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Europeans Seek Competitive Advantage From Continuous Processing

The pharmaceutical patent cliff is driving firms to look more closely at improving manufacturing processes

by Alex Scott
May 27, 2013 | A version of this story appeared in Volume 91, Issue 21

Credit: CMAC
CMAC Research Associate Thomas McGlone is developing methods and equipment to avoid fouling in a continuous crystallization process.
This is a photo of scientists testing a continuous process.
Credit: CMAC
CMAC Research Associate Thomas McGlone is developing methods and equipment to avoid fouling in a continuous crystallization process.

The spate of drug patent expirations known as the patent cliff is sharpening minds. Pharmaceutical companies have been looking under every rock to save money, and one idea they have found is continuous chemical manufacturing. Momentum to develop continuous processes is especially building in Europe, where firms hope that by working together and with academia they can get a jump on the competition.

Delegates at a meeting held recently at AstraZeneca’s R&D center in Alderley Park, England, took home the message that continuous processing has technical and cultural challenges but, if well designed, can be straightforward and deliver financial and other benefits compared with traditional processes that make chemicals one batch at a time.

“The protection that pharma companies have had for years has masked their inefficiency, but now we have the patent cliff. The competitive focus is changing, and process efficiency is paramount,” Tony Warr, head of process technology for India’s Dr. Reddy’s Laboratories, told attendees. Batch is a “wonderful technology for ensuring that quality sticks, but its problem is that you are up and then you are down,” said Warr at the meeting, which was organized by YCF, a networking organization based in Huddersfield, England. More than 90 delegates from 30 firms, mostly from the U.K. and elsewhere in Europe, attended.


Continuous processes have advantages over batch ones, but they also have challenges.


Potential financial savings

Low capital investment

Potential for intellectual property protection

Less space required

Greater flexibility and controllability of facilities

Safer with energetic chemistry

Suitable for large-scale production

Better product quality

Rapid scale-up

Good at handling gases


New engineering and operating skill sets required

Perception of higher risk

Mind-set change needed

Up-front setup costs if batch process already under way

Mastery of start-up and shutdown

In continuous-flow reactors, reactions occur as reactants are on the move through piping. For pharmaceutical production, the tubular reactors often used range from 6 to 50 mm in diameter. According to engineering firm Foster Wheeler, a plant featuring 50-mm tubing is able to produce about 106 L of product per minute, equivalent to 4,800 metric tons per year. A continuous-processing plant with a capacity of multiple metric tons per year takes up an area of just a few square meters.

Science funding organizations in the U.K. and the European Union are investing in programs to develop continuous-processing methodologies. In 2011, AstraZeneca, GlaxoSmithKline, Novartis, and several U.K. science bodies and universities created the Centre for Innovative Manufacturing in Continuous Manufacturing & Crystallisation, or CMAC, to advance manufacturing research and deployment. Meanwhile, the European Commission (EC) has created several continuous-flow process research consortia.

It’s not just European organizations that are seeking to implement continuous processing. U.S. companies with programs in the field include Pfizer, Eli Lilly & Co., and Merck & Co. Novartis established the Novartis-MIT Center for Continuous Manufacturing with Massachusetts Institute of Technology. And Janet Woodcock, a U.S. Food & Drug Administration director, indicated in a 2011 speech that continuous processing will likely play a key role in pharmaceutical manufacturing.

India could also emerge as a strong player in continuous processing. “European firms may be further ahead of many of their U.S. counterparts, but the revolution in continuous processing will come from India,” said Girish Malhotra, president of Epcot International, a process technology consulting firm based in Pepper Pike, Ohio. India is “more open to more efficient approaches,” Malhotra argued.

Indeed, Indian drug firms, such as Dr. Reddy’s, are investing in continuous processing. In one example, a continuous process developed by Dr. Reddy’s replaced a batch one for less than $250,000, excluding purification equipment, to generate annual savings of $1.1 million, Warr said. The savings included a 25% reduction in the cost of raw materials.

Another advantage is that continuous processes can provide benefits related to intellectual property. “Every problem you solve when you develop a competitive process can be a barrier for the competition,” Warr said.

AstraZeneca and GSK are among European pharma firms actively developing continuous processes. Both firms see clear benefits, including lower costs, intellectual property advantages, and improvements in product quality and supply chains.

For Tina Atkin, lead process engineer for GSK, the first battle in the adoption of continuous processing is getting colleagues to seriously consider it. “One of the challenges is to change the way that people think,” Atkin said.

Switching to continuous processing has its technical challenges, she acknowledged. Among the issues GSK has been grappling with are setting a flow rate to ensure product uniformity and deploying a reliable and accurate feeding technology for raw materials. “Product quality is paramount,” Atkin said.

GSK has some drugs in late-stage development for which key products have been synthesized continuously. The firm is currently putting in place an end-to-end commercial process.

Continuous granulation of active ingredients as a prelude to making tablets is also being pursued by GSK. Tests show that continuous granulation processes potentially have advantages over existing batch processes, including a reduction in the variability of particle size and in cracking of drug tablets made with the granules, Atkin said. And ultimately “less variability of product saves money.”

AstraZeneca is attracted to continuous processing partly because of the technology’s promise to improve product quality and manufacturing flexibility. “But we are not where we want to be yet,” Jon-Paul Sherlock, a director for pharmaceutical development at AstraZeneca, emphasized at the meeting. “Batch manufacturing hides a multitude of sins. We need to better understand the process before we can move to continuous.”

AstraZeneca has already used continuous processing to deliver a pharmaceutical chemical for early-phase clinical studies, according to Sherlock. The firm has explored the use of continuous wet granulation for drug production but has yet to install a manufacturing facility. Its first large-scale use of continuous production likely will be to supply a new medicine rather than replace an existing process. And “this is likely to be in the five- to 10-year time frame,” Sherlock said.

Despite the uptick in interest, few firms seem to have implemented continuous processing yet. “We have yet to see a pickup in inquiries for continuous plants,” said Brian Ashton, business development manager for Projex Solutions, an English engineering design firm that builds clean-room facilities for the pharmaceutical sector.

If technical issues are keeping drug companies from embracing continuous processing, then they should ensure that their chemists and chemical engineers are working closely together, said Oliver Tames, a partner with IntensiChem, a continuous-processing services start-up, based in Sandwich, England.

One of CMAC’s main goals is to build understanding of continuous-processing best practices among academia, users, technology companies, and research organizations. AstraZeneca, GSK, and Novartis are founding members.

CMAC seeks to train students so they are experts in implementing continuous processes. Seven universities, 13 professors, and 50 Ph.D. students and postdocs are currently involved. “We’ve got to have a talent pipeline to develop and operate novel processes and equipment,” said Craig Johnston, operations director for CMAC.

Housed within the University of Strathclyde in Glasgow, Scotland, CMAC has raised $46 million from industry and a range of funding organizations since its launch in 2011.

Other groups in Europe are also developing expertise in continuous processing. Synflow, which was created in 2010, has secured $14 million in funding from industrial partners and the EC to develop continuous catalytic processes. Synflow participants include AstraZeneca, Bayer, England-based process technology firm Britest, Evonik Industries, Johnson Matthey, and 12 universities from across Europe.

European companies are hoping that collaborating with academia, research institutes, and other firms will accelerate their own continuous-processing programs. But as Dr. Reddy’s has already shown, it is not just European firms that are in this race.


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