Continuous bioprocessing has the potential to provide many benefits with respect to time, cost, quality, and sustainability. Several misconceptions and actual hurdles have led to much slower adoption than expected, with more successes realized for small molecule drugs. Perfusion has been of interest for decades, while insufficient titers initially limited interest in downstream applications. Higher productivity levels combined with wider adoption of automation and single-use technologies have created opportunities in both upstream and downstream continuous processing. Today, the pace of movement toward continuous bioprocessing is accelerating as advances in enabling technologies, from single-use equipment to inline analytics to data management and integration capabilities, combined with increased regulatory guidance, make realizing the benefits of continuous manufacturing feasible.
Potential Advantages of Continuous Bioprocessing
Continuous processing has been leveraged by a variety of industries for many decades, providing a considerable range of benefits, including increased productivity in a smaller footprint, greater process consistency, lower resource consumption and waste generation for reduced environmental impacts, improved quality, reduced costs, and enhanced flexibility to respond to market demands. Combined, these advantaged afford operational efficiencies and reduced risk.1–3
These benefits, among others, can also potentially be realized by switching from batch to continuous processing in biomanufacturing, particularly when implemented using disposable production equipment. Continuous bioprocessing in single-use equipment can greatly reduce capital and operating expenses, simplify manufacturing systems, reduce setup and changeover times, and support multiproduct facilities.4 In addition, because successful continuous bioprocessing requires ongoing, real-time control, processes are inherently more robust.5 Finally, scaling is simpler for continuous processes, as the process can be run for a longer time, or multiple identical systems can be run in parallel, with no need for additional development work.6
Challenges Limiting Wider Implementation
Despite the obvious advantages that continuous processing has provided in other manufacturing sectors, many misunderstandings about continuous bioprocessing for biologics production persist, including that the technology is complex and difficult to implement, is not suited for large-scale production, actually adds costs rather than reducing them, is not accepted by regulatory authorities, and is only applicable for limited types of biologic drug substances.7 The conservative nature of the pharmaceutical industry — combined with these misperceptions —has resulted in a slow adoption rate, even though regulatory agencies have provided encouragement over the last decade or more. Only a few approved biologic drugs are currently manufactured using continuous processes.1
These issues remain today. In a recent industry survey, approximately half of respondents indicated they believe upstream continuous processing is too expensive and complex, while more than 60% think that technology for downstream continuous processing remains immature.1 It has been shown that economic benefits can be dependent on the company, process, and product involved.8
Other factors commonly cited as inhibitors of the adoption of continuous manufacturing for biologics include the lack of sufficient high-performing, cost-effective online process analytical technologies (PATs), the need for greater regulatory clarity, and the requirement for changes in company culture.4 Integrating upstream and downstream processes requires collaboration between groups that typically have not worked together.7 Time and resources are required to develop a trained and skilled workforce.9,10 Bioburden control and mitigation of risks, such as process interruptions, can be challenging as well. Many companies can be hesitant to introduce new manufacturing strategies due to the introduction of unknown risks that could have serious consequences for patients.11 Finally, a major practical impediment is the large, existing batch-based infrastructure within the industry.3
These issues have all been raised for mammalian cell culture systems. There can be additional challenges to implementing continuous microbial fermentation processes.12 The most significant reflects the fact, that in many microbial systems, the product accumulates in the cell rather than being expressed in the supernatant. Induced systems also can suffer from high temporary metabolic loads, further limiting production times.
Perfusion’s Role in Continuous Bioprocessing
Continuous upstream bioprocessing, known as perfusion, involves the continuous addition of media, nutrients, and supplements to the bioreactor, along with continuous removal of the expressed protein from the bioreactor. Perfusion cell culture has been used for biologics production for approximately three decades, and particularly for production of monoclonal antibodies (mAbs).3,8 The very low titers achieved during the late 1980s and early 1990s could be boosted using perfusion.12
As production titers increased, however, the need for perfusion decreased.13 In addition, perfusion processing often suffered from technical issues, most notably fouling of the spin-filter cell retention devices available at the time.8 Nonetheless, perfusion was still used for manufacture of sensitive mAbs that degraded when exposed to cell culture conditions.
In the meantime, advances in cell culture technology (e.g., cell lines, media formulations) continued to lead to increases in product titers, with concentrations as high as 10 g/L now achievable. These high titers mean that bioprocesses can be implemented in much smaller equipment, allowing the adoption of single-use technology for commercial manufacturing. Interest in perfusion has thus increased as a way to achieve even higher titers and minimize facility footprints while also reducing risk and capital investment.
