As a concept, continuous manufacturing — which relies on a fully integrated process that runs uninterrupted from beginning to end — has been around for many years, providing an alternative to traditional batch manufacturing in which drug production is segmented into a series of slow-moving steps.
Despite the potential efficiencies and the FDA encouraging manufacturers to make the switch from batch processing, the pharmaceutical industry has been slow to adopt continuous manufacturing due in large part to general conservatism and the cost implications of such investments.
However, a shift to continuous manufacturing technologies appears to be gaining momentum.
According to the results of CRB’s Horizons: Life Sciences survey released in October 2024, 75% of respondents are using or plan to use continuous technologies almost exclusively within the next five years, based on a survey of 500 industry leaders including therapeutic developers and CDMO executives.
Batch processing involves sequentially loading a fixed amount of material into the first part of the manufacturing process, processing it, and then discharging the material in preparation for the next phases of manufacturing. However, continuous manufacturing involves material constantly being loaded, processed and unloaded without interruption through the various phases of the process.
“By operating continuously, the manufacturing process becomes intensified, and the specific productivity of the facility is improved, with increased efficiency in use of space, time, labor and raw materials,” CRB contends. “Most importantly, continuous operations can improve both product yield and quality.”
When it comes to sustainability, CRB notes that continuous facilities offer significant energy savings per unit of production.
“Most cGMP manufacturing cleanrooms and some labs require HVAC systems to run 24/7, regardless of whether other systems are operating or not,” CRB states. “Since a continuous facility runs a more intensified process with higher system utilization, continuous facilities reduce energy costs per production unit. According to an energy model, a continuous manufacturing facility can operate 33% more efficiently than a comparable batch process.”
Thermo Fisher Scientific’s facility in Greenville, North Carolina is the company’s first site to feature a fully functional continuous manufacturing line.
“We did announce the sunset of our [traditional batch] oral solid dose business,” said Michelle Logan, vice president and general manager of the Drug Product Division North America at Thermo Fisher, who is also Greenville’s interim general manager. “We will keep continuous manufacturing, which is a new technology, for oral solid dose here. As that continues to grow, we will expand in that space.”
Logan said Thermo Fisher is seeing “a lot of interest” in continuous manufacturing from customers. She called out the “robustness” of the process.
“With continuous manufacturing, we actually load the raw materials on to the start of the line and it’s real-time feeding, granulating in a vacuum system to the line — straight into either capsules or tableting,” Logan said. “We’re in the process of adding coating as an option with real-time [process analytical technology]. So, we’re doing all our measurements in-line instead of having to send them to the lab for testing.”
“You have the real-time quality indicators, you’re not relying on a batch review 30 days afterward,” she added. “You have all the data there in real time that you can assess quality. The equipment actually makes adjustments for you in real time so if you start to trend out on a critical process parameter, it adjusts and fixes it.”
While Thermo Fisher has been using continuous manufacturing at Greenville on the clinical side, the first commercial product is slated for this year, according to Logan. Although the site is sunsetting its oral solid dose business, the company is serving OSD customers at additional sites throughout its global network.
Atul Dubey, senior principal scientist at US Pharmacopeia, contends that continuous manufacturing is not a one-size-fits-all approach. While it can be valuable for certain drug substance and drug product manufacturing processes, it’s not suitable for every situation, he asserts.
Dubey estimates that there are only a little more than 15 drug products in the market today that are being manufactured using continuous manufacturing.
“Those are through the FDA,” he said. “The ones that don’t go through the FDA are made for local markets in India and China. There are companies who are doing it, but we don’t know about them because they don’t come here.”
Piecemeal adoption, solid dose
While continuous technologies have been adopted for individual processes, CRB noted in its report that the implementation of end-to-end continuous manufacturing in the pharma industry remains elusive.
Dubey asserts that end-to-end continuous manufacturing is “very rare” and frankly not needed, pointing to the International Council for Harmonization (ICH) Q13 guidance, Continuous Manufacturing of Drug Substances and Drug Products.
The ICH Q13 guideline “says if you want your process to be designated as a continuous manufacturing process, all you need to have is a minimum of two unit operations that are connected together and are running in continuous mode,” according to Dubey.
