Vertex's cystic fibrosis medicine Kalydeco (ivacaftor) is made in much the same way pharmaceuticals across the industry are manufactured.
A batch of raw ingredients are chemically synthesized into the drug's main active component before being further transformed into a light blue tablet stamped with "V 150." Along the way, that collection of medicine-to-be likely moved in and out of quality testing, stopping and starting in the step-by-step production process that the pharma industry has relied on for decades.
The journey from bulk drug compound to pill looks a little different for the biotech's two other medicines for the genetic lung condition. Orkambi (lumacaftor/ivacaftor) and Symdeko (tezacaftor/ivacaftor) are made in whole or in part with an increasingly used production technique known as continuous manufacturing.
Widespread in other industries, continuous manufacturing features what's essentially an end-to-end assembly line, through which raw materials are steadily fed and constructed into final products.
It's seen as faster and more flexible than the tried-and-true system of batching that forms the foundation of pharma manufacturing. The Food and Drug Administration is eagerly encouraging its use and Vertex is among the first adopters.
But, on a whole, the industry remains wedded to batch production. The reasons for why are many, but foremost is a reluctance to overhaul finely tuned manufacturing networks or to introduce new risks into drug development.
"Doing something different like continuous was going outside the box," explained Douglas Hausner, associate director of a manufacturing research center at the Rutgers School of Engineering. "For people in pharma, as a heavily regulated industry, that was a frightening proposition."
Vertex won approval for Orkambi in July 2015. The Boston biotech believes it was the first to secure an OK from the FDA for a fully continuous drug product manufacturing process, which it uses internally to make Orkambi.
Since then, larger pharmas like Johnson & Johnson and Eli Lilly have explored using the technique. J&J, for example, secured another first in 2016 when the FDA cleared the drugmaker to switch from batch to continuous production for its HIV medicine Prezista.
First adopters of continuous manufacturing
|Orkambi||Vertex||Cystic fibrosis||July 2015|
|Prezista||J&J||HIV||April 2016 (when switched from batch to continuous)|
|Verzenio||Eli Lilly||Cystic fibrosis||September 2017|
|Symdeko||Eli Lilly||Cystic fibrosis||February 2018|
From an operational standpoint, the advantages of shifting toward continuous manufacturing are clear.
Using an uninterrupted production process eliminates, or significantly reduces, the "hold times" in between steps that are typical in batch manufacturing. For J&J, production of Prezista used to take about two weeks from start to finish using batch methods. Now, through continuous manufacturing, production takes only three days.
And since the raw ingredients don't need to transition in and out of production for quality testing, continuous manufacturing systems can run over a longer period of time, potentially upping output.
"As we considered the potential benefits of [continuous manufacturing], the potential to increase speed and agility for developing our new products/processes was a key driver for us," said David Pappa, Lilly's head of technical services and manufacturing science, in an email.
Lilly currently makes its cancer drug Verzenio using a continuous process, and has several other experimental compounds that rely on the method.
In theory, continuous manufacturing could also be safer, as it eliminates the transition steps where drug product needs to be handled and safely stored. But it also introduces new questions, such as how a manufacturer defines a product batch for monitoring and safety recall purposes.
It's not just commercial output, either. Continuous manufacturing can help drugmakers during clinical development, when product needs are potentially more variable. Rather than set up production to manufacture a fixed quantity of drug product, continuous lines can adapt to company needs as the compound advances.
"We see continuous manufacturing as an enabler for us to be able to keep up with clinical development," said Hayden Thomas, senior direct of formulation development at Vertex, in an interview. "It allows us to go quickly through clinical development to get medicines quicker to patients."
Only one piece of the puzzle
Biopharma companies aren't making decisions about manufacturing in a vacuum, though. For all of the advantages of continuous manufacturing over batch production, drugmakers must weigh switching over against retooling carefully crafted production networks.
