Enhancing Biopharmaceutical Manufacturing with Single-Use Bioreactors: A Transformative Solution for CRDMO Operations

The adoption of Single-Use Bioreactors (SUBs) is transforming biopharmaceutical manufacturing by addressing the industry’s need for flexibility, speed, and scalability. As CRDMOs (Contract Research, Development, and Manufacturing Organizations) increasingly navigate multi-product pipelines, compressed timelines, and global manufacturing demands, SUBs offer a compelling alternative to traditional stainless-steel systems. Their modular, pre-sterilized, and rapidly deployable design significantly reduces cross-contamination risk, infrastructure burden, and batch changeover time, making them ideally suited for dynamic manufacturing environments.

However, the true potential of SUBs is unlocked when they are integrated with Process Analytical Technology (PAT) and process intensification strategies, which together transform these systems from passive culture vessels into smart, high-performance manufacturing platforms. This synergy enables CRDMOs to deliver biologics with enhanced speed, quality, and cost-efficiency.

The need for flexible, efficient, and scalable systems is driving the adoption of SUBs across CRDMOs and biopharmaceutical manufacturers.

Conventional stainless-steel bioreactors, though time-tested, present challenges in multi-product environments—requiring extensive cleaning, validation, and costly infrastructure. As biologic portfolios expand and personalized therapies gain prominence, manufacturing paradigms must evolve. SUBs provide a modular, pre-sterilized alternative that minimizes cross-contamination risk and allows for rapid changeovers, making them ideal for CRDMOs operating under compressed timelines and diverse production demands.

SUBs facilitate decentralized manufacturing models and meet local demand without compromising process fidelity.

Emerging markets are contributing significantly to the global biologics landscape, often with mandates for in-country production. However, the therapeutic demand within these regions may not justify large-scale stainless-steel investments. SUBs address this challenge by supporting:

• Flexible deployment in low-to-medium volume settings
• Rapid facility commissioning with minimal infrastructure
• Standardized design for consistent process performance across sites
• Agile tech transfer for faster scalability and regulatory alignment

These attributes allow CRDMOs to implement localized manufacturing strategies that respond to regional healthcare needs while adhering to global standards.

SUBs are engineered to deliver robust bioprocess performance through advanced materials, configurations, and control integration.

Single-Use Bioreactors (SUBs) represent a paradigm shift in biomanufacturing, enabling flexible, rapid, and contamination-controlled production environments. Their design and functional elements are strategically engineered to meet the evolving needs of biologics manufacturing—from early-stage development through commercial scale. This section outlines the critical design attributes and operational features that define the utility and robustness of modern SUB platforms.

1. Materials and Construction

SUBs are built from multi-layered polymeric films selected for their chemical inertness, biocompatibility, and barrier properties. These films are typically composed of polyethylene-based layers, with an inner contact surface that minimizes leachables and extractables while maintaining flexibility and mechanical strength.

• Gamma-Irradiated, Sterile Assemblies: All contact components are sterilized via gamma irradiation, ensuring sterility assurance levels (SAL) suitable for cGMP operations.
• Multi-Layer Film Architecture: Advanced barrier films with gas permeability control support extended culture durations while maintaining low levels of volatile organic compounds and particulates.

2. Mixing Strategy and Fluid Dynamics

Efficient and scalable mixing is essential for maintaining homogeneous culture conditions, ensuring nutrient distribution, pH/ dissolved oxygen (DO) uniformity, and effective gas-liquid mass transfer.

• Impeller-Based Mixing: Most SUBs employ bottom-mounted or top-driven impellers (marine or axial-radial hybrid) designed to provide low-shear, high-efficiency mixing compatible with shear-sensitive mammalian cell cultures.
• CFD-Optimized Geometry: Computational fluid dynamics (CFD) is often used in SUB design to simulate and validate mixing profiles, power input (P/V), and shear stress distribution across the working volume.

