Introduction
Multispecific antibodies represent a transformative advancement in biologic therapeutics, offering the ability to simultaneously engage multiple antigens or pathways. By targeting complex disease mechanisms with enhanced precision, these next-generation molecules hold great promise for improving treatment outcomes in oncology, immunology, and other therapeutic areas. However, their structural complexity introduces significant scientific, technical, and regulatory challenges that must be carefully navigated to ensure successful development and commercialization.
Unlike traditional monoclonal antibodies (mAbs), multispecific antibodies require precise heavy and light chain pairing, optimized protein folding, and consistent expression in host cell systems. These factors complicate manufacturability of multispecific antibodies, impacting yield, stability, and scalability. Additionally, as the biopharmaceutical industry moves toward more sophisticated biologic modalities, multispecific antibodies must be engineered to maintain favorable pharmacokinetics, reduce immunogenicity, and achieve the desired therapeutic effect.
Meeting these challenges requires specialized expertise in cell line development, process optimization, and analytical characterization, as well as manufacturing infrastructure capable of supporting complex biologics. Developers must consider not only the design and functionality of multispecific antibodies, but also the impact of production strategies on quality, regulatory compliance, and cost-effectiveness.
Trends in Multispecific Antibody Development
Multispecific antibodies are rapidly emerging as a critical class of biotherapeutics, driven by their potential to address complex disease mechanisms through engagement of dual or multiple targets. While mAbs have been the cornerstone of biologic drug development, the ability to simultaneously modulate multiple pathways has led to a surge in multispecific antibody programs. Recent market projections indicate significant growth, with the multispecific antibody sector expected to expand at a compound annual growth rate of 9.5% in the coming years (Figure 1).1 This growth is fueled by increasing investment, promising clinical results, and regulatory approvals of pioneering multispecific therapies.
Figure 1. Multispecific Antibodies Market Size 2019-2030 (USD million)1
The primary therapeutic focus of multispecific antibodies has been oncology, where they are used to enhance immune cell engagement, block redundant signaling pathways, or improve tumor specificity. Bispecific T cell engagers, for example, help recruit cytotoxic T cells to tumor cells, while dual checkpoint inhibitors enhance immune response modulation. In addition to oncology, multispecific antibodies are gaining traction in the treatment of autoimmune and infectious diseases, as well as neurodegenerative disorders. Their ability to fine-tune immune system interactions makes them an attractive alternative to combination therapies, potentially reducing drug resistance and improving patient outcomes.
Several multispecific antibodies have already reached the market, with numerous others advancing through clinical pipelines. The success of several immunotherapies approved for commercial use has validated the feasibility of multispecific modalities, leading to an influx of new investigational therapies targeting previously untreatable conditions. As pharmaceutical companies and biotech firms expand their multispecific antibody portfolios, the demand for efficient, scalable production is increasing.
Developers are leveraging various molecular architectures to optimize multispecific antibody function. These formats can be categorized as IgG-like and non-IgG-like structures:
IgG-like structures retain characteristics of traditional mAbs to improve stability and half-life. Examples include knob-in-hole and quadromas, which facilitate correct heavy and light chain pairing, IgG-single-chain Fv (scFv) formats, and dual-variable domain Ig for enhanced target engagement while maintaining manufacturability.
Non-IgG-like structures depart from the IgG scaffold to provide alternative binding and functional capabilities. Examples include tandem scFvs, diabody formats, single-chain diabodies, nanobodies, and dock-and-lock methods, which enable novel binding mechanisms while optimizing flexibility in targeting multiple antigens.
While these structures offer enhanced functionality, they also introduce complexity in terms of manufacturability, requiring innovations in cell line engineering, process optimization, and analytical characterization to ensure consistent product quality.
Challenges and Key Considerations in Development and Manufacturing
While multispecific antibodies offer tremendous therapeutic potential, their development and large-scale production introduce significant scientific, technical, and regulatory challenges. Unlike mAbs, which are relatively straightforward to design and manufacture, multispecific antibodies require careful engineering to ensure correct chain pairing, structural stability, and consistent expression. These complexities can impact yield, scalability, and product quality, making tailored approaches essential for cell line development, process optimization, and analytical characterization.
