The complexity of new biologics means that these life-changing therapeutics require complicated development and manufacturing processes. Product-specific chemistry, manufacturing and controls (CMC) platforms are required at all stages throughout the development of biologics. By partnering with external organizations that offer integrated CMC solutions, biopharma companies can ensure the successful development and manufacturing of complex biologics and deliver therapies to patients sooner. 

In this article, Jiwoo Bae, Senior Scientist in Complex Antibody Downstream Process at Samsung Biologics, explores how integrated CMC solutions can bring success to the development and manufacturing of complex biologics. She shares unique insights into the evolution of biologics, the rising demand for more complex therapies and hitting key development milestones, with information on how integrated CMC platforms can bring these areas together and deliver successful biologics development and manufacturing. 

The Evolution of Biologics

Development in the biologics sector has led to the evolution of therapies such as monoclonal antibodies (mAbs). Engineered in the laboratory for precise target binding, mAbs have come to the fore as a therapeutic avenue with immense potential. Antibody-based therapeutics hold the promise of addressing a wide array of medical conditions, making them a versatile asset in the search for effective treatments. Although there is increasing interest in other modalities, mAbs are expected to maintain market leadership with a projected compound annual growth rate of 11.04% until 2030. The global mAbs market, valued at $210 billion in 2022, is expected to grow to $494 billion [1].

Continued innovations, supported by CMC platforms, have enabled the design of advanced therapeutics. These advanced therapies can offer advantages over traditional mAb products, such as increased efficacy and specificity or reduced side effects. Furthermore, innovation continues to flourish beyond mAbs, with the following intricate therapeutic constructs emerging as a result:

Bispecific Antibodies (BsAbs): Designed to simultaneously target two distinct antigens, potentially heightening treatment efficacy and diversifying therapeutic possibilities.

Complex antibody treatments are becoming more prominent and are designed to target a wider range of medical conditions. However, the development of new therapeutic modalities is more complex compared to traditional mAb therapeutics. The pressing demand for advanced medical solutions and innovative treatments drives the need for integrated CMC solutions in development and delivery. However, the development and manufacturing of biologics at pace is not simple. 

The Rising Need for Complex Biologics

In the dynamic landscape of biologics development, the demand for increasingly complex therapeutic molecules has surged. BsAbs offer a novel approach to disease intervention, often targeting intricate pathways and enabling synergistic mechanisms of action. Their capacity to simultaneously engage multiple therapeutic targets presents a potential solution for ailments with complex pathogenic pathways that single-target therapies may struggle to address effectively. This versatility in targeting pathological pathways has ignited BsAb application across a wide spectrum of diseases, spanning oncology, autoimmune disorders and infectious diseases, among others. Following the first BsAbs product approval in 2009, the number of these innovative therapies, either approved or under clinical evaluation, has grown to more than 220 [2].

However, the remarkable potential of BsAbs comes hand in hand with intricacies that set them apart from conventional antibodies with singular biological targets. Ensuring the precise assembly of multi-target antibodies, which can exhibit either IgG-like or non-IgG-like structures, demands rigorous development and manufacturing strategies. Furthermore, their multi-target nature increases the risk of unintended side effects or interactions, necessitating specialized design considerations and stringent evaluation methods.

BsAbs manufacturing in particular presents several issues that developers must learn to address, including:

Stable Expression System and Yield: Establishing a robust expression system is essential for consistent BsAbs production. Achieving a high and stable yield ensures a reliable supply of therapeutic molecules, supporting successful clinical outcomes.

Precise BsAb Assembly and Function: Precise assembly of BsAbs, whether resembling IgG antibodies or having distinct structures, is critical. This ensures that the therapeutic molecule functions as intended, targeting specific cells or molecules effectively.

Unwanted Species Minimization: During BsAbs production, the formation of undesired molecular variants must be minimized. This helps maintain product consistency and reduces the risk of unexpected interactions or effects in patients.

Immunogenicity Risk Assessment: Evaluating the potential for immune responses against BsAbs is crucial. Thoroughly assessing immunogenicity risk ensures that the therapeutic remains effective over time and does not elicit harmful immune reactions.

BsAb Efficacy and Safety: Besides addressing structural concerns, ensuring the efficacy and safety of BsAbs is paramount. Rigorous testing and analysis guarantee that the therapeutic not only functions well but is also safe for patient use.

Drug Stability Safeguarding: The stability of BsAbs over their shelf life is vital to their efficacy. Developers must optimize formulation and storage conditions to prevent degradation, maintaining therapeutic potency from production to patient administration.

In contrast with traditional mAbs, which typically target a single antigen, the design, production and assessment of BsAbs introduces an elevated level of complexity. Additionally, in comparison to the well-established processes employed in mAb production, the absence of standardized protocols in the development and manufacturing of complex biologics might amplify uncertainties in the developmental phase.