3. Gas Transfer and Sparging Systems

SUBs support robust gas transfer to sustain high cell densities and metabolic activity, using integrated spargers and overlay systems.

• Sparging Configurations: Macro- and micro-spargers are used to deliver oxygen and strip carbon dioxide efficiently, with consideration for minimizing bubble-induced shear and foaming.
• Overlay and Headspace Control: Supplemental gas input via overlay ports allows for precise control of oxygen tension and carbon dioxide removal while maintaining pressure stability.
• High kLa Design: SUBs are engineered to provide oxygen transfer coefficients (kLa) suitable for supporting intensified processes and perfusion operations.

4. Sensor and Process Control Integration

Modern SUBs are fully integrated with control systems and single-use sensors, enabling real-time monitoring and closed-loop feedback control of critical process parameters.

• Pre-Calibrated Sensors: Disposable, pre-validated sensors for pH, DO, temperature, and pressure are embedded within the biocontainer, reducing calibration burden and contamination risk.
• Control System Compatibility: SUB platforms are designed to interface with Distributed Control Systems (DCS), Programmable Logic Controllers (PLC), and advanced supervisory software for automation and batch record management.
• PAT-Readiness: Many SUBs are compatible with process analytical technology tools including Raman spectroscopy, near-infrared spectroscopy, and capacitance-based biomass monitoring to support real-time release
  strategies and quality by design implementation.

5. Scalability and Geometrical Consistency

A defining feature of SUBs is their scalability from small-scale development systems to commercial manufacturing volumes (typically 50 L to 6,000 L), while maintaining process fidelity.

• Geometric Similarity: SUB systems often follow proportional geometries and impeller-to-vessel diameter ratios to ensure predictable scale-up and consistent hydrodynamic conditions.
• Modular Scale-Out Options: Systems are designed for parallel batch or perfusion operations using multi-bioreactor trains, especially beneficial for continuous or intensified manufacturing.

These advantages empower CRDMOs to deliver faster, safer, and more cost-effective manufacturing solutions that directly benefit their customers.

To realize the full capability of SUBs, cutting-edge enhancements such as Process Analytical Technologies (PAT) and process intensification tools are being seamlessly integrated into modern upstream bioprocessing strategies. These advancements are redefining how CRDMOs approach biologics manufacturing—boosting productivity, responsiveness,
and product quality while reducing operational complexity.

Process intensification, when coupled with PAT, transforms SUBs from static culture vessels into adaptive, high-performance production systems, capable of delivering higher titers, improved consistency, and accelerated development timelines.

Enhancing SUB Capability Through PAT

PAT empowers SUBs with a deep layer of process intelligence, enabling real-time monitoring, predictive control, and continuous quality assurance. It allows critical process variables and quality attributes to be measured and managed directly within the bioreactor, with minimal intervention.

• Real-Time Insight for Dynamic Control: Advanced PAT sensors monitor key variables—such as glucose, lactate, viable cell density, and cell viability—in real time. This data feeds into automated control loops that adjust feed rates, gas flows, and agitation parameters on the
  fly, maintaining optimal culture conditions throughout the run.
• Enabling Predictive Quality and Compliance:
  PAT tools support Quality by Design (QbD) by enabling data-rich, science-based decisions. For example, Raman spectroscopy—a label-free, non-invasive PAT tool—can quantify multiple metabolites simultaneously with high
  specificity. Integrated into SUBs, it supports feedback-based control of nutrient feeding, enabling steady-state culture conditions and reduced batch variability.
• Minimizing Manual Touchpoints:
  By eliminating the need for frequent offline sampling, PAT reduces contamination risk, enhances operator safety, and streamlines operations. Inline cell count, capacitance-based biomass probes, and metabolite analyzers enable
  full culture profiling without opening the system.
  
• Scalable Across Platforms:
  PAT systems can be deployed consistently from benchtop to production scale, facilitating seamless technology transfer and enabling CRDMOs to replicate validated processes across facilities with minimal revalidation.
  

