Monthly Archives: September 2019

Antibody Drug Conjugate (ADC) Development and Manufacturing Challenges and Solutions

In this podcast, we interviewed Dr. J.J. Luo, Executive Director and Dr. Lily Yin, Head of Biologics Conjugation Development, at WuXi Biologics about the state of the ADC marketplace and the challenges in developing antibody drug conjugates. We then dove into reasons behind why they built a dedicated manufacturing facility for ADCs and other bioconjugates and how a single-source development platform can benefit bioconjugate drug development efforts.

Podcast Notes:

I began the podcast by asking Dr. Luo about WuXi Biologics’ investment in and construction of multiple clinical and commercial scale facilities around the world. I pointed out that nearly all of these facilities are dedicated to the GMP production of Drug Substance and Drug Product of antibody or recombinant protein therapeutics, but their new facility appears to be dedicated for a very specific niche within the biologics industry. JJ explained that the new facility was purpose-built for the manufacture of a wide range of bioconjugates, in which the largest class of these products would be Antibody Drug Conjugates. He went on to say that this new facility is part of WuXi Biologics’ new state-of-the-art integrated Biologics Conjugation Solution Center in Wuxi City, China. The center will consolidate all bioconjugate drug development and commercial manufacturing of bioconjugates in the future.

I followed up by asking JJ about the drivers behind building a facility dedicated solely to ADCs and other bioconjugates. He stated that although bioconjugates are a subset of the greater biological therapeutic marketplace, various market research reports have shown a year on year increase in the number of ADCs and other bioconjugates entering clinical trials over the past 5 years by roughly 12% per year worldwide. Some estimate that commercial sales of ADCs will grow 22% annually for the next 5 to 10 years. In addition, based on drug company pipeline data, it appears that this trend will continue into the foreseeable future. JJ made it clear that WuXi Biologics’ mission is to provide open access drug development platforms to ensure that every drug can be made and every disease can be treated. Given WuXi Biologics’ expertise, vast capabilities, and resources they believe that they can provide a single-source product development and supply chain for companies developing these novel therapeutics.

Dr. Yin added that WuXi Biologics has a strong history of providing extensive product development and manufacturing services to clients. They have developed a wide variety of bioconjugates from idea to GMP manufacturing for clinical study. She goes on to share that they have provided full CMC services for 11 IND filings for bioconjugate products in just the last few years and 25% of the total IND filings for ADCs in 2018. With the new bioconjugation facility, WuXi Biologics’ has increased GMP manufacturing capacity for both drug substance and drug product and can meet their client’s needs for clinical supply while still offering additional capacity for new clients.

Next, I asked Dr. Yin about their ability to provide a single-source for all bioconjugate needs. I clarified that ADCs and other bioconjugates are complex molecules with both chemical and biological components. I wanted to know how they would be able to provide all the services required to get from early discovery to clinical supply and if there were any gaps. Lily said that WuXi Biologics is known for their ability to take clients from early discovery and lead generation of antibody therapeutics into development and the clinic. Through WuXi Biologics’ expertise and single-source services they are able to provide this without having to use another service vendor. She went on to say WuXi Biologics is now a separate company, but it is still a member of the WuXi AppTec Group of companies. They still work very closely with the Group and utilize its vast resources and capabilities in discovery chemistry, development and GMP manufacture of small molecule payloads and linkers. In addition, WuXi Biologics, along with WuXi AppTec, can provide the essential preclinical services such as DMPK, oncology research, early stage IND-enabling toxicology amongst other critical services. Couple these single-source services with the fact all of these services and the entire supply chain are within minutes to a couple hours from each other and WuXi Biologics can provide a significant advantage in time and also risk reduction for any company wanting to develop these type of drugs. Lily encouraged listeners to go to their website to learn more about their comprehensive capabilities.

Then we discussed how some of the new bioconjugate modalities often contain highly potent or highly toxic payloads thus requiring development and manufacture of these intermediates and the subsequent conjugation to be done in special facilities equipped to handle these compounds. They often also require additional oversight from regulatory authorities. I asked JJ how WuXi Biologics is addressing these types of intermediates and compounds. JJ described how their new facility has been purpose-built to handle highly potent and toxic materials. The design and construction were set to meet U.S. FDA, EMA and China National Medical Products Administration (NMPA) standards for those compounds.

