Speeding up ADC Development With the Right Partner Organization

As antibody–drug conjugate (ADC) programs progress from the early to late stages of clinical development, and more of these therapies actually penetrate the market, there is a clear need to manufacture ADCs efficiently, cost-effectively and with an eye toward commercial production from the earliest stages of development. Accelerating ADC production is integral to supplying patients with these potentially life-saving therapies while also securing a competitive advantage within the market and guaranteeing shareholders a return on investment. 

Partnering for ADC Advancement

To successfully compete in the ADC space, a strategic approach for reducing time to market is key. Strategic process/analytical development and characterization, commercial manufacturing site selection, and manufacturing-scale process performance qualification (PPQ) are all part of expediting time to launch. Undergoing these activities sooner decreases the risk of unexpected issues arising later in development, which would impact chemistry, manufacturing and control (CMC) activities and be more expensive to correct further down the line.

To avoid any potential missteps in ADC production and speed time to commercialization, partnering with an expert contract development and manufacturing organization (CDMO) that has a history of successes is key for the advancement of an ADC program. The ideal CDMO candidate will demonstrate expertise in early phase process understanding and possess a team of experts with proven scientific and technical knowledge, as well as staff versed in operations and program management, and also be equipped to handle diverse regulatory requirements. Finding the right CDMO partner can mean the difference between a commercial-ready ADC program and one that is unable to move past the clinic. 

ADC Growth and Manufacturing Challenges

Using specific antibodies for targeted cell death, ADCs offer a more advanced treatment for cancer than chemotherapy. This potential has not gone unnoticed in the market. ADC therapeutics are predicted to reach a value of nearly $10 billion by 2025.¹ The success of ADCs against tumors has helped spur the approval of five ADC drugs for oncology indications within the last decade.^2,3 Further potential indications for ADCs coupled with steroids for inflammatory diseases and antibiotics for the treatment of infectious diseases are also currently in development.^4,5

ADCs offer tremendous potential as life-saving therapies for a number of indications, which means pushing them rapidly from the clinic to market is critical. However, the manufacture of ADCs presents a unique set of challenges. Moving an ADC program through a complex supply chain, in which several manufacturing facilities are tasked with producing the antibody, payload, linker, conjugate and final drug product can add substantial time, cost and difficulty to the process. ADCs must also be handled with extreme caution to prevent their contamination and the exposure of handlers to the potent compound. Partnering with a CDMO that is experienced in minimizing risk and assuring product quality can keep an ADC program on track throughout the life cycle.  

A CDMO can help navigate a partner organization through regulatory hurdles and even accelerate approval. To get drugs to patients who are in critical need as quickly as possible, the FDA created the Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review  programs, all of which can potentially be used for the advancement of ADCs. In order to qualify for these accelerated pathways, a CDMO must work to expedite a drug through each phase of the lifecycle, including process design (stage 1), process qualification (stage 2) and continued process verification (stage 3).

Strategic Supplier Selection

Manufacturing ADCs at the designated commercial site is another way to speed up development while allowing the multi-stage process characterization program to begin sooner, eliminating the need for late stage tech transfer and process-intensive comparability studies before regulatory submission. If a partner organization is able to manufacture multiple components of the ADC, product supply lead times are considerably reduced. Operating under an integrated system also creates flexibility. The selected supplier must demonstrate strong program management abilities, especially if multiple phases of the process are mediated by one organization. 

A strategic supplier will also know to begin process characterization in phase I, instead of waiting for phase II. Applying process characterization, which is essential for process validation, to the process after phase I leads to earlier PPQ. For tight timelines, PPQ runs may be tiered to overlap with process characterization. Even though PPQ is typically performed after process characterization, an experienced CDMO will suggest a tiered approach in order to implement PPQ faster. 

The process characterization step ensures that the process is robust enough to deliver a quality target product profile (QTPP) appropriate for commercial launch. In order to successfully carry this out, expertise in analytical method development and application is a priority. The supplier organization should have experience creating representative laboratory scale-down models (SDMs) in order to establish QTPP, which should be embedded in their process for both conjugation and purification, as well as small-volume liquid-handling robots for chromatography. 

Analytical studies, including range-finding, process mapping, impurity spiking/clearance studies, resin/membrane cleaning/storage studies, resin/membrane aging studies, virus clearance validation studies and leachable/extractable analyses help define parameters and can be implemented at other stages of validation, including structural elucidation, extended characterization for comparability and QC release. An organization that conducts the proper analytical tests from the onset spares the sponsor organization costly changes or unpredictable issues further into the timeline. 

Although crunched timelines may theoretically hinder process optimization before launch, robust comparability studies can work to support any pre- or postapproval changes. A reliable comparability package gives sponsors the tools to enhance process robustness, improve product yield, or reduce cycle time.

Working With a Trustworthy and Experienced Partner 

ADCs have the potential to impact the lives of millions of patients, but getting these programs from the clinic into the market creates challenges. A sponsor’s decision to partner with a supplier organization is the single most important decision for a program. AbbVie Contract Manufacturing is equipped to handle the ADC life cycle from start to finish. We rely on comprehensive experience to provide partners with unparalleled expertise in delivering launch-ready ADCs that can support accelerated timelines, from analytical understanding, a well-defined process characterization strategy that enables PPQ, manufacturing expertise, process validation and comparability strategies, to regulatory submissions. 

References

1. Antibody Drug Conjugate Market Size Worth USD 9.93 Billion By 2025. Grand View Research, Inc. 23 Jan. 2019. Web.
2. Hedrich, William D. et al. “Antibody–Drug Conjugates: Pharmacokinetic/Pharmacodynamic Modeling, Preclinical Characterization, Clinical Studies, and Lessons Learned.” Clinical Pharmacokinetics. 57:687–703 (2018).
3. FDA Approves New Kind of Treatment for Hairy Cell Leukemia. U.S. Food and Drug Administration. 13 Sep. 2018. Web.
4. Liu, Renhe, Rongsheng E. Wang and Feng Wang. “Antibody–drug conjugates for non-oncological indications.” Expert Opinion on Biological Therapy. 16:591–593 (2016).
5. Yasunaga, Masahiro, Shino Manabe and Yasuhiro Matsumura. “Immunoregulation by IL-7R-targeting antibody-drug conjugates: overcoming steroid-resistance in cancer and autoimmune disease.” Nature Scientific Reports. 7: 10735 (2017).