuous in design, as the size of the rollers for a manufacturing size roller compactor are only somewhat larger than that of a laboratory scale system. Additionally, continuous processing equipment operates for the majority of the time at a steady state, thus easily lending itself to automation and process monitoring via PAT.

The manufacture of solid oral dosage forms can be broken into three major methodologies. The simplest one of them, direct compression, involves blending with excipients followed by tableting. A continuous direct compression system could be envisioned as several individual powder feeders that introduce the materials into a continuous blender, i.e. ribbon blender. The last section of this process would be feeding of the blended powder to a tablet press. Some activity is already ongoing in this area [19]. Next, slightly more involved, is the dry granulation process. Here the active and selected excipients are blended and processed through a roller compactor or slugging equipment, followed by a mill. The milled material is blended with suitable excipients and tableted. The most involved, and the most common, situation includes wet granulation. Figure 3 shows the unit operations involved when wet granulation is required for making a solid oral dosage form.

To conceive a solid oral dosage form process that is continuous, it would be necessary to conduct wet granulation, drying, milling, blending and tablet coating, in a continuous manner. Of these, milling, blending, wet granulation and drying have been successfully done in continuous mode. Continuous coating has been performed in food, flavor, and nutraceutical processing but there are no published examples of the technique being utilized in the manufacture of ethical pharmaceutical products.

4.1 Continuous Wet Granulation and Drying

For pharmaceutical processing, the early accounts of this approach, in concept, were published in two separate articles in mid 1980’s. Koblitz and Ehrhardt [20] reported on continuous wet granulation and drying. The article focused on continuous variable frequency fluid bed drying, but gave no details on granulation aspects. Berkovitch in a Manufacturing Chemist article [21] 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 [22]. Since then, several articles have been published over the last two decades where semi-continuous and continuous wet granulation techniques have been discussed.

4.1.1 Semi-Continuous Wet Granulation and Drying

A multi cell system has been recently introduced that falls in this scheme of operation. Leuenberger [23] has written several articles on functional aspects of GMC and overall advantages of continuous processing. Figure 4 shows a schematic diagram of the system comprising of a high shear granulator followed by three stages of fluid bed drying. In the commercial scale system, the granulator is charged with 7-10 Kg of the powder blend. After granulation and wet milling, the material is conveyed sequentially through three stages of drying. In this way, four small batches (one in granulator and three in drying) are processed simultaneously and the cycle repeats for semi-continuous operation.

4.1.2 Continuous Fluidized Bed Wet Granulation and Drying

Continuous fluid bed systems have five or more functional zones. These are product in-feed zone, product mixing and preheating zone, spraying zone, drying and cooling zone and discharge zone. These have been reviewed in detail elsewhere [24].

4.1.3 Continuous Granulation Using Iverson Mixer

In this technique, powders and liquid are metered into a narrow space at the periphery of the grooved disc, which rotates at high speed. For detailed accounts, the reader is referred to the following articles. Lindberg [25] used it for studying wet granulation of placebo as well as active formulations, whereas Applegren and co-workers [26] used it for studying continuous melt granulation.

4.1.4 Continuous Wet Granulation and Drying Using a Planetary Extruder and Microwave Energy

A system is currently available, which uses a planetary extruder to granulate and a microwave tube through which the granulation is dried in a continuous manner.

4.1.5 Continuous Wet Granulation Using Twin Screw Mixer

A twin screw mixer is a modified twin screw extruder for conducting wet granulation. The process uses twin intermeshing screws that convey, mix, wet granulate and wet mill the powder blend. They offer several advantages over other wet granulation processes, and the modular nature of screw elements and a large variety available provide the user with tremendous flexibility. Detailed accounts are available in the literature [27]. Twin screw extruders themselves have also been utilized for wet granulation since the 1980’s [28-30].

4.1.6 Continuous Drying Using Radiofrequency Energy

Both microwave and radiofrequency are electromagnetic forms of energy, commonly referred to as the dielectric energy. Microwave heating in combination with vacuum has been used extensively for drying in pharmaceutical processing [31,32]. However, until recently, radiofrequency heating has been used mainly in other industries such as food, paper, ceramic etc. Jones and Rowley [33] have reviewed several applications for drying where dielectric heating is used by itself or in combination with other methods. Ghebre-Sellassie et al. [34] have disclosed a continuous wet granulation and drying system that combines twin screw mixer (for wet granulation and wet milling) with radiofrequency energy (for drying).

5.0 Other Continuous Processing Areas

Other oral dosage forms including capsule filling are processed by unit operations that are intrinsically continuous, and a continuous encapsulation process, hard or soft-gel, could be envisioned in a process similar to the one previously described for direct compression of tablets. Some very interesting concepts on continuous or semi-continuous lyophilization technology were described by Rey [35]. The author looked at the food industry where continuous freeze drying is used and described a vision of what a pharmaceutical continuous freeze dryer may look like. Continuous processing concepts have also been implemented in the area of sterilization, solution manufacture, and cell culture. While no biopharmaceutical products, to our knowledge, are industrially produced by true continuous processing, several do utilize perfusion culture which can run for weeks to months, and process optimization of fed-batch fermentation has been shown to improve efficiency via continuous feeding of inducers [36]. Lastly, packaging equipment has been designed to be continuous in operation, and it is routinely used in this manner in other industries as the last section of a full continuous operation from individual starting materials until final “ready to ship” carton.

Conclusions

The pharmaceutical industry is poised to change radically in the next 5-10 years in response to a changing marketplace. New risk models will need to be implemented to stay competitive and rapidly respond to these changing dynamics. The urgent need to dramatically improve efficiency and productivity within the pharmaceutical manufacturing sector will be a requirement for the future. The design of new production facilities utilizing new technology and implementing continuous processing strategies will be one way to remain competitive as the industry undergoes the next wave of change.

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