Continuous teaching and research at DiPP

Dr Kevin Robinson was on site when the University of Sheffield officially opened its fully integrated continuous manufacturing pilot plant in the Faculty of Engineering’s Diamond building teaching facility

It was a fulgent evening in April when the University of Sheffield officially opened the doors of its Diamond Pilot Plant (DiPP) to a receptive congregation of students, staff, members of the press and representatives from the food, pharmaceutical and chemical industries.

This pioneering new facility boasts a world-leading continuous powder processing plant — the first of its kind in any UK university — and will manufacture pharmaceutical tablets from mixtures of model active ingredients and excipients.

DiPP will include key powder process steps for formulated product manufacture, such as crystallisation, blending, granulation and tableting. In a statement from the university, Communications Officer Mr Philip Strafford noted: “DiPP will spearhead industry driven research and learning for engineering students across the globe. Researchers will target industry based problems to understand the different mechanisms involved in modelling the whole continuous process.”

“Students will use the facility to test design models for individual unit operations and also use the integrated manufacturing process for open-ended research and design projects, making sure they are industry ready after graduation.”

DiPP’s key features also include a dedicated industrial control room, a “Power-to-X” pilot plant, which can be used to run experiments to examine the optimal conversion of renewable energy to diesel, and biomanufacturing equipment such as fermenters, bioreactors and downstream processing apparatus to investigate scale-up processes.

The Diamond itself is one of the university’s largest ever investments in teaching and learning. The six-storey building hosts specialist educational facilities, including a range of lecture theatres, seminar rooms, open plan learning spaces, a library, areas for informal study and a café, and is where all first and second year chemical and biological engineering (CBE) students will undertake their work.

In his opening remarks, Professor Mike Hounslow, Vice-President and Head of Faculty (Engineering), described the new facility as the ultimate blend of teaching and research, adding: “There are also opportunities to use DiPP for training and continuing education for employees in the pharmaceutical industry and those sectors that manufacture formulated products.”

Comparing his own large-scale industrial experience with the small-scale experiments of the students, Mike explained his vision for the plant by saying he hoped that the undergraduates would “play with it, discover how the mass of stainless steel works or what the huge impeller does.”

Yes, some measurement and theory might be useful, he adds, but he feels that the university has the capacity for the students to teach themselves about chemical engineering. Having closed the original “sad” pilot plant and opened another, Mike is committed to “industrial-scale education,” and the launch event made him, he said: “Very happy and very proud.”

As one of the university’s key supporters, Reinhard Behringer, Head, Institute of Materials Science at Nestlé, then took to the podium to provide some food industry perspective. After a potted history of the company’s 150-plus year pedigree in powder science and technology, physical chemistry and freeze drying/agglomeration, Reinhard explained Nestlé’s responsibility to encourage the next generation of technicians and engineers, to provide training platforms, make new discoveries, enhance quality of life and contribute to a healthier future.

Speaking specifically about continuous processing, he noted: “Building on a strong foundation of scientific excellence, I’m delighted to be involved in the inauguration of the DiPP. It’s not just a milestone or breakthrough for the University of Sheffield, the fact that this is a continuous plant is truly unique. It will surely help to further develop competencies that we don’t have today, motivate students to go further, faster and discover new products. Continuous processing, combined with digitalisation, will make this diamond shine.”

Dafni Bika, Global Head, Pharmaceutical Technology and Development, AstraZeneca, then added: “The overriding purpose of using this [continuous] technology is to provide the medicines that people need and be part of a community of engineers and scientists with a common goal. By supporting continuous manufacturing in the pharmaceutical industry, we can accelerate that process and both design and deliver drugs that address unmet medical requirements in a seamless way: from development to manufacturing, it’s fast, it meets industry needs by differentiating products and delivers the high quality that’s expected from this sector.”

“Continuous manufacturing also offers a lot of benefits in terms of a small footprint, just-in-time production, built-in value and the ability to incorporate Quality by Design during process development. We won’t be able to do this alone, though, we must partner with suppliers such as GEA, who provided the equipment, academics, regulators and ingredient companies, etc., to move through the innovation process and capitalise on the power of this technology,” she said.

