Courtney Morgret, senior scientist, AbbVie

Morgret’s presentation focused on antibody–drug conjugate (ADC) manufacturing and ways to accelerate it. She pointed out that ADCs have the potential to be filed for market approval based on phase 2 data. A few such products have been approved and are on the market today, with many more in the pipeline. ADCs provide an opportunity to address unmet medical needs. The task of a CMC (chemistry manufacturing and controls) group is to move a product forward to get it to patients as fast as possible.

Morgret offered some examples of the mechanisms by which such a program can be accelerated. When there is an unmet medical need, and efficacy has been demonstrated early on in clinical trials, a company can file with phase 2 data instead of the typical phase 3 data required for most programs. Such acceleration can happen at many different points in the development process for an ADC, so manufacturers need to be ready to go at a moment’s notice and bring forward that program as fast as possible.
CMC is a critical part of the filing dossier, demonstrating that a company can manufacture its product consistently and reproducibly every single time. That cannot be bypassed in an accelerated program. “You might have fantastic clinical data, but you still need to show that you can make the product the same way every single time,” Morgret said. “Our objective is to leverage prior knowledge and use some tools to make the CMC program go as fast as possible, considering that the clinical data are compelling enough to file soon.”

She spoke about manufacturing challenges associated with ADCs, products made by linking biologics with small molecules. A complex supply chain has to support biomanufacturing as well as synthesis of highly potent small molecules. The two entities get conjugated and purified before a final filling step. All this can require different facilities and a great amount of orchestration.

Morgret brought up handling and safety issues as well as product heterogeneity. ADC manufacturers need a suite of analytical tools for characterizing their products and making them under a state of control. Another important consideration is the selection of a contract development and manufacturing organization (CDMO) because there are many different manufacturing nodes associated with that process as well as techniques and expertise required to manufacture an ADC. Partnering with an experienced CDMO can help accelerate your program and keep CMC off the critical path.

Morgret pointed out that when possible, it’s good to have a CDMO that can manufacture multiple components of your ADC. This provides flexibility in scheduling as well as reduced shipping costs. When operating under one quality system, you can forward process materials with a limited subset of testing because all are part of the same supply chain. It’s also important to have a strong project manager to support those different modes as they happen at the same time. Another consideration is to transfer a project early to your commercial supplier because that prevents a need for technology transfer later on in development, which requires additional time and resources. If you can get it to your supplier sooner, it helps make filing more straightforward.

When choosing a CDMO, look for demonstrated product understanding, manufacturing experience, and regulatory experience. In terms of product understanding, ADCs often are heterogeneous, so it’s important for manufacturers to understand the analytical techniques available to characterize and then control such products. Process characterization is a key component of the development program and of a CMC dossier, so having a history of characterizing other programs would be beneficial. Developers also should look for comparability strategies in cases of changes to process, site, or material: Is the material comparable to what has been made historically? The primary aim is to ensure that a process is appropriately robust for commercial launch. Companies need to ensure that process ranges are defined so they make consistent product every time.

Morgret stressed that the core of process characterization is patient safety and efficacy. She commented on the importance of analytical techniques, upon which the control strategy depends; the role of comparability studies to support the life cycle of a product; the importance of reproducibility following site transfer; and approaches to process validation. And she concluded by noting that the goal is to get safe and efficacious products to patients as soon as possible. Because CMC is not bypassed in an accelerated program, partnering with a supplier experienced in manufacturing, analytical, and regulatory interactions is beneficial. Process and analytical understating are paramount to knowing what you are making and being able to provide that evidence in your filing.