We then focused on how ADCs have historically had many challenges in development and also challenges in demonstrating efficacy in humans. I asked Lily what is the industry doing to help mitigate these development challenges, reduce risks, and help ensure success to move more of these treatments into the clinic and hopefully to commercialization. Lily acknowledged that there have been set-backs and challenges in the field, but stated that bioconjugates are still a relatively young field with a lot left to learn on how we can more effectively develop successful drugs. She went on to say that the good news is that there are 5 ADCs on the market with approximately another 10 in late stage clinical trials with over half of those having obtained “Fast-track” status. WuXi Biologics believes that this demonstrates that the industry is beginning to turn the corner with better understanding of how to develop these molecules for clinical success. She shared that there is a better understanding of how to engineer antibodies to find suitable targets, how to select an active toxin, and how to use better linker chemistry to create better targeted binding characteristics, improved in vivo half-life, more consistently controlled drug-to-antibody ratio, residual free drug levels and better payload release to control drug levels in vivo.

I then asked Lily what specifically WuXi Biologics is doing to help further the ADC field. She said that they have now worked with so many different antibody or other biological molecules, linker and payload chemistries and combinations thereof, that they are uniquely qualified to advise clients on development strategies that will best suit their needs and ensure success. They have strong manufacturability and developability strategies when evaluating the various technologies and bioconjugation options to provide sound data driven decisions for lead selection and throughout development in order to generate a robust GMP process. Looking at many of the challenges and pitfalls of certain linker and bioconjugation schemes WuXi Biologics has continually developed their own new technology platforms for linkers and in some cases proprietary modifications to enhance certain payloads to increase their effectiveness for first in human trials.

I followed up by asking Lily to elaborate on the proprietary technologies she mentioned and also to discuss the benefits of WuXi Biologics’ IP. Lily said that they have developed a novel linker for Lysine-based conjugation that demonstrates higher reactivity, better solubility and a more flexible range of conjugation temperatures and the ability to conjugate this linker to other molecules beyond IgGs. Their unique payload chemistry involves more homogenous drug loading for cysteine conjugation. She went on to say that they would be happy to discuss more under a CDA with any company who is interested.

Next I asked JJ if these technologies were scale-able. He clarified that WuXi Biologics designed all of these technologies with an eye for ease of formulation and to be able to scale up for clinical trial scale and beyond.

I followed up with JJ and asked what manufacturing scales could be achieved at the new facility. He said that the new facility could produce up to 50 batches per year with up to 2 kilograms per batch for drug substance. He said that they can perform both liquid and lyophilization for Drug Product fills with a maximum of 100,000 2R vials per batch for liquid fills and 25,000 2R vials per batch for lyophilized fills. In addition, they are able to provide GMP lyophilization of ADCs in various vial sizes including 2R, 6R, 10R, 20R and 50R. He also mentioned that the facility could perform filling of other non-bioconjugate products such as small molecule or peptide therapeutics as long as they require liquid or lyo type fills. He added that since this is a multi-product and multi-use facility, they are utilizing single-use systems including single-use compounding vessels, tubing, bags, and filling needles for the entire bioconjugation and drug product compounding, filling and finishing process. They do this to greatly reduce risk during the GMP manufacturing runs and provide the highest level of quality assurance for their clients.

I asked that since they are working with highly potent and toxic compounds in this facility were there any special equipment requirements. JJ shared that isolator-based systems are widely utilized in the industry for working with highly potent or highly toxic materials, so they utilize isolator-based systems for payload and linker dispensing and dissolution, filling and lyophilization. In addition, fully automated equipment is used for vial washing and depyrogenation, filling, and for automated loading and unloading the drug product containers into and out of the lyophilizer. Filling is operated by an automated peristaltic pump dosing system and weight check is performed using on-line weighing system for automatic fill weight adjustment. If required, the filling line is also equipped with Nitrogen blanketing capabilities and light protected material handling is also available from start of fill processing to final package steps.

Lastly, I asked when they will start GMP ADC manufacturing activities. JJ said that they have just started operating the facility and their first GMP production will be in the third quarter of this year. There are nearly 20 lots that are scheduled including 10 GMP lots by the end of this year. So, although he said that they will be busy, there is still capacity for this year and next year as well.

I closed by thanking JJ and Lily for their time. The interview was very informative and provided good insight into the current state of the ADC/bioconjugate marketplace and how the industry and WuXi Biologics is working to overcome the historical challenges. It looks like a bright future for bioconjugated therapeutics is ahead of us.