Continuous Biomanufacturing in Design and Operations

Introduction

Continuous biomanufacturing (CBM) is an advanced manufacturing paradigm in which biological products are produced through uninterrupted, integrated processing rather than discrete batch operations (8,9). The concept has emerged as one of the most transformative developments in the biopharmaceutical industry, particularly for monoclonal antibodies (mAbs), recombinant proteins, vaccines, viral vectors, and cell-based therapeutics. Unlike conventional batch manufacturing, where materials are processed stepwise with intermediate holding tanks and pauses between unit operations, continuous biomanufacturing integrates upstream and downstream operations into a coordinated, dynamic system operating over extended periods.

The growing interest in CBM is driven by several industrial pressures:

• Rising global demand for biologics
• Increasing cost of goods (COGs)
• Need for flexible and decentralized manufacturing
• Desire for higher product consistency
• Regulatory encouragement for advanced manufacturing technologies (1)
• Expansion of biosimilars and personalized medicines

Continuous processing has already transformed sectors such as petrochemicals and small-molecule pharmaceuticals. Biopharmaceutical manufacturing is now undergoing a similar transition.

Figure 1. A conceptual End-to-End integrated continuous biomanufacturing process.

Fundamentals of Continuous Biomanufacturing

Continuous biomanufacturing refers to the integrated production of biologics in which raw materials are continuously introduced, and products are continuously removed over time, often with real-time monitoring and control. The process may involve:

• Continuous upstream processing (e.g., perfusion culture) (6,7)
• Continuous downstream purification
• Integrated process analytical technology (PAT)
• Automated process control systems

The most mature implementations involve monoclonal antibody manufacturing platforms combining perfusion bioreactors with multicolumn chromatography systems.

Historical Development

Historically, the biopharmaceutical industry has relied on batch processing due to its simpler validation requirements, easier contamination control, established regulatory acceptance, and flexibility during process development. Despite these advantages, batch manufacturing presents several challenges, including large facility footprints, high capital costs, lengthy turnaround times, batch-to-batch variability, and inefficient equipment utilization. Although perfusion-based continuous processing technologies were introduced decades ago, their adoption accelerated with advancements in cell retention systems, single-use bioreactors, multicolumn chromatography, sensor technologies, and automation. Industry interest in continuous biomanufacturing (CBM) gained significant momentum following the 2014 Continuous Manufacturing Symposium and subsequent white papers, which highlighted its potential to improve productivity, product quality, and manufacturing efficiency (10).

The biopharmaceutical industry traditionally relied on batch processing because of:

• Simpler validation
• Easier contamination management
• Established regulatory pathways
• Flexibility in process development

However, batch systems exhibit limitations:

• Large facility footprints
• High capital expenditures
• Long turnaround times
• Significant variability between batches
• Underutilization of equipment

Early perfusion technologies appeared decades ago but gained renewed interest due to advances in (11):

• Cell retention technologies
• Single-use bioreactors
• Multicolumn chromatography
• Sensor technologies
• Automation and digital control

Core Components of Continuous Biomanufacturing

The core components of CBM include integrated upstream and downstream processes designed to enable uninterrupted production of biopharmaceuticals. Continuous upstream processing commonly uses perfusion cell culture, where fresh medium is continuously supplied, waste is removed, and cells are retained within the bioreactor to achieve high cell densities, stable conditions, and consistent product quality. Cell retention technologies such as Alternating Tangential Flow (ATF), Tangential Flow Filtration (TFF), acoustic settlers, and centrifuges support efficient continuous operation. Continuous downstream processing incorporates multicolumn chromatography systems, continuous viral inactivation, and continuous ultrafiltration/diafiltration (UF/DF) to improve productivity, reduce resource consumption, and maintain product purity. Together, these integrated technologies enhance manufacturing efficiency, scalability, and process control compared to traditional batch production methods.

Continuous Upstream Processing
Continuous biomanufacturing relies heavily on continuous upstream processing, particularly perfusion cell culture, which is the dominant technology in this area. In perfusion systems, fresh medium is continuously added while spent medium is removed, cells are retained within the bioreactor, and product-containing harvest is continuously collected. This approach supports extremely high cell densities—often exceeding 100–200 million cells/mL—while maintaining stable metabolic conditions, longer production durations, and improved product consistency compared to traditional fed-batch cultures. Efficient cell retention is achieved through technologies such as ATF which uses cyclic pumping across hollow-fiber membranes for gentle handling and high viability; TFF which minimizes membrane fouling through continuous tangential flow; and acoustic settlers or centrifuges, which separate cells from product-containing supernatant using physical forces (1,3).

