December 9, 2020 PAP-Q4-20-CL-014
ADCs are complex, multicomponent drug substances designed to deliver highly potent pharmaceutically active agents to specific cells known to play crucial roles in various diseases. Their ability to effectively target disease-associated cells while minimizing off-target effects on healthy or non-diseased cells has drawn significant interest. Nine ADCs are currently on the market, and hundreds are in development, with seven or eight candidates expected to receive approval in the near future.
Most ADCs approved to-date were developed to target various types of cancer, but non-potent bioconjugates are also gaining prominence in non-oncology fields. We also expect ADCs, which are currently administered largely as second or third-line treatments, to soon begin to receive approval as first-line therapies. ADCs will also be used more often as components of combination therapies and for multiple indications. All of these trends will drive growth in demand for a new class of drugs. The global market for ADCs is projected to reach $10 billion by 2025.1
Since the first ADCs were approved, much has been learned about the requirements for effective conjugation of cytotoxic payloads to antibodies. Conjugation was not site-specific in first-generation ADCs, resulting in multiple conjugated isomers that caused characterization challenges. That has led to the development of technologies that provide more control over the conjugation sites, and thus better safety profiles and more predictable in vivo results.
A variety of methods have been developed to enable site-specific conjugation and consequently improved therapeutic indexes. In some cases, the antibody is engineered or modified to enable site-specific conjugation. Linker technologies have also been introduced that do not require antibody modification but still achieve directed conjugation. A third approach involves enzyme-mediated conjugation technology.
In addition to advances in linker and conjugation technologies, MilliporeSigma has provided a solution to the manufacturing process with the application of single-use (SU) equipment. Using disposable systems eliminates the need for cleaning and cleaning validation, reduces changeover times between products, and lowers the risk of cross-contamination. The result is higher throughput with reduced risk.
We have worked with our internal resources who are already supplying Mobius mixers for mAb production and other processes to make these systems more suitable for ADC production, which involves the use of organic solvents. Those efforts have included the performance of solvent compatibility assessment and addressing questions about extractables and leachables so that our customers can be confident in the switch from traditional glass or stainless steel reactors to SU technologies. We have also shown that we can reliably transition from small-scale glass reactors at the development stage to larger-scale GMP SU reactors for clinical and commercial production.
The manufacture of ADCs is often outsourced, because production of these complex molecules requires expertise in biologics and small molecules, conjugation technologies, and the containment of highly potent compounds. It is also expensive to implement the infrastructure necessary for ADC manufacturing.
Pharma companies — both large and small — often elect to leverage the capabilities of a CDMO that has the infrastructure, in-depth technical expertise, and demonstrated success handing different ADC constructs at the development and commercial scales.
CDMOs such as MilliporeSigma, that have worked with multiple conjugation technologies and can use that knowledge when tackling new projects are preferred. Commercial experience is equally important, because the needs for early-stage development are significantly different from those during late-stage clinical studies and commercialization. Working with a CDMO that knows exactly what to do to get ready for customers’ commercial regulatory filings is very important.
MilliporeSigma is a global CDMO offering support for biologic, small molecule, and biopolymer projects, including drug substances and excipients. MilliporeSigma offers a full line of ADC services, including process and analytical development, manufacturing, product characterization, GMP testing, and quality and regulatory support. We also provide testing and characterization services for mAbs as well as ADCs from one of the business units, Process Solutions Services. Our GMP facilities are located around the world and integrated with non-GMP facilities that produce starting materials for further processing at our other sites. Each project is assessed to determine, based on the customer’s needs, which facility will be the best match.
Within each facility, our project management teams are led by managers that have a wide range of expertise, including experience with both clinical and commercial programs. Different groups within each CDMO facility work closely together, with technical and manufacturing teams sharing information on a regular basis. There is also close interaction between the different CDMO sites, which is a great advantage in sharing lessons learned and for supporting customers when projects span multiple locations. Our project management organization is designed to ensure the comprehensive management of such projects, which is critical for projects with complex supply chains, such as ADCs.
