Three guys and a molecule walk into a contract manufacturing facility.
It sounds like an chemistry joke, but actually happens quite often. Small biotechs rarely have the infrastructure to produce a drug in-house, so they turn to CDMOs — contract development and manufacturing organizations — to fill their clinical and commercial supply needs. That relationship has become especially important with the rising popularity of continuous manufacturing.
As its name suggests, continuous manufacturing offers a steady stream of drug product by using a fully-integrated assembly line that does everything from synthesis to blending to tablet formation. The process has been a long-time favorite in other industries such as petroleum and food, but only in the last two decades or so has it started to gain momentum in the pharmaceutical world.
CDMOs are now receiving more and more interest from drugmakers looking to take advantage of the technology's potential cost-savings and efficiency. The interest isn't just from biotechs either, as big pharma has also looked to outsource continuous manufacturing work.
The trend has put pressure on CDMOs like Lonza and Patheon to show clients they're ahead of the curve. Many argue they're well-prepared for the shift, but the relatively recent adoption of continuous manufacturing means there are plenty of intricacies left to iron out.
The whys and hows of implementing
At Patheon, questions about implementing continuous manufacturing have started with "how" rather than "if," according to the Dutch CDMO's director of continuous manufacturing Eric Jayjock.
"Trying to justify this as a business case was not something that we had to wrestle with," he said in an interview with BioPharma Dive.
A similar tone can be found at Switzerland-based Lonza, where the adoption of perfusion technologies and single-use systems over the last 20-plus years has given the company a foothold in the market for continuous manufacturing services.
"Lonza does have a track record in the building blocks for continuous manufacturing," Atul Mohindra, head of R&D, biomanufacturing at Lonza's Pharma & Biotech unit, told BioPharma Dive. "And as demand for the product types and the actual customers that come to us with their different product types is changing, we're keeping in line with that industrial trend and ... investing quite significantly in this field at the moment."
CDMOs face several obstacles setting up the building blocks of continuous manufacturing, one being the money required for new equipment like the sensors that check for quality as drug product moves along the assembly line.
But more challenging than buying the technology is recruiting the people, such as automation experts and process scientists, who understand it — something that's less common than might be assumed, according to Jayjock.
Whereas food, candy and agricultural plants often have on-site engineers who can explain why the facility is designed the way it is, it's rarer to find that kind of person at a drug manufacturing facility, Jayjock said. "We tend to really, in essence as an industry, outsource process knowledge. That doesn't work with continuous manufacturing, because now we're talking about integrating a process together and putting together a unique control strategy."
Different conversations for different manufacturing
Another thing that doesn't work with continuous manufacturing is a one-size-fits-all approach when talking to clients.
Both Jayjock and Mohindra have noticed that the discussions they're having about this technology are more detailed than those for batch production, with clients particularly focused on things like process controls, logistics and skills tests.
"The strength and the weakness of continuous is that they are going to be somewhat customized processes for each product, even though it's common equipment," Jayjock said. "So right now the early conversations have been much more tailored, and I would say much more attention has been given from the technical staff ... than what you'd typically have within the batch world."
The growing popularity of continuous manufacturing has also meant CDMOs see clients who want to adopt it even if other options make more sense.
"Both continuous and batch have pros and cons, and since we have an established infrastructure we can apply whatever fits best," Uwe Gottschalk, chief scientific officer at Lonza Pharma & Biotech, told BioPharma Dive. "But of course you always run into clients that have a certain mindset and then are maybe even difficult to convince [otherwise]."
Looking down the line
Drugmakers' reliance on contract services providers has grown stronger as of late. An EY report published last September determined the CDMO industry was worth $62 billion in 2016 and sports an annual growth rate of 6-7%, slightly above that of the pharma sector. The reasons for that growth were numerous, but many had to do with widespread pricing pressures and the high cost of in-house manufacturing.
EY also identified Lonza, Patheon and Catalent as examples of a larger trend: CDMOs using M&A to become one-stop shops for drug manufacturing needs. Despite the large demand, there was a cautionary note.
"A lot is at stake for pharmaceutical companies when choosing a partner for their manufacturing outsourcing needs," the report said. "Therefore, for small and large pharmaceutical sponsors alike, proven reliability and impeccable quality standards are key to choosing a CDMO."
To that point, CDMOs looking to establish a lasting presence in continuous manufacturing must prove they not only have command over the technology right now, but can adapt to how the technology will advance in the coming years.
"When it comes to technological changes, they are happening at the higher speed today," said Gottschalk, who hypothesized that in the not-too-distant future, CDMOs will have to come up with some sort of justification to clients and regulators if they aren't using the latest technologies, including continuous manufacturing.
CDMOs aren't alone in having to reckon with the new technology, however.
"The number one lesson learned for me is that this is a real decision point for the pharmaceutical industry, and they have to decide if they want to really be the owner and the stewards of the technology or not," Jayjock said.
"And that's one of the things that is very difficult," he added. "It goes against the last 25, 30 years of a how the pharmaceutical industry operates, which is really: buy the equipment, it's kind of like a black box and we just crunch stuff out of it."