One of the primary challenges in multispecific antibody development lies in molecular design and engineering. Since these molecules require multiple binding domains to function, ensuring the correct assembly of heavy and light chains is key. Mispairing of chains can lead to reduced potency and increased heterogeneity, requiring innovative engineering technologies to promote correct pairing. Additionally, multispecific formats often introduce structural elements that may compromise stability, leading to a higher risk of aggregation and degradation. Furthermore, immunogenicity assessments evaluate potential risks associated with structural modifications. Addressing these issues requires a combination of protein engineering techniques and in-depth structural characterization to optimize manufacturability while preserving therapeutic efficacy.
Beyond molecular design, the expression of multispecific antibodies presents a unique challenge. Traditional mAbs can be efficiently produced using well-established Chinese hamster ovary cell lines, but multispecific formats place a greater metabolic burden on host cells. Ensuring equimolar expression of multiple polypeptide chains is essential to maintaining a consistent product profile, yet achieving balanced expression remains difficult. Genetic modifications to improve productivity, along with optimized feeding strategies and cell culture conditions, can mitigate these challenges. However, maintaining long-term stability in cell lines remains a key consideration, as prolonged production cycles may increase variability and reduce batch-to-batch consistency.
Process development and scalability pose additional obstacles, as mAb manufacturing methods do not always translate to multispecific formats. Upstream processing must be adjusted to accommodate higher cell densities and more complex metabolic requirements, while downstream purification must be tailored to separate correctly assembled molecules from mispaired variants. Conventional affinity chromatography techniques may not be sufficient, requiring the use of multistep purification methods, such as multimodal chromatography or custom resin development. Optimizing buffer conditions and filtration steps is also essential to minimize aggregation and ensure product stability throughout the purification process.
Analytical characterization is another key consideration, as the structural complexity of multispecific antibodies requires more sophisticated testing than for traditional mAbs. Standard methods such as mass spectrometry and size-exclusion chromatography must be supplemented with additional assays to confirm correct chain assembly, assess binding affinity, and detect impurities. Given the increased likelihood of structural heterogeneity, manufacturers must develop high-resolution analytical platforms that identify minor variations impacting therapeutic efficacy. Additionally, real-time process monitoring through process analytical technology (PAT) can help ensure quality control by allowing for early detection of deviations in production.
Regulatory and compliance considerations further add to the complexity of multispecific antibody development. Unlike mAbs, which follow well-defined regulatory pathways, multispecifics require additional scrutiny due to their novel mechanisms of action and complex structures. Regulatory agencies expect manufacturers to provide extensive comparability studies demonstrating that different production lots maintain consistent quality attributes. Since regulatory frameworks for multispecifics are still evolving, manufacturers must remain agile in adapting to new requirements and expectations.
Scaling up multispecific antibody production in a cost-effective manner also requires a flexible manufacturing infrastructure capable of handling complex process variations. Standardized facilities designed for mAb production may not always be suitable for multispecific formats, requiring adjustments in facility design and equipment configuration. Single-use bioreactors offer advantages in terms of flexibility and contamination control, but hybrid stainless-steel systems may be needed for certain high-yield processes. Supply chain management is another key factor, as specialized reagents and chromatography resins tailored for multispecific purification must be consistently available to avoid production delays. Temperature-controlled logistics and stability studies also play a crucial role in ensuring that these biologics remain effective from manufacturing to patient administration.
Despite these challenges, ongoing innovations in bioprocessing help improve the efficiency and scalability of multispecific antibody manufacturing. Artificial intelligence (AI)-driven process optimization allow manufacturers to predict and control production outcomes with greater accuracy, reducing variability and improving yields. Automated high-throughput screening tools accelerate cell line development, while next-generation purification platforms improve separation efficiency. Digitalized manufacturing systems also enable real-time process monitoring and data-driven decision-making, ensuring that quality remains consistent across production runs.