Perfusion Cell Culture
Perfusion cell culture is the dominant upstream technology in continuous biomanufacturing, enabling sustained production through the continuous addition of fresh medium and removal of spent medium while retaining cells within the bioreactor. Product-containing harvest is continuously collected, allowing uninterrupted operation over extended periods. This approach maintains a stable metabolic environment, supports very high cell densities—often exceeding 100–200 million cells/mL, far greater than typical fed-batch cultures—and enhances overall productivity. As a result, perfusion culture offers longer production durations, improved process control, and greater product consistency, making it a key platform for modern continuous manufacturing processes.

In perfusion systems:

• Fresh medium is continuously added
• Spent medium is continuously removed
• Cells are retained within the bioreactor
• Product-containing harvest is continuously collected

This enables:

• Very high cell densities
• Stable metabolic environments
• Extended production durations
• Improved product consistency

Cell Retention Devices
Cell retention devices are essential components of perfusion cell culture systems, enabling continuous harvest while maintaining high cell concentrations within the bioreactor. These technologies separate cells from the product-containing culture fluid and return the cells to the reactor, supporting prolonged cultivation and enhanced productivity. Common cell retention methods include ATF, TFF, acoustic settlers, and centrifuges, each using different separation mechanisms to achieve efficient cell retention and continuous operation.

Alternating Tangential Flow
ATF is a cell-retention technology that cyclically pumps culture fluid back and forth across hollow-fiber membranes, enabling efficient separation while minimizing shear stress on cells. This gentle filtration process maintains high cell viability and density by retaining cells within the bioreactor while continuously removing product-containing supernatant. Due to its efficient cell retention, low fouling tendency, and robust performance, ATF is one of the most widely used systems in continuous bioprocessing applications.
ATF systems cyclically pump culture fluid across hollow-fiber membranes. They are widely used because they provide:

• Gentle cell handling
• High viability
• Efficient retention

Tangential Flow Filtration
TFF systems continuously circulate culture fluid tangentially across membranes to minimize fouling. TFF is a cell-retention technology that continuously circulates culture fluid tangentially across a membrane surface, reducing membrane fouling and maintaining efficient filtration performance. As the culture flows parallel to the membrane, cells are retained and returned to the bioreactor while product-containing supernatant passes through the membrane for collection. This approach supports high cell-density cultures, enables continuous product harvest, and enhances overall bioprocess productivity and scalability.

Acoustic Settlers and Centrifuges
These systems use physical separation mechanisms to retain cells while removing product-containing supernatant. Acoustic settlers and centrifuges are cell-retention technologies that use physical separation mechanisms to keep cells in the bioreactor while continuously removing product-containing supernatant. Acoustic settlers apply ultrasonic waves to aggregate and concentrate cells, allowing clarified liquid to be withdrawn with minimal cell loss. Centrifuges use centrifugal force to separate cells from the culture fluid based on density differences, enabling efficient harvesting of cell-free supernatant. Both systems support continuous bioprocessing by maintaining high cell densities, improving productivity, and facilitating ongoing product recovery.

Continuous Downstream Processing
Continuous downstream processing is a critical component of continuous biomanufacturing (CBM), enabling seamless integration with upstream operations and improving overall process efficiency. A key technology is continuous capture chromatography, particularly multicolumn systems such as simulated moving bed (SMB) and periodic counter-current chromatography (PCC), where multiple smaller columns operate asynchronously instead of sequentially as in traditional batch chromatography. These systems improve resin utilization, reduce buffer consumption, minimize column size, and increase productivity. Continuous viral inactivation is achieved using plug-flow, tubular, or coiled flow reactors that maintain the required residence times for effective viral clearance. In addition, ultrafiltration/diafiltration (UF/DF) processes are increasingly being adapted to semi-continuous or continuous formats, although challenges such as membrane fouling, concentration polarization, and complex process control remain important considerations (1).
Continuous downstream processing is essential for realizing the full benefits of CBM.

Continuous Capture Chromatography
Continuous capture chromatography is a downstream purification approach that enables uninterrupted product capture by continuously processing feed streams through multiple chromatography columns. Unlike traditional batch chromatography, continuous systems maintain ongoing operation, improving resin utilization, reducing equipment size and buffer requirements, and increasing overall process productivity. This technology enhances efficiency and supports the integration of fully continuous biomanufacturing processes.

