Manufacturing

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Hailed as the ultimate in lean manufacturing, continuous processing is rapidly gaining momentum within the pharmaceutical industry. Professor Bernhardt Trout, Trout Research Group, discusses how continuous processing is superior to batch processing and where the technology will go in the future.

ontinuous processing is not a new concept. This manufacturing model has been used in industries such as food, petrochemicals and electronics processing for many years and has been explored in the past by pharmaceutical manufacturers. However, it has only recently become a viable option for pharmaceuticals. Bernhardt Trout, The Trout Research Group, with Walter Bisson, project manager at Novartis, and their colleagues believe the increasing interest can be attributed to a combination of three factors: The beginning of more flexible regulatory approaches directly related to process analytical technology and science-based initiatives implemented by the USFDA roughly ten years ago Increasing cost pressure Increasing quality and controls specifications of pharmaceuticals

are also driving factors as they are rapidly evolving to meet the demands of pharmaceutical manufacturing. When we discuss continuous, we mean a fully integrated system, which is the ultimate quality by design, says Trout. We now have a relatively high level of understanding about each process involved, including mathematical modelling, analytical technology and, therefore, well developed control systems.

Batch vs continuous
Batch process manufacturing, the current industry standard, is segmented into many individual steps that are often performed at separate facilities, thereby requiring frequent interruptions in production. In this manufacturing model, specific quantities of a drug are produced to fill an order (batch) and quality is assessed through sampling, using destructive analytical tests and measurements. If the quality standards are not met, the entire batch is rejected and sent back for reprocessing. It is estimated that rejected batches, rework and investigations can use as much as 25% of pharmaceutical company revenues. Though batch processing is tried and true, it is inherently wasteful and often complicates future project planning because manufacturing design and scale-up for a new drug

This vision was an outcome from a discussion between Daniel Vasella, CEO Novartis, and Tom van Laar, head of Global Technical Operations, Novartis. The case can be made that recent advances in continuous processing technologies

Contributor profile Bernhardt L Trout, professor of Chemical Engineering at Massachusetts Institute of Technology (MIT), is director of the Novartis-MIT Center for Continuous Manufacturing and co-chair of the Singapore-MIT Alliance Program in Chemical and Pharmaceutical Engineering. His research focuses on the development and application of molecular engineering techniques for pharmaceutical and biopharmaceutical processing and formulation of small molecule pharmaceuticals.

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to develop and bring a drug to market, as well as increasing competition and consumer pressure to reduce prices. Everyone says why worry about manufacturing, its a small percentage of the cost of producing a pharmaceutical, he says. But any cost pharmaceutical companies can cut these days would be an advantage. Where continuous processing can fall short is in its application to biologic drugs compounds manufactured from living organisms. Though manufacturers of biologics are beginning to implement continuous processing components, the technology has not yet evolved enough to contemplate a full scale switchover. However, the implications for chemical-based, solid dosage pharmaceuticals seem promising. For example, active pharmaceutical ingredients could be manufactured using continuous processing with existing technology. Studies to date have shown continuous systems can be far more accurate in maintaining product quality standards with APIs. New technology that allows real time tablet testing, such as TeraViews terahertz imaging system, could replace wet dissolution testing in the near future. The terahertz system comprises a series of spectroscopic sensors that can be used to quickly and accurately measure the coating thickness of tablets in rapid motion, as proven by independent study results released from the USFDA. Another added benefit is these same sensors can be used to control the coating and production processes during manufacturing by using simple feedback systems.

are costly and time-consuming. In comparison, within a continuous manufacturing model, raw materials are put into an automated system that is capable of carrying out complex chemical tests according to predetermined quality parameters. These quality checks occur throughout the manufacturing process and without interruptions. Rejected products can be handled through recycling loops, enabling the reuse of some or all component parts. Trout envisages this will one day be a completely selfcontained process from beginning to end, subsequently reducing overall labour costs as well as increasing production volume by eliminating the downtime associated with batch processing. Continuous processing technology also has an added benefit of being far more compact than batch equipment, allowing pharmaceutical manufacturers to reduce the size of their production facilities and associated overheads. For example, a newly built batch processing facility, capable of producing 4 billion single dose units would cost in excess of $132 million and require 460,000ft of space. However, a similar facility using continuous processing would only require an estimated 190,000ft and would cost 60% less than its batch counterpart. New-generation microreactors could eliminate the need for traditional dedicated plants while retaining the necessary flexibility in process and giving an added bonus of better selectivity at high temperatures, coupled with high throughput. AstraZeneca and Organon have both begun to use microreactors for some processes.