Seven Strategic Pillars in Multispecific Antibody Development and Manufacturing
To address the unique challenges of multispecific antibody development and manufacturing, a structured approach is required — integrating technical expertise, advanced process solutions, and scalable, flexible infrastructure. Samsung Biologics has established a framework based on seven strategic pillars that enable the efficient production of multispecific antibodies while ensuring quality, scalability, and regulatory compliance. These pillars — technological innovation, capacity, agility, flexibility, efficiency, quality, and sustainability — are the foundation for Samsung Biologics’ ability to support pharmaceutical and biotech companies in bringing complex biologics to market.
Figure 2. Foundation of Samsung Biologics’ advanced CDMO capabilities
Technological Innovation: Enhancing Productivity, Facility Utilization, and Integrated Services
Technological innovation is fundamental to the successful development and manufacturing of multispecific antibodies, which require sophisticated production strategies to ensure structural integrity, efficacy, and scalability. Given their complex architectures — often involving multiple binding domains and precise molecular configurations — multispecific antibodies present unique challenges in expression, purification, and quality control. Addressing these challenges demands cutting-edge technologies that enhance process efficiency, improve product consistency, and accelerate time to market.
Samsung Biologics is at the forefront of biomanufacturing innovation, leveraging state-of-the-art technologies to enhance the productivity, efficiency, and reliability of multispecific antibody production. By integrating computational fluid dynamics modeling, AI-driven process optimization, and high-throughput automation, the company continuously refines manufacturing processes to improve facility utilization and maximize production capacity while ensuring consistent product quality.
A key technological advancement is the use of AI-powered digital twins, which simulate real-time manufacturing processes to predict potential deviations, optimize resource allocation, and proactively adjust process parameters. This predictive modeling approach not only enhances operational efficiency but also minimizes downtime and ensures seamless scalability across production sites. Additionally, the integration of robotics and smart automation has streamlined workflows, reduced manual interventions, and improved process consistency.
To support comprehensive laboratory and manufacturing services, Samsung Biologics employs advanced in-line monitoring technologies, such as Raman spectroscopy and bio-capacitance probes, ensuring that critical quality attributes are maintained throughout production. These real-time analytical tools provide continuous process feedback, allowing for immediate adjustments to optimize yield, purity, and overall manufacturing efficiency. Furthermore, the adoption of cloud-based data integration platforms enables seamless collaboration between laboratory and production teams, ensuring that analytical insights drive real-time process improvements.
By combining advanced automation, AI-powered analytics, and next-generation biomanufacturing technologies, Samsung Biologics is enhancing efficient multispecific antibody production while optimizing facility utilization and expanding its development and manufacturing capabilities. Commitment to continuous innovation ensures that clients benefit from faster, more reliable, and highly scalable bioprocessing.
Capacity: Adapting to Evolving Needs and Scaling Multispecific Antibody Production
The increasing adoption of multispecific antibodies requires manufacturing infrastructure that not only supports high production volumes, but also adapts to diverse and evolving needs of biopharmaceutical companies. Scalability is a critical consideration, as clinical-stage programs must seamlessly transition to commercial-scale production without compromising efficiency or quality. Samsung Biologics has built one of the world’s most advanced biologics manufacturing networks, with a total production capacity of 784,000 liters across five plants. This extensive capacity enables a flexible, demand-driven approach, allowing customers to scale their manufacturing programs in alignment with market needs and clinical development timelines.
Figure 3. Snapshot of Samsung Biologics’ facility footprint, manufacturing capabilities, and track record
To support rapid scale-up and process adaptability, Samsung Biologics employs a multi-plant strategy that standardizes facility designs across different production sites. This consistency ensures that processes can be easily transferred between scales, reducing the risks associated with scale-up variability. Additionally, Plant 5, part of the company’s Bio Campus II expansion, features a modular facility design that enables tailored production setups through flexible bioreactor configurations, adaptable downstream processing lines, and scalable purification systems. This modularity ensures that clients working with multispecifics can seamlessly transition between clinical- and commercial-scale production while optimizing process parameters to meet the requirements of each molecule.
Beyond capacity, Samsung Biologics offers scalable process development and manufacturing services, including small-scale clinical production capabilities that transition to large-scale commercial operations. This approach is particularly advantageous for multispecific antibodies, which often require iterative optimization before reaching full-scale production. By integrating customized scale-up strategies, adaptable bioreactor configurations, and flexible purification technologies, Samsung Biologics ensures that clients progress from early development to high-yield manufacturing while maintaining process consistency.
