The ADC Landscape
There are currently only two ADCs available on the market—Seattle Genetics’ Adcetris (brentuximab vedotin), for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma; and Kadcyla, Genentech’s therapeutic for metastatic HER2-positive breast cancer. Behind these marketed molecules, there is a robust pipeline in clinical development. According to U.S.-based analysts Roots Analysis, the ADC market could be worth more than $600 million by the end of 2014, and $10 billion by 20241.
In 2014, there were around 238 Phase I to Phase IV clinical trials underway, involving 45 ADCs in the pipeline along with the two already on the market. The majority of the trials were in Phase I and II (see Figure 1).2.
A Challenging Supply Chain
Around 70-80% of ADC manufacturing is outsourced1 through a complex and fragmented supply chain. For sponsors, or innovator companies, one of the key challenges in the process is logistics. To begin with, the antibodies and the source materials for the linkers and payloads may have to be sourced from multiple locations, and then shipped to the contract manufacturing organization (CMO) that will carry out the conjugation. The conjugated ADC molecule may then have to be shipped to another CMO for the fill/finish step—maybe even across country boundaries.
As rapid advances are being made in the ADC field, a wider variety of novel and proprietary payloads and platforms are being used. This advancement not only increases the challenges of sourcing and handling materials, but the greater potency also calls for more sophisticated analytical testing.
Collaborating to Meet Customer Needs
Closer collaboration between contract manufacturers at various stages of the production process could help smooth the path to clinical trials for sponsor companies. A recent collaboration, announced in September of 2014, between SAFC and Baxter BioPharma Solutions, is based on this concept, and the belief that integrating individual capabilities presents a logical solution for providing customers with a more seamless and safe development of process and analytical methods through to final product3.
Under the terms of the agreement, SAFC contributes expertise in conjugation and the manufacture of drug linkers, and Baxter BioPharma Solutions provides formulation development support and sterile fill/finish services for the final step in the production of ADC products for customers. It is the first collaboration of its kind in the industry, with the simple goal of getting customers’ ADC products to the market more efficiently.
Simplifying the Path to the Patient
For their own cost-efficiency, many CMOs try to operate facilities at high occupancy, and so the sponsor company may experience further delays while waiting for available slots. Delays in production of clinical trial supplies can slow the completion of the clinical trial program, elongating the drug’s route to market, and wasting precious time and resources that could be focused on drug development or the laborious process of piecing together the supply chain.
By collaborating with complementary platforms, facilities and skills, SAFC and Baxter work to mitigate many of these challenges in an effort to speed up customer timelines. Production and completion of the ADC products are scheduled in local facilities to minimize transport time, as well as eliminate waiting time between stages. Once the bulk drug substance is conjugated by SAFC, it is transferred directly to Baxter using established protocols. The teams collaborate to take care of filling specifications, regulatory testing and validation, packaging and import/export paperwork so that the product can be more easily processed and approved for distribution.
Efficient Technology Transfer
Each step of drug manufacturing and handling involves proprietary company information, and CMOs need to be privy to this information—for example, how to carry out product process and release testing—for efficient technology transfer. All parties must understand the value and importance of confidential information, regardless of which party it belongs to, and have a clear understanding of how it will be managed throughout the process. All work is done under confidential disclosure agreements to protect shared intelligence throughout the transfer.
In the case of the SAFC/Baxter collaboration, there are ironclad nondisclosure agreements in place, and each customer works with one point of contact for the duration of the project so that a proper rapport can be created. Behind the scenes, that point person coordinates with internal teams to create a consolidated timeline and manage transparent transfer from stage to stage using established protocols. Operations are simplified on the customer side by having one point of contact, and on the supplier side because all parties are informed and understand the process flow of each project.
When handling cytotoxic materials, safety and time are of the essence. Both the drug substance manufacturer and the drug product manufacturer need to align and standardize practices. It is extremely important that they understand the chemistry of the products being handled. The greatest risk presents itself when toxins are in solid, unconjugated form and are being dissolved prior to the conjugation step. As the ADC is created, the residual levels of toxicity decrease, but handling remains a critical safety issue.
