Adoption and Implementation of Innovative Technologies in CMC

CMC is a critical multidisciplinary function in the biopharmaceutical industry. It plays an indispensable role in the successful development of every drug by establishing the processes and methods required to produce safe, effective, and high-quality medicines. Although it often operates in the background, CMC’s impact on drug development cannot be overstated. It is responsible for several key advances in the field, including the development of new biopharmaceutical technologies, optimizing drug delivery systems, managing costs, increasing patient adherence, and ensuring broader access to treatment, particularly for underserved populations.

Figure 1: Module 3 of an IND application describes CMC.

Despite its importance, CMC has historically been overshadowed by clinical development, which tends to dominate the focus of drug development teams and funding. However, recent trends show a shift, with CMC leaders beginning to recognize the power of innovative technologies like advanced analytics, data science, digitalization, and automation. These advancements hold the promise of significant improvements in the efficiency and effectiveness of CMC operations. Yet, although there has been progress, the function has a long way to go before fully embracing these modern tools and systems. Legacy processes, siloed data, unstructured information, and a lack of standardized systems continue to impede the full realization of CMC’s potential.

The challenge is particularly evident when attempting to integrate novel equipment, systems, and data management solutions needed for research and development and preclinical and clinical production. Meeting the rigorous data requirements for CMC, Investigational New Drug (IND) applications, and clinical lot production (see Figure 1) often demands advanced capabilities that many organizations are still striving to implement effectively.

Demands for Advanced Capabilities in CMC for Biologics

The development and commercialization of biologic drugs involve intricate and specialized processes that demand a high level of expertise, precision, and consistency. The CMC phase of biologic drug development is a critical component that ensures the safety, quality, and efficacy of biologics. As the biologics landscape continues to evolve, the need for advanced capabilities in CMC has become more pronounced. These advancements are necessary to address the growing complexity of biologic therapies, streamline manufacturing processes, and meet rigorous regulatory standards.

Complexity of Biologic Products

Biologic drugs, such as monoclonal antibodies, gene therapies, and recombinant proteins, are large, complex molecules derived from living organisms. Unlike small molecule drugs, biologics are subject to considerable variability due to differences in production processes, the cells used for manufacturing, and the inherent complexity of their structures. This complexity introduces several challenges:

• Product heterogeneity: Biologics are often heterogeneous, meaning they can exist in multiple forms with slightly different molecular profiles. Ensuring uniformity across batches is a key challenge.
• Manufacturing variability: Biologics are typically produced in living cells, and variations in cell culture conditions, expression systems, and downstream processing can impact the final product’s quality.
• Regulatory complexity: Regulatory authorities require extensive documentation and data to ensure biologics’ quality, consistency, and safety. This requires robust systems for tracking every stage of development and manufacturing.

As a result, biologic drug development requires advanced capabilities to address these complexities and ensure that the product is both safe and effective.

Advanced Capabilities in CMC for Biologics

To meet the demands of biologic drug development, the CMC phase must incorporate a range of advanced capabilities, including innovative technologies, innovative processes, and a deep understanding of biologic behavior.

Improved Analytical Techniques

The need for sophisticated analytical methods to characterize biologics is critical during the CMC phase. Advanced capabilities in analytical technologies are essential for ensuring product quality and consistency across production batches. Key analytical techniques include mass spectrometry (MS), chromatography, and cryo-electron microscopy (cryo-EM).

Advanced MS techniques, such as high-resolution MS and ion mobility spectrometry, allow for detailed characterization of biologics, including the identification of post-translational modifications, glycosylation patterns, and higher-order structure. High-performance liquid chromatography (HPLC) and other chromatographic techniques are integral for the separation and purification of biologics, ensuring product purity and identifying isoforms or impurities that might affect therapeutic efficacy. Cryo-EM enables the direct visualization of biologic molecules at high resolution, providing detailed insights into their structural integrity and functionality.

Cell Line Development and Optimization

The cell line used for the production of biologics is one of the most critical factors in ensuring a consistent and high-quality product. Advances in cell line development and optimization are necessary to improve yields and reduce variability. Techniques include Chinese hamster ovary (CHO) cell line engineering and genome editing technologies (e.g., CRISPR-Cas9).

