Continuous Manufacturing: To Be Continued…

Continuous manufacturing offers obvious advantages to the pharmaceutical sector but has not yet evolved into a major alternative to batch. Are things about to change? Dr. Andrew Warmington spoke with some of the leading CDMOs and API manufacturers to find out how the landscape is shifting.

"I don’t know why it’s not more widely used… this is the future,” said Janet Woodcock, director of the Center for Drug Evaluation & Research at the U.S. Food & Drug Administration (FDA), when asked to explain the benefits of continuous production in pharmaceutical manufacturing.¹

The Journey to Continuous Continues

Shortly afterwards in July 2015, the FDA approved the use of continuous manufacturing in Vertex’s new cystic fibrosis drug Orakambi (lumacaftor, ivacaftor) at a 4,000 ft² (370 m²) facility in Boston. It is a wet granulator product and is manufactured on a production line developed in-house.

In March 2016, Vertex signed an agreement with Portuguese CDMO Hovione, a long-term collaborator, to install a commercial-scale continuous manufacturing facility at Hovione’s site in Windsor, New Jersey. Due for completion in early 2018, this will also be open to third parties. It will include continuous blending, wet and dry granulation, fluid bed drying, tableting and coating operations.

Meanwhile, a few months back in December 2015, the FDA issued its draft guidance ‘Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base,’ with a view towards helping manufacturers implement various technological advances.² The agency believes that this facilitated another breakthrough: In April 2016, Janssen Supply Chain (JSC), a division of Johnson & Johnson (J&J), received the first approval to switch from batch to continuous processing for the HIV-1 treatment Prevista (darunavir).

JSC can now produce 600 mg tablets on a continuous manufacturing line at its site in Gurabo, Puerto Rico, which integrates weighing, milling, blending and compression. The ultimate aim for J&J and JSC is to manufacture 70% of their highest-volume products using continuous manufacturing within eight years.

Product vs. Substance

Both of these approvals refer to drug product rather than drug substance, but industry insiders say that the technological possibilities and the economic case are fundamentally similar in both fields. Contract development and manufacturing organizations (CDMOs) active in both fields are invariably interested in applying the technology to both.

Immediately afterwards, Lawrence Yu, Deputy Director of the FDA’s Office of Pharmaceutical Quality, said in a blog: “Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts.”³

The potential advantages of continuous production are well understood: reduced costs, shorter production times (in some cases reducing many weeks to a single day), greater flexibility (especially when responding to increasing levels of growth), reduced waste and environmental impact, reduced factory size, fewer locations and more efficient capacity utilization. Some also see it as a way to bring drug manufacturing back to the West.

Looking Outside Pharma

For some perspective on this prospect, however, Google ‘continuous processing’ and ‘small molecule’; the first hit will be an excellent article by Dr. Matthew Mollan and Dr. Mayur Lodaya of Pfizer, reviewing the potential of continuous processing to replace or complement batch in pharmaceutical manufacturing. The authors point to the plethora of other industries which have moved in that direction, FDA support, the pressures from rising costs and the growing need for customized smaller- volume drugs.

Mollan and Lodaya conclude: “The pharmaceutical industry is poised to change radically in the next 5-10 years in response to a changing marketplace. New risk models will need to be implemented to stay competitive and rapidly respond to these changing dynamics… The level of ongoing research activity and the partnership approach signaled by the FDA suggest that the changeover from batch to continuous processing in the pharmaceutical manufacturing environment will happen soon.”⁴

This article was published in 2004! To point this fact out is not to be wise after the event at the expense of other authors. Yet continuous processing has taken an awfully long time to arrive in this industry. Why, given the obvious advantages and the continued encouragement from the regulators? And on what basis can we say that it will be different this time?

The Challenges to Continuous Manufacturing

The main reason continuous processing has struggled to gain any traction is that manufacturing processes are virtually set in stone when a drug is patented. For the vast majority, the cost of validating a technically superior continuous process and then seeking marketing approval outweighs any reduced cost from a better process, particularly if registrations have been filed in multiple regions. Indeed, the same applies to a better batch process.

There has also been a perception that continuous manufacturing can only compete at very high volumes, though some dispute it. Then there is also simple inertia. Drug makers, CMOs and CDMOs have large investments in batch reactors that have already been written down. And to change to continuous means a change in mind-set about how process R&D is done.

“What has held us back has been an asset-heavy industry,” says Dr. Roger Viney, Senior Director for Off-patent Products at Hovione. “Companies can be forward-looking but they are tied to the equipment they have, and from a scientific perspective this is a big obstacle too. Thousands of scientists are used to batch production, and this is another big reason why it has taken longer than expected.”

Perhaps predictably, given that his firm is actually installing continuous processing equipment at one of its sites, Viney is an optimist when it comes to the potential for the technology. “The real advantage is speed of development,” he says. “We have gone in with a partner and will work with them, but we also have free capacity to sell to the market or use for our own projects.”