With 35 years of experience in biologics and different types of bioconjugates at our St. Louis, Missouri site, and a facility in Madison, Wisconsin that specializes in highly potent APIs (HPAPIs), it was an obvious development for MilliporeSigma to enter the ADC space.2 St. Louis was chosen as the main ADC production site because it was already established for small molecule manufacturing and also had biologics experience. With this dual expertise, we just needed to build the necessary infrastructure.
Our journey to commercialization started with determining what was required and expected for commercial ADC manufacturing, including control strategies, risk assessment, process characterization, and validation.
Establishing microbial control is essential for biopharmaceuticals. Our approach involves setting in-process endotoxin acceptance criteria based on the worst-case raw material input and historical process data. As the process advances into commercialization, continuous process verification (CPV) is leveraged; acceptance criteria defined based on data gathered during qualification are monitored on an ongoing basis.
A quality-by-design (QbD) approach is leveraged to understand the inputs and outputs of the conjugation and ADC purification process needed to establish controls to ensure that critical quality attributes (CQAs) are consistently achieved. A step attribute matrix (SAM) is used to determine how material inputs and unit operations affect product quality attributes. A parameter attribute map (PAM) is then created to identify how variation within the process parameters could affect these quality attributes and to select those parameters that are critical to maintaining product quality. For example, the SAM/PAM exercise can help answer questions, such as the degree to which variation in the operating parameters of tangential flow filtration can affect impurity levels.
The process knowledge gained at this stage is then used to determine areas for investigation at development scale in order to characterize the process and provide a design space. Qualification of an appropriate scale-down model is essential to ensure that the bench-scale model will be predictive of the GMP scale. Qualification may include the utilization of equivalent raw materials, various mixing studies, and use of reference standards and controls where appropriate.
We also apply a range of experiments to understand how the process parameters — both independent and dependent of one another — affect quality attributes of the process. These experiments can include design of experiments (DoE) and one factor at a time (OFAT) experiments, among others.
Because ADCs combine the complexity of biologics manufacturing with the environmental controls required for highly potent compounds, we adopt a holistic view when building a detailed roadmap for commercialization that includes validation master plan scoping, risk assessment, and demonstration of process control and process performance qualification (PPQ). While many of the activities needed to move into process validation are completed as part of clinical ADC manufacturing, all potential risks and aspects of control and commercial requirements are formally reviewed.
As part of the validation master plan scoping, additional risk assessments needed for commercial manufacturing are also identified, and existing risk assessments are reviewed and updated to support additional controls for commercial manufacture. These risk assessments span all areas of the process, including process risks, operational and equipment risks, raw material risks, and microbial risks. Any necessary final studies or process changes are outlined before moving into validation, and critical process parameters are locked down.
To ensure commercial ADC manufacturing readiness, we also develop a detailed and robust commercial control strategy that incorporates risk assessment conclusions and mitigations, manufacturing process controls, critical process parameters (CPPs) and their relationship to product CQAs, rationale for acceptance criteria, process characterization data, and general quality management system controls. As a result, the commercial control strategy provides a complete outline of the process control space and clearly identifies how the manufacturing process is controlled to meet the CPPs. It is important to ensure that process control and knowledge are clearly outlined, as this is critical for supporting approval and the preapproval inspection audit (PAI).
Once the validation master plan deliverables required for PPQ are completed and the process is ready to move into validation, the PPQ protocol is developed to allow for the execution of the PPQ batches. The PPQ protocol outlines the validation strategy for the process and the test plans to be incorporated, including the required acceptance criteria. Once the batches are completed, a PPQ report is written to provide a summary of execution and adherence to acceptance criteria, and ultimately present a conclusion regarding the validation status of the process.
The PAI of our commercial ADC manufacturing facility was approached differently from how we had traditionally hosted inspections for small molecules at the same site. For non-biologics, the inspection was driven by the quality assurance team, with support from subject matter experts as needed. For ADCs, our subject matter experts were the core of the inspection team, given that much of the audit was focused on control strategies and the facility itself.