CHO cells are commonly used for the production of therapeutic proteins. Optimizing these cells through genetic engineering and culture condition optimization can lead to improved product yields and quality. Genome editing enables the creation of stable cell lines with enhanced productivity and improved quality attributes, making the process more efficient and scalable.

Advanced Bioreactor Design and Control Systems

Bioreactors are essential for growing cells at a large scale and producing biologics. Advanced bioreactor technologies enable more precise control of the culture environment, leading to higher yields and better product quality. These advancements include single-use bioreactors and real-time process monitoring. Single-use bioreactors have gained popularity due to their flexibility, reduced risk of cross-contamination, and ease of scalability. They are particularly useful for smaller-scale production and for clinical trials. For process monitoring, modern control systems with real-time monitoring capabilities allow for better control over variables such as pH, temperature, and dissolved oxygen, helping optimize cell growth and product quality.

Process Analytical Technology (PAT)

PAT is a critical approach for monitoring and controlling the manufacturing process of biologics in real time. By integrating advanced sensors, data analytics, and automation, PAT enables real-time quality control and increased process understanding. PAT allows for continuous monitoring of critical quality attributes (CQAs) and process parameters, ensuring that the biologic product remains within desired specifications throughout production. And by collecting and analyzing large datasets, PAT helps deepen the understanding of the manufacturing process, allowing for better predictions and process optimizations.

Quality by Design (QbD) Approach

The QbD approach emphasizes the proactive design of a manufacturing process to ensure product quality from the start. This approach incorporates several advanced capabilities. Risk-based analysis identifies potential risks early in the process, allowing for better management of variables that could affect product quality. Process optimization uses data-driven approaches, such as design of experiments (DOE), to optimize the production process and ensure consistent quality. Implementing robust control strategies helps mitigate risks and maintain product consistency during scale-up and commercial manufacturing.

Supply Chain and Logistics Innovations

The global nature of biologic drug development requires highly efficient and reliable supply chain and logistics capabilities. New developments in the supply chain include:

• Cold Chain Management: Biologics often require stringent temperature controls to maintain their stability. Advances in cold chain logistics, such as real-time temperature monitoring and advanced packaging solutions, ensure that biologics remain viable throughout transportation and storage.
• Supply Chain Digitization: Digital platforms and blockchain technology can be used to track and trace biologic products throughout the supply chain, improving transparency, reducing errors, and ensuring compliance with regulatory requirements.

Regulatory Demands and Compliance

The increasing complexity of biologic products has led to more stringent regulatory demands in the CMC phase. Regulatory bodies, such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), require comprehensive documentation and data to ensure that biologics meet safety, efficacy, and quality standards. Meeting these demands requires advanced CMC capabilities in:

• Data integrity and documentation: With increasing regulatory scrutiny, it is vital to maintain rigorous documentation and ensure data integrity at every stage of the CMC process.
• Adaptive manufacturing processes: Regulatory agencies are increasingly open to more flexible, adaptive manufacturing processes, provided that the product quality is maintained. This requires the implementation of real-time monitoring, predictive modeling, and robust quality control systems.
• Global harmonization: Regulatory requirements vary across regions, and biologic manufacturers must navigate these differences to ensure international market access. Advanced regulatory knowledge and the ability to design processes that can meet multiple regulatory standards are essential.

Enhancing Analytical Methods in Biologics

The development and commercialization of biologic drugs have revolutionized modern medicine, offering treatments for a wide range of diseases, including cancer, autoimmune disorders, and rare genetic conditions. However, the complexity of biologics—biopharmaceutical products such as monoclonal antibodies, gene therapies, and recombinant proteins—presents significant challenges in their characterization, quality control, and regulatory approval. Therefore, enhancing analytical methods used to assess biologics is crucial to ensuring their safety, efficacy, and consistency.

Current Challenges in Biologic Drug Development

Biologics differ from small molecule drugs in that they are large, complex molecules derived from living cells. Their structure, post-translational modifications, and function can be highly variable, making their analysis more challenging. The current challenges in biologic drug development include the following. Because biologics often exhibit variability due to the production process, differences in cell lines, and the nature of post-translational modifications, heterogeneity is a challenge. Stability is a concern because biologics can degrade over time, Stability is influenced by factors such as temperature, pH, and agitation. Immunogenicity must be considered because biologics may induce immune responses, potentially leading to adverse effects or loss of efficacy. Finally, regulatory compliance always is a consideration to ensure consistency across production batches and compliance with regulatory standards, which is critical for market approval.