Multicolumn Chromatography
Continuous capture chromatography uses multicolumn systems to overcome the limitations of traditional batch chromatography, where a single column operates sequentially. In continuous processes, multiple smaller columns operate asynchronously, allowing uninterrupted product capture and improved process efficiency. Common configurations include Simulated Moving Bed (SMB) and Periodic Counter-Current Chromatography (PCC), which maximize resin utilization by keeping columns in near-continuous operation. These systems offer several advantages, including higher resin efficiency, smaller column volumes, reduced buffer consumption, and increased overall productivity, making them well suited for continuous biomanufacturing applications.
Traditional chromatography columns operate sequentially in batch mode. Continuous systems use multiple smaller columns operating asynchronously.

Common configurations include:
Simulated moving bed (SMB)
Periodic counter-current chromatography (PCC)

Advantages include:

• Higher resin utilization
• Smaller column volumes
• Reduced buffer consumption
• Increased productivity

Continuous Viral Inactivation
Continuous viral inactivation systems maintain required residence times through:

• Plug-flow reactors
• Tubular reactors
• Coiled flow systems

Continuous Filtration and Ultrafiltration/Diafiltration
Continuous filtration and UF/DF are increasingly being adapted from traditional batch operations to semi-continuous and continuous processing formats to support integrated biomanufacturing. These systems enable continuous product concentration, buffer exchange, and formulation while improving process efficiency and reducing hold times. However, successful implementation requires addressing challenges such as membrane fouling, concentration polarization that can reduce filtration performance, and the increased complexity of process monitoring and control needed to maintain stable continuous operation.

UF/DF operations have also evolved toward semi-continuous or continuous configurations.
Challenges include:

• Membrane fouling
• Concentration polarization
• Process control complexity

Integrated Continuous Bioprocessing

Integrated Continuous Bioprocessing (ICB) is a manufacturing approach that seamlessly connects upstream and downstream operations into a synchronized, continuous production system. A typical ICB workflow includes a perfusion bioreactor with a cell retention device, followed by clarification, Protein A capture chromatography, viral inactivation, polishing chromatography, UF/DF, and final formulation. By integrating these unit operations, ICB minimizes hold times, reduces manufacturing footprint, improves process efficiency, and enables consistent product quality throughout production.

Integrated continuous bioprocessing links upstream and downstream operations into a synchronized system.
A typical integrated process includes:

1. Perfusion bioreactor
2. Cell retention device
3. Clarification
4. Protein A capture chromatography
5. Viral inactivation
6. Polishing chromatography
7. UF/DF
8. Final formulation

Several companies and consortia have demonstrated end-to-end integrated systems.

Advantages of Continuous Biomanufacturing

Increased Productivity
Continuous systems maintain cells in optimal physiological states for extended periods.
This results in:

• Higher volumetric productivity
• Greater equipment utilization
• Reduced downtime

Perfusion cultures can generate significantly more product per reactor volume compared with fed-batch systems.

Improved Product Quality
Continuous processing creates more stable microenvironments, leading to:

• Reduced product heterogeneity
• Consistent glycosylation profiles
• Lower aggregate formation
• Reduced impurity accumulation

The narrower residence-time distribution in perfusion systems contributes to enhanced product consistency.

Reduced Facility Footprint
Continuous systems require:

• Smaller bioreactors
• Smaller chromatography columns
• Fewer hold tanks

This enables compact facilities with lower capital investment.

Lower Manufacturing Costs
Cost reductions arise from:

• Improved resin utilization
• Reduced labor
• Reduced media and buffer usage
• Smaller facilities
• Higher throughput
• Less utilities requirements

Economic modeling studies suggest substantial reductions in cost of goods compared with conventional batch processing (1, Chapter 7, and Appendix 1).

Operational Flexibility
Continuous manufacturing supports:

• Modular production
• Rapid scale-out
• Distributed manufacturing (2) (12)
• On-demand production
• Support localized manufacturing

These capabilities are especially relevant for:
Pandemic preparedness

• Personalized medicine
• Biosimilars
• Emerging markets

Process Analytical Technology

Importance of PAT
Continuous systems require real-time monitoring and control (1,4,5).
Key monitored parameters include:

• pH
• Dissolved oxygen
• Glucose
• Lactate
• Cell density
• Product concentration
• Aggregation
• Conductivity

PAT tools enable:

• Real-time release testing
• Dynamic process control
• Fault detection
• Process optimization

Advanced Analytics
Emerging analytical technologies include:

• Raman spectroscopy
• Near-infrared spectroscopy (NIR)
• Mass spectrometry
• Soft sensors
• Machine learning models

These technologies facilitate predictive control and digital biomanufacturing (5).

