The world of Advanced Therapy Medicinal Products (ATMPs) is rapidly evolving, presenting both significant opportunities and unique challenges.
With Oliver Kraemer, a seasoned expert in the biotech field, we dive into the complexities of ATMP development, discuss the differences between biologics and cell therapies, and explore the impact of these differences on development timelines and strategies.
This concept is discussed in greater detail in an episode of the Smart Biotech Scientist Podcast, hosted by David Brühlmann, founder of Brühlmann Consulting.
Differences Between Biologics and ATMPs
Complexity of ATMPs
One key difference between biologics and ATMPs is the latter's inherent complexity. While biologics, such as monoclonal antibodies, represent a significant advancement over small-molecule drugs, ATMPs—such as cell and gene therapies—are considerably more complex.
As living entities, cells have thousands of active pathways that are regulated in intricate ways and respond to their environment. This living aspect makes working with cells as drugs significantly more challenging than working with biologics, which are non-living entities.
Additionally, biologics have a long development history, over 40 to 50 years, with established platforms and a wealth of knowledge accumulated over time. In contrast, ATMPs are still relatively new, and no existing platform can be leveraged to mass-produce cell and gene therapies.
Each ATMP product is unique, requiring individualized development, manufacturing, and regulatory pathways, making the process more complex and time-consuming.
Manufacturing and Supply Chain Challenges
The manufacturing challenges for ATMPs are also more pronounced. Biologics benefit from well-established manufacturing processes that have been optimized over decades.
In contrast, ATMPs often face significant hurdles in manufacturing, particularly related to raw materials and supply chain logistics. Many components used in ATMPs are based on research-grade materials, which are not readily available in the quantities needed for large-scale production under good manufacturing practices (GMP).
Moreover, the supply chain for ATMPs is also more complex. Cell and gene therapies often require specialized storage conditions, such as ultra-low temperatures, and may not be easily accessible worldwide. This can limit the ability to deliver therapies to patients promptly and efficiently. The unique storage and transportation requirements of ATMPs are an ongoing challenge for the industry.
Oliver Kraemer's Biotech Journey
Oliver Kraemer's path into the biotech industry began with a deep interest in biology and genetics.
Early on, he knew he wanted to study something related to cells and genetics, though the specifics of his career path were not yet defined. His interest in bioprocess engineering began during his university studies in Germany, where he was exposed to the intersection of biology and engineering.
This shift towards bioprocess engineering became a defining moment in his career, leading him to focus on biotechnology from an academic and industrial perspective.
After completing his studies, Oliver's career began at Boehringer Ingelheim, where he learned the intricacies of large biopharma companies, regulatory frameworks, and the broader landscape of the biopharma industry.
His journey continued with roles at Sanofi, where he worked on cell therapy products, and later at Bristol Myers Squibb (BMS) and smaller startups like Tune Therapeutics. Now, Oliver is with Flagship Pioneering, working in the exciting and challenging cell and gene therapy (CGT) field.
Predictability and Transferability of Knowledge in ATMP Development
Given the complexity of ATMPs, transferring knowledge from one product to another is often challenging, primarily when products differ in key aspects, such as the source of cells or the type of therapy being developed.
- Gene therapies: Knowledge gained from one gene therapy product may be transferable if similar vectors, delivery methods, or target genes are involved. However, even in gene therapy, there are significant variations between products, particularly in viral vectors and delivery systems.
- Cell therapies: Cell therapies are particularly variable. Autologous therapies, which use a patient's cells, introduce variability from the beginning, as the starting material differs from patient to patient. On the other hand, allogeneic therapies use cells from healthy donors and introduce their challenges, particularly in terms of cell line stability and scalability.
Each type of therapy requires distinct development approaches, making it difficult to apply a one-size-fits-all strategy across different ATMPs.
Development Strategy for ATMPs
The lack of a platform approach in ATMP development significantly impacts the overall strategy. Unlike biologics, where the separation between research and development can be clear and streamlined, ATMPs require more integrated development strategies.
Decisions around cell lines, manufacturing processes, and product characteristics must be made much earlier. For example, in the case of induced pluripotent stem cells (iPSCs), deciding early on which cell line to use is crucial, as this decision will affect every aspect of product development, from research to clinical trials.
Using a cell line only available for research can cause delays when switching to a clinically approved line later in the process. Similarly, decisions around manufacturing, such as whether to use a 2D or 3D system or which media and cofactors to employ, can significantly impact product quality and timeline.
In summary, ATMP development requires a more proactive and integrated approach, with decisions made early to avoid costly delays and complications later on.