Today, perfusion is widely used across the biopharmaceutical industry. While most applications are not for the final protein or mAb cell-culture process, its benefits are leveraged in seed-banking, seed expansion, and for the N-1 step in bioprocessing trains.13 This increase in use has been enabled by the introduction of alternating tangential flow (ATF) filtration13 and more recently tangential flow depth filtration (TFDF),14 technology for cell retention and removal of the protein product from the bioreactor.
Perfusion processes have successfully been implemented using a wide variety of cell types, including Chinese hamster ovary (CHO), human embryonic kidney (HEK), insect cells, and pluripotent stem cells (PSCs).14 With these technologies it is now possible to maintain cell densities as high as 150 million cells per milliliter over long run times, leading to increased productivity and scalability compared with traditional batch processing.
Big Impact of Advances in Single-Use, Automation, and Process Analytical Technologies
The introduction of high-performing cell-retention devices for perfusion processes was accompanied by advances in other technologies that have proven to be enablers of both upstream and downstream bioprocessing. A key driver of these advances is the desire to realize “Biopharma 4.0,” or the digital transformation of bioprocessing leveraging advanced automation, modeling, data analytics, and manufacturing equipment solutions.15,16 In 2023, for instance, and industry survey found that the top areas for investment by survey participants were single-use technologies and automation.1
The bioprocessing industry has slowly been moving toward Biopharma 4.0, increasing the use of disposable technologies for both clinical and commercial manufacturing across entire bioprocesses (e.g., upstream, downstream, fill/finish), introducing integrated digital operational and data management systems, deploying automation technologies in both the laboratory and GMP manufacturing settings, and leveraging both artificial intelligence and machine learning in state-of-the-art predictive modeling systems and Big Data analytics.4
These changes are simultaneously supporting process intensification initiatives by biologics producers to increase productivity, efficiency, and sustainability while reducing costs.3 Concentrated fed-batch reactions, for instance, can reach extremely high cell concentrations. With concentrated perfusion, meanwhile, it is possible to achieve 3 g/L/day, with titers as high as 5 g/L/day anticipated in the future.13 These higher titers can readily support continuous downstream bioprocessing.3
Single-use technologies are important in continuous bioprocessing because they afford a high level of flexibility and modularity, which makes the setup of continuous processes fairly straightforward.17,18 To date, they have largely been deployed for continuous processing of single unit operations combined in a hybrid manner with batch-based unit operation. In future, though, with greater standardization of disposable technologies and advances in integrated control and data management systems, the integration of multiple continuous unit operations will be achieved.
The ultimate goal is end-to-end continuous processing in fully, digitally connected plants that leverage single-use technologies and at-line analytics to enable fully closed process monitored in real time and controlled using predictive algorithms, all of which support adaptive facilities.4 Upstream perfusion processes will be linked to continuous purification processes (e.g., various forms of continuous chromatography, continuous viral inactivation, single-pass tangential-flow filtration (SPTFF)) that are currently under investigation by many biopharma manufacturers.
Innovation Fueled by Industry Demand
Over the last 10 years, progress toward that goal has been made possible by numerous advances in technology. While perfusion processes have been used for the last three decades, continuous downstream processing was not feasible until sufficiently high protein titers were generated by upstream cell culture processes. Notable discussion about multicolumn chromatography first appeared in the early 2000s, with practical lab-scale solutions entering the market by the end of the decade and GMP-scale equipment introduced more recently.2 Success with continuous chromatography provided the impetus for the development of solutions for other downstream unit operations, including ultrafiltration/diafiltration, virus inactivation, and buffer generation.6
The introduction of quality by design (QbD) in the 2000s, meanwhile, led to increasing emphasis on building quality into processes and the development of platform processes that were highly suitable for conversion to continuous operation.8 Using a QbD approach generates the deep process knowledge necessary for establishing continuous processes, while platform technologies are essential to ensuring development of highly robust processes that can operate continuously for long periods.19
Process intensification efforts have already led to significant reductions in the number of steps required to produce mAbs, owing to improved cell lines and media formulations, shorter seed trains, perfusion cell culture, and implementation of select continuous downstream unit operations (e.g., flow-through and membrane chromatography, inline virus inactivation, and inline buffer production).4
A few contract manufacturers have leveraged the introduction of single-use devices and systems designed for continuous manufacturing to establish end-to-end manufacturing platforms. One example is the EnzeneX™ commercially validated continuous manufacturing platform from Enzene.7 Intensified processing has also been expanded beyond recombinant proteins and mAbs to next-generation modalities, including cell and gene therapies14 and messenger RNA.20,21
Regulatory Guidance and Roadmaps for Adoption Now in Place
In addition to advances in enabling technologies, regulatory guidances specifically regarding continuous processing and the development of standards and implementation roadmaps issued by industry groups have begun to result in increased movement toward practical pursuit of continuous manufacturing solutions for biopharmaceuticals.