Innovative Analytical Methods

To address these challenges, the following innovative analytical methods are being explored and implemented in the biologics field.

Advanced MS

MS has become a cornerstone technique for the characterization of biologics. Recent advancements in MS technology, such as high-resolution MS and ion mobility spectrometry, provide enhanced sensitivity and the ability to analyze complex biologic samples with greater accuracy. These methods allow for:

• Detailed characterization: MS is capable of determining the primary structure, post-translational modifications, and sequence of proteins, which is essential for understanding biologic activity.
• Quantitative analysis: MS can be used to quantify protein levels with high precision, ensuring the consistency of drug formulations.
• Glycan profiling: MS plays a critical role in analyzing glycosylation patterns, which are key to the functional activity and immunogenicity of biologics.

Chromatographic techniques

Chromatographic methods, such as HPLC and affinity chromatography, remain essential for the analysis and purification of biologics. Recent improvements in chromatographic technologies, like multidimensional chromatography, provide better resolution and efficiency in separating complex biologic samples. These advancements aid in:

• Purity assessment: Ensuring the purity of biologics is vital for their safety and effectiveness.
• Isoform characterization: Differentiating between product variants that might influence efficacy and immunogenicity.
• Accelerated development: The application of modern chromatography techniques enables faster and more reliable screening of biologic candidates during development.

Structural biology and cryo-EM

Cryo-EM has emerged as a groundbreaking technique for visualizing the three-dimensional structures of large biomolecules, such as antibodies and viral particles, without the need for crystallization. This technique has significantly enhanced our ability to:

• Visualize molecular structures: Detailed three-dimensional images of biologics provide insights into their structural integrity, which is critical for understanding their function and mechanism of action.
• Monitor conformational changes: Cryo-EM allows researchers to study conformational changes in biologic molecules that can impact their activity and stability.

Cell-based assays and bioanalytics

Cell-based assays and bioanalytical techniques are crucial for assessing the biological activity of therapeutics. Innovations in this area have led to more predictive, high-throughput assays that provide information on the potency, mechanism of action, and pharmacodynamics of biologics. The advancements include:

• Cellular imaging: Using advanced imaging technologies to study cellular interactions with biologic drugs in real time.
• Reporter gene assays: These assays can help in assessing the immunogenicity and potency of biologics by detecting specific responses in cells.
• Biosensors: New biosensor technologies can continuously monitor real-time biological responses, improving the accuracy and speed of testing.

Regulatory Implications and Standardization

As analytical methods evolve, regulatory agencies such as the FDA and EMA must adapt their standards to ensure biologics are rigorously evaluated for safety and efficacy. The following areas are crucial for enhancing regulatory processes:

• Harmonization of analytical standards: Collaborating internationally to standardize analytical methods and quality control protocols will streamline the approval process for biologics across markets.
• Risk-based approaches: Regulatory bodies are increasingly adopting risk-based approaches to ensure that new biologics meet safety and quality standards without overburdening development timelines.
• Real-time monitoring: Regulatory agencies are beginning to explore real-time monitoring technologies, which will allow for more flexible and adaptive quality control during manufacturing.

Future Directions

The future of biologic drug development lies in integrating new technologies and improving the efficiency of analytical methods. Some promising developments include:

• Artificial Intelligence (AI) and machine learning (ML): These technologies can help in data interpretation, predictive modeling, and identifying new biomarkers, thereby accelerating the development process.
• Microfluidics and lab-on-a-chip technologies: These innovations enable high-throughput and miniaturized testing systems that could revolutionize biologic drug development by providing more efficient, cost-effective analyses.
• Advanced high-throughput screening: More rapid and reliable screening platforms will help in identifying potential biologics with higher efficacy and fewer side effects.

