Fast-Tracking ADC Development and Commercialization

Antibody–drug conjugates are highly complex, and their manufacture involves multiple and disparate technologies. Most biopharmaceutical companies, therefore, rely on contract service providers. Working with different suppliers for each part of the process can potentially add risks, time and cost to an ADC production program. The PROVEO™ Alliance overcomes these difficulties by offering streamlined support from antibody production through conjugation and fill-finish to labeling and packaging.

Positive ADC Outcomes Driving Market Growth

Antibody-drug conjugates (ADCs) are next-generation antibody therapies that provide targeted delivery of cytotoxic anti-cancer agents to cancer cells. They comprise an antibody and a cytotoxic payload that are conjugated via a linker. By avoiding systemic delivery and attacking the cancer cells directly, ADCs offer increased efficacy with reduced side effects. As technology has advanced, second- and third-generation ADCs have become safer and even more precisely targeted.

There are currently six marketed ADCs and approximately 250 ADC candidates under development.¹ Of those, nearly 40% are undergoing clinical studies, with over half targeting solid tumors. ADCs account for approximately 20% of the clinical pipeline of antibodies for cancer.² With 11 additional drugs in late-stage clinical development, double-digit approvals are expected in the next few years.³

Significant R&D effort is focused on expanding the types of conjugated payloads, targeted indications and treatment protocols, particularly their use in combination therapies.⁴ In addition, 40 trials are underway involving ADC/checkpoint inhibitor combination therapies for the treatment of various cancers. ADCs are also being developed with payloads other than small molecules, such as proteins, enzymes and Fab fragments, the latter of which generates bispecific antibodies.

The value of the global market for ADCs is estimated to be expanding at a compound annual growth rate in excess of 20% and expected to reach $15 billion by 2030.¹ Notably, more than $5 billion has been invested in this ADC sector, and partnership activity has increased at an annual rate of 30%.¹

Complex Products and Manufacturing Processes

Monoclonal antibodies used in ADCs should be designed for manufacturability at scale.⁵ They need to be robust, stable biomolecules that can withstand the further processing conditions involved in ADC production and contain the appropriate sites for conjugation to the cytotoxic payload via the desired linker chemistry. The drug (payload)–antibody ratio (DAR) and sites of conjugation must be carefully controlled and verified, as they directly impact the potency and efficacy of the ADC. Undesired payload binding and other modifications of the antibody can potentially lead to reduced stability (i.e., aggregation), reduced efficacy and immunogenicity and other adverse patient reactions. ADC purification often requires unique equipment and capabilities.

ADC drug substance manufacturing needs to balance bioburden-controlled activities while ensuring protection of operators and the environment from exposure to the highly potent payloads. Achieving these two goals requires conflicting control of air flows and air pressure in the facility. Extensive use of isolators in combination with unique facility designs is required to protect the product components, operators and the environment. As such, facilities for the production of ADCs require high capital investment and extensive operator training.⁵

Manufacturers must have capabilities in cell culture and synthetic chemistry and a deep understanding of conjugation chemistry, which must be highly controlled to ensure proper site selectivity and prevention of aggregation.⁶ Fill-finish capabilities, including lyophilization, are also necessary. Furthermore, because ADCs are highly complex, structurally heterogeneous and often contain not just a single product, but many product-related species, analytical expertise that bridges biology and chemistry is absolutely essential to ADC characterization and control.⁷

Reliance on Contract Manufacturers

The complexity of ADC development and manufacturing has led many biopharmaceutical companies to turn to contract development and manufacturing organizations (CDMOs) for assistance with their ADC projects. According to one estimate, at least 70% of ADC manufacturing is outsourced, and this level will increase, owing to the fact that many third-generation ADCs are being developed by small biotech and specialty pharma firms that require extensive support and access to the specialized expertise and facilities required for ADC production.⁵

Integrated Solutions Facilitate Accelerated Development

Only a few CDMOs have the capability to perform all of the steps involved in ADC manufacturing, including production of antibodies, linkers and payloads, conjugation and fill-finish. Integrated service offerings provide several advantages, most notably reduced time to market due to elimination of multiple suppliers (antibody, linker, payload and ADC producers, as well as potential separate fill-finish, packaging and distribution service providers) and to transfer product from one service provider to another.⁶ Most importantly, potential scheduling snafus are avoided. Working with an integrated ADC CDMO also reduces and de-risks supply chain complexity while freeing up management time and resources.

