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Continuous tablet manufacturing: an innovation that is set to transform modern day processing of pharmaceutical products.

In today's increasingly competitive pharmaceuticals market there is intense demand to both accelerate and streamline drug development. Continuous manufacturing technology is at the forefront of meeting this challenge by improving efficiency, speed, quality and reliability in processing. Commercial pressures are leading the drive towards continuous processing to shorten development times, improve efficiency of the development process and to reduce the amount of API used. Moreover, the drive also comes from regulators that demand the creation of reliable processes, supported by concepts that include Quality by Design (QbD) and Process Analytical Technology (PAT).

Classic batch manufacture incorporating blending, granulation, drying, compression and coating has faced no major innovation during the last 50 years. Continuous tablet manufacturing brings innovation through its connectivity of precisely the same processes as the batch process. It offers the opportunity to catch-up with the food processing industry which has essentially been focused on continuous technology for many years.

To date outside of the traditional continuous nature of compressing tablets, the main focus of continuous manufacturing has been in the field of coating where novel continuous coaters are seen as a cost effective solution for manufacturing high volume over the counter products. This is especially the case in the United States.

In more recent times, equipment suppliers such as GEA have been developing solutions to link all processes from the blending of excipients and API at the commencement to the output of coated tablets at the finish. The technology is now available to link a range of processes prior to table compression. The feed material to the compression machine can be granulated by dry or wet compaction processes and can be subject to additional blending or milling before or after the granulation step. This allows for a reduction in the time from initial blending to the creation of uncoated tablets to just 20 to 30 minutes.

While many pharmaceutical companies have been researching end-to-end processes in house, Aesica has announced the introduction of the technology into its manufacturing facilities, with the commercial manufacture of the first pharmaceutical product, developed and manufactured by the technology in collaboration with a partner, expected in the next two years.

A key advantage of continuous processing is that it enables process development and clinical scale manufacture as well as full scale manufacture to be carried out on the same piece of equipment using the same parameters and within the same variable space. This means that the development process is never lengthened by delays in supply of product and there can be a very rapid collection of data to demonstrate the robustness and quality of the manufacturing process to support regulatory packages. For fast tracked products, this results in a decreased time to launch and a shorter time scale for the product reaching full patient access on the market.

Continuous processing lends itself to developing processes using so called QbD. This ensures that process parameters are fully understood across what is typically a complex variable space, reducing risk and providing a robust and reliable scientific approach to process validation. In a continuous process, changes in a product can be set-up, run and monitored at regular and short intervals using small volumes of potentially highly valuable materials, covering multiple variable combinations in a relatively short period of time. By contrast, using a batch based manufacturing system, the volumes required limit the number of combinations that can be explored and hence the statistical robustness of the validation.

Consequently, the amount of API required is kept to a minimum. From a development perspective, significant expenditure is saved as less API is used. This is critical as APIs become more complex and increasingly expensive to produce.

PAT is a key component to continuous processing. By using different analytical methodologies, such as raman spectroscopy, infrared and lazer diffraction, key process parameters can be measured non-invasively in real-time. Post compression hardness and tablet dimensions can be measured using auto sampling. This greatly enhances the amount of relevant data that can be analyzed and with modern computational techniques, allows for precise analysis of the robustness of the process validation. Theoretically with PAT demonstrating that a process in running within the validated variable space, the final batch quality control testing can minimized to microbiological checks. This must be acceptable to regulators before implementation.

The regulatory agencies, including the FDA and EMA, have long been supportive of QbD and have outlined frameworks for PAT implementation. The novelty of end-to-end continuous tablet manufacture has clearly been a concern to pharmaceutical company regulatory departments. This is primarily because it overlays an extra layer of uncertainty to any new product application. The regulatory agencies have always been open to discussion on new technologies, particularly when they embrace QbD and PAT. To this end, Aesica in collaboration with its partners, has hosted pre-operation visits for FDA, MHRA and EMA to discuss continuous processing.

Another key advantage of continuous processing lies in reduced floor space requirements as the same equipment can be used for the development and commercial manufacturing stages. To add to this the combined unit has an overall smaller footprint. Aesica has been able to demonstrate that an existing GMP area can be refurbished, a continuous line installed and the first registration batches produced for clinical trial supply in as little as 6 months.

Clearly there is significant investment required to install continuous tablet processing equipment. Once in place it has the versatility to be used for a variety of products whilst lending itself to 24/7 continuous production to lower production costs. By its very nature it is highly flexible. If more product is required, the process is simply run for a longer period of time.

LOOKING TO THE FUTURE

Continuing processing is set to play a central role in modern pharmaceutical manufacturing. It is already established in other industries and in single units of operation in pharmaceutical manufacture such as compression and coating. With CDMOs like Aesica having equipment available for third party use, and regulators becoming more familiar with the technology and positively encouraging it's take-up, the perceived barriers to using the technology are disappearing.

To conclude, continuous processing has enormous scope to improve the efficiency of pharmaceutical development and manufacture. It reduces development times, goes hand-in-hand with Quality By Design and PAT, uses up much less API in development and provides cost effective and robust production and rapid process validation.

By Jeremy Drummond PhD., Sales Director - Finished Dose, Aesica
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Title Annotation:SOLID DOSAGE
Author:Drummond, Jeremy
Publication:Pharmaceutical Processing
Date:Jul 1, 2014
Words:1067
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