Accelerating Time to Market

In an increasingly competitive biopharmaceutical landscape, accelerating time to market is not just a priority—it’s a necessity. To remain relevant and maintain market share, companies must find ways to speed up the development process without compromising quality. Several strategies can be implemented to achieve this goal:

• Optimize workflows: Streamlining processes across the entire product life cycle—from design and development through production—can help identify and eliminate bottlenecks that slow progress.
• Adopt agile methodologies: Using agile development practices allows for iterative progress, making it easier to adapt to changes quickly, incorporate feedback, and speed up product delivery.
• Leverage advanced technologies: The integration of AI, ML, and automation into CMC operations can significantly reduce decision-making time, improve predictive capabilities, and help streamline development cycles.

By optimizing workflows, adopting agile strategies, and embracing cutting-edge technologies, companies can dramatically improve CMC efficiency. This, in turn, enhances competitiveness and enables organizations to meet market demands faster and more effectively.

Together, these innovations not only enhance CMC’s overall performance but also reshape how the entire drug development process unfolds. By reimagining the role of CMC and leveraging advanced tools, the pharmaceutical industry can achieve faster, more efficient development cycles, delivering life-saving therapies to patients.

Setting Specifications for Biopharmaceuticals

Setting specifications is a vital part of a comprehensive control strategy for ensuring the quality and consistency of biopharmaceutical products. Although specifications are fundamental for confirming product quality, they are just one piece of the larger strategy. Other components of this strategy include thorough product characterization during development, adherence to GMPs, validated manufacturing processes, raw material testing, in-process testing, and stability assessments.

For specifications, therefore, it is important to focus primarily on key molecular and biological characteristics that are critical for ensuring the safety, efficacy, and overall quality of the drug product. However, specifications are not designed to fully characterize the product but to confirm that it aligns with required relevant and phase-appropriate standards at various stages of production and throughout its life cycle.

Physicochemical Properties

Physicochemical characterization is an essential aspect of the product development process. This typically involves a thorough assessment of the composition, physical properties, and primary structure of the intended product. For many biologics, particularly proteins, understanding their higher-order structures is also important, as these structures are often directly linked to their biological activity.

A characteristic feature of biopharmaceutical products, particularly proteins, is their inherent structural heterogeneity. This heterogeneity arises due to the complexity of biological production processes, which often result in a mix of post-translationally modified forms, such as different glycoforms. These variations may be biologically active and, in many cases, do not negatively impact the safety or efficacy of the product. It is critical for manufacturers to define the acceptable pattern of this heterogeneity and demonstrate its consistency with the product used in preclinical and clinical trials.

If this pattern remains consistent across different production batches, it may not be necessary to evaluate each variant individually for its activity, safety, or immunogenicity. However, when process changes or degradation during storage introduce unexpected variations in the heterogeneity, these changes should be carefully evaluated for potential effects on the product’s quality.8

Biological Activity

The assessment of biological activity is crucial for confirming that a drug product performs as intended within the biological system. Biological activity refers to the product’s specific ability to elicit a defined biological response, and it is typically quantified through biological assays. The manufacturer should select and validate appropriate assays, which can include:

• Animal-based assays, which measure the biological response in an organism exposed to the product
• Cell culture–based assays, which valuate biochemical or physiological changes at the cellular level
• Biochemical assays, which quantify biological activity through enzymatic reactions or immunological interactions

Potency, which quantifies biological activity in units, is distinct from the measurement of quantity, which is typically expressed in mass (e.g., protein content). In many cases, biological assays are essential to measure potency, especially for complex biological molecules. It is important to establish a correlation between the biological activity observed in assays and the expected clinical response, either through pharmacodynamic studies or clinical trials.

Biological assays should ideally be calibrated against an international or national reference standard. If no such standard exists, the manufacturer must establish an in-house reference material. Although physicochemical methods can provide valuable information, they may not always fully confirm the higher-order structure. In such cases, a biological assay with acceptable confidence limits may be used, supplemented by physicochemical data for a more comprehensive evaluation.8

Purity

Determining the purity of a biopharmaceutical product is a complex task, as it involves distinguishing the active drug from various molecular entities or variants that may be present due to the biosynthetic processes used to produce the product. Purity assessments are performed using a combination of analytical methods to differentiate between the desired product and product-related substances or impurities.