PROVEO™ 

Combining the strengths and expertise of three industry leaders into one simplified ADC solution, PROVEO delivers streamlined support from antibody production through conjugation and fill-finish to labeling and packaging, all tailored to each client. The service is designed to provide significant efficiency gains in the ADC manufacturing process by bringing together specialized companies that are globally qualified and able to provide product development and manufacturing support, creating value through integrated project and supply chain management.

PROVEO is a solution provided by AGC Biologics, Cerbios and Oncotec Pharma Produktion GmbH to simplify the complexity of ADC outsourcing. All three companies are well-established, global suppliers that work together to reduce the time, cost and resources required for ADC manufacturing, giving customers multiple development and manufacturing options.

PROVEO supports the entire ADC supply chain: the development of a microbial or mammalian cell line, as well as production and purification processes to deliver the purified binding protein for the ADC; design of appropriate manufacturing processes for the payload, linker and bioconjugation step with cGMP production of the ADC drug substance; and sterile filling and labeling of the drug product.

“Safe” early transfer steps were identified and supported by a transfer framework that enables fast development of optimized ADC processes and products. Across all sites, we use harmonized basic analytical methods and share the analytical methods specific to each phase of a project. As a result, we are able to compare results and reduce or avoid the need for method transfer. In addition, harmonization of quality assurance across the whole supply chain is achieved through a shared quality agreement and cross-auditing, making it possible to guarantee a high level of QA standards throughout the entire manufacturing process from monoclonal antibody (mAb) to packaged ADC product.

PROVEO also employs a fully integrated project management system across the supply chain with a single program manager that works with project managers at each site. This approach allows for seamless transitions across the network and enables complete integration of development and manufacturing efforts. As a result, we can provide risk-free timeline compression, reducing the time it takes from DNA to fill-finish from 30 months for the traditional supply chain with four separate providers to 20 months.

Antibody Manufacturing Expertise 

AGC Biologics is one of the largest global biologics CDMOs specializing in the clinical and commercial development of therapeutic proteins, with a 15+ year track record of technical success in development and cGMP manufacturing. A leader in the implementation of innovative technologies and solutions that accelerate time to market, AGC has an agile, entrepreneurial culture and a commitment to cultivating strong partnerships that enable client success. AGC Biologics also has experience successfully transferring processes and technologies between sites to facilitate scale-up or market expansion

Monoclonal antibodies are produced at AGC’s FDA- and EMA-approved sites in Copenhagen, Denmark and Seattle, Washington using the CHEF1^® proprietary expression technology platform with four commercial products in the market, as well as other available expression systems. Mammalian capacities range from 100 to 12,000 L in single-use and stainless-steel equipment, and mAb manufacturing is supported by experts in process, analytical and drug substance/drug product formulation development, including stability testing and bioassays.

Payload and Conjugation Expertise 

Cerbios has over 40 years of experience in the development of processes for the production of APIs and 25 years of experience handling highly potent compounds, with products marketed in over 60 countries. Payload and linker production and ADC conjugation are performed at Cerbios’ FDA-, PMDA- and SwissMedic-approved facility in Lugano, Switzerland. The facility is designed to handle highly potent payloads to category 4 and has dedicated conjugation units. Analytical experts provide process characterization, stability testing, product release testing and other QC/QA support on site, while regulatory experts assist clients with preparation for filing of INDs and NDAs.

The Cerbios site includes three cGMP payload and linker production units supporting clinical and commercial batch sizes from 10 to 30 kg. Specialized equipment available for payload and linker production and conjugation processes include Biotage and PLC chromatography units, a photoreaction unit and continuous flow chemistry solutions, all benefiting from modular containment. Conjugation is performed in two cGMP production units at batch sizes from 5 to 200 L, leveraging purification technologies such as single-use bio-chromatography and tangential-flow filtration, also in modular containment.