The new rig allows Hovione increased capabilities at commercial scale, including direct compression and both wet and dry granulation in continuous mode for the production of coated tablets. All of these processes are rapid, so the advantage is accelerated development. The company has also been working on applying continuous processing to drug substances at lab scale.

“We now, as of fairly recently, screen all our development projects to see if continuous processing is applicable to them,” Viney says. Equally important, is the appointment of Nuno Matos to take full charge of continuous processing for both drug product and drug substance.

“We have recently worked on screening criteria to see if continuous processing is applicable to specific projects; there are technological ones but also commercial ones. When we start a drug substance project, we ask if there is an advantage to using continuous processing. One criterion would be cost — but it is also necessary to ask if there is actually a need to reduce costs. So we try to pick products where there is a need, and this kind of process can give an advantage.

“Another is purity of product — could continuous processing lead to a purer product? A third is IP — is there potentially something a continuous process could yield that would lead to greater IP generation? Other possible advantages include whether it might lead to greater product differentiation, or the possibility of reengineering after the product development phase.”

Commercial within Reach

U.K.-based CDMO Aesica, which now belongs to Consort Medical alongside drug device development and manufacturing firm Bespak, has also been a pioneer in continuous processing for finished dosage forms and believes that it had the first commercial rig available for continuous processes.

“We worked with customers and equipment suppliers to develop it,” says Managing Director Ian Muir. “The rig has been in place at our Queenborough site near London for just over four years. This was triggered in the first instance by a special customer relationship with a Big Pharma company that was interested in looking at continuous processes for finished dose manufacture.”

Muir believes there are equally strong possibilities in drug substance too. “Continuous processing is ideally suited to high-value, low-volume niche molecules where conservation of the API is a critical element of value. Thus, smaller-volume therapeutic classes with high-value molecules makes the economics of continuous processing as attractive in APIs as in finished doses. These classes include orphan drug classifications and others which target themselves at particular sub-sets, as well as high-potency drugs.”

Capability for Continuous

Patheon, another multinational, multi-site CDMO, draws on a long DSM heritage in working with microreactors — Lukas Utiger, President of Drug Substance, remembers using disposable glass micro-reactors back in 1998. The company has worked on continuous processing for both drug substance and drug product and is ready to manufacture at a scale into the tons when the market is ready.

“We already do continuous tableting at our site at Greenville, North Carolina, and our site at Linz in Austria has continuous capability for drug substance at all three levels, from lab to pilot plant to commercial production,” he says.

Another U.K. CMO, Robinson Brothers (RBL), has only a small proportion of its activity in pharma. Nonetheless, both Managing Director Adrian Hanrahan and Bal Kalirai, Ph.D., R&D Business Manager, are strong advocates of being proactive in adopting new technologies.

RBL started work a year ago on an Innovate U.K. project with flow reactor maker AM Technology to see if a pharmaceutical process of several tons could switch from batch to continuous hydrogenation. This, he says, has been completed successfully, showing not only that the switch could be made but that an additional purification step needed in batch was not needed in continuous.

More recently, RBL has begun involvement in the Advanced Manufacturing Supply Chain Initiative (AMSCII) project led by GSK and covering all areas of pharmaceutical supply from formulation to clinical trials, in one of four “Applications,” covering continuous hydrogenation, a continuous carbon disulphide reaction, and microwave chemistry.

There have been promising results in some areas, and AstraZeneca and Pfizer are expected to get involved too. “I am optimistic for the outcome and believe that at least one supplier will launch a drug at large scale using it, and that RBL will within five years have a large-scale continuous processing rig producing one or two products at large scale, coupled with the use of process analytical technology (PAT),” Kalirai says.

Waiting for a Viable Pathway

Matt Hanson, Global Head of the API Franchise at Millipore Sigma, who was involved in work on continuous flow reactors at R&D scale when the business was still part of Sigma-Aldrich, cautions that there has been a lot of interest in the technology, “but until there is a viable alternative pathway and the FDA has approved a lot of development candidates, there will be a reluctance.”

It is easy to spend a few hundred thousand dollars playing in the space, Hanson adds, but making this part of the supply chain for a drug is quite another matter. There is also a circular problem: Where the process could most usefully have continuous processing investigated, in the very early stages, is also where financial imperatives tend to lead to the lock-in of a batch process with its own impurity profiles. The alternative is likelier to be more viable once the project reaches phase II, but when the money is likelier to be available the options are diminishing.

Muir also points to the regulatory framework and having controls in place. “One advantage of batch is that it is easy to segregate parts of the process and see exactly where issues arise. The other part is to do with the technology: There has been a lot of work to put the hardware — the reactors — and the software together and ensure that they work together well. It has taken companies time to get from concept to commercial.”