When these molecular variants arise from anticipated post-translational modifications, they are considered part of the desired product and not impurities. However, when variants result from changes in the manufacturing process or degradation during storage, they must be carefully evaluated for their impact on the product’s overall quality. The acceptance criteria for product-related substances should be based on their biological activity, safety, and efficacy profiles.

The challenge of purity testing is amplified by the unique nature of biotechnologically derived products. For instance, proteins produced in living systems may exhibit different forms (such as glycoforms or phosphorylated variants), which may still meet the required therapeutic standards. Establishing the level of acceptable purity involves assessing these variations and ensuring they do not adversely affect the therapeutic properties.8

Impurities

In addition to assessing the purity of the drug product, manufacturers must consider the presence of impurities. Impurities may be process-related (derived from the manufacturing process, such as host cell proteins or residual DNA) or product-related (e.g., degradation products or incomplete post-translational modifications). These impurities must be evaluated for their potential impact on product quality.

Impurities can be classified into known, partially characterized, or unidentified substances. Whenever possible, manufacturers should characterize these impurities and assess their potential biological activity. Acceptance criteria for impurities are typically based on data from preclinical and clinical studies, as well as manufacturing consistency lots.

Under certain circumstances, the need for specific impurity acceptance criteria may be waived, depending on the impurity’s nature and its demonstrated lack of impact on product safety and efficacy.8

Contaminants

Contaminants, which include adventitiously introduced substances like microbial species or chemical contaminants (such as microbial proteases), pose a significant risk to product safety. Contaminants must be strictly controlled and eliminated from the manufacturing process. In the case of adventitious viral or mycoplasma contamination, it is essential to follow specialized guidelines to evaluate and control these risks, as action limits are not applicable. Manufacturers should refer to ICH Harmonised Tripartite Guidelines to manage viral safety and contamination risks effectively.8

Quantity

The quantity of active ingredients in a biopharmaceutical product is typically measured as protein content, which is critical for ensuring therapeutic efficacy. This quantity is usually determined using physicochemical assays. In some cases, a correlation may exist between the quantity and biological activity, allowing for the measurement of protein quantity rather than conducting full biological assays. This correlation may be particularly relevant during the production process, including steps such as filling and lot release.8

Immunochemical Properties

For biologic products such as monoclonal antibodies, immunochemical characterization is essential for establishing product identity, homogeneity, and purity. The binding affinity and specificity of the antibody for its target antigen should be thoroughly evaluated using binding assays. These assays can assess the affinity, avidity, and immunoreactivity, including potential cross-reactivity with other molecules.8

For some products, immunochemical methods like enzyme-linked immunosorbent assay (ELISA) or Western blotting are used to identify and quantify specific epitopes or determine homogeneity. Immunochemical testing can also serve to ensure that the product meets release criteria for identity and purity. When immunochemical properties are part of lot release specifications, manufacturers must provide comprehensive data on the antibody’s behavior and characteristics.8

Gap Analysis in CMC

For decades, the structure of CMC organizations has remained relatively stable, with specialized groups managing laboratories and systems that focused on clearly defined small molecule and biologics platforms. This traditional model has served the industry well in the past, ensuring consistent quality and predictable timelines. However, in recent years, several industry trends have exposed limitations in this approach, highlighting the need for significant change.

The Need for Change in CMC

Several key factors are driving the evolution of the CMC operating model.

Faster Pace of Pharmaceutical Development

The increasing speed of pharmaceutical development is placing more pressure on CMC teams. With drug development cycles shrinking due to innovations in trial designs, optimized clinical operations, and expedited regulatory pathways, CMC departments are under pressure to adapt their timelines and workflows accordingly. This shift means that CMC processes, traditionally slower and more methodical, now need to move at a faster pace, making them a more critical component in the overall development timeline.

Increasing Complexity of Product Development

The biopharmaceutical landscape is becoming more complex as the industry diversifies into new modalities. These innovations include biologics, cell and gene therapies, and RNA-based therapeutics. Alongside this complexity, manufacturing processes are becoming more intricate, and product specifications are broadening, incorporating components such as medical devices and software. CMC must evolve to handle these complex products and processes, ensuring quality while navigating new regulatory and technological landscapes.