I don't think that automation, for example, is the ultimate solution for advancing CGT development at this point in time. It is probably good for future iterations, but I think when we look at ATMPs and the complexity of these processes, automation usually thrives in standardized processes that have minimum variability. And CGTs, what we have seen is that they often require a lot of customization and they are very finicky.
Key Considerations in Advanced Therapy Medicinal Products (ATMP) Development
Developing Advanced Therapy Medicinal Products (ATMPs) requires a distinct approach compared to biologics or small molecules. These therapies, which include gene and cell therapies, involve a complex process with unique challenges that necessitate careful planning and early decision-making.
Additionally, there is a growing recognition that the strict separation of research and development (R&D) does not function well for ATMPs. The challenges of ATMP development necessitate more integrated approaches, and the current models often fail to address these needs.
Early Process Development Integration
In ATMPs, integrating process development and research earlier in the development process is critical. Unlike traditional biologics or small molecule drugs, ATMPs benefit from an early focus on the process, which can significantly reduce the likelihood of failure and prevent unnecessary repetition of tasks later. Starting the process development early ensures a more successful and efficient pathway to clinical trials and market introduction.
Complexity and Cost of ATMP Development
ATMPs are notably more complex and costly to develop than biologics. The financial burden of the development phase can be surprising to those new to the field. This complexity requires careful planning and resource allocation to ensure the successful development of these therapies. The high costs are driven by the specialized techniques and resources needed, from cell line selection to clinical testing.
Early Decision-Making in ATMP Development
Early decisions are crucial in the development of ATMPs. This contrasts with biologics, where decisions about processes and product specifications can often be made later in the development cycle.
For ATMPs, decisions regarding cell line selection, process design, and scalability need to be made earlier to avoid costly delays later in the process. Identifying and addressing potential challenges in the early stages of development helps streamline the process and mitigate risk.
The Role of the Process in Cell Therapy Development
The Impact of Process on Cell Behavior
In ATMPs, particularly cell therapies, the process plays a fundamental role in determining the product's final characteristics. Unlike biologics, where the mantra "the process is the product" generally applies, for cell therapies, the process and biology set the boundaries. In other words, the process influences the cells' biology.
The concept of "biological fitness" highlights how the behavior of cells in culture can vary even when starting from the same initial cell line. Small environmental changes, such as shifting from a 2D to a 3D culture system or altering the production media, can lead to significant differences in cell behavior, stability, and growth. Considering that the cell is the product, this variability directly impacts the product's quality, yield, and efficacy.
The Transition from Research to Commercial Scale
One of the major challenges in cell therapy development is the transition from research-grade cell lines to those that can be used in clinical trials or commercial production. While cells may behave predictably in research settings, scaling up the process often introduces new variables that can alter the outcome.
For example, some cell lines may perform well in 2D systems but become genetically unstable or fail to grow effectively when transitioned to 3D systems. This unpredictability underscores the importance of early-stage testing and process validation.
Bridging the Gap Between Research, Development, and Clinical Trials
Integrated Team Approaches
As mentioned, to manage the complexities of ATMP development, some organizations opt for a more integrated approach between research and development teams. This approach eliminates the traditional boundaries between these two areas, allowing for a seamless exchange of expertise and early consideration of all relevant factors.
This integrated team model helps ensure that critical aspects of the development process, such as cell line selection and media compatibility, are addressed from the outset.
Addressing the Interconnectedness of Key Variables
The interconnected nature of the cell line, media, and process presents another significant challenge. Developing a robust process for ATMPs requires carefully considering how each variable influences the others.
While conducting large-scale experiments to test all possible variables would be ideal, resource limitations often make this approach impractical. Instead, a stepwise approach is used, evaluating individual factors and progressively validating their impact on the final product.
Early cell line testing in media with a clear path to GMP (Good Manufacturing Practice) or commercial production is essential to minimize the risk of encountering issues later in the process.
Practical Testing Strategies
Testing cell lines in different media and under various conditions early in development is key to ensuring their suitability for clinical use. This testing does not need to be conducted at a large scale but should focus on evaluating how the cells behave in potential production conditions. By testing cell lines early, developers can identify issues such as genetic instability, changes in pluripotency, or altered growth characteristics before scaling up the process.
Automation in ATMP Development: Not the Ultimate Solution
While automation is a valuable tool in addressing some challenges in ATMP development, it is not the ultimate solution, especially at the current stage of the industry.
Automation typically thrives in standardized processes with minimal variability. However, ATMP processes often require high customization and can be highly variable. For instance, CAR-T cell therapies and viral manufacturing processes frequently do not perform as predicted, making automation less effective in these areas for the time being.