While the inspection was conducted according to Q7 (International Council for Harmonisation) guidelines, there are many different areas that the U.S. Food and Drug Administration (FDA) focuses on with regard to biologics. Scripts and storyboards, consisting of four to five slides, were used to describe complex processes. An example of a process that could benefit from a script is the raw material receipt process or any procedure at the site that would benefit from a very organized script to describe the workflow. Storyboards can also be used to describe complex gaps in the process, repeat deviations, or the validation narrative to the inspector. This approach ensures that the subject matter experts are comfortable with how they will relate the narrative of their department, their process, or the deviation that they helped investigate.
We also ensured the readiness of both our facility and staff. This is essential, as the inspectors may question staff members other than the subject matter experts when touring the facility; in many cases, the inspectors want to question the operators on the floor that are performing a particular action. Site-wide training reminds individuals how they may want to respond to inspectors and provides insight into the questions they may receive during the audit.
It was also beneficial to clarify the roles and responsibilities of each participant in the audit well ahead of time. Walk-throughs and mock audits were invaluable for helping subject matter experts become comfortable with the audit process and know what to expect. Team members were enlisted to play the role of inspectors and ask critical questions to ensure that our experts could explain their process effectively and concisely.
Finally, inspection logistics were coordinated and included establishing a timeline for preparation as well as the process flow and organization of documents. To ensure a robust and streamlined process flow, we had an audit team dedicated to each inspector or audit stream and a host who was well-versed in general quality systems at the site. The host answered general quality system questions and enlisted subject matter experts to discuss the individual process capabilities or any deviations. All of these efforts led to successful FDA approval of the site.
Regulatory guidance for ADCs continues to evolve. Given that ADCs combine the complexities of biologic and HPAPI manufacturing, current regulatory guidance pulls from both sectors. However, there are not yet as many specific guidances for ADCs as there are for biologics or small molecule APIs and formulated products. Complicating the situation for many ADCs is their receipt of Breakthrough and/or Fast Track designations from the FDA, resulting in the need to accelerate development activities.
Fortunately, the agency and other regulatory bodies have been very willing to work through the regulatory requirements with ADC developers to ensure that these novel therapies can reach the market as quickly as possible. Much of the information relating to expectations specifically for potent antibodies and conjugates, is gained via communication and discussions with the agencies.
As more ADCs are approved, we believe that greater clarity will be provided in the guidelines, and the expectations of regulatory authorities will become clearer. As an example, we anticipate that the FDA and other agencies will demand more thorough characterization of manufacturing processes and more control over both the manufacture and testing of ADCs.
The progression of ADCs through the clinical pipeline is closely monitored by the industry, and both pharmaceutical companies and CDMOs are expanding production capacity in anticipation of the large number of approvals expected in the near future.
There is an acute need for CDMOs that understand how to execute late-stage studies to support a filing strategy. CDMOs with plans to support commercial-scale ADC manufacturing are establishing processes to handle challenging supply chains and investing in facilities and processes to ensure efficiency, quality, and security.
MilliporeSigma has proactively implemented several technologies to make sure that we are ready for customers when they need our support. We are also expanding capacity, not just for the production of final ADC products, but also for the production of linkers and payloads.
For instance, our ADC facility in St. Louis was constructed in 2008 for clinical programs, and in 2015 we expanded our capabilities to manufacture commercial programs. Additionally, we expanded our development capabilities in 2017 to enable production of larger development batches of ADCs. We recently announced a $65 million investment in Wisconsin for the production of HPAPIs and are already assessing what might be needed beyond that. There are many other projects in the works, all of which are designed to meet our customer’s future needs.