Accelerating Key Milestones

The pressure is on companies to swiftly usher their groundbreaking biologics to significant milestones and ultimately to the patients who await them. This urgency stems from the aspiration to enhance patient care and address unmet medical needs more expeditiously.

To meet these ambitious goals, biopharma companies find themselves at a juncture where they must identify innovative strategies for both development and manufacturing. These strategies are not just about advancing therapeutic candidates but also about achieving rapid and efficient scalability, ensuring that these life-changing biologics can be made available to a larger patient population.

The complexity of novel biologics adds layers of intricacy to their developmental pathways. These challenges can arise from their unique mechanisms of action, the intricate interactions between different components and the distinctive manufacturing processes required to produce them effectively. 

As a result, there is a growing need for robust strategies in complex drug manufacturing to allow biotechs to rapidly progress and scale their therapeutics. These strategies must aim to minimize the risk that arises from working with unique and unfamiliar therapeutics that could cause delays to market, with every day potentially furthering financial losses. When striving for speed in drug development and manufacturing, quality must remain uncompromised. 

Integrated Solutions for Complex Biologics Development

Aware of the changing needs for biologics and antibody-based therapeutics, contract development organizations (CDOs) are offering integrated CMC solutions to support the accelerated production of these challenging products. Overcoming hurdles to developing complex biologics requires a multi-faceted approach that contains several key elements: 

Adopting an Integrated Development Strategy

Navigating the complexities of biologics development necessitates a seamless fusion of various disciplines, where an integrated development strategy ensures a holistic perspective.

Achieving such integration requires strategic coordination between all teams. This synergy will enable seamless information exchange and an understanding of how changes in processes could impact the critical quality attributes (CQAs) of the therapeutic throughout production. A key step in surmounting complex biologics challenges is the strategic incorporation of platforms designed for swift progress.

Identifying and Addressing Risk Through Enhanced Expertise and Understanding

The road to success in complex biologics is paved with thorough risk assessment. A comprehensive understanding of the molecule’s attributes, potential risk and clinical implications is crucial. Teams armed with technical capability and competency are paramount to success in complex biologics development. As complex biologics are typically unique, diverse expertise can anticipate challenges in areas like stability, immunogenicity and production scalability. By systematically evaluating these risks, developers can tailor their strategies to address specific weakness.

For instance, during the production of a BsAb, developers and manufacturers must establish the ratio of correctly paired desired BsAb to unwanted variants early in the process. Armed with this insight, they can then fine-tune elements in the upstream processing, such as cell culture media. This optimization enables the mitigation of undesired variant production, partial product formation and aggregate generation within the cell culture harvests.

Building Platforms with Acceleration in Mind

Understanding the developability risks of a complex biologics project as early as possible is critical to minimizing potential delays. Assuring an asset has developability and manufacturability is also key to avoiding financial losses later in development. By assessing the risks involved in progressing a molecule at an early development stage, assets with the best potential for advancement to Investigational New Drug (IND) and Biological License Application (BLA) can be selected. 

However, since complex biologics tend to be distinctive compared to the typical mAb materials, standardized production approaches are frequently lacking. By harnessing innovative technologies and capitalizing on expertise, a forward-thinking CDO can devise platforms geared toward optimizing discovery and screening phases.

For instance, by integrating evaluation methods that can screen substances against criteria, it is possible to prioritize potential therapeutic candidates from the early development stage. 

Gaining insights into the molecule’s attributes at this initial juncture supplies crucial information for subsequent stages, including formulation.

Partnerships with CDOs Bring Integrated CMC Solutions to Complex Biologics 

The biopharma industry is marked by unprecedented therapeutic possibilities, advanced by ambitious and effective molecular designs such as BsAbs. As the number of complex biologics entering the development pipeline increases, drug development success will increasingly rely on the ability to minimize the inherent development and manufacturing risks of these products. 

The path toward these possibilities, however, is laden with complexities that demand unwavering dedication and adept problem-solving. 

Partnerships with CDOs provide integrated CMC solutions with the extensive experience, flexible production and capacity needed to successfully scale to commercial levels, along with critical speed in delivery. By partnering with a competitive CDO that offers technical expertise and a holistic development strategy, complex biologics developers can take advantage of integrated CMC solutions, reaching critical milestones and patients sooner. 

References

1. https://www.grandviewresearch.com/industry-analysis/monoclonal-antibodies-market
2. https://www.businesswire.com/news/home/20230705487168/en/Global-Bispecific-Antibodies-Market-Report-2023-Rising-Interest-in-Bispecific-Antibody-Therapeutics-Drives-Growth---ResearchAndMarkets.com#:~:text=It%20is%20worth%20mentioning%20that%2C%20currently%2C%20over%20220%20bispecific%20antibodies,in%20preclinical%20stages%20of%20development.

Author’s bio:

Jiwoo Bae researches and develops recombinant therapeutic proteins and biosimilars at Samsung Biologics as Senior Scientist in CDO Downstream Process Development. She holds a master's degree in Biomedical Engineering at CHA University.