Driving Process Efficiency Through Intensification

Process intensification transforms traditional batch processes into high-output, resource-efficient operations. By extending culture duration or increasing volumetric productivity, intensification strategies optimize facility utilization and reduce cost per gram of product.

• Perfusion Mode for Extended Productivity:
  SUBs equipped for perfusion operation use integrated cell retention devices—such as alternating tangential flow (ATF), tangential flow filtration (TFF), or membrane-based technology (for wave bioreactor)—to continuously remove spent media while retaining viable cells. This supports ultra-high cell densities and extended production runs, ideal for labile or low-yield products.
  
• Automated Media Exchange and Cell Density Control:
  Integration of automated flow control, perfusion pumps, and real-time cell density sensors allows precise regulation of perfusion rates based on actual biomass levels. This dynamic control optimizes media consumption while maintaining cell health and productivity.
  
• Reduced Bioreactor Footprint with Higher Yield:
  Intensified SUBs can deliver commercial-scale titers in smaller volumes, reducing facility and equipment demands. This is particularly valuable in multi-product or multi-client manufacturing environments requiring flexibility and speed.
  
• Seed Train Intensification:
  Wave-based bioreactor systems—featuring rocking motion and disposable bags—offer gentle culture conditions and can be adapted for perfusion operation. Combined with inline cell counting and media exchange, these systems enable rapid expansion of inoculum into production volumes, shortening campaign timelines.
  

Synergistic Integration of PAT and Process Intensification in CRDMO Operations

The intersection of PAT and process intensification creates a self-optimizing environment in SUB-based manufacturing—one that is data-rich, adaptive, and highly scalable. While PAT provides the real-time visibility and control to maintain consistent product quality, intensification tools maximize productivity and operational efficiency.

Together, they empower CRDMOs to:

• Unlock higher titers without proportionally increasing bioreactor volume
• Accelerate time-to-clinic and time-to-market for clients
• Enable closed-loop, automated manufacturing with reduced manual oversight
• Drive down manufacturing costs through efficient resource utilization
• De-risk process scale-up by standardizing control strategies from lab to GMP

This strategic convergence enables CRDMOs to meet the growing demand for biologics with agility, precision, and cost-effectiveness—making single-use bioreactor systems not just a vessel, but a platform for innovation.

Single-use bioreactors (SUBs) have emerged as a foundational technology enabling CRDMOs to meet the increasing complexity and urgency of biologics manufacturing. Their modular design, disposability, and integration-readiness make them ideally suited for flexible, multi-product operations across global facilities. When coupled with advanced enablers like PAT and process intensification tools, SUBs evolve into intelligent and adaptive platforms that drive both performance and compliance.

By embedding real-time analytics, feedback control, and high-efficiency perfusion capabilities, CRDMOs can unlock higher titers, faster development timelines, and improved product consistency—without proportional increases in infrastructure or operational complexity. As the industry advances toward more responsive, scalable, and patient-centric models of biologics production, SUBs integrated with PAT and intensification strategies will continue to define the future of efficient, high-quality biomanufacturing.

Aragen is a global Contract Research, Development, and Manufacturing Organization (CRDMO) with 30+ years of experience serving the biopharmaceutical industry. With a presence across the US, Europe, and India, Aragen offers integrated services for both small and large molecules, from discovery to clinical manufacturing.

Aragen offers a comprehensive, phase-appropriate development model—starting from high-yielding CHO-based cell line development to clinical-grade GMP manufacturing—ensuring speed, flexibility, and compliance. With strong capabilities in process intensification, analytical characterization, and quality systems aligned to global regulatory standards, Aragen reduces time to clinic while maintaining product quality. Its modular approach supports both platform and custom development strategies, making it ideal for early-stage, first-in-human studies as well as late-stage scalability. By offering seamless integration between discovery and manufacturing, Aragen becomes a strategic partner committed to accelerating biologics development with reliability, technical depth, and cost efficiency.