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Leon: Fantastic! Now I think everyone in the audience and around the world understands why we’ve invited three experts who definitely have many decades of experience in their respective fields, so let’s dive into it today. First, we will talk about how CMC plays such an important role in ADC drug development around the world. Second, we will talk about how CMC plays a role in deal-making on the global stage and third, we would like to invite three speakers to share some often-overlooked aspects.

The first is the essential role of CMC in ADC drug development, which includes drug discovery, preclinical and clinical, IND filing and commercialization. Jimmy, can you share some of your perspective on how you are enabling small biotechs in particular to really get into these areas. Obviously you are focused on ADC, but can you talk broadly about how you are helping them through drug development and also submission for drug approval? Thank you!

Jimmy: Thank you Leon. I think that’s a great question. The majority of our audience online today is probably scientists or executives by training. Drug development is very different from drug discovery. It is a marathon process that requires a full range of expertise. It often happens that a scientist who discovers the drug or has a great idea about the drug probably has very little knowledge or understanding or expertise about how to commercialize the drug in terms of making it stable, high quality and affordable. That is basically what we do as a CRDMO. We help and turn the ideas of scientists or entrepreneurs into a consistent, robust and scalable process.

In terms of ADC, it actually starts at the discovery stage because as I just briefly mentioned, ADC is where chemistry meets biology, so even at the discovery stage, our customers will actually need support because they may be an antibody-focused company that doesn’t have much knowledge of payload-linker, which is a small molecule, or they may be a chemistry-focused company that has a lot of expertise in payload-linker but doesn’t have much experience in antibodies. For ADC, even at the discovery stage, we have found that many of our customers will actually come to us and ask us to basically provide some support and sometimes guidance on how to pair the antibody with the payload or payload plus linker. That happens a lot at the discovery stage.
The CMC phase is even more complex. We often say that developing ADC is almost like developing three drugs, you basically have three different drugs – the antibody intermediate, the payload linker and the conjugates – you have three drug substances and then a final drug product. In a way, you could almost say that developing an ADC is like tripling the work of a typical small molecule or large molecule. We face a lot of cross-disciplinary challenges when you have biology and chemistry coming together in a single molecule. By helping our clients to basically integrate all that different expertise into a single platform, we can get the asset into the clinic as quickly as possible.
Traditionally, many ADC-focused companies have had to contract with multiple service providers because each service provider has different expertise in the large molecule or the small molecule or the conjugates. They might have up to three or even more service companies doing different parts of the work. It takes a very long time. By integrating all the capabilities into a single platform, we can do it all in parallel.

For the ADC CMC work we will have three sub-teams focusing on mAb intermediates, linker payload and conjugation. The three sub-teams are working in parallel and that’s the only way to get the asset into the clinics as quickly as possible.

For example, we call it from DNA to IND in less than fifteen months. If you do it in three separate parts, it could easily take two or three years or even longer. But if you bring all the expertise together under one platform, you can shorten the timeline significantly. Timing is obviously the most important aspect of drug development. Otherwise, first-in-class becomes second- or third-in-class if you don’t get assets into the clinic quickly. That’s extremely important in terms of time-to-IND. Bringing in the full range of expertise and capabilities can go a long way to helping clients reach those critical milestones.

Later on, when it gets to late stage, it’s even more complex. At the BLA stage, there are a lot of very strict regulatory requirements in terms of CMC because it typically takes about three years to get a BLA. This means that the applicant companies have to start preparing the BLA about three years before the date of approval. The work itself leading up to the BLA submission can easily take about two years or more because there is the most important event – PPQ (Process Performance Qualification) – traditionally called process validation.

At GMP scale, you need to demonstrate that your process and product are robust and of high quality. This means that prior to PPQ, you need to carry out process characterization to show that you have a thorough understanding of your process and then that it can withstand some perturbations in terms of parameters.

But PPQ itself is not just about the process. You need to qualify your facility, your manufacturing equipment, your QC labs, and validate each of your analytical methods. All of this must be in place and ready to go before you run PPQ. PPQ is almost like the college entrance exam (gao kao), you do a lot of the lab work upfront and then you run it three or more times to make sure it’s consistent.

But the BLA is much more than that. Because from BLA to approval, there’s always this pre-approval inspection, sometimes it’s called pre-license inspection. It’s like an interview (mian shi) – you’ve done all the work, you’ve got good grades, you’ve submitted everything for the application, then you find out that the FDA or MNPA want to come to your site to see you actually do everything again and ask a lot of questions. So BLA is actually very challenging.

I still remember when I led the first Wuxi Biologics BLA and prepared for the inspection, it took the whole company about a year to prepare because it was the first FDA submission from China in terms of biologics. We put a lot of effort into making sure the whole system was ready for the inspection. Pharmaceuticals are very complex, and biologics are even more complex. What you see in terms of quality is just the tip of the iceberg.