Advancements in Technology

The rapid introduction of new technologies is another major driver of change. Innovations in automation, digitalization, production systems, and testing methods are reshaping how CMC functions. These advancements require the recruitment of specialized talent, the development of new skills, and the formation of strategic partnerships to stay at the forefront of innovation. Additionally, data from equipment, prediction models, and external partners is growing exponentially, necessitating a stronger focus on data governance and knowledge management to ensure efficiency and compliance in product development.

Creating a Paradigm Shift in CMC

The challenge of accelerating the development and supply of new medicinal products requires a shift in the way CMC organizations approach product development and manufacturing. Industry stakeholders, including regulators, have already begun addressing these needs through collaborative efforts. Key insights have emerged from various forums and publications aimed at defining a new path forward:

• In 2016, a joint industry and FDA group published a report, “Examining Manufacturing Readiness for Breakthrough Drug Development,” outlining principles to accelerate the development of breakthrough therapies2
• The European Federation of Pharmaceutical Industries and Associations (EFPIA) further refined these principles in a 2017 proposal, emphasizing risk-based and science-driven approaches to developing high-quality medicines3
• In 2018, the EMA and FDA conducted a PRIME/Breakthrough Quality Workshop, which expanded on these principles with real-world case studies from the evolving biopharmaceutical landscape4^, 5
• Most recently, in 2020, the EFPIA’s paper on COVID-19 pandemic medicines further refined these principles to facilitate rapid development in response to urgent global health needs6
• In 2021, the EMA also released a draft CMC acceleration toolbox, based on insights gathered during previous workshops and consultations, providing concrete strategies to speed up the regulatory approval processes for new therapies7

Figure2: Lifecycle of an ETP1

Advanced Manufacturing Technologies

A critical aspect of the paradigm shift in CMC is the adoption of advanced manufacturing technologies. These technologies enable more efficient production, ensure higher product quality, and facilitate faster time to market. Key advanced manufacturing innovations include the following.

Continuous Manufacturing (CM)

Traditional drug manufacturing processes, typically batch or fed batch, involve halting production between stages. Continuous manufacturing, on the other hand, integrates all production steps into a continuous flow, allowing for ongoing production without interruptions. This method helps improve efficiency, reduce costs, and improve the consistency of product quality.

3D Printing (Additive Manufacturing)

In biopharmaceuticals, 3D printing enables the creation of personalized medicines, allowing for the precise customization of dosages and drug delivery systems tailored to individual patient needs. This technology can also improve the efficiency of drug production, particularly for complex therapies that require highly specific formulations.

PAT

PAT involves the use of sensors and digital analytics to monitor the CQAs of a product during production. With real-time data collection and analysis, PAT ensures that products meet regulatory standards without the need for post-production batch testing, streamlining the manufacturing process and improving quality control.

Automation and Robotics

The use of automation and robotics in the manufacturing process ensures the precise handling of materials, consistent measurement of ingredients, and control of environmental conditions. Artificial intelligence (AI) and machine learning (ML) can also be integrated into these systems to optimize production schedules and predict potential issues, further enhancing the efficiency and scalability of manufacturing processes. These advanced manufacturing technologies offer significant opportunities to reduce variability, improve scalability, and meet the growing demand for personalized and complex therapeutics.

Regulatory Emerging Technology Program (ETP)

To address challenges from rapidly evolving biopharmaceutical manufacturing technologies, the FDA launched the Emerging Technology Program (ETP) in 2014 to support and accelerate the adoption of advanced manufacturing techniques.

The ETP provides a collaborative platform where industry stakeholders can engage with the FDA’s Emerging Technology Team (ETT) to discuss potential regulatory and technical issues associated with novel technologies. This program aims to address concerns about delays caused by unfamiliar technologies and regulatory frameworks. By facilitating early dialogue, the ETP helps industry representatives identify and resolve potential roadblocks before regulatory submissions, ensuring smoother approval processes.

The ETP includes representatives from the FDA’s Office of Pharmaceutical Quality (OPQ), Office of Compliance (OC), and the Office of Regulatory Affairs (ORA). By engaging with these regulatory experts, companies can gain a better understanding of how to align their technologies with existing regulatory standards and accelerate the development and approval of innovative therapies (Figure 2).