She concluded by expressing her surprise that the pharmaceutical industry has not moved faster to adopt this technology, given its widespread use in less regulated markets, but was excited to see what the students would discover and produce in this “new playground.”

Continuous powder processing plant

The first of its scale in any UK university, the continuous powder processing plant provides a platform to unite and integrate expertise in the area of oral solid dosage (OSD) manufacturing and address the challenges within the field.

Head of Department Professor Jim Litster said: “The pharmaceutical industry is undergoing the most significant change in production processes in the last 30 years. It is tremendous that our students can use this cutting-edge technology during their MEng, MSc and PhD level studies.”

“The new plant emphasises the importance of complex particulate products — and formulated products more broadly — in modern chemical engineering … and we are reflecting this in our new curriculum. It is truly research led teaching,” he added.

The global drug manufacturing sector is increasingly integrating continuous production technology to make OSD forms because of the higher levels of quality and consistency, and the reduced development costs. Students using this facility are immersed in the culture of product engineering using high class characterisation equipment to measure both the properties of the formulations and the attributes of the tablets they produce.

Project Lead, Professor Agba Salman, noted: “Product development using continuous powder processing platforms is becoming the first choice in the pharmaceutical industry. The integrated powder processing line here at Sheffield will help to address knowledge gaps using experimental and modelling techniques and support industry’s drive to adopt continuous solid oral dosage manufacturing technologies.”

“We were hoping to develop a new facility at the university that we could use for both research and teaching,” he said: “And now, we have something that’s not only unique in the UK, I think it might be the only plant of this quality in any academic establishment in the whole world."

At the heart of the university’s plant is GEA’s ConsiGma, a multipurpose platform that has been designed to transfer powder into coated tablets in development, pilot, clinical and production volumes in a single compact unit

"It’s useful for us to be able to teach the whole spectrum of continuous manufacturing — from powder to final product — to our students and move away from simply using pictures and text to the actual hands-on reality of the equipment. We’re moving beyond a simple description of the process to a true scientific understanding of the concept and the ability to model and manipulate it.”

“It’s actually industrial-scale equipment,” he notes, “exactly the same as that used in pharmaceutical manufacturing. We can produce up to 25 kg per hour. Our approach is to research how we can make medicines in a time- and cost-effective way with lower amounts of the trial drug. Based on 20 years of experience in this area — highlighted in the biannual International Granulation Conference — and a lot of work using batch-based techniques, we’re now moving into an era of continuous manufacturing to fully exploit the drug production process.”

Asked how the plant might benefit the university and the greater life science industry, Professor Salman said: “So far, even before the launch, a couple of major pharmaceutical players have enquired about using it. They’ve sponsored some PhD students to experiment with model systems and we’re currently negotiating with two more international companies about training their technical staff and engineers."

"So, already, industry understands the potential benefits of what we have. Plus, we’re moving away from an old-fashioned process to a continuous one that eliminates a lot of the quality control issues that have historically been associated with some batch technologies. At the same time, we’re reaching new levels of data management and process control.”

At the heart of the university’s plant is GEA’s ConsiGma, a multipurpose platform that has been designed to transfer powder into coated tablets in development, pilot, clinical and production volumes in a single compact unit. The system can perform dosing and mixing of raw materials, wet granulation, drying, tableting and quality control, all in one line. By producing granules continuously, batch sizes are determined by how long you run the machine; and, because of ConsiGma’s innovative design, the amount of waste produced during start-up and shutdown is significantly reduced compared with conventional methods.

“We’re delighted to be playing a fundamental role in this project,” said Steve Holt, Head of Chemical/Pharma Sales at GEA.

“With 14 years of inspiration, GEA has firmly established its longevity in the continuous manufacturing market. And, having completed more than 70 projects involving a variety of filed and authorised products, including the first ever FDA-approved breakthrough therapy developed and manufactured using the ConsiGma platform, no other company has as much experience and done more to pioneer continuous manufacturing for the pharmaceutical industry.”

He continued: “We were invited to tender about 3 years ago and, in December 2016, amidst fierce competition from other established suppliers, we successfully received an order. The challenge was to find a suitable process line that fitted within the allotted space, complied with the appropriate regulations and also met the university’s requirements to be able to present their skills and capabilities.”