"Introducing continuous manufacturing is really a fundamental change to a manufacturing network," explained Markus Hayek, a managing director at Accenture Strategy's supply chain and operations practice, in an interview.
Large multinational pharmaceuticals companies already have an expansive base of manufacturing facilities, with supply chains stretching across borders.
With production up and running, taking on the cost of adopting continuous manufacturing may not make sense for products already on market. Continuous systems must be bought and installed all at once, whereas upgrading to a batch production unit can be done piecemeal.
Vertex, for example, has continued to produce Kalydeco using batch production methods, even as it forges ahead with continuous manufacturing for Orkambi, Symdeko and a triple combination therapy in development.
"Kalydeco has been very successful for us," said Vertex's Thomas. "It's a great therapeutic and it's running well with our batch process. We currently don't have plans to switch it over because we are looking to invest development time and effort into our new products."
Regulatory risk looms large
More importantly, production lines for marketed products are tied to regulatory approvals encompassing the manufacturing methods currently in use. Investing in new methods, then, brings not only the expense and time of upgrading, but regulatory risk.
"A lot of companies that are looking to get into continuous are global companies," explained Rutgers' Hausner. "Even though the U.S. Food and Drug Administration is a strong advocate of this, there is to a certain extent the uncertainty from other markets in terms of how easy it would be to get approvals."
That uncertainty certainly seems to be top of mind for a number companies. When the FDA solicited input from industry on continuous manufacturing in September 2017, AstraZeneca, Merck, Pfizer and J&J also emphasized regulatory alignment as particularly important.
"The lack of global harmonization of regulatory requirements for [continuous manufacturing] has been identified as the primary barrier to adopting this promising emerging technology," wrote a spokesperson for industry trade group PhRMA in an emailed statement to BioPharma Dive.
While the FDA and the European Medicines Agency are usually on the same page, Hayek of Accenture Strategy noted companies may be particularly concerned about emerging markets like China and Brazil.
This past June, the International Conference on Harmonization, an international regulatory forum, decided to take up continuous manufacturing for further study, suggesting some progress.
Even when regulators agree, though, the mere risk of a product delay may tilt a decision toward sticking with existing methods.
"If it is going to take another six months or a year, that could be enough to change the business case," said Hausner.
The center which Hausner works at, Rutgers' Center for Structured Organic Particulate Systems, works with industry to help test and plan the new processes involved in continuous manufacturing. Its partners include a long list of pharma leaders, including J&J, Pfizer, Merck, GlaxoSmithKline and Bristol-Myers Squibb.
Things have changed
Faster adoption of continuous methods might also be helped by a change in mindset among drugmakers to value innovation in manufacturing more highly.
Since the 2000s, the industry has steadily moved away from the mass-market pills that previously supported many drugmaker bottom lines. Increasingly, biotechs and pharmas are focused on more expensive biologic drugs, which are made from biological material and are costlier to produce. Emergence of cell and gene therapy has further upped the importance of improving manufacturing capabilities.
"Fifteen years ago, the talk in industry was: 'The first pill takes a billion dollars to make. For the second pill, it's 10 cents,'" said Laks Pernenkil, a principal in Deloitte's life sciences operations practice, in an interview.
"Manufacturing was not an area of focus because manufacturing was not necessarily where the value was created. Since then, things have changed," he continued.
More and more, companies are defining value through manufacturing.
In CAR-T cell therapy, which uses genetic engineering to modify patient immune cells, manufacturing is critical and production speeds paramount. Top companies in the space like Gilead are considering ways to automate what's now a heavily manual process.
And when Novartis bought AveXis for $8.7 billion this year, the pharma touted the gene therapy biotech's manufacturing capabilities as a key part of the deal.
With manufacturing enjoying higher billing, process innovations like continuous production might get a longer look.
"I think that we are either at or just past the tipping point," said Hausner, regarding adoption of continuous manufacturing. "There's a lot of the iceberg that we don't see."