Going with the flow: continuous manufacturing

As manufacturing models embrace process analytical technology, big pharma has to reassess the way it produces drugs. Elisabeth Fischer profiles the opportunities and stumbling blocks of continuous manufacturing and finds out how it will revolutionise the industry's operations in years to come.


Continuous manufacturing has been the norm in almost all manufacturing industries. The pharmaceutical industry however has so far shied away from the continuous model, instead clinging onto batch manufacturing since the beginnings of the blockbuster drug era.

"Continuous manufacturing will reduce cycle times and enhance process reliability and quality across the entire manufacturing chain."

Few other industries would survive if they presided over utilisation rates of around 30%-40% and took as long as one month to manufacture a product that could be made in two days. But in pharma, the profits coming from the established blockbuster discovery model have covered manufacturing inefficiency. Moreover, heavy regulation has held back transformation in the field.

However, with another recession looming around the corner, the pressure on all parts of the pharmaceutical value chain has increased. Like any other department, manufacturing has to take its part of the job and improve its outcome, reducing time, waste and cost.

Since 2004, initiatives such as quality by design (QbD) and process analytical technology (PAT) have taken off in the US and Europe and a small number of companies, including Novartis Pharma, have gone one step further and increasingly concentrate on the development of continuous production technology as part of the movement.

For the industry this could be the impetus to finally realise the need to embrace continuous, uninterrupted processing. But before the first technologies can make their way from the research pipeline to commercial use, a mindset shift has to take place.

Only then big pharma can shake off the outdated model of batch processing and enter a new era of drug production.

Revolutionising drug manufacturing

Over the years, pharmaceutical manufacturing has been scaled up from manual to automated technology: processes have been fine-tuned and improved, the introduction of IT has eliminated paperwork and shortened output cycles.

It has been going fairly well, as Novartis Pharma head of global technical operations Tom van Laar explained: "Right now the manufacturing process is reasonably well and we get the good quality products supply to the patients on time. In a way, there is not a need to change pharmaceutical production."

However, when Novartis started sponsoring the Massachusetts Institute of Technology (MIT) with $65m in September 2007, the goal was clearly aligned in this exact direction. By creating a research programme that is aimed at revolutionising the way drugs are made, pharmaceutical manufacturing will finally have to move on from the islands of automation where every unit of operation is independent from each other.

Since then, scientists and engineers from both organisations have been working at the Novartis-MIT Center for Continuous Manufacturing to develop new technologies that eventually lead to a continuous flow-through.

A new approach to technology

According to MIT professor and programme director Bernhardt L Trout, the scope of research includes everything from chemistry to reaction and reactor engineering to separations processes, as well as new ways of forming the final dosage.

"Big pharma owns extensive, expensive facilities, employing people and practices that yield high-profit margin products which seem to be of sufficient quality."

"We're also working on new systems design and modelling approaches, in addition to end-to-end integrated control," he added, drawing a wide picture of opportunities.

Bernhardt L Trout believes that once the industry will see the success of the new technologies, it will nucleate change. Also, Tom van Laar is convinced of the enormous opportunities: "Continuous manufacturing will transform the way we develop and manufacture pharmaceuticals, it will reduce cycle times and further enhance process reliability and quality across the entire manufacturing chain, from drug substance to the final product."

According to van Laar, the most significant benefits include the reduction of development and production time, the need for less equipment, infrastructure and building costs, as well as improved process reliability and reproducibility.

Moreover, he argues the implementation of continuous manufacturing reduces the safety risk to pharmaceutical operators, decreases the use of energy and raw materials and generates less waste, which ultimately leads to a smaller impact on the environment.

An example of one of the technologies developed at the centre is micro-reactors, as opposed to bigger reactors used today. This technology will eventually be pushed to a level where they can produce drugs on a commercial scale in volumes that will be necessary for the future.

"They will run non-stop, so even though they're smaller they're producing more in the course of the day, a week or a month," said Tom van Laar. Furthermore, they will allow much smaller quantities of active ingredients into the process, deactivate them more quickly and create a much smaller footprint than current technologies.

Thin-film technology is another new design that will help the implementation of continuous manufacturing in the long run.

The technology puts out active ingredients as films, almost looking the same as small pieces of plastic, which then can be transformed into any possible form of medication, as tablets, capsules or liquids. According to van Laar, this also opens up the opportunity to tailor dosages to certain types of patients.

Regulatory and organisational barriers

Tom van Laar however knows all too well that the transformation from batch to continuous will not happen overnight. Once the technology is ready for commercial scale-up, one of the biggest barriers will be getting commercial approval from regulators such as the Food and Drug Administration (FDA) in the US or the European Medicines Agency (EMEA).

In a forward-looking strategy, Novartis has involved both agencies since the beginnings of the Novartis-MIT Center for Continuous Manufacturing in 2007.

"We give them annual updates and tell them where we are. By the time we have to get them to approve this, it will not only be us working by ourselves and then we throw it over the wall and give it to them to approve," he said.

"Both agencies have never had to regulate something like this so we've been involving them almost from the beginning."

Another major challenge will be the organisation of a new type of facility, which goes hand in hand with the investment in the whole new form of production equipment.

"Right now we're organised around drug substance manufacturing and pharmaceutical manufacturing with different people and different capabilities at different locations," explained van Laar.

"That will completely change and we have to figure out what the right set-up in the future will look like, design that set-up and also develop new capabilities for the technology."

To overcome these barriers, Novartis is currently finalising a lab-scale pilot facility, called 'Technikum', where only a few months ago MIT scientists produced one of the company's drugs in a continuous way for the first time ever. Now, developers at Novartis will try to develop the continuous manufacturing unit and 'play with it' to make it at least big enough to go commercial.

Challenging the mindset of business as usual

"Since 2004, initiatives such as quality by design and process analytical technology have been taken up in the US and Europe."

Novartis plans to make the step of commercially implementing the technologies in 2015, eight years after setting off the project at MIT.

Both Tom van Laar and Bernhard L Trout are convinced that they helped to shape the future of pharmaceutical manufacturing to finally make the step towards more profitable and effective production.

"Like a lot of these things, this needs a real paradigm shift in order to get it done. It takes a lot of work to get the mindset around this. You can imagine people get very comfortable in doing things they have always done and just optimising that," said Tom van Laar.

"But I think this is the next big breakthrough in manufacturing. The future is continuous manufacturing."

The reason for the rollout of continuous manufacturing being so late is that so far the industry has not seen the need to change its mindset of its business as usual. Big pharma owns extensive and expensive facilities, employing people and practices that yield high-profit margin products that seem to be of sufficient quality.

However, in the long run, the switchover to continuous is without question more cost-effective than continuing in the same way. Increased asset utilisation, reduced work in progress levels and shorter cycle times are only a few of the benefits to be named.