Continuus Pharmaceuticals, a spin-out company from a multiyear collaboration between MIT and Novartis, specializes in end-to-end integrated continuous manufacturing. The company’s mission is to transform the pharmaceutical manufacturing industry, which it says loses over $50 billion annually due to wasteful processes, by moving it away from “outdated” batch systems to state-of-the-art continuous processes.
Bhakti Halkude, associate director and head of drug product at Continuus who focuses on oral solid dosage, contends that what is needed in the industry is a major shift — both ideologically and technologically — driven by the need for greater efficiency, cost reduction, and improved product quality.
“I think the biggest change needs to be unlearning — that is one big hurdle that we all have been struggling with,” Halkude said. “Letting go of the older practices is critical because the industry has been set on certain practices and we all have been just following them.”
At the same time, industry has adapted with “bits and pieces of continuous manufacturing, mostly a lot of development has happened on the drug product manufacturing side,” Halkude said. “However, the drug substance or the API, the chemistry part has been a little slow with actual adoption, actual acceptance and bringing anything in the market.”
Continuus is working with multiple clients to convert their existing process into continuous manufacturing lines. While developing a drug substance continuous manufacturing process is more complicated than a drug product one, Halkude claims that when it comes to the company’s end-to-end offering, theirs is the only technology which integrates drug substance and drug product.
“It is a higher quality, higher kind of technology so that entails higher capital investment, which is definitely not an easy step for any company,” Halkude said. “Companies that are adopting [continuous manufacturing] much faster are actually saving and seeing the benefits, helping them get over that capital investment issue.”
However, Dubey contends that when it comes to generic drugs — which make up 90% of the prescription volume in the U.S. — there is a resistance to adopting continuous manufacturing.
“If you have a working [batch] process and the equipment and everything is lined up, it does not make sense to switch financially especially when you have razor-thin margins for your products,” Dubey said.
Additionally, Dubey makes the case that other challenges for implementing continuous manufacturing include workforce training for a unique skillset of highly specialized workers.
Nonetheless, Halkude argues that among the advantages of Continuus’ technology is it is compact in size without the need for massive solvent and waste tanks, while operating with reduced power consumption. “Smaller equipment equals easier maintenance — our technology for drug product manufacturing is the size of a dining room table, literally five feet by nine feet.”
Halkude contends that another major advantage of continuous manufacturing is the lead time required for production.
“Our tablets, for example, the one that we made come out in a matter of minutes,” she said. “From the time I get an order, I can get the tablet out in 20 minutes versus it takes months with batch manufacturing or at least weeks in certain cases.”
Time is money and continuous manufacturing reduces costs by condensing processes that used to take months into days — and even minutes. The use of automation and robotics can also cut labor costs, while improving quality controls and minimizing waste.
Another significant difference between batch and continuous manufacturing is how materials are fed into their respective processes.
Feeder designs are “an advantage for continuous manufacturing because you’re feeding lesser quantity at a time,” according to Halkude. “It’s easier on the operator to feed smaller quantities and you can have more control over what you’re feeding, and you have more control over what raw material went into what final product.”
While Halkude is a self-described oral solid dosage expert, she contends that “there is a lot that can be adopted from the small molecule side, which is already quite well developed in terms of continuous manufacturing — a lot of these technologies can be extracted and applied to bioprocessing.”
However, a significant amount of technological development is required for biologics processing, according to Halkude.
When it comes to oral solid doses, Dubey points out that a chemical process converts raw materials into active pharmaceutical ingredients, and then those APIs are converted into solid dosage form. With biologics, he notes that you typically have cells or organisms that produce materials which are ultimately converted into drugs — a much more complex and challenging process.
Biologics on the rise
Although global sales of all drugs continue to heavily favor small molecules — by as much as a factor of 9:1 — the demand for biologics keeps rising, according to CRB’s Horizons: Life Sciences survey.
CRB found that manufacturers are eager to embrace new innovations in the production of biologics, including the move away from batch processing in favor of continuous technologies.