Numbering Up

Most regard the two recent FDA approvals as a significant moment in terms of the acceptance of continuous processing and possibly the start of something more substantial. Hanson, for one, says that they “will help move the technology forward,” while Viney agrees that FDA support is crucial in driving acceptance. None, however, sees it as the opening of the floodgates so much as the start of a trickle.

“Five years ago we knew what continuous processing was, but now we have got a rig and processes in place and are now in a place where academic ideas can come to industrial fruition,” Viney says. “I think other companies are in a similar position, in that the equipment is there and they can consider continuous processing as an option at the start of a project.”

As well as depreciated assets and the innate conservatism of the pharmaceutical industry at all scales, Utiger points to the need for very reaction-specific conditions in continuous processing, particularly during crystallization. ‘Numbering up’ is cheaper than scaling-up, but many complexities are involved, he notes; it takes far more than adding another pump and another microreactor.

Kalirai of RBL says: “Pharma companies were held back mostly by concerns about the FDA accepting continuous processes, partly on the basis that it can very quickly generate a lot of off-spec product if something goes wrong. But in practice we find less variability when using  continuous. It takes someone to take a bold step, validate the equipment and go to the FDA with the process.”

Muir, meanwhile, sees the approvals as the culmination of longer-term movements. “All of the regulatory agencies have traditionally regarded pharma as a batch process, so all of the process controls and final releases have been assumed to be built around a segregated batch system,” he says. “They have been doing a lot of work behind the scenes with companies and built up a body of knowledge to show that products made through extended processes can be controlled.”

Creating a Fit

Mark Griffiths, CEO of the Swiss-based CDMO Carbogen Amcis and of its parent company the Dishman Group, is more skeptical, at least where it comes to heightened expectations. The company has, however, been working with microreactors and continuous flow chemistry for over ten years, and currently has its first GMP prep project at phase II under way for continuous flow chemistry.

“This is a piece of work for a U.S. client where there were challenges and this fit very well — the chemistry was energetic, it was low volume and the low residence time made it suitable, so we suggested this alternative to the client,” Griffiths says.

Nonetheless, he adds, “What we are seeing now is typically work up to clinical phase II, but there is a reluctance to invest to make materials fit in with flow chemistry. We have done quite a bit of work with clients towards parallel development but [find] reluctance where clients are trying to get the chemistry ‘fixed’ and the NDA done. Speed is critical in the early phases.”

Having seen many fads come and go, Griffiths draws an analogy with what was said back in the 1990s about chiral chemistry or more recently about biocatalysis. Some people, he thinks, see continuous processing as a panacea rather than just another part of the toolbox.

There is a general consensus as to where in the chemistry set continuous processing will have its most immediate viability: in large volumes, where the ability to run 24/7 gives cost advantages, and/or where energetic chemistry leads to exotherms that cause safety issues to arise in batch.

As Griffiths says, “When you have 500 grams of explosive and expensive material in a pot and the process safety considerations put you on the ragged edge in terms of costs, you can go to the customer and suggest a cost-benefit analysis.” It is probably less useful, he adds, with complex molecules that require complicated assembly.

“You still need a chemist in a lab with a 500-liter reactor. This is a nice-to-have for a CMO and enables us to offer benefits to customers, but will it be 25% of the market in ten years’ time? No,” Griffiths concludes. Muir adds that the technology will be increasingly better understood, “but I don’t see established products going wholesale over to continuous processing.”

It is striking, though, that the more optimistic advocates do not fundamentally disagree with this figure. Few put a figure on the proportion of reactions that might use it but Viney suggests 10% to 20%. Utiger, most cautiously of all, does not yet see a reason to depart from the figure of 1% to 5% that he first guessed in the late 1990s. Only gas and liquid reactions with rapid kinetics are suited to it at the present state of technology, in his view.

The Continuous Bell curve

Companies that already have a large amount invested in traditional batch processing, Viney adds, will be slower to change: Continuous processing will be more suited to virtual companies and/or those which have already outsourced a large amount of their manufacturing. It will also be less suited to those working in niche areas where there is limited access to API in the development stages, because they cannot afford to buy more API than they need to use.

Adapting to continuous processing on a large scale is about more than equipment and software, however — it is also about the mind-set. For a start, says Muir, producing in continuous mode means testing during the process instead of at the end. To keep a process within the requisite parameters requires the use of Quality by Design (QbD) and using many sensors that were not needed before.

He and Griffiths both note that more analytical chemists and an enhanced technical analytical capability are required because more samples need to be taken during the development stage, and there are more process controls. This is also tending to bid up the cost of analytical chemists, who are not always easy to find.

Adding that continuous processing goes hand in hand with QbD, Viney adds that the way batch processes have historically been validated is very inexact — typically making three batches and examining a couple of parameter changes. This should no longer be acceptable because it means that the full parameters of the reaction are often not sufficiently understood, even when it is set in stone.