Many people are probably familiar with the term data integrity. It means that every piece of data that you generate in GMP manufacturing has to be traceable, and at any time the FDA can come into your laboratory, the facility that does the testing, and ask you to show where the original data is. You have to show that this data cannot be easily altered. It has to be authentic. There are huge amounts of detailed requirements and regulations that apply in a pharmaceutical GMP operation, not something you can learn from a textbook. It is very likely that people in the biotech industry will have this experience once or twice in their working life.

It’s rare that many CMC people get the chance to go through the whole process, which is why CRDMOs with many successful track records are extremely valuable partners in helping companies get their products to market. The CMC roadmap is full of challenges, spanning the entire drug development process from discovery to IND-enabling, late-stage filing and inspection, GMP compliance and quality requirements.

Leon: Jimmy, you rightly identify a lot of audience actually run in their start-up and most of them come from small biotechs. We all know that the development of these three modalities is very challenging for small biotech to take their assets all the way to approval, commercialization or even manufacturing themselves. The vast majority of these assets are going to be transferred to big pharma, which involves a lot of global dealmaking.

I understand that WuXi XDC has been involved in a lot of ADC out-licensing deals, providing CMC support, particularly to those based in Asia. Can you share with us what the typical due diligence process is when small biotechs get involved with the MNC from a CMC perspective? It would be great if you could share with us any “do’s and don’ts”. Thank you very much!

Jimmy: Sure. For any kind of deal, whether it is a licensing or merge & acquisition, due diligence is an important part of the process. CMC plays a very important role in any of these types of due diligence, especially when a big pharma company is taking over an asset or some assets that are already in the clinic.

For Big Pharma or Big Biotech, when they do their due diligence, they want to make sure of several things. First, where the drug is being manufactured. They need to be sure of the quality system, because they may need to continue to get the drug from the current manufacturer so that the clinical programs don’t get interrupted.

Firstly, where the drug is manufactured. They need to be reassured about the quality system, because they may need to continue to get the drug from the current manufacturer so that the clinical programs don’t get interrupted.

Second, large biotech and biopharma companies tend to have very stringent requirements for CMC. They need to make sure that what they see is basically what they expect from their own lens. For example, their in-house programs, how they do CMC, what their requirements are for CMC, the quality system, whether it matches what they expect to meet FDA requirements or other regulatory requirements.

Third, from a due diligence point of view, these are obviously very critical elements that big pharma will pay attention to. Typically, when it comes to quality, they have some kind of concrete veto power.

It doesn’t matter how good the clinical data is, it doesn’t matter how good the assets are, if they don’t feel comfortable with the CMC, if they don’t feel comfortable with the quality or the compliance, then they don’t have the confidence that they can move the assets into their own hands to continue the clinical trial. If they don’t feel comfortable with the assets, they may have to basically move somewhere else, even if they really like the assets. The consequence is that it will potentially have a significant impact on clinical timelines.

In our case, because of the large client base we already have, many of them are already familiar with us in terms of CMC expectations, quality systems and experience of working together. In many cases we were not even involved in the due diligence, which means that the big pharma or big biotech companies skip the due diligence on the CMC part because they know us so well. We are actually the ones who have been told or found out on the news that one of the assets that our clients are working on is actually going to be acquired or licensed out because the pharma company has basically just skipped the due diligence.

It obviously helps a lot to have that kind of strong support in terms of the CMC part, it makes it so much easier for the client to accelerate the due diligence and hopefully seal the deal.

Leon: That is very good point for your team’s expertise in ADC in terms of the phrase “process is the product”.

Jimmy: That’s a phrase we hear a lot in biologics. It’s very common here and that’s also the reason why in the small molecule space you have the generics that are basically completely interchangeable if the innovator has basically an off-patent, but in biologics you only have biosimilars because it’s always almost impossible to get the identical and that obviously has a lot to do with processes.

Each individual process, or even the transfer of a process from one from one place to another can lead to subtle differences in product quality. That’s why you always hear the phrase process is the product and that’s the inherent challenge associated with biologics. And of course, this also applies to ADCs because you have mAb intermediates. It makes it even more important in terms of CMC to make sure that you have a thorough understanding of your process.

You can demonstrate that the process is robust that when you scale up or move from one facility to another, you have all these quality attributes. You do these compatibility assessments to show that you know that the products are in fact equivalent.

ADC does not have a biosimilar at the moment, so that also says a lot about the complexity of ADC CMC. If you ask the FDA to try to define what the ADC biosimilar would look like, it’s actually a very challenging task.

Leon: Thank you very much. I really enjoyed it. I have learnt so much. Thank you to all the viewers around the world who have dialed into today’s discussion. See you next time and enjoy your day. Thank you and goodbye.