Make Strategic Development Choices To Help Accelerate mAb Production

Streamline your mAb manufacturing with strategic development and CDMO compatibility By Robin Dothager, Senior Manager of Process Development; Jing Huang, Supervisor, Process Development; Henry Hymas, Supervisor, Process Development; and Buzz Lobbezoo, Senior Field Application Scientist Antibody therapeutics White paper | Bioprocess resins Monoclonal antibodies (mAbs), including bispecific antibodies and antibody drug conjugates, continue to take the biopharmaceutical industry by storm. The ability of mAbs to provide highly personalized and specific treatments for cancer, autoimmune disorders, central nervous system conditions, and metabolic indications is one of many reasons their expansion is among the fastest in the pharmaceutical world.¹ The journey to delivering these therapeutics to patients begins at lab scale, where executing highly complex processes is still manageable. However, to adequately supply a clinical trial and later, commercial distribution, a mAb manufacturing process must be streamlined and easily scalable to 2,000 L production scale and above. Often, drug sponsors fail to design their early processes with largescale or commercial manufacturing in mind, leading to challenges during tech transfer and scaleup with a contract development and manufacturing organization (CDMO). Luckily, there are plenty of strategies available to tailor your mAb process to facilitate scalability, and with the right manufacturing partner, your mAb workflow will be strategically designed to increase speed-to-market and cost savings while providing a high-quality product for patients. How to overcome common challenges in mAb tech transfer and manufacture In the earliest stages of development, when sponsors are working on bench scales not exceeding 10 L bioreactor volumes, executing processes with extraneous steps or narrow parameter ranges is feasible. However, CDMOs generally find success because of their ability to standardize processes and minimize excessive customization, allowing them to produce consistent batches within reliable time frames. When assessing a potential client’s process for compatibility, a CDMO will consider volume footprint, equipment and facility fit, and temperature control. An elaborate bench scale process will not always translate well to an at-scale GMP process. For example, a sponsor might conduct multiple titrations and dilutions at bench scale with the goal of mitigating risk without procuring any data to confirm that these additional steps are necessary. While this approach is manageable at small volumes, the time and volume of each added step becomes significantly more burdensome as a process scales up. Another common obstacle due to the growth of temperature-sensitive biologics has been the temperature dependency of the process and the resulting need for temperature control. For many CDMOs, this creates substantial work and potential capital investment in equipment to generate additional data for the process steps that had been executed at restricted temperatures. Ideally, a sponsor will develop a process that is performed within the validated temperature range of the manufacturing suites of the receiving sites. Yet another challenge is the reliance on legacy technologies across the industry. Often, sponsors prefer to use technology, i.e., resins or membranes, that have gone through commercialization many times over, proving their reliability. With products growing increasingly complex and requiring higher concentrations, these technologies are becoming outdated. Sponsors find themselves attempting to adapt their processes to older technologies rather than introducing innovative alternatives that could increase efficiency. For example, if you introduce a multi-specific which exhibits high aggregate levels or significant product-related impurities such as half antibodies or mis-paired molecules, the use of traditional platform technology may become cumbersome, resulting in low purity or yield. More modern resins may provide improved resolution, which will yield a more efficient and scalable process. Evaluating these advanced purification tools in the early development phase can provide valuable data when building a preliminary downstream process for future scale up or transfer to a CDMO. A CDMO must also assess whether they have the capabilities and resources needed to accommodate the unique needs of a sponsor’s material and deliver the product within the agreedupon timeframe. Some sponsors may prefer specific equipment for their process, which, in most cases, obligates them to provide the necessary capital to fund it. As CDMOs intensify their focus on driving standardization and ensuring SOP-trained personnel, introducing extraneous steps and new equipment can make consistent process performance even more challenging. Mitigating obstacles across mAb development In the pursuit of finding tech transfer and scale-up success with your chosen CDMO, strive to streamline and simplify your process as much as possible from the start. This reduces obstacles and allows your team to maintain a reliable timeline. Work closely with your manufacturing partner to understand the true scope of your project and outline a realistic timeline