Those customers include big pharma as well as small and emerging pharma and biotech firms and virtual organizations with limited development, commercialization, and manufacturing resources and capacities. Big pharma companies often come to us with early-stage projects but then have the power and resources to take programs in-house if they advance to later stages. Customers that work with CDMOs such as MilliporeSigma are variable, ranging from big pharma to small and emerging pharma and biotech firms. While the rationale for collaboration with MilliporeSigma may be different for each, it is clear that this collaboration offers many advantages, such as being able to utilize the extensive development, commercialization, and manufacturing knowledge and resources that MilliporeSigma can provide.
What is unique about MilliporeSigma is that we have the experience and capabilities to support ADC projects from the earliest stages to clinical programs and on through commercialization, including inspection and approval readiness and ultimately commercial manufacturing. For smaller companies just starting their ADC journeys, we can be a great partner, because we understand exactly what it takes to get programs to the commercial market.
ADC ExpressTM was developed to help companies with ADC concepts but lack the expertise and infrastructure to go forward. This service is designed to take a customer’s concept all the way to the clinic. For instance, we can help a customer determine how a clinically active antibody will behave as an ADC. Our technical teams can prepare multiple ADC constructs with the antibody using different linkers and payloads, and the customers can screen constructs to select a lead candidate, which we can then help with development and GMP activities.
For ADCs with an established production process, the MilliporeSigma team of technical experts is equipped to support the transfer of that technology to our sites, whether they have processes that initially require scale-up or that have been optimized for commercial scale.
We can also transfer processes to our facility for companies that already have a commercial program but have discovered that the existing supply chain cannot meet rising demand. We conduct process transfer and validation activities and help customers file our facility as an alternate manufacturing facility with the appropriate regulatory authorities.
MilliporeSigma provides solutions across the entire ADC supply chain — from antibody production all the way to conjugation — including the testing services that are needed along the way. Some of the other CDMOs can only perform subsets of these services, so pharma and biotech companies engaging them must adopt a multi-CDMO model that can be challenging to manage.
MilliporeSigma’s experience with ADCs includes more than 65 unique development projects and more than 600 development batches spanning many ADC technologies from conventional antibody projects to bispecific and antibody fragments, as well as a range of cleavable and non-cleavable linkers and many types of cytotoxic payloads.
We built upon over 12 years of experience in clinical-scale supply of ADCs, as well as commercial-scale production of linker payloads, small molecules, and bio-organics and an extensive knowledge base in biologics manufacturing to establish commercial-scale ADC manufacturing capabilities. That extensive preparation led to the approval to manufacture commercial ADC batches.
Since first offering ADC manufacturing services in 2008, MilliporeSigma has produced more than 160 GMP batches, including more than 20 commercial batches. These batches have enabled more than 30 investigational new drugs (INDs) to enter the clinic.
Ten years from now, we will be continuing our investments in ADC capabilities to ensure that we maintain the ability to meet the growing demand for development and manufacturing support across the entire spectrum with respect to the value chain and the development to commercialization cycle. MilliporeSigma is the very first CDMO with an approved commercial ADC manufacturing facility in the United States. We are excited to work on more commercial programs as the first supplier for novel ADCs and as a second or third supplier for the existing, previously approved drugs that are experiencing growing demand.
Antibody Drug Conjugate Market Size Worth USD 9.93 Billion By 2025. Grand View Research, Jan. 2019. Web.
Spies, Jake, Elizabeth McKee, and Kerry Keith. “Establishing Commercial Manufacturing Services for Antibody-Drug Conjugates.” MilliporeSigma. Sep. 2020. Web.
Jyothi Swamy has been in the pharmaceutical industry for over 25 years covering areas ranging from analytical method development, method validation, cleaning validation, stability, project management, and marketing. Jyothi has been with MilliporeSigma, a business of Merck KGaA, Darmstadt Germany, for 15 years in various roles, including Sr. Chemist, Quality Control Supervisor, Sr. Project Manager. She received her B.S. and M.S. at Bangalore University, India, M.S. at Indian Institute of Science, India, and her Ph.D. in synthetic organic chemistry at University of Missouri, St. Louis.