Automation and Digitalization

Continuous manufacturing depends heavily on automation.
Automation and digitalization are fundamental to continuous manufacturing, enabling real-time monitoring, control, and optimization of interconnected process operations. Advanced automation systems integrate sensors, process analytical technologies (PAT), data analytics, and control algorithms to maintain stable operating conditions and consistent product quality. By reducing manual intervention and supporting rapid decision-making, digitalized continuous manufacturing improves process efficiency, reliability, and regulatory compliance while facilitating the implementation of fully integrated bioprocessing systems.

Control Strategies
Sophisticated control systems manage:

• Flow synchronization
• Residence time
• Product quality attributes
• Equipment transitions

Digital Twins
Digital twins are virtual replicas of manufacturing systems that use real-time data and predictive models to mirror physical process behavior. In continuous manufacturing, they enable advanced capabilities such as predictive maintenance, process optimization, and failure prediction by simulating different operating conditions and identifying potential issues before they occur. By integrating data from sensors and process controls, digital twins enhance decision-making, improve process reliability, and support more efficient and robust biomanufacturing operations.
Digital twins simulate manufacturing systems in real time to support:

• Predictive maintenance
• Process optimization
• Failure prediction

Artificial Intelligence and Machine Learning
Artificial intelligence (AI) and machine learning (ML) are increasingly used in bioprocessing to enhance monitoring, control, and optimization of manufacturing systems. Key applications include fault detection to identify process anomalies, predictive modeling to forecast system behavior, adaptive control to maintain optimal operating conditions, and process optimization to improve efficiency and product quality. By leveraging large datasets from sensors and process analytics, AI/ML enables more robust, data-driven decision-making in continuous manufacturing environments.

AI applications include:

• Fault detection
• Predictive modeling
• Adaptive control
• Process optimization

Regulatory Considerations

Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) support the adoption of advanced manufacturing technologies, including continuous manufacturing, due to their potential to improve product quality and efficiency. However, several regulatory challenges remain, particularly in defining batch boundaries within continuous processes, establishing appropriate validation strategies, ensuring full traceability of materials and product streams, implementing real-time release testing, and managing deviations that may occur during extended production runs (13).

Key concerns include:

• Defining batch boundaries
• Validation strategies
• Traceability
• Real-time release
• Deviations during extended runs

Control Strategy Requirements

Continuous systems require integrated control strategies addressing:

• Material traceability
• Residence time distribution
• Process disturbances
• Product diversion during excursions

The N-mAb case study has become an important educational framework for regulatory and industrial implementation (12).

Technical Challenges

Process Integration
Synchronizing upstream and downstream operations remains difficult (9,14).
Issues include:

• Flow mismatches
• Variable harvest composition
• Equipment compatibility

Fouling and Membrane Stability
Long-duration operations increase risks of:

• Membrane fouling
• Filter degradation
• Biofilm formation

Contamination Risk
Continuous operations run for extended periods, increasing contamination exposure time.
Mitigation strategies include:

• Closed systems
• Single-use technologies
• Advanced monitoring

Data Management
Continuous systems generate enormous datasets requiring:

• Advanced storage
• Real-time analytics
• Cybersecure infrastructure

Workforce and Organizational Barriers
Adoption requires personnel skilled in:

• Automation
• Systems engineering
• Advanced analytics
• Integrated process design

Organizational resistance to replacing established batch paradigms also remains significant.

Economic Implications

Capital Efficiency
CBM facilities can be:

• Smaller
• Faster to build
• More modular

Supply Chain Resilience
Continuous systems may enable localized manufacturing and reduced dependency on centralized mega-facilities.

Biosimilar Competition
Lower manufacturing costs may improve accessibility of biologics worldwide (1).

Modular Facilities

Portable and modular manufacturing units may enable (6,7):

• Regional production
• Emergency response manufacturing
• Flexible deployment

Smart Factories

Integration of:

• AI
• Robotics
• Digital twins
• Cloud analytics
• Could create autonomous biomanufacturing facilities (6,7).