Agility: Enabling Swift Execution and Optimizing Timelines
The complexity of multispecific antibody production requires an agile approach that minimizes delays in project execution. Accelerating development timelines without compromising quality ensures that promising multispecific therapies reach patients as quickly as possible. Samsung Biologics employs an integrated development and manufacturing strategy that streamlines early-phase activities, optimizes technology transfer, and enables rapid scale-up to commercial production.
A key driver of agility is Samsung Biologics’ parallel processing approach, which enables sequential steps — such as process development, analytical validation, and regulatory preparation — to occur simultaneously. This strategy reduces time-to-market by ensuring that bottlenecks are identified and mitigated early in the development cycle. The company’s risk-based facility fit assessments also ensure that production processes are seamlessly integrated into existing manufacturing platforms, allowing for faster transition from clinical to commercial-scale production.
Samsung Biologics also leverages real-time data analytics and predictive modeling to anticipate and resolve potential technical issues before they impact production timelines. By integrating advanced process monitoring tools and AI-driven risk assessments, the company ensures that manufacturing remains on schedule and that any necessary adjustments are made proactively. These strategies have enabled technology transfer timelines as short as six months for select multispecific antibody projects, demonstrating Samsung Biologics’ ability to efficiently adapt and execute development programs with precision.
Flexibility: Facility Fit for a Range of Complex Molecules and Processes
The structural and functional diversity of multispecific antibodies requires highly adaptable manufacturing infrastructure capable of supporting a wide range of molecular forms. These antibodies involve complex architectures, such as knob-in-hole, CrossMAb, and dual-variable domain designs, which present unique challenges in expression, purification, and scalability. To accommodate these complexities, Samsung Biologics has developed a flexible facility model that allows for seamless, efficient integration of diverse bioprocesses while maintaining scalability.
A critical aspect of this flexibility is Samsung Biologics’ facility fit approach, which ensures that each multispecific antibody program is matched with an optimized manufacturing setup. The company employs a hybrid bioreactor system, incorporating both single-use and stainless-steel bioreactors, to provide adaptable processing solutions that can accommodate varying batch sizes and production scales. This hybrid model allows for rapid process adjustments, supporting clients as they transition from clinical to commercial manufacturing without requiring significant reconfiguration of production lines.
In addition to scalable upstream processes, Samsung Biologics has implemented purification strategies tailored to specific separation challenges. Unlike standard mAbs, multispecifics often require advanced chromatography techniques to achieve high purity and consistent product quality. Samsung Biologics utilizes multimodal purification approaches, buffer optimization, and high-resolution separation technologies to effectively remove impurities, ensuring that each product meets stringent regulatory and quality standards.
By integrating flexible facility fit strategies with advanced process customization, Samsung Biologics enables seamless manufacturing of diverse multispecific antibody formats, ensuring that each program benefits from optimized, scalable, and high-quality production.
Efficiency: Ensuring Risk-Based, Phase-Appropriate Process Optimization
Efficiency is a key factor in multispecific antibody manufacturing, as these biologics require intricate upstream and downstream processing that can drive up production costs and extend timelines. To ensure both agility and reliability, Samsung Biologics has implemented risk-based, phase-appropriate process controls and validation strategies. Manufacturing can then scale efficiently while regulatory compliance is maintained.
Samsung Biologics employs PAT and AI-driven predictive modeling to optimize production at each phase of development. These tools allow for continuous real-time monitoring, ensuring that critical parameters remain within specification while reducing batch variability. This data-driven approach to process monitoring enables early detection of process deviation, allowing corrective actions to be implemented proactively.
For upstream, Samsung Biologics has optimized N-1 perfusion strategies and fed-batch processes to maximize cell density and improve productivity while maintaining control over nutrient feed rates and metabolite accumulation. These approaches ensure that cell cultures remain viable throughout extended production cycles, reducing batch failure risks.
For downstream, the company has invested in high-resolution purification methods, multimodal chromatography, and automated filtration systems, designed to support the complex separation requirements of multispecific antibodies. By implementing a phase-appropriate strategy for process validation, Samsung Biologics ensures that analytical methods, purification approaches, and equipment maintenance schedules are tailored to each stage of development, balancing regulatory requirements with process flexibility.