Emerging Technologies

As the pharmaceutical landscape rapidly evolves, emerging technologies are transforming both small molecule and biologic drug manufacturing processes. These innovative technologies are being integrated across all stages of drug development to improve product quality, reduce manufacturing costs, and accelerate time to market. Here, we explore the latest advancements in small molecule and biologic drug production, as well as the systems designed to enhance the overall manufacturing ecosystem.

Emerging Equipment and Systems Technologies

Continuous manufacturing of drug substance

Traditional drug substance manufacturing often involves batch processing, where production occurs in distinct stages. Continuous manufacturing integrates all production steps into a continuous, uninterrupted process. This approach enhances efficiency by reducing downtime between stages, improving product consistency, and providing real-time monitoring and control over critical process parameters.

Continuous manufacturing of drug product

Similar to the continuous manufacturing of drug substances, continuous manufacturing of drug products involves a seamless, integrated process for product formulation and finishing. By maintaining a continuous production flow, this method can improve scalability, reduce production costs, and enhance supply chain flexibility, particularly for high-demand or personalized medicines.

Model-based control strategy for continuous manufacturing

As continuous manufacturing becomes more widespread, model-based control strategies are being developed to optimize the manufacturing process. These strategies use mathematical models to predict and control CQAs in real time, ensuring product quality and reducing the need for extensive post-production testing.

Continuous aseptic spray drying

Spray drying is an important technique for producing dry powders for inhalation or oral solid dosage forms. Aseptic spray drying ensures the sterility of the drug substance while maintaining high manufacturing efficiency. The continuous nature of the process improves scalability and consistency, whereas the aseptic environment ensures that the drug remains free from contamination.

3D printing manufacturing

3D printing (additive manufacturing) offers the possibility of personalized dosing, allowing for precise customization of drug formulations to meet individual patient needs. In drug manufacturing and production, 3D printing can facilitate the creation of complex dosage forms that are difficult to achieve through traditional manufacturing methods. It also holds potential for enhancing the development of combination products involving drugs and medical devices.

Ultra-long-acting oral formulation

Traditional oral formulations often require frequent dosing. Ultra-long-acting oral formulations aim to extend the duration of action of drugs, reducing the frequency of administration. This can significantly improve patient adherence and convenience. Technologies such as controlled-release and sustained-release formulations, alongside advanced drug delivery systems, are being explored to develop these long-acting therapies.

Emerging Technologies for Biological Molecules

Controlled ice nucleation for lyophilization processes

Lyophilization (freeze-drying) is a critical process for stabilizing biologics, such as proteins and vaccines, by removing water while maintaining product integrity. Controlled ice nucleation improves the uniformity and efficiency of the lyophilization process, ensuring better preservation of the biologic’s structure and activity.

Advanced process control (APC)

Predictive modeling and closed-loop bioreactor control are reshaping the way biologics are manufactured. APC systems use real-time data and ML algorithms to predict outcomes, monitor critical process parameters, and adjust in real time to maintain product quality throughout the production process. This approach reduces variability and enhances the efficiency of biologic manufacturing.

Multi-attribute method (MAM)

MAM is an advanced analytical approach that allows for the simultaneous measurement of multiple attributes of a biologic product, such as purity, potency, and stability. This holistic method provides a more comprehensive understanding of the product’s quality and can replace traditional batch testing, enabling more efficient release testing and process monitoring.

Next-generation sequencing (NGS)

NGS is revolutionizing the development of biologics by enabling comprehensive, high-throughput genomic analysis. This technology allows researchers to quickly sequence genes, genomes, and transcriptomes, accelerating the discovery of novel biologic drugs and improving the characterization of biologic products, such as monoclonal antibodies and gene therapies.

Continuous manufacturing for downstream processes

Traditionally, downstream processing in biologic production (e.g., purification and formulation) has been performed in discrete, batch-based stages. Continuous manufacturing for downstream processes integrates purification and product recovery into a continuous workflow, increasing efficiency, reducing waste, and improving the scalability of biologic production.

Pharmacy on demand

The concept of pharmacy on demand refers to a compact, on-site manufacturing platform for biologic products that allows for the continuous production of therapies in a controlled, decentralized environment. This technology could enable faster delivery of personalized treatments, reduce transportation costs, and provide localized solutions for remote or underserved populations.