“Both our project and construction manager, as well as the university staff, deserve a lot of credit for completing the installation on time and within budget. It was a novel experience working with an academic engineering department as opposed to our regular pharma clients. The University of Sheffield is globally renowned for its expertise in particle science and granulation and, as such, we’re also collaborating on some other assignments and providing a spray dryer and a homogeniser for the department.”

The installation of continuous plant is “quite a statement” for the university, notes Steve: “It’s unusual — if not unique — to find commercial-scale, state-of-the-art equipment in an academic environment that’s been made available for undergraduate and post-doc students to use. They should be able to produce graduates who will seamlessly segue into industry … and I think there are already examples of students who have secured employment with GSK, AstraZeneca, etc.”

“It’s key for the future of the pharmaceutical industry — and even more so in the UK — to be able to place properly trained, educated and experienced new talent into the market, particularly during this period of political uncertainty. And, it’s testament to GEA being at the cutting-edge of equipment design to be selected by Sheffield during a competitive tender process,” he added.

The NiTech unit supplied to Sheffield University was a DN15 Lite glass continuous oscillatory baffled crystalliser (COBC), which will be used for the research and development of crystallisation processes.

In an interview with NiTech Solutions, Jim Litster explained the reasons for choosing the crystalliser. He said that the next biggest employer of its graduates after oil and gas is the food, pharma and formulated products sectors and the university chose a NiTech crystalliser because they were looking for equipment to reflect where its graduates would eventually be employed. He noted that NiTech’s technology is regarded as cutting-edge, particularly in the pharma industry. Initially, the university will use the equipment in its undergraduate labs from first year to Master's level, firstly doing simple crystallisations and using it as a demonstration facility and lab for the first and second year students doing their mass and energy balances and introduction to chemical engineering design.

In a year or two, the department plans to have a new specialist Master's programme in pharmaceutical engineering and formulated products and when that is available, NiTech’s equipment will be used at a higher level. NiTech Solutions patented reactors and crystallisers have applications in the manufacture of chemicals, pharmaceutical, food and drink, and biotechnology, where the technology is safer, greener, faster and cheaper than traditional batch reactors. The technology is proven to reduce footprint by 70%, capex by 50% and operating costs by 30%, and at the same time improve yield by 10%.

“GEA has been successfully demonstrating its late-stage development-to-manufacturing capabilities for many years. With collaborations such as this one with the University of Sheffield, GEA and its partners are leading the way toward smaller, more flexible, continuous processing technologies that have the potential to transform the future of pharmaceutical development and manufacturing — and deliver customised quantities of drugs to patients in need in a quick and efficient way,” contributed GEA’s Phil Gabb, Head of Solid Dosage Sales Support.

He added: “I was really impressed by both the superb organisation and hospitality of the event, and the professional quality of the facility itself. The University of Sheffield is clearly a well organised, forward-thinking institution. Continuous manufacturing will form an increasing part of solid dosage production in the future, and the industry needs well trained graduates who understand the processes involved."

"GEA recognises the need to collaborate with academics, as well as other suppliers to the industry, to ensure that the full potential of this exciting technology is achieved. We are delighted to be involved with such a prestigious investment that will make a real contribution to education and industry for years to come.”

With its ground floor position in the Diamond in the heart of Sheffield, DiPP is the Faculty of Engineering’s window to the world. For the equipment, software and product manufacturing companies that sponsor DiPP, around 500 students per year use the facility and are exposed to their products and engineering philosophies. DiPP can also be used for training and upskilling employees in modern engineering processes and tools.

“DiPP demonstrates that our engineers are part of the solution to the grand challenges that our communities face in the world today,” concluded Professor Litster. “We are really excited that our students, from first year undergraduates to postgraduate research students, will get a hands-on, active learning experience on some truly state-of-the-art, integrated processing equipment."

"We have recently completed a top down transformation of our curriculum and DiPP has been the catalyst to make that happen. The continuous powder processing plant is also key to the research and training partnerships we are developing with the pharmaceutical industry. DiPP truly embodies the University of Sheffield vision. We value action compared with rhetoric.”

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