By Trisha Gladd, Editor, Life Science Connect
When Seattle Genetics first entered the antibody drug conjugate (ADC) market, Nathan Ihle, Ph.D., VP of CMC Strategy and Management at the biotech company, says there was limited information available about how to approach the manufacture and control of ADCs. CMOs were not familiar with these molecules, and health authorities had not really worked out their expectations. Furthermore, he says the lessons learned from earlier efforts in the field were not always applicable to the types of molecules under development in the early 2000s.
Because of the state of the market, Ihle explains that Seattle Genetics had to spend a lot of time working through scientific issues with their research colleagues in order to build a better understanding of the most important attributes of the molecules. “We then had to translate this information into a set of manufacturing steps that would produce consistent, appropriate material, and teach manufacturing organizations how to handle the unique unit operations,” he says. “We also worked very closely with health authorities to demonstrate that appropriate control measures were in place.” It is through this process that they have greatly expanded their scientific understanding and effectively established a model for how ADCs can be successfully developed and delivered to patients in need.
Based on Seattle Genetics’ experience of bringing Adcetris to market in 2011, it’s clear that breaking into the
growing ADC market will be both challenging and time-consuming. And because not all companies have the capabilities to create all three components of an ADC—antibody, linker, and cytotoxin—in-house, the next option is to work with at least one other partner. In doing so, you should anticipate encountering several challenges along the way. The question is—will you be surprised to find out what they are?
Thomas Rohrer, senior manager of ADC evaluation at Lonza Group, a contract development and manufacturing organization, oversees project evaluations for their internal ADC team. Because of his experience in this role, he says he believes one of the challenges associated with the ADC supply chain is that companies do not anticipate all the fractional timelines that impact delivery of the drug substance, and therefore, do not plan accordingly. Specifically, many clients underestimate the timeline for sourcing raw materials and developing analytical methods in preparation for GMP clinical manufacturing.
"The antibody can have the longest lead time, depending on whether or not a company has to develop the cell line first. If they have to go through several rounds of clone selection and so on, it can take a period of 9 to 12 months until they’ve actually made a GMP antibody,” explains Rohrer. “As far as the toxin is concerned, the timeline depends on the complexity of the toxin and whether or not it’s semi-synthetic. Semi-synthetic toxins require fermentation followed by several chemical modification steps to produce a functional cytotoxin. This can take anywhere from 6 to 9 months until GMP material is available.” He adds that, as with any potential therapeutic, there is also the research-related activities and functionality of the product and its efficacy. The timeframe for that work should also be taken into consideration.
“The supply chain of an ADC is intrinsically complex,” adds Ihle. “The production of the antibody and the small-molecule components typically require different manufacturing facilities and different skill sets. Conjugation of the individual components typically presents another unique set of requirements. Factoring in the need for special safety protection, due to the high potency of the molecules, and you end up with a complex network of production facilities, each with highly-specialized capabilities. Coordinating the activities across the different parts of the supply chain can be difficult, and the total time required for production is quite a bit longer than for a typical biologic product.”
Rohrer also believes companies may not realize the lead time for development of analytical methods specifically for the ADC, and those have to be taken into consideration as well. “The conjugation doesn’t require a huge amount of time relative to production of the raw materials, but by the time you schedule a GMP manufacturing facility, develop and validate your analytical methods to support release of your drug substance, you can have another six months tagged onto that.” He explains that, since this is a biological product, many of them require not only a cell-killing assay but also an antigen binding enzyme-linked immuno assay (ELISA). Just to develop those methods and supporting reagents, Rohrer says it could take six to nine months, and those assays are required before you can make GMP material. “Companies pursuing an ADC need to put together all of these fractional timelines to understand availability of the drug substance for clinical trials.”
Capacity In Qualified Facilities Is Limited
Dan Bell, vice president of regulatory compliance and technical affairs for Marken, a supply chain logistics company for the life sciences industry, says there are two main areas of risk when it comes to ADCs. The first is the need to maintain the stability of the product through temperature control, especially if you’re crossing borders. However, he says that while temperature excursion is a concern with any biologic, the temperature control supply chain is becoming more sophisticated and that will translate over well for ADCs.
“The second part is meeting the requirements for handling the cytotoxin,” continues Bell. “Toxic products need special handling in the storage and dispensing locations. Not only is a dedicated space a requirement for manufacturing but you also need to ensure there's no opportunity for cross-contamination to which ADCs are particularly susceptible. ADCs also have to be segregated during storage, and if you’re using a depot strategy for distributing your product, there’s a real challenge to how you segregate these types of products from other more conventional medicines stored at the same location.”
Because of these very specific needs, he believes the one of the biggest challenges is finding suppliers that have appropriately licensed and qualified facilities to store ADCs. “As you scale up, you have more and more of this type of product that needs special considerations when it comes to storage, segregation, and how it's handled from a disposal and environmental perspective,” he says. “When I talk to people, they're usually surprised because they've made the assumption that there will be adequate facilities with appropriately trained staff. At the moment, I do not think there are enough facilities qualified to store and distribute ADCs.”
In addition, because of the limited number of companies in the industry qualified to manufacture ADCs, there is some concern that pharma is not going to have the CMO capacity to meet the projected market demand. “You need a very skilled R&D team to be able to support the operations group who will make the drug product in a GMP environment,” explains Rohrer. “You need all of the safety personnel set up to evaluate the program and make sure that they’re creating an environment that is safe for the operations personnel to work with these very dangerous drugs. You also have a lot of analytical activities that are ongoing that involve a biological and a small molecule. The analytics are extremely important for these programs because you have not only full gambit testing in terms of what one would typically perform for a biological, but you’re also performing, in many cases, tests that are unique for small molecule functionality. There aren’t a lot of CMOs that have this fully integrated capability for dealing with both the biological and a small molecule, and that’s the reason the capacity is a bit limiting right now for ADCs. Those that do have the capacity are filling it out a year in advance.”
However, Seattle Genetic’s Ihle believes the industry will be able to catch up in time. “There are encouraging developments that suggest the production needs can be met,” he says. “A number of CMOs and biopharmaceutical companies are expanding their ADC production capacity, and a number of new facilities, both for clinical scale and for commercial scale production, have been announced recently. Furthermore, the high potency of these drugs will allow commercial markets to be satisfied with relatively small volume manufacturing. With continued investment, and implementation of more streamlined manufacturing practices, the industry should be able to meet the market demand.”
In What Is the Industry Underestimating About An ADC Supply Chain? – Part 2, Dan Bell will discuss the regulatory challenges of ADCs, and both he and Nathan Ihle will offer best practices to apply when planning your ADC supply chain.