accordingly. At every stage, your team and your partner’s teams will need to collaborate on drafting, reviewing, and approval of all quality documentation. Be transparent and honest with your selected partner to minimize delays. When a client misrepresents the type of mAb they are working on, i.e., purporting that it is a standard mAb when it is a bispecific, a CDMO’s lack of knowledge of the biochemical properties of the molecule will hamper their ability to adequately prepare. With a thorough context around the process and molecule, a CDMO can make accurate recommendations on the development process and technology transfer, enabling an accurate timeline rather than one that is constantly extended as both parties recognize the need to generate additional data from an expanded scope of work. If a client has experience with intermediate scale production of their therapeutic, i.e., insight on hold times or opportunities for optimization, either in-house or with a different CDMO, that data should be shared with their new partner to help them prepare to execute a scaled-up process. At times, it is the CDMO that possesses the proprietary data specific to a process, rather than the sponsor. This can lead to a lengthy data retrieval process, resulting in a need to reverse engineer a process if that effort is unsuccessful. When evaluating potential CDMO partners, ensure that you will own all your process data, including batch records. Choosing the right CDMO for you In your assessment of potential CDMO partners, watch out for red flags in quality and compliance as well as their average time for remediation. Assess their previous experience with regulatory agencies, including how they have handled audits, how often they have manufactured approved drugs, and how they have dealt with deviations and change controls. In biopharmaceutical manufacturing, a project never unfolds exactly as planned; thus, it’s important to review a CDMO’s approach to risk management and change management. What procedures do they have in place to identify risks, escalate them, and mitigate them via cross-functional collaboration? From a soft-skills perspective, pay close attention to your early meetings and communications. Do their teams prioritize collaboration and transparency? Can you envision solving problems together? Finally, does a CDMO offer end-to-end capabilities across platforms and therapeutic modalities? Without the silos that often exist when multiple vendors are involved in the drug pathway, i.e., drug substance, drug product, and packaging, a one-source partner can facilitate the transfer of information between departments and enable more streamlined project management. Furthermore, a one-source CDMO will have a variety of materials in-house, allowing you to bring down lead times, mitigate risks, and maximize cost savings; they will take responsibility for procuring materials and assume the corresponding logistical risks. At Thermo Fisher Scientific, our clients can leverage our wide range of resin profiles for different modalities to suit their molecule’s needs. Options include our CaptureSelect™ affinity resins, Thermo Scientific™ MabCaptureC Affinity Matrix , POROS™ ion exchange resins, POROS™ hydrophobic interaction resins, and POROS™ mixed mode cation exchange chromatography resins. 2 thermofisher.com/antibody-derived-therapeutics POROS: Pharmaceutical Grade Reagent. For Manufacturing and Laboratory Use Only. CaptureSelect: For Research Use or Further Manufacturing. Not for diagnostic use or direct administration in humans or animals. © 2025 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified. WTP-11222354 0625 If a client is facing a tight deadline, we recommend they work with our POROS resins, which are proven to be reliable, robust, and easy to work with, and used in many on-market manufacturing processes. If time is not a critical factor, we work with our clients to explore any challenges they are having, guiding resin selection with the science at hand. From there, we conduct a rapid resin screening. While our Protein A resin is typically the first choice for mAbs due to their specificity, this isn’t always the best fit. Guided by the experience of Thermo Fisher Scientific’s experienced professionals, our customers can consider our available alternatives for purifying complex mAbs at GMP scale, ultimately selecting the resin most appropriate for their process and goals with speed and accuracy. Conclusion It is never too early to prepare for scale-up and commercial manufacturing in your mAb development. Prioritizing these outcomes from the beginning can help minimize obstacles throughout your relationship with a CDMO. Therefore, as you assess potential partners, be sure to prioritize those with the experience and commitment to innovation needed to successfully manufacture your mAb therapeutic, enabling you to deliver a high-quality product to patients with efficiency. References 1. Quinteros, D. A., Bermúdez, J. M., Ravetti, S., Cid, A., Allemandi, D. A., & Palma, S. D. (2017). Therapeutic use of monoclonal antibodies: general aspects and challenges for drug delivery. Nanostructures for Drug Delivery, 807–833. https://doi.org/10.1016/B978-0-323-46143-6.00025-7 Learn more at thermofisher.com/antibody-derived-therapeutics