Figure 3: Interaction with CBER/OTP

CATT: CBER Advanced Technology Team; BLA: biologics license application, PAS: postapproval study, IND: Investigational New Drug, BT: breakthrough therapy, RMAT: designation and regenerative medicine advanced therapy, EOP: end of phase

Emerging Technologies for Multiple Products

Closed aseptic filling system

A closed aseptic filling system ensures that products, particularly injectable biologics, are filled into containers in a sterile environment without exposure to contaminants. This system maintains sterility throughout the filling process, reducing the risk of contamination and improving product quality.

Isolator and robotic arm for aseptic filling

The integration of isolators and robotic arms in aseptic filling processes ensures precision and minimizes human intervention, further reducing the risk of contamination. These automated systems enhance the efficiency of filling, while improving reproducibility and compliance with stringent regulatory standards.

Novel Container and Closure Systems for Injectables

The development of novel container and closure systems is essential for enhancing the stability, sterility, and shelf-life of injectable products. Innovations in packaging materials, such as prefilled syringes, polymeric vials, and wearable injectors, are improving patient convenience, ease of administration, and overall product performance.

Interactions with the Office of Therapeutic Products

The OTP, part of the FDA’s Center for Biologics Evaluation and Research (CBER), is responsible for regulatory oversight of biologic products. The OTP plays a critical role in ensuring that biologic therapies, including cellular and gene therapies, meet rigorous safety and efficacy standards.

The OTP oversees a diverse range of advanced therapies, including recombinant proteins, gene therapies, cell therapies, therapeutic vaccines, and xenotransplantation products. (Xenotransplantation involves transplanting cells, tissues, or organs from nonhuman animals into human recipients and presents unique regulatory challenges.) Developers of advanced therapies regulated by the OTP have multiple opportunities to engage with the office through both informal and formal meetings. Formal meetings follow established processes for requesting, scheduling, preparing, conducting, and documenting the interactions. These meetings provide sponsors with the opportunity to clarify regulatory requirements, discuss data submissions, and address any concerns about product development.

By embracing these technological advancements, the biologic drug development process becomes more adaptable, enabling faster time to market and enhanced product quality.

In the context of biologics and advanced therapies, the sponsor is typically the entity responsible for initiating clinical investigations and regulatory applications, such as IND applications. Sponsors may be pharmaceutical companies, academic institutions, or government agencies that seek regulatory guidance and support for their product development. By fostering close interactions between the FDA and industry sponsors, the OTP ensures that innovative therapies are developed in compliance with regulatory standards, enabling faster access to safe and effective treatments for patients (see Figure 3).

Conclusion

The integration of emerging technologies in biologic drug development is paving the way for faster, more efficient, and cost-effective manufacturing processes. Innovations such as continuous manufacturing, advanced process controls, and personalized drug delivery systems are reshaping the biopharmaceutical industry, whereas regulatory frameworks like those provided by the OTP help ensure that these technologies align with safety and efficacy standards. As the industry continues to evolve, these technological advancements promise to drive the next generation of therapies, improving patient outcomes and transforming healthcare.

The adoption and implementation of innovative technologies in the CMC phase is pivotal to the advancement of biologics development. As biologics become increasingly complex, these technologies provide the tools needed to address the challenges of product consistency, regulatory compliance, and manufacturing scalability. Innovations such as advanced analytical methods, real-time process monitoring, automation, and data-driven decision-making empower manufacturers to produce high-quality biologic therapies with greater efficiency and precision.

By embracing these technological advancements, the biologic drug development process becomes more adaptable, enabling faster time to market and enhanced product quality. Furthermore, the integration of cutting-edge technologies in CMC not only improves the robustness and reliability of biologic products, but also fosters the flexibility needed to meet the dynamic regulatory demands and global market expectations. Ultimately, the continued evolution of CMC through the adoption of these innovations will lead to safer, more effective biologic therapies, benefiting patients and the broader healthcare landscape.

The strategic adoption and seamless implementation of innovative technologies in CMC are essential for maintaining the high standards required in biologic drug development, ensuring that these complex therapies can meet the growing demands of modern medicine.