Samsung Biologics also employs predictive maintenance strategies to enhance operational reliability, reducing unplanned downtime and improving overall facility throughput. Through real-time equipment performance data, maintenance and validation activities are conducted at optimal intervals, minimizing disruptions without compromising compliance.
Through these efficiency-focused strategies—rooted in risk-based validation, process monitoring, and phase-appropriate manufacturing controls—Samsung Biologics enables the cost-effective, scalable production of multispecific antibodies, ensuring commercial viability without sacrificing quality or compliance.
Quality: Ensuring Consistency, Compliance, and Regulatory Readiness
Maintaining product quality is particularly challenging for multispecific antibodies due to their structural complexity and potential for mispairing. To enhance the chain-pairing success rate, Samsung Biologics developed an asymmetric bispecific antibody platform, S-DUAL™, in 2022. S-DUAL™ combines a knob-in-hole design with an asymmetric antibody structure, achieving 99% heavy chain-light chain pairing success.
Additionally, Samsung Biologics employs a comprehensive quality management system that includes real-time batch monitoring, advanced analytical characterization, and rigorous comparability studies to ensure product integrity.
The company’s regulatory expertise spans multiple global agencies, including the U.S. Food and Drug Administration, European Medicines Agency, Japan’s Pharmaceuticals and Medical Devices Agency, and Korea’s Ministry of Food and Drug Safety, allowing clients to navigate evolving regulatory expectations with confidence. By integrating digitalized batch records, automated deviation management, and Six Sigma methodologies, Samsung Biologics ensures that every production batch meets the highest industry standards.
Sustainability: Commitment to Eco-Friendly Biomanufacturing
As the biopharmaceutical industry moves toward greater environmental responsibility, Samsung Biologics has committed to sustainable manufacturing practices that reduce carbon emissions and optimize resource utilization. The company is actively working toward net-zero greenhouse gas emissions by 2050, with intermediate goals that include transitioning to 100% renewable electricity and reducing energy consumption across its facilities.
Samsung Biologics has also implemented waste reduction programs, water recycling systems, and energy-efficient cleanroom technologies to minimize the environmental impact of biopharmaceutical production.
In addition to its environmental sustainability efforts, Samsung Biologics prioritizes business continuity and operational resilience. The company became the first Korean pharmaceutical company to achieve ISO 22301 certification in 2018 and has since expanded its business continuity management system to ensure comprehensive risk preparedness and uninterrupted operations. ISO 22301, an internationally recognized standard, represents the highest level of commitment to disaster preparedness and supply chain resilience, further reinforcing Samsung Biologics’ dedication to sustainability, regulatory compliance, and corporate social responsibility goals.
Conclusion
The development and production of multispecific antibodies require a sophisticated approach that balances innovation, efficiency, and regulatory compliance. Samsung Biologics has established itself as a trusted contract development and manufacturing organization partner by integrating seven strategic pillars that support the unique demands of multispecific antibody manufacturing. With industry-leading capacity, flexible production, cutting-edge technologies, and a commitment to sustainability, Samsung Biologics is well-positioned to help biopharma companies navigate the complexities of multispecific antibody development and accelerate the delivery of life-changing therapies to patients worldwide.
Reference
1. Meravath, Muni Kumar. 2025. “Multi Specific Antibodies Market Size, Share, Growth, Trends, and Global Industry Analysis: By Type (Bispecific Antibody, Tri specific Antibody, Tetra specific Antibody, Multi Specific Antibody), By Drug– (Multispecific (Amivantamab, Blinatumomab), Bispecific (Glofitamab, Epcoritamab, Mosunetuzumab, Teclistamab, Faricimab, Tebentafusp, Emicizumab)), By Indication (Autoimmune Disorders, Genetic Disorders, Haematological Malignancies, Ophthalmic Disorders, Skin Cancers, Solid Tumours), By End User (Hospital, Pharmacies, Others) and Region Forecast 2019-2030.” Precision Business Insights. 9 Jan. 9, 2025.