“There’s a growing consensus that continuous processing during production enhances productivity through process intensification,” according to CRB. “This advantage extends to downstream processes, such as continuous chromatography, as evidenced by current purification trends.
While perfusion-based biologics manufacturing has been around for many years, the biopharma industry has traditionally favored fed-batch processes. However, continuous bioprocessing is getting a second look, according to CRB.
At the same time, CRB found that while continuous technologies are developed in individual processes such as chromatography and perfusion, they remain elusive for end-to-end continuous processing of the entire biomanufacturing process.
Enzene Biosciences, a CDMO with patented technology for continuous manufacturing, says it has manufactured commercial monoclonal antibodies and converted biologics from fed-batch production to fully-connected continuous manufacturing.
The technology, called EnzeneX, has enabled Enzene to integrate the full production process from bioreactor to downstream purification in a seamless flow. EnzeneX leverages a combination of intensified perfusion and multi-column chromatography.
“We have a technology that has not only been developed but deployed and validated,” according to Russell Miller, vice president of global sales and marketing at Enzene. “It has been demonstrated to support programs all the way through the path from development to commercial.”
Miller contends that Enzene’s platform has been demonstrated on more than 40 development programs, and the company uses the technology to manufacture three products on a commercial basis.
Among the benefits of its fully-connected continuous manufacturing platform are a reduction in the cost of goods, an increase in productivity, and the ability to handle complex biotherapeutics using a flexible design, according to Miller. Productivity is a critical metric when it comes to biologics manufacturing, he said, as mammalian-based processes can take 18, 20 and 25 days to execute.
Given its advantages, Miller predicts that ultimately continuous manufacturing will “eclipse and remove fed-batch on a commercial process basis as the platform of choice — is that going to happen in two years? Absolutely not.”
However, over the next 30 years, Miller foresees a time when 90% of products utilized some continuous-based process and only 10% of products were tied to a fed-batch process.
RNA continuous manufacturing
ReciBioPharm, the biologics division of CDMO Recipharm, is looking to have a shorter-term impact on the industry when it comes to RNA continuous manufacturing.
Vikas Gupta, president of ReciBioPharm, sees continuous manufacturing as the “Holy Grail” and a challenge to the industry that “remains somewhat utopian.” However, the company is focused on a lofty but what it sees as achievable humanitarian goal of making potentially lifesaving technologies more accessible to underserved regions of the world.
In January 2025, ReciBioPharm was awarded a three-year grant from the Bill & Melinda Gates Foundation to support the global deployment of RNA continuous manufacturing technologies to low- and middle-income countries (LMICs).
The grant will enable worldwide implementation of an RNA continuous manufacturing platform and Process Analytical Technologies (PAT) — developed through an $82 million MIT project funded by the FDA — as well as predictive analytics software.
A portion of the MIT project was subcontracted to ReciBioPharm to implement an end-to-end process developed by researchers in a pilot-scale manufacturing facility.
“We reduced the time it takes for the entire mRNA process, which typically takes about 21 to 25 days. We were able to take it down to five days,” Gupta said, while noting that the company’s goal is to reduce the process to just one day.
As part of the project, ReciBioPharm has created a modular PAT skid with six different analytical tools/assays integrated into one unifying software platform to make it easier for users to operate.
“The Gates Foundation wants to see this work happen with the PAT skids,” Gupta said. “This is a plug-and-play solution and we can train people in our facility if it was to be deployed in Indonesia, India, or Africa. We can even run this remotely because of all the software development and features we have built into it.”
ReciBioPharm believes that its miniaturized platform will improve the scalability, quality, and accessibility of RNA-based medicines in LMICs, while helping to advance the company’s goal of developing fully integrated, continuous processes across the biomanufacturing industry.
At the BIO International Convention, held this week in Boston, ReciBioPharm on Tuesday unveiled its PAT platform — dubbed “QC on Wheels” — for real-time process analytics and intelligent manufacturing.
“We designed the PAT platform to fundamentally shift how manufacturers approach analytical testing,” Gupta said in a statement. “It’s about putting insights directly into the hands of those running the process, optimizing quality in real time, and enabling scalable, sustainable biomanufacturing.”