Although it is commonly believed that automation will drive down costs and make manufacturing more accessible, this is not expected in the near future. The complexity of ATMP processes requires more tailored approaches, and automation will likely become more relevant in future iterations of these therapies.
Enhancing Patient Access to ATMPs
Autologous vs. Allogeneic Therapies
The shift toward allogeneic therapies is a critical factor in increasing patient access to ATMPs. While autologous therapies derived from a patient's cells have specific challenges, such as immunogenicity and efficacy concerns, they are often more costly and complex to produce.
Allogeneic therapies derived from a donor's cells offer the potential for more efficient manufacturing processes, which can significantly reduce the cost of goods and, ultimately, the price of the therapy. Shifting focus toward more allogeneic therapies could increase patient access by making treatments more affordable.
Efficiency in Gene Editing and Manufacturing
In addition to the development of allogeneic therapies, advances in gene editing and manufacturing efficiency are essential for reducing costs and improving patient access.
Investments in optimizing the production process, whether through gene editing technologies or more efficient cell line and media development, can reduce the cost of ATMPs. As the industry continues to refine its processes and technologies, it is hoped that these efforts will make life-saving gene and cell therapies more accessible to a wider range of patients.
Reducing Risk and Improving Efficiency in ATMP Development
Leveraging Experience from Biologics
Reducing the risk of failure in ATMP development is a gradual process that will be refined over time. As in biologics, experience plays a key role in understanding what works and what doesn't.
However, many lessons from biologics can be applied to ATMPs, such as streamlining the process and identifying best practices for cell line development, production scaling, and regulatory compliance. Drawing on this experience will help to avoid pitfalls and accelerate the development of these therapies.
Bridging the Biologics and ATMP Worlds
There remains a divide between the biologics and ATMP sectors, with each industry operating in its silo. However, the growing intersection of these two fields presents an opportunity to bridge the gap and leverage the expertise and technologies developed in the biologics space.
This cross-industry collaboration can enhance the development of ATMPs by introducing new perspectives and solutions to existing challenges. Connecting professionals across these fields will foster innovation and speed up development.
Key Takeaways
- Early Integration of Process and Research: Process development should be incorporated earlier in the ATMP development process to reduce the risk of failure and avoid unnecessary delays.
- Increased Complexity and Cost: ATMPs are more complex and costly to develop than traditional biologics. Awareness of these challenges is crucial for successful development.
- Importance of Early Decision-Making: Early decisions like cell line selection and process design are critical in ensuring a smooth transition to clinical trials and commercial production.
The development of ATMPs offers immense potential but also requires navigating numerous complexities. By adopting a proactive, integrated approach and learning from biologics, the industry can continue to make strides in delivering these life-saving therapies to a broader patient population.
Some decisions in ATMP development have to be taken a lot earlier compared to biologics. We talked about cell line selection, maybe process design, maybe your scale question. What are you actually aiming for to supply later on? And that changes a little bit how you develop this product.
Final Remarks
The development of advanced therapy medicinal products (ATMPs), particularly cell and gene therapies, presents unique challenges compared to biologics and small molecules. These therapies are highly complex and costly to develop, requiring careful consideration of process development and research integration from the outset to reduce failure rates and avoid redundant efforts.
Key factors such as the choice of cell lines, media, production systems, and the biological behavior of cells in culture significantly impact product outcomes. Close alignment between research, clinical trials, and the final product is essential, with a collaborative approach between research and development teams offering an effective strategy. Additionally, shifting toward more allogeneic therapies and enhancing production efficiency could improve accessibility and lower costs, enabling broader patient access.
As the industry continues to evolve, leveraging lessons from biologics and fostering cross-disciplinary collaboration will be critical to accelerating advancements and ensuring success in this field.
About Oliver Kraemer
Oliver Kraemer is leading the technical development at a new biotechnology venture within Flagship Pioneering. He holds a PhD in molecular biotechnology from the University of Bielefeld. Oliver began his career as a PostDoc in cell line development for biopharmaceuticals at Boehringer Ingelheim. He then transitioned to Sanofi Frankfurt, where he led the German upstream development department, before moving to BMS in Seattle to work on iPSC- and donor-derived allogeneic and autologous cell treatments. He also briefly worked at Tune Therapeutics, an epigenetic editing startup. Throughout his career, Oliver has contributed to multiple Investigational New Drug (IND) applications and Biologics License Applications (BLAs) for biologics and cell therapies.
Connect with Oliver Kraemer on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.
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