Hovione now employs mathematicians and data scientists, some of who have worked with petrochemical companies, who can evaluate such things as the feedstock input and explore all the parameters and process questions. “This is a very different science to traditional organic chemistry, but once you have it in place and use it, it generates a lot of other possibilities,” Viney says.

“Design of Experiments is very powerful because it gives you a complete understanding of what is critical to the process. You can map critical parameters and even generate a 5D model showing what will happen to any of them if one is varied. This is a completely different level of understanding to the one you get from making three batches.”

Anticipating the New Wave

With the technology increasingly understood and the regulatory authorities encouraging adoption, what will actually drive the next wave of progress? For Griffiths, the real challenge is looking at the product life cycle and seeing where the sweet spot is where flow chemistry could add value. In some cases, he says, it might be possible for the customer to file with a traditional manufacturing route, then look at flow chemistry.

“Probably the dynamic will be driven by larger pharma companies, who are a bit braver and likelier to have more direct experience, as well as deeper pockets, than smaller companies,” he suggests. “There is a better chance that they will take a look at options like continuous processing before taking a project to a CMO.” The biotechs are more driven by speed, generally speaking. He also sees potential with older products, “especially generics, where drug companies are trying to drive every dollar they can out of the process and want to get the costs of raw materials down too.”

Having worked on both sides of the fence, Kalirai says that, while CMOs are able to move quicker to implement new technologies like this, they have actually been slower to adopt it than larger pharma companies because they lack the resources to invest — or are simply stuck in their comfort zone in relatively good times when their batch reactors are fully occupied. Passionate advocates of the technology will be vital.

Kalirai also believes that many more pharmaceutical companies are using continuous processing in-house but staying silent about it, meaning that some suppliers are in for a shock when it takes off. “The future is continuous and those who don’t grasp the nettle will have a limited life span,” he says. Anecdotally, plenty of continuous equipment has been sold in China — “We will struggle to compete if we do not adapt.”

Another big challenge will be skills, in Kalirai’s opinion. As more and more companies adapt to continuous processing, so universities will need to teach skills related to it, including PAT. At the moment, very few do. AMSCII is also looking at that.

“More successes,” is Hanson’s simple answer. “The more you have, the more people can tangibly understand it. We are mostly trained as batch chemists, and one of the other challenges is that you have to develop an alternative flow process alongside the batch process. This is often not really viable for small companies who have only one or two drug compounds that have a high chance of failure.”

Millipore Sigma, he adds, has worked on the technology for some time and developed expertise, so it understands a lot about designing the equipment it can apply to certain chemistries at the Milwaukee, Wisconsin site, carrying them out on a larger scale at Sheboygan, Michigan. Mostly this has been non-GMP. Now the company is looking to expand to GMP-capable processes that customers would be interested in.

“We try to educate customers to look at the applicability of continuous processing for a specific reaction and ask if they would like us to do some additional development. This means asking them to take a chance — though that is what we, as a CMO, do anyway,” Hanson says.

Utiger agrees that getting the right portfolio of reactions and flexibility on both sides are crucial. It will also require cross-disciplinary work because of the different mind-set needed. “Chemists know about kinetics but they don’t know about reactor design in the way an engineer does,” he says. They will have to learn to work together.

Nonetheless, Patheon is in place for a big switchover, should it come to fruition. “We are already well set up, we can produce several tons of material out of our existing facilities, we have numbered up, developed proof of concept. From that point of view we are ready and we will have plenty of capacity when customers are ready for it,” says Utiger.

“Now there have been a couple of approvals, more companies will want to go down this path,” says Muir. “I believe that continuous processing does indeed play well to the strengths of CDMOs like us. The kind of compounds that suit it do not come on all the time. Similar to technologies like spray drying and lyophilization, companies will want to access them as and when they need them rather than being captive to them.”

There have been some false dawns on this road before but, says Viney, “I believe it is different this time. We have a rig, we have a man and we are looking at continuous processing for all our operations, so it does feel different to me now. With the two recent approvals, the chances are that it won’t be a damp squib, though it will also not happen overnight.”

References

1. Brennan, Zachary. “FDA Calls on Manufacturers to Begin Switch from Batch to Continuous.” In-Pharma Technologist. 1 May 2015. Web.
2. Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry. U.S. Food and Drug Administration. Dec. 2015. Web.
3. Yu, Lawrence. “Continuous Manufacturing has a Strong Impact on Drug Quality.” FDA Voice. U.S. Food & Drug Administration. 12 Apr. 2016. Web.
4. Mollan, Matthew J., Mayur Lodaya. “Continuous Processing in Pharma Manufacturing.” Pharmaceutical Manufacturing. Web.