Fill-Finish Expertise 

Oncotec has been manufacturing sterile products for oncological indications since 1999, providing contract manufacturing services for highly potent substances to more than 20 companies. The plant in Dessau, Germany has been successfully inspected by numerous regulatory authorities, including the FDA, ANVISA, PMDA, FDA Saudi-Arabia and the Turkish, Libyan and Russian MoHs.

The final formulation, sterile filling, packaging and labeling of final ADC drug products takes place at Oncotec. Both small- and large-scale aseptic filing lines with lyophilization and vial-washing capabilities are available for the production of highly potent ADCs. Vial sizes from 2 to 200 mL are supported. The freeze dryers have capacities of 0.6 and 30 m². The filling machine is robotic, and filling is achieved using peristaltic pumps with a line speed of 5000 vials/hour. The system can handle products formulated in solvents. There is also the possibility to fill ADCs into disposable bags.

Case Studies Underscore PROVEO Alliance Benefits

Given a mAb sequence, PROVEO developed an initial lab-scale process and limited analytics and then established a stable, monoclonal CHO cell line using the CHEF1 platform (3.2 g/L). Upstream and downstream processes and analytics were developed based on the existing platform. The yield was then further improved by 25%, with acidic species reduced during upstream process development. The production process was successfully scaled, providing GMP material just 12 months after initiation of the project.

A medicinal chemistry process for milligram-scale production of a payload did not afford any robustness or reproducibility, and the product had an insufficient quality (90%) and contained unidentified impurities. Using a quality-by-design (QbD) approach and following Q11 rules, process and analytical development efforts were pursued. A process controls strategy was then developed in collaboration with the customer. The resulting process was robust and reproducible and afforded a much higher yield at significantly reduced COGS. Both the synthesis and HPLC purification steps were scaled successfully. Several cGMP lots were completed at the hundred-gram scale and the analytical methods were validated for the late clinical-phase investigational drug.

For an ADC product, a laboratory-scale process using novel, site-specific bioconjugation technology and with limited established analytical methods needed to be scaled up for cGMP manufacturing. A QbD-like approach was used to design an optimized (time, yield and COGS), robust, reproducible process that generated the ADC drug product in a form that enabled integration of pre-formulation into the sterile fill-finish process. Analytics were also developed for both in-process control and GMP release. A GMP lot of the ADC drug substance was produced for use in a phase I clinical study.

A laboratory-scale fill-finish process that did not include lyophilization and had limited established analytical methods required scale-up and the addition of a lyophilization step. A formulation compatible with freeze drying was developed in collaboration with the client, and an efficient lyophilization cycle was identified following completion of a designed experiments study. The optimized process was first scaled to the pilot plant and then to GMP manufacturing, with GMP batches of the ADC drug product successfully produced.

Getting Medicines to Patients Sooner

By offering the services of specialists across multiple teams within a single, global service backed by years of experience, PROVEO helps companies save time, cost and resources across all aspects of the ADC production cycle.

References

1. Harper, Rachel. “Antibody drug conjugates market to be worth $15bn by 2030.” European Pharmaceutical Review. 30 Aug. 2019. Web.

2. “Antibody Drug Conjugates in Cancer Drug Development.” IQVIA. 2018. Web.

3. Hofland, Peter. “Experts Forecasts CMOs to Benefit from Double Digit Approvals of ADCs.” ADC Review. 23 Oct. 2018. Web.

4. Johnson, Charlie. “The Evolving Market for Antibody-drug Conjugates: How Widening Applications and Manufacturing Improvements help Meet Growing Demand.” ADC Review. 1 Apr. 2019. Web.

5. Scanian, Claire et al. “Antibody-drug Conjugates: Manufacturing Challenges and Trends.” ADC Directory. 15 Jan. 2019. Web.

6. Sharma, Vivek. “CPhI Annual Report 2018: ADCs Growth Driven by Lack of In-House Facilities, Oncology and Integrated CDMOs.” Pharmaceutical Outsourcing. 10 Oct. 2018. Web.

7. Wagh, Anil, Hantian Song, Ming Zeng, Li Tao and Tapan K. Das. “Challenges and new frontiers in analytical characterization of antibody-drug conjugates.” MAbs. 10: 222–243 (2018).