Bioconjugation CMC: Successfully Executing a Complex Process

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Scott A. Miller, senior scientific advisor, Carbogen Amcis AG

Miller provided an overview of bioconjugation followed by a brief discussion of the project management aspects of this highly complex process. Developing and manufacturing antibody–drug conjufgtes (ADCs) is complicated, so it’s important to understand how to manage the processes involved. Some general considerations for developing ADCs include understanding the current phase of a project, the number and status of analytical methods required, the scale of conjugation, the sourcing of both antibody and payload, where and how fill–finish and stability studies will be performed, and related regulatory requirements.

Several challenges arise with conjugation chemistry:

  • Will you use fixed, dedicated technologies or single-use materials?
  • How are you going to purify and scale up your process?
  • How will the drug substance be packaged?
  • What analytics do you need? They are a crucial aspect of development but often get overlooked.
  • What environmental safety and health concerns are at issue?
  • What are the associated costs?
  • What is your regulatory approach?

For companies looking for a contract manufacturing organization (CMO), Miller offered some questions to consider in the selection process:

  • Who will own the intellectual property (IP)? If you are the innovator, then you should be the one who owns the IP.
  • What is the CMO’s philosophy of project management?
  • What is its approach to process R&D?
  • What is its regulatory overview approach?

Other factors also need to be considered, including cost and speed. “As an innovator or developer, you may have a timeline that may not mesh with the real world,” Miller said. “That’s important to keep in mind.” Legal and quality-related paperwork could prevent a project from starting on time.

More general considerations include a CMO’s reputation, corporate culture, and the levels of bureaucracy in both your company and the CMO. Is there a strong analytical QA process and appropriate regulatory experience?

ADCs present even more specific considerations: e.g., a complex supply chain overall, issues related to the safe handling of highly potent compounds, and a good supply chain for both payload and antibody. Can a CMO manufacture products other than antibodies, such as synthetic vaccines? What are its analytical capabilities? Can it work with external providers? That is, if you need to bring in other suppliers, will the CMO work with you on that? If the company requires exclusive supply of all components, that will limit your flexibility.

Setting realistic timelines is critical, as is capturing the results of all the work of formulating your request for proposal. It’s also important to agree on regulatory approaches. And when it comes to technology transfer, it’s imperative to work face to face and to build a strong relationship. Many times, project management problems arise when people on one side don’t get enough interaction with their counterparts on the other. Communication and clear timelines are key to helping a project succeed, as is establishing a system for handling unexpected results and challenges.

ADC development and manufacturing are highly complex, from the toxic payload through the multistep process, complicated syntheses with many purification steps involving challenges related to both the components and the ADC overall, analytical requirements for those as well, and associated environmental and health and safety concerns. All these elements should be evaluated when you consider a CMO to help you develop and manufacture your ADC.

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