The U.S. Food and Drug Administration (FDA) has been a vocal supporter for more than a decade of continuous processing for more both small and large molecule drugs.3 Legislation in the United States has also focused on emerging technologies. Examples include the Prescription Drug User Fee Act (PDUFA VII) passed in 2022 and the Consolidated Appropriations Act 2023 under the Food and Drug Omnibus Reform Act of 2022 (FDORA).22 President Biden’s 2022 Executive Order launching the National Biotechnology and Biomanufacturing Initiative, meanwhile, focused on encouraging the development and implementation of advanced manufacturing solutions.
The ICH guideline Q13 on continuous manufacturing of drug substances and drug products – Step 5,23 issued in 2023 and accepted by FDA and the European Medicines Agency (EMA) the same year, provides guidelines specifically related to continuous manufacturing across development and commercial production. It provides information on concepts that must be addressed for continuous processing but leaves the specific approaches up to manufacturers.
While the focus is largely on small molecule drugs, additional information is anticipated through the publication of annexes. Other topics that still need to be addressed include the use of PAT, modeling tools, continuous process verification, and demonstration of equivalency following process transfers. Despite these limitations, the regulation represents the first step in global harmonization of guidance on continuous processing for biopharmaceutical applications.24
It has also been noted that the recently updated version of ICH Q9(R1) guideline on Quality Risk Management25 issued in January 2025 addressing the management of supply chains and equipment to support robust manufacturing processes can be seen as an additional driver for the adoption of continuous bioprocessing.10
Industry activity focused on continuous bioprocessing has been led by BioPhorum, which issued a document outlining technological and regulatory gaps hindering adoption of continuous downstream processing of therapeutic proteins and a proposed roadmap for overcoming them,26 a blueprint and risk assessment template for establishing control of continuous biomanufacturing processes,27 and a guide to designing and implementing continuous processes.28
Despite a Slow Start, Big Expectations for the Future
The recent regulatory guidance and advances in enabling technologies are leading to movement in the biopharmaceutical industry toward continuous manufacturing. A recent survey by BioPlan Associates found that nearly 70% of respondents expect to adopt continuous chromatography over the next two years, with nearly three quarters expecting adoption of perfusion in most facilities.1
A separate survey by EMD Millipore about trends in process intensification, meanwhile, found that intensified fed-batch (a form of perfusion) and continuous capture chromatography were likely to be adopted by 60% of respondents in the next 5–10 years, followed by cell-line and media optimization (53%), new approaches to buffer management (50%), new capture chromatography technologies (43%), and perfusion (40%).4 In 10 years, respondents anticipate just over one-quarter of commercially manufactured drug substances to be produced using some form of intensified upstream processing and slightly more than one-third to be made using intensified downstream processing solutions.
This movement is supported by approximately 80 companies were developing and supplying continuous manufacturing equipment.10 Large and medium-sized biotech and pharma companies account for the largest percentage of manufacturers implementing continuous processes, with biosimilar producers least likely to leverage this technology.4 Most continuous processes are implemented for new novel molecules or as second-generation processes for existing products, but they can be found equally in new and existing facilities. Finally, most current intensified and continuous processes leverage a combination of single-use and stainless-steel equipment at the commercial scale and largely rely on disposable technologies at the clinical scale.
Various market research firms estimate the global continuous bioprocessing market is expanding at a compound annual growth rate as low as 6.4% and as high as 22%.29–31 Continued advances in technology, particularly expanding available at-line PAT tools, data and knowledge management systems, and solutions for integration of multiple individual unit operations, particularly across upstream and downstream processing, will all further facilitate acceptance and utilization of intensified processing, including continuous processing, for the manufacture of biopharmaceuticals.32
Wider Adoption in Small Molecule API and Drug Product Manufacturing
Adoption of flow chemistry for small molecule active pharmaceutical ingredient (API) manufacturing and continuous processes for the production of solid dosage drugs has occurred at a much faster rate than the implementation of continuous bioprocessing. The first FDA approval for a continuous manufacturing process went to Vertex Pharmaceuticals in 2015 for Okambi. Additional approvals were granted by the agency in 2018 for Symdeco/Symkevi and in 2019 for Trikafta, both also from Vertex.10 By 2022, a total of 15 drugs manufacturing using some form of continuous processing had been approved by the FDA (an average of two per year from 2015 to 2022), with Vertex, Pfizer, and GlaxoSmithKline the predominant suppliers. Several were products that initially received their approvals for batch-based processes.
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