New-generation microreactors could eliminate the need for traditional dedicated plants while retaining the necessary flexibility.
But new technologies come at a price. Though the cost of building new continuous processing facilities are significantly less than batch, it is still widely believed that the cost to upgrade existing pharmaceutical manufacturing facilities exceeds any potential benefit. Still, Trout believes this assumption has little basis in fact. There will be situations where continuous would be more beneficial and there are many factors involved in the decision, he explains. Whether or not to use continuous processing should be assessed on a case-by-case basis. All companies want to maximise their capital investment. It would not be cost effective to throw existing equipment out after a couple of years. However, the various equipment could be reused for other purposes.

Next steps
Trout believes continuous processing is the way forward for an industry constantly under the strain of rising costs

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As more technology is developed, Trout envisions that continuous processing will eventually become more beneficial in all scenarios. There has been no direct resistance to switching over within the pharmaceutical sector. Everyone is talking about continuous processing and there is a large push towards it, he adds. Indirectly, however, this is a very conservative industry due to regulatory issues and the critical nature of the products, and this leads to the need for a strong case among pharma for continuous processing. It is very exciting time for pharmaceutical manufacturing, and there is a great deal of enthusiasm that comes with innovation.

ExPEctEd BEnEFits oF continuous ManuFacturing

this project on paper and in application, says Trout.

Bigger picture
Although the benefits of continuous processing include less waste, higher quality, more flexibility in process and cost savings, there has been a dearth of research data from large-scale applications of continuous processing models within the pharmaceutical industry. In September 2007, MIT and Novartis announced a joint research project, the Novartis-MIT Center for Continuous Manufacturing, aimed specifically at proving the superiority of continuous processing. The objective is to create highly specific technologies for streamlining future pharmaceutical manufacturing and to document performance.

The introduction of new drugs to market will be accelerated Building and capital costs will be lowered Minimal waste Energy consumption and raw material use will be reduced Quality will be monitored continuously rather than post-production Reliability and flexibility will be increased within the production process

Breaking barriers
Trout is confident that the results will help to dispel lingering misconceptions that continuous processing is difficult to manage. He believes that continuous processing is well controlled and that the controls are not just equal, but superior to batch methods because continuous processing is run at a steady state rather than dynamically.

The controls for continuous processing are based on understanding, he says. Knowledge combined with process control means we have far more flexibility in terms of how we run the process. We can easily implement changes when necessary as opposed to current batch models. Trout also points out that hurdles in regulatory guidelines are beginning to dissolve. We are working closely with regulatory bodies, and they are very positive about us moving forward and implementing continuous processing, he says. The USFDA openly supported the MIT/Novartis project following its announcement last year and has been advocating continuous processing systems as stated in its Pharmaceutical cGMPs for the 21st Century. The executive summary states that pharmaceutical manufacturing is both inefficient and costly and fraught with self-imposed constraints, which perpetuate this low efficiency. It also states that pharmaceutical manufacturing will need to employ innovation, cuttingedge scientific and engineering knowledge, and the best principles of quality management to respond to the challenges of new discoveries.

Continuous processing is well controlled and the controls are not just equal to, but are superior to batch methods.
The technologies created through this collaboration are expected to benefit patients as well as healthcare providers by increasing the availability of supply and medication quality while simultaneously reducing the environmental impact of pharmaceutical manufacturing processes by reducing waste and the use of solvents. Although still in its fledgling stages, Trout is optimistic about the eventual outcomes of the ten-year study. The success of our project will be a motivating factor for change, he says. Were working on a variety of new technologies across the board, from chemical, synthetic methods and reactors to separation methods and new approaches for final finishing of the product. In parallel to developing all those new technologies, a bench-scale unit is being set up at MIT to be implemented on a research basis and eventually moved on to be used in production at Novartis. I think all of those combined will create a tremendous impetus when pharmaceutical companies actually see the results of

Visionary approach
Trout believes his team at the Novartis-MIT Center for Continuous Manufacturing will deliver these state-of-the-art technologies. The excitement of this is the integration from beginning to end from inlet to outlet, he says. That includes the synthesis between the drug substance and drug product. It also includes designing the entire process on a modelbased approach, based on rigorous understanding in such a way that we no longer have step one, two and three. Instead, everything is fully integrated. I think that makes this a visionary approach and its the next wave in our view after the quality by design wave. Continuous processing allows for the development of all kinds of new technologies that are not possible with batch. WPF

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