In this article, Jimin Kim and Jangick Lee, Senior Specialists in Contract Development Organisation (CDO) Business Strategy at Samsung Biologics, explore the role of competitive CDO partnerships in overcoming the challenges of producing complex biologics at speed.
Providing their unique insights, Kim and Lee also emphasise the need to implement innovative technologies in the early stages of drug development and discovery through proprietary development platforms to accelerate timelines without impacting quality.
The rapidly evolving biologics space
Since the first monoclonal antibody (mAb) gained approval in 1986, the biologics space has grown rapidly and has subsequently dominated the biotherapeutics market with more than 150 therapies approved to date.1,2
Leveraging the ability of mAbs to bind specifically to certain cells or proteins and stimulate an immune response, these therapeutics have been developed to treat a wide variety of diseases — ranging from cancer indications to autoimmune diseases and neurodegenerative disorders.
Although there is increasing interest in other modalities, mAbs will continue to lead the market with a CAGR of 11.04% projected until 2030. The expansion of the global mAbs market size, which was valued at $210 billion in 2022, is expected to reach $494 billion.3
As our understanding of molecular biology and biochemistry has expanded, so has the potential of antibody based therapies.
Continued innovations have enabled the design of increasingly powerful advanced therapeutics that offer advantages compared with traditional mAb products, such as increased efficacy and specificity or reduced side-effects. These therapies include
- bispecific antibodies (BsAbs) that are designed to improve target specificity by binding two antigens or epitopes
- fusion proteins: these chimeric proteins are created by joining two or more genes that encode for separate proteins (one often being an antibody) to impart specific functional properties
- antibody-drug conjugates (ADCs) that comprise an antibody linked to a biologically active cytotoxic payload or drug.
These revolutionary biologic modalities can provide previously unattainable therapeutic benefits. However, their development and manufacturing are not so simple.
The need for increasingly complex biologics
Complex biologics such as BsAbs have disrupted the biotherapeutics landscape. Following the first BsAbs product approval in 2009, the number of these innovative therapies in the development pipeline — either approved or under clinical evaluation — has grown to more than 220.4
Although complex biologics provide new opportunities to treat complex diseases, including cancers such as non-small lung cell cancer, multiple myeloma, acute lymphoblastic leukaemia and cervical cancer, their development and manufacturing pose inherent challenges.
The optimisation of new therapeutic modalities is more complex than traditional mAb therapeutics. BsAbs manufacturing presents several issues in particular that developers must learn to address, including
- attaining a stable expression system and production yield
- ensuring the correct assembly of intact BsAb (IgG like or non-IgG like) form with the desired function
- minimising the generation of unwanted species
- performing comprehensive immunogenicity risk assessment to ensure BsAb efficacy and safety
- safeguarding the stability of a drug.
Compared with the well-established processes involved in mAb production, a lack of standardisation in the development and manufacturing of complex biologics could also lead to further uncertainty in development.
An unrelenting need for accelerated timelines
Drug developers are under constant pressure to deliver therapeutics to market at an accelerated pace. From the desire to provide life-changing drugs to patients sooner to needing to demonstrate return on investment (ROI) potential to investors, the demand to quickly reach key milestones comes from all stakeholders.
As a result, there is a growing need for robust strategies in complex drug manufacturing to allow biotech companies to rapidly progress and scale their therapeutics.
These strategies must aim to minimise 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 not be impacted.
Overcoming complex biologic development challenges
For drug developers looking to outsource their complex biologic development project, partnering with a contract development and manufacturing organisation (CDMO) that understands the difficulties in accelerating complex biologics pathways is key to success.
Several key elements that a competitive CDMO must have to bring success in complex biologic development are as follows.
An integrated development strategy: When developing complex biologics, their unique characteristics can cause development and manufacturing issues and subsequent delays.
For example, the molecular and biochemical characteristics of a BsAb could mean that certain cell lines are more likely to produce unwanted species as opposed to the correctly assembled product.
Changing the selected cell line to minimise undesired species production and enable higher yields to be achieved becomes more difficult as the project scales.
An integrated development strategy ensures a holistic understanding of how decisions at an early stage will impact all subsequent stages.
This requires all teams to work together, enabling the free flow of information and an understanding of how changes in processes could impact the critical quality attributes (CQAs) of the therapeutic throughout production.
A CDMO that offers end-to-end services is well-positioned to ensure an effective integrated development strategy. By facilitating transparent communication between everyone involved, an end-to-end CDMO can ease tech transfer processes and enable proactive troubleshooting if issues arise.
Expertise and understanding to ascertain risk: Technical capability and competency are paramount to success in complex biologic development.
As biologics are typically unique, a detailed understanding of the molecule and its characteristics is needed to identify potential risks as the project progresses.
A competitive CDMO will be able to forecast potential issues at each development phase and, should they arise, present solutions by utilising its depth of experience and expertise in developing complex molecules.
When producing a BsAb, for example, developers and manufacturers need to determine the proportion of desired BsAb produced with the correct chain pairing compared with undesirable variants at an early stage.
With this understanding, factors in upstream processing, such as cell culture media, can be optimised to minimise the production of undesired variants, partial products and aggregates in cell culture harvests.
The understanding needed to build a successful development strategy and overcome critical manufacturing risks comes not only from previous experience and a wealth of expertise, but also from proactive discussions with clients.
If there is a need to re-engineer processes, the in-depth knowledge gained from the client, including an understanding of their goals, is a critical part of finding the appropriate solution.
Platforms built with acceleration in mind: To minimise potential delays, it is critical to understand the developability risks of a complex biologic project as early as possible.
Ensuring that an asset has developability and manufacturability is also key to avoiding financial losses later in the process chain.
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, as complex biologics are typically unique, there is often no standardised approach for their production. By employing innovative technologies and leveraging expertise, a pioneering CDMO can develop platforms to streamline discovery and screening stages.
By implementing tools that score candidates based on developability criteria at the discovery stage, for example, the molecule with the highest development and manufacturing potential is progressed. Understanding the molecule at this early stage provides critical information for downstream stages such as formulation.
CDMOs driving the future of complex biologics
As the number of complex biologics such as BsAbs entering the development pipeline increases, drug development success will increasingly rely on the ability to minimise the inherent development and manufacturing risks of these products.
Delivering these innovative medicines to patients that urgently need them requires an integrated development strategy bolstered by extensive expertise to overcome issues and prevent delays to market.
Stepping up to the challenge, CDMOs are adapting their capabilities to support these pioneering products, offering innovative platforms with accelerated capabilities built in.
By partnering with a competitive CDMO that offers technical expertise and a holistic development strategy, complex biologic developers can ensure that their project reaches critical milestones and, therefore, patients, sooner.
References
- J.K. Liu, “The History of Monoclonal Antibody Development: Progress, Remaining Challenges and Future Innovations,” Ann. Med. Surg. (Lond.) 3(4), 113–116 (2014).
- X. Lyu, et al., “The Global Landscape of Approved Antibody Therapies,” Antib. Ther. 5(4), 233–257 (2022).
- www.grandviewresearch.com/industry-analysis/monoclonal-antibodies-market.
- 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%20
currently%2C%20over%20220%20bispecific%20antibodies,in%20preclinical%20stages%20of%20development.