Sustainability

Continuous systems may reduce:

• Water use
• Energy consumption
• Raw material waste
• Facility emissions

Conclusion

Continuous biomanufacturing represents a major evolution in biologics production. By integrating upstream and downstream operations into coordinated continuous processes, CBM offers substantial improvements in productivity, quality consistency, operational flexibility, and economic efficiency. Advances in perfusion culture, continuous chromatography, PAT, automation, and digital technologies have accelerated industrial adoption.

Despite important technical, regulatory, and organizational challenges, the trajectory of the industry strongly suggests that continuous manufacturing will become increasingly central to future biopharmaceutical production. The convergence of process intensification, automation, data science, and systems engineering is transforming biologics manufacturing from a labor-intensive batch paradigm into a digitally enabled continuous enterprise.

References and notes

1. Dream R, et al. Continuous Manufacturing of Biological Products. Good Practice Guide. ISPE; December 2025. Available from: https://ispe.org/publications/guidance-documents/good-practice-guide-continuous-manufacturing-biological-products
2. Dream R. Continuous Manufacturing Progress and the Bio/Pharmaceutical Industry: “Reality or Fad”. American Pharmaceutical Review. August 15, 2017. Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/341193-Continuous-Manufacturing-Progress-and-the-Bio-Pharmaceutical-Industry-Reality-or-Fad/
3. Dream R. Modernizing Biopharmaceutical Manufacturing: From Batch to Continuous Production. Biopharma Asia. March 2017. Available from: https://biopharma-asia.com/magazine-articles/modernizing-biopharmaceutical-manufacturing-batch-continuous-production/
4. Dahlgren G, Macias KA, Moreira AR, Thompson DR, Herwig C, Dream R. Quality & Regulatory Solutions for PAT in Continuous Manufacturing. Pharmaceutical Engineering. September/October 2020. Available from: https://ispe.org/pharmaceutical-engineering/september-october-2020/quality-regulatory-solutions-pat-continuous
5. Dream R. Real Time Analytics Implementation in Continuous Manufacturing. American Pharmaceutical Review. December 1, 2024. Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/616708-Real-Time-Analytics-Implementation-in-Continuous-Manufacturing/
6. Dream R. The Factory of the Future. American Pharmaceutical Review. March 24, 2022. Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/584572-The-Factory-of-the-Future/
7. Dream R. End-to-End Biomanufacturing: Challenges and Opportunities in Implementation. American Pharmaceutical Review. June 1, 2023. Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/597597-End-to-End-Biomanufacturing-Challenges-and-Opportunities-in-Implementation/
8. Dream R. Continuous Preparation and Feed of Media in Bioprocessing. American Pharmaceutical Review. February 17, 2026. Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/624165-Continuous-Preparation-and-Feed-of-Media-in-Bioprocessing/
9. Dream R, Herwig C, Pelletier E. CM in Biotech Processes – Challenges for Implementation. Pharmaceutical Engineering. November/December 2018. Article of the Year. Available from: https://ispewebassets.org/files/attachments/public/PE_NovDec18_CompleteIssue_v2c_0.pdf
10. Achieving Continuous Manufacturing: May 20–21, 2014 Continuous Manufacturing Symposium. J Pharm Sci. Available from: https://jpharmsci.org/article/S0022-3549(16)30004-1/abstract
11. Distributed manufacturing is a decentralized production model where goods are produced across multiple geographically dispersed facilities, often closer to end-users, rather than in a single centralized factory.
12. The N-mAb case study refers to a model monoclonal antibody manufacturing scenario used by industry and regulatory agencies to study and demonstrate the implementation of continuous bioprocessing. It serves as a standardized example for evaluating how integrated upstream and downstream processes, real-time monitoring, and advanced control strategies can be applied in practice. As an educational framework, N-mAb helps illustrate key considerations in regulatory compliance, process validation, and manufacturing design, making it a widely used reference for guiding the adoption of continuous manufacturing technologies in biologics production.
13. Dream R, Odum J, Menezes JC, Moreira AR. Opportunities in Continuous Manufacturing of Large Molecules. Pharmaceutical Engineering. July/August 2021. Available from: https://ispe.org/pharmaceutical-engineering/july-august-2021/opportunities-continuous-manufacturing-large-molecules
14. Dream R, Odum J. Continuous Viral Vector Manufacturing. Pharmaceutical Engineering. May/June 2025. Available from: https://ispe.org/pharmaceutical-engineering/may-june-2025/continuous-viral-vector-manufacturing