The toxicity component of ADC production is critical, and demands that suppliers be properly equipped to handle the complexity each project presents. In certain cases, suppliers apply for industry certifications to prove expertise. The most highly regarded, SafeBridge Certification, provides an objective and scientific assessment of a company’s ability to safely handle and manufacture highly potent compounds (such as those found in ADCs) to industry standards.
Baxter has SafeBridge-certified facilities in Halle/Westalen and Bielefeld in Germany for parenteral drug substance synthesis and parental drug product manufacturing and testing and SAFC has expanded its expertise in cytotoxic and toxic material handling, with SafeBridge-certified facilities in Madison and Verona, WI. This helps ensure that customers of the collaboration have access to highly certified suppliers across the globe, which is crucial for ADC manufacturers.
Collaborating for the Future
With so much change happening in the biopharmaceutical industry, customers need to have seamless service from their supplier(s). The collaboration between SAFC and Baxter BioPharma Solutions is just one example of how suppliers can help meet this need as they look to support customers through the development process and eliminate their roadblocks to innovation. To remain competitive, and meet regulatory demands of high-risk products like ADCs, collaborations such as this will likely be critical to helping customers bypass the issues a fragmented supply chain present.
This business model creates the potential for products to pass through clinical trials more quickly and cost effectively, while accelerating access to highly targeted and effective medicines for the seriously ill patients that need them.
- Antibody Drug Conjugates Market, 2014-2024. Roots Analysis. August 4, 2014. Available from: http://www.rootsanalysis.com/reports/view_document/antibody-drug-conjugates-market-2014-2024/63.html
- Rostami, S., I. Qazi, and R. Sikorski, The Clinical Landscape of Antibody-drug Conjugates. ADC Review. August 1, 2014.
- SAFC and Baxter BioPharma Solutions Collaborate on Complete ADC Offering. September 24, 2014. Sigma-Aldrich Corporation. Accessed: October 3, 2014. Available from: http://www.sigmaaldrich.com/safc/news-and-resource-center/press-releases/baxter-biopharma-solutions.html
Dr. Cynthia Wooge applies more than two decades of experience in custom product development, technology transfer, process validation and business development to her role as Global Strategic Marketing Manager for SAFC. She works to facilitate pharmaceutical contract manufacturing opportunities for GMP ADC and bioconjugation facilities with a focus on antibody-drug conjugates, therapeutic proteins and bio-organic polymers, in addition to pursuing collaborations such as the one with Baxter BioPharma Solutions. Dr. Wooge received her B.S. in biology from Indiana University, her Ph.D. in pharmacology at the University of Iowa College of Medicine, and completed a post-doctoral fellowship in physiology and biophysics at the University of Illinois.
Dr. Jyothi Swamy has more than two decades of experience in analytical method development, method validation, cleaning validation and stability. She came to SAFC nine years ago as a Senior Chemist, and transitioned into Quality Control Supervisor and Project Management roles. In her current role as Global Project Manager, Dr. Swamy is responsible for custom products with a focus on antibody-drug conjugate projects, and was an integral part of SAFC’s collaboration with Baxter BioPharma Solutions. She holds a Ph.D. in synthetic organic chemistry from the University of Missouri, St. Louis, as well as a B.S. in general science, M.S. in inorganic chemistry from Bangalore University, India, as well as an M.S. in chemical metallurgy from the Indian Institute of Science.
Jennifer Wendorf has been a Senior Marketing Manager for Baxter BioPharma Solutions for more than four years. In this role, she is responsible for coordination between customers and internal manufacturing facility contacts for both complex and traditional sterile manufacturing projects. Ms. Wendorf is constantly gathering valuable insight to apply for the benefit of Baxter customers, and complements her industry experience with a B.S. in communications and a minor in marketing